To Transplant or Not to Transplant – That Is the Question

  • Sherman J. Silber
  • Teresa K. Woodruff
  • Lonnie D. Shea
Part of the Cancer Treatment and Research book series (CTAR, volume 156)


Thousands of human ovaries have been stored for desperate cancer patients by practitioners around the world. Unfortunately, most of these ovaries were stored without a clear idea about how they could be used by the eventual survivor. Recent advances in ovarian tissue freezing and transplant technology and in the emerging area of in vitro follicle growth provide the opportunities the patients and providers were banking on. In this chapter, we review the state of the art of ovarian tissue transplantation and identify where transplant is advisable (many of the cases) and conditions where transplant is ill advised (e.g., ovarian malignancy, BRCA gene mutation, metastatic disease). In vitro follicle maturation has now succeeded in pre-clinical models but has not yet been attempted in the human. These follicle maturation strategies are reviewed with their technical and utilization limitations, and a discussion of the next steps that will proceed the first attempt at fertilization of an in vitro matured human follicle with egg maturation and embryo transfer will be provided.


Ovarian Tissue Ovarian Follicle Fertility Preservation Premature Ovarian Failure Preantral Follicle 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This research was supported by the oncofertility consortium NIH 8UL1DE019587, 5RL1HD058296.


  1. 1.
    Gosden RG, Baird DT, et al. Restoration of fertility to oophorectomized sheep by ovarian autografts stored at –196 degrees C. Hum Reprod. 1994; 9(4):597–603.PubMedGoogle Scholar
  2. 2.
    Silber SJ, Lenahan KM, et al. Ovarian transplantation between monozygotic twins discordant for premature ovarian failure. N Engl J Med. 2005; 353(1):58–63.PubMedCrossRefGoogle Scholar
  3. 3.
    Silber SJ, DeRosa M, et al. A series of monozygotic twins discordant for ovarian failure: ovary transplantation (cortical versus microvascular) and cryopreservation. Hum Reprod. 2008; 23(7):1531–7.PubMedCrossRefGoogle Scholar
  4. 4.
    Silber SJ, Gosden RG Ovarian transplantation in a series of monozygotic twins discordant for ovarian failure. N Engl J Med. 2007; 356(13):1382–4.PubMedCrossRefGoogle Scholar
  5. 5.
    Silber SJ, Grudzinskas G, et al. Successful pregnancy after microsurgical transplantation of an intact ovary. N Engl J Med. 2008; 359(24):2617–8.PubMedCrossRefGoogle Scholar
  6. 6.
    Donnez J, Dolmans MM, et al. Livebirth after orthotopic transplantation of cryopreserved ovarian tissue. Lancet. 2004; 364(9443):1405–10.PubMedCrossRefGoogle Scholar
  7. 7.
    Baird DT, Webb R, et al. Long-term ovarian function in sheep after ovariectomy and transplantation of autografts stored at –196 C. Endocrinology. 1999; 140(1):462–71.PubMedCrossRefGoogle Scholar
  8. 8.
    Candy CJ, Wood MJ, et al. Restoration of a normal reproductive lifespan after grafting of cryopreserved mouse ovaries. Hum Reprod. 2000; 15(6):1300–4.PubMedCrossRefGoogle Scholar
  9. 9.
    Sanchez M, Alama P, et al. Fresh human orthotopic ovarian cortex transplantation: long-term results. Hum Reprod. 2007; 22(3):786–91.PubMedCrossRefGoogle Scholar
  10. 10.
    Anderson RA, Cameron DA Assessment of the effect of chemotherapy on ovarian function in women with breast cancer. J Clin Oncol. 2007; 25(12):1630–1, author reply 1632.PubMedCrossRefGoogle Scholar
  11. 11.
    Demeestere I, Simon P, et al. Fertility preservation: successful transplantation of cryopreserved ovarian tissue in a young patient previously treated for Hodgkin’s disease. Oncologist. 2007; 12(12):1437–42.PubMedCrossRefGoogle Scholar
  12. 12.
    Meirow D, Levron J, et al. Pregnancy after transplantation of cryopreserved ovarian tissue in a patient with ovarian failure after chemotherapy. N Engl J Med. 2005; 353(3):318–21.PubMedCrossRefGoogle Scholar
  13. 13.
    Donnez J, Martinez-Madrid B, et al. Ovarian tissue cryopreservation and transplantation: a review. Hum Reprod Update. 2006; 12(5):519–35.PubMedCrossRefGoogle Scholar
  14. 14.
    Kagawa N, Silber S, et al. Successful vitrification of bovine and human ovarian tissue. Reprod Biomed Online. 2009; 18(4):568–77.PubMedCrossRefGoogle Scholar
  15. 15.
    Faddy MJ, Gosden RG, et al. Accelerated disappearance of ovarian follicles in mid-life: implications for forecasting menopause. Hum Reprod. 1992; 7(10):1342–6.PubMedGoogle Scholar
  16. 16.
    Telfer EE, McLaughlin M, et al. A two-step serum-free culture system supports development of human oocytes from primordial follicles in the presence of activin. Hum Reprod. 2008; 23(5):1151–8.PubMedCrossRefGoogle Scholar
  17. 17.
    West ER, Xu M, et al. Physical properties of alginate hydrogels and their effects on in vitro follicle development. Biomaterials. 2007; 28(30):4439–48.PubMedCrossRefGoogle Scholar
  18. 18.
    West-Farrell ER, Xu M, et al. The mouse follicle microenvironment regulates antrum formation and steroid production: alterations in gene expression profiles. Biol Reprod. 2009; 80(3):432–9.PubMedCrossRefGoogle Scholar
  19. 19.
    Xu M, Kreeger PK, et al. Tissue-engineered follicles produce live, fertile offspring. Tissue Eng. 2006; 12(10):2739–46.PubMedCrossRefGoogle Scholar
  20. 20.
    Arav A, Revel A, et al. Oocyte recovery, embryo development and ovarian function after cryopreservation and transplantation of whole sheep ovary. Hum Reprod. 2005; 20(12):3554–9.PubMedCrossRefGoogle Scholar
  21. 21.
    Bedaiwy MA, Falcone T Harvesting and autotransplantation of vascularized ovarian grafts: approaches and techniques. Reprod Biomed Online. 2007; 14(3):360–71.PubMedCrossRefGoogle Scholar
  22. 22.
    Jeruss JS, Woodruff TK Preservation of fertility in patients with cancer. N Engl J Med. 2009; 360(9):902–11.PubMedCrossRefGoogle Scholar
  23. 23.
    Bleyer WA The impact of childhood cancer on the United States and the world. CA Cancer J Clin. 1990; 40(6):355–67.PubMedCrossRefGoogle Scholar
  24. 24.
    Ries LAG Cancer incidence and survival among children and adolescents: United States SEER program 1975–1995. Bethesda: National Cancer Institute; 1999.Google Scholar
  25. 25.
    Anderson RA, Themmen AP, et al. The effects of chemotherapy and long-term gonadotrophin suppression on the ovarian reserve in premenopausal women with breast cancer. Hum Reprod. 2006; 21(10):2583–92.PubMedCrossRefGoogle Scholar
  26. 26.
    Meirow D, Nugent D The effects of radiotherapy and chemotherapy on female reproduction. Hum Reprod Update. 2001; 7(6):535–43.PubMedCrossRefGoogle Scholar
  27. 27.
    Meirow D, Schenker JG The link between female infertility and cancer: epidemiology and possible aetiologies. Hum Reprod Update. 1996; 2(1):63–75.PubMedCrossRefGoogle Scholar
  28. 28.
    Schover LR, Brey K, et al. Knowledge and experience regarding cancer, infertility, and sperm banking in younger male survivors. J Clin Oncol. 2002; 20(7):1880–9.PubMedCrossRefGoogle Scholar
  29. 29.
    Schover LR, Rybicki LA, et al. Having children after cancer. A pilot survey of survivors’ attitudes and experiences. Cancer. 1999; 86(4):697–709.PubMedCrossRefGoogle Scholar
  30. 30.
    Homburg R, van der Veen F, Silber SJ Oocyte vitrification – Women’s emancipation set in stone. Fertil Steril. 2009; 91(4):1319–20.PubMedCrossRefGoogle Scholar
  31. 31.
    Lampic C, Svanberg AS, et al. Fertility awareness, intentions concerning childbearing, and attitudes towards parenthood among female and male academics. Hum Reprod. 2006; 21(2):558–64.PubMedCrossRefGoogle Scholar
  32. 32.
    Leridon H Can assisted reproduction technology compensate for the natural decline in fertility with age? A model assessment. Hum Reprod. 2004; 19(7):1548–53.PubMedCrossRefGoogle Scholar
  33. 33.
    Maheshwari A, Porter M, et al. Women’s awareness and perceptions of delay in childbearing. Fertil Steril. 2008; 90(4):1036–42.PubMedCrossRefGoogle Scholar
  34. 34.
    Devroey P Female age predicts embryonic implantation after ICSI: a case-controlled study. Hum Reprod. 1996; 11(6):1324–7.PubMedCrossRefGoogle Scholar
  35. 35.
    Fretts RC. Effect of advanced age on fertility and pregnancy in women. In: Up to date online.; 2007.
  36. 36.
    SART. Assisted reproductive technology success rates. National summary and fertility clinic reports. Atlanta: Centers for Disease Control and Prevention; 2005.Google Scholar
  37. 37.
    Silber SJ, Nagy Z, et al. The effect of female age and ovarian reserve on pregnancy rate in male infertility: treatment of azoospermia with sperm retrieval and intracytoplasmic sperm injection. Hum Reprod. 1997; 12(12):2693–700.PubMedCrossRefGoogle Scholar
  38. 38.
    Spears N, Boland NI, et al. Mouse oocytes derived from in vitro grown primary ovarian follicles are fertile. Hum Reprod. 1994; 9(3):527–32.PubMedGoogle Scholar
  39. 39.
    Yin H, Wang X, Kim SS, Chen H, Tan SL, Gosden RG. Transplantation of intact rat gonads using vascular anastomosis: effects of cryopreservation, ischaemia and genotype. Hum Reprod. 2003; 18:1165–1172.PubMedCrossRefGoogle Scholar
  40. 40.
    Aubard Y, Piver P, et al. Orthotopic and heterotopic autografts of frozen-thawed ovarian cortex in sheep. Hum Reprod. 1999; 14(8):2149–54.PubMedCrossRefGoogle Scholar
  41. 41.
    Newton H, Aubard Y, et al. Low temperature storage and grafting of human ovarian tissue. Hum Reprod. 1996; 11(7):1487–91.PubMedCrossRefGoogle Scholar
  42. 42.
    Salle B, Lornage J, Demirci B, Vaudoyer F, Poirel MT, Franck M, Rudigoz RC, Guerin JF. Restoration of ovarian steroid secretion and histologic assessment after freezing, thawing and autograft of a hemi-ovary in sheep. Fertil Steril. 1999; 72:366–370.PubMedCrossRefGoogle Scholar
  43. 43.
    Andersen CY, Rosendahl M, Byskov AG, Loft A, Ottosen C, Dueholm M, Schmidt KLT, Andersen AY, Ernst E. Two successful pregnancies following autotransplantation of frozen/thawed ovarian tissue. Hum Reprod. 2008; 23:2266–2272.PubMedCrossRefGoogle Scholar
  44. 44.
    Demeestere I, Simon P, et al. Ovarian function and spontaneous pregnancy after combined heterotopic and orthotopic cryopreserved ovarian tissue transplantation in a patient previously treated with bone marrow transplantation: case report. Hum Reprod. 2006; 21(8):2010–14.PubMedCrossRefGoogle Scholar
  45. 45.
    Falcone T, Attaran M, Bedaiwy MA, Goldberg JM. Ovarian function preservation in the cancer patient. Fertil Steril. 2004; 81:243–257.PubMedCrossRefGoogle Scholar
  46. 46.
    Gadducci A, Cosio S, Genazzani AR. Ovarian function and childbearing issues in breast cancer survivors. Gynecol Endocrinol. 2007; 23:625–631.PubMedCrossRefGoogle Scholar
  47. 47.
    Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ. Cancer statistics, 2008. CA Cancer J Clin. 2008; 58:71–96.PubMedCrossRefGoogle Scholar
  48. 48.
    Lobo RA. Potential options for preservation of fertility in women. N Engl J Med. 2005; 353:64–73.PubMedCrossRefGoogle Scholar
  49. 49.
    Colgan TJ, Murphy J, Cole DE, Narod S, Rosen B. Occult carcinoma in prophylactic oophorectomy specimens: prevalence and association with BRCA germline mutation status. Am J Surg Pathol. 2001; 25:1283–1289.PubMedCrossRefGoogle Scholar
  50. 50.
    Elizur SE. Detection of microscopic metastasis of solid tumors and hematological malignancies in cryopreserved ovaries. Fertil Steril. 2004; 82.Google Scholar
  51. 51.
    Meirow D, Hardan I, Dor J, Fridman E, Elizur S, Ra’anani H, Slyusarevsky E, Amariglio N, Schiff E, Rechavi G, Nagler A, Ben Yehuda D. Searching for evidence of disease and malignant cell contamination in ovarian tissue stored from hematologic cancer patients. Hum Reprod. 2008; 23:1007–1013.PubMedCrossRefGoogle Scholar
  52. 52.
    Nakayama K. Gonadal failure after treatment of hematologic malignancies: from recognition to management for health-care providers. Nat Clin Pract Oncol. 2008; 5:78–89.PubMedCrossRefGoogle Scholar
  53. 53.
    Sklar CA, Mertens AC, Mitby P, Whitton J, Stovall M, Kasper C, Mulder J, Green D, Nicholson HS, Yasui Y, Robison LL. Premature menopause in survivors of childhood cancer: a report from the childhood cancer survivor study. J Natl Cancer Inst. 2006; 98:890–896.PubMedCrossRefGoogle Scholar
  54. 54.
    Schroder CP, Timmer-Bosscha H, et al. An in vitro model for purging of tumour cells from ovarian tissue. Hum Reprod. 2004; 19(5):1069–75.PubMedCrossRefGoogle Scholar
  55. 55.
    Xu M, West E, et al. Identification of a stage-specific permissive in vitro culture environment for follicle growth and oocyte development. Biol Reprod. 2006; 75(6):916–23.PubMedCrossRefGoogle Scholar
  56. 56.
    Monterrosso V, Jaffe ES, Merino MJ, Medeiros LJ. Malignant lymphomas involving the ovary: a clinocopathologic analysis of 39 cases. Am J Surg Pathol. 1993; 17:154–170.CrossRefGoogle Scholar
  57. 57.
    Perlman S, Ben-Arie A, Feldberg E, Hagay Z. Non-Hodgkins lymphoma presenting as advanced ovarian cancer: a case report and review of the literature. Int J Gynecol Cancer. 2005; 15:554–557.PubMedCrossRefGoogle Scholar
  58. 58.
    Fox H, Langley FA, Govan AD, Hill AS, Bennett MH. Malignant lymphoma presenting as an ovarian tumor: a clinicopathologic analysis of 34 cases. Br Obstet Gynecol. 1998; 105.Google Scholar
  59. 59.
    Kim JW, Cho M-K, Cheo HK, et al. Ovarian and multiple lymph nodes recurrence of acute lymphoblastic leukemia: a case report and review of the literature. Ped Surg Intl. 2008; 24:1269–1273.CrossRefGoogle Scholar
  60. 60.
    Elharoudi H, Ismali N, Ernihani H, Jalil A. Primary lymphoma of the ovary. J Cancer. Res Ther. 2008; 4:195–196.CrossRefGoogle Scholar
  61. 61.
    Gosden RG, Newton H, et al. The cryopreservation of human ovarian tissue. In: Kempers RD, Cohen J, Haney AF, Younger JB, Eds. Fertility and reproductive medicine. Proceedings of the XVI world congress on fertility and sterility. Amsterdam: Elsevier; 1998:615–20.Google Scholar
  62. 62.
    Eppig JJ, O’Brien MJ Development in vitro of mouse oocytes from primordial follicles. Biol Reprod. 1996; 54(1):197–207.PubMedCrossRefGoogle Scholar
  63. 63.
    Cortvrindt R, Smitz J, et al. In-vitro maturation, fertilization and embryo development of immature oocytes from early preantral follicles from prepuberal mice in a simplified culture system. Hum Reprod. 1996; 11(12):2656–66.PubMedCrossRefGoogle Scholar
  64. 64.
    Nogueira D, Cortvrindt R, et al. Effects of long-term in vitro exposure to phosphodiesterase type-3 inhibitors on follicle and oocyte development. Reproduction. 2005; 130(2):177–86.PubMedCrossRefGoogle Scholar
  65. 65.
    Papanikolaou EG, Platteau P, et al. Immature oocyte in-vitro maturation: clinical aspects. Reprod Biomed Online. 2005; 10(5):587–92.PubMedCrossRefGoogle Scholar
  66. 66.
    Smitz J, Picton HM, et al. Principal findings from a multicenter trial investigating the safety of follicular-fluid meiosis-activating sterol for in vitro maturation of human cumulus-enclosed oocytes. Fertil Steril. 2007; 87(4):949–64.PubMedCrossRefGoogle Scholar
  67. 67.
    Matzuk MM, Burns KH, et al. Intercellular communication in the mammalian ovary: oocytes carry the conversation. Science. 2002; 296(5576):2178–80.PubMedCrossRefGoogle Scholar
  68. 68.
    Kreeger PK, Fernandes NN, et al. Regulation of mouse follicle development by follicle-stimulating hormone in a three-dimensional in vitro culture system is dependent on follicle stage and dose. Biol Reprod. 2005; 73(5):942–50.PubMedCrossRefGoogle Scholar
  69. 69.
    O’Brien MJ, Pendola JK, et al. A revised protocol for in vitro development of mouse oocytes from primordial follicles dramatically improves their developmental competence. Biol Reprod. 2003; 68(5):1682–6.PubMedCrossRefGoogle Scholar
  70. 70.
    Pangas SA, Saudye H, et al. Novel approach for the three-dimensional culture of granulosa cell-oocyte complexes. Tissue Eng. 2003; 9(5):1013–21.PubMedCrossRefGoogle Scholar
  71. 71.
    Amsden B, Turner N Diffusion characteristics of calcium alginate gels. Biotechnol Bioeng. 1999; 65(5):605–10.PubMedCrossRefGoogle Scholar
  72. 72.
    Rowley JA, Madlambayan G, et al. Alginate hydrogels as synthetic extracellular matrix materials. Biomaterials. 1999; 20(1):45–53.PubMedCrossRefGoogle Scholar
  73. 73.
    Lee DM, Yeoman RR, et al. Live birth after ovarian tissue transplant. Nature. 2004; 428(6979):137–8.PubMedCrossRefGoogle Scholar
  74. 74.
    Oktay K, Buyuk E, et al. Embryo development after heterotopic transplantation of cryopreserved ovarian tissue. Lancet. 2004; 363(9412):837–40.PubMedCrossRefGoogle Scholar
  75. 75.
    Gunasena KT, Villines PM, et al. Live births after autologous transplant of cryopreserved mouse ovaries. Hum Reprod. 1997; 12(1):101–6.PubMedCrossRefGoogle Scholar
  76. 76.
    Shaw JM, Bowles J, et al. Fresh and cryopreserved ovarian tissue samples from donors with lymphoma transmit the cancer to graft recipients. Hum Reprod. 1996; 11(8):1668–73.PubMedCrossRefGoogle Scholar
  77. 77.
    Jahnukainen K, Ehmcke J, et al. Clinical potential and putative risks of fertility preservation in children utilizing gonadal tissue or germline stem cells. Pediatr Res. 2006; 59(4 Pt 2):40R–47R.PubMedCrossRefGoogle Scholar
  78. 78.
    Abir R, Fisch B, et al. Morphological study of fully and partially isolated early human follicles. Fertil Steril. 2001; 75(1):141–6.PubMedCrossRefGoogle Scholar
  79. 79.
    Wandji SA, Srsen V, et al. Initiation of growth of baboon primordial follicles in vitro. Hum Reprod. 1997; 12(9):1993–2001.PubMedCrossRefGoogle Scholar
  80. 80.
    Abir R, Nitke S, et al. In vitro maturation of human primordial ovarian follicles: clinical significance, progress in mammals, and methods for growth evaluation. Histol Histopathol. 2006; 21(8):887–98.PubMedGoogle Scholar
  81. 81.
    Picton HM, Harris SE, et al. Prospects for follicle culture. In: Tulandi T, Gosden RG, Eds. Preservation of fertility. New York: Taylor & Francis; 2004:191–205.Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Sherman J. Silber
    • 1
  • Teresa K. Woodruff
    • 2
  • Lonnie D. Shea
    • 3
    • 4
  1. 1.Infertility Center of St. LouisSt. LouisUSA
  2. 2.Feinberg School of MedicineNorthwestern UniversityChicagoUSA
  3. 3.Department of Chemical and Biological EngineeringThe Robert H. Lurie Comprehensive Cancer Center, Northwestern UniversityChicagoUSA
  4. 4.Northwestern UniversityEvanstonUSA

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