Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Expert Recommendation
  • Published:

Frequency, morbidity and equity — the case for increased research on male fertility

Abstract

Currently, most men with infertility cannot be given an aetiology, which reflects a lack of knowledge around gamete production and how it is affected by genetics and the environment. A failure to recognize the burden of male infertility and its potential as a biomarker for systemic illness exists. The absence of such knowledge results in patients generally being treated as a uniform group, for whom the strategy is to bypass the causality using medically assisted reproduction (MAR) techniques. In doing so, opportunities to prevent co-morbidity are missed and the burden of MAR is shifted to the woman. To advance understanding of men’s reproductive health, longitudinal and multi-national centres for data and sample collection are essential. Such programmes must enable an integrated view of the consequences of genetics, epigenetics and environmental factors on fertility and offspring health. Definition and possible amelioration of the consequences of MAR for conceived children are needed. Inherent in this statement is the necessity to promote fertility restoration and/or use the least invasive MAR strategy available. To achieve this aim, protocols must be rigorously tested and the move towards personalized medicine encouraged. Equally, education of the public, governments and clinicians on the frequency and consequences of infertility is needed. Health options, including male contraceptives, must be expanded, and the opportunities encompassed in such investment understood. The pressing questions related to male reproductive health, spanning the spectrum of andrology are identified in the Expert Recommendation.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Worldwide, limited data exist on sperm concentration in men.

Similar content being viewed by others

References

  1. WHO. Infecundity, infertility, and childlessness in Developing Countries - DHS Comparative reports no. 9. WHO https://www.who.int/publications/m/item/infecundity-infertility-and-childlessness-in-developing-countries---dhs-comparative-reports-no.-9 (2004).

  2. Forti, G. & Krausz, C. Clinical review 100: evaluation and treatment of the infertile couple. J. Clin. Endocrinol. Metab. 83, 4177–4188 (1998).

    CAS  PubMed  Google Scholar 

  3. De Jonge, C. & Barratt, C. L. R. The present crisis in male reproductive health: an urgent need for a political, social, and research roadmap. Andrology 7, 762–768 (2019).

    Article  PubMed  Google Scholar 

  4. 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 

  5. Boitrelle, F. et al. The sixth edition of the WHO manual for human semen analysis: a critical review and SWOT analysis. Life 11, 1368 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Eisenberg, M. L., Li, S., Behr, B., Pera, R. R. & Cullen, M. R. Relationship between semen production and medical comorbidity. Fertil. Steril. 103, 66–71 (2015).

    Article  PubMed  Google Scholar 

  7. Lismer, A. & Kimmins, S. Emerging evidence that the mammalian sperm epigenome serves as a template for embryo development. Nat. Commun. 14, 2142 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Houston, B. J. et al. A systematic review of the validated monogenic causes of human male infertility: 2020 update and a discussion of emerging gene-disease relationships. Hum. Reprod. Update 28, 15–29 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  Google Scholar 

  10. Datta, J. et al. Prevalence of infertility and help seeking among 15 000 women and men. Hum. Reprod. 31, 2108–2118 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Barratt, C. L. R. et al. The diagnosis of male infertility: an analysis of the evidence to support the development of global WHO guidance-challenges and future research opportunities. Hum. Reprod. Update 23, 660–680 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Baker, H. W. G. in Endocrinology (eds Jameson J. L. & DeGroot, L. J.) Ch. 141, 2556–2579 (Saunders Elsevier, 2010).

  13. 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 

  14. Schlegel, P. N. et al. Diagnosis and treatment of infertility in Men: AUA/ASRM guideline part I. J. Urol. 205, 36–43 (2021).

    Article  PubMed  Google Scholar 

  15. Schlegel, P. N. et al. Diagnosis and treatment of infertility in Men: AUA/ASRM guideline part II. J. Urol. 205, 44–51 (2021).

    Article  PubMed  Google Scholar 

  16. 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 

  17. Practice Committee of the American Society for Reproductive Medicine. Diagnostic evaluation of the infertile male: a committee opinion. Fertil. Steril. 103, e18–e25 (2015).

    Article  Google Scholar 

  18. 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 

  19. Punab, M. et al. Causes of male infertility: a 9-year prospective monocentre study on 1737 patients with reduced total sperm counts. Hum. Reprod. 32, 18–31 (2017).

    CAS  PubMed  Google Scholar 

  20. Campbell, M. J. et al. Distribution of semen examination results 2020 — A follow up of data collated for the WHO semen analysis manual 2010. Andrology 9, 817–822 (2021).

    Article  PubMed  Google Scholar 

  21. Bohring, C. & Krause, W. Serum levels of inhibin B in men with different causes of spermatogenic failure. Andrologia 31, 137–141 (1999).

    Article  CAS  PubMed  Google Scholar 

  22. Sikaris, K. et al. Reproductive hormone reference intervals for healthy fertile young men: evaluation of automated platform assays. J. Clin. Endocrinol. Metab. 90, 5928–5936 (2005).

    Article  CAS  PubMed  Google Scholar 

  23. Waller, E.-J., Conceicao, J., Matson, P. & Yovich, J. Proposed age-stratified reference intervals of FSH derived from normozoospermic men. Asian Pac. J. Reprod. 10, 162–167 (2021).

    Article  CAS  Google Scholar 

  24. Nahoul, K. & Roger, M. Age-related decline of plasma bioavailable testosterone in adult men. J. Steroid Biochem. 35, 293–299 (1990).

    Article  CAS  PubMed  Google Scholar 

  25. Neaves, W. B., Johnson, L., Porter, J. C., Parker, C. R. Jr. & Petty, C. S. Leydig cell numbers, daily sperm production, and serum gonadotropin levels in aging men. J. Clin. Endocrinol. Metab. 59, 756–763 (1984).

    Article  CAS  PubMed  Google Scholar 

  26. Bjørnerem, A. et al. Endogenous sex hormones in relation to age, sex, lifestyle factors, and chronic diseases in a general population: the Tromsø Study. J. Clin. Endocrinol. Metab. 89, 6039–6047 (2004).

    Article  PubMed  Google Scholar 

  27. Gray, A., Feldman, H. A., McKinlay, J. B. & Longcope, C. Age, disease, and changing sex hormone levels in middle-aged men: results of the Massachusetts Male Aging Study. J. Clin. Endocrinol. Metab. 73, 1016–1025 (1991).

    Article  CAS  PubMed  Google Scholar 

  28. Andersson, A. M., Jorgensen, N., Frydelund-Larsen, L., Rajpert-De Meyts, E. & Skakkebaek, N. E. Impaired Leydig cell function in infertile men: a study of 357 idiopathic infertile men and 318 proven fertile controls. J. Clin. Endocrinol. Metab. 89, 3161–3167 (2004).

    Article  CAS  PubMed  Google Scholar 

  29. 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 

  30. 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 

  31. Jungwirth, A et al. EAU Guidelines on Male Infertility https://d56bochluxqnz.cloudfront.net/media/EAU-Guidelines-on-Male-Infertility-2019.pdf (EAU, 2019).

  32. Australia and New Zealand Assisted Reproduction Database ANZARD https://www.fertilitysociety.com.au/anzard/#anzard (2019).

  33. Nixon, B. et al. New horizons in human sperm selection for assisted reproduction. Front. Endocrinol. 14, 1145533 (2023).

    Article  Google Scholar 

  34. You, J. B. et al. Machine learning for sperm selection. Nat. Rev. Urol. 18, 387–403 (2021).

    Article  PubMed  Google Scholar 

  35. 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 

  36. Hviid Malling, G. M. et al. ‘Doing it in the right order’: childless men’s intentions regarding family formation. Hum. Fertil. 25, 188–196 (2020).

    Article  Google Scholar 

  37. Priskorn, L. et al. RUBIC (ReproUnion Biobank and Infertility Cohort): a binational clinical foundation to study risk factors, life course, and treatment of infertility and infertility-related morbidity. Andrology 9, 1828–1842 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Mazzilli, R. et al. Severe male factor in in vitro fertilization: definition, prevalence, and treatment. An update. Asian J. Androl. 24, 125–134 (2022).

    Article  CAS  PubMed  Google Scholar 

  39. Tournaye, H., Krausz, C. & Oates, R. D. Concepts in diagnosis and therapy for male reproductive impairment. Lancet Diabetes Endocrinol. 5, 554–564 (2017).

    Article  PubMed  Google Scholar 

  40. Young, J. et al. Clinical management of congenital hypogonadotropic hypogonadism. Endocr. Rev. 40, 669–710 (2019).

    Article  PubMed  Google Scholar 

  41. Butz, H., Nyiro, G., Kurucz, P. A., Liko, I. & Patocs, A. Molecular genetic diagnostics of hypogonadotropic hypogonadism: from panel design towards result interpretation in clinical practice. Hum. Genet. 140, 113–134 (2021).

    Article  PubMed  Google Scholar 

  42. Chudnovsky, A. & Niederberger, C. S. Gonadotropin therapy for infertile men with hypogonadotropic hypogonadism. J. Androl. 28, 644–646 (2007).

    Article  PubMed  Google Scholar 

  43. Avellino, G. J., Lipshultz, L. I., Sigman, M. & Hwang, K. Transurethral resection of the ejaculatory ducts: etiology of obstruction and surgical treatment options. Fertil. Steril. 111, 427–443 (2019).

    Article  PubMed  Google Scholar 

  44. Heidenreich, A., Altmann, P. & Engelmann, U. H. Microsurgical vasovasostomy versus microsurgical epididymal sperm aspiration/testicular extraction of sperm combined with intracytoplasmic sperm injection. A cost-benefit analysis. Eur. Urol. 37, 609–614 (2000).

    Article  CAS  PubMed  Google Scholar 

  45. Aggour, A., Mostafa, H. & Maged, W. Endoscopic management of ejaculatory duct obstruction. Int. Urol. Nephrol. 30, 481–485 (1998).

    Article  CAS  PubMed  Google Scholar 

  46. Modgil, V., Rai, S., Ralph, D. J. & Muneer, A. An update on the diagnosis and management of ejaculatory duct obstruction. Nat. Rev. Urol. 13, 13–20 (2016).

    Article  PubMed  Google Scholar 

  47. Wosnitzer, M., Goldstein, M. & Hardy, M. P. Review of azoospermia. Spermatogenesis 4, e28218 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  Google Scholar 

  49. Colpi, G. M. et al. European Academy of Andrology guideline management of oligo-astheno-teratozoospermia. Andrology 6, 513–524 (2018).

    Article  CAS  PubMed  Google Scholar 

  50. Nicopoullos, J. D. et al. Use of surgical sperm retrieval in azoospermic men: a meta-analysis. Fertil. Steril. 82, 691–701 (2004).

    Article  PubMed  Google Scholar 

  51. Punjani, N., Kang, C. & Schlegel, P. N. Two decades from the introduction of microdissection testicular sperm extraction: how this surgical technique has improved the management of NOA. J. Clin. Med. 10, 1374 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  52. Krausz, C. et al. Genetic dissection of spermatogenic arrest through exome analysis: clinical implications for the management of azoospermic men. Genet. Med. 22, 1956–1966 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Ji, C. et al. Potential of testis-derived circular RNAs in seminal plasma to predict the outcome of microdissection testicular sperm extraction in patients with idiopathic non-obstructive azoospermia. Hum. Reprod. 36, 2649–2660 (2021).

    Article  CAS  PubMed  Google Scholar 

  54. Rastrelli, G., Corona, G., Mannucci, E. & Maggi, M. Factors affecting spermatogenesis upon gonadotropin-replacement therapy: a meta-analytic study. Andrology 2, 794–808 (2014).

    Article  CAS  PubMed  Google Scholar 

  55. Boeri, L., Capogrosso, P. & Salonia, A. Gonadotropin treatment for the male hypogonadotropic hypogonadism. Curr. Pharm. Des. 27, 2775–2783 (2020).

    Article  Google Scholar 

  56. Ferlin, A. et al. Management of male factor infertility: position statement from the Italian Society of Andrology and Sexual Medicine (SIAMS): endorsing organization: Italian Society of Embryology, Reproduction, and Research (SIERR). J. Endocrinol. Invest. 45, 1085–1113 (2022).

    Article  CAS  PubMed  Google Scholar 

  57. Lee, J. A. & Ramasamy, R. Indications for the use of human chorionic gonadotropic hormone for the management of infertility in hypogonadal men. Transl. Androl. Urol. 7, S348–S352 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  58. Prior, M., Stewart, J., McEleny, K., Dwyer, A. A. & Quinton, R. Fertility induction in hypogonadotropic hypogonadal men. Clin. Endocrinol. 89, 712–718 (2018).

    Article  CAS  Google Scholar 

  59. Ramasamy, R., Stahl, P. J. & Schlegel, P. N. Medical therapy for spermatogenic failure. Asian J. Androl. 14, 57–60 (2012).

    Article  CAS  PubMed  Google Scholar 

  60. Omar, M. I. et al. Benefits of empiric nutritional and medical therapy for semen parameters and pregnancy and live birth rates in couples with idiopathic infertility: a systematic review and meta-analysis. Eur. Urol. 75, 615–625 (2019).

    Article  PubMed  Google Scholar 

  61. Behre, H. M. Clinical use of FSH in male infertility. Front. Endocrinol. 10, 322 (2019).

    Article  Google Scholar 

  62. Caroppo, E. & Colpi, G. M. Hormonal treatment of men with nonobstructive azoospermia: what does the evidence suggest? J. Clin. Med. 10, 387 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Barbonetti, A. et al. The use of follicle stimulating hormone (FSH) for the treatment of the infertile man: position statement from the Italian Society of Andrology and Sexual Medicine (SIAMS). J. Endocrinol. Invest. 41, 1107–1122 (2018).

    Article  CAS  PubMed  Google Scholar 

  64. Del Giudice, F. et al. A systematic review and meta-analysis of clinical trials implementing aromatase inhibitors to treat male infertility. Asian J. Androl. 22, 360–367 (2020).

    Article  PubMed  Google Scholar 

  65. 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 

  66. Thaker, H. et al. Empirical medical therapy for idiopathic male infertility. F. S Rep. 1, 15–20 (2020).

    PubMed  PubMed Central  Google Scholar 

  67. Ferlin, A. et al. Toward a pharmacogenetic approach to male infertility: polymorphism of follicle-stimulating hormone beta-subunit promoter. Fertil. Steril. 96, 1344–1349.e2 (2011).

    Article  CAS  PubMed  Google Scholar 

  68. Simoni, M. et al. Treatment with human, recombinant FSH improves sperm DNA fragmentation in idiopathic infertile men depending on the FSH receptor polymorphism p.N680S: a pharmacogenetic study. Hum. Reprod. 31, 1960–1969 (2016).

    Article  PubMed  Google Scholar 

  69. Casamonti, E. et al. Short-term FSH treatment and sperm maturation: a prospective study in idiopathic infertile men. Andrology 5, 414–422 (2017).

    Article  CAS  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  71. Agarwal, A. et al. A global survey of reproductive specialists to determine the clinical utility of oxidative stress testing and antioxidant use in male infertility. World J. Mens. Health 39, 470–488 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  72. Barati, E., Nikzad, H. & Karimian, M. Oxidative stress and male infertility: current knowledge of pathophysiology and role of antioxidant therapy in disease management. Cell Mol. Life Sci. 77, 93–113 (2020).

    Article  CAS  PubMed  Google Scholar 

  73. Aitken, R. J. Antioxidant trials — the need to test for stress. Hum. Reprod. Open. 2021, hoab007 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  74. Schisterman, E. F. et al. 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 

  75. Zini, A., San Gabriel, M. & Baazeem, A. Antioxidants and sperm DNA damage: a clinical perspective. J. Assist. Reprod. Genet. 26, 427–432 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  76. Aitken, R. J. Reactive oxygen species as mediators of sperm capacitation and pathological damage. Mol. Reprod. Dev. 84, 1039–1052 (2017).

    Article  CAS  PubMed  Google Scholar 

  77. Houston, B., Curry, B. & Aitken, R. J. Human spermatozoa possess an IL4I1 l-amino acid oxidase with a potential role in sperm function. Reproduction 149, 587–596 (2015).

    Article  CAS  PubMed  Google Scholar 

  78. Lee, D., Moawad, A. R., Morielli, T., Fernandez, M. C. & O’Flaherty, C. Peroxiredoxins prevent oxidative stress during human sperm capacitation. Mol. Hum. Reprod. 23, 106–115 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Aitken, R. J. & Baker, M. A. Oxidative stress, sperm survival and fertility control. Mol. Cell Endocrinol. 250, 66–69 (2006).

    Article  CAS  PubMed  Google Scholar 

  80. Aitken, R. J. & Roman, S. D. Antioxidant systems and oxidative stress in the testes. Oxid. Med. Cell Longev. 1, 15–24 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  81. Gharagozloo, P. & Aitken, R. J. The role of sperm oxidative stress in male infertility and the significance of oral antioxidant therapy. Hum. Reprod. 26, 1628–1640 (2011).

    Article  PubMed  Google Scholar 

  82. Kowalczyk, A. The role of the natural antioxidant mechanism in sperm cells. Reprod. Sci. 29, 1387–1394 (2022).

    Article  CAS  PubMed  Google Scholar 

  83. O’Flaherty, C. Orchestrating the antioxidant defenses in the epididymis. Andrology 7, 662–668 (2019).

    Article  PubMed  Google Scholar 

  84. Aitken, R. J. & Bakos, H. W. Should we be measuring DNA damage in human spermatozoa? New light on an old question. Hum. Reprod. 36, 1175–1185 (2021).

    Article  CAS  PubMed  Google Scholar 

  85. Smits, R. M. et al. Antioxidants for male subfertility. Cochrane Database Syst. Rev. 3, CD007411 (2019).

    PubMed  Google Scholar 

  86. Steiner, A. Z. et al. The effect of antioxidants on male factor infertility: the Males, Antioxidants, and Infertility (MOXI) randomized clinical trial. Fertil. Steril. 113, 552–560.e3 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Tuttelmann, F., Ruckert, C. & Ropke, A. Disorders of spermatogenesis: perspectives for novel genetic diagnostics after 20 years of unchanged routine. Med. Genet. 30, 12–20 (2018).

    PubMed  PubMed Central  Google Scholar 

  88. Tuttelmann, F. et al. Clinical experience with azoospermia: aetiology and chances for spermatozoa detection upon biopsy. Int. J. Androl. 34, 291–298 (2011).

    Article  CAS  PubMed  Google Scholar 

  89. Krausz, C. & Riera-Escamilla, A. Genetics of male infertility. Nat. Rev. Urol. 15, 369–384 (2018).

    Article  CAS  PubMed  Google Scholar 

  90. Wyrwoll, M. J. et al. Genetic architecture of azoospermia-time to advance the standard of care. Eur. Urol. 83, 452–462 (2022).

    Article  PubMed  Google Scholar 

  91. Toure, A. et al. The genetic architecture of morphological abnormalities of the sperm tail. Hum. Genet. 140, 21–42 (2021).

    Article  CAS  PubMed  Google Scholar 

  92. Salas-Huetos, A. et al. Disruption of human meiotic telomere complex genes TERB1, TERB2 and MAJIN in men with non-obstructive azoospermia. Hum. Genet. 140, 217–227 (2021).

    Article  CAS  PubMed  Google Scholar 

  93. Wyrwoll, M. J. et al. Bi-allelic mutations in M1AP are a frequent cause of meiotic arrest and severely impaired spermatogenesis leading to male infertility. Am. J. Hum. Genet. 107, 342–351 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Kasak, L. et al. Bi-allelic recessive loss-of-function variants in FANCM cause non-obstructive azoospermia. Am. J. Hum. Genet. 103, 200–212 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Hardy, J. J. et al. Variants in GCNA, X-linked germ-cell genome integrity gene, identified in men with primary spermatogenic failure. Hum. Genet. 140, 1169–1182 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Liu, C. et al. Deleterious variants in X-linked CFAP47 induce asthenoteratozoospermia and primary male infertility. Am. J. Hum. Genet. 108, 309–323 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Zhu, F. et al. Biallelic SUN5 mutations cause autosomal-recessive acephalic spermatozoa syndrome. Am. J. Hum. Genet. 99, 942–949 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Coutton, C. et al. Bi-allelic mutations in ARMC2 lead to severe astheno-teratozoospermia due to sperm flagellum malformations in humans and mice. Am. J. Hum. Genet. 104, 331–340 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Tang, S. et al. Biallelic mutations in CFAP43 and CFAP44 cause male infertility with multiple morphological abnormalities of the sperm flagella. Am. J. Hum. Genet. 100, 854–864 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Veltman, J. A. & Brunner, H. G. De novo mutations in human genetic disease. Nat. Rev. Genet. 13, 565–575 (2012).

    Article  CAS  PubMed  Google Scholar 

  101. Hodzic, A. et al. De novo mutations in idiopathic male infertility — a pilot study. Andrology 9, 212–220 (2021).

    Article  CAS  PubMed  Google Scholar 

  102. Oud, M. S. et al. Exome sequencing reveals variants in known and novel candidate genes for severe sperm motility disorders. Hum. Reprod. 36, 2597–2611 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Oud, M. S. et al. A de novo paradigm for male infertility. Nat. Commun. 13, 154 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Xavier, M. J., Salas-Huetos, A., Oud, M. S., Aston, K. I. & Veltman, J. A. Disease gene discovery in male infertility: past, present and future. Hum. Genet. 140, 7–19 (2021).

    Article  CAS  PubMed  Google Scholar 

  105. Krausz, C. et al. Phenotypic variation within European carriers of the Y-chromosomal gr/gr deletion is independent of Y-chromosomal background. J. Med. Genet. 46, 21–31 (2009).

    Article  CAS  PubMed  Google Scholar 

  106. Romerius, P. et al. Estrogen receptor alpha single nucleotide polymorphism modifies the risk of azoospermia in childhood cancer survivors. Pharmacogenet Genomics 21, 263–269 (2011).

    Article  CAS  PubMed  Google Scholar 

  107. Visscher, P. M., Yengo, L., Cox, N. J. & Wray, N. R. Discovery and implications of polygenicity of common diseases. Science 373, 1468–1473 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Townsley, K. G., Brennand, K. J. & Huckins, L. M. Massively parallel techniques for cataloguing the regulome of the human brain. Nat. Neurosci. 23, 1509–1521 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Groopman, E. E., Povysil, G., Goldstein, D. B. & Gharavi, A. G. Rare genetic causes of complex kidney and urological diseases. Nat. Rev. Nephrol. 16, 641–656 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  110. Zhu, X. B. et al. Vertical transmission of the Yq AZFc microdeletion from father to son over two or three generations in infertile Han Chinese families. Asian J. Androl. 12, 240–246 (2010).

    Article  CAS  PubMed  Google Scholar 

  111. Smits, R. M. et al. De novo mutations in children born after medical assisted reproduction. Hum. Reprod. 37, 1360–1369 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Yu, X. W., Wei, Z. T., Jiang, Y. T. & Zhang, S. L. Y chromosome azoospermia factor region microdeletions and transmission characteristics in azoospermic and severe oligozoospermic patients. Int. J. Clin. Exp. Med. 8, 14634–14646 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Beaud, H., Tremblay, A. R., Chan, P. T. K. & Delbes, G. Sperm DNA damage in cancer patients. Adv. Exp. Med. Biol. 1166, 189–203 (2019).

    Article  CAS  PubMed  Google Scholar 

  114. 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 

  115. Diamanti-Kandarakis, E. et al. Endocrine-disrupting chemicals: an Endocrine Society scientific statement. Endocr. Rev. 30, 293–342 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Salas-Huetos, A., James, E. R., Aston, K. I., Jenkins, T. G. & Carrell, D. T. Diet and sperm quality: nutrients, foods and dietary patterns. Reprod. Biol. 19, 219–224 (2019).

    Article  PubMed  Google Scholar 

  117. Wu, H. et al. Preconception urinary phthalate concentrations and sperm DNA methylation profiles among men undergoing IVF treatment: a cross-sectional study. Hum. Reprod. 32, 2159–2169 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Skakkebæk, N. E. et al. Environmental factors in declining human fertility. Nat. Rev. Endocrinol. 18, 139–157 (2021).

    Article  PubMed  Google Scholar 

  119. Sharpe, R. M. Environmental/lifestyle effects on spermatogenesis. Philos. Trans. R. Soc. Lond. B Biol. Sci. 365, 1697–1712 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Bergman, A. et al. State of the science of endocrine disrupting chemicals 2012 (eds Bergman, Å et al.) (World Health Organization, 2012).

  121. Gore, A. C. et al. EDC-2: the Endocrine Society’s second scientific statement on endocrine-disrupting chemicals. Endocr. Rev. 36, E1–E150 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Istvan, M. et al. Maternal occupational exposure to endocrine-disrupting chemicals during pregnancy and semen parameters in adulthood: results of a nationwide cross-sectional study among Swiss conscripts. Hum. Reprod. 36, 1948–1958 (2021).

    Article  CAS  PubMed  Google Scholar 

  123. Bonde, J. P. et al. The epidemiologic evidence linking prenatal and postnatal exposure to endocrine disrupting chemicals with male reproductive disorders: a systematic review and meta-analysis. Hum. Reprod. Update 23, 104–125 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  124. Aneck-Hahn, N. H., Schulenburg, G. W., Bornman, M. S., Farias, P. & de Jager, C. Impaired semen quality associated with environmental DDT exposure in young men living in a malaria area in the Limpopo Province, South Africa. J. Androl. 28, 423–434 (2007).

    Article  CAS  PubMed  Google Scholar 

  125. Krewski, D. et al. Toxicity testing in the 21st century: progress in the past decade and future perspectives. Arch. Toxicol. 94, 1–58 (2020).

    Article  CAS  PubMed  Google Scholar 

  126. Barrow, P. & Schmitt, G. Regulatory approaches to nonclinical reproductive toxicity testing of anti-cancer drugs. Anticancer. Agents Med. Chem. 17, 1171–1183 (2017).

    Article  CAS  PubMed  Google Scholar 

  127. Kortenkamp, A. et al. Combined exposures to bisphenols, polychlorinated dioxins, paracetamol, and phthalates as drivers of deteriorating semen quality. Env. Int. 165, 107322 (2022).

    Article  CAS  Google Scholar 

  128. Marcho, C., Oluwayiose, O. A. & Pilsner, J. R. The preconception environment and sperm epigenetics. Andrology 8, 924–942 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  129. Short, A. K. et al. Elevated paternal glucocorticoid exposure alters the small noncoding RNA profile in sperm and modifies anxiety and depressive phenotypes in the offspring. Transl. Psychiatry 6, e837 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Komninos, D. et al. High fat diet-induced obesity prolongs critical stages of the spermatogenic cycle in a Ldlr−/−.Leiden mouse model. Sci. Rep. 12, 430 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Nassan, F. L. et al. Association between intake of soft drinks and testicular function in young men. Hum. Reprod. 36, 3036–3048 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. 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 

  133. Sominsky, L. et al. Linking stress and infertility: a novel role for ghrelin. Endocr. Rev. 38, 432–467 (2017).

    Article  PubMed  Google Scholar 

  134. Abu-Musa, A. A., Nassar, A. H., Hannoun, A. B. & Usta, I. M. Effect of the Lebanese civil war on sperm parameters. Fertil. Steril. 88, 1579–1582 (2007).

    Article  PubMed  Google Scholar 

  135. Fenster, L. et al. Effects of psychological stress on human semen quality. J. Androl. 18, 194–202 (1997).

    Article  CAS  PubMed  Google Scholar 

  136. Leisegang, K., Henkel, R. & Agarwal, A. Obesity and metabolic syndrome associated with systemic inflammation and the impact on the male reproductive system. Am. J. Reprod. Immunol. 82, e13178 (2019).

    Article  CAS  PubMed  Google Scholar 

  137. Leisegang, K., Sengupta, P., Agarwal, A. & Henkel, R. Obesity and male infertility: mechanisms and management. Andrologia 53, e13617 (2021).

    Article  PubMed  Google Scholar 

  138. Kleeman, E. A., Gubert, C. & Hannan, A. J. Transgenerational epigenetic impacts of parental infection on offspring health and disease susceptibility. Trends Genet. 38, 662–675 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Gapp, K. et al. Alterations in sperm long RNA contribute to the epigenetic inheritance of the effects of postnatal trauma. Mol. Psychiatry 25, 2162–2174 (2020).

    Article  CAS  PubMed  Google Scholar 

  140. Maciejewski, R., Radzikowska-Büchner, E., Flieger, W., Kulczycka, K., Baj, J., Forma, A. & Flieger, J. An overview of essential microelements and common metallic nanoparticles and their effects on male fertility. Int. J. Env. Res. Public. Health 19, 11066 (2022). Sep 4.

    Article  CAS  Google Scholar 

  141. 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 

  142. Schjenken, J. E. et al. High fat diet alters male seminal plasma composition to impair female immune adaptation for pregnancy in mice. Endocrinology 162, bqab123 (2021).

    Article  PubMed  Google Scholar 

  143. Maleki-Saghooni, N., Amirian, M., Sadeghi, R. & Latifnejad Roudsari, R. Effectiveness of infertility counseling on pregnancy rate in infertile patients undergoing assisted reproductive technologies: a systematic review and meta-analysis. Int. J. Reprod. Biomed. 15, 391–402 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  144. Rimmer, M. P. et al. Outcome reporting across randomized controlled trials evaluating potential treatments for male infertility: a systematic review. Hum. Reprod. Open. 2022, hoac010 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  145. World Drug Report 2021. United Nations Office on Drugs and Crime https://www.unodc.org/unodc/en/data-and-analysis/wdr2021.html (2021).

  146. Fronczak, C. M., Kim, E. D. & Barqawi, A. B. The insults of illicit drug use on male fertility. J. Androl. 33, 515–528 (2012).

    Article  CAS  PubMed  Google Scholar 

  147. Sakib, S., Voigt, A., Goldsmith, T. & Dobrinski, I. Three-dimensional testicular organoids as novel in vitro models of testicular biology and toxicology. Env. Epigenet 5, dvz011 (2019).

    Article  Google Scholar 

  148. Martus, H. J. et al. Summary of major conclusions from the 7th International Workshop on Genotoxicity Testing (IWGT), Tokyo, Japan. Mutat. Res. 852, 503134 (2020).

    Article  CAS  Google Scholar 

  149. Greally, J. M. Endocrine disruptors and the epigenome (OECD review) (Organisation for Economic Co-operation and Development, 2011).

  150. 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 

  151. Priskorn, L. et al. Increasing trends in childlessness in recent birth cohorts — a registry-based study of the total Danish male population born from 1945 to 1980. Int. J. Androl. 35, 449–455 (2012).

    Article  CAS  PubMed  Google Scholar 

  152. Boulicault, M. et al. The future of sperm: a biovariability framework for understanding global sperm count trends. Hum. Fertil. 25, 888–902 (2021). 1-15.

    Article  Google Scholar 

  153. 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 

  154. Slama, R. et al. Time to pregnancy and semen parameters: a cross-sectional study among fertile couples from four European cities. Hum. Reprod. 17, 503–515 (2002).

    Article  CAS  PubMed  Google Scholar 

  155. Nelson, C. M. & Bunge, R. G. Semen analysis: evidence for changing parameters of male fertility potential. Fertil. Steril. 25, 503–507 (1974).

    Article  CAS  PubMed  Google Scholar 

  156. MacLeod, J. & Wang, Y. Male fertility potential in terms of semen quality: a review of the past, a study of the present. Fertil. Steril. 31, 103–116 (1979).

    Article  CAS  PubMed  Google Scholar 

  157. Carlsen, E., Giwercman, A., Keiding, N. & Skakkebaek, N. E. Evidence for decreasing quality of semen during past 50 years. BMJ 305, 609–613 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. 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 

  159. Lv, M. Q. et al. Temporal trends in semen concentration and count among 327 373 Chinese healthy men from 1981 to 2019: a systematic review. Hum. Reprod. 36, 1751–1775 (2021).

    Article  PubMed  Google Scholar 

  160. Vahidi, S., Moein, M. R., Yazdinejad, F., Ghasemi-Esmailabad, S. & Narimani, N. Iranian temporal changes in semen quality during the past 22 years: a report from an infertility center. Int. J. Reprod. Biomed. 18, 1059–1064 (2020).

    PubMed  PubMed Central  Google Scholar 

  161. Rosa-Villagrán, L., Barrera, N., Montes, J., Riso, C. & Sapiro, R. Decline of semen quality over the last 30 years in Uruguay. Basic. Clin. Androl. 31, 8 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  162. Sengupta, P., Nwagha, U., Dutta, S., Krajewska-Kulak, E. & Izuka, E. Evidence for decreasing sperm count in African population from 1965 to 2015. Afr. Health Sci. 17, 418–427 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  163. Mishra, P., Negi, M. P. S., Srivastava, M., Singh, K. & Rajender, S. Decline in seminal quality in Indian men over the last 37 years. Reprod. Biol. Endocrinol. 16, 103 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. 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 

  165. Jorgensen, N. et al. Are worldwide sperm counts declining? Fertil. Steril. 116, 1457–1463 (2021).

    Article  PubMed  Google Scholar 

  166. Tiegs, A. W., Landis, J., Garrido, N., Scott, R. T. Jr. & Hotaling, J. M. Total motile sperm count trend over time: evaluation of semen analyses from 119,972 men from subfertile couples. Urology 132, 109–116 (2019).

    Article  PubMed  Google Scholar 

  167. Jorgensen, N. et al. East-West gradient in semen quality in the Nordic-Baltic area: a study of men from the general population in Denmark, Norway, Estonia and Finland. Hum. Reprod. 17, 2199–2208 (2002).

    Article  PubMed  Google Scholar 

  168. Paasch, U. et al. Semen quality in sub-fertile range for a significant proportion of young men from the general German population: a co-ordinated, controlled study of 791 men from Hamburg and Leipzig. Int. J. Androl. 31, 93–102 (2008).

    Article  PubMed  Google Scholar 

  169. Mendiola, J., Stahlhut, R. W., Jorgensen, N., Liu, F. & Swan, S. H. Shorter anogenital distance predicts poorer semen quality in young men in Rochester, New York. Env. Health Perspect. 119, 958–963 (2011).

    Article  Google Scholar 

  170. Fernandez, M. F. et al. Semen quality and reproductive hormone levels in men from Southern Spain. Int. J. Androl. 35, 1–10 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Iwamoto, T. et al. Semen quality of 1559 young men from four cities in Japan: a cross-sectional population-based study. BMJ Open 3, e002222 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  172. Jorgensen, N., Asklund, C., Carlsen, E. & Skakkebaek, N. E. Coordinated European investigations of semen quality: results from studies of Scandinavian young men is a matter of concern. Int. J. Androl. 29, 54–61 (2006). discussion 105–108.

    Article  PubMed  Google Scholar 

  173. Smarr, M. M. et al. Is human fecundity changing? A discussion of research and data gaps precluding us from having an answer. Hum. Reprod. 32, 499–504 (2017).

    PubMed  PubMed Central  Google Scholar 

  174. Belladelli, F., Muncey, W. & Eisenberg, M. L. Reproduction as a window for health in men. Fertil. Steril. 120, 429–437 (2023).

    Article  PubMed  Google Scholar 

  175. Economist Intelligence Unit. Fertile ground. How can Japan raise its fertility rate? Economist Intelligence Unit https://www.eiu.com/graphics/marketing/pdf/Fertility-in-Japan-EIU.pdf (2018).

  176. Hauser, R. et al. Male reproductive disorders, diseases, and costs of exposure to endocrine-disrupting chemicals in the European Union. J. Clin. Endocrinol. Metab. 100, 1267–1277 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Attina, T. M. et al. Exposure to endocrine-disrupting chemicals in the USA: a population-based disease burden and cost analysis. Lancet Diabetes Endocrinol. 4, 996–1003 (2016).

    Article  PubMed  Google Scholar 

  178. Institute for Health Metrics and Evaluation. Global Burden of Disease. IHME https://www.healthdata.org/research-analysis/gbd (2023).

  179. Arya, S. T. & Dibb, B. The experience of infertility treatment: the male perspective. Hum. Fertil. 19, 242–248 (2016).

    Article  Google Scholar 

  180. Koert, E., Takefman, J. & Boivin, J. Fertility quality of life tool: update on research and practice considerations. Hum. Fertil. 24, 236–248 (2019).

    Article  Google Scholar 

  181. Salonia, A. et al. Are infertile men less healthy than fertile men? Results of a prospective case-control survey. Eur. Urol. 56, 1025–1031 (2009).

    Article  PubMed  Google Scholar 

  182. Ventimiglia, E. et al. Infertility as a proxy of general male health: results of a cross-sectional survey. Fertil. Steril. 104, 48–55 (2015).

    Article  PubMed  Google Scholar 

  183. Eisenberg, M. L. et al. 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 

  184. Jacobsen, R. et al. Risk of testicular cancer in men with abnormal semen characteristics: cohort study. BMJ 321, 789–792 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. 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 

  186. Del Giudice, F. et al. Association between male infertility and male-specific malignancies: systematic review and meta-analysis of population-based retrospective cohort studies. Fertil. Steril. 114, 984–996 (2020).

    Article  PubMed  Google Scholar 

  187. Al-Jebari, Y. et al. Risk of prostate cancer for men fathering through assisted reproduction: nationwide population based register study. BMJ 366, l5214 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  Google Scholar 

  189. Hanson, H. A. et al. Subfertility increases risk of testicular cancer: evidence from population-based semen samples. Fertil. Steril. 105, 322–328.e1 (2016).

    Article  PubMed  Google Scholar 

  190. 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 

  191. Eisenberg, M. L., Betts, P., Herder, D., Lamb, D. J. & Lipshultz, L. I. Increased cancer risk and azoospermia. Fertil. Steril. 100, 681–685 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  192. Swerdlow, A. J., Bruce, C., Cooke, R., Coulson, P. & Jones, M. E. Infertility and risk of breast cancer in men: a national case-control study in England and Wales. Breast Cancer Res. 24, 29 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  193. Man, Y. et al. Whole-exome sequencing identifies the VHL mutation (c.262T > C, p.Try88Arg) in non-obstructive azoospermia-associated cystic renal cell carcinoma. Curr. Oncol. 29, 2376–2384 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  194. Chen, P. C. et al. Male infertility increases the risk of cardiovascular diseases: a nationwide population-based cohort study in Taiwan. World J. Mens. Health 40, 490–500 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  195. Elenkov, A., Melander, O., Nilsson, P. M., Zhang, H. & Giwercman, A. Impact of genetic risk score on the association between male childlessness and cardiovascular disease and mortality. Sci. Rep. 11, 18526 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. 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 

  197. 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 (2015).

    Article  PubMed  Google Scholar 

  198. Glazer, C. H. et al. Male factor infertility and risk of multiple sclerosis: a register-based cohort study. Mult. Scler. 24, 1835–1842 (2017).

    Article  PubMed  Google Scholar 

  199. Glazer, C. H. et al. Risk of diabetes according to male factor infertility: a register-based cohort study. Hum. Reprod. 32, 1474–1481 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  200. Latif, T. et al. Semen quality as a predictor of subsequent morbidity: a Danish cohort study of 4,712 men with long-term follow-up. Am. J. Epidemiol. 186, 910–917 (2017).

    Article  PubMed  Google Scholar 

  201. Latif, T. et al. Semen quality associated with subsequent hospitalizations — can the effect be explained by socio-economic status and lifestyle factors? Andrology 6, 428–435 (2018).

    Article  CAS  PubMed  Google Scholar 

  202. Jensen, T. K., Jacobsen, R., Christensen, K., Nielsen, N. C. & Bostofte, E. Good semen quality and life expectancy: a cohort study of 43,277 men. Am. J. Epidemiol. 170, 559–565 (2009).

    Article  PubMed  Google Scholar 

  203. Glazer, C. H. et al. Male factor infertility and risk of death: a nationwide record-linkage study. Hum. Reprod. 34, 2266–2273 (2019).

    PubMed  Google Scholar 

  204. 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 

  205. 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 

  206. 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 

  207. Choy, J. T. & Eisenberg, M. L. Male infertility as a window to health. Fertil. Steril. 110, 810–814 (2018).

    Article  PubMed  Google Scholar 

  208. Uhlen, M. et al. Proteomics. Tissue-based map of the human proteome. Science 347, 1260419 (2015).

    Article  PubMed  Google Scholar 

  209. Fagerberg, L. et al. Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics. Mol. Cell Proteom. 13, 397–406 (2014).

    Article  CAS  Google Scholar 

  210. Djureinovic, D. et al. The human testis-specific proteome defined by transcriptomics and antibody-based profiling. Mol. Hum. Reprod. 20, 476–488 (2014).

    Article  CAS  PubMed  Google Scholar 

  211. Bonadona, V. et al. Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA 305, 2304–2310 (2011).

    Article  CAS  PubMed  Google Scholar 

  212. Ji, G. et al. Common variants in mismatch repair genes associated with increased risk of sperm DNA damage and male infertility. BMC Med. 10, 49 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. 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 

  214. Gunes, S. et al. Microtubular dysfunction and male infertility. World J. Mens. Health 38, 9–23 (2020).

    Article  PubMed  Google Scholar 

  215. Day, F. R. et al. Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair. Nat. Genet. 47, 1294–1303 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. O’Bryan, M. K. & Hedger, M. P. Inflammatory networks in the control of spermatogenesis : chronic inflammation in an immunologically privileged tissue? Adv. Exp. Med. Biol. 636, 92–114 (2008).

    Article  PubMed  Google Scholar 

  217. Meinhardt, A. & Hedger, M. P. Immunological, paracrine and endocrine aspects of testicular immune privilege. Mol. Cell Endocrinol. 335, 60–68 (2011).

    Article  CAS  PubMed  Google Scholar 

  218. Meseguer, M. et al. Sperm cryopreservation in oncological patients: a 14-year follow-up study. Fertil. Steril. 85, 640–645 (2006).

    Article  PubMed  Google Scholar 

  219. Liu, W., Schulster, M. L., Alukal, J. P. & Najari, B. B. Fertility preservation in male to female transgender patients. Urol. Clin. North. Am. 46, 487–493 (2019).

    Article  CAS  PubMed  Google Scholar 

  220. Cooper, H. C., Long, J. & Aye, T. Fertility preservation in transgender and non-binary adolescents and young adults. PLoS ONE 17, e0265043 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  221. Lambertini, M. et al. Fertility preservation and post-treatment pregnancies in post-pubertal cancer patients: ESMO clinical practice guidelines(dagger). Ann. Oncol. 31, 1664–1678 (2020).

    Article  CAS  PubMed  Google Scholar 

  222. Lee, S. J. et al. American Society of Clinical Oncology recommendations on fertility preservation in cancer patients. J. Clin. Oncol. 24, 2917–2931 (2006).

    Article  PubMed  Google Scholar 

  223. Kuczynski, W. et al. The outcome of intracytoplasmic injection of fresh and cryopreserved ejaculated spermatozoa-a prospective randomized study. Hum. Reprod. 16, 2109–2113 (2001).

    Article  CAS  PubMed  Google Scholar 

  224. Hervas, I. et al. TESE-ICSI outcomes per couple in vasectomized males are negatively affected by time since the intervention, but not other comorbidities. Reprod. Biomed. Online 43, 708–717 (2021).

    Article  PubMed  Google Scholar 

  225. Newton, H. L. et al. Inconsistencies in fertility preservation for young people with cancer in the UK. Arch. Dis. Child. 107, 265–270 (2022).

    Article  PubMed  Google Scholar 

  226. Anazodo, A. et al. The development of an international oncofertility competency framework: a model to increase oncofertility implementation. Oncologist 24, e1450–e1459 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  227. Anazodo, A. et al. How can we improve oncofertility care for patients? A systematic scoping review of current international practice and models of care. Hum. Reprod. Update 25, 159–179 (2019).

    Article  PubMed  Google Scholar 

  228. Delgouffe, E., Braye, A. & Goossens, E. Testicular tissue banking for fertility preservation in young boys: which patients should be included? Front. Endocrinol. 13, 854186 (2022).

    Article  Google Scholar 

  229. Martinez, F. & International Society for Fertility Preservation. Update on fertility preservation from the Barcelona International Society for Fertility Preservation-ESHRE-ASRM 2015 expert meeting: indications, results and future perspectives. Fertil. Steril. 108, 407–415.e11 (2017).

    Article  PubMed  Google Scholar 

  230. Mulder, R. L. et al. Fertility preservation for male patients with childhood, adolescent, and young adult cancer: recommendations from the PanCareLIFE Consortium and the International Late Effects of Childhood Cancer Guideline Harmonization Group. Lancet Oncol. 22, e57–e67 (2021).

    Article  PubMed  Google Scholar 

  231. Ghidei, L. et al. Current gaps in fertility preservation for men: how can we do better? J. Clin. Oncol. 40, 2524–2529 (2022).

    Article  PubMed  Google Scholar 

  232. Goossens, E. et al. Fertility preservation in boys: recent developments and new insights. Hum. Reprod. Open. 2020, hoaa016 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. Sharma, S., Wistuba, J., Pock, T., Schlatt, S. & Neuhaus, N. Spermatogonial stem cells: updates from specification to clinical relevance. Hum. Reprod. Update 25, 275–297 (2019).

    Article  CAS  PubMed  Google Scholar 

  234. Wyns, C., Curaba, M., Vanabelle, B., Van Langendonckt, A. & Donnez, J. Options for fertility preservation in prepubertal boys. Hum. Reprod. Update 16, 312–328 (2010).

    Article  PubMed  Google Scholar 

  235. Kliesch, S. [Androprotect and prospects for fertility treatment]. Urol. A 55, 898–903 (2016).

    Article  CAS  Google Scholar 

  236. Kanbar, M., Delwiche, G. & Wyns, C. Fertility preservation for prepubertal boys: are we ready for autologous grafting of cryopreserved immature testicular tissue? Ann. Endocrinol. 83, 210–217 (2022).

    Article  Google Scholar 

  237. Abdelaal, O., Barber, H., Atala, A. & Sadri-Ardekani, H. Purging of malignant cell contamination prior to spermatogonia stem cell autotransplantation to preserve fertility: progress & prospects. Curr. Opin. Endocrinol. Diabetes Obes. 26, 166–174 (2019).

    Article  PubMed  Google Scholar 

  238. Shetty, G. et al. Postpubertal spermatogonial stem cell transplantation restores functional sperm production in rhesus monkeys irradiated before and after puberty. Andrology 9, 1603–1616 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  239. Fayomi, A. P. et al. Autologous grafting of cryopreserved prepubertal rhesus testis produces sperm and offspring. Science 363, 1314–1319 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  240. Alves-Lopes, J. P., Soder, O. & Stukenborg, J. B. Use of a three-layer gradient system of cells for rat testicular organoid generation. Nat. Protoc. 13, 248–259 (2018).

    Article  CAS  PubMed  Google Scholar 

  241. Mincheva, M. et al. Reassembly of adult human testicular cells: can testis cord-like structures be created in vitro. Mol. Hum. Reprod. 24, 55–63 (2018).

    Article  CAS  PubMed  Google Scholar 

  242. Oliver, E. et al. Self-organising human gonads generated by a Matrigel-based gradient system. BMC Biol. 19, 212 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  243. 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.e9 (2021).

    Article  CAS  PubMed  Google Scholar 

  244. Saitou, M. & Hayashi, K. Mammalian in vitro gametogenesis. Science 374, eaaz6830 (2021).

    Article  CAS  PubMed  Google Scholar 

  245. Pennings, G., Couture, V. & Ombelet, W. Social sperm freezing. Hum. Reprod. 36, 833–839 (2021).

    Article  CAS  PubMed  Google Scholar 

  246. Degraeve, A. et al. European countries have different rates of sperm cryopreservation before vasectomy and at the time of reversal. Andrology 10, 1286–1291 (2022).

    Article  PubMed  Google Scholar 

  247. Marinaro, J., Hayden, R. P., Shin, P. & Tanrikut, C. The utility of sperm cryopreservation at the time of vasectomy reversal. J. Urol. 205, 236–240 (2021).

    Article  PubMed  Google Scholar 

  248. Ravitsky, V. & Kimmins, S. The forgotten men: rising rates of male infertility urgently require new approaches for its prevention, diagnosis and treatment. Biol. Reprod. 101, 872–874 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  249. 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 

  250. Taylor, J. L. et al. Paternal-age-related de novo mutations and risk for five disorders. Nat. Commun. 10, 3043 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  251. Sartorius, G. A. & Nieschlag, E. Paternal age and reproduction. Hum. Reprod. Update 16, 65–79 (2010).

    Article  PubMed  Google Scholar 

  252. Couture, V., Delisle, S., Mercier, A. & Pennings, G. The other face of advanced paternal age: a scoping review of its terminological, social, public health, psychological, ethical and regulatory aspects. Hum. Reprod. Update 27, 305–323 (2021).

    Article  PubMed  Google Scholar 

  253. Urhoj, S. K. et al. Advanced paternal age and childhood cancer in offspring: a nationwide register-based cohort study. Int. J. Cancer 140, 2461–2472 (2017).

    Article  CAS  PubMed  Google Scholar 

  254. Cao, M. et al. High-resolution analyses of human sperm dynamic methylome reveal thousands of novel age-related epigenetic alterations. Clin. Epigenetics 12, 192 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  255. Salas-Huetos, A. et al. The combined effect of obesity and aging on human sperm DNA methylation signatures: inclusion of BMI in the paternal germ line age prediction model. Sci. Rep. 10, 15409 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  256. Laurentino, S. et al. A germ cell-specific ageing pattern in otherwise healthy men. Aging Cell 19, e13242 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  257. Berntsen, S. et al. The health of children conceived by ART: ‘the chicken or the egg?’. Hum. Reprod. Update 25, 137–158 (2019).

    Article  PubMed  Google Scholar 

  258. Horne, G. et al. Live birth with sperm cryopreserved for 21 years prior to cancer treatment: case report. Hum. Reprod. 19, 1448–1449 (2004).

    Article  CAS  PubMed  Google Scholar 

  259. Rotondo, J. C., Lanzillotti, C., Mazziotta, C., Tognon, M. & Martini, F. Epigenetics of male infertility: the role of DNA methylation. Front. Cell Dev. Biol. 9, 689624 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  260. Erkek, S. et al. Molecular determinants of nucleosome retention at CpG-rich sequences in mouse spermatozoa. Nat. Struct. Mol. Biol. 20, 868–875 (2013).

    Article  CAS  PubMed  Google Scholar 

  261. Siklenka, K. et al. Disruption of histone methylation in developing sperm impairs offspring health transgenerationally. Science 350, aab2006 (2015).

    Article  PubMed  Google Scholar 

  262. Sendler, E. et al. Stability, delivery and functions of human sperm RNAs at fertilization. Nucleic Acids Res. 41, 4104–4117 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  263. Cavalli, G. & Heard, E. Advances in epigenetics link genetics to the environment and disease. Nature 571, 489–499 (2019).

    Article  CAS  PubMed  Google Scholar 

  264. Janssen, S. M. & Lorincz, M. C. Interplay between chromatin marks in development and disease. Nat. Rev. Genet. 23, 137–153 (2021).

    Article  PubMed  Google Scholar 

  265. Lin, H. piRNAs in the germ line. Science 316, 397 (2007).

    Article  CAS  PubMed  Google Scholar 

  266. Trasler, J. M. Epigenetics in spermatogenesis. Mol. Cell Endocrinol. 306, 33–36 (2009).

    Article  CAS  PubMed  Google Scholar 

  267. Glaser, S. et al. The histone 3 lysine 4 methyltransferase, Mll2, is only required briefly in development and spermatogenesis. Epigenetics Chromatin 2, 5 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  268. Kimmins, S. et al. Differential functions of the Aurora-B and Aurora-C kinases in mammalian spermatogenesis. Mol. Endocrinol. 21, 726–739 (2007).

    Article  CAS  PubMed  Google Scholar 

  269. Peters, A. H. et al. Loss of the Suv39h histone methyltransferases impairs mammalian heterochromatin and genome stability. Cell 107, 323–337 (2001).

    Article  CAS  PubMed  Google Scholar 

  270. Nagirnaja, L. et al. Variant PNLDC1, defective piRNA processing, and azoospermia. N. Engl. J. Med. 385, 707–719 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  271. Fellmeth, J. E., Ghanaim, E. M. & Schindler, K. Characterization of macrozoospermia-associated AURKC mutations in a mammalian meiotic system. Hum. Mol. Genet. 25, 2698–2711 (2016).

    CAS  PubMed  Google Scholar 

  272. Dieterich, K. et al. Homozygous mutation of AURKC yields large-headed polyploid spermatozoa and causes male infertility. Nat. Genet. 39, 661–665 (2007).

    Article  CAS  PubMed  Google Scholar 

  273. Eloualid, A. et al. Prevalence of the Aurora kinase C c.144delC mutation in infertile Moroccan men. Fertil. Steril. 101, 1086–1090 (2014).

    Article  CAS  PubMed  Google Scholar 

  274. Ben Khelifa, M. et al. Identification of a new recurrent aurora kinase C mutation in both European and African men with macrozoospermia. Hum. Reprod. 27, 3337–3346 (2012).

    Article  PubMed  Google Scholar 

  275. Tremblay, A., Beaud, H. & Delbes, G. Transgenerational impact of chemotherapy: would the father exposure impact the health of future progeny [French]? Gynecol. Obstet. Fertil. Senol. 45, 609–618 (2017).

    CAS  PubMed  Google Scholar 

  276. Carrell, D. T. Epigenetics of the male gamete. Fertil. Steril. 97, 267–274 (2012).

    Article  CAS  PubMed  Google Scholar 

  277. Santiago, J., Silva, J. V., Howl, J., Santos, M. A. S. & Fardilha, M. All you need to know about sperm RNAs. Hum. Reprod. Update 28, 67–91 (2021).

    Article  PubMed  Google Scholar 

  278. Kobayashi, H. et al. Aberrant DNA methylation of imprinted loci in sperm from oligospermic patients. Hum. Mol. Genet. 16, 2542–2551 (2007).

    Article  CAS  PubMed  Google Scholar 

  279. Marques, C. J. et al. Abnormal methylation of imprinted genes in human sperm is associated with oligozoospermia. Mol. Hum. Reprod. 14, 67–74 (2008).

    Article  CAS  PubMed  Google Scholar 

  280. Minor, A., Chow, V. & Ma, S. Aberrant DNA methylation at imprinted genes in testicular sperm retrieved from men with obstructive azoospermia and undergoing vasectomy reversal. Reproduction 141, 749–757 (2011).

    Article  CAS  PubMed  Google Scholar 

  281. Donkin, I. et al. Obesity and bariatric surgery drive epigenetic variation of spermatozoa in humans. Cell Metab. 23, 369–378 (2016).

    Article  CAS  PubMed  Google Scholar 

  282. Velotti, N. et al. Effect of bariatric surgery on in vitro fertilization in infertile men with obesity. Surg. Obes. Relat. Dis. 17, 1752–1759 (2021).

    Article  PubMed  Google Scholar 

  283. Keyhan, S. et al. Male obesity impacts DNA methylation reprogramming in sperm. Clin. Epigenetics 13, 17 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  284. Stokes, V. J., Anderson, R. A. & George, J. T. How does obesity affect fertility in men – and what are the treatment options? Clin. Endocrinol. 82, 633–638 (2015).

    Article  Google Scholar 

  285. Chan, D. et al. Customized methylC-capture sequencing to evaluate variation in the human sperm DNA methylome representative of altered folate metabolism. Env. Health Perspect. 127, 87002 (2019).

    Article  Google Scholar 

  286. Pembrey, M., Saffery, R. & Bygren, L. O. Human transgenerational responses to early-life experience: potential impact on development, health and biomedical research. J. Med. Genet. 51, 563–572 (2014).

    Article  PubMed  Google Scholar 

  287. Radford, E. J. et al. In utero effects. In utero undernourishment perturbs the adult sperm methylome and intergenerational metabolism. Science 345, 1255903 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  288. Chen, Q. et al. Sperm tsRNAs contribute to intergenerational inheritance of an acquired metabolic disorder. Science 351, 397–400 (2016).

    Article  CAS  PubMed  Google Scholar 

  289. Lismer, A. et al. Histone H3 lysine 4 trimethylation in sperm is transmitted to the embryo and associated with diet-induced phenotypes in the offspring. Dev. Cell 56, 1–16 (2021).

    Article  Google Scholar 

  290. Hammoud, S. S. et al. Distinctive chromatin in human sperm packages genes for embryo development. Nature 460, 473–478 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  291. Brykczynska, U. et al. Repressive and active histone methylation mark distinct promoters in human and mouse spermatozoa. Nat. Struct. Mol. Biol. 17, 679–687 (2010).

    Article  CAS  PubMed  Google Scholar 

  292. Lambrot, R. et al. Whole-genome sequencing of H3K4me3 and DNA methylation in human sperm reveals regions of overlap linked to fertility and development. Cell Rep. 36, 109418 (2021).

    Article  CAS  PubMed  Google Scholar 

  293. Ly, L. et al. Intergenerational impact of paternal lifetime exposures to both folic acid deficiency and supplementation on reproductive outcomes and imprinted gene methylation. Mol. Hum. Reprod. 23, 461–477 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  294. Lambrot, R. et al. Low paternal dietary folate alters the mouse sperm epigenome and is associated with negative pregnancy outcomes. Nat. Commun. 4, 2889 (2013).

    Article  CAS  PubMed  Google Scholar 

  295. Sharma, U. et al. Biogenesis and function of tRNA fragments during sperm maturation and fertilization in mammals. Science 351, 391–396 (2016).

    Article  CAS  PubMed  Google Scholar 

  296. Yoshida, K. et al. ATF7-dependent epigenetic changes are required for the intergenerational effect of a paternal low-protein diet. Mol. Cell 78, 445–458 e446 (2020).

    Article  CAS  PubMed  Google Scholar 

  297. Watkins, A. J. et al. Paternal diet programs offspring health through sperm- and seminal plasma-specific pathways in mice. Proc. Natl Acad. Sci. USA 115, 10064–10069 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  298. Terashima, M. et al. Effect of high fat diet on paternal sperm histone distribution and male offspring liver gene expression. Epigenetics 10, 861–871 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  299. de Castro Barbosa, T. et al. High-fat diet reprograms the epigenome of rat spermatozoa and transgenerationally affects metabolism of the offspring. Mol. Metab. 5, 184–197 (2016).

    Article  PubMed  Google Scholar 

  300. Pepin, A. S., Lafleur, C., Lambrot, R., Dumeaux, V. & Kimmins, S. Sperm histone H3 lysine 4 tri-methylation serves as a metabolic sensor of paternal obesity and is associated with the inheritance of metabolic dysfunction. Mol. Metab. 59, 101463 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  301. Rodgers, A. B., Morgan, C. P., Leu, N. A. & Bale, T. L. Transgenerational epigenetic programming via sperm microRNA recapitulates effects of paternal stress. Proc. Natl Acad. Sci. USA 112, 13699 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  302. Beck, D., Ben Maamar, M. & Skinner, M. K. Integration of sperm ncRNA-directed DNA methylation and DNA methylation-directed histone retention in epigenetic transgenerational inheritance. Epigenetics Chromatin 14, 6 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  303. Lismer, A., et al. Exposure of Greenlandic Inuit and South African VhaVenda men to the persistent DDT metabolite is associated with an altered sperm epigenome at regions implicated in paternal epigenetic transmission and developmental disease — a cross-sectional study. Preprint at bioRxiv https://doi.org/10.1101/2022.08.15.504029 (2022).

  304. Amor, D. J. & Halliday, J. A review of known imprinting syndromes and their association with assisted reproduction technologies. Hum. Reprod. 23, 2826–2834 (2008).

    Article  PubMed  Google Scholar 

  305. Lazaraviciute, G., Kauser, M., Bhattacharya, S., Haggarty, P. & Bhattacharya, S. A systematic review and meta-analysis of DNA methylation levels and imprinting disorders in children conceived by IVF/ICSI compared with children conceived spontaneously. Hum. Reprod. Update 20, 840–852 (2014).

    Article  CAS  PubMed  Google Scholar 

  306. Novakovic, B. et al. Assisted reproductive technologies are associated with limited epigenetic variation at birth that largely resolves by adulthood. Nat. Commun. 10, 3922 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  307. Chen, W. et al. Integrated multi-omics reveal epigenomic disturbance of assisted reproductive technologies in human offspring. EBioMedicine 61, 103076 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  308. Katari, S. et al. DNA methylation and gene expression differences in children conceived in vitro or in vivo. Hum. Mol. Genet. 18, 3769–3778 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  309. Katagiri, Y. et al. Effects of assisted reproduction technology on placental imprinted gene expression. Obstet Gynecol. Int. 2010, 437525, (2010).

    Article  Google Scholar 

  310. Lou, H. et al. Assisted reproductive technologies impair the expression and methylation of insulin-induced gene 1 and sterol regulatory element-binding factor 1 in the fetus and placenta. Fertil. Steril. 101, 974–980.e972 (2014).

    Article  CAS  PubMed  Google Scholar 

  311. Loke, Y. J., Galati, J. C., Saffery, R. & Craig, J. M. Association of in vitro fertilization with global and IGF2/H19 methylation variation in newborn twins. J. Dev. Orig. Health Dis. 6, 115–124 (2015).

    Article  CAS  PubMed  Google Scholar 

  312. Sakian, S. et al. Altered gene expression of H19 and IGF2 in placentas from ART pregnancies. Placenta 36, 1100–1105 (2015).

    Article  CAS  PubMed  Google Scholar 

  313. Choux, C. et al. The epigenetic control of transposable elements and imprinted genes in newborns is affected by the mode of conception: ART versus spontaneous conception without underlying infertility. Hum. Reprod. 33, 331–340 (2018).

    Article  CAS  PubMed  Google Scholar 

  314. Tierling, S. et al. Assisted reproductive technologies do not enhance the variability of DNA methylation imprints in human. J. Med. Genet. 47, 371–376 (2010).

    Article  CAS  PubMed  Google Scholar 

  315. Zechner, U. et al. Quantitative methylation analysis of developmentally important genes in human pregnancy losses after ART and spontaneous conception. Mol. Hum. Reprod. 16, 704–713 (2010).

    Article  CAS  PubMed  Google Scholar 

  316. Li, L. et al. Evaluation of DNA methylation status at differentially methylated regions in IVF-conceived newborn twins. Fertil. Steril. 95, 1975–1979 (2011).

    Article  CAS  PubMed  Google Scholar 

  317. Feng, C. et al. General imprinting status is stable in assisted reproduction-conceived offspring. Fertil. Steril. 96, 1417–1423.e1419 (2011).

    Article  CAS  PubMed  Google Scholar 

  318. Oliver, V. F. et al. Defects in imprinting and genome-wide DNA methylation are not common in the in vitro fertilization population. Fertil. Steril. 97, 147–153.e147 (2012).

    Article  CAS  PubMed  Google Scholar 

  319. Rancourt, R. C., Harris, H. R. & Michels, K. B. Methylation levels at imprinting control regions are not altered with ovulation induction or in vitro fertilization in a birth cohort. Hum. Reprod. 27, 2208–2216 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  320. Penova-Veselinovic, B. et al. DNA methylation patterns within whole blood of adolescents born from assisted reproductive technology are not different from adolescents born from natural conception. Hum. Reprod. 36, 2035–2049 (2021).

    Article  CAS  PubMed  Google Scholar 

  321. Litzky, J. F. et al. Placental imprinting variation associated with assisted reproductive technologies and subfertility. Epigenetics 12, 653–661 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  322. Song, S. et al. DNA methylation differences between in vitro- and in vivo-conceived children are associated with ART procedures rather than infertility. Clin. Epigenetics 7, 41 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  323. Hansen, M., Bower, C., Milne, E., de Klerk, N. & Kurinczuk, J. J. Assisted reproductive technologies and the risk of birth defects — a systematic review. Hum. Reprod. 20, 328–338 (2005).

    Article  PubMed  Google Scholar 

  324. Albertini, D. F. et al. Birth defects and congenital health risks in children conceived through assisted reproduction technology (ART): a meeting report. J. Assist. Reprod. Genet. 31, 947–958 (2014).

    Article  Google Scholar 

  325. Hansen, M. & Bower, C. The impact of assisted reproductive technologies on intra-uterine growth and birth defects in singletons. Semin. Fetal Neonatal Med. 19, 228–233 (2014).

    Article  PubMed  Google Scholar 

  326. Qin, J. et al. Assisted reproductive technology and risk of congenital malformations: a meta-analysis based on cohort studies. Arch. Gynecol. Obstet. 292, 777–798 (2015).

    Article  PubMed  Google Scholar 

  327. Boulet, S. L. et al. Assisted reproductive technology and birth defects among liveborn infants in Florida, Massachusetts, and Michigan, 2000–2010. JAMA Pediatr. 170, e154934 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  328. Palomba, S., Homburg, R., Santagni, S., La Sala, G. B. & Orvieto, R. Risk of adverse pregnancy and perinatal outcomes after high technology infertility treatment: a comprehensive systematic review. Reprod. Biol. Endocrinol. 14, 76 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  329. Luke, B. et al. The risk of birth defects with conception by ART. Hum. Reprod. 36, 116–129 (2021).

    Article  PubMed  Google Scholar 

  330. Catford, S. R., McLachlan, R. I., O’Bryan, M. K. & Halliday, J. L. Long-term follow-up of ICSI-conceived offspring compared with spontaneously conceived offspring: a systematic review of health outcomes beyond the neonatal period. Andrology 6, 635–653 (2018).

    Article  CAS  PubMed  Google Scholar 

  331. Belva, F. et al. Semen quality of young adult ICSI offspring: the first results. Hum. Reprod. 31, 2811–2820 (2016).

    Article  CAS  PubMed  Google Scholar 

  332. Belva, F. et al. Reproductive hormones of ICSI-conceived young adult men: the first results. Hum. Reprod. 32, 439–446 (2017).

    Article  CAS  PubMed  Google Scholar 

  333. Catford, S. R. et al. Reproductive function in men conceived with in vitro fertilization and intracytoplasmic sperm injection. Fertil. Steril. 117, 727–737 (2022).

    Article  PubMed  Google Scholar 

  334. Belva, F. et al. Serum reproductive hormone levels and ultrasound findings in female offspring after intracytoplasmic sperm injection: first results. Fertil. Steril. 107, 934–939 (2017).

    Article  CAS  PubMed  Google Scholar 

  335. Guo, X. Y. et al. Cardiovascular and metabolic profiles of offspring conceived by assisted reproductive technologies: a systematic review and meta-analysis. Fertil. Steril. 107, 622–631.e5 (2017).

    Article  PubMed  Google Scholar 

  336. Belva, F. et al. Body fat content, fat distribution and adipocytokine production and their correlation with fertility markers in young adult men and women conceived by intracytoplasmic sperm injection (ICSI). Clin. Endocrinol. 88, 985–992 (2018)

    Article  CAS  Google Scholar 

  337. Belva, F. et al. Metabolic syndrome and its components in young adults conceived by ICSI. Int. J. Endocrinol. 2018, 8170518 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  338. Zhu, J. L., Basso, O., Obel, C., Hvidtjorn, D. & Olsen, J. Infertility, infertility treatment and psychomotor development: the Danish National Birth Cohort. Paediatr. Perinat. Epidemiol. 23, 98–106 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  339. Diop, H. et al. Early autism spectrum disorders in children born to fertile, subfertile, and ART-treated women. Matern. Child. Health J. 23, 1489–1499 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  340. Hargreave, M. et al. Association between fertility treatment and cancer risk in children. JAMA 322, 2203–2210 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  341. Schendelaar, P. et al. Increased time to pregnancy is associated with less optimal neurological condition in 4-year-old singletons, in vitro fertilization itself is not. Hum. Reprod. 29, 2773–2786 (2014).

    Article  CAS  PubMed  Google Scholar 

  342. Jenkins, T. G., Liu, L., Aston, K. I. & Carrell, D. T. Pre-screening method for somatic cell contamination in human sperm epigenetic studies. Syst. Biol. Reprod. Med. 64, 146–155 (2018).

    Article  CAS  PubMed  Google Scholar 

  343. Leitao, E. et al. The sperm epigenome does not display recurrent epimutations in patients with severely impaired spermatogenesis. Clin. Epigenetics 12, 61 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  344. Asenius, F., Danson, A. F. & Marzi, S. J. DNA methylation in human sperm: a systematic review. Hum. Reprod. Update 26, 841–873 (2020).

    Article  PubMed  Google Scholar 

  345. Economidis, M. A. & Mishell, D. R. Jr. Pharmacological female contraception: an overview of past and future use. Expert. Opin. Investig. Drugs 14, 449–456 (2005).

    Article  CAS  PubMed  Google Scholar 

  346. Thirumalai, A. & Amory, J. K. Emerging approaches to male contraception. Fertil. Steril. 115, 1369–1376 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  347. Reynolds-Wright, J. J., Cameron, N. J. & Anderson, R. A. Will men use novel male contraceptive methods and will women trust them? A systematic review. Ann. Rev. Sex. Res. 58, 838–849 (2021).

    Article  Google Scholar 

  348. World Health Organisation Task Force on Methods for the Regulation of Male Fertility. Contraceptive efficacy of testosterone-induced azoospermia and oligozoospermia in normal men. Fertil. Steril. 65, 821–829 (1996).

    Article  Google Scholar 

  349. Behre, H. M. et al. Efficacy and safety of an injectable combination hormonal contraceptive for men. J. Clin. Endocrinol. Metab. 101, 4779–4788 (2016).

    Article  CAS  PubMed  Google Scholar 

  350. Long, J. E., Lee, M. S. & Blithe, D. L. Update on novel hormonal and nonhormonal male contraceptive development. J. Clin. Endocrinol. Metab. 106, e2381–e2392 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  351. Mommers, E. et al. Male hormonal contraception: a double-blind, placebo-controlled study. J. Clin. Endocrinol. Metab. 93, 2572–2580 (2008).

    Article  CAS  PubMed  Google Scholar 

  352. North, B. B. et al. Evaluation of the novel vaginal contraceptive agent PPCM in preclinical studies using sperm hyaluronan binding and acrosome status assays. Andrology 10, 367–376 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  353. Noman, M. A. A., Kyzer, J. L., Chung, S. S. W., Wolgemuth, D. J. & Georg, G. I. Retinoic acid receptor antagonists for male contraception: current status. Biol. Reprod. 103, 390–399 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  354. Male Contraceptive Initiative. The Drug Development Pipeline. MCI https://www.malecontraceptive.org/the-drug-development-pipeline.html (2023).

  355. Gruber, F. S., Johnston, Z. C., Barratt, C. L. & Andrews, P. D. A phenotypic screening platform utilising human spermatozoa identifies compounds with contraceptive activity. Elife 9, e51739 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  356. Chamberlain, S. G. et al. Reboot contraceptives research — it has been stuck for decades. Nature 587, 543–545 (2020).

    Article  CAS  PubMed  Google Scholar 

  357. Hinton, L. & Miller, T. Mapping men’s anticipations and experiences in the reproductive realm: (in)fertility journeys. Reprod. Biomed. Online 27, 244–252 (2013).

    Article  PubMed  Google Scholar 

  358. Mossman, J. A. & Pacey, A. A. The fertility fitness paradox of anabolic-androgenic steroid abuse in men. J. Intern. Med. 286, 231–232 (2019).

    Article  CAS  PubMed  Google Scholar 

  359. Practice Committee of the American Society for Reproductive Medicine. Smoking and infertility: a committee opinion. Fertil. Steril. 110, 611–618 (2018).

    Article  Google Scholar 

  360. Healthy Male. Engaging Men in Primary Health Care. Healthy Male https://www.healthymale.org.au/health-professionals/engaging-men-primary-health-care (2023).

  361. Smith, J. A., Braunack-Mayer, A., Wittert, G. & Warin, M. “It’s sort of like being a detective”: understanding how Australian men self-monitor their health prior to seeking help. BMC Health Serv. Res. 8, 56 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  362. Pearson, L., Holton, S., McLachlan, R. & Hammarberg, K. Australian men’s fertility information seeking attitudes and behaviour: a qualitative investigation. Sex. Reprod. Healthc. 29, 100621 (2021).

    Article  PubMed  Google Scholar 

  363. Stevenson, E. L. & McEleny, K. R. Male subfertility as a chronic illness: the role of adaptive challenges. Hum. Fertil. 20, 148–154 (2017).

    Article  Google Scholar 

  364. Hadley, R. & Hanley, T. Involuntarily childless men and the desire for fatherhood. J. Reprod. Infant. Psychol. 29, 56–68 (2011).

    Article  Google Scholar 

  365. Hammarberg, K., Collins, V., Holden, C., Young, K. & McLachlan, R. Men’s knowledge, attitudes and behaviours relating to fertility. Hum. Reprod. Update 23, 458–480 (2017).

    Article  PubMed  Google Scholar 

  366. Sørensen, N. O. et al. Fertility awareness and attitudes towards parenthood among Danish university college students. Reprod. Health 13, 146 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  367. Prior, E., Lew, R., Hammarberg, K. & Johnson, L. Fertility facts, figures and future plans: an online survey of university students. Hum. Fertil. 22, 283–290 (2019).

    Article  CAS  Google Scholar 

  368. De Jonge, C. J., Gellatly, S. A., Vazquez-Levin, M. H., Barratt, C. L. R. & Rautakallio-Hokkanen, S. Male attitudes towards infertility: results from a global questionnaire. World J. Mens. Health 41, 204–214 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  369. Pedro, J., Brandão, T., Schmidt, L., Costa, M. E. & Martins, M. V. What do people know about fertility? A systematic review on fertility awareness and its associated factors. Ups. J. Med. Sci. 123, 71–81 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  370. Daumler, D., Chan, P., Lo, K. C., Takefman, J. & Zelkowitz, P. Men’s knowledge of their own fertility: a population-based survey examining the awareness of factors that are associated with male infertility. Hum. Reprod. 31, 2781–2790 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  371. Victoria State Government Department of Health. Infertility in women. Victoria State Government https://www.betterhealth.vic.gov.au/health/conditionsandtreatments/infertility-in-women (2021).

  372. Daniluk, J. C. & Koert, E. Fertility awareness online: the efficacy of a fertility education website in increasing knowledge and changing fertility beliefs. Hum. Reprod. 30, 353–363 (2015).

    Article  CAS  PubMed  Google Scholar 

  373. Goodyear, V. & Quennerstedt, M. #Gymlad — young boys learning processes and health-related social media. Qual. Res. Sport. Exerc. Health 12, 18–33 (2020).

    Article  PubMed  Google Scholar 

  374. Sangster, S. L. & Lawson, K. L. Is any press good press? the impact of media portrayals of infertility on young adults’ perceptions of infertility. J. Obstet. Gynaecol. Can. 37, 1072–1078 (2015).

    Article  PubMed  Google Scholar 

  375. Berthelsen, A. S. N., Gamby, A. L. N., Christensen, U., Schmidt, L. & Koert, E. How do young men want to receive information about fertility? Young men’s attitudes towards a fertility campaign targeting men in Copenhagen, Denmark. Hum. Reprod. Open. 2021, hoab027 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  376. Goldfarb, E. S. & Lieberman, L. D. Three decades of research: the case for comprehensive sex education. J. Adolesc. Health 68, 13–27 (2021).

    Article  PubMed  Google Scholar 

  377. Warner, J. N. & Frey, K. A. The well-man visit: addressing a man’s health to optimize pregnancy outcomes. J. Am. Board. Fam. Med. 26, 196–202 (2013).

    Article  PubMed  Google Scholar 

  378. Choiriyyah, I. et al. Men aged 15–44 in need of preconception care. Matern. Child. Health J. 19, 2358–2365 (2015).

    Article  PubMed  Google Scholar 

  379. Bodin, M., Tydén, T., Käll, L. & Larsson, M. Can reproductive life plan-based counselling increase men’s fertility awareness? Ups. J. Med. Sci. 123, 255–263 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  380. Grau Grau, M. & Riley Bowles, H. in Engaged Fatherhood for Men, Families and Gender Equality: Healthcare, Social Policy, and Work Perspectives (eds Grau Grau, M, las Heras Maestro, M. & Bowles, H. R.) 1–12 (Springer International Publishing, 2022).

  381. Hogg, K., Rizio, T., Manocha, R., McLachlan, R. I. & Hammarberg, K. Men’s preconception health care in Australian general practice: GPs’ knowledge, attitudes and behaviours. Aust. J. Prim. Health 25, 353–358 (2019).

    Article  PubMed  Google Scholar 

  382. Barnes, L. W. Conceiving Masculinity. Male Infertility, Medicine, and Identity (Temple University Press, 2014).

  383. WHO. Laboratory Manual for the examination of human semen and sperm-cervical mucus interaction (Cambridge University Press, 1999).

  384. WHO. WHO laboratory manual for the examination and processing of human semen 5th edn (World Health Organization, 2010).

  385. Rodprasert, W. et al. An update on semen quality among young Finnish men and comparison with Danish data. Andrology 7, 15–23 (2019).

    Article  CAS  PubMed  Google Scholar 

  386. Jorgensen, N. et al. Recent adverse trends in semen quality and testis cancer incidence among Finnish men. Int. J. Androl. 34, e37–e48 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  387. Jorgensen, N. et al. Human semen quality in the new millennium: a prospective cross-sectional population-based study of 4867 men. BMJ Open 2, e000990 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  388. Gyllenborg, J. et al. Secular and seasonal changes in semen quality among young Danish men: a statistical analysis of semen samples from 1927 donor candidates during 1977-1995. Int. J. Androl. 22, 28–36 (1999).

    Article  CAS  PubMed  Google Scholar 

  389. Huang, C. et al. Decline in semen quality among 30,636 young Chinese men from 2001 to 2015. Fertil. Steril. 107, 83–88.e2 (2017).

    Article  PubMed  Google Scholar 

  390. Rao, M. et al. Evaluation of semen quality in 1808 university students, from Wuhan, Central China. Asian J. Androl. 17, 111–116 (2015).

    Article  PubMed  Google Scholar 

  391. Zou, Z. et al. Semen quality analysis of military personnel from six geographical areas of the People’s Republic of China. Fertil. Steril. 95, 2018–2023.e3 (2011).

    Article  PubMed  Google Scholar 

  392. Li, Y. et al. Semen quality of 1346 healthy men, results from the Chongqing area of southwest China. Hum. Reprod. 24, 459–69 (2009).

    Article  Google Scholar 

  393. Junqing, W. et al. Reference value of semen quality in Chinese young men. Contraception 65, 365–368 (2002).

    Article  PubMed  Google Scholar 

  394. Gao, J. et al. Semen quality in a residential, geographic and age representative sample of healthy Chinese men. Hum. Reprod. 22, 477–484 (2007).

    Article  CAS  PubMed  Google Scholar 

  395. Wang, C. et al. Cross-sectional study of semen parameters in a large group of normal Chinese men. Int. J. Androl. 8, 257–274 (1985).

    Article  CAS  PubMed  Google Scholar 

  396. Itoh, N. et al. Have sperm counts deteriorated over the past 20 years in healthy, young Japanese men? Results from the Sapporo area. J. Androl. 22, 40–44 (2001).

    Article  CAS  PubMed  Google Scholar 

  397. Medras, M. et al. The quality of semen among a sample of young, healthy men from Lower Silesia (AndroLS). Endokrynol. Pol. 68, 668–675 (2017).

    CAS  PubMed  Google Scholar 

  398. Rahban, R. et al. Semen quality of young men in Switzerland: a nationwide cross-sectional population-based study. Andrology 7, 818–826 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  399. Lopez-Teijon, M., Elbaile, M. & Alvarez, J. G. Geographical differences in semen quality in a population of young healthy volunteers from the different regions of Spain. Andrologia 40, 318–328 (2008).

    Article  CAS  PubMed  Google Scholar 

  400. Mendiola, J. et al. Reproductive parameters in young men living in Rochester, New York. Fertil. Steril. 101, 1064–1071 (2014).

    Article