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Journal of Clinical Oncology, Vol 25, No 22 (August 1), 2007: pp. 3185-3187 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.11.5097
Regeneration of Oocytes After Chemotherapy: Connecting the Evidence From Mouse to HumanDepartment of Obstetrics and Gynecology, Weill Medical College of Cornell University, New York, NY In this issue, Dr Tilly's laboratory presents another challenge to a half century–old dogma that ovarian reserve, made up of primordial follicles, cannot be replenished after birth.1 Their earlier work indicated that egg manufacturing continued into adult life in mice and that germ stem cells could have originated from the bone marrow2,3; this work was met with much skepticism.4 It has been known for some time that bone marrow transplantation (BMT) and hematopoietic stem-cell transplantation (HSCT) are associated with extremely high rates of ovarian failure and infertility as a result of the preconditioning chemotherapy and radiotherapy.5,6 However, there are numerous reports of spontaneous pregnancies, even years after BMT or HSCT.7-10 Building on those observations and in response to various criticisms of their earlier work, Lee at al1 have tested the question of how BMTs can restore fertility in a rodent model. They found, to their surprise, that the donor-derived eggs from BMTs were not responsible for preservation of fertility in the recipients. All pups that were born after BMT were of recipient origin, even though a small fraction of immature oocytes of donor origin was found in recipient ovaries by cell tracking. The current concept that the ovary has a static ovarian reserve is entirely at odds with the germ cell dynamics in its counterpart, the testis. The testis contains a sizeable number of germ stem cells and continuously generates new gametes, even into old age. Although sperm numbers may diminish slightly at the extreme end of aging, recent research in mice suggested that this is mainly a result of aging of the niche rather than a defect in germ cells.11 The message that is given by Lee at al1 is that the ovary is more like the testis, at least when exposed to chemotherapy. It is not a static organ and continues to produce new germ cells into adult life. Speculatively, perhaps chemotherapy does not simply take away a number of eggs from a fixed ovarian reserve but interferes with the ability of the ovary to regenerate oocytes. If the mice born after BMT had the genetic background of the recipient, how did that procedure restore fertility? The fact that BMTs help maintain fertility despite the reduction in the size of follicle population after chemotherapy suggests that the transplantation may restore the lost germ stem cells, which then enables the ovary to maintain its reserve. Lee et al1 cleverly pointed out that the BMT treatment might have repaired chemotherapy-induced damage to the niche or the ovarian stroma. Indeed, our recent research showed that human ovarian samples taken from women who were previously exposed to various chemotherapy agents produce less estrogen than controls, indicating that chemotherapy may alter ovarian stromal function.12 In addition, there are clinical examples that suggest a role for ovarian niche in recovery from chemotherapy-induced ovarian failure. In a recent report, we described a Hodgkin's lymphoma survivor who underwent subcutaneous ovarian transplantation with previously frozen autologous ovarian tissue.13 Before the transplantation, she was menopausal for 2.5 years as a consequence of an HSCT. Given the spontaneous recovery of ovarian function in the remaining menopausal ovary and recurrent spontaneous pregnancies concurrent with follicle development in the grafted ovary, we speculated that autologous ovarian transplantations may provide the necessary stromal oocyte recruitment/regeneration signals to the ovary that might have been damaged by previous chemotherapy. There could also be additional explanations for the better maintenance of fertility after BMTs. Because the animals that were administered sublethal doses of chemotherapy followed by BMT had lower mortality than the controls, the improved fertility might simply have been a result of improvement of the overall quality of life by that procedure. It would have been interesting to see whether mice treated with BMT better maintained their ovarian cyclicity compared with controls. Unfortunately, vaginal smears were not obtained in the study by Lee et al.1 If a higher fraction of animals continued to cycle in the BMT group, this would explain the higher pregnancy rates. The authors also observed that BMT had less benefit if mating was delayed for 2 months. Although they interpreted this as evidence for potential interaction between the hormonal milieu of pregnancy and BMT treatment in favor of future fertility, this could have also been a result of an accelerated loss of follicles during the months after chemotherapy. Previous work has suggested that primordial follicles that were exposed to chemotherapy and that seem to be morphologically normal under light microscopy may have ultrastructural damage and are eventually cleared from the ovary.14 In support of the interpretation of Lee et al,1 fertility was more severely impaired if BMT was also delayed for 2 months. Thus, it seems that, if BMT is to have a beneficial effect on fertility preservation, it should be performed as soon as the chemotherapy agents are cleared from the systemic circulation. The study did not address the mechanism of fertility protection by BMT, but the authors ruled out the possibility of an immediate germ cell bolus or a salvaging effect on pre-existing oocytes by the transplantations based on the fact that, even though the BMT-treated animals had severely diminished follicle reserve, the fertility rescuing effect was long lasting. They also found only a small number of donor-originated oocytes, which were not mature enough to be ovulated, and none of the newborns were of donor origin. Thus, the authors hypothesized that the BMT works through reinitiating new oocyte production in the host. It will be important to see whether the BMT-treated animals will have delayed reproductive senescence compared with controls because this would support the authors' hypothesis. In support of possible new oocyte production in the adult ovary, we observed longer than expected ovarian function in patients undergoing ovarian transplantation with frozen-banked ovarian tissue. In one example, a breast cancer survivor underwent ovarian tissue cryopreservation at the age of 30 years, before undergoing HSCT. She then became menopausal. We transplanted her ovarian tissue 6 years later. Before ovarian transplantation, her follicle density was determined histologically, and given the low numbers, we only expected a short duration of graft function.15 Because of the initial ischemia after ovarian transplantation, further diminishment occurs in the oocyte reserve of grafts.16 Despite these circumstances, not only was this patient's menopause reversed shortly after ovarian transplantation, but she also continues to have cyclical follicle development in her graft 4 years later. Furthermore, in a fetal ovarian xenograft model, we recently observed that there might be a recovery in primordial follicle numbers after chemotherapy. Because fetal ovary contains predominantly primordial follicles that cannot be distinguished from those in postnatal ovaries, we used it to study the impact of cyclophosphamide on human ovarian reserve in immunodeficient mice. Although 93% of follicles were lost 48 hours after chemotherapy, we observed an increase in the primordial follicle numbers 24 hours later17 (Fig 1). Although this is a preliminary observation and will need further confirmation, and although fetal ovarian tissue may have regenerative capabilities that are not retained in the postnatal life, this observation nevertheless shows that ovaries can at least partially recover from chemotherapy.
It should also be stressed that, even though BMT may be associated with return of fertility in a portion of patients, this is a rare event, and patients of reproductive age should still be referred for fertility preservation by established techniques, when feasible.18 It should also be remembered that BMTs are currently performed with purified hematopoietic stem cells and differ from the crude preparation used in this rodent study. As the authors showed in their previous work,2 the bone marrow cells that express germ cell markers are not of hematopoietic lineage. This point, in addition to the fact that many of these females also receive sterilizing doses of radiotherapy and many others remain on oral contraceptives for presumed ovarian failure, may explain the rarity of pregnancies after HSCT. These are exciting times for fertility preservation. Although assisted reproduction techniques are being perfected and new methods of fertility preservation are being developed to help young cancer survivors live a more fulfilled life, there is hope for less invasive treatments in the future. If the benefit of BMTs in improving the overall quality of life of survivors (and especially the fertility) is corroborated in clinical trials, a new chapter will emerge in fertility preservation. In the meantime, it is extremely important to determine the mechanism by which the BMTs improve fertility in mice and to continue to counsel young patients regarding available cryopreservation technologies.18 AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. AUTHOR CONTRIBUTIONS Conception and design: Kutluk Oktay Administrative support: Kutluk Oktay Provision of study materials or patients: Kutluk Oktay Collection and assembly of data: Ozgur Oktem Data analysis and interpretation: Kutluk Oktay, Ozgur Oktem Manuscript writing: Kutluk Oktay Final approval of manuscript: Kutluk Oktay
REFERENCES
1. Lee H-J, Selesniemi K, Niikura Y, et al: Bone marrow transplantation generates immature oocytes and rescues long-term fertility in a preclinical mouse model of chemotherapy-induced premature ovarian failure. J Clin Oncol 25:3198-3204, 2007 2. Johnson J, Canning J, Kaneko T, et al: Germline stem cells and follicular renewal in the postnatal mammalian ovary. Nature 428:145-150, 2004[CrossRef][Medline] 3. Johnson J, Bagley J, Skaznik-Wikiel M, et al: Oocyte generation in adult mammalian ovaries by putative germ cells derived from bone marrow and peripheral blood. Cell 122:303-315, 2005[CrossRef][Medline] 4. Telfer EE, Gosden RG, Byskov AG, et al: On regenerating the ovary and generating controversy. Cell 122:821-822, 2005[CrossRef][Medline] 5. Sanders JE, Buckner CD, Amos D, et al: Ovarian function following marrow transplantation for aplastic anemia or leukaemia. J Clin Oncol 6:813-818, 1988 6. Sonmezer M, Oktay K: Fertility preservation in female patients. Hum Reprod Update 10:251-266, 2004 7. Salooja N, Chatterjee R, McMillan AK, et al: Successful pregnancies in women following single autotransplant for acute myeloid leukemia with a chemotherapy ablation protocol. Bone Marrow Transplant 13:431-435, 1994[Medline] 8. Sanders JE, Hawley J, Levy W, et al: Pregnancies following high-dose cyclophosphamide with or without high-dose busulfan or total-body irradiation and bone marrow transplantation. Blood 87:3045-3052, 1996 9. Salooja N, Szydlo R, Socie G, et al: Pregnancy outcomes after peripheral blood or bone marrow transplantation: A retrospective study. Lancet 358:271-276, 2001[CrossRef][Medline] 10. Hershlag A, Schuster MW: Return of fertility after autologous stem cell transplantation. Fertil Steril 77:419-421, 2002[CrossRef][Medline] 11. Ryu BY, Orwig KE, Oatley JM, et al: Effects of aging and niche microenvironment on spermatogonial stem cell self-renewal. Stem Cells 24:1505-1511, 2006 12. Oktem O, Oktay K: Quantitative assessment of the impact of chemotherapy on ovarian follicle reserve and stromal function. Cancer [in press] 13. Oktay K: Spontaneous conceptions and live birth after heterotopic ovarian transplantation: Is there a germline stem cell connection? Hum Reprod 21:1345-1348, 2006 14. Familiari G, Caggiati A, Nottola SA, et al: Ultrastructure of human ovarian primordial follicles after combination chemotherapy for Hodgkin's disease. Hum Reprod 8:2080-2087, 1993 15. Oktay K, Buyuk E, Veeck L, et al: Embryo development after heterotopic transplantation of cryopreserved ovarian tissue. Lancet 363:837-840, 2004[CrossRef][Medline] 16. Baird DT, Webb R, Campbell BK, et al: Long-term ovarian function in sheep after ovariectomy and transplantation of autografts stored at –196 C. Endocrinology 140:462-471, 1999 17. Oktay K, Oktem O: Evidence for primordial follicle regeneration post-chemotherapy in human ovarian xenografts. Reprod Sci 14:A790, 2007 18. Lee SJ, Schover LR, Partridge AH, et al: American Society of Clinical Oncology recommendations on fertility preservation in cancer patients. J Clin Oncol 24:2917-2931, 2006 Related Article
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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