臨床婦人科産科68巻1号

2014年01月発行

合併増大号　今月の臨床 生殖医療の進歩と課題─安全性の検証から革新的知見まで

ARTの発展

2．精巣組織の凍結保存

著者： 横西哲広¹ 小川毅彦¹²

所属機関： ¹横浜市立大学大学院医学研究科泌尿器病態学 ²横浜市立大学医学群分子生命医科学系列プロテオーム科学（生命医科学）

ページ範囲：P.54 - P.63

文献概要

●生殖腺毒性を有する治療を行う際に，後遺症の1つとして不妊症があることを説明する必要がある．性成熟した男性がん患者が妊孕能の温存を希望した場合は治療前の精液保存が奨励される．

●性未成熟な患者においては，研究段階であるが精子幹細胞凍結保存法，精巣組織凍結保存法がある．しかし臨床応用において安全な分化誘導技術がない．近年マウス精巣組織の器官培養法が改良され，精子産生が可能となった．これは凍結精巣組織の分化誘導法として多くの恩恵があると考えられる．

●今後，効率的な精巣組織の凍結保存法の確立と，ヒト精巣組織のin vitro分化誘導法の開発が期待される．

参考文献

1） Schover LR, Brey K, Lichtin A, et al : Knowledge and experience regarding cancer, infertility, and sperm banking in younger male survivors. J Clin Oncol 20 : 1880─1889, 2002

2） Saito K, Suzuki K, Iwasaki A, et al : Sperm cryopreservation before cancer chemotherapy helps in the emotional battle against cancer. Cancer 104 : 521─524, 2005

3） Reuben SH : in President’s Cancer Panel 2003─2004 Annual Report 17. National Cancer Institute, National Institutes of Health, 2004

4） Lee SJ. Schower LR, Partridge AH, et al : American Society of Clinical Oncology recommendations on fertility preservation in cancer patients. J Clin Oncol 24 : 2917─2931, 2006

5） Armuand GM, Rodriguez-Wallberg KA, Wettergren L, et al : Sex differences in fertility-related information received by young adult cancer survivors. J Clin Oncol 17 : 2147─2153, 2012

6） Green DM, Kawashima T, Stovall 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

7） Clermont Y : Spermatogenesis in man. A study of the spermatogonial population. Fertil Steril 17 : 705─721, 1966

8） Clermont Y, Leblond CP : Differentiation and renewal of spermatogonia in the monkey, Macaca rhesus. Am J Anat 104 : 237─273, 1959

9） Clermont Y : Two classes of spermatogonial stem cells in the monkey（Cercopithecus aethiops）. Am J Anat 126 : 57─71, 1969

10） Sklar C : Reproductive physiology and treatment-related loss of sex hormone production. Medical and Pediatric Oncology 33 : 2, 1999

11） van Alphen MM, van de Kant HJ, de Rooij DG : Depletion of the spermatogonia from the seminiferous epithelium of the rhesus monkey after X irradiation. Radiat Res 133 : 473, 1988

12） de Rooij DG, van de Kant HJ, Dol R, et al : Long-term effects of irradiation before adulthood on reproductive function in the male rhesus monkey. Biol Reprod 66 : 486, 2002

13） van Alphen MM, van den Kant HJG, de Rooij DG : Repopulation of the seminiferous epithelium of the rhesus monkey after Xirradiation. Radiat Res 113 : 487─500, 1988

14） van Alphen MM, van den Kant HJ, Davids JA, et al : Dose-response studies on the spermatogonial stem cells of the Rhesus monkey（Macaca mulatta）after X-irradiation. Radiat Res 199 : 443─451, 1989

15） Meseguer M, Garrido N, Remohi J, et al : Testicular sperm extraction（TESE） and ICSI in patients with permanent azoospermia after chemotherapy. Hum Reprod 18 : 1281, 2003

16） Robbins WA, Meistrich ML, Moore D, et al : Chemotherapy induces transient sex chromosomal and autosomal aneuploidy in human sperm. Nat Genet 16 : 74─78, 1997

17） Frias S, Van Hummelen P, Meistrich ML, Lowe XR, Hagemeister FB, Shelby MD, Bishop JB, Wyrobek AJ : NOVP chemotherapy for Hodgkin’s disease transiently induces sperm aneuploidies associated with the major clinical aneuploidy syndromes involving chromosomes X, Y, 18, and 21. Cancer Res 63 : 44─51, 2003

18） Tempest HG, Ko E, Chan P, et al : Sperm aneuploidy frequencies analysed before and after chemotherapy in testicular cancer and Hodgkin’s lymphoma patients. Hum Reprod 23 : 251─258, 2008

19） Marleen AE, van der Kaaij MA, Heutte N, et al : Gonadal function in males after chemotherapy for early-stage Hodgkin’s lymphoma treated in four subsequent trials by the European Organisation for Research and Treatment of Cancer : EORTC Lymphoma Group and the Grouped’Etude des Lymphomes de l’Adulte. J Clin Oncol 25 : 2825─2832, 2007

20） Lampe H, Horwich A, Norman A, et al : Fertility after chemotherapy for testicular germ cell cancers. J Clin Oncol 15 : 239─245, 1997

21） Pont J, Albrecht W : Fertility after chemotherapy for testicular germ cell cancer. Fertil Steril 68 : 1─5, 1977

22） Sklar C : Reproductive physiology and treatment-related loss of sex hormone production. Med Pediatr Oncol 33 : 2─8, 1999

23） Meistrich ML, Wilson G, Brown BW, et al : Impact of cyclophosphamide on long-term reduction in sperm count in men treated with combination chemotherapy for Ewing and soft tissue sarcomas. Cancer 70 : 2703─2712, 1992

24） Heikens J, Behrendt H, Adriaanse R, et al : Irreversible gonadal damage in male survivors of pediatric Hodgkin’s disease. Cancer 78 : 2020─2024, 1996

25） Bramswig JH, Heimes U, Heiermann E, et al : The effects of different cumulative doses of chemotherapy on testicular function. Results in 75 patients treated for Hodgkin’s disease during childhood or adolescence. Cancer 65 : 1298─1302, 1990

26） Anserini P, Chiodi S, Spinelli S, et al : Semen analysis following allogeneic bone marrowtransplantation. Additional data for evidence-based counselling. Bone Marrow Transplantat 30 : 447─451, 2002

27） Budgell GJ, Cowan RA, Hounsell AR : Prediction of scattered dose to the testes in abdominopelvic radiotherapy. Clin Oncol 13 : 120─125, 2001

28） Rowley MJ, Leach DR, Warner GA, et al : Effect of graded doses of ionizing radiation on the human testis. Radiation Research 59 : 665─678, 1974

29） Brauner R, Czernichow P, Cramer P, et al : Leydig cell function in children after direct testicular irradiation for acute lymphoblastic leukemia. N Engl J Med 309 : 25─28, 1983

30） Centola GM, Keller JW, Henzler M, et al : Effect of low-dose testicular irradiation on sperm count and fertility in patients with testicular seminoma. J Androl 15 : 608─613, 1994

31） Littley MD, Shalet SM, Beardwell CG, et al : Radiation-induced hypopituitarism is dose-dependent. Clin Endocrinol 31 : 363─373, 1989

32） Castillo LA, Craft AW, Kernahan J, et al : Gonadal function after 12-Gy testicular irradiation in childhood acute lymphoblastic leukaemia. Med Pediatr Oncol 18 : 185─189, 1990

33） Brennemann W, Brensing KA, Leipner N, et al : Attempted protection of spermatogenesis from irradiation in patients with seminoma by D-Tryptophan-6 luteinizing hormone releasing hormone. Clin Investig 72 : 838─842, 1994

34） Johnson DH, Linde R, Hainsworth JD, 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

35） Fossa SD, 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

36） Kalsi J, Thum MY, Muneer A, et al : Analysis of the outcome of intracytoplasmic sperm injection using fresh or frozen sperm. BJU Int 107 : 1124─1128, 2011

37） Nicopoullos JD, Gilling-Smith C, Almeida PA, et al : Use of surgical sperm retrieval in azoospermic men : a meta-analysis. Fertil Steril 82 : 691─701, 2004

38） Ulug U, Bener F, Karagenc, L, et al : Outcomes in couples undergoing ICSI : comparison between fresh and frozen-thawed surgically retrieved spermatozoa. Int J Androl 28 : 343─349, 2005

39） Schaefer F, Marr J, Seidel C, et al : Assessment of gonadal maturation byevaluation of spermaturia. Arch Dis Child 65 : 1205─1207, 1990

40） Hagenäs I, Jørgensen N, Rechnitzer C, et al : Clinical and biochemical correlates of successful semen collection forcryopreservation from 12-18-year-old patients : a single-center study of 86 adolescents. Hum Reprod 25 : 2031─2038, 2010

41） Bahadur G, Ling KL, Hart R, et al : Semen quality and cryopreservation in adolescent cancer patients. Hum Reprod 17 : 3157─3161, 2002

42） Kamischke A, Jurgens H, Hertle L, et al : Cryopreservation of sperm from adolescents and adults with malignancies. J Androl 25 : 586─592, 2004

43） Feldschuh J, Brassel J, Durso N, et al : Successful sperm storage for 28 years. Fertil Steril 84 : 1017, 2005

44） Chung K, Irani J, Knee G, et al : Sperm cryopreservation for male patients with cancer : an epidemiological analysis at the University of Pennsylvania. Eur J Obstet Gynecol Reprod Biol 113 : 7─11, 2004

45） Lass A, Akagbosu F, Abusheikha N, 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

46） Agarwal A, Ranganathan P, Kattal N, et al : Fertility after cancer : a prospective review of assisted reproductive outcome with banked semen specimens. Fertil Steril 81 : 342─348, 2004

47） van Casteren NJ, van Santbrink EJ, van Inzen W, et al : Use rate and assisted reproduction technologies outcome of cryopreserved semen from 629 cancer patients. Fertil Steril 90 : 2245, 2008

48） Brinster RL, Zimmermann JW : Spermatogenesis following male germ-cell transplantation. Proc Natl Acad Sci USA 91 : 11298─11302, 1994

49） Hermann BP, Sukhwani M, Winkler F, et al : Spermatogonial stem cell transplantation into rhesus testes regenerates spermatogenesis producing functional sperm. Cell Stem Cell 11 : 715─726, 2012

50） Brook P, Radford J, Shalet S, et al : Isolation of germ cells from human testicular tissue for low temperature storage and autotransplantation. Fertil Steril 75 : 269─274, 2001

51） Schlatt S, Rosiepen G, Weinbauer C, et al : Germ cell transfer into rat, bovine, monkey, and human testes. Hum Reprod 14 : 144─150, 1999

52） 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

53） Radford J : Restoration of fertility after treatment for cancer. Horm Res 59 : 21─23, 2003

54） Muller J, Skakkebaeck N : Quantification of germ cells and seminiferoustubules by stereological examination of testicles from 50 boys whosuffered sudden death. Int J Androl 6 : 143─156, 1983

55） Nagano MC : Homing efficiency and proliferation kinetics of male germ line stem cells following transplantation in mice. Biol Reprod 69 : 701─707, 2003

56） Honaramooz A, Snedaker A, Boiani M, et al : Sperm from neonatal mammalian testes grafted in mice. Nature 418 : 778─781, 2002

57） Schlatt S, Kim S, Gosden R : Spermatogenesis and steroidogenesis in mouse, hamster and monkey testicular tissue after cryopreservation and heterotopic grafting to castrated hosts. Reproduction 124 : 339─346, 2002

58） Shinohara T, Inoue K, Ogonuki N, et al : Birth of offspring following transplantation of cryopreserved immature testicular pieces and in-vitro microinsemination. Hum Reprod 17 : 3039─3045, 2002

59） Honaramooz A, Li MW, Penedo CT, et al : Accelerated maturation of primate testis by xenografting into mice. Biol Reprod 70 : 1500─1503, 2004

60） Jahnukainen K, Ehmcke J, Nurmio M, et al : Autologous ectopic grafting of cryopreserved testicular tissue preserves the fertility of prepubescent monkeys that receive sterilizing cytotoxic therapy. Cancer Res 72 : 5174─5178, 2012

61） Schlatt S, Honaramooz A, Ehmcke J, et al : Limited survival of adult human testicular tissue as ectopic xenograft. Hum Reprod 21 : 384─389, 2006

62） Geens M, De Block G, Goossens E, et al : Spermatogonial survival after grafting human testicular tissue to immunodeficient mice. Hum Reprod 21 : 390─396, 2006

63） Keros V, Hultenby K, Borgström B, 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

64） Keros V, Rosenlund B, Hultenby K, et al : Optimizing cryopreservation of human testicular tissue : comparison of protocols with glycerol, propanediol and dimethylsulphoxide as cryoprotectants. Hum Reprod 20 : 1676─1687, 2005

65） Jahnukainen K, Ehmcke J, Hergenrother SD, et al : Effect of cold storage and cryopreservation of immature nonhumanprimate testicular tissue on spermatogonial stem cell potential in xenografts. Hum Reprod 22 : 1060─1067, 2007

66） Wyns C, Curaba M, Vanabelle B, et al : Options for fertility preservation in prepubertal boys. Hum Reprod Update 16 : 312─328, 2010

67） Curaba M, Poels J, van Langendonckt A, et al : Can prepubertal human testicular tissue be cryopreserved by vitrification? Fertil Steril 95 : 2123e9─2123e12, 2011

68） Jahnukainen K, Hou M, Petersen C, et al : Intratesticular transplantation of testicular cells from leukemic rats causes transmission of leukemia. Cancer Res 61 : 706─710, 2001

69） Fujita K, Ohta H, Tsujimura A, et al : Transplantation of spermatogonial stem cells isolatedfrom leukemic mice restores fertility without inducing leukemia. J Clin Invest 115 : 1855─1861, 2005

70） Fujita K, Tsujimura A, Miyagawa Y, 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

71） Patience C, Takeuchi Y, Weiss RA : Zoonosis in xenotransplantation. Curr Opin Immunol 10 : 539─542, 1998

72） Sato T, Katagiri K, Gohbara A, et al : In vitro production of functional sperm in cultured neonatal mouse testes. Nature 471 : 504─507, 2011