Abstract
Improvements in the success of cancer treatments have resulted in increased awareness of the long-term effects of treatment, of which gonadal failure is the most significant. Thus, preservation of fertility potential has become a major goal and could be realized by preventing ovarian toxicity or by cryopreservation of reproductive cells/tissues. This review aimed to critically discuss the current protocols for the management of chemotherapy-inducced/radiotherapy-induced premature ovarian failure (POF). A medical approach using the gonadotropin-releasing hormone analog (GnRHa) may act to protect the gonads during radiation and/or chemotherapy by preferentially steering cells into cell cycle arrest with a decline in responsibility to the chemotherapeutic agents. Ovarian protection by GnRHa cotreatment against chemotherapy can enable the preservation of future fertility in survivors and prevent the bone demineralization and osteoporosis associated with hypestrogenism and POF. In vitro fertilization of retrieved oocytes could enable embryo freezing in some patients. Embryo cryopreservation is considered standard practice and widely available, but may seldom be used because of a lack of a male partner, the need to postpone cancer therapy for a few weeks and the possibility that an estrogen rise may be undesirable in sensitive cancer patients. Improvement in oocyte cryopreservation may offer additional possibilities; the prolonged culture of primordial and primary follicles in vitro is still unfeasible. Currently, the cryopreservation of ovarian cortex, which hosts thousands of immature follicles, is an investigational method, but has the advantage of requiring neither a sperm donor nor ovarian stimulation. Fertility preservation is often possible in women undergoing cancer treatment. To preserve the full range of options, fertility preservation procedures should be considered as early as possible during therapy planning.
Similar content being viewed by others
References
Revel A, Laufer N. Protecting female fertility from cancer therapy. Mol Cell Endocrinol 2002; 187: 83–91.
Maltaris T, Seufert R, Fischl F et al. The effect of cancer treatment on female fertility and strategies for preserving fertility. Eur J Obstet Gynecol Reprod Biol 2007; 130: 148–155.
Yap J, Davies M. Fertility preservation in female cancer survivors. J Obstet Gynaecol 2007; 27: 390–400.
Mertens A, Ramsay N, Kouris S, Neglia J. Patterns of gonadal dysfunction following bone marrow transplantation. Bone Marrow Transplant 1998; 22: 345–350.
Teinturier C, Hartmann O, Valteau-Couanet DEB, Bougneres P. Ovarian function after autologous bone marrow transplantation in childhood: high-dose busulfan is a major cause of ovarian failure. Bone Marrow Transplant 1998; 22: 989–994.
Oktay K, Kan M, Rosenwaks Z. Recent progress in oocyte and ovarian tissue cryopreservation and transplantation. Curr Opin Obstet Gynecol 2001; 13: 263–268.
Howell S, Shalet S. Gonadal damage from chemotherapy and radiotherapy. Endocrinol Metab Clin North Am 1998; 27: 927–943.
Meirow D. Reproduction post-chemotherapy in young cancer patients. Mol Cell Endocrinol 2000; 169: 123–131.
Meirow D, Nugent D. The effects of radiotherapy and chemotherapy on female reproduction. Hum Reprod Update 2001; 7: 535–543.
Larsen E, Muller J, Schmiegelow K, Rechnitzer C, Andersen A. Reduced ovarian function in long-term survivors of radiation-and chemotherapy-treated childhood cancer. J Clin Endocrinol Metab 2003; 88: 5307–5314.
Travis L, Hill D, Dores G et al. Breast cancer following radiotherapy and chemotherapy among young women with Hodgkin disease. JAMA 2003; 290: 465–475.
Howell S, Shalet S. Testicular function following chemotherapy. Hum Reprod Update 2001; 7: 363–369.
Lee S, Schover L, Partridge A et al. American Society of Clinical Oncology recommendations on fertility preservation in cancer patients. J Clin Oncol 2006; 20: 2917–1931.
Marhhom E, Cohen I. Fertility preservation options for women with malignancies. Obstet Gynecol Surv 2007; 62: 58–72.
Heath J, Stern C. Fertility preservation in children newly diagnosed with cancer: existing standards of practice in Australia and New Zealand. Med J Aust 2006; 185: 538–541.
Burstein H, Winer E. Primary care for survivors of breast cancer. N Engl J Med 2000; 343: 1089–1094.
Goodwin P, Ennis M, Pritchard K, Trudeau M, Hood N. Risk of menopause during the first year after breast cancer diagnosis. J Clin Oncol 1999; 17: 2365–2370.
Grigg A. The impact of conventional and high-dose therapy for lymphoma on fertility. Clin Lymphoma 2004; 5: 84–88.
Wallace W, Anderson R, Irvine D. Fertility preservation for young patients with cancer: who is at risk and what can be offered? Lancet Oncol 2005; 6: 209–218.
Brydøy M, Fosså S, Dahl O, Bjøro T. Gonadal dysfunction and fertility problems in cancer survivors. Acta Oncol 2007; 46: 480–490.
Meirow D. Ovarian injury and modern options to preserve fertility in female cancer patients treated with high dose radio-chemotherapy for hemato-oncological neoplasias and other cancers. Leuk Lymphoma 1999; 33: 65–76.
Schimmer A, Quatermain M, Imrie K et al. Ovarian function after autologous bone marrow transplantation. J Clin Oncol 1998; 16: 2359–2363.
Clark S, Radford D, Crowther R, Swindell S, Shalet S. Gonadal function following chemotherapy for Hodgkin’s disease: a comparative study of MVPP and a seven-drug hybrid regimen. J Clin Oncol 1995; 13: 134–139.
Meirow D, Ben Yehuda D, Prus D et al. Ovarian tissue banking in patients with Hodgkin’s disease: is it safe? Fertil Steril 1998; 69: 996–998.
Blumenfeld Z. Preservation of fertility and ovarian function and minimalization of chemotherapy associated gonadotoxicity and premature ovarian failure: the role of inhibin-A and -B as markers. Mol Cell Endocrinol 2002; 187: 93–105.
Blumenfeld Z, Dann E, Avivi I, Epelbaum R, Rowe J. Fertility after treatment for Hodgkin’s disease. Ann Oncol 2002; 13: 138–147.
Blumenfeld Z. Ovarian rescue/protection from chemotherapeutic agents. J Soc Gynecol Invest 2001; 8: S60-S64.
Blumenfeld Z, Shapiro D, Shteinberg M, Avivi I, Nahir M. Preservation of fertility and ovarian function and minimizing gonadotoxicity in young women with systemic lupus erythematosus treated by chemotherapy. Lupus 2000; 9: 401–405.
Chapman R, Sutcliffe S, Malpas J. Cytotoxic-induced ovarian failure in women with Hodgkin’s disease. I. Hormone function. J Am Med Assoc 1979; 242: 1877–1881.
Familiari G, Caggiati A, Nottola S, Ermini M, Di Benedetto M, Motta P. Ultrastructure of human ovarian primordial follicles after combination chemotherapy for Hodgkin’s disease. Hum Reprod 1993; 8: 2080–2097.
Critchley H, Bath L, Wallace W Radiation damage to the uterus — review of the effects of treatment of childhood cancer. Hum Fertil (Camb) 2002; 5: 61–66.
Critchley H, Wallace W. Impact of cancer treatment on uterine function. J Natl Cancer Inst Monogr 2005; 34: 64–68.
Sugiyama M, Imai A, Takahashi S, Hirano S, Furui T, Tamaya T. Advanced indications for gonadotropin-releasing hormone (GnRH) analogues in gynecological oncology. Int J Oncol 2003; 25: 445–452.
Howell S, Shalet S. Effect of cancer therapy on pituitarytesticular axis. Int J Androl 2002; 25: 269–276.
Howell S, Shalet S. Fertility preservation and management of gonadal failure associated with lymphoma therapy. Curr Oncol Rep 2002; 4: 443–452.
Barlow D. Premature ovarian failure. Baillieres Clin Obstet Gynaecol 1996; 10: 361–384.
Thomson A, Critchley H, Kelnar C, Wallace W. Late reproductive sequelae following treatment of childhood cancer and options for fertility preservation. Best Pract Res Clin Endocrinol Metab 2002; 16: 311–334.
Davis V. Female gamete preservation. Cancer 2006; 107: 1690–1694.
Cohen I, Speroff L. Premature ovarian failure: update. Obstet Gynecol Surv 1991; 46: 156–162.
Cusido L, Pujol R, Egozcue J, Garcia M. Cyclophosphamideinduced synaptonemal complex damage during meiotic prophase of female Rattus norvegicus. Mutat Res 1995; 329: 131–141.
Pacheco B, Ribas J, Milone G et al. Use of GnRH analogs for functional protection of the ovary and preservation of fertility during cancer treatment in adolescents: a preliminary report. Gynecol Oncol 2001; 81: 391–397.
Imai A, Sugiyama M, Furui T, Tamaya T. Protective action of gonadotropin-releasing hormone (GnRH) analogue against chemotherapy-associated ovarian failure and female fertility. Trend Reprod Biol 2005; 1: 57–61.
Huirne J, Lambalk C. Gonadotropin-releasing-hormonereceptor antagonists. Lancet 2001; 358: 1793–1803.
Imai A, Furui T, Sugiyama M, Tamaya T. Gonadotropinreleasing hormone (GnRH) analogues in anticancer management: clinical applications and antiproliferative signaling. Curr Top Pharmacol 2002; 6: 119–128.
Mardesic T, Snajderova M, Sramkova L, Keslova P, Sedlacek P, Stary J. Protocol combining GnRH agonists and GnRH antagonists for rapid suppression and prevention of gonadal damage during cytotoxic therapy. Eur J Gynaecol Oncol 2004; 25: 90–92.
Meirow D, Assad G, Dor J, Rabinovici J. The GnRH antagonist cetrorelix reduces cyclophosphamide-induced ovarian follicular destruction in mice. Hum Reprod 2004; 19: 1294–1299.
Ataya K, Pydyn E, Ramahi-Ataya A, Orton C. Is radiationinduced ovarian failure in rhesus monkeys preventable by luteinizing hormone-releasing hormone agonists?: preliminary observations. J Clin Endocrinol Metab 1995; 80: 790–795.
Ataya K, Rao L, Lawrence E, Kimmel R. Luteinizing hormonereleasing hormone agonist inhibits cyclophosphamide-induced ovarian follicular depletion in rhesus monkeys. Biol Reprod 1995; 52: 365–372.
Blumenfeld Z, Avivi I, Linn S, Epelbaum R, Ben-Shahar M, Haim N. Prevention of irreversible chemotherapy-induced ovarian damage in young women with lymphoma by a gonadotrophin-releasing hormone agonist in parallel to chemotherapy. Hum Reprod 1997; 11: 1620–1626.
Blumenfeld Z, Haim N. Prevention of gonadal damage during cytotoxic therapy. Ann Med 1997; 29: 199–206.
Recchia F, Sica G, De Filippis S, Saggio G, Rosselli M, Rea S. Goserelin as ovarian protection in the adjuvant treatment of premenopausal breast cancer: a phase II pilot study. Anticancer Drugs 2002; 13: 417–424.
Lee P, Houk C. Gonadotropin-releasing hormone analog therapy for central precocious puberty and other childhood disorders affecting growth and puberty. Treat Endocrinol 2006; 5: 287–296.
Wildiers H, Neven P, Amant F, D’hooghe T, Paridaens R. Fertility preservation in (breast) cancer patients: is it safe? J Clin Oncol 2006; 24: 5335–5336.
Imai A, Tamaya T. GnRH receptor and apoptotic signaling. Vitam Horm 2000; 59: 1–33.
Sealfon S, Weinstein H, Millar R. Molecular mechanisms of ligand interaction with the gonadotropin-releasing hormone receptor. Endocr Rev 1997; 18: 180–205.
Imai A, Iida K, Tamaya T. Tight coupling of gonadotropinreleasing hormone receptor to stimulated phosphoinositide turnover and antigonadotropic action in granulosa cells. Gynecol Obstet Invest 1992; 33: 36–41.
Grundker C, Schulz K, Gunthert A, Emons G. Luteinizing hormone-releasing hormone induces nuclear factor kappaB-activation and inhibits apoptosis in ovarian cancer cells. J Clin Endocrinol Metab 2000; 85: 3810–3820.
Hsueh A, Eisenhauer K, Chun S, Hsu S, Billig H. Gonadal cell apoptosis. Recent Prog Horm Res 1996; 51: 433–455.
Yuan W, Giudice L. Programmed cell death in human ovary is a function of follicle and corpus luteum status. J Clin Endocrinol Metab 1997; 82: 3148–3155.
Hernandez E. Embryo implantation and GnRH antagonists: embryo implantation: the Rubicon for GnRH antagonists. Hum Reprod 2000; 15: 1211–1216.
Lockshin R, Zakeri Z. Programmed cell death and apoptosis: origins of the theory. Nat Rev Mol Cell Biol 2001; 2: 545–550.
Funston R, Seidel Gj. Gonadotropin-releasing hormone increases cleavage rates of bovine oocytes fertilized in vitro. Biol Reprod 1995; 53: 541–545.
Morita Y, Perez G, Paris F et al. Oocyte apoptosis is suppressed by disruption of the acid sphingomyelinase gene or by sphingosine-1-phosphate therapy. Nat Med 2000; 6: 1109–1114.
Azim A, Oktay K. Letrozole for ovulation induction and fertility preservation by embryo cryopreservation in young women with endometrial carcinoma. Fertil Steril 2007; 88: 657–664.
Mitwally M. Fertility preservation and minimizing reproductive damage in cancer survivors. Expert Rev Anticancer Ther 2007; 7: 989–1001.
Oktay K, Pelin A, Bang H. Efficiency of oocyte cryopreservation: a meta-analysis. Fetil Steril 2006; 86: 70–80.
West E, Shea L, Woodruff T. Engineering the follicle microenvironment. Semin Reprod Med 2007; 25: 287–299.
Sonmezer M, Oktay K. Fertility preservation in young women undergoing breast cancer therapy. Oncologist 2006; 11: 422–434.
Oktay K, Buyuk E, Libertella N, Akar M, Rosenwaks Z. Fertility preservation in breast cancer patients: a prospective controlled comparison of ovarian stimulation with tamoxifen and letrozole for embryo cryopreservation. J Clin Oncol 2005; 23: 4347–4353.
Ginsburg E, Yanushpolsky E, Jackson K. In vitro fertilization for cancer patients and survivors. Fertil Steril 2001; 75: 705–710.
Meirow D, Lewis H, Nugent D, Epstein M. Subclinical depletion of primordial follicular reserve in mice treated with cyclophosphamide: clinical importance and proposed accurate investigative tool. Hum Reprod 1999; 14: 1903–1907.
Oktay K. Further evidence on the safety and success of ovarian stimulation with letrozole and tamoxifen in breast cancer patients undergoing in vitro fertilization to cryopreserve their embryos for fertility preservation. J Clin Oncol 2005; 23: 3858–3859.
Practice Committee of the American Society for Reproductive Medicine. Ovarian tissue and oocyte cryopreservation. Fertil Steril 2006; 86: S142-S147.
Kuwayama M. Highly efficient vitrification for cryopreservation of human oocytes and embryos: the Cryotop method. Theriogenology 2007; 67: 73–80.
Kuwayama M, Vajta G, Kato O, Leibo S. Highly efficient vitrification method for cryopreservation of human oocytes. Reprod Biomed Online 2005; 11: 300–308.
Shamonki M, Oktay K. Oocyte and ovarian tissue cryopreservation: indications, techniques and applications Semin Reprod Med 2005; 23: 266–276.
Sonmezer M, Shamonki M, Oktay K. Ovarian tissue cryopreservation: benefits and risk. Cell Tissue Res 2005; 322: 125–132.
Borini A, Lagalla C, Cattoli M et al. Predictive factors for embryo implantation potential. Reprod Biomed Online 2005; 10: 653–668.
Borini A, Sciajno R, Bianchi V, Sereni E, Flamigni C, Coticchio G. Clinical outcome of oocyte cryopreservation after slow cooling with a protocol utilizing a high sucrose concentration. Hum Reprod 2006; 21: 512–517.
Zenzes M, Bielecki R, Casper R, Leibo S. Effects of chilling to 0 degrees C on the morphology of meiotic spindles in human metaphase II oocytes. Fertil Steril 2001; 75: 769–777.
Yamawaki K, Aono N, Yoshida H, Sato E. Cryopreservation and in vitro maturation of germinal vesicle stage oocytes of animals for application in assisted reproductive technology. Reprod Med Biol 2007; 6: 61–68.
Demeestere I, Simon P, Emiliani S, Delbaere A, Englert Y Options to preserve fertility before oncological treatment: cryopreservation of ovarian tissue and its clinical application. Acta Clin Belg 2006; 61: 259–263.
Martin J, Kodaman P, Oktay K, Taylor H. Ovarian cryopreservation with transposition of a contralateral ovary: a combined approach for fertility preservation in women receiving pelvic radiation. Fertil Steril 2007; 87: e5-e7.
Moffa F, Biacchiardi C, Fagioli F et al. Ovarian tissue cryostorage and grafting: an option to preserve fertility in pediatric patients with malignancies. Pediatr Hematol Oncol 2007; 24: 29–44.
Donnez J, Martinez-Madrid B, Jadoul P, Van Langendonckt A, Demylle D, Dolmans M. Ovarian tissue cryopreservation and transplantation: a review. Hum Reprod Update 2006; 12: 519–535.
Maltaris T, Dragonas C, Hoffmann I, Mueller A, Beckmann M, Dittrich R. Simple prediction of the survival of follicles in cryopreserved human ovarian tissue. J Reprod Dev 2006; 52: 577–582.
Weintraub M, Gross E, Kadari A et al. Should ovarian cryopreservation be offered to girls with cancer. Pediatr Blood Cancer 2007; 48: 4–9.
Hasegawa A, Koyama K. In vitro growth and maturation of mouse oocyte-granulosa cell complex from cryopreserved ovaries and achievement of pup birth. Reprod Med Biol 2007; 6: 77–83.
Meirow D, Levron J, Eldar-Geva T et al. Pregnancy after transplantation of cryopreserved ovarian tissue in a patient with ovarian failure after chemotherapy. N Engl J Med 2005; 21: 318–321.
Oktay K. Fertility preservation: an emerging discipline in the care of young patients with cancer. Lancet Oncol 2005; 6: 192–193.
Jakimiuk A, Grzybowski W. Ovarian tissue preservation, present and clinical perspectives. Gynecol Endocrinol 2007; 23: 87–93.
Feigin E, Abir R, Fisch B et al. Laparoscopic ovarian tissue preservation in young patients at risk for ovarian failure as a result of chemotherapy/irradiation for primary malignancy. J Pediatr Surg 2007; 42: 862–864.
Poirot C, Vacher-Lavenu M, Helardot P, Guibert J, Brugieres L, Jouannet P. Human ovarian tissue cryopreservation: indications and feasibility. Hum Reprod 2002; 17: 1447–1452.
Oktay K. Evidence for limiting ovarian tissue harvesting for the purpose of transplantation to women younger than 40 years of age. J Clin Endocrinol Metab 2002; 87: 1907–1908.
Oktay K, Karlikaya G. Ovarian function after transplantation of frozen, banked autologous ovarian tissue. N Engl J Med 2000; 342: 1919.
Donnez J, Dolmans M, Demylle D et al. Livebirth after orthotopic transplantation of cryopreserved ovarian tissue. Lancet 2004; 364: 1405–1410.
Shaw J, Bowles J, Koopman P, Wood E, Trounson A. Fresh and cryopreserved ovarian tissue samples from donors with lymphoma transmit the cancer to graft recipients. Hum Reprod 1996; 11: 1668–1673.
Nishio S, Ushijima K, Fukui A et al. Fertility-preserving treatment for patients with malignant germ cell tumors of the ovary. J Obstet Gynaecol Res 2006; 32: 416–421.
Posada M, Kolp L, Gaivia J. Fertility options for female cancer patients: facts and fiction. Fertil Steril 2001; 75: 647–653.
Carter J, Lewin S, Abu-Rustum N, Sonoda Y. Reproductive issues in the gynecologic cancer patient. Oncology (Williston Park) 2007; 21: 606–609.
Author information
Authors and Affiliations
Corresponding author
About this article
Cite this article
Imai, A., Furui, T. & Yamamoto, A. Preservation of female fertility during cancer treatment. Reprod Med Biol 7, 17–27 (2008). https://doi.org/10.1111/j.1447-0578.2007.00197.x
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1111/j.1447-0578.2007.00197.x