Kemoterapötiklerin erkek üreme sistemi üzerindeki yan etkileri ve koruyucu stratejiler

Year 2013, Volume: 17 Issue: 2, 73 - 92, 24.10.2014

Gaffari Türk

Abstract

Sitotoksik kemoterapi pek çok kanser türünün tedavisinde etkili bir yöntem olmasına
rağmen organizmada sayısız yan etkilere neden olmaktadır. İnfertilite de kemoterapötik ilaçların
hem erkek hem de dişilerde meydana getirdiği en önemli yan etkilerden biridir. Cinsel
isteksizlik, oligo-, azoo-, astenozoo- ve teratozoo-spermi, testiküler yapı, spermatogenesis
ve steroidogenesisteki bozukluklar, gonadotropin düzeylerindeki değişiklikler, sperm DNA
ve kromozomlarındaki hasarlar ve hatta tam sterilite hem kanserli erkekler hem de sağlıklı
deney hayvanlarında bildirilen kemoterapi kaynaklı yan etkilerdir. Kemoterapötiklerin erkeklerdeki
gonadotoksik etkilerinin önlenmesine yönelik hormon ve antioksidan uygulamalar ile
sperma ve germ hücrelerinin dondurularak saklanması gibi birtakım yöntemler kullanılmaktadır.
Bu derlemede kanser tedavisinde yaygın olarak kullanılan kemoterapötiklerin kanserli
ve sağlıklı erkeklerin üreme organ, doku ve hücrelerinde meydana getirdiği yan etkiler ve bu
etkilerin azaltılması veya önlenmesine yönelik koruyucu stratejiler ile ilgili literatür bilgiler
sunulmaktadır.

Keywords

Antioksidan; kemoterapötik; kriyoprezervasyon; oksidatif stres; sperm; testis

References

• Wright NA. Cell proliferation in carcinogenesis. In: The Cancer Handbook. Editor: MR Alison, Nature Publishing Group, London. 2002, pp. 114-25.
• Boerner JL, Biscardi JS, Parsons SJ. Overview of oncogenesis. The Cancer Handbook. Editor: MR Alison, Nature Publishing Group, London. 2002, pp. 25-34.
• Pizzo PA, Poplack DG. Principles and Practice of Pediatric Oncology. Lippincott: Williams & Wilkins, Philadelphia. 2001.
• Page R, Takimoto C. Principles of chemotherapy. In: Cancer Management: A Multidisciplinary Approach Medical, Surgical & Radiation Oncology. Editors: R Pazdur, LR Coia, WJ Hoskins, LD Wagman. PRR, New York. 200 pp. 21-38. Sabanegh ES, Ragheb AM. Male fertility after cancer. Urology 2009;73:225-31.
• Demirci U, Benekli M, Büyükberber S, Coşkun U. Late side effects of cancer therapy. Int J Hematol Oncol 2010;4:250-61.
• Ragheb AM, Sabanegh ES. Male fertility-implications of anticancer treatment and strategies to mitigate gonadotoxicity. Anticancer Agents Med Chem 2010;10:92-102.
• Sharlip ID, Jarow JP, Belker AM, Lipshultz LI, Sigman M, Thomas AJ, Schlegel PN, Howards SS, Nehra A, Damewood MD, Overstreet JW, Sadovsky R. Best practice policies for male infertility. Fertil Steril 2002;77:873-82.
• World Health Organization. WHO laboratory manual for the examination of human semen and semen-cervical mucus interaction. Cambridge University Press, Cambridge. 1999, pp. 1-86.
• Bokemeyer C, Schmoll HJ, van Rhee J, Kuczyk M, Schuppert F, Poliwoda H. Long-term gonadal toxicity after therapy for hodgkin’s and non-hodgkin’s lymphoma. Ann Hematol 1994;68:105-10.
• Petersen PM, Giwercman A, Skakkebaek NE, Rorth M. Gonadal function in men with testicular cancer. Semin Oncol 1998;25:224-33.
• Schrader M, Müller M, Straub B, Miller K. The impact of chemotherapy on male fertility: a survey of the biologic, basis and clinical aspects. Reprod Toxicol 2001;15:611-7.
• Averette HE, Boike GM, Jarrell MA. Effects of cancer chemotherapy on gonadal function and reproductive capacity. CA Cancer J Clin 1990;4:199-209.
• Meistrich ML. Restoration of spermatogenesis by hormone treatment after cytotoxic therapy. Acta Paediatr Suppl 1999;88:19-22.
• Oktay K, Meirow D. Planning for fertility preservation before cancer treatment. Sex Reprod Menop 2007;5:17-22.
• Meistrich ML. Male gonadal toxicity. Pediatr Blood Cancer 2009;53:261-6.
• Delbes G, Hales BF, Robaire B. Toxicants and human sperm chromatin integrity. Mol Hum Reprod 2010;16:14-22.
• Colpi GM, Contalbi GF, Nerva F, Sagone P, Piediferro G. Testicular function following chemo-radiotherapy. Eur J Obstet Gynecol Reprod Biol 2004;113(Suppl 1):S2-6.
• Tempest HG, Ko E, Chan P, Robaire B, Rademaker A, Martin RH. Sperm aneuploidy frequencies analysed before and after chemotherapy in testicular cancer and Hodgkin’s lymphoma patients. Hum Reprod 2008;23:251-8.
• Agarwal A, Sekhon LH. The role of antioxidant therapy in the treatment of male infertility. Hum Fertil 2010;13:217-25.
• Ateşşahin A, Karahan İ, Türk G, Gür S, Yılmaz S, Çeribaşı AO. Protective role of lycopene on cisplatin-induced changes in sperm characteristics, testicular damage and oxidative stress in rats. Reprod Toxicol 2006;21:42-7.
• Ateşşahin A, Şahna E, Türk G, Çeribaşı AO, Yılmaz S, Yüce A, Bulmuş Ö. Chemoprotective effect of melatonin against cisplatin-induced testicular toxicity in rats. J Pineal Res 2006;41:21-7.
• Ateşşahin A, Türk G, Karahan İ, Yılmaz S, Çeribaşı AO, Bulmuş Ö. Lycopene prevents adriamycin-induced testicular toxicity in rats. Fertil Steril 2006;85(Suppl 1):1216-22.
• Muslimovic A, Nyström S, Gao Y, Hammarsten O. Numerical Analysis of Etoposide Induced DNA Breaks. PLoS One 2009;4:e5859.
• Padmanabhan S, Tripathi DN, Vikram A, Ramarao P, Jena GB. Methotrexate-induced cytotoxicity and genotoxicity in germ cells of mice: intervention of folic and folinic acid. Mutat Res 2009;673:43-52.
• Türk G, Çeribaşı AO, Sakin F, Sönmez M, Ateşşahin A. Antiperoxidative and anti-apoptotic effects of lycopene and ellagic acid on cyclophosphamide induced testicular lipid peroxidation and apoptosis. Reprod Fertil Dev 2010;22:587-96.
• Türk G, Çeribaşı AO, Şahna E, Ateşşahin A. Lycopene and ellagic acid prevent testicular apoptosis induced by cisplatin. Phytomedicine 2011;18:356-61.
• Aitken RJ, Roman SD. Antioxidant systems and oxidative stress in the testes. Oxid Med Cell Longev 2008;1:15-24.
• Hess RA, de Franca LR. Spermatogenesis and cycle of the seminiferous epithelium. In: Molecular Mechanisms in Spermatogenesis. Editor: CY Cheng. Adv Exp Med Biol (Book Series) 2008;636:1-15.
• Codrington AM, Hales BF, Robaire B. Exposure of male rats to cyclophosphamide alters the chromatin structure and basic proteome in spermatozoa. Hum Reprod 2007;22:1431-42.
• Codrington AM, Hales BF, Robaire B. Chronic cyclophosphamide exposure alters the profile of rat sperm nuclear matrix proteins. Biol Reprod 2007;77:303-11.
• Türk G, Aksu EH, Bozkurt T. Spermatozoon DNA’sı hasarı. FÜ Sağlık Bil Vet Derg 2006;20:85-95.
• Tremellen K. Oxidative stress and male infertility-a clinical perspective. Hum Reprod Update 2008;14:243-58.
• Johnson GD, Lalancette C, Linnemann AK, Leduc F, Boissonneault G, Krawetz SA. The sperm nucleus: chromatin, RNA, and the nuclear matrix. Reproduction 2011;141:21-36.
• O’Flaherty C, Hales BF, Chan P, Robaire B. Impact of chemotherapeutics and advanced testicular cancer or hodgkin lymphoma on sperm deoxyribonucleic acid integrity. Fertil Steril 2010;94:1374-9.
• Grenier L, Robaire B, Hales BF. Paternal exposure to cyclophosphamide affects the progression of sperm chromatin decondensation and activates a DNA damage response in the prepronuclear rat zygote. Biol Reprod 2010;83:195-204.
• Agarwal A, Cocuzza M, Abdelrazik H, Sharma RK. Oxidative stress measurement in patients with male or female factor infertility. In: Handbook of Chemiluminescent Methods in Oxidative Stress Assessment. Editors: I Popov, G Lewin. Transworld Research Network, KeralaIndia. 2008. pp. 195-218.
• Ford WCL. Regulation of sperm function by reactive oxygen species. Hum Reprod Update 2004;10:387-99.
• Sanocka D, Kurpisz M. Reactive oxygen species and sperm cells. Reprod Biol Endocrinol 2004;2:12, (1-7).
• Kothari S, Thompson A, Agarwal A, du Plessis SS. Free radicals: their beneficial and detrimental effects on sperm function. Indian J Exp Biol 2010;48:425-35.
• Donya SM, Aly FA, Abo-Zeid MAM. Antigenotoxic efficacy of some vitamins against the mutagenicity induced by ifosfamide in mice. Nature Sci 2010;8:55-66.
• Ghasemi FM, Faghani M, Khajehjahromi S, Bahadori M, Nasiri EE, Hemadi M. Effect of melatonin on proliferative activity and apoptosis in spermatogenic cells in mouse under chemotherapy. J Reprod Contracept 2010;21:79-94.
• Alam SS, Hafiz NA, El-Rahim AHA. Protective role of taurine against genotoxic damage in mice treated with methotrexate and tamoxfine. Environ Toxicol Pharmacol 2011;31:143-52.
• Dejaco C, Mittermaier C, Reinisch W, Gasche C, Waldhoer T, Strohmer H, Moser G. Azathioprine treatment and male fertility in inflammatory bowel disease. Gastroenterology 2001;121:1048-53.
• Damani MN, Masters V, Meng MV, Burgess C, Turek P, Oates RD. Postchemotherapy ejaculatory azoospermia: fatherhood with sperm from testis tissue with intracytoplasmic sperm injection. J Clin Oncol 2002;20:930-6.
• Sakamoto H, Oohta M, Inoue K, Fuji K, Fukagai T, Yoshida H. Testicular sperm extraction in patients with persistent azoospermia after chemotherapy for testicular germ cell tumor. Int J Urol 2007;14:167-70.
• Fossa SD, Magelssen H. Fertility and reproduction after chemotherapy of adult cancer patients: malignant lymphoma and testicular cancer. Ann Oncol 2004;15(Suppl 4): iv259-65.
• Chatterjee R, Haines GA, Perera DM, Goldstone A, Morris ID. Testicular and sperm DNA damage after treatment with fludarabine for chronic lymphocytic leukaemia. Hum Reprod 2000;15:762-6.
• Chatzidarellis E, Makrilia N, Giza L, Georgiadis E, Alamara C, Syrigos KN. Effects of taxane-based chemotherapy on inhibin B and gonadotropins as biomarkers of spermatogenesis. Fertil Steril 2010;94:558-63.
• Norgard B, Pedersen L, Jacobsen J, Rasmussen SN, Sorensen HT. The risk of congenital abnormalities in children fathered by men treated with azathioprine or mercaptopurine before conception. Aliment Pharmacol Ther 2004;19:679-85.
• Shamberger RC, Rosenberg SA, Seipp CA, Sherins RJ. Effects of high-dose methotrexate and vincristine on ovarian and testicular functions in patients undergoing postoperative adjuvant treatment of osteosarcoma. Cancer Treat Rep 1981;65:739-46.
• Grunnet E, Nyfors A, Hansen KB. Studies on human semen in topical corticosteroid-treated and in methotrexate-treated psoriatics. Dermatologica 1977;154:78-84.
• French AE, Koren G, Team M. Effect of methotrexate on male fertility. Can Fam Physician 2003;49:577-8.
• Meistrich ML, Chawla SP, da Cunha MF, Johnson SL, Plager C, Papadopoulos NE, Lipshultz LI, Benjamin RS. Recovery of sperm production after chemotherapy for osteosarcoma. Cancer 1989;63:2115-23.
• Thomson AB, Campbell AJ, Irvine DC, Anderson RA, Kelnar CJ, Wallace WH. Semen quality and spermatozoal DNA integrity in survivors of childhood cancer: a case-control study. Lancet 2002;360:361-7.
• Doerksen T, Trasler JM. Developmental exposure of male germ cells to 5-azacytidine results in abnormal preimplantation development in rats. Biol Reprod 1996;55:1155-62.
• Karawya FS, El-Nahas AF. The protective effect of vitamin C on azathioprine induced seminiferous tubular structural changes and cytogenetic toxicity in albino rats. Cancer Ther 2006;4:125-34.
• Elelaimy IA, Elfiky SA, Hassan AM, Ibrahim HM, Elsayad RI. Genotoxicity of anticancer drug azathioprine (Imuran): role of omega-3 (ω-3) oil as protective agent. J Appl Pharmaceut Sci 2012;2:14-23.
• D’Souza Urban JA, Narayana K. Induction of seminiferous tubular atrophy by single dose of 5- fluorouracil (5-FU) in wistar rats. Indian J Physiol Pharmacol 2001;45:87-94.
• D’Souza Urban JA. Toxic effects of 5-fluorouracil on sperm count in wistar rats. Malaysian J Med Sci 2003;10:43-45.
• Takizawa S, Horii I. Endocrinological assessment of toxic effects on the male reproductive system in rats treated with 5-fluorouracil for 2 or 4 weeks. J Toxicol Sci 2002;27: 49Mohammed BMA, Kheravii SKQ. Evaluation of genotoxic potential of Hypericum triquetrifolium extract in somatic and germ cells of male albino mice. Res Opin Anim Vet Sci 2011;1:231-9.
• Generoso WM, Preston RJ, Brewen JG. 6-Mercaptopurine, an inducer of cytogenetic and dominant-lethal effects in premeiotic and early meiotic germ cells of male mice. Mutat Res 1975;28:437-47.
• Russell LB, Hunsicker PR. Study of the base analog 6-mercaptopurine in the mouse specific-locus test. Mutat Res 1987;176:47-52.
• Karl PI, Katz R, Daum F, Fisher SE. 6-mercaptopurine and spermatogenesis in the young rat. Dig Dis Sci 1991;36:1569-73.
• Ligumsky M, Badaan S, Lewis H, Meirow D. Effects of 6-mercaptopurine treatment on sperm production and reproductive performance: a study in male mice. Scand J Gastroenterol 2005;40:444-9.
• Meistrich ML, Finch M, da Cunha MF, Hacker U, Au WW. Damaging effects of fourteen chemotherapeutic drugs on mouse testis cells. Cancer Res 1982;42:122-31.
• Johnson FE, Farr SA, Mawad M, Woo YCS. Testicular cytotoxicity of intravenous methotrexate in rats. J Surg Oncol 1994;55:175-8.
• Serati Nouri H, Azarmi YA, Movahedin M. Effect of growth hormone on testicular dysfunction induced by methotrexate in rats. Andrologia 2009;41:105-10.
• Vardı N, Parlakpınar H, Ateş B, Otlu A. Metotreksatın neden olduğu testiküler hasara karşı klorogenik asidin koruyucu etkileri. Türkiye Klinikleri J Med Sci Işık A, Işılay L, Erdemli EA, Akbay C, Anafarta K. Sıçan testisinde metotreksat’ın ışık ve elektron mikroskop düzeyinde etkileri. Ank Ünv Tıp Fak Mec 1997;50:125-9.
• Saxena AK, Dhungel S, Bhattacharya S, Jha CB, Srivastava AK. Effect of chronic low dose of methotrexate on cellular proliferation during spermatogenesis in rats. Arch Androl 2004;50:33-5.
• Palo AK, Choudhury RC. Modulation of methotrexateinduced cytogenotoxicity in mouse spermatogonia and its transmission in the male germline by caffeine. Environ Toxicol Pharmacol 2006;21:254-9.
• Padmanabhan S, Tripathi DN, Vikram A, Ramarao P, Jena GB. Cytotoxic and genotoxic effects of methotrexate in germ cells of male swiss mice. Mutat Res 2008;655:59-67.
• Sparreboom A, Nooter K, Verweij J. Mechanisms of action of cancer chemotherapeutic agents: antitumour antibiotics. In: The Cancer Handbook. Editor: MR Alison. Nature Publishing Group, London. 2002. pp. 1333-46.
• Lemez P. Cryopreservation of sperm from patients with leukemia. Cancer 1999;86:2184-5.
• Spermon JR, Ramos L, Wetzels AM, Sweep CG, Braat DD, Kiemeney LA, Witjes JA. Sperm integrity pre- and post-chemotherapy in men with testicular germ cell cancer. Hum Reprod 2006;21:1781-6.
• Martin RH, Ernst S, Rademaker A, Barclay L, Ko E, Summers N. Analysis of sperm chromosome complements before, during, and after chemotherapy. Cancer Genet Cytogenet 1999;108:133-6.
• Aly FA, Donya SM, Abo-Zeid MAM. The protective role of folic acid, vitamin B12 and vitamin C on the mutagenicity of the anticancer drug daunorubicin. Researcher 2009;1:16-26.
• Saalu LC, Enye LA, Osinubi AA. An assessment of the histomorphometric evidences of doxorubicin-induced testicular cytotoxicity in wistar rats. Int J Med Medic Sci 2009;1:370-4.
• Xin Y-F, You Z-Q, Gao H-Y, Zhou G-L, Chen Y-X, Yu J, Xuan YX. Protective effect of Lycium barbarum polysaccharides against doxorubicin-induced testicular toxicity in rats. Phytother Res 2012;26:716-21.
• Trivedi PP, Kushwaha S, Tripathi DN, Jena GB. Evaluation of male germ cell toxicity in rats: correlation between sperm head morphology and sperm comet assay. Mutat Res 2010;703:115-21.
• Yeh Y-C, Liu T-J, Wang L-C, Lee H-W, Ting C-T, Lee W-L, Hung CJ, Wang KY, Lai HC, Lai HC. A standardized sxtract of Ginkgo biloba suppresses doxorubicin-induced oxidative stress and p53-mediated mitochondrial apoptosis in rat testes. Br J Pharmacol 2009;156:48-61.
• Das J, Ghosh J, Manna P, Sil PS. Taurine protects rat testes against doxorubicin-induced oxidative stress ss well ss p53, Fas and caspase 12-mediated apoptosis. Amino Acids 2012;42:1839-55.
• Çeribaşı AO, Sakin F, Türk G, Sönmez M, Ateşşahin A. Impact of ellagic acid on adriamycin-induced testicular histopathological lesions, apoptosis, lipid peroxidation and sperm damages. Exp Toxicol Pathol 2012;64:717-24.
• Zanetti RS, Maldonado EN, Aveldano MI. Doxorubicin affects testicular lipids with long-chain (C18-C22) and very long-chain (C24-C32) polyunsaturated fatty acids. Cancer Res 2007;67:6973-80.
• Takahashi H, Tainaka H, Umezawa M, Tkeda K, Tanaka H, Nishimune Y, Oshio S. Evaluation of testicular toxicology doxorubicin based on microarray analysis of testicular specific gene expression. J Toxicol Sci 2011;36:559-67.
• Sato K, Sueoka K, Tanigaki R, Tajima H, Nakabayashi A, Yoshimura Y, Hosoi Y. Green tea extracts attenuate doxorubicin-induced spermatogenic disorders in conjunction with higher telomerase activity in mice. J Assist Reprod Genet 2010;27:501-8.
• Caneguim BH, Serpeloni JM, Maciel MAM, de Syllos Colus IM, de Fatima Paccola Mesquita S. Reduction of DNA-damage by croton cajucara methanolic extract but not the testicular alterations induced by doxorubicin. J Med Plants Res 2011;5:3277-85.
• Tohamy AA, El-Ghor AA, El-Nahas SM, Noshy MM. β-glucan inhibits the genotoxicity of cyclophosphamide, adriamycin and cisplatin. Mutat Res 2003;541:45-53.
• Yeh Y-C, Lai H-C, Ting C-T, Lee W-L, Wang L-C, Wang K-Y, Lai H-C, Liu T-J. Protection by doxycycline against doxorubicin-induced oxidative stress and apoptosis in mouse testes. Biochem Pharmacol 2007;74:969-80.
• Geng J, Fan J, Jiang H-W, Fang Z-J, Wang X, Sun J-L, Ding Q, Chen G. Elevated serum soluble Fas ligand is a promising marker of testicular toxicity induced by epirubicin in rats. Toxicol Lett 2009;186:96-103.
• Arrebola DFA, Novoa AV, Fernandez LAR, Roche LD. Comparison of the sprague dawley rats response against cyclophosphamide and bleomycin in the head sperm morphology assay. Ars Pharmaceut 2010;51:155-62.
• Hansen PV, Sorensen D. Effect of vincristine or bleomycin on radiation-induced cell killing of mice spermatogonial stem cells: the importance of sequence and time interval. Int J Radiat Oncol Biol Phys 1991;20:339-41.
• Yongguang G, Xuliang L, Guanghui W, et al. Influence of vincristine and dactinomycin on spermatogenetic cells of testes in juvenile rats. Chinese J Pediatr Surg 2002;23:454-7.
• Siddik ZH. Mechanisms of cancer chemotherapeutic agents: DNA-interactive alkylating agents and antitumour platinum-based drugs. In: The Cancer Handbook. Editor: MR Alison. Nature Publishing Group, London. 200 pp. 1295-313.
• Marmor D, Grob-Menendez F, Duyck F, Delafontaine D. Very late return of spermatogenesis after chlorambucil therapy: case reports. Fertil Steril 1992;58:845-6.
• Guesry MDP, Lenoir MDG, Broyer MDM. Gonadal effects of chlorambucil given to prepubertal and pubertal boys for nephrotic syndrome. J Pediatr 1978;92:29930
• Callis MDL, Nieto J, Vila A, Rende J. Chlorambucil treatment in minimal lesion nephrotic syndrome: A reappraisal of its gonadal toxicity. J Pediatr 1980;97:653-6.
• Williams D, Crofton PM, Levitt G. Does ifosfamide affect gonadal function? Pediatr Blood Cancer 2008;50:347-51. van der Kaaij MAE, van Echten-Arends J, Simons AHM, Kluin-Nelemans HC. Fertility preservation after chemotherapy for Hodgkin lymphoma. Hematol Oncol
• Levy MJ, Stillman RJ. Reproductive potential in survivors of childhood malignancy. Pediatrician 1991;18:61-70.
• Aslam I, Fishel S, Moore H, Dowell K, Thornton S. Fertility preservation of boys undergoing anti-cancer therapy: a review of the existing situation and prospects for the future. Hum Reprod 2000;15:2154-9.
• Kenney LB, Laufer MR, Grant FD, Grier H, Diller L. High risk of infertility and long term gonadal damage in males treated with high dose cyclophosphamide for sarcoma during childhood. Cancer 2001;91:613-21.
• Meistrich ML, Wilson G, Brown BW, da Cunha MF, Lipshultz LI. Impact of cyclophosphamide on long-term reduction in sperm count in men treated with combination chemotherapy for Ewing and soft tissue sarcomas. Cancer 1992;70:2703-12.
• Socie G, Salooja N, Cohen A, Rovelli A, Carreras E, Locasciulli A, Korthof E, Weis J, Levy V, Tichelli A; Late Effects Working Party of the European Study Group for Blood and Marrow Transplantation. Nonmalignant late effects after allogeneic stem cell transplantation. Blood 2003;101:3373-85.
• Ahmed SR, Shalet SM, Campbell RHA, Deakin DP. Primary gonadal damage following treatment of brain tumors in childhood. J Pediatr 1983;103:562-65.
• Reiter WJ, Kratzik C, Brodowicz T, Haitel A, Pokorny A, Zielinski CC, Marberger M. Sperm analysis and serum follicle-stimulating hormone levels before and after adjuvant single-agent carboplatin therapy for clinical stage I seminoma. Urology 1998;52:117-9.
• Ishikawa T, Kamidono S, Fujisawa M. Fertility after high-dose chemotherapy for testicular cancer. Urology 2004;63:137-40.
• De Mas P, Daudin M, Vincent MC, Bourrouillou G, Calvas P, Mieusset R, Bujan L. Increased aneuploidy in spermatozoa from testicular tumour patients after chemotherapy with cisplatin, etoposide and bleomycin. Hum Reprod 2001;16:1204-8.
• Martin RH, Ernst S, Rademaker A, Barclay L, Ko E, Summers N. Analysis of human sperm karyotypes in testicular cancer patients before and after chemotherapy. Cytogenet Cell Genet 1997;78:120-3.
• Gerl A, Mühlbayer D, Hansmann G, Mraz W, Hiddemann W. The impact of chemotherapy on Leydig cell function in long term survivors of germ cell tumors. Cancer 2001;91:1297-303.
• Sanders JE, Hawley J, Levy W, Gooley T, Buckner CD, Deeg HJ, Doney K, Storb R, Sullivan K, Witherspoon R, Appelbaum FR. Pregnancies following high-dose cyclophosphamide with or without high-dose busulfan or total-body irradiation and bone marrow transplantation. Blood 1996;87:3045-52.
• Generoso WM, Witt KL, Cain KT, Hughes L, Cacheiro NLA, Lockhart AMC, Shelby MD. Dominant lethal and heritable translocation tests with chlorambucil and melphalan in male mice. Mutat Res 1995;345:167-80.
• Barnett LB, Lewis SE. Chlornaphazine and chlorambucil induce dominant lethal mutations in male mice. Mutat Res 2003;543:145-54.
• Ypsilantis P, Papaioannou N, Psalla D, Politou M, Simopoulos C. Effects of single dose administration of ifosfamide on testes and semen characteristics in the rabbit. Reprod Toxicol 2003;17:237-45.
• Donya SM, Aly FA, Abo-Zeid MAM. The protective role of folic acid, vitamin B12 and vitamin C on the mutagenicity of the anticancer drug ifosfamide. J Genet Engineer Biotechnol 2009;7:41-50.
• Russell LB, Hunsicker PR, Cacheiro NL, Rinchik EM. Genetic, cytogenetic, and molecular analyses of mutations induced by melphalan demonstrate high frequencies of heritable deletions and other rearrangements from exposure of postspermatogonial stages of the mouse. Proc Natl Acad Sci USA 1992;89:6182-6.
• Cordelli E, Fresegna AM, D’Alessio A, Eleuteri P, Spano M, Pacchierotti F, Villani P. ReProComet: a new in vitro method to assess DNA damage in mammalian sperm. Toxicol Sci 2007;99:545-52.
• Goldstein LS. Dominant lethal mutations induced in mouse spermatogonia by mechlorethamine, procarbazine and vincristine administered in 2-drug and 3-drug combinations. Mutat Res 1987;191:171-6. 1 İlbey YÖ, Özbek E, Şimşek A, Ötünçtemur A, Çekmen M, Somay A. Potential chemoprotective effect of melatonin in cyclophosphamide- and cisplatin-induced testicular damage in rats. Fertil Steril 2009;92:1124-32. 1 Çeribaşı AO, Türk G, Sönmez M, Sakin F, Ateşşahin A. Toxic effect of cyclophosphamide on sperm morphology, testicular histology and blood oxidant-antioxidant balance, and protective roles of lycopene and ellagic acid. Basic Clin Pharmacol Toxicol 2010;107:730-6. 1 Ghosh D, Das UB, Misro M. Protective role of α-tocopherol-succinate (provitamin-E) in cyclophosphamide induced testicular gametogenic and steroidogenic disorders: a correlative approach to oxidative stress. Free Radic Res 2002;36:1209-18. 1 Codrington AM, Hales BF, Robaire B. Spermiogenic germ cell phase-specific DNA damage following cyclophosphamide exposure. J Androl 2004;25:354-62. 1 Aguilar-Mahecha A, Hales BF, Robaire B. Effects of acute and chronic cyclophosphamide treatment on meiotic progression and the induction of DNA double-strand breaks in rat spermatocytes. Biol Reprod 2005;72:1297-304. 1 Elangovan N, Chiou T-J, Tzeng W-F, Chu S-T. Cyclophosphamide treatment causes impairment of sperm and its fertilizing ability in mice. Toxicology 2006;222:60-70. 1 Tripathi DN, Jena GB. Astaxanthin inhibits cytotoxic and genotoxic effects of cyclophosphamide in mice germ cells. Toxicology 2008;248:96-103. 1 Sakr SA, Mahram HA, El-Yazid SMA. Effect of fenugreek seeds extracton cyclophosphamide-induced histomorphometrical, ultrastructural and biochemical changes in testes of albino mice. Toxicol Indust Health 2012;28:276 1 Ehling UH, Adler ID, Favor J, Neuhauser-Klaus A. Induction of specific-locus and dominant lethal mutations in male mice by 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU). Mutat Res 1997;379:219-31. 1 Reddy YVK, Reddy PS, Shivalingam MR, Devi BS, Pravallika CNNS, Anusha DN. Carboplatin-mediated changes in the activity levels of steroidogenic marker enzymes, serum hormones and testicular architecture in male rats. Drug Invent Today 2010;2:42-8. 1 Reddy YVK, Reddy PS, Shivalingam MR. Testosterone mediated partial recovery of carboplatin induced reproductive toxicity in male wistar rats. J Biomed Sci Res 2010;2:46-53. 1 Türk G, Ateşşahin A, Sönmez M, Çeribaşı AO, Yüce A. Improvement of cisplatin-induced injuries to sperm quality, the oxidant-antioxidant system, and the histologic structure of the rat testis by ellagic acid. Fertil Steril 2008;89(5 Suppl):1474-81. 1 Silici S, Ekmekcioglu O, Eraslan G, Demirtaş A. Antioxidative effect of royal jelly in cisplatin-induced testes damage. Urology 2009;74:545-51. 1 Azu OO, Duru FIO, Osinubi AA, Oremosu AA, Noronha CC, Elesha SO, Okanlawon AO. Histomorphometric effects of kigelia africana (bignoniaceae) fruit extract on the testis following short-term treatment with cisplatin in male sprague–dawley rats. Mid East Fertil Soc J 2010;15:200-8. 1 Çiftçi O, Beytur A, Çakır O, Gürbüz N, Vardı N. Comparison of reproductive toxicity caused by cisplatin and novel platinum-n-heterocyclic carbene complex in male rats. Basic Clin Pharmacol Toxicol 2011;109:328-33. 1 Beytur A, Ciftci O, Oguz F, Oguzturk H, Yılmaz F. Montelukast attenuates side effects of cisplatin including testicular, spermatological, and hormonal damage in male rats. Cancer Chemother Pharmacol 2012;69:207-13. 1 Amin A, Hamza AA, Kambal A, Daoud S. Herbal extracts counteract cisplatin-mediated cell death in rat testis. Asian J Androl 2008;10:291-7. 1 Azu OO, Duru FIO, Osinubi AA, Oremosu AA, Norohna CC, Okanlawon AO, Elesha SO. Long-term treatment with kigelia africana fruit extract ameliorates the testicular toxicity following cisplatin administration in male sprague-dawley rats. J Med Plants Res 2011;5:388-97. 1 Ahmed EA, Omar HM, El-Ghaffar SKhA, Ragb SMM, Nasser AY. The antioxidant activity of vitamin C, DPPD and L-cysteine against cisplatin-induced testicular oxidative damage in rats. Food Chem Toxicol 2011;49:1115-21. 1 İlbey YÖ, Özbek E, Çekmen M, Şimşek A, Ötünçtemur A, Somay A. Protective effect of curcumin in cisplatininduced oxidative injury in rat testis: mitogen-activated protein kinase and nuclear factor-kappa B signaling pathways. Hum Reprod 2009;24:1717-25. 1 İlbey YÖ, Özbek E, Şimşek A, Çekmen M, Ötünçtemur A, Somay A. Chemoprotective effect of a nuclear factor-kB inhibitor, pyrrolidine dithiocarbamate, against cisplatininduced testicular damage in rats. J Androl 2009;30:505-14. 1 Favareto APA, Fernandez CDB, da Silva DAF, AnselmoFranci JA, Kempinas WDG. Persistent impairment of testicular histology and sperm motility in adult rats treated with cisplatin at peri-puberty. Basic Clin Pharmacol Toxicol 2011;109:85-96. 1 Narayana K, Verghese S, Jacob SS. L-ascorbic acid partially protects two cycles of cisplatin chemotherapy-induced testis damage and oligo-astheno-teratospermia in a mouse model. Exp Toxicol Pathol 2009;61:553-63. 1 Narayana K. Cisplatin induces duplex 3′ overhangs and 5′ blunt ends in epididymal epithelium in a Bax-dependent manner without any protection from L-ascorbic acid. Eur J Pharmacol 2010;641:238-45. 1 Anjamrooz SH, Movahedin M, Mowla SJ, Bairanvand SP. Assessment of morphological and functional changes in the mouse testis and epididymal sperms following busulfan treatment. Iranian Biomed J 2007;11:15-22. 1 Ji M, Minami N, Yamada M, Imai H. Effect of protopanaxatriol saponin on spermatogenic stem cell survival in busulfan-treated male mice. Reprod Med Biol 2007;6:99-108. 1 Perez-Crespo M, Pericuesta E, Perez-Cerezales S, Arenas MI, Lobo MVT, Diaz-Gil JJ, Guiterrez-Adan A. Effect of liver growth factor on both testicular regeneration and recovery of spermatogenesis in busulfan-treated mice. Reprod Biol Endocrinol 2011;9:21. 1 Ghasemi FM, Faghani M, Karkan FM. The protective effect of melatonin on sperm parameters, epididymis and seminal vesicle morphology in adult mouse treated with busulfan. J Iranian Anat Sci 2010;8:25-36. 1 Bucci LR, Meistrich ML. Effects of busulfan on murine spermatogenesis: cytotoxicity, sterility, sperm abnormalities, and dominant lethal mutations. Mutat Res 1987;176:259-68. 1 Kumar SG, Narayana K, Bairy KL, D’Souza UJ, Samuel VP, Gopalakrishna K. Dacarbazine induces genotoxic and cytotoxic germ cell damage with concomitant decrease in testosterone and increase in lactate dehydrogenase concentration in the testis. Mutat Res 2006;607:240-52. 1 Parchuri N, Wilson G, Meistrich ML. Protection by gonadal steroid hormones against procarbazine-induced damage to spermatogenic function in LBNF1 hybrid rats. J Androl 1993;14:257-66. 1 Johnson FE, Doubek WG, Tolman KC, Janney CG. Testicular cytotoxicity of intravenous procarbazine in rats. Surg Oncol 1993;2:77-81. 1 Delic JI, Bush C, Peckham MJ. Protection from procarbazine-induced damage of spermatogenesis in the rat by androgen. Cancer Res 1986;46:1909-14. 1 Velez de la Calle JF, Soufirt JCI, Chodorget F, Boisseau CI, Kercret H, Jegou B. Reproductive effects of the anticancer drug procarbazine in male rats at different ages. J Reprod Fertil 1988;84:51-61. 1 Ward JA, Robinson J, Furr BJA, Shalet SM, Morris ID. Protection of spermatogenesis in rats from the cytotoxic procarbazine by the depot formulation of zoladex, a gonadotropin-releasing hormone agonist. Cancer Res 1990;50:568-74. 1 Horstman MG, Meadows GG, Yost GS. Separate mechanisms for procarbazine spermatotoxicity and anticancer activity. Cancer Res 1987;47:1547-50. 1 Singh H, Kozel T, Jackson S. Effect of procarbazine on sperm morphology in syrian hamsters. J Toxicol Environ Health 1989;27:107-21. 1 Dancey J, Arbuck S. Cancer drugs and cancer drug development for the new millennium. In: Progress in Anti-cancer Chemotherapy. Editors: D Khayat, GN Hortobagyi. Springer, France, Berlin, Heidelberg. 2000. pp. 911 Gobello C, Corrada Y. Effects of vincristine treatment on semen quality in a dog with a transmissible venereal tumour. J Small Anim Pract 2002;43:416-7. 1 Saratsis PH, Ypsilantis P, Tselkas K. Semen quality during vincristine treatment in dogs with transmissible venereal tumor. Theriogenology 2000;53:1185-92. 1 Palo AK, Pandit RS, Choudhury RC. Vinblastine-induced cytogenotoxicity in spermatogonia and its transmission in the germline cells of swiss mice. J Environ Pathol Toxicol Oncol 2011;30:113-21. 1 Dobrzynska MM, Czajka U, Slowikowska MG. Reproductive effects after exposure of male mice to vincristine and to a combination of X-rays and vincristine. Reprod Fertil Dev 2005;17:759-67. 1 Sonawane T, Chaudhari N, Udani J, Thayyil L, Bhiwgade DA. Alteration in testicular protein profile following administration of embelin and vincristine: potent reproductive toxicants. J Cell Tis Res 2011;11:2815-20. 1 Averal HI, Stanley A, Murugaian P, Palanisamy M, Akbarsha MA. Specific effect of vincristine on epididymis. Indian J Exp Biol 1996;34:53-6. 1 Zhang Y, Sun K. Unscheduled DNA synthesis induced by the antitumor drug vincristine in germ cells of male mice. Mutat Res 1992;281:25-9. 1 Dobrzynska MM, Slowikowska MG, Mikulska U. The change in reproductive ability of male mice exposed to vinblastine and X-rays. Rocz Panstw Zakl Hig 2004;55:147-57. 1 Koehler-Samouilidou G, Kaldrymidou E, Papaioannou N, Kotsaki-Kovatsi VP, Vadarakis A. The effect of paclitaxel (taxol) on the reproductive system and the semen parameters as well as on other organs of male rats. J Hellenic Vet Med Soc 2001;52:23-31. 1 Gerres L, Bramswig JH, Schlegel W, Jurgens H, Schellong G. The effects of etoposide on testicular function in boys treated for Hodgkin’s disease. Cancer 1998;83:2217-22. 1 Bush LA, Herr JC, Wolkowicz M, Sherman NE, Shore A, Flickinger CJ. A novel asparaginase-like protein is a sperm autoantigen in rats. Mol Reprod Develop 2002;62:233-47. 1 Pryzant RM, Meistrich ML, Wilson G, Brown B, McLaughlin P. Long-term reduction in sperm count after chemotherapy with and without radiation therapy for non-Hodgkin’s lymphomas. J Clin Oncol 1993;11:239-47. 1 Mancini RE, Lavieri JC, Muller F, Andrada JA, Saraceni DJ. Effect of prednisolone upon normal and pathologic human spermatogenesis. Fertil Steril 1966;17:500-13. 1 Koyun M, Baysal YE, Usta MF, Akman S, Güven AG. Evaluation of reproductive functions in male adolescents following renal transplantation. Pediatr Transplant 2009;13:697-700. 1 Raman JD, Schlegel PN. Aromatase inhibitors for male infertility. J Urol 2002;167:624-9. 1 Meriggiola MC, Bremner WJ, Costantino A, Di Cintio G, Flamigni C. Low dose of cyproterone acetate and testosterone enanthate for contraception in men. Hum Reprod 1998;13:1225-9. 1 Seshadri T, Seymour JF, McArthur GA. Oligospermia in a patient receiving imatinib therapy for the hypereosinophilic syndrome. N Engl J Med 2004;351:2134-5. 1 Mariani S, Basciani S, Fabbri A, Agati L, Ulisse S, Lubrano C, Spera G, Gnessi L. Severe oligozoospermia in a young man with chronic myeloid leukemia on long-term treatment with imatinib started before puberty. Fertil Steril 2011;95:1120.e15-7. 1 Schilsky RL, Davidson HS, Magid D, Daiter S, Golomb HM. Gonadal and sexual function in male patients with hairy cell leukemia: lack of adverse effects of recombinant alpha 2-interferon treatment. Cancer Treat Rep 1987;71:179-81. 1 Longo I, Sanchez-Mateos P, Lazaro P, Longo N. Azoospermia in a patient receiving interferon alpha for a stage III melanoma. Acta Derm Venereol 2002;82:389-90. 1 Pecou S, Moinard N, Walschaerts M, Pasquier C, Daudin M, Bujan L. Ribavirin and pegylated interferon treatment for hepatitis C was associated not only with semen alterations but also with sperm deoxyribonucleic acid fragmentation in humans. Fertil Steril 2009;91:933.e17-22. 1 Bian SL, Jin HB, Wang SZ, Zhang HF, Gu CR, Zhang W, Yu XG. Effects of interferon-gamma and tumor necrosis factor-alpha on the fertilizing capacity of human sperm and their mechanisms. Zhonghua Nan Ke Xue, 2007;13:681-4. 1 Stumpp T, Sasso-Cerri E, Freymüller E, Miraglia SM. Apoptosis and testicular alterations in albino rats treated with etoposide during the prepubertal phase. Anat Rec A 2004;279(A):611-2. 1 Freitas FEL, Mori FC, Cerri ES, Lucas SRR, Miraglia SM. Alterations in spermatogenesis in etoposide-treated rats: a stereological study. Interciencia 2002;27:227-35. 1 Palo AK, Sahu P, Choudhury RC. Etoposide-induced cytogenotoxicity in mouse spermatogonia and its potential transmission. J Appl Toxicol 2005;25:94-100. 1 Marchetti F, Pearson FS, Bishop JB, Wyrobek AJ. Etoposide induces chromosomal abnormalities in mouse spermatocytes and stem cell spermatogonia. Hum Reprod 2006;21:888-95. 1 Gür S, Bozkurt T, Türk G. Short term effects of dexamethasone on hyaluronidase activity and sperm characteristics in rams. Anim Reprod Sci 2005;90:255-63. 1 Goyal HO, Braden TD, Mansour M, Williams CS, Kamaleldin A, Srivastava KK. Diethylstilbestrol-treated adult rats with altered epididymal sperm numbers and sperm motility parameters, but without alterations in sperm production and sperm morphology. Biol Reprod 2001;64:927-34. 1 Gerardin DCC, Pereira OCM. Reproductive changes in male rats treated perinatally with an aromatase inhibitor. Pharmacol Biochem Behav, 2002;71:301-5. 1 Motrich RD, Ponce AA, Rivero VE. Effect of tamoxifen treatment on the semen quality and fertility of the male rat. Fertil Steril 2007;88:452-61. 1 D’Souza Urban JA. Effect of tamoxifen on spermatogenesis and tubular morphology in rats. Asian J Androl, 2004;6:223-6. 1 Yaghmaei P, Parivar K, Gharibi A, Nabiuni M. The biological effects of imatinib on male fertility of wistar rats. Int J Fertil Steril 2009;3:135-42. 1 Prasad M, Ramnarayan K, Bairy KL. Effect of imatinib on the reproductive function in male swiss albino mice. Pharmacologyonline 2010;1:469-78. 1 Prasad M, Ramnarayan K, Bairy KL. Effect of imatinib on histological parameters in male swiss albino mice. Int J Pharmaceut Sci Rev Res 2010;4:117-22. 1 Nurmio M, Kallio J, Toppari J, Jahnukainen K. Adult reproductive functions after early postnatal inhibition by imatinib of the two receptor tyrosine kinases, c-kit and PDGFR, in the rat testis. Reprod Toxicol 2008;25:442-6. 1 Satie AP, Mazaud-Guittot S, Seif I, Mahe D, He Z, Jouve G, Jegou B, Dejucq-Rainsford N. Excess type I interferon signaling in the mouse seminiferous tubules leads to germ cell loss and sterility. J Biol Chem 2011;286:23280-95. 1 Meikle AW, Cardoso de Sousa JC, Dacosta N, Bishop DK, Samlowski WE. Direct and indirect effects of murine interleukin-2, gamma interferon, and tumor necrosis factor on testosterone synthesis in mouse leydig cells. J Androl 1992;13:437-43. 1 Trottmann M, Becker AJ, Stadler T, Straub J, Soljanik I, Schlenker B, Stief CG. Semen quality in men with malignant diseases before and after therapy and the role of cryopreservation. Eur Urol 2007;52:355-67. 1 Mitchell RT, Saunders PTK, Sharpe RM, Kelnar CJH, Wallace WHB. Male fertility and strategies for fertility preservation following childhood cancer treatment. Endocr Dev 2009;15:101-34. 1 Glode LM, Robinson J, Gould SF. Protection from cyclophosphamide-induced testicular damage with an analogue of gonadotropin releasing hormone. Lancet 1981;1:1132-4. 1 Meistrich ML, Parchuri N, Wilson G, Kurdoglu B, Kangasniemi M. Hormonal protection from cyclophosphamide-induced inactivation of rat stem spermatogonia. J Androl 1995;16:334-41. 200. 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 1997;79:1014-21. 20 Udagawa K, Ogawa T, Watanabe T, Yumura Y, Takeda M, Hosaka M. GnRH analog, leuprorelin acetate, promotes regeneration of rat spermatogenesis after severe chemical damage. Int J Urol 2001;8:615-22. 20 Weissenberg R, Lahav M, Raanani P, Singer R, Regev A, Sagiv M, Giler S, Theodor E. Clomiphene citrate reduces procarbazine-induced sterility in a rat model. Br J Cancer 1995;71:48-51. 20 Satoh K, Ohyama K, Nakagomi Y, Ohta M, Shimura Y, Sano T, Ishikawa H, Amemiya S, Nakazawa S. Effects of growth hormone on testicular dysfunction induced by cyclophosphamide (CP) in GH-deficient rats. Endocr J 2002;49:611-9. 20 Afshin KA, Serati Nouri H, Azarmi YA, Nouri M, Khaki AA, Roushangar L. Survey of growth hormone effects on methotrexate side effects in rat testis. Scientific J Hamadan Univ Med Sci Health Serv 2007;14:40-7. 20 Afshin KA. Effect of growth hormone on testicular dysfunction and apoptosis induced by methotrexate in rats. Yakhteh 2008;10(Suppl 1):41. 20 Nonomura M, Okada K, Hida S, Yoshida O. Does a gonadotropin-releasing-hormone analog prevent cisplatininduced spermatogenic impairment? An experimental study in the mouse. Urol Res 1991;19:135-40. 20 da Cunha MF, Meistrich ML, Nader S. Absence of testicular protection by a gonadotropin-releasing hormone analogue against cyclophosphamide-induced testicular cytotoxicity in the mouse. Cancer Res 1987;47:1093-7. 20 Shetty G, Meistrich ML. Hormonal approaches to preservation and restoration of male fertility after cancer treatment. J Natl Cancer Inst Monogr 2005;34:36-9. 20 Lee SJ, Schover LR, Partridge AH, Patrizio P, Wallace WH, Hagerty K, Beck LN, Brennan LV, Oktay K; American Society of Clinical Oncology. American society of clinical oncology recommendations on fertility preservation in cancer patients. J Clin Oncol 2006;24:2917-31. 2 Hallak J, Kolettis PN, Sekhon VS, Thomas AJ Jr, Agarwal A. Cryopreservation of sperm from patients with leukemia. Is it worth the effort? Cancer 1999;85:1973-8. 2 Schover LR, Brey K, Lichtin A, Lipschultz LI, Jeha S. Knowledge and experience regarding cancer, infertility, and sperm banking in younger male survivors. J Clin Oncol 2002;20:1880-9. 2 Saito K, Suzuki K, Iwasaki A, Yumura Y, Kubota Y. Sperm cryopreservation before cancer chemotherapy helps in the emotional battle against cancer. Cancer 2005;104:521-4. 2 Edge B, Holmes D, Makin G. Sperm banking in adolescent cancer patients. Arch Dis Child 2006;91:149-52. 2 Wald M, Ross LS, Prins GS, Cieslak-Janzen J, Wolf G, Niederberger CS. Analysis of outcomes of cryopreserved surgically retrieved sperm for IVF/ICSI. J Androl 2006;27:60-65. 2 Neal MS, Nagel K, Duckworth J, Bissessar H, Fischer MA, Portwine C, Tozer R, Barr RD. Effectiveness of sperm banking in adolescents and young adults with cancer: a regional experience. Cancer 2007;110:1125-9. 2 van Casteren NJ, van Santbrink EJ, van Inzen W, Romijn JC, Dohle GR. Use rate and assisted reproduction technologies outcome of cryopreserved semen from 629 cancer patients. Fertil Steril 2008;90:2245-50. 2 Wu X, Goodyear SM, Abramowitz LK, Bartolomei MS, Tobias JW, Avarbock MR, Brinster RL. Fertile offspring derived from mouse spermatogonial stem cells cryopreserved for more than 14 years. Hum Reprod 2012;27:1249-59. 2 Dohle GR. Male infertility in cancer patients: review of the literature. Int J Urol 2010;17:327-31. 2 Orwig KE, Schlatt S. Cryopreservation and transplantation of spermatogonia and testicular tissue for preservation of male fertility. J Natl Cancer Inst Monogr 2005;34:51-6. 2 Zhang Z, Shao S, Meistrich M. The radiation-induced block in spermatogonial differentiation is due to damage to the somatic environment, not the germ cells. J Cell Physiol 2007;211:149-58. 2 Honaramooz A. Cryopreservation of testicular tissue. In: Current Frontiers in Cryobiology. Editor: II Katkov. InTech, California. 2012. pp. 209-28. 2 Hovatta O. Cryopreservation of testicular tissue in young cancer patients. Hum Reprod Update 2001;7:378-83. 2 Keros V, Hultenby K, Borgström B, Fridstrom M, Jahnukainen K, Hovatta O. Methods of cryopreservation of testicular tissue with viable spermatogonia in pre-pubertal boys undergoing gonadotoxic cancer treatment. Hum Reprod 2007;22:1384-95. 2 Wyns C, Langendonckt AV, Wese F-X, Donnez J, Curaba M. Long-term spermatogonial survival in cryopreserved and xenografted immature human testicular tissue. Hum Reprod 2008;23:2402-14. 2 Nagano M, Patrizio P, Brinster RL. Long-term survival of human spermatogonial stem cells in mouse testes. Fertil Steril 2002;78:1225-33. 2 Geens M, De Block G, Goossens E, Frederickx V, Van Steirteghem A, Tournaye H. Spermatogonial survival after grafting human testicular tissue to immunodeficient mice. Hum Reprod 2006;21:390-6. 2 Schlatt S, Honaramooz A, Boiani M, Scholer HR, Dobrinski I. Progeny from sperm obtained after ectopic grafting of neonatal mouse testes. Biol Reprod 2003;68:2331-5. 2 Lee DR, Kim KS, Yang YH, Oh HS, Lee SH, Chung TG, Cho JH, Kim HJ, Yoon TK, Cha KY. Isolation of male germ stem cell-like cells from testicular tissue of nonobstructive azoospermic patients and differentiation into haploid male germ cells in vitro. Hum Reprod 2006;21:471-6. 2 Klempner SJ, Bubley G. Complementary and alternative medicines in prostate cancer: from bench to bedside? Oncologist 2012;17:830-7. 2 Saalu L, Kpela T, Shittu LAJ, Ashiru OA. Grapefruit seed extract moderates morphologic, functional and biochemical evidences of epidoxorubicin-induced testicular toxicity. J Med Sci 2007;7:650-4. 2 Saalu L, Osinubi AA, Jewo PI, Oyewopo AO, Ajayi GO. An evaluation of influence of citrus paradisi seed extract on doxorubicin-induced testicular oxidative stress and impaired spermatogenesis. Asian J Sci Res 2010;3:51-61. 2 Saalu L, Osinubi AA, Oguntpla JA, Adeneye IO, Benebo AS. The delayed testicular morphologic effects of doxorubicin and the rejuvinating role of grapefruit seed extract. Int J Pharmacol 2010;6:192-9. 2 Sabuncuoglu S, Özgüneş H. Sisplatin toksisitesi: oksidatif stresin önemi ve antioksidanların etkisi. İst Tıp Fak Derg 2011;74:18-25. 2 Kandemir FM, Benzer F, Yildirim NC, Ozdemir N. Compensatory effects of curcumin on cisplatininduced toxicity in rabbit testis. J Med Plants Res 2011;5:456-61. 2 Selvakumar E, Prahalathan C, Mythili Y, Varalakshmi P. Beneficial effects of DL-α-lipoic acid on cyclophosphamide-induced oxidative stress in mitochondrial fractions of rat testis. Chem Biol Interact 2005;152:59-66. 2 Selvakumar E, Prahalathan C, Sudharsan PT, Varalakshmi P. Chemoprotective effect of lipoic acid against cyclophosphamide-induced changes in the rat sperm. Toxicology 2006;217:71-8. 2 Rodriguez-Sosa JR, Dobrinski I. Recent developments in testis tissue xenografting. Reproduction 2009;138:187-94.