Fertility preservation strategies for male patients with cancer

Nature Reviews Urology

Volumn 10, Issue 8, 2013, Pages 463-472

  Katz, Darren J ^a   Kolon, Thomas F ^b   Feldman, Darren R ^a   Mulhall, John P ^a  

^a MEMORIAL SLOAN KETTERING CANCER CENTER   (United States)

^b UNIVERSITY OF PENNSYLVANIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALPHA INTERFERON; BEVACIZUMAB; BLEOMYCIN; CARBOPLATIN; CHLORAMBUCIL; CISPLATIN; CYCLOPHOSPHAMIDE; DACARBAZINE; DOXORUBICIN; IMATINIB; PREDNISOLONE; PROCARBAZINE; RADIOACTIVE IODINE; SUNITINIB; VINBLASTINE;

ACUTE LYMPHOBLASTIC LEUKEMIA; AUTOTRANSPLANTATION; AZOOSPERMIA; BREAST CANCER; CANCER CHEMOTHERAPY; CANCER OF UNKNOWN PRIMARY SITE; CANCER RADIOTHERAPY; CANCER THERAPY; CELL MATURATION; CHRONIC MYELOID LEUKEMIA; COLORECTAL CANCER; CRYOPRESERVATION; DRUG CYTOTOXICITY; GASTROINTESTINAL STROMAL TUMOR; GERM CELL TUMOR; GONAD FUNCTION; HEAD AND NECK CANCER; HODGKIN DISEASE; HUMAN; IN VITRO STUDY; KIDNEY CANCER; LUNG CANCER; LYMPHOMA; MALE FERTILITY; MALE INFERTILITY; MITOSIS RATE; NEOPLASM; NONHODGKIN LYMPHOMA; NONHUMAN; OLIGOSPERMIA; PLURIPOTENT STEM CELL; PRIORITY JOURNAL; QUALITY OF LIFE; RADIATION DOSE; REPRODUCTIVE PROCEDURE; REVIEW; SARCOMA; SPERMATOGENESIS; SPERMATOGONIUM; STEM CELL; TESTIS CANCER; THYROID CANCER; WHOLE BODY RADIATION;

CRYOPRESERVATION; FERTILITY PRESERVATION; HUMANS; INFERTILITY, MALE; MALE; NEOPLASMS; SPERMATOGONIA; SPERMATOZOA;

EID: 84881611617     PISSN: 17594812     EISSN: 17594820     Source Type: Journal    
DOI: 10.1038/nrurol.2013.145     Document Type: Review

References (136)

1. Living beyond cancer: finding a new balance. President's Cancer Panel 2003-2004 Annual Report 17 [online], http://deainfo.nci.nih.gov/advisory/pcp/ annualReports/pcp03-04rpt/Survivorship.pdf (2013).
2. Lee, S. J. et al. American Society of Clinical Oncology recommendations on fertility preservation in cancer patients. J. Clin. Oncol. 24, 2917-2931 (2006).
3. Jemal, A. et al. Global cancer statistics. CA Cancer J. Clin. 61, 69-90 (2011).
4. Siegel, R., Naishadham, D. & Jemal, A. Cancer statistics, 2013. CA Cancer J. Clin. 63, 11-30 (2013).
5. Bleyer, A. Young adult oncology: the patients and their survival challenges. CA Cancer J. Clin. 57, 242-255 (2007).
6. American Cancer Society. Cancer Facts and Figures 2012 [online], http://www.cancer.org/research/cancerfactsfigures/cancerfactsfigures/ cancer-facts-figures-2012 (2013).
7. Tschudin, S. & Bitzer, J. Psychological aspects of fertility preservation in men and women affected by cancer and other life-threatening diseases. Hum. Reprod. Update 15, 587-597 (2009).
8. Schover, L. R., Brey, K., Lichtin, A., Lipshultz, L. I. & Jeha, S. Knowledge and experience regarding cancer, infertility, and sperm banking in younger male survivors. J. Clin. Oncol. 20, 1880-1889 (2002).
9. Rieker, P. P., Fitzgerald, E. M. & Kalish, L. A. Adaptive behavioral responses to potential infertility among survivors of testis cancer. J. Clin. Oncol. 8, 347-355 (1990).
10. Saito, K., Suzuki, K., Iwasaki, A., Yumura, Y. & Kubota, Y. Sperm cryopreservation before cancer chemotherapy helps in the emotional battle against cancer. Cancer 104, 521-524 (2005).
11. Wallace, W. H. & Thomson, A. B. Preservation of fertility in children treated for cancer. Arch. Dis. Child. 88, 493-496 (2003).
12. Nieman, C. L. et al. Fertility preservation and adolescent cancer patients: lessons from adult survivors of childhood cancer and their parents. Cancer Treat. Res. 138, 201-217 (2007).
13. Peate, M. et al. It's now or never: fertility-related knowledge, decision-making preferences, and treatment intentions in young women with breast cancer - an Australian fertility decision aid collaborative group study. J. Clin. Oncol. 29, 1670-1677 (2011).
14. Anderson, R. A. et al. Do doctors discuss fertility issues before they treat young patients with cancer? Hum. Reprod. 23, 2246-2251 (2008).
15. Green, D. M. et al. Fertility of male survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. J. Clin. Oncol. 28, 332-339 (2010).
16. Thomson, A. B. et al. Semen quality and spermatozoal DNA integrity in survivors of childhood cancer: a case-control study. Lancet 360, 361-367 (2002).
17. Lass, A. et al. A programme of semen cryopreservation for patients with malignant disease in a tertiary infertility centre: lessons from 8 years' experience. Hum. Reprod. 13, 3256-3261 (1998).
18. Chung, K. et al. Sperm cryopreservation for male patients with cancer: an epidemiological analysis at the University of Pennsylvania. Eur. J. Obstet. Gynecol. Reprod. Biol. 113 (Suppl. 1), S7-S11 (2004).
19. Pietzak, E. J. et al. Histology of testicular biopsy specimens obtained for cryopreservation and future re-implantation as a fertility-preserving technique. Presented at the 2012 American Academy of Pediatrics National Conference in New Orleans.
20. Agarwal, A. & Allamaneni, S. S. Disruption of spermatogenesis by the cancer disease process. J. Natl Cancer Inst. Monogr. 2005, 9-12 (2005).
21. Paduch, D. A. Testicular cancer and male infertility. Curr. Opin. Urol. 16, 419-427 (2006).
22. Hall, E. & Burt, V. K. Male fertility: psychiatric considerations. Fertil. Steril. 97, 434-439 (2012).
23. Pereira, M. L. & Garcia e Costa, F. The blood-testis barrier as a target of some chemotherapeutic agents. Chemotherapy 53, 446-448 (2007).
24. Bucci, L. R. & Meistrich, M. L. Effects of busulfan on murine spermatogenesis: cytotoxicity, sterility, sperm abnormalities, and dominant lethal mutations. Mutat. Res. 176, 259-268 (1987).
25. Ginsberg, J. P. New advances in fertility preservation for pediatric cancer patients. Curr. Opin. Pediatr. 23, 9-13 (2011).
26. van der Kaaij, M. A., van Echten-Arends, J., Simons, A. H. & Kluin-Nelemans, H. C. Fertility preservation after chemotherapy for Hodgkin lymphoma. Hematol. Oncol. 28, 168-179 (2010).
27. Mackie, E. J., Radford, M. & Shalet, S. M. Gonadal function following chemotherapy for childhood Hodgkin's disease. Med. Pediatr. Oncol. 27, 74-78 (1996).
28. DeSantis, M., Albrecht, W., Holtl, W. & Pont, J. Impact of cytotoxic treatment on long-term fertility in patients with germ-cell cancer. Int. J. Cancer 83, 864-865 (1999).
29. Colpi, G. M., Contalbi, G. F., Nerva, F., Sagone, P. & Piediferro, G. Testicular function following chemo-radiotherapy. Eur. J. Obstet. Gynecol. Reprod. Biol. 113 (Suppl. 1), S2-S6 (2004).
30. 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).
31. Centola, G. M., Keller, J. W., Henzler, M. & Rubin, P. Effect of low-dose testicular irradiation on sperm count and fertility in patients with testicular seminoma. J. Androl. 15, 608-613 (1994).
32. Speiser, B., Rubin, P. & Casarett, G. Aspermia following lower truncal irradiation in Hodgkin's disease. Cancer 32, 692-698 (1973).
33. Budgell, G. J., Cowan, R. A. & Hounsell, A. R. Prediction of scattered dose to the testes in abdominopelvic radiotherapy. Clin. Oncol. (R. Coll. Radiol.) 13, 120-125 (2001).
34. Brenner, D. J. & Hall, E. J. Computed tomography - an increasing source of radiation exposure. N. Engl. J. Med. 357, 2277-2284 (2007).
35. Feldschuh, J., Brassel, J., Durso, N. & Levine, A. Successful sperm storage for 28 years. Fertil. Steril. 84, 1017 (2005).
36. Hourvitz, A. et al. Intracytoplasmic sperm injection (ICSI) using cryopreserved sperm from men with malignant neoplasm yields high pregnancy rates. Fertil. Steril. 90, 557-563 (2008).
37. Fossa, S. D. & Magelssen, H. Fertility and reproduction after chemotherapy of adult cancer patients: malignant lymphoma and testicular cancer. Ann. Oncol. 15 (Suppl. 4), iv259-iv265 (2004).
38. Sunkara, S. K. et al. Association between the number of eggs and live birth in IVF treatment: an analysis of 400 135 treatment cycles. Hum. Reprod. 26, 1768-1774 (2011).
39. O'Connell, M., McClure, N. & Lewis, S. E. The effects of cryopreservation on sperm morphology, motility and mitochondrial function. Hum. Reprod. 17, 704-709 (2002).
40. Pacey, A. A. Fertility issues in survivors from adolescent cancers. Cancer Treat. Rev. 33, 646-655 (2007).
41. 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).
42. Sabanegh, E. Male Infertility - Problems and Solutions (ed. Klein, E. A.) (Humana Press, New York, 2011).
43. Schlegel, P. N. Testicular sperm extraction: microdissection improves sperm yield with minimal tissue excision. Hum. Reprod. 14, 131-135 (1999).
44. Hsiao, W. et al. Successful treatment of postchemotherapy azoospermia with microsurgical testicular sperm extraction: the Weill Cornell experience. J. Clin. Oncol. 29, 1607-1611 (2011).
45. Schrader, M. et al. "Onco-tese": testicular sperm extraction in azoospermic cancer patients before chemotherapy-new guidelines? Urology 61, 421-425 (2003).
46. Katz, D. J., Matsushita, K., Bennett, N. & Mulhall, J. P. Outcomes of fertility preservation strategies in male teenagers with cancer [abstract 1985]. J. Urol. 187 (Suppl.), e801 (2012).
47. Binsaleh, S., Sircar, K. & Chan, P. T. Feasibility of simultaneous testicular microdissection for sperm retrieval and ipsilateral testicular tumor resection in azoospermic men. J. Androl. 25, 867-871 (2004).
48. Kalsi, J. et al. Analysis of the outcome of intracytoplasmic sperm injection using fresh or frozen sperm. BJU Int. 107, 1124-1128 (2011).
49. Nicopoullos, J. D. et al. Use of surgical sperm retrieval in azoospermic men: a meta-analysis. Fertil. Steril. 82, 691-701 (2004).
50. Ulug, U., Bener, F., Karagenc, L., Ciray, N. & Bahceci, M. Outcomes in couples undergoing ICSI: comparison between fresh and frozen-thawed surgically retrieved spermatozoa. Int. J. Androl. 28, 343-349 (2005).
51. Bieri, S., Rouzaud, M. & Miralbell, R. Seminoma of the testis: is scrotal shielding necessary when radiotherapy is limited to the para-aortic nodes? Radiother. Oncol. 50, 349-353 (1999).
52. Harris, S. J. & Buchanan, R. B. Irradiation of the scrotum: what some men need MOST: the Manual Orchid Shielding Technique. Clin. Oncol. (R. Coll. Radiol.) 8, 254-256 (1996).
53. Fraass, B. A., Kinsella, T. J., Harrington, F. S. & Glatstein, E. Peripheral dose to the testes: the design and clinical use of a practical and effective gonadal shield. Int. J. Radiat. Oncol. Biol. Phys. 11, 609-615 (1985).
54. Ishiguro, H. et al. Gonadal shielding to irradiation is effective in protecting testicular growth and function in long-term survivors of bone marrow transplantation during childhood or adolescence. Bone Marrow Transplant. 39, 483-490 (2007).
55. Bazzi, W. M. et al. Partial orchiectomy and testis intratubular germ cell neoplasia: world literature review. Urol. Ann. 3, 115-118 (2011).
56. Lawrentschuk, N., Zuniga, A., Grabowksi, A. C., Rendon, R. A. & Jewett, M. A. Partial orchiectomy for presumed malignancy in patients with a solitary testis due to a prior germ cell tumor: a large North American experience. J. Urol. 185, 508-513 (2011).
57. Toren, P. J. et al. Small incidentally discovered testicular masses in infertile men - is active surveillance the new standard of care? J. Urol. 183, 1373-1377 (2010).
58. 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).
59. Shetty, G. & Meistrich, M. L. Hormonal approaches to preservation and restoration of male fertility after cancer treatment. J. Natl Cancer Inst. Monogr. 2005, 36-39 (2005).
60. Meistrich, M. L. & Shetty, G. Inhibition of spermatogonial differentiation by testosterone. J. Androl. 24, 135-148 (2003).
61. Morris, I. D. Protection against cytotoxic-induced testis damage - experimental approaches. Eur. Urol. 23, 143-147 (1993).
62. Manabe, F., Takeshima, H. & Akaza, H. Protecting spermatogenesis from damage induced by doxorubicin using the luteinizing hormone-releasing hormone agonist leuprorelin: an image analysis study of a rat experimental model. Cancer 79, 1014-1021 (1997).
63. Kangasniemi, M., Wilson, G., Parchuri, N., Huhtaniemi, I. & Meistrich, M. L. Rapid protection of rat spermatogenic stem cells against procarbazine by treatment with a gonadotropin-releasing hormone antagonist (Nal-Glu) and an antiandrogen (flutamide). Endocrinology 136, 2881-2888 (1995).
64. Brennemann, W., Brensing, K. A., Leipner, N., Boldt, I. & Klingmuller, D. Attempted protection of spermatogenesis from irradiation in patients with seminoma by D-Tryptophan-6 luteinizing hormone releasing hormone. Clin. Investig. 72, 838-842 (1994).
65. Fossa, S. D., Klepp, O. & Norman, N. Lack of gonadal protection by medroxyprogesterone acetate-induced transient medical castration during chemotherapy for testicular cancer. Br. J. Urol. 62, 449-453 (1988).
66. Johnson, D. H. et al. Effect of a luteinizing hormone releasing hormone agonist given during combination chemotherapy on posttherapy fertility in male patients with lymphoma: preliminary observations. Blood 65, 832-836 (1985).
67. Redman, J. & Bajorunas, D. in Workshop on Psychosexual and Reproductive Issues Affecting Patients with Cancer 90-94 (American Cancer Society, New York, 1987).
68. Waxman, J. Preserving fertility in Hodgkin's disease. Baillieres Clin. Haematol. 1, 185-190 (1987).
69. Kelnar, C. J. et al. Testicular changes during infantile 'quiescence' in the marmoset and their gonadotrophin dependence: a model for investigating susceptibility of the prepubertal human testis to cancer therapy? Hum. Reprod. 17, 1367-1378 (2002).
70. Ogawa, T., Dobrinski, I., Avarbock, M. R. & Brinster, R. L. Leuprolide, a gonadotropin-releasing hormone agonist, enhances colonization after spermatogonial transplantation into mouse testes. Tissue Cell 30, 583-588 (1998).
71. Kanter, M., Topcu-Tarladacalisir, Y. & Parlar, S. Antiapoptotic effect of l-carnitine on testicular irradiation in rats. J. Mol. Histol. 41, 121-128 (2010).
72. Okada, F. K., Stumpp, T. & Miraglia, S. M. Carnitine reduces testicular damage in rats treated with etoposide in the prepubertal phase. Cell Tissue Res. 337, 269-280 (2009).
73. Carmely, A. et al. Protective effect of the immunomodulator AS101 against cyclophosphamide-induced testicular damage in mice. Hum. Reprod. 24, 1322-1329 (2009).
74. Lirdi, L. C., Stumpp, T., Sasso-Cerri, E. & Miraglia, S. M. Amifostine protective effect on cisplatin-treated rat testis. Anat. Rec. (Hoboken) 291, 797-808 (2008).
75. Brook, P. F., Radford, J. A., Shalet, S. M., Joyce, A. D. & Gosden, R. G. Isolation of germ cells from human testicular tissue for low temperature storage and autotransplantation. Fertil. Steril. 75, 269-274 (2001).
76. 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).
77. Ginsberg, J. P. et al. An experimental protocol for fertility preservation in prepubertal boys recently diagnosed with cancer: a report of acceptability and safety. Hum. Reprod. 25, 37-41 (2010).
78. Sato, T. et al. In vitro production of functional sperm in cultured neonatal mouse testes. Nature 471, 504-507 (2011).
79. 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).
80. de Rooij, D. G. The spermatogonial stem cell niche. Microsc. Res. Tech. 72, 580-585 (2009).
81. Curaba, M., Poels, J., van Langendonckt, A., Donnez, J. & Wyns, C. Can prepubertal human testicular tissue be cryopreserved by vitrification? Fertil. Steril. 95, 2123.e9-2123.e12 (2011).
82. Poels, J., Van Langendonckt, A., Dehoux, J. P., Donnez, J. & Wyns, C. Vitrification of non-human primate immature testicular tissue allows maintenance of proliferating spermatogonial cells after xenografting to recipient mice. Theriogenology 77, 1008-1013 (2012).
83. Brinster, R. L. Male germline stem cells: from mice to men. Science 316, 404-405 (2007).
84. Trefil, P. et al. Restoration of spermatogenesis after transplantation of c-Kit positive testicular cells in the fowl. Theriogenology 74, 1670-1676 (2010).
85. Brinster, R. L. & Zimmermann, J. W. Spermatogenesis following male germ-cell transplantation. Proc. Natl Acad. Sci. USA 91, 11298-11302 (1994).
86. Honaramooz, A. et al. Fertility and germline transmission of donor haplotype following germ cell transplantation in immunocompetent goats. Biol. Reprod. 69, 1260-1264 (2003).
87. Schlatt, S., Foppiani, L., Rolf, C., Weinbauer, G. F. & Nieschlag, E. Germ cell transplantation into X-irradiated monkey testes. Hum. Reprod. 17, 55-62 (2002).
88. Schlatt, S. et al. Germ cell transfer into rat, bovine, monkey and human testes. Hum. Reprod. 14, 144-150 (1999).
89. 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).
90. Chuma, S. et al. Spermatogenesis from epiblast and primordial germ cells following transplantation into postnatal mouse testis. Development 132, 117-122 (2005).
91. Jahnukainen, K. et al. Testicular recovery after irradiation differs in prepubertal and pubertal non-human primates, and can be enhanced by autologous germ cell transplantation. Hum. Reprod. 26, 1945-1954 (2011).
92. Ogawa, T., Arechaga, J. M., Avarbock, M. R. & Brinster, R. L. Transplantation of testis germinal cells into mouse seminiferous tubules. Int. J. Dev. Biol. 41, 111-122 (1997).
93. Schlatt, S., von Schonfeldt, V. & Nieschlag, E. Germ cell transplantation in the male: animal studies with a human perspective. Hum. Fertil. (Camb.) 2, 143-148 (1999).
94. Ohta, H. & Wakayama, T. Generation of normal progeny by intracytoplasmic sperm injection following grafting of testicular tissue from cloned mice that died postnatally. Biol. Reprod. 73, 390-395 (2005).
95. Shinohara, T. et al. Birth of offspring following transplantation of cryopreserved immature testicular pieces and in-vitro microinsemination. Hum. Reprod. 17, 3039-3045 (2002).
96. Honaramooz, A. et al. Sperm from neonatal mammalian testes grafted in mice. Nature 418, 778-781 (2002).
97. Wu, X. et al. Prepubertal human spermatogonia and mouse gonocytes share conserved gene expression of germline stem cell regulatory molecules. Proc. Natl Acad. Sci. USA 106, 21672-21677 (2009).
98. Goossens, E., Geens, M., De Block, G. & Tournaye, H. Spermatogonial survival in long-term human prepubertal xenografts. Fertil. Steril. 90, 2019-2022 (2008).
99. Nagano, M., Patrizio, P. & Brinster, R. L. Long-term survival of human spermatogonial stem cells in mouse testes. Fertil. Steril. 78, 1225-1233 (2002).
100. Kanatsu-Shinohara, M. et al. Long-term culture of male germline stem cells from hamster testes. Biol. Reprod. 78, 611-617 (2008).
101. Aponte, P. M. et al. Propagation of bovine spermatogonial stem cells in vitro. Reproduction 136, 543-557 (2008).
102. Cremades, N., Sousa, M., Bernabeu, R. & Barros, A. Developmental potential of elongating and elongated spermatids obtained after in-vitro maturation of isolated round spermatids. Hum. Reprod. 16, 1938-1944 (2001).
103. Sousa, M., Cremades, N., Alves, C., Silva, J. & Barros, A. Developmental potential of human spermatogenic cells co-cultured with Sertoli cells. Hum. Reprod. 17, 161-172 (2002).
104. Sa, R. et al. Cytological and expression studies and quantitative analysis of the temporal and stage-specific effects of follicle-stimulating hormone and testosterone during cocultures of the normal human seminiferous epithelium. Biol. Reprod. 79, 962-975 (2008).
105. Tesarik, J., Guido, M., Mendoza, C. & Greco, E. Human spermatogenesis in vitro: respective effects of follicle-stimulating hormone and testosterone on meiosis, spermiogenesis, and Sertoli cell apoptosis. J. Clin. Endocrinol. Metab. 83, 4467-4473 (1998).
106. Aslam, I. & Fishel, S. Short-term in-vitro culture and cryopreservation of spermatogenic cells used for human in-vitro conception. Hum. Reprod. 13, 634-638 (1998).
107. Sadri-Ardekani, H. et al. Propagation of human spermatogonial stem cells in vitro. JAMA 302, 2127-2134 (2009).
108. 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).
109. Zhu, Y. et al. Generation of male germ cells from induced pluripotent stem cells (iPS cells): an in vitro and in vivo study. Asian J. Androl. 14, 574-579 (2012).
110. Yang, S. et al. Derivation of male germ cells from induced pluripotent stem cells in vitro and in reconstituted seminiferous tubules. Cell Prolif. 45, 91-100 (2012).
111. Knoepfler, P. S. Deconstructing stem cell tumorigenicity: a roadmap to safe regenerative medicine. Stem Cells 27, 1050-1056 (2009).
112. Marion, R. M. et al. A p53-mediated DNA damage response limits reprogramming to ensure iPS cell genomic integrity. Nature 460, 1149-1153 (2009).
113. Okita, K., Ichisaka, T. & Yamanaka, S. Generation of germline-competent induced pluripotent stem cells. Nature 448, 313-317 (2007).
114. Zhou, H. et al. Generation of induced pluripotent stem cells using recombinant proteins. Cell Stem Cell 4, 381-384 (2009).
115. Shi, Y. et al. Induction of pluripotent stem cells from mouse embryonic fibroblasts by Oct4 and Klf4 with small-molecule compounds. Cell Stem Cell 3, 568-574 (2008).
116. Okita, K., Nakagawa, M., Hyenjong, H., Ichisaka, T. & Yamanaka, S. Generation of mouse induced pluripotent stem cells without viral vectors. Science 322, 949-953 (2008).
117. Patel, R. P. et al. Testicular microlithiasis and antisperm antibodies following testicular biopsy in boys with cryptorchidism. J. Urol. 174, 2008-2010 (2005).
118. Wyns, C. et al. Management of fertility preservation in prepubertal patients: 5 years' experience at the Catholic University of Louvain. Hum. Reprod. 26, 737-747 (2011).
119. Franck, P. et al. Testicular relapse after 13 years of complete remission of acute lymphoblastic leukemia. Urol. Int. 60, 239-241 (1998).
120. 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).
121. Fujita, K. et al. Isolation of germ cells from leukemia and lymphoma cells in a human in vitro model: potential clinical application for restoring human fertility after anticancer therapy. Cancer Res. 66, 11166-11171 (2006).
122. Geens, M. et al. The efficiency of magnetic-activated cell sorting and fluorescence-activated cell sorting in the decontamination of testicular cell suspensions in cancer patients. Hum. Reprod. 22, 733-742 (2007).
123. Hou, M. et al. Decontamination of leukemic cells and enrichment of germ cells from testicular samples from rats with Roser's T-cell leukemia by flow cytometric sorting. Reproduction 134, 767-779 (2007).
124. Sato, T. et al. In vitro production of fertile sperm from murine spermatogonial stem cell lines. Nat. Commun. 2, 472 (2011).
125. Boneva, R. S. & Folks, T. M. Xenotransplantation and risks of zoonotic infections. Ann. Med. 36, 504-517 (2004).
126. Fortunato, A. & Tosti, E. The impact of in vitro fertilization on health of the children: an update. Eur. J. Obstet. Gynecol. Reprod. Biol. 154, 125-129 (2011).
127. Goossens, E., Frederickx, V., de Block, G., van Steirteghem, A. & Tournaye, H. Evaluation of in vivo conception after testicular stem cell transplantation in a mouse model shows altered post-implantation development. Hum. Reprod. 21, 2057-2060 (2006).
128. Barton, S. E. et al. Population-based study of attitudes toward posthumous reproduction. Fertil. Steril. 98, 735.e5-740.e5 (2012).
129. Ethics Committee of the American Society for Reproductive Medicine. Fertility preservation and reproduction in cancer patients. Fertil. Steril. 83, 1622-1628 (2005).
130. Schover, L. R., Brey, K., Lichtin, A., Lipshultz, L. I. & Jeha, S. Oncologists' attitudes and practices regarding banking sperm before cancer treatment. J. Clin. Oncol. 20, 1890-1897 (2002).
131. Schaefer, F., Marr, J., Seidel, C., Tilgen, W. & Scharer, K. Assessment of gonadal maturation by evaluation of spermaturia. Arch. Dis. Child. 65, 1205-1207 (1990).
132. Rutter, M. Normal psychosexual development. J. Child. Psychol. Psychiatry 11, 259-283 (1971).
133. Kinsey, A. C., Pomeroy, W. R. & Martin, C. E. Sexual behavior in the human male. 1948. Am. J. Public Health. 93, 894-898 (2003).
134. 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).
135. Bahadur, G. et al. Semen quality and cryopreservation in adolescent cancer patients. Hum. Reprod. 17, 3157-3161 (2002).
136. Kreuser, E. D., Hetzel, W. D., Hautmann, R. & Pfeiffer, E. F. Reproductive toxicity with and without LHRHA administration during adjuvant chemotherapy in patients with germ cell tumors. Horm. Metab. Res. 22, 494-498 (1990).