Middle East Fertility Society Journal

Vol. 10, No. 1, 2005

Copyright © Middle East Fertility Society

REVIEW

Strategies for fertility preservation and gonadal protection during gonadotoxic chemotherapy and radiotherapy Mohamed A. Bedaiwy, M.D. Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Toronto, and Mount Sinai Hospital, ON, Canada.

ABSTRACT With the recent report of a pregnancy and delivery after autotransplantation of cryopreserved-thawed ovarian cortical strips, preservation of the reproductive potential resurfaced. There is a growing academic and public interest in exploring the available strategies for fertility preservation in patients at risk. This is due to the increasing incidence of cancer during the reproductive age. The overall survival and cure rates of reproductive age cancers are improving due to improvements in cancer therapy. Reproductive derangement is one of the major consequences of cytotoxic chemotherapy and radiotherapy. GnRh analogues concomitant therapy, laparoscopic ovarian transposition, oocyte cryopreservation, embryo cryopreservation and transplantation of cryopreserved-thawed ovarian tissue, are all strategies for fertility preservation in patients at risk. However, no evidence-based strategy is available yet. This article discusses the mechanisms of reproductive failure after gonadotoxic therapy and the currently available fertility preservation strategies. Key words: chemotherapy/fertility preservation/ovarian failure/radiotherapy.

INTRODUCTION About 15 % of treatments of childhood and adolescent cancer carry a substantial risk to future fertility. This risk varies according to the presenting pathology and requires treatment. It has been estimated that at the year of 2000, one in 1000 adults will be a survivor of childhood cancer (1, 2). This was due to the current use of multiagent chemotherapy regimens and/or well-tailored radiotherapy. However, this was on the expense of reproductive functions and future fertility of those patients (3, 4). Consequently, better attention has been paid to prevent reproductive failure in those patients. Address of Correspondence: Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Toronto, and Mount Sinai Hospital, 600 University Avenue, Room 876, Toronto, Ontario M5G 1X5, Canada. Tel: 416-586 - 4800 ext. 2451 Fax: 416-586-8588 e-mail: [email protected]

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Moreover, it was also reported that 650,000 new female cancer cases are estimated to be diagnosed in 2003 in the USA (2). Approximately 8% of them occur during the reproductive years (5). In addition, there is a steady incremental decline of cancer mortality rates for all malignancies in women. It was estimated that the decline rate is 0.6% per year during the period from 1992 to 1999 despite an increase in the incidence by 0.3% per year from 1987 to 1999 (2). The National Cancer Institute (NCI) estimated the number of survivors of all child hood cancers to be 1 per 1000 population in 1997 (6). It is estimated that by the year 2010, 1 in 250 patients will have survived malignancies (7). Summary of the distribution of cancers among women in the reproductive age is shown in table 1. Besides the expected premature ovarian failure and its consequences, multi-agent chemotherapy and high dose radiotherapy may be associated with early

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Fertility preservation in cancer patients

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Table 1. Distribution of cancers among women in the reproductive age Variable Female cancer cases in 2003 Percentage of cancers below the age of 40 ys Survivors of all childhood cancers Survivors of all childhood cancers in 2010

Number/percent/ratio

Source

650,000 8% 270,000 (1/1000 population) 1/250 patients

Jemal et al 2003 Oktay and Yih 2002 Simon 2003 Bleyer 1990

pregnancy loss, premature labor and low birth weight (8, 9). There is a growing concern regarding the future reproductive functions in pediatric oncology survivors. Moreover, the safety of offsprings of those survivors may be subjects to future abnormalities. Consequently, there is increasing demand for a fertility preserving interventions. On the other side, there is an increase in the techniques to preserve fertility via medical protection, surgical procedures, assisted reproduction and cryopreservation (10). In this article we will review the pathophysiology of chemotherapy/radiotherapy induced gonadal toxicity and current techniques of fertility preservation. Possible future options will also be discussed.

CHEMOTHERAPY-INDUCED OVARIAN FAILURE Reproductive age malignancies treated with chemotherapy Premature ovarian failure (POF) is a well-known consequence of exposure of the female gonad to chemotherapeutic drugs (11, 12). A wide variety of malignant and non-malignant conditions during the reproductive age are treated with gonadotoxic chemotherapy (Table 2). Patients are exposed to these agents for treatment of malignancies such as acute lymphoblastic leukemia (ALL). ALL is the commonest childhood malignancy and it is estimated that more than 2000 patients are destined to be longterm survivors of ALL each year (13). In addition to leukemias, patients with Hodgkin's lymphoma, neuroblastoma, non-Hodgkin's lymphoma, Wilm's tumor, Ewing's sarcoma and osteosarcoma of the pelvis and genital rhabdomyosarcoma receiving chemotherapy are at risk of developing POF (14-17).

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Fertility preservation in cancer patients

In addition, breast cancer is the commonest malignancy in women during the reproductive age (18). There is steady rise in the incidence and decline of the case fatality rate of female breast cancer (18). It is estimated that 1 out of every 228 women will develop breast cancer before the age of 40. Moreover, 15% of all breast cancer cases are estimated to occur at 90% for Hodgkin's disease -2000 patients are estimated to become long-term survivors of ALL/year.

Breast cancer

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of cryopreserved ovary induces the generation of antiovary antibodies in sheep. Fertil Steril 2003; 80: 1062-4. 159. Bedaiwy MA and Falcone T. Ovarian tissue banking for cancer patients: reduction of post-transplantation ischaemic injury: intact ovary freezing and transplantation. Hum Reprod 2004; 19: 1242-4. 160. Bedaiwy MFT, Biscotti C, Hussein M. Cryopreservation of intact human ovary with its vascular pedicle. Hum Reprod 2004; i77. 161. Oktay K and Karlikaya G. Ovarian function after transplantation of frozen, banked autologous ovarian tissue. N Engl J Med 2000; 342: 1919. 162. Brook PF, Radford JA, Shalet SM, Joyce AD and Gosden RG. Isolation of germ cells from human testicular tissue for low temperature storage and autotransplantation. Fertil Steril 2001; 75: 269-74. 163. Oktay K, Economos K, Kan M, Rucinski J, Veeck L and Rosenwaks Z. Endocrine function and oocyte retrieval after autologous transplantation of ovarian cortical strips to the forearm. Jama 2001; 286: 1490-3. 164. Callejo J, Salvador C, Miralles A, Vilaseca S, Lailla JM and Balasch J. Long-term ovarian function evaluation after autografting by implantation with fresh and frozenthawed human ovarian tissue. J Clin Endocrinol Metab 2001; 86: 4489-94. 165. Oktay K, Buyuk E, Veeck L, Zaninovic N, Xu K, Takeuchi T, Opsahl M and Rosenwaks Z. Embryo development after heterotopic transplantation of cryopreserved ovarian tissue. Lancet 2004; 363: 837-40. 166. Donnez MMD, Demylle D, Jadoul P, Pirard C, Squifflet J, Martinez-Madrid B, Van Langendonckt A. Livebirth after orthotopic transplantation of cryopreserved ovarian tissue. The Lancet 2004; 364. 167. Oktay K, Nugent D, Newton H, Salha O, Chatterjee P and Gosden RG. Isolation and characterization of primordial follicles from fresh and cryopreserved human ovarian tissue. Fertil Steril 1997; 67: 481-6.

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168. Aubard Y. Ovarian tissue graft: from animal experiment to practice in the human. Eur J Obstet Gynecol Reprod Biol 1999; 86: 1-3. 169. Wang X, Chen H, Yin H, Kim SS, Lin Tan S. and Gosden RG. Fertility after intact ovary transplantation. Nature 2002; 415: 385. 170. Oktay K, Newton H, Mullan J and Gosden RG. Development of human primordial follicles to antral stages in SCID/hpg mice stimulated with follicle stimulating hormone. Hum Reprod 1998; 13: 1133-8. 171. Oktay K, Newton H and Gosden RG. Transplantation of cryopreserved human ovarian tissue results in follicle growth initiation in SCID mice. Fertil Steril 2000; 73: 599-603. 172. Weissman A, Gotlieb L, Colgan T, Jurisicova A, Greenblatt EM and Casper RF. Preliminary experience with subcutaneous human ovarian cortex transplantation in the NOD-SCID mouse. Biol Reprod 1999; 60: 1462-7. 173. Van den Broecke R, Liu J, Van der Elst J and Dhont M. Timing of FSH-stimulation and follicular development in cryopreserved human ovarian grafts. Reprod Biomed Online 2002; 4: 21-6. 174. Abir R, Orvieto R, Raanani H, Feldberg D, Nitke S and Fisch B. Parameters affecting successful transplantation of frozen-thawed human fetal ovaries into immunodeficient mice. Fertil Steril 2003; 80: 421-8. 175. Damewood MD and Grochow LB. Prospects for fertility after chemotherapy or radiation for neoplastic disease. Fertil Steril 1986; 45: 443-59. 176. The ESHRE Task Force on Ethics and Law Taskforce 7. Ethical considerations for the cryopreservation of gametes and reproductive tissues for self use Hum Reprod 2004; 19: 460-462 Received on October 19, 2004; revised and accepted on November 14, 2004

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