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Male infertility

Nature Reviews Disease Primers volume 9, Article number: 49 (2023) Cite this article

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Abstract

Clinical infertility is the inability of a couple to conceive after 12 months of trying. Male factors are estimated to contribute to 30–50% of cases of infertility. Infertility or reduced fertility can result from testicular dysfunction, endocrinopathies, lifestyle factors (such as tobacco and obesity), congenital anatomical factors, gonadotoxic exposures and ageing, among others. The evaluation of male infertility includes detailed history taking, focused physical examination and selective laboratory testing, including semen analysis. Treatments include lifestyle optimization, empirical or targeted medical therapy as well as surgical therapies that lead to measurable improvement in fertility. Although male infertility is recognized as a disease with effects on quality of life for both members of the infertile couple, fewer data exist on specific quantification and impact compared with other health-related conditions.

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Fig. 1: Global fertility rates.
Fig. 2: Anatomy of the male reproductive tract.
Fig. 3: The role of the hypothalamic–pituitary–gonadal axis in male fertility.
Fig. 4: Stages of spermatogenesis in mice and humans.
Fig. 5: Gametogenesis in humans.
Fig. 6: Scrotal ultrasonography for measurement of spermatic veins.
Fig. 7: MRI assessment of male pelvic anatomy.
Fig. 8: Internal spermatic vein ligation.

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References

  1. WHO TEAM: Sexual and Reproductive Health and Research. Infertility Prevalence Estimates, 1990–2021 (WHO, 2023).

  2. Practice Committee of the American Society for Reproductive Medicine. Fertility evaluation of infertile women: a committee opinion. Fertil. Steril. 116, 1255–1265 (2021).

    Article  Google Scholar 

  3. Schlegel, P. N. et al. Diagnosis and treatment of infertility in men: AUA/ASRM guideline part I. Fertil. Steril. 115, 54–61 (2021).

    Article  PubMed  Google Scholar 

  4. Thonneau, P. et al. Incidence and main causes of infertility in a resident population (1,850,000) of three French regions (1988–1989). Hum. Reprod. 6, 811–816 (1991).

    Article  CAS  PubMed  Google Scholar 

  5. Agarwal, A., Mulgund, A., Hamada, A. & Chyatte, M. R. A unique view on male infertility around the globe. Reprod. Biol. Endocrinol. 13, 37 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Samplaski, M. K. et al. Reproductive endocrinologists are the gatekeepers for male infertility care in North America: results of a North American survey on the referral patterns and characteristics of men presenting to male infertility specialists for infertility investigations. Fertil. Steril. 112, 657–662 (2019).

    Article  PubMed  Google Scholar 

  7. Eisenberg, M. L., Lathi, R. B., Baker, V. L., Westphal, L. M., Milki, A. A. & Nangia, A. K. Frequency of the male infertility evaluation: data from the national survey of family growth. J. Urol. 189, 1030–1034 (2013).

    Article  PubMed  Google Scholar 

  8. Bonde, J. P. et al. Relation between semen quality and fertility: a population-based study of 430 first-pregnancy planners. Lancet 352, 1172–1177 (1998).

    Article  CAS  PubMed  Google Scholar 

  9. Zinaman, M. J., Brown, C. C., Selevan, S. G. & Clegg, E. D. Semen quality and human fertility: a prospective study with healthy couples. J. Androl. 21, 145–153 (2000).

    CAS  PubMed  Google Scholar 

  10. Guzick, D. S. et al. Sperm morphology, motility, and concentration in fertile and infertile men. N. Engl. J. Med. 345, 1388–1393 (2001).

    Article  CAS  PubMed  Google Scholar 

  11. Buck Louis, G. M. et al. Semen quality and time to pregnancy: the Longitudinal Investigation of Fertility and the Environment Study. Fertil. Steril. 101, 453–462 (2014).

    Article  PubMed  Google Scholar 

  12. Jedrzejczak, P., Taszarek-Hauke, G., Hauke, J., Pawelczyk, L. & Duleba, A. J. Prediction of spontaneous conception based on semen parameters. Int. J. Androl. 31, 499–507 (2008).

    Article  PubMed  Google Scholar 

  13. Minhas, S. et al. European Association of Urology Guidelines on Male Sexual and Reproductive Health: 2021 Update on Male Infertility. Eur. Urol. 80, 603–620 (2021).

    Article  PubMed  Google Scholar 

  14. World Health Organization. WHO Laboratory Manual for the Examination and Processing of Human Semen 6th edn (WHO, 2021).

  15. Wang, C. et al. Evolution of the WHO “Semen” processing manual from the first (1980) to the sixth edition (2021). Fertil. Steril. 117, 237–245 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Bjorndahl, L. et al. The sixth edition of the WHO Laboratory Manual for the Examination and Processing of Human Semen: ensuring quality and standardization in basic examination of human ejaculates. Fertil. Steril. 117, 246–251 (2022).

    Article  PubMed  Google Scholar 

  17. Bjorndahl, L. et al. Standards in semen examination: publishing reproducible and reliable data based on high-quality methodology. Hum. Reprod. 37, 2497–2502 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Barratt, C. L. R. et al. What advances may the future bring to the diagnosis, treatment, and care of male sexual and reproductive health? Fertil. Steril. 117, 258–267 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Vasconcelos, A., Henedi, Z. & Barratt, C. L. R. WHO 2021 and 2030 reference values for semen assessment: three challenges for andrology in the journey ahead. Reprod. Biomed. Online 45, 187–190 (2022).

    Article  PubMed  Google Scholar 

  20. Vasconcelos, A. L., Campbell, M. J., Barratt, C. L. R. & Gellatly, S. A. Do studies published in two leading reproduction journals between 2011 and 2020 demonstrate that they followed WHO5 recommendations for basic semen analysis? Hum. Reprod. 37, 2255–2263 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kruger, T. F., Acosta, A. A., Simmons, K. F., Swanson, R. J., Matta, J. F. & Oehninger, S. Predictive value of abnormal sperm morphology in in vitro fertilization. Fertil. Steril. 49, 112–117 (1988).

    Article  CAS  PubMed  Google Scholar 

  22. Lamb, D. J. Semen analysis in 21st century medicine: the need for sperm function testing. Asian J. Androl. 12, 64–70 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Silber, S. J. The relationship of abnormal semen parameters to male fertility. Hum. Reprod. 4, 947–953 (1989).

    Article  CAS  PubMed  Google Scholar 

  24. Sokol, R. Z. & Sparkes, R. Demonstrated paternity in spite of severe idiopathic oligospermia. Fertil. Steril. 47, 356–358 (1987).

    Article  CAS  PubMed  Google Scholar 

  25. Burris, A. S., Clark, R. V., Vantman, D. J. & Sherins, R. J. A low sperm concentration does not preclude fertility in men with isolated hypogonadotropic hypogonadism after gonadotropin therapy. Fertil. Steril. 50, 343–347 (1988).

    Article  CAS  PubMed  Google Scholar 

  26. Kruger, T. F. et al. Sperm morphologic features as a prognostic factor in in vitro fertilization. Fertil. Steril. 46, 1118–1123 (1986).

    Article  CAS  PubMed  Google Scholar 

  27. Katz, D. F., Overstreet, J. W., Samuels, S. J., Niswander, P. W., Bloom, T. D. & Lewis, E. L. Morphometric analysis of spermatozoa in the assessment of human male fertility. J. Androl. 7, 203–210 (1986).

    Article  CAS  PubMed  Google Scholar 

  28. Bostofte, E., Serup, J. & Rebbe, H. Relation between morphologically abnormal spermatozoa and pregnancies obtained during a twenty-year follow-up period. Int. J. Androl. 5, 379–386 (1982).

    Article  CAS  PubMed  Google Scholar 

  29. Aitken, R. J., Best, F. S., Warner, P. & Templeton, A. A prospective study of the relationship between semen quality and fertility in cases of unexplained infertility. J. Androl. 5, 297–303 (1984).

    Article  CAS  PubMed  Google Scholar 

  30. Bartoov, B., Eltes, F., Pansky, M., Lederman, H., Caspi, E. & Soffer, Y. Estimating fertility potential via semen analysis data. Hum. Reprod. 8, 65–70 (1993).

    Article  CAS  PubMed  Google Scholar 

  31. Stahl, P. J., Stember, D. S. & Schlegel, P. N. Interpretation of the semen analysis and initial male factor management. Clin. Obstet. Gynecol. 54, 656–665 (2011).

    Article  PubMed  Google Scholar 

  32. Mascarenhas, M. N., Flaxman, S. R., Boerma, T., Vanderpoel, S. & Stevens, G. A. National, regional, and global trends in infertility prevalence since 1990: a systematic analysis of 277 health surveys. PLoS Med. 9, e1001356 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Andrade, D. L., Viana, M. C. & Esteves, S. C. Differential diagnosis of azoospermia in men with infertility. J. Clin. Med. 10, 3144 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Esteves, S. C. Who cares about oligozoospermia when we have ICSI. Reprod. Biomed. Online 44, 769–775 (2022).

    Article  CAS  PubMed  Google Scholar 

  35. Esteves, S. C., Miyaoka, R. & Agarwal, A. An update on the clinical assessment of the infertile male [corrected]. Clinics 66, 691–700 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Esteves, S. C., Santi, D. & Simoni, M. An update on clinical and surgical interventions to reduce sperm DNA fragmentation in infertile men. Andrology 8, 53–81 (2020).

    Article  PubMed  Google Scholar 

  37. Fraietta, R., Zylberstejn, D. S. & Esteves, S. C. Hypogonadotropic hypogonadism revisited. Clinics 68, 81–88 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Gunes, S. & Esteves, S. C. Role of genetics and epigenetics in male infertility. Andrologia 53, e13586 (2021).

    Article  PubMed  Google Scholar 

  39. Hamada, A. J., Esteves, S. C. & Agarwal, A. A comprehensive review of genetics and genetic testing in azoospermia. Clinics 68, 39–60 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Jensen, C. F. S., Østergren, P., Dupree, J. M., Ohl, D. A., Sønksen, J. & Fode, M. Varicocele and male infertility. Nat. Rev. Urol. 14, 523–533 (2017).

    Article  PubMed  Google Scholar 

  41. Teixeira, T. A. et al. Viral infections and implications for male reproductive health. Asian J. Androl. 23, 335–347 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. World Health Organization. Infections, pregnancies, and infertility: perspectives on prevention. Fertil. Steril. 47, 964–968 (1987).

    Article  Google Scholar 

  43. Polis, C. B., Cox, C. M., Tunçalp, Ö., McLain, A. C. & Thoma, M. E. Estimating infertility prevalence in low-to-middle-income countries: an application of a current duration approach to demographic and health survey data. Hum. Reprod. 32, 1064–1074 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Khandwala, Y. S., Zhang, C. A., Lu, Y. & Eisenberg, M. L. The age of fathers in the USA is rising: an analysis of 168 867 480 births from 1972 to 2015. Hum. Reprod. 32, 2110–2116 (2017).

    Article  PubMed  Google Scholar 

  45. Bertoncelli Tanaka, M., Agarwal, A. & Esteves, S. C. Paternal age and assisted reproductive technology: problem solver or trouble maker? Panminerva Med. 61, 138–151 (2019).

    Article  PubMed  Google Scholar 

  46. Esteves, S. C., Carvalho, J. F., Bento, F. C. & Santos, J. A novel predictive model to estimate the number of mature oocytes required for obtaining at least one euploid blastocyst for transfer in couples undergoing in vitro fertilization/intracytoplasmic sperm injection: the ART calculator. Front. Endocrinol. 10, 99 (2019).

    Article  Google Scholar 

  47. Esteves, S. C. et al. Cumulative delivery rate per aspiration IVF/ICSI cycle in POSEIDON patients: a real-world evidence study of 9073 patients. Hum. Reprod. 36, 2157–2169 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  48. Fauser, B. C. Towards the global coverage of a unified registry of IVF outcomes. Reprod. Biomed. Online 38, 133–137 (2019).

    Article  PubMed  Google Scholar 

  49. Chambers, G. M. et al. International Committee for Monitoring Assisted Reproductive Technologies World Report: Assisted Reproductive Technology, 2014. Hum. Reprod. 36, 2921–2934 (2021).

    Article  PubMed  Google Scholar 

  50. Sunderam, S. et al. Assisted Reproductive Technology Surveillance – United States, 2018. MMWR Surveill. Summ. 71, 1–19 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  51. Dyer, S. et al. International Committee for Monitoring Assisted Reproductive Technologies World Report: Assisted Reproductive Technology 2008, 2009 and 2010. Hum. Reprod. 31, 1588–1609 (2016).

    Article  CAS  PubMed  Google Scholar 

  52. Boulet, S. L., Mehta, A., Kissin, D. M., Warner, L., Kawwass, J. F. & Jamieson, D. J. Trends in use of and reproductive outcomes associated with intracytoplasmic sperm injection. JAMA 313, 255–263 (2015).

    Article  PubMed  Google Scholar 

  53. Wyn, C. et al. ART in Europe, 2018: results generated from European registries by ESHRE. Hum. Reprod. Open 2022, hoac022 (2022).

    Article  Google Scholar 

  54. Esteves, S. C., Roque, M., Bedoschi, G., Haahr, T. & Humaidan, P. Intracytoplasmic sperm injection for male infertility and consequences for offspring. Nat. Rev. Urol. 15, 535–562 (2018).

    Article  CAS  PubMed  Google Scholar 

  55. Jewett, A. et al. Assisted reproductive technology cycles involving male factor infertility in the United States, 2017-2018: data from the National Assisted Reproductive Technology Surveillance System. FS Rep. 3, 124–130 (2022).

    Google Scholar 

  56. Buttorff, C., Ruder, T. & Bauman, M. Multiple Chronic Conditions in the United States (Rand, 2017).

  57. Chen, T., Belladelli, F., Del Giudice, F. & Eisenberg, M. L. Male fertility as a marker for health. Reprod. Biomed. Online 44, 131–144 (2022).

    Article  PubMed  Google Scholar 

  58. Eisenberg, M. L., Li, S., Brooks, J. D., Cullen, M. R. & Baker, L. C. Increased risk of cancer in infertile men: analysis of U.S. claims data. J. Urol. 193, 1596–1601 (2015).

    Article  PubMed  Google Scholar 

  59. Faja, F. et al. Environmental disruptors and testicular cancer. Endocrine 78, 429–435 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Brubaker, W. D., Li, S., Baker, L. C. & Eisenberg, M. L. Increased risk of autoimmune disorders in infertile men: analysis of US claims data. Andrology 6, 94–98 (2018).

    Article  CAS  PubMed  Google Scholar 

  61. Del Giudice, F. et al. The association between mortality and male infertility: systematic review and meta-analysis. Urology 154, 148–157 (2021).

    Article  PubMed  Google Scholar 

  62. Del Giudice, F. et al. Increased mortality among men diagnosed with impaired fertility: analysis of US claims data. Urology 147, 143–149 (2021).

    Article  PubMed  Google Scholar 

  63. Dohle, G. R. Male infertility in cancer patients: review of the literature. Int. J. Urol. 17, 327–331 (2010).

    Article  PubMed  Google Scholar 

  64. Glazer, C. H. et al. Male factor infertility and risk of multiple sclerosis: a register-based cohort study. Mult. Scler. 24, 1835–1842 (2018).

    Article  PubMed  Google Scholar 

  65. Gunnes, M. W. et al. Reproduction and marriage among male survivors of cancer in childhood, adolescence and young adulthood: a national cohort study. Br. J. Cancer 114, 348–356 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Kohn, T. P., Kohn, J. R., Owen, R. C. & Coward, R. M. The prevalence of Y-chromosome microdeletions in oligozoospermic men: a systematic review and meta-analysis of European and North American studies. Eur. Urol. 76, 626–636 (2019).

    Article  CAS  PubMed  Google Scholar 

  67. Peña, V. N., Kohn, T. P. & Herati, A. S. Genetic mutations contributing to non-obstructive azoospermia. Best Pract. Res. Clin. Endocrinol. Metab. 34, 101479 (2020).

    Article  PubMed  Google Scholar 

  68. Liu, J. L., Peña, V., Fletcher, S. A. & Kohn, T. P. Genetic testing in male infertility – reassessing screening thresholds. Curr. Opin. Urol. 30, 317–323 (2020).

    Article  PubMed  Google Scholar 

  69. Kurinczuk, J. J. & Bhattacharya, S. Rare chromosomal, genetic, and epigenetic-related risks associated with infertility treatment. Semin. Fetal Neonatal Med. 19, 250–253 (2014).

    Article  PubMed  Google Scholar 

  70. Pinho, A., Barros, A. & Fernandes, S. Clinical and molecular characterization of Y microdeletions and X-linked CNV67 implications in male fertility: a 20-year experience. Andrology 8, 307–314 (2020).

    Article  CAS  PubMed  Google Scholar 

  71. Liu, X. G., Hu, H. Y., Guo, Y. H. & Sun, Y. P. Correlation between Y chromosome microdeletion and male infertility. Genet. Mol. Res. 15, gmr.15028426 (2016).

    Google Scholar 

  72. Bianco, S. D. & Kaiser, U. B. The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism. Nat. Rev. Endocrinol. 5, 569–576 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Lee, P. A., O’Leary, L. A., Songer, N. J., Coughlin, M. T., Bellinger, M. F. & LaPorte, R. E. Paternity after bilateral cryptorchidism. A controlled study. Arch. Pediatr. Adolesc. Med. 151, 260–263 (1997).

    Article  CAS  PubMed  Google Scholar 

  74. Trsinar, B. & Muravec, U. R. Fertility potential after unilateral and bilateral orchidopexy for cryptorchidism. World J. Urol. 27, 513–519 (2009).

    Article  PubMed  Google Scholar 

  75. Mak, V. et al. Proportion of cystic fibrosis gene mutations not detected by routine testing in men with obstructive azoospermia. JAMA 281, 2217–2224 (1999).

    Article  CAS  PubMed  Google Scholar 

  76. Cai, Z. & Li, H. Congenital bilateral absence of the vas deferens. Front. Genet. 13, 775123 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Yu, J., Chen, Z., Ni, Y. & Li, Z. CFTR mutations in men with congenital bilateral absence of the vas deferens (CBAVD): a systemic review and meta-analysis. Hum. Reprod. 27, 25–35 (2012).

    Article  CAS  PubMed  Google Scholar 

  78. Sharma, H., Mavuduru, R. S., Singh, S. K. & Prasad, R. Increased frequency of CFTR gene mutations identified in Indian infertile men with non-CBAVD obstructive azoospermia and spermatogenic failure. Gene 548, 43–47 (2014).

    Article  CAS  PubMed  Google Scholar 

  79. Siwen, W., Wang, L. & Cheng, C. Y. in Infertility in the Male 5th Edn (eds Lipshultz, L. I., Howards, S. S., Niederberger, C. S. & Lamb, D. J.) Ch. 2 (Cambridge Univ. Press, 2023).

  80. Schlegel, P. N. et al. Diagnosis and treatment of infertility in men: AUA/ASRM guideline part II. Fertil. Steril. 115, 62–69 (2021).

    Article  PubMed  Google Scholar 

  81. Mayerhofer, A. Peritubular cells of the human testis: prostaglandin E(2) and more. Andrology 8, 898–902 (2020).

    Article  CAS  PubMed  Google Scholar 

  82. Ruthig, V. A. & Lamb, D. J. Updates in Sertoli cell-mediated signaling during spermatogenesis and advances in restoring Sertoli cell function. Front. Endocrinol. 13, 897196 (2022).

    Article  Google Scholar 

  83. Liebich, A. et al. The molecular signature of human testicular peritubular cells revealed by single-cell analysis. Cells 11, 3685 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Mayerhofer, A. Human testicular peritubular cells: more than meets the eye. Reproduction 145, R107–R116 (2013).

    Article  CAS  PubMed  Google Scholar 

  85. Brinster, R. L. & Zimmermann, J. W. Spermatogenesis following male germ-cell transplantation. Proc. Natl Acad. Sci. USA 91, 11298–11302 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Guan, K. et al. Pluripotency of spermatogonial stem cells from adult mouse testis. Nature 440, 1199–1203 (2006).

    Article  CAS  PubMed  Google Scholar 

  87. Abid, S. N. et al. A-single spermatogonia heterogeneity and cell cycles synchronize with rat seminiferous epithelium stages VIII–IX. Biol. Reprod. 90, 32 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  88. Griswold, M. D. Spermatogenesis: the commitment to meiosis. Physiol. Rev. 96, 1–17 (2016).

    Article  CAS  PubMed  Google Scholar 

  89. Heller, C. G. & Clermont, Y. Spermatogenesis in man: an estimate of its duration. Science 140, 184–186 (1963).

    Article  CAS  PubMed  Google Scholar 

  90. Clermont, Y. The cycle of the seminiferous epithelium in man. Am. J. Anat. 112, 35–51 (1963).

    Article  CAS  PubMed  Google Scholar 

  91. Dohle, G. R., Smit, M. & Weber, R. F. Androgens and male fertility. World J. Urol. 21, 341–345 (2003).

    Article  CAS  PubMed  Google Scholar 

  92. Khodamoradi, K., Parmar, M., Khosravizadeh, Z., Kuchakulla, M., Manoharan, M. & Arora, H. The role of leptin and obesity on male infertility. Curr. Opin. Urol. 30, 334–339 (2020).

    Article  PubMed  Google Scholar 

  93. Coviello, A. D. et al. Low-dose human chorionic gonadotropin maintains intratesticular testosterone in normal men with testosterone-induced gonadotropin suppression. J. Clin. Endocrinol. Metab. 90, 2595–2602 (2005).

    Article  CAS  PubMed  Google Scholar 

  94. Jarow, J. P., Chen, H., Rosner, T. W., Trentacoste, S. & Zirkin, B. R. Assessment of the androgen environment within the human testis: minimally invasive method to obtain intratesticular fluid. J. Androl. 22, 640–645 (2001).

    CAS  PubMed  Google Scholar 

  95. Rahnema, C. D., Lipshultz, L. I., Crosnoe, L. E., Kovac, J. R. & Kim, E. D. Anabolic steroid-induced hypogonadism: diagnosis and treatment. Fertil. Steril. 101, 1271–1279 (2014).

    Article  CAS  PubMed  Google Scholar 

  96. Meachem, S. J., Nieschlag, E. & Simoni, M. Inhibin B in male reproduction: pathophysiology and clinical relevance. Eur. J. Endocrinol. 145, 561–571 (2001).

    Article  CAS  PubMed  Google Scholar 

  97. Tsatsanis, C., Dermitzaki, E., Avgoustinaki, P., Malliaraki, N., Mytaras, V. & Margioris, A. N. The impact of adipose tissue-derived factors on the hypothalamic–pituitary–gonadal (HPG) axis. Hormones 14, 549–562 (2015).

    Article  PubMed  Google Scholar 

  98. Hammoud, A. O., Gibson, M., Peterson, C. M., Meikle, A. W. & Carrell, D. T. Impact of male obesity on infertility: a critical review of the current literature. Fertil. Steril. 90, 897–904 (2008).

    Article  PubMed  Google Scholar 

  99. Liu, P. Y., Swerdloff, R. S., Christenson, P. D., Handelsman, D. J. & Wang, C. Rate, extent, and modifiers of spermatogenic recovery after hormonal male contraception: an integrated analysis. Lancet 367, 1412–1420 (2006).

    Article  CAS  PubMed  Google Scholar 

  100. Kohn, T. P. et al. Age and duration of testosterone therapy predict time to return of sperm count after human chorionic gonadotropin therapy. Fertil. Steril. 107, 351–357 e351 (2017).

    Article  CAS  PubMed  Google Scholar 

  101. Gu, Y. et al. Multicenter contraceptive efficacy trial of injectable testosterone undecanoate in Chinese men. J. Clin. Endocrinol. Metab. 94, 1910–1915 (2009).

    Article  CAS  PubMed  Google Scholar 

  102. Ly, L. P., Liu, P. Y. & Handelsman, D. J. Rates of suppression and recovery of human sperm output in testosterone-based hormonal contraceptive regimens. Hum. Reprod. 20, 1733–1740 (2005).

    Article  CAS  PubMed  Google Scholar 

  103. Meistrich, M. L. Effects of chemotherapy and radiotherapy on spermatogenesis in humans. Fertil. Steril. 100, 1180–1186 (2013).

    Article  CAS  PubMed  Google Scholar 

  104. Nicholson, H. S. & Byrne, J. Fertility and pregnancy after treatment for cancer during childhood or adolescence. Cancer 71, 3392–3399 (1993).

    Article  CAS  PubMed  Google Scholar 

  105. Stahl, O. et al. Sperm DNA integrity in testicular cancer patients. Hum. Reprod. 21, 3199–3205 (2006).

    Article  CAS  PubMed  Google Scholar 

  106. Harman, S. M., Metter, E. J., Tobin, J. D., Pearson, J. & Blackman, M. R. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J. Clin. Endocrinol. Metab. 86, 724–731 (2001).

    Article  CAS  PubMed  Google Scholar 

  107. Frattarelli, J. L., Miller, K. A., Miller, B. T., Elkind-Hirsch, K. & Scott, R. T. Jr. Male age negatively impacts embryo development and reproductive outcome in donor oocyte assisted reproductive technology cycles. Fertil. Steril. 90, 97–103 (2008).

    Article  PubMed  Google Scholar 

  108. Wyrobek, A. J. et al. Advancing age has differential effects on DNA damage, chromatin integrity, gene mutations, and aneuploidies in sperm. Proc. Natl Acad. Sci. USA 103, 9601–9606 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Brandt, J. S., Cruz Ithier, M. A., Rosen, T. & Ashkinadze, E. Advanced paternal age, infertility, and reproductive risks: a review of the literature. Prenat. Diagn. 39, 81–87 (2019).

    Article  PubMed  Google Scholar 

  110. Penrose, L. S. Parental age and mutation. Lancet 269, 312–313 (1955).

    Article  CAS  PubMed  Google Scholar 

  111. Krooth, R. S. Comments on the estimation of the mutation rate for achondroplasia. Am. J. Hum. Genet. 5, 373–376 (1953).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Lorentz, C. P., Wieben, E. D., Tefferi, A., Whiteman, D. A. & Dewald, G. W. Primer on medical genomics part I: History of genetics and sequencing of the human genome. Mayo Clin. Proc. 77, 773–782 (2002).

    Article  CAS  PubMed  Google Scholar 

  113. Francioli, L. C. et al. Genome-wide patterns and properties of de novo mutations in humans. Nat. Genet. 47, 822–826 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Kong, A. et al. Rate of de novo mutations and the importance of father’s age to disease risk. Nature 488, 471–475 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Acuna-Hidalgo, R., Veltman, J. A. & Hoischen, A. New insights into the generation and role of de novo mutations in health and disease. Genome Biol. 17, 241 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  116. Sharlip, I. D. et al. Best practice policies for male infertility. Fertil. Steril. 77, 873–882 (2002).

    Article  PubMed  Google Scholar 

  117. Rowe, P. J., Comhaire, F. H., Hargreave, T. B. & Mahmoud, A. M. WHO Manual for the Standardized Investigation and Diagnosis of the Infertile Male (Cambridge Univ. Press, 2000).

  118. Cendron, M., Keating, M. A., Huff, D. S., Koop, C., Snyder, H. M. III & Duckett, J. W. Cryptorchidism, orchiopexy and infertility: a critical long-term retrospective analysis. J. Urol. 142, 559–562 (1989).

    Article  CAS  PubMed  Google Scholar 

  119. Goldstein, M. & Schlegel, P. N. (eds) Surgical and Medical Management of Male Infertility (Cambridge Univ. Press, 2013).

  120. Kasman, A. M. et al. Association between preconception paternal health and pregnancy loss in the USA: an analysis of US claims data. Hum. Reprod. 36, 785–793 (2021).

    Article  PubMed  Google Scholar 

  121. Richmond, E. & Rogol, A. D. Traumatic brain injury: endocrine consequences in children and adults. Endocrine 45, 3–8 (2014).

    Article  CAS  PubMed  Google Scholar 

  122. Deforge, D. et al. Male erectile dysfunction following spinal cord injury: a systematic review. Spinal Cord 44, 465–473 (2006).

    Article  CAS  PubMed  Google Scholar 

  123. Ibrahim, E., Lynne, C. & Brackett, N. Male fertility following spinal cord injury: an update. Andrology 4, 13–26 (2016).

    Article  CAS  PubMed  Google Scholar 

  124. Hackett, G., Cole, N., Saghir, A., Jones, P., Strange, R. C. & Ramachandran, S. Testosterone undecanoate improves sexual function in men with type 2 diabetes and severe hypogonadism: results from a 30‐week randomized placebo‐controlled study. BJU Int. 118, 804–813 (2016).

    Article  CAS  PubMed  Google Scholar 

  125. DasGupta, R. & Fowler, C. J. Bladder, bowel and sexual dysfunction in multiple sclerosis. Drugs 63, 153–166 (2003).

    Article  CAS  PubMed  Google Scholar 

  126. Samplaski, M. K., Lo, K., Grober, E. & Jarvi, K. Finasteride use in the male infertility population: effects on semen and hormone parameters. Fertil. Steril. 100, 1542–1546 (2013).

    Article  CAS  PubMed  Google Scholar 

  127. Samplaski, M. K. & Nangia, A. K. Adverse effects of common medications on male fertility. Nat. Rev. Urol. 12, 401–413 (2015).

    Article  CAS  PubMed  Google Scholar 

  128. Amory, J. K. et al. The effect of 5alpha-reductase inhibition with dutasteride and finasteride on semen parameters and serum hormones in healthy men. J. Clin. Endocrinol. Metab. 92, 1659–1665 (2007).

    Article  CAS  PubMed  Google Scholar 

  129. Durairajanayagam, D., Agarwal, A. & Ong, C. Causes, effects and molecular mechanisms of testicular heat stress. Reprod. Biomed. Online 30, 14–27 (2015).

    Article  CAS  PubMed  Google Scholar 

  130. Holtmann, N. et al. Assessment of SARS-CoV-2 in human semen-a cohort study. Fertil. Steril. 114, 233–238 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Lundy, S. D. & Vij, S. C. Male infertility in renal failure and transplantation. Transl Androl. Urol. 8, 173 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  132. Eckersten, D., Giwercman, A. & Christensson, A. Male patients with terminal renal failure exhibit low serum levels of antimüllerian hormone. Asian J. Androl. 17, 149 (2015).

    Article  CAS  PubMed  Google Scholar 

  133. Moody, J. A., Ahmed, K., Yap, T., Minhas, S. & Shabbir, M. Fertility managment in testicular cancer: the need to establish a standardized and evidence‐based patient‐centric pathway. BJU Int. 123, 160–172 (2019).

    Article  PubMed  Google Scholar 

  134. Michailov, Y., Lunenfeld, E., Kapelushnik, J. & Huleihel, M. Leukemia and male infertility: past, present, future. Leuk. Lymphoma 60, 1126–1135 (2019).

    Article  PubMed  Google Scholar 

  135. Costabile, R. A. The effects of cancer and cancer therapy on male reproductive function. J. Urol. 149, 1327–1330 (1993).

    Article  CAS  PubMed  Google Scholar 

  136. Wasilewski-Masker, K. et al. Male infertility in long-term survivors of pediatric cancer: a report from the childhood cancer survivor study. J. Cancer Survivorship 8, 437–447 (2014).

    Article  CAS  Google Scholar 

  137. Harlev, A., Agarwal, A., Gunes, S. O., Shetty, A. & du Plessis, S. S. Smoking and male infertility: an evidence-based review. World J. Men’s Health 33, 143–160 (2015).

    Article  Google Scholar 

  138. La Vignera, S., Condorelli, R. A., Balercia, G., Vicari, E. & Calogero, A. E. Does alcohol have any effect on male reproductive function? A review of literature. Asian J. Androl. 15, 221 (2013).

    Article  PubMed  Google Scholar 

  139. Greenberg, D. R. et al. ALDH2 expression, alcohol intake and semen parameters among East Asian men. J. Urol. 208, 406–413 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  140. Jensen, T. K. et al. Habitual alcohol consumption associated with reduced semen quality and changes in reproductive hormones; a cross-sectional study among 1221 young Danish men. BMJ Open. 4, e005462 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  141. Gundersen, T. D. et al. Association between use of marijuana and male reproductive hormones and semen quality: a study among 1,215 healthy young men. Am. J. Epidemiol. 182, 473–481 (2015).

    Article  PubMed  Google Scholar 

  142. Belladelli, F. et al. Effects of recreational cannabis on testicular function in primary infertile men. Andrology 10, 1172–1180 (2022).

    Article  CAS  PubMed  Google Scholar 

  143. Sermondade, N. et al. BMI in relation to sperm count: an updated systematic review and collaborative meta-analysis. Hum. Reprod. Update 19, 221–231 (2013).

    Article  CAS  PubMed  Google Scholar 

  144. Davidson, L. M., Millar, K., Jones, C., Fatum, M. & Coward, K. Deleterious effects of obesity upon the hormonal and molecular mechanisms controlling spermatogenesis and male fertility. Hum. Fertil. 18, 184–193 (2015).

    Article  CAS  Google Scholar 

  145. Jóźków, P. & Rossato, M. The impact of intense exercise on semen quality. Am. J. Men’s Health 11, 654–662 (2017).

    Article  Google Scholar 

  146. Minguez-Alarcon, L., Chavarro, J. E., Mendiola, J., Gaskins, A. J. & Torres-Cantero, A. M. Physical activity is not related to semen quality in young healthy men. Fertil. Steril. 102, 1103–1109 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  147. Gaskins, A. J. et al. Physical activity and television watching in relation to semen quality in young men. Br. J. Sports Med. 49, 265–270 (2015).

    Article  PubMed  Google Scholar 

  148. Moxthe, L. C., Sauls, R., Ruiz, M., Stern, M., Gonzalvo, J. & Gray, H. L. Effects of bariatric surgeries on male and female fertility: a systematic review. J. Reprod. Infertil. 21, 71–86 (2020).

    PubMed  PubMed Central  Google Scholar 

  149. Andersen, E. et al. Sperm count is increased by diet-induced weight loss and maintained by exercise or GLP-1 analogue treatment: a randomized controlled trial. Hum. Reprod. 37, 1414–1422 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Sermondade, N. et al. Sperm parameters and male fertility after bariatric surgery: three case series. Reprod. Biomed. Online 24, 206–210 (2012).

    Article  PubMed  Google Scholar 

  151. Lazaros, L. et al. Dramatic reduction in sperm parameters following bariatric surgery: report of two cases. Andrologia 44, 428–432 (2012).

    Article  CAS  PubMed  Google Scholar 

  152. Carette, C. et al. Changes in total sperm count after gastric bypass and sleeve gastrectomy: the BARIASPERM prospective study. Surg. Obes. Relat. Dis. 15, 1271–1279 (2019).

    Article  PubMed  Google Scholar 

  153. Wijesekara, G. U. S., Fernando, D. M. S., Wijerathna, S. & Bandara, N. Environmental and occupational exposures as a cause of male infertility. Ceylon Med. 60, 52–56 (2015).

    Article  CAS  Google Scholar 

  154. Guerrero-Bosagna, C. & Skinner, M. K. Environmentally induced epigenetic transgenerational inheritance of male infertility. Curr. Opin. Genet. Dev. 26, 79–88 (2014).

    Article  CAS  PubMed  Google Scholar 

  155. Rao, M. et al. Effect of transient scrotal hyperthermia on sperm parameters, seminal plasma biochemical markers, and oxidative stress in men. Asian J. Androl. 17, 668 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Sheynkin, Y., Jung, M., Yoo, P., Schulsinger, D. & Komaroff, E. Increase in scrotal temperature in laptop computer users. Hum. Reprod. 20, 452–455 (2005).

    Article  PubMed  Google Scholar 

  157. Nieschlag, E. & Vorona, E. Medical consequences of doping with anabolic androgenic steroids: effects on reproductive functions. Eur. J. Endocrinol. 173, 47 (2015).

    Article  Google Scholar 

  158. Meriggiola, M. C., Bremner, W. J., Costantino, A., Pavani, A., Capelli, M. & Flamigni, C. An oral regimen of cyproterone acetate and testosterone undecanoate for spermatogenic suppression in men. Fertil. Steril. 68, 844–850 (1997).

    Article  CAS  PubMed  Google Scholar 

  159. Katz, N. & Mazer, N. A. The impact of opioids on the endocrine system. Clin. J. Pain 25, 170–175 (2009).

    Article  PubMed  Google Scholar 

  160. Amory, J. K. et al. The effect of 5α-reductase inhibition with dutasteride and finasteride on semen parameters and serum hormones in healthy men. J. Clin. Endocrinol. Metab. 92, 1659–1665 (2007).

    Article  CAS  PubMed  Google Scholar 

  161. Hellstrom, W. J., Giuliano, F. & Rosen, R. C. Ejaculatory dysfunction and its association with lower urinary tract symptoms of benign prostatic hyperplasia and BPH treatment. Urology 74, 15–21 (2009).

    Article  PubMed  Google Scholar 

  162. Bala, A., Nguyen, H. M. T. & Hellstrom, W. J. G. Post-SSRI sexual dysfunction: a literature review. Sex. Med. Rev. 6, 29–34 (2018).

    Article  PubMed  Google Scholar 

  163. Tanrikut, C., Feldman, A. S., Altemus, M., Paduch, D. A. & Schlegel, P. N. Adverse effect of paroxetine on sperm. Fertil. Steril. 94, 1021–1026 (2010).

    Article  CAS  PubMed  Google Scholar 

  164. O’moráin, C., Smethurst, P., Doré, C. J. & Levi, A. Reversible male infertility due to sulphasalazine: studies in man and rat. Gut 25, 1078–1084 (1984).

    Article  PubMed  PubMed Central  Google Scholar 

  165. Gubatan, J. et al. Paternal medications in inflammatory bowel disease and male fertility and reproductive outcomes: a systematic review and meta-analysis. Clin. Gastroenterol. Hepatol. 21, 2222–2238 (2023).

    Article  CAS  PubMed  Google Scholar 

  166. Rovira, J., Diekmann, F., Ramírez-Bajo, M. J., Bañón-Maneus, E., Moya-Rull, D. & Campistol, J. M. Sirolimus-associated testicular toxicity: detrimental but reversible. Transplantation 93, 874–879 (2012).

    Article  CAS  PubMed  Google Scholar 

  167. Roa, J. et al. The mammalian target of rapamycin as novel central regulator of puberty onset via modulation of hypothalamic Kiss1 system. Endocrinology 150, 5016–5026 (2009).

    Article  CAS  PubMed  Google Scholar 

  168. Semet, M. et al. The impact of drugs on male fertility: a review. Andrology 5, 640–663 (2017).

    Article  CAS  PubMed  Google Scholar 

  169. Sansone, A., Romanelli, F., Sansone, M., Lenzi, A. & Di Luigi, L. Gynecomastia and hormones. Endocrine 55, 37–44 (2017).

    Article  CAS  PubMed  Google Scholar 

  170. Crawford, P. F. III & Crop, J. A. Evaluation of scrotal masses. Am. Fam. Physician 89, 723–727 (2014).

    PubMed  Google Scholar 

  171. Charny, C. W. The spermatogenic potential of the undescended testis before and after treatment. J. Urol. 83, 697–705 (1960).

    Article  CAS  PubMed  Google Scholar 

  172. Bahk, J. Y., Jung, J. H., Jin, L. M. & Min, S. K. Cut-off value of testes volume in young adults and correlation among testes volume, body mass index, hormonal level, and seminal profiles. Urology 75, 1318–1323 (2010).

    Article  PubMed  Google Scholar 

  173. Lipshultz, L. I. & Corriere, J. N. Jr Progressive testicular atrophy in the varicocele patient. J. Urol. 117, 175–176 (1977).

    Article  CAS  PubMed  Google Scholar 

  174. Schlesinger, M. H., Wilets, I. F. & Nagler, H. M. Treatment outcome after varicocelectomy: a critical analysis. Urologic Clin. North. Am. 21, 517–529 (1994).

    Article  CAS  Google Scholar 

  175. Chiba, K., Ramasamy, R., Lamb, D. J. & Lipshultz, L. I. The varicocele: diagnostic dilemmas, therapeutic challenges and future perspectives. Asian J. Androl. 18, 276 (2016).

    Article  PubMed  Google Scholar 

  176. Boeri, L. et al. Normal sperm parameters per se do not reliably account for fertility: A case–control study in the real‐life setting. Andrologia 53, e13861 (2021).

    Article  PubMed  Google Scholar 

  177. Keihani, S. et al. Semen parameter thresholds and time-to-conception in subfertile couples: how high is high enough?. Hum. Reprod. 36, 2121–2133 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  178. Matin-du-Pan, R. & Bischof, P. Increased follicle stimulating hormone in infetile men: Is increased plasma FSH always due to damaged germinal epithelium? Hum. Reprod. 10, 1940–1945 (1995).

    Article  Google Scholar 

  179. Clementini, E., Palka, C., Iezzi, I., Stuppia, L., Guanciali-Franchi, P. & Tiboni, G. Prevalence of chromosomal abnormalities in 2078 infertile couples referred for assisted reproductive techniques. Hum. Reprod. 20, 437–442 (2005).

    Article  CAS  PubMed  Google Scholar 

  180. VINCENT, M. C. et al. Cytogenetic investigations of infertile men with low sperm counts: a 25‐year experience. J. Androl. 23, 18–22 (2002).

    Article  PubMed  Google Scholar 

  181. Johnson, M. D. Genetic risks of intracytoplasmic sperm injection in the treatment of male infertility: recommendations for genetic counseling and screening. Fertil. Steril. 70, 397–411 (1998).

    Article  CAS  PubMed  Google Scholar 

  182. Colaco, S. & Modi, D. Genetics of the human Y chromosome and its association with male infertility. Reprod. Biol. Endocrinol. 16, 14 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  183. Ferlin, A. et al. Molecular and clinical characterization of Y chromosome microdeletions in infertile men: a 10-year experience in Italy. J. Clin. Endocrinol. Metab. 92, 762–770 (2007).

    Article  CAS  PubMed  Google Scholar 

  184. De Boeck, K. Cystic fibrosis in the year 2020: a disease with a new face. Acta Paediatrica 109, 893–899 (2020).

    Article  PubMed  Google Scholar 

  185. Bieniek, J. M., Juvet, T., Margolis, M., Grober, E. D., Lo, K. C. & Jarvi, K. A. Prevalence and management of incidental small testicular masses discovered on ultrasonographic evaluation of male infertility. J. Urol. 199, 481–486 (2018).

    Article  PubMed  Google Scholar 

  186. Kolettis, P. N. & Sandlow, J. I. Clinical and genetic features of patients with congenital unilateral absence of the vas deferens. Urology 60, 1073–1076 (2002).

    Article  PubMed  Google Scholar 

  187. Donohue, R. E. & Fauver, H. E. Unilateral absence of the vas deferens. A useful clinical sign. JAMA 261, 1180–1182 (1989).

    Article  CAS  PubMed  Google Scholar 

  188. Boivin, J., Bunting, L., Collins, J. A. & Nygren, K. G. International estimates of infertility prevalence and treatment-seeking: potential need and demand for infertility medical care. Hum. Reprod. 22, 1506–1512 (2007).

    Article  PubMed  Google Scholar 

  189. Aitken, R. J. Not every sperm is sacred; a perspective on male infertility. Mol. Hum. Reprod. 24, 287–298 (2018).

    CAS  PubMed  Google Scholar 

  190. Turner, K. A. et al. Male infertility is a women’s health issue-research and clinical evaluation of male infertility is needed. Cells 9, 990 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Kolettis, P. N. & Sabanegh, E. S. Significant medical pathology discovered during a male infertility evaluation. J. Urol. 166, 178–180 (2001).

    Article  CAS  PubMed  Google Scholar 

  192. Honig, S. C., Lipshultz, L. I. & Jarow, J. Significant medical pathology uncovered by a comprehensive male infertility evaluation. Fertil. Steril. 62, 1028–1034 (1994).

    Article  CAS  PubMed  Google Scholar 

  193. Dubin, J. M., Greer, A. B., Kohn, T. P., Masterson, T. A., Ji, L. & Ramasamy, R. Men with severe oligospermia appear to benefit from varicocele repair: a cost-effectiveness analysis of assisted reproductive technology. Urology 111, 99–103 (2018).

    Article  PubMed  Google Scholar 

  194. Meng, M. V., Greene, K. L. & Turek, P. J. Surgery or assisted reproduction? A decision analysis of treatment costs in male infertility. J. Urol. 174, 1926–1931 (2005).

    Article  PubMed  Google Scholar 

  195. Schlegel, P. N. Is assisted reproduction the optimal treatment for varicocele-associated male infertility? A cost-effectiveness analysis. Urology 49, 83–90 (1997).

    Article  CAS  PubMed  Google Scholar 

  196. Stierman, B. et al. National Health and Nutrition Examination Survey 2017–March 2020 Prepandemic Data Files—Development of Files and Prevalence Estimates for Selected Health Outcomes. National Health Statistics Report No. 158 (CDC, 2021).

  197. Craig, J. R., Jenkins, T. G., Carrell, D. T. & Hotaling, J. M. Obesity, male infertility, and the sperm epigenome. Fertil. Steril. 107, 848–859 (2017).

    Article  PubMed  Google Scholar 

  198. Eisenberg, M. L., Kim, S., Chen, Z., Sundaram, R., Schisterman, E. F., Buck & Louis, G. M. The relationship between male BMI and waist circumference on semen quality: data from the LIFE study. Hum. Reprod. 29, 193–200 (2014).

    Article  PubMed  Google Scholar 

  199. Gonzalez-Campoy, J. M. et al. Clinical practice guidelines for healthy eating for the prevention and treatment of metabolic and endocrine diseases in adults: cosponsored by the American Association of Clinical Endocrinologists/American College of Endocrinology and the Obesity Society. Endocr. Pract. 19 (Suppl. 3), 1–82 (2013).

    Article  PubMed  Google Scholar 

  200. Galdas, P. M., Cheater, F. & Marshall, P. Men and health help-seeking behaviour: literature review. J. Adv. Nurs. 49, 616–623 (2005).

    Article  PubMed  Google Scholar 

  201. Ramasamy, R., Bryson, C., Reifsnyder, J. E., Neri, Q., Palermo, G. D. & Schlegel, P. N. Overweight men with nonobstructive azoospermia have worse pregnancy outcomes after microdissection testicular sperm extraction. Fertil. Steril. 99, 372–376 (2013).

    Article  PubMed  Google Scholar 

  202. Hammoud, A. et al. Effect of Roux-en-Y gastric bypass surgery on the sex steroids and quality of life in obese men. J. Clin. Endocrinol. Metab. 94, 1329–1332 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Roth, M. Y., Amory, J. K. & Page, S. T. Treatment of male infertility secondary to morbid obesity. Nat. Clin. Pract. Endocrinol. Metab. 4, 415–419 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  204. Moran, L. J. et al. Long-term effects of a randomised controlled trial comparing high protein or high carbohydrate weight loss diets on testosterone, SHBG, erectile and urinary function in overweight and obese men. PLoS ONE 11, e0161297 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  205. Hayden, R. P., Flannigan, R. & Schlegel, P. N. The role of lifestyle in male infertility: diet, physical activity, and body habitus. Curr. Urol. Rep. 19, 56 (2018).

    Article  PubMed  Google Scholar 

  206. Salas-Huetos, A., Bullo, M. & Salas-Salvado, J. Dietary patterns, foods and nutrients in male fertility parameters and fecundability: a systematic review of observational studies. Hum. Reprod. Update 23, 371–389 (2017).

    Article  PubMed  Google Scholar 

  207. de Ligny, W., Smits, R. M. et al. Antioxidants for male subfertility. Cochrane Database Syst. Rev. 5, CD007411 (2022).

    PubMed  Google Scholar 

  208. Creta, M. et al. Toxicity of antioxidant supplements in patients with male factor infertility: a systematic review and meta-analysis of randomized controlled trials. Antioxidants 11, 89 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  209. Garolla, A. et al. Dietary supplements for male infertility: a critical evaluation of their composition. Nutrients 12, 1472 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Schisterman, E. F. Effect of folic acid and zinc supplementation in men on semen quality and live birth among couples undergoing infertility treatment: a randomized clinical trial. JAMA 323, 35–48 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Payne, K. S., Mazur, D. J., Hotaling, J. M. & Pastuszak, A. W. Cannabis and male fertility: a systematic review. J. Urol. 202, 674–681 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  212. Pizzol, D. et al. Pollutants and sperm quality: a systematic review and meta-analysis. Env. Sci. Pollut. Res. Int. 28, 4095–4103 (2021).

    Article  CAS  Google Scholar 

  213. Cannarella, R., Gül, M., Rambhatla, A. & Agarwal, A. Temporal decline of sperm concentration: role of endocrine disruptors. Endocrine 79, 1–16 (2023).

    Article  CAS  PubMed  Google Scholar 

  214. Knapke, E. T., Magalhaes, D. P., Dalvie, M. A., Mandrioli, D. & Perry, M. J. Environmental and occupational pesticide exposure and human sperm parameters: a navigation guide review. Toxicology 465, 153017 (2022).

    Article  CAS  PubMed  Google Scholar 

  215. Shefi, S., Tarapore, P. E., Walsh, T. J., Croughan, M. & Turek, P. J. Wet heat exposure: a potentially reversible cause of low semen quality in infertile men. Int. Braz. J. Urol. 33, 50–56 (2007).

    Article  PubMed  Google Scholar 

  216. Gautam, R., Priyadarshini, E., Nirala, J. & Rajamani, P. Impact of nonionizing electromagnetic radiation on male infertility: an assessment of the mechanism and consequences. Int. J. Radiat. Biol. 98, 1063–1073 (2022).

    Article  CAS  PubMed  Google Scholar 

  217. Shindel, A. W., Nelson, C. J., Naughton, C. K., Ohebshalom, M. & Mulhall, J. P. Sexual function and quality of life in the male partner of infertile couples: prevalence and correlates of dysfunction. J. Urol. 179, 1056–1059 (2008).

    Article  PubMed  Google Scholar 

  218. Lotti, F. & Maggi, M. Sexual dysfunction and male infertility. Nat. Rev. Urol. 15, 287–307 (2018).

    Article  PubMed  Google Scholar 

  219. Ding, J. et al. FDA-approved medications that impair human spermatogenesis. Oncotarget 8, 10714–10725 (2017).

    Article  PubMed  Google Scholar 

  220. Irfan, H. et al. Prolactinoma: clinical characteristics, management and outcome. Cureus 14, e29822 (2022).

    PubMed  PubMed Central  Google Scholar 

  221. Ko, E. Y., Siddiqi, K., Brannigan, R. E. & Sabanegh, E. S. Jr. Empirical medical therapy for idiopathic male infertility: a survey of the American Urological Association. J. Urol. 187, 973–978 (2012).

    Article  PubMed  Google Scholar 

  222. Thaker, H., Ko, E. Y., Sabanegh, E. S., Brannigan, R. E., Alukal, J. P. & Samplaski, M. K. Empirical medical therapy for idiopathic male infertility. FS Rep. 1, 15–20 (2020).

    Google Scholar 

  223. Keihani, S., Alder, N. J., Cheng, P. J., Stoddard, G. J., Pastuszak, A. W. & Hotaling, J. M. Obesity and baseline estradiol levels are independent predictors for initiation of anastrozole in hypogonadal men on clomiphene citrate. World J. Mens Health 38, 582–590 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  224. Alder, N. J., Keihani, S., Stoddard, G. J., Myers, J. B. & Hotaling, J. M. Combination therapy with clomiphene citrate and anastrozole is a safe and effective alternative for hypoandrogenic subfertile men. BJU Int. 122, 688–694 (2018).

    Article  CAS  PubMed  Google Scholar 

  225. Halpern, J. A., Brannigan, R. E. & Schlegel, P. N. Fertility-enhancing male reproductive surgery: glimpses into the past and thoughts for the future. Fertil. Steril. 112, 426–437 (2019).

    Article  PubMed  Google Scholar 

  226. Chehval, M. J. & Purcell, M. H. Deterioration of semen parameters over time in men with untreated varicocele: evidence of progressive testicular damage. Fertil. Steril. 57, 174–177 (1992).

    Article  CAS  PubMed  Google Scholar 

  227. Schauer, I., Madersbacher, S., Jost, R., Hubner, W. A. & Imhof, M. The impact of varicocelectomy on sperm parameters: a meta-analysis. J. Urol. 187, 1540–1547 (2012).

    Article  PubMed  Google Scholar 

  228. Practice Committee of the American Society for Reproductive Medicine–Society for Male Reproduction and Urology. The management of obstructive azoospermia: a committee opinion. Fertil. Steril. 111, 873–880 (2019).

    Article  Google Scholar 

  229. Esteves, S. C., Roque, M., Bradley, C. K. & Garrido, N. Reproductive outcomes of testicular versus ejaculated sperm for intracytoplasmic sperm injection among men with high levels of DNA fragmentation in semen: systematic review and meta-analysis. Fertil. Steril. 108, 456–467.e1 (2017).

    Article  CAS  PubMed  Google Scholar 

  230. Ibrahim, E., Aballa, T. C., Brackett, N. L. & Lynne, C. M. Electroejaculation in men with spinal cord injury: a step-by-step video demonstration. Fertil. Steril. 115, 1344–1346 (2021).

    Article  PubMed  Google Scholar 

  231. Di Bello, F. et al. Male sexual dysfunction and infertility in spinal cord injury patients: state-of-the-art and future perspectives. J. Pers. Med. 12, 873 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  232. Belker, A. M., Thomas, A. J. Jr., Fuchs, E. F., Konnak, J. W. & Sharlip, I. D. Results of 1,469 microsurgical vasectomy reversals by the Vasovasostomy Study Group. J. Urol. 145, 505–511 (1991).

    Article  CAS  PubMed  Google Scholar 

  233. Marmar, J. L. Modified vasoepididymostomy with simultaneous double needle placement, tubulotomy and tubular invagination. J. Urol. 163, 483–486 (2000).

    Article  CAS  PubMed  Google Scholar 

  234. Farley, S. & Barnes, R. Stenosis of ejaculatory ducts treated by endoscopic resection. J. Urol. 109, 664–666 (1973).

    Article  CAS  PubMed  Google Scholar 

  235. Engin, G., Celtik, M., Sanli, O., Aytac, O., Muradov, Z. & Kadioglu, A. Comparison of transrectal ultrasonography and transrectal ultrasonography-guided seminal vesicle aspiration in the diagnosis of the ejaculatory duct obstruction. Fertil. Steril. 92, 964–970 (2009).

    Article  PubMed  Google Scholar 

  236. Turek, P. J., Magana, J. O. & Lipshultz, L. I. Semen parameters before and after transurethral surgery for ejaculatory duct obstruction. J. Urol. 155, 1291–1293 (1996).

    Article  CAS  PubMed  Google Scholar 

  237. Xu, B., Niu, X. & Wang, Z. et al. Novel methods for the diagnosis and treatment of ejaculatory duct obstruction. BJU Int. 108, 263–266 (2011).

    Article  PubMed  Google Scholar 

  238. Schlegel, P. N. Testicular sperm extraction: microdissection improves sperm yield with minimal tissue excision. Hum. Reprod. 14, 131–135 (1999).

    Article  CAS  PubMed  Google Scholar 

  239. Bernie, A. M., Mata, D. A., Ramasamy, R. & Schlegel, P. N. Comparison of microdissection testicular sperm extraction, conventional testicular sperm extraction, and testicular sperm aspiration for nonobstructive azoospermia: a systematic review and meta-analysis. Fertil. Steril. 104, 1099–1103.e3 (2015).

    Article  PubMed  Google Scholar 

  240. Ohlander, S., Hotaling, J., Kirshenbaum, E., Niederberger, C. & Eisenberg, M. L. Impact of fresh versus cryopreserved testicular sperm upon intracytoplasmic sperm injection pregnancy outcomes in men with azoospermia due to spermatogenic dysfunction: a meta-analysis. Fertil. Steril. 101, 344–349 (2014).

    Article  PubMed  Google Scholar 

  241. Mousavi, S. A., Masoumi, S. Z., Keramat, A., Pooralajal, J. & Shobeiri, F. Assessment of questionnaires measuring quality of life in infertile couples: a systematic review. J. Reprod. Infertil. 14, 110–119 (2013).

    PubMed  PubMed Central  Google Scholar 

  242. Duffy, J. M. N. et al. Top 10 priorities for future infertility research: an international consensus development study. Fertil. Steril. 115, 180–190 (2021).

    Article  CAS  PubMed  Google Scholar 

  243. Haraldstad, K. et al. A systematic review of quality of life research in medicine and health sciences. Qual. Life Res. 28, 2641–2650 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  244. Koert, E., Takefman, J. & Boivin, J. Fertility quality of life tool: update on research and practice considerations. Hum. Fertil. 24, 236–248 (2021).

    Article  CAS  Google Scholar 

  245. Pedro, J., Canavarro, M. C., Boivin, J. & Gameiro, S. Positive experiences of patient-centred care are associated with intentions to comply with fertility treatment: findings from the validation of the Portuguese version of the PCQ-Infertility tool. Hum. Reprod. 28, 2462–2472 (2013).

    Article  PubMed  Google Scholar 

  246. Peterson, B. D., Pirritano, M., Christensen, U., Boivin, J., Block, J. & Schmidt, L. The longitudinal impact of partner coping in couples following 5 years of unsuccessful fertility treatments. Hum. Reprod. 24, 1656–1664 (2009).

    Article  CAS  PubMed  Google Scholar 

  247. Sobral, M. P., Costa, M. E., Schmidt, L. & Martins, M. V. COMPI Fertility Problem Stress Scales is a brief, valid and reliable tool for assessing stress in patients seeking treatment. Hum. Reprod. 32, 375–382 (2017).

    Article  PubMed  Google Scholar 

  248. Ware, J. E. Jr. & Sherbourne, C. D. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med. Care 30, 473–483 (1992).

    Article  PubMed  Google Scholar 

  249. World Health Organization. WHOQOL: measuring quality of life. WHO https://www.who.int/tools/whoqol (2012).

  250. Boivin, J., Takefman, J. & Braverman, A. The fertility Quality of Life (FertiQoL) tool: development and general psychometric properties. Hum. Reprod. 26, 2084–2091 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  251. Newton, C. R., Sherrard, W. & Glavac, I. The Fertility Problem Inventory: measuring perceived infertility-related stress. Fertil. Steril. 72, 54–62 (1999).

    Article  CAS  PubMed  Google Scholar 

  252. Boivin, J., Takefman, J. & Braverman, A. The Fertility Quality of Life (FertiQoL) tool: development and general psychometric properties. Fertil. Steril. 96, 409–415 e403 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  253. Huppelschoten, A. G., van Dongen, A. J., Verhaak, C. M., Smeenk, J. M., Kremer, J. A. & Nelen, W. L. Differences in quality of life and emotional status between infertile women and their partners. Hum. Reprod. 28, 2168–2176 (2013).

    Article  CAS  PubMed  Google Scholar 

  254. Brandes, M. et al. When and why do subfertile couples discontinue their fertility care? A longitudinal cohort study in a secondary care subfertility population. Hum. Reprod. 24, 3127–3135 (2009).

    Article  CAS  PubMed  Google Scholar 

  255. Verberg, M. F. et al. Why do couples drop-out from IVF treatment? A prospective cohort study. Hum. Reprod. 23, 2050–2055 (2008).

    Article  CAS  PubMed  Google Scholar 

  256. Walschaerts, M., Bujan, L., Parinaud, J., Mieusset, R. & Thonneau, P. Treatment discontinuation in couples consulting for male infertility after failing to conceive. Fertil. Steril. 99, 1319–1323 (2013).

    Article  PubMed  Google Scholar 

  257. Chachamovich, J. R., Chachamovich, E., Ezer, H., Fleck, M. P., Knauth, D. & Passos, E. P. Investigating quality of life and health-related quality of life in infertility: a systematic review. J. Psychosom. Obstet. Gynaecol. 31, 101–110 (2010).

    Article  PubMed  Google Scholar 

  258. Shiraishi, K., Oka, S. & Matsuyama, H. Assessment of quality of life during gonadotrophin treatment for male hypogonadotrophic hypogonadism. Clin. Endocrinol. 81, 259–265 (2014).

    Article  CAS  Google Scholar 

  259. Esteves, S. C. Evolution of the World Health Organization semen analysis manual: where are we? Nat. Rev. Urol. 19, 439–446 (2022).

    Article  PubMed  Google Scholar 

  260. Jayasena, C. N. et al. Burdens and awareness of adverse self-reported lifestyle factors in men with sub-fertility: a cross-sectional study in 1149 men. Clin. Endocrinol. 93, 312–321 (2020).

    Article  Google Scholar 

  261. Olisa, N. P., Campo-Engelstein, L. & Martins da Silva, S. Male infertility: what on earth is going on? Pilot international questionnaire study regarding clinical evaluation and fertility treatment for men. Reprod. Fertil. 3, 207–215 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  262. Lee, R. et al. Automated rare sperm identification from low-magnification microscopy images of dissociated microsurgical testicular sperm extraction samples using deep learning. Fertil. Steril. 118, 90–99 (2022).

    Article  PubMed  Google Scholar 

  263. Ito, Y. et al. A method for utilizing automated machine learning for histopathological classification of testis based on Johnsen scores. Sci. Rep. 11, 9962 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  264. Ahrenfeldt, L. J. et al. Impaired fecundity as a marker of health and survival: a Danish twin cohort study. Hum. Reprod. 36, 2309–2320 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  265. Eisenberg, M. L., Betts, P., Herder, D., Lamb, D. J. & Lipshultz, L. I. Increased cancer risk and azoospermia. Fertil. Steril. 100, e12 (2013).

    Article  PubMed  Google Scholar 

  266. Eisenberg, M. L., Betts, P., Herder, D., Lamb, D. J. & Lipshultz, L. I. Increased risk of cancer among azoospermic men. Fertil. Steril. 100, 681–685 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  267. Eisenberg, M. L. et al. The relationship between anogenital distance and the androgen receptor CAG repeat length. Asian J. Androl. 15, 286–289 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  268. Eisenberg, M. L. et al. Semen quality, infertility and mortality in the USA. Hum. Reprod. 29, 1567–1574 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  269. Eisenberg, M. L., Li, S., Betts, P., Herder, D., Lamb, D. J. & Lipshultz, L. I. Testosterone therapy and cancer risk. BJU Int. 115, 317–321 (2015).

    Article  CAS  PubMed  Google Scholar 

  270. Eisenberg, M. L., Li, S., Cullen, M. R. & Baker, L. C. Increased risk of incident chronic medical conditions in infertile men: analysis of United States claims data. Fertil. Steril. 105, 629–636 (2016).

    Article  PubMed  Google Scholar 

  271. Eisenberg, M. L., Li, S., Herder, D., Lamb, D. J. & Lipshultz, L. I. Testosterone therapy and mortality risk. Int. J. Impot. Res. 27, 46–48 (2015).

    Article  CAS  PubMed  Google Scholar 

  272. Eisenberg, M. L., Murthy, L., Hwang, K., Lamb, D. J. & Lipshultz, L. I. Sperm counts and sperm sex ratio in male infertility patients. Asian J. Androl. 14, 683–686 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  273. Hanson, B. M., Eisenberg, M. L. & Hotaling, J. M. Male infertility: a biomarker of individual and familial cancer risk. Fertil. Steril. 109, 6–19 (2018).

    Article  CAS  PubMed  Google Scholar 

  274. Kasak, L. et al. Actionable secondary findings following exome sequencing of 836 non-obstructive azoospermia cases and their value in patient management. Hum. Reprod. 37, 1652–1663 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  275. Walsh, T. J. et al. Increased risk of high-grade prostate cancer among infertile men. Cancer 116, 2140–2147 (2010).

    PubMed  Google Scholar 

  276. Hotaling, J. M. & Walsh, T. J. Male infertility: a risk factor for testicular cancer. Nat. Rev. Urol. 6, 550–556 (2009).

    Article  CAS  PubMed  Google Scholar 

  277. Ostrowski, K. A. & Walsh, T. J. Infertility with testicular cancer. Urol. Clin. North Am. 42, 409–420 (2015).

    Article  PubMed  Google Scholar 

  278. Rogers, M. J. & Walsh, T. J. Male Infertility and risk of cancer. Semin. Reprod. Med. 35, 298–303 (2017).

    Article  PubMed  Google Scholar 

  279. Walsh, T. J. Male reproductive health and prostate cancer risk. Curr. Opin. Urol. 21, 506–513 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  280. Walsh, T. J., Croughan, M. S., Schembri, M., Chan, J. M. & Turek, P. J. Increased risk of testicular germ cell cancer among infertile men. Arch. Intern. Med. 169, 351–356 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  281. Walsh, T. J. et al. Testosterone treatment and the risk of aggressive prostate cancer in men with low testosterone levels. PLoS ONE 13, e0199194 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  282. Punjani, N. & Lamb, D. J. Male infertility and genitourinary birth defects: there is more than meets the eye. Fertil. Steril. 114, 209–218 (2020).

    Article  CAS  PubMed  Google Scholar 

  283. Tannour-Louet, M. et al. Identification of de novo copy number variants associated with human disorders of sexual development. PLoS ONE 5, e15392 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  284. Tannour-Louet, M. et al. Increased gene copy number of VAMP7 disrupts human male urogenital development through altered estrogen action. Nat. Med. 20, 715–724 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  285. Jorgez, C. J. et al. Genitourinary defects associated with genomic deletions in 2p15 encompassing OTX1. PLoS ONE 9, e107028 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  286. Pryor, J. L. et al. Microdeletions in the Y chromosome of infertile men. N. Engl. J. Med. 336, 534–539 (1997).

    Article  CAS  PubMed  Google Scholar 

  287. Vogt, P., Chandley, A. C., Hargreave, T. B., Keil, R., Ma, K. & Sharkey, A. Microdeletions in interval 6 of the Y chromosome of males with idiopathic sterility point to disruption of AZF, a human spermatogenesis gene. Hum. Genet. 89, 491–496 (1992).

    Article  CAS  PubMed  Google Scholar 

  288. Ma, K. et al. Towards the molecular localisation of the AZF locus: mapping of microdeletions in azoospermic men within 14 subintervals of interval 6 of the human Y chromosome. Hum. Mol. Genet. 1, 29–33 (1992).

    Article  CAS  PubMed  Google Scholar 

  289. Haller, M., Au, J., O’Neill, M. & Lamb, D. J. 16p11.2 transcription factor MAZ is a dosage-sensitive regulator of genitourinary development. Proc. Natl Acad. Sci. USA 115, E1849–E1858 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  290. Haller, M., Mo, Q., Imamoto, A. & Lamb, D. J. Murine model indicates 22q11.2 signaling adaptor CRKL is a dosage-sensitive regulator of genitourinary development. Proc. Natl Acad. Sci. USA 114, 4981–4986 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  291. Punjani, N. & Lamb, D. J. Canary in the coal mine? Male infertility as a marker of overall health. Annu. Rev. Genet. 54, 465–486 (2020).

    Article  CAS  PubMed  Google Scholar 

  292. Punjani, N., Kang, C. & Lamb, D. J. Genetic implications of male-reproductive-health-associated comorbidities. Turk. J. Urol. 48, 363–374 (2020).

    Article  Google Scholar 

  293. Medina-Martinez, O. et al. The transcription factor Maz is essential for normal eye development. Dis. Model. Mech. 13, dmm044412 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  294. Guo, J. et al. The adult human testis transcriptional cell atlas. Cell Res. 28, 1141–1157 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  295. Guo, J. et al. Chromatin and single-cell RNA-seq profiling reveal dynamic signaling and metabolic transitions during human spermatogonial stem cell development. Cell Stem Cell 21, 533–546.e6 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  296. Blaurock, J., Baumann, S., Grunewald, S., Schiller, J. & Engel, K. M. Metabolomics of human semen: a review of different analytical methods to unravel biomarkers for male fertility disorders. Int. J. Mol. Sci. 23, 9031 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  297. Ishikura, Y. et al. In vitro reconstitution of the whole male germ-cell development from mouse pluripotent stem cells. Cell Stem Cell 28, 2167–2179 (2021).

    Article  CAS  PubMed  Google Scholar 

  298. Brinster, R. L. Germline stem cell transplantation and transgenesis. Science 296, 2174–2176 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  299. Sanou, I. et al. Spermatogonial stem cell-based therapies: taking preclinical research to the next level. Front. Endocrinol. 13, 850219 (2022).

    Article  Google Scholar 

  300. Delessard, M. et al. Achievement of complete in vitro spermatogenesis in testicular tissues from prepubertal mice exposed to mono- or polychemotherapy. Sci. Rep. 12, 7407 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  301. Skakkebaek, N. E. et al. Male reproductive disorders and fertility trends: influences of environment and genetic susceptibility. Physiol. Rev. 96, 55–97 (2016).

    Article  CAS  PubMed  Google Scholar 

  302. World Health Organization. WHO Laboratory Manual for the Examination of Human Semen and Sperm–Cervical Mucus Interaction 5th edn (Cambridge Univ. Press, 2010).

  303. Roser, M. Fertility rate. OurWorldInData.org https://ourworldindata.org/fertility-rate (2017).

  304. UN Department of Economic and Social Affairs, Population Division. World Population Prospects 2022. population.un.org https://population.un.org/wpp/ (2022).

  305. GBD 2017 Population and Fertility Collaborators. Population and fertility by age and sex for 195 countries and territories, 1950-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet 392, 1995–2051 (2018).

    Article  Google Scholar 

  306. GBD 2019 Demographics Collaborators. Global age-sex-specific fertility, mortality, healthy life expectancy (HALE), and population estimates in 204 countries and territories, 1950-2019: a comprehensive demographic analysis for the Global Burden of Disease Study 2019. Lancet 396, 1160–1203 (2020).

    Article  Google Scholar 

  307. Aitken, R. J. The changing tide of human fertility. Hum. Reprod. 37, 629–638 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  308. Levine, H. et al. Temporal trends in sperm count: a systematic review and meta-regression analysis. Hum. Reprod. Update 23, 646–659 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  309. Skakkebæk, N. E. et al. Environmental factors in declining human fertility. Nat. Rev. Endocrinol. 18, 139–157 (2022).

    Article  PubMed  Google Scholar 

  310. Levine, H. et al. Temporal trends in sperm count: a systematic review and meta-regression analysis of samples collected globally in the 20th and 21st centuries. Hum. Reprod. Update 29, 157–176 (2023).

    Article  PubMed  Google Scholar 

  311. Cocuzza, M. & Esteves, S. C. Shedding light on the controversy surrounding the temporal decline in human sperm counts: a systematic review. ScientificWorldJournal 2014, 365691 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  312. Priskorn, L. et al. Average sperm count remains unchanged despite reduction in maternal smoking: results from a large cross-sectional study with annual investigations over 21 years. Hum. Reprod. 33, 998–1008 (2018).

    Article  CAS  PubMed  Google Scholar 

  313. Sharma, R., Harlev, A., Agarwal, A. & Esteves, S. C. 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. 70, 635–645 (2016).

    Article  PubMed  Google Scholar 

  314. Glazer, C. H., Li, S., Zhang, C. A., Giwercman, A., Bonde, J. P. & Eisenberg, M. L. Racial and sociodemographic differences of semen parameters among US men undergoing a semen analysis. Urology 123, 126–132 (2019).

    Article  PubMed  Google Scholar 

  315. Paffoni, A., Somigliana, E., Boeri, L. & Viganò, P. The statistical foundation of the reference population for semen analysis included in the sixth edition of the WHO manual: a critical reappraisal of the evidence. Hum. Reprod. 37, 2237–2245 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  316. Esteves, S. C. Clinical relevance of routine semen analysis and controversies surrounding the 2010 World Health Organization criteria for semen examination. Int. Braz. J. Urol. 40, 443–453 (2014).

    Article  PubMed  Google Scholar 

  317. Esteves, S. C., Zini, A., Aziz, N., Alvarez, J. G., Sabanegh, E. S. Jr & Agarwal, A. Critical appraisal of World Health Organization’s new reference values for human semen characteristics and effect on diagnosis and treatment of subfertile men. Urology 79, 16–22 (2012).

    Article  PubMed  Google Scholar 

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Acknowledgements

The authors thank V. Ruthig for helpful pre-review comments.

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Authors and Affiliations

  1. Department of Urology, Stanford University School of Medicine, Stanford, CA, USA

    Michael L. Eisenberg

  2. Department of Obstetrics & Gynecology, Stanford University School of Medicine, Stanford, CA, USA

    Michael L. Eisenberg

  3. ANDROFERT Andrology and Human Reproduction Clinic, Campinas, Brazil

    Sandro C. Esteves

  4. Division of Urology, Department of Surgery, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas, Brazil

    Sandro C. Esteves

  5. Center for Reproductive Genomics, Weill Cornell Medical College, New York, NY, USA

    Dolores J. Lamb

  6. Englander Institute for Precision Medicine, Weill Cornell Medical College, New York, NY, USA

    Dolores J. Lamb

  7. Department of Urology, Weill Cornell Medical College, New York, NY, USA

    Dolores J. Lamb

  8. Division of Urology, Department of Surgery, University of Utah School of Medicine, Salt Lake City, UT, USA

    James M. Hotaling

  9. Department of Translational Medicine, Lund University, Malmö, Sweden

    Aleksander Giwercman

  10. University of Pittsburgh Medical Center, Pittsburgh, PA, USA

    Kathleen Hwang

  11. Department of Urology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan

    Yu-Sheng Cheng

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The authors contributed equally to all aspects of the article.

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Correspondence to Michael L. Eisenberg.

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Competing interests

M.L.E. is an adviser to Ro, Inc., Doveras, Next and VSeat. J.M.H. is an equity holder and co-founder of Paterna Biosciences, a consultant for Turtle Health and Carrot. K.H. is a medical director at Reprosource. D.J.L is an equity holder of Fellow Health, and serves on the Scientific Advisory Board for Ro, Inc. (stock options not executed and compensation). D.J.L. is supported in part by the Frederick J. and Theresa Dow Wallace Fund of the New York Community Trust and the Robert S. Dow Professorship in Urology. The other authors declare no competing interests.

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Eisenberg, M.L., Esteves, S.C., Lamb, D.J. et al. Male infertility. Nat Rev Dis Primers 9, 49 (2023). https://doi.org/10.1038/s41572-023-00459-w

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