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.

  • Review Article
  • Published:

Fertility preservation in boys facing gonadotoxic cancer therapy

Nature Reviews Urology volume 19, pages 71–83 (2022)Cite this article

Subjects

Abstract

Patient survival following childhood cancer has increased with contemporary radiation and chemotherapy techniques. However, gonadotoxicity associated with treatments means that infertility is a common consequence in survivors. Novel fertility preservation options are emerging, but knowledge about these options amongst urologists and other medical professionals is lacking. Pre-pubertal boys generally do not produce haploid germ cells. Thus, strategies for fertility preservation require cryopreservation of tissue containing spermatogonial stem cells (SSCs). Few centres worldwide routinely offer this option and fertility restoration (including testicular tissue engraftment, autotransplantation of SSCs and in vitro maturation of SSCs to spermatozoa) post-thaw is experimental. In pubertal boys, the main option for fertility preservation is masturbation and cryopreservation of the ejaculate. Assisted ejaculation using penile vibratory stimulation or electroejaculation and surgical sperm retrieval can be used in a sequential manner after failed masturbation. Physicians should inform boys and parents about the gonadotoxic effects of cancer treatment and offer fertility preservation. Preclinical experience has identified challenges in pre-pubertal fertility preservation, but available options are expected to be successful when today’s pre-pubertal boys with cancer become adults. By contrast, fertility preservation in pubertal boys is clinically proven and should be offered to all patients undergoing cancer treatment.

Key points

  • Childhood cancer therapy often results in infertility. Physicians should inform patients and caregivers and offer fertility preservation.

  • Freezing testis tissue with spermatogonial stem cells (SSCs) from pre-pubertal boys is possible, but fertility restoration techniques are still experimental.

  • Experimental options for fertility restoration in pre-pubertal boys include testicular tissue engraftment, autotransplantation of SSCs and in vitro maturation of SSCs to spermatozoa.

  • As a result of the progress in fertility restoration techniques, today’s pre-pubertal boys with cancer will most probably have opportunities to biologically father children when they become adults.

  • Semen cryopreservation (via masturbation or assisted ejaculation) is a clinically proven technique and is the preferred option among pubertal boys.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Fig. 1: Gonadotoxic effects of cancer treatment on the germ cell population of the testes.
Fig. 2: Assisted ejaculation.

Similar content being viewed by others

References

  1. Winther, J. F. et al. Childhood cancer survivor cohorts in Europe. Acta Oncol. 54, 655–668 (2015).

    Article  PubMed  Google Scholar 

  2. Ward, Z. J. et al. Global childhood cancer survival estimates and priority-setting: a simulation-based analysis. Lancet. Oncol. 20, 972–983 (2019).

    Article  PubMed  Google Scholar 

  3. Ward, Z. J., Yeh, J. M., Bhakta, N., Frazier, A. L. & Atun, R. Estimating the total incidence of global childhood cancer: a simulation-based analysis. Lancet Oncol. 20, 483–493 (2019).

    Article  PubMed  Google Scholar 

  4. Trottmann, M. et al. Semen quality in men with malignant diseases before and after therapy and the role of cryopreservation. Eur. Urol. 52, 355–367 (2007).

    Article  PubMed  Google Scholar 

  5. Tournaye, H., Dohle, G. R. & Barratt, C. L. Fertility preservation in men with cancer. Lancet 384, 1295–1301 (2014).

    Article  PubMed  Google Scholar 

  6. Jungwirth, A. et al. EAU Guidelines: Male Infertility (EAU Guidelines Office, 2019).

  7. 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 

  8. 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 

  9. Phillips, B. T., Gassei, K. & Orwig, K. E. Spermatogonial stem cell regulation and spermatogenesis. Philos. Trans. R. Soc. Lond. B Biol. Sci. 365, 1663–1678 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Vakalopoulos, I., Dimou, P., Anagnostou, I. & Zeginiadou, T. Impact of cancer and cancer treatment on male fertility. Hormones 14, 579–589 (2015).

    PubMed  Google Scholar 

  11. Petersen, P. M., Skakkebaek, N. E. & Giwercman, A. Gonadal function in men with testicular cancer: biological and clinical aspects. APMIS 106, 24–34 (1998). discussion 34–36.

    Article  CAS  PubMed  Google Scholar 

  12. Pettus, J. A., Carver, B. S., Masterson, T., Stasi, J. & Sheinfeld, J. Preservation of ejaculation in patients undergoing nerve-sparing postchemotherapy retroperitoneal lymph node dissection for metastatic testicular cancer. Urology 73, 328–331 (2009). discussion 331–332.

    Article  PubMed  Google Scholar 

  13. Rowley, M. J., Leach, D. R., Warner, G. A. & Heller, C. G. Effect of graded doses of ionizing radiation on the human testis. Radiat. Res. 59, 665–678 (1974).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  15. Vatner, R. E. et al. Endocrine deficiency as a function of radiation dose to the hypothalamus and pituitary in pediatric and young adult patients with brain tumors. J. Clin. Oncol. 36, 2854–2862 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Shalet, S. M., Tsatsoulis, A., Whitehead, E. & Read, G. Vulnerability of the human Leydig cell to radiation damage is dependent upon age. J. Endocrinol. 120, 161–165 (1989).

    Article  CAS  PubMed  Google Scholar 

  17. Hansen, P. V., Trykker, H., Svennekjaer, I. L. & Hvolby, J. Long-term recovery of spermatogenesis after radiotherapy in patients with testicular cancer. Radiother. Oncol. 18, 117–125 (1990).

    Article  CAS  PubMed  Google Scholar 

  18. Giwercman, A. & Petersen, P. M. Cancer and male infertility. Best. Pract. Res. Clin. Endocrinol. Metab. 14, 453–471 (2000).

    Article  CAS  Google Scholar 

  19. Sieniawski, M. et al. Assessment of male fertility in patients with Hodgkin’s lymphoma treated in the German Hodgkin Study Group (GHSG) clinical trials. Ann. Oncol. 19, 1795–1801 (2008).

    Article  CAS  PubMed  Google Scholar 

  20. Viviani, S. et al. Gonadal toxicity after combination chemotherapy for Hodgkin’s disease. Comparative results of MOPP vs ABVD. Eur. J. Cancer Clin. Oncol. 21, 601–605 (1985).

    Article  CAS  PubMed  Google Scholar 

  21. Paoli, D. et al. Spermatogenesis in Hodgkin’s lymphoma patients: a retrospective study of semen quality before and after different chemotherapy regimens. Hum. Reprod. 31, 263–272 (2016).

    CAS  PubMed  Google Scholar 

  22. Meacham, L. R., Burns, K., Orwig, K. E. & Levine, J. Standardizing risk assessment for treatment-related gonadal insufficiency and infertility in childhood adolescent and young adult cancer: the Pediatric Initiative Network risk stratification system. J. Adolesc. Young Adult Oncol. 9, 662–666 (2020).

    Article  PubMed  Google Scholar 

  23. Goossens, E., Van Saen, D. & Tournaye, H. Spermatogonial stem cell preservation and transplantation: from research to clinic. Hum. Reprod. 28, 897–907 (2013).

    Article  CAS  PubMed  Google Scholar 

  24. Onofre, J., Baert, Y., Faes, K. & Goossens, E. Cryopreservation of testicular tissue or testicular cell suspensions: a pivotal step in fertility preservation. Hum. Reprod. Update 22, 744–761 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Keros, V. et al. Methods of cryopreservation of testicular tissue with viable spermatogonia in pre-pubertal boys undergoing gonadotoxic cancer treatment. Hum. Reprod. 22, 1384–1395 (2007).

    Article  CAS  PubMed  Google Scholar 

  26. Poels, J., Van Langendonckt, A., Many, M. C., Wese, F. X. & Wyns, C. Vitrification preserves proliferation capacity in human spermatogonia. Hum. Reprod. 28, 578–589 (2013).

    Article  CAS  PubMed  Google Scholar 

  27. Wyns, C. et al. Spermatogonial survival after cryopreservation and short-term orthotopic immature human cryptorchid testicular tissue grafting to immunodeficient mice. Hum. Reprod. 22, 1603–1611 (2007).

    Article  PubMed  Google Scholar 

  28. Wyns, C., Van Langendonckt, A., Wese, F. X., Donnez, J. & Curaba, M. Long-term spermatogonial survival in cryopreserved and xenografted immature human testicular tissue. Hum. Reprod. 23, 2402–2414 (2008).

    Article  PubMed  Google Scholar 

  29. Wu, J. J. et al. Cryopreservation of adult bovine testicular tissue for spermatogonia enrichment. Cryo Lett. 32, 402–409 (2011).

    CAS  Google Scholar 

  30. 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 

  31. Valli-Pulaski, H. et al. Testicular tissue cryopreservation: 8 years of experience from a coordinated network of academic centers. Hum. Reprod. 34, 966–977 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Martinez, F. 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 

  33. Oktay, K. et al. Fertility preservation in patients with cancer: ASCO clinical practice guideline update. J. Clin. Oncol. 36, 1994–2001 (2018).

    Article  PubMed  Google Scholar 

  34. Jadoul, P. et al. Efficacy of ovarian tissue cryopreservation for fertility preservation: lessons learned from 545 cases. Hum. Reprod. 32, 1046–1054 (2017).

    Article  CAS  PubMed  Google Scholar 

  35. Schlatt, S., Honaramooz, A., Boiani, M., Scholer, H. R. & Dobrinski, I. Progeny from sperm obtained after ectopic grafting of neonatal mouse testes. Biol. Reprod. 68, 2331–2335 (2003).

    Article  CAS  PubMed  Google Scholar 

  36. Liu, Z. et al. Generation of macaques with sperm derived from juvenile monkey testicular xenografts. Cell Res. 26, 139–142 (2016).

    Article  PubMed  Google Scholar 

  37. Sato, Y. et al. Xenografting of testicular tissue from an infant human donor results in accelerated testicular maturation. Hum. Reprod. 25, 1113–1122 (2010).

    Article  CAS  PubMed  Google Scholar 

  38. Luetjens, C. M., Stukenborg, J. B., Nieschlag, E., Simoni, M. & Wistuba, J. Complete spermatogenesis in orthotopic but not in ectopic transplants of autologously grafted marmoset testicular tissue. Endocrinology 149, 1736–1747 (2008).

    Article  CAS  PubMed  Google Scholar 

  39. Jahnukainen, K., Ehmcke, J., Nurmio, M. & Schlatt, S. Autologous ectopic grafting of cryopreserved testicular tissue preserves the fertility of prepubescent monkeys that receive sterilizing cytotoxic therapy. Cancer Res. 72, 5174–5178 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. 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 

  41. 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 

  42. Gassei, K., Shaw, P. H., Cannon, G. M., Meacham, L. R. & Orwig, K. E. in Pediatric and Adolescent Oncofertility: Best Practices and Emerging Technologies (eds Woodruff, T. K. & Gosiengfiao, Y. C.) 119–142 (Springer International Publishing, 2017).

  43. Nagano, M., Avarbock, M. R. & Brinster, R. L. Pattern and kinetics of mouse donor spermatogonial stem cell colonization in recipient testes. Biol. Reprod. 60, 1429–1436 (1999).

    Article  CAS  PubMed  Google Scholar 

  44. Hermann, B. P. et al. Spermatogonial stem cell transplantation into rhesus testes regenerates spermatogenesis producing functional sperm. Cell Stem Cell 11, 715–726 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Radford, J., Shalet, S. & Lieberman, B. Fertility after treatment for cancer. Questions remain over ways of preserving ovarian and testicular tissue. BMJ 319, 935–936 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Medrano, J. V. et al. Basic and clinical approaches for fertility preservation and restoration in cancer patients. Trends Biotechnol. 36, 199–215 (2018).

    Article  CAS  PubMed  Google Scholar 

  47. Sadri-Ardekani, H. et al. Propagation of human spermatogonial stem cells in vitro. JAMA 302, 2127–2134 (2009).

    Article  CAS  PubMed  Google Scholar 

  48. Sadri-Ardekani, H., Akhondi, M. A., van der Veen, F., Repping, S. & van Pelt, A. M. In vitro propagation of human prepubertal spermatogonial stem cells. JAMA 305, 2416–2418 (2011).

    Article  CAS  PubMed  Google Scholar 

  49. David, S. & Orwig, K. E. in The Biology of Mammalian Spermatogonia (eds Oatley, J. M. & Griswold, M. D.) 315–341 (Springer, 2017).

  50. Kumar, M., Kumar, K., Jain, S., Hassan, T. & Dada, R. Novel insights into the genetic and epigenetic paternal contribution to the human embryo. Clinics 68 (Suppl 1), 5–14 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  51. Goodyear, S. & Brinster, R. Spermatogonial stem cell transplantation to the testis. Cold Spring Harb. Protoc. 2017, pdb.prot094235 (2017).

    Article  PubMed  Google Scholar 

  52. David, S. & Orwig, K. E. Spermatogonial stem cell culture in oncofertility. Urol. Clin. 47, 227–244 (2020).

    Article  Google Scholar 

  53. Moraveji, S. F. et al. Suppression of transforming growth factor-beta signaling enhances spermatogonial proliferation and spermatogenesis recovery following chemotherapy. Hum. Reprod. 34, 2430–2442 (2019).

    Article  CAS  PubMed  Google Scholar 

  54. Murdock, M. H. et al. Human testis extracellular matrix enhances human spermatogonial stem cell survival in vitro. Tissue Eng. Part A 25, 663–676 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Dong, L. et al. Xeno-free propagation of spermatogonial stem cells from infant boys. Int. J. Mol. Sci. 20, 5390 (2019).

    Article  CAS  PubMed Central  Google Scholar 

  56. Chen, B. et al. Xeno-free culture of human spermatogonial stem cells supported by human embryonic stem cell-derived fibroblast-like cells. Asian J. Androl. 11, 557–565 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  57. Sadri-Ardekani, H. et al. Eliminating acute lymphoblastic leukemia cells from human testicular cell cultures: a pilot study. Fertil. Steril. 101, 1072–1078.e1 (2014).

    Article  PubMed  Google Scholar 

  58. Dovey, S. L. et al. Eliminating malignant contamination from therapeutic human spermatogonial stem cells. J. Clin. Invest. 123, 1833–1843 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Faes, K., Lahoutte, T., Hoorens, A., Tournaye, H. & Goossens, E. In search of an improved injection technique for the clinical application of spermatogonial stem cell transplantation. Reprod. Biomed. Online 34, 291–297 (2017).

    Article  PubMed  Google Scholar 

  60. Schlatt, S. et al. Germ cell transfer into rat, bovine, monkey and human testes. Hum. Reprod. 14, 144–150 (1999).

    Article  CAS  PubMed  Google Scholar 

  61. Faes, K. et al. Testicular cell transplantation into the human testes. Fertil. Steril. 100, 981–988 (2013).

    Article  PubMed  Google Scholar 

  62. Tesarik, J., Bahceci, M., Ozcan, C., Greco, E. & Mendoza, C. Restoration of fertility by in-vitro spermatogenesis. Lancet 353, 555–556 (1999).

    Article  CAS  PubMed  Google Scholar 

  63. Sato, T. et al. In vitro production of functional sperm in cultured neonatal mouse testes. Nature 471, 504–507 (2011).

    Article  CAS  PubMed  Google Scholar 

  64. de Michele, F. et al. Preserved seminiferous tubule integrity with spermatogonial survival and induction of Sertoli and Leydig cell maturation after long-term organotypic culture of prepubertal human testicular tissue. Hum. Reprod. 32, 32–45 (2017).

    PubMed  Google Scholar 

  65. Medrano, J. V. et al. Influence of temperature, serum, and gonadotropin supplementation in short- and long-term organotypic culture of human immature testicular tissue. Fertil. Steril. 110, 1045–1057.e3 (2018).

    Article  CAS  PubMed  Google Scholar 

  66. de Michele, F. et al. Haploid germ cells generated in organotypic culture of testicular tissue from prepubertal boys. Front. Physiol. 9, 1413 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  67. Tanaka, A. et al. Fourteen babies born after round spermatid injection into human oocytes. Proc. Natl Acad. Sci. USA 112, 14629–14634 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Alves-Lopes, J. P., Soder, O. & Stukenborg, J. B. Testicular organoid generation by a novel in vitro three-layer gradient system. Biomaterials 130, 76–89 (2017).

    Article  CAS  PubMed  Google Scholar 

  69. Baert, Y. et al. Primary human testicular cells self-organize into organoids with testicular properties. Stem Cell Rep. 8, 30–38 (2017).

    Article  CAS  Google Scholar 

  70. Pendergraft, S. S., Sadri-Ardekani, H., Atala, A. & Bishop, C. E. Three-dimensional testicular organoid: a novel tool for the study of human spermatogenesis and gonadotoxicity in vitro. Biol. Reprod. 96, 720–732 (2017).

    Article  PubMed  Google Scholar 

  71. Müller J., Nielsen, T., & Schaerbeek, N. E. in The Physiology of Human Growth (eds Preece, M. A. & Tanner, J. M.) 201–207 (Cambridge University Press, 1989).

  72. Laron, Z., Arad, J., Gurewitz, R., Grunebaum, M. & Dickerman, Z. Age at first conscious ejaculation: a milestone in male puberty. Helv. Paediatr. Acta 35, 13–20 (1980).

    CAS  PubMed  Google Scholar 

  73. Hagenas, I. et al. Clinical and biochemical correlates of successful semen collection for cryopreservation from 12–18-year-old patients: a single-center study of 86 adolescents. Hum. Reprod. 25, 2031–2038 (2010).

    Article  PubMed  Google Scholar 

  74. Klosky, J. L. et al. Prevalence and predictors of sperm banking in adolescents newly diagnosed with cancer: examination of adolescent, parent, and provider factors influencing fertility preservation outcomes. J. Clin. Oncol. 35, 3830–3836 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  75. Kliesch, S., Behre, H. M., Jurgens, H. & Nieschlag, E. Cryopreservation of semen from adolescent patients with malignancies. Med. Pediatr. Oncol. 26, 20–27 (1996).

    Article  CAS  PubMed  Google Scholar 

  76. Bahadur, G. et al. Semen quality before and after gonadotoxic treatment. Hum. Reprod. 20, 774–781 (2005).

    Article  CAS  PubMed  Google Scholar 

  77. Skakkebaek, N. E., Rajpert-De Meyts, E. & Main, K. M. Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects. Hum. Reprod. 16, 972–978 (2001).

    Article  CAS  PubMed  Google Scholar 

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

    Article  Google Scholar 

  79. Bahadur, G. et al. Semen quality and cryopreservation in adolescent cancer patients. Hum. Reprod. 17, 3157–3161 (2002).

    Article  CAS  PubMed  Google Scholar 

  80. Daudin, M. et al. Sperm cryopreservation in adolescents and young adults with cancer: results of the French national sperm banking network (CECOS). Fertil. Steril. 103, 478–486.e1 (2015).

    Article  PubMed  Google Scholar 

  81. DiNofia, A. M. et al. Analysis of semen parameters in a young cohort of cancer patients. Pediatr. Blood Cancer 64, 381–386 (2017).

    Article  PubMed  Google Scholar 

  82. WHO. WHO Laboratory Manual for the Examination and Processing of Human Semen. 5th edn. (World Health Organization, 2010).

  83. Schmiegelow, M. L. et al. Penile vibratory stimulation and electroejaculation before anticancer therapy in two pubertal boys. J. Pediatr. Hematol. Oncol. 20, 429–430 (1998).

    Article  CAS  PubMed  Google Scholar 

  84. Brackett, N. L., Ibrahim, E., Iremashvili, V., Aballa, T. C. & Lynne, C. M. Treatment for ejaculatory dysfunction in men with spinal cord injury: an 18-year single center experience. J. Urol. 183, 2304–2308 (2010).

    Article  PubMed  Google Scholar 

  85. Sønksen, J., Ohl, D. A. & Wedemeyer, G. Sphincteric events during penile vibratory ejaculation and electroejaculation in men with spinal cord injuries. J. Urol. 165, 426–429 (2001).

    Article  PubMed  Google Scholar 

  86. Hovav, Y., Dan-Goor, M., Yaffe, H. & Almagor, M. Electroejaculation before chemotherapy in adolescents and young men with cancer. Fertil. Steril. 75, 811–813 (2001).

    Article  CAS  PubMed  Google Scholar 

  87. Adank, M. C. et al. Electroejaculation as a method of fertility preservation in boys diagnosed with cancer: a single-center experience and review of the literature. Fertil. Steril. 102, 199–205.e1 (2014).

    Article  PubMed  Google Scholar 

  88. Gat, I. et al. Sperm preservation by electroejaculation in adolescent cancer patients. Pediatr. Blood Cancer 61, 286–290 (2014).

    Article  PubMed  Google Scholar 

  89. Berookhim, B. M. & Mulhall, J. P. Outcomes of operative sperm retrieval strategies for fertility preservation among males scheduled to undergo cancer treatment. Fertil. Steril. 101, 805–811 (2014).

    Article  PubMed  Google Scholar 

  90. Jensen, C. F. et al. Multiple needle-pass percutaneous testicular sperm aspiration as first-line treatment in azoospermic men. Andrology 4, 257–262 (2016).

    Article  CAS  PubMed  Google Scholar 

  91. Friedler, S. et al. Testicular sperm retrieval by percutaneous fine needle sperm aspiration compared with testicular sperm extraction by open biopsy in men with non-obstructive azoospermia. Hum. Reprod. 12, 1488–1493 (1997).

    Article  CAS  PubMed  Google Scholar 

  92. Ho, W. L. C. et al. A short report on current fertility preservation strategies for boys. Clin. Endocrinol. 87, 279–285 (2017).

    Article  Google Scholar 

  93. Logan, S. & Anazodo, A. The psychological importance of fertility preservation counseling and support for cancer patients. Acta Obstet. Gynecol. Scand. 98, 583–597 (2019).

    Article  PubMed  Google Scholar 

  94. Klosky, J. L. et al. Provider influences on sperm banking outcomes among adolescent males newly diagnosed with cancer. J. Adolesc. Health 60, 277–283 (2017).

    Article  PubMed  Google Scholar 

  95. Wyns, C. et al. Fertility preservation in the male pediatric population: factors influencing the decision of parents and children. Hum. Reprod. 30, 2022–2030 (2015).

    Article  CAS  PubMed  Google Scholar 

  96. Klipstein, S., Fallat, M. E. & Savelli, S. Fertility preservation for pediatric and adolescent patients with cancer: medical and ethical considerations. Pediatrics 145, e20193994 (2020).

    Article  PubMed  Google Scholar 

  97. Gao, F. et al. Origin of HIV-1 in the chimpanzee Pan troglodytes troglodytes. Nature 397, 436–441 (1999).

    Article  CAS  PubMed  Google Scholar 

  98. Daniel, M. D. et al. Long-term persistent infection of macaque monkeys with the simian immunodeficiency virus. J. Gen. Virol. 68, 3183–3189 (1987).

    Article  PubMed  Google Scholar 

  99. Smith, C. E., Simpson, D. I., Bowen, E. T. & Zlotnik, I. Fatal human disease from vervet monkeys. Lancet 2, 1119–1121 (1967).

    Article  CAS  PubMed  Google Scholar 

  100. Chant, K., Chan, R., Smith, M., Dwyer, D. E. & Kirkland, P. Probable human infection with a newly described virus in the family Paramyxoviridae. The NSW Expert Group. Emerg. Infect. Dis. 4, 273–275 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Dixon, T. C., Meselson, M., Guillemin, J. & Hanna, P. C. Anthrax. N. Engl. J. Med. 341, 815–826 (1999).

    Article  CAS  PubMed  Google Scholar 

  102. Paton, N. I. et al. Outbreak of Nipah-virus infection among abattoir workers in Singapore. Lancet 354, 1253–1256 (1999).

    Article  CAS  PubMed  Google Scholar 

  103. Brown, J., Matthews, A. L., Sandstrom, P. A. & Chapman, L. E. Xenotransplantation and the risk of retroviral zoonosis. Trends Microbiol. 6, 411–415 (1998).

    Article  CAS  PubMed  Google Scholar 

  104. Schlatt, S., Westernstroer, B., Gassei, K. & Ehmcke, J. Donor-host involvement in immature rat testis xenografting into nude mouse hosts. Biol. Reprod. 82, 888–895 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Arregui, L. et al. Suppression of spermatogenesis before grafting increases survival and supports resurgence of spermatogenesis in adult mouse testis. Fertil. Steril. 97, 1422–1429 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  106. Kim, T. H. et al. Pretreatment testicular biopsy in childhood acute lymphocytic leukaemia. Lancet 2, 657–658 (1981).

    Article  CAS  PubMed  Google Scholar 

  107. Franck, P. et al. Testicular relapse after 13 years of complete remission of acute lymphoblastic leukemia. Urol. Int. 60, 239–241 (1998).

    Article  CAS  PubMed  Google Scholar 

  108. Quaranta, B. P., Halperin, E. C., Kurtzberg, J., Clough, R. & Martin, P. L. The incidence of testicular recurrence in boys with acute leukemia treated with total body and testicular irradiation and stem cell transplantation. Cancer 101, 845–850 (2004).

    Article  PubMed  Google Scholar 

  109. Jahnukainen, K., Hou, M., Petersen, C., Setchell, B. & Soder, O. Intratesticular transplantation of testicular cells from leukemic rats causes transmission of leukemia. Cancer Res. 61, 706–710 (2001).

    CAS  PubMed  Google Scholar 

  110. 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 

  111. von Kopylow, K. & Spiess, A. N. Human spermatogonial markers. Stem Cell Res. 25, 300–309 (2017).

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Urology, Copenhagen University Hospital, Herlev and Gentofte Hospital, Herlev, Denmark

    Christian F. S. Jensen, Mikkel Fode & Jens Sønksen

  2. Laboratory of Reproductive Biology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark

    Lihua Dong, Murat Gul & Claus Y. Andersen

  3. Department of Urology, Selcuk University School of Medicine, Konya, Turkey

    Murat Gul

  4. Department of Pediatric Surgery, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark

    Simone Hildorf & Jorgen Thorup

  5. Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Jorgen Thorup, Eva Hoffmann, Dina Cortes, Claus Y. Andersen & Jens Sønksen

  6. Center for Chromosome Stability, Institute of Molecular and Cellular Medicine, University of Copenhagen, Copenhagen, Denmark

    Eva Hoffmann

  7. Department of Pediatrics, Copenhagen University Hospital, Hvidovre, Copenhagen, Denmark

    Dina Cortes

  8. Centre of Andrology & Fertility Clinic, Department D, Odense University Hospital, Odense, Denmark

    Jens Fedder

  9. Research Unit of Human Reproduction, Institute of Clinical Research, University of Southern Denmark, Odense, Denmark

    Jens Fedder

Authors
  1. Christian F. S. Jensen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lihua Dong
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Murat Gul
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mikkel Fode
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Simone Hildorf
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jorgen Thorup
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Eva Hoffmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Dina Cortes
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jens Fedder
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Claus Y. Andersen
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jens Sønksen
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

C.F.S.J., L.D. and M.G. researched data for the article; C.F.S.J., L.D., M.G., M.F., S.H., J.T., E.H., D.C., J.F., C.Y.A., and J.S. made a substantial contribution to discussion of content; C.F.S.J., L.D. and M.G. wrote the article; and C.F.S.J. L.D., M.G., M.F., S.H., J.T., E.H., D.C., J.F., C.Y.A., and J.S. reviewed and/or edited the manuscript prior to submission.

Corresponding author

Correspondence to Christian F. S. Jensen.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Urology thanks the anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Cryopreservation protection agent

(CPA). Agent used for prevention of damaging ice crystal formation when freezing biological tissue.

Intracytoplasmic sperm injection

(ICSI). An in vitro fertilization procedure where a spermatozoon is injected directly into the cytoplasm of an oocyte.

Zoonosis

An infectious disease transferred from animals to humans.

Transplantation assay

Transplantation of stem cells into recipient organs as a functional measure of stem cell capacity.

Differential plating method

A method used for enrichment of spermatogonial stem cells by using coated and non-coated cell-culture dishes that differentially adhere spermatogonial stem cells and other cells.

Spermarche

The beginning of sperm development in the testicles of pubertal boys.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jensen, C.F.S., Dong, L., Gul, M. et al. Fertility preservation in boys facing gonadotoxic cancer therapy. Nat Rev Urol 19, 71–83 (2022). https://doi.org/10.1038/s41585-021-00523-8

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41585-021-00523-8

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing