Abstract
The natural depletion of the finite number of follicles present in the ovaries can be accelerated by cancer treatment, leading to acute ovarian failure or premature menopause. The negative impact of cancer therapy on ovarian follicular reserve, hypothalamic-pituitary-ovarian axis function, uterine function, and cardiac function can impact the ability of female cancer survivors to conceive or carry a biologic pregnancy to term. Chemotherapeutic agents that affect the cell cycle interfere with growing follicles, whereas alkylating agents have a non-cycle-specific mechanism of action leading to single- and double-strand DNA breaks, thereby potentially affecting both quiescent and dividing cells in the ovary. Chemotherapy can also lead to cortical fibrosis, blood vessel damage, and stromal damage in the ovary. The impact of cancer treatment on reproductive potential depends on the age of the patient, the chemotherapeutic agents used, the duration of treatment, the total cumulative dose administered, and patient-specific factors. Current efforts are focusing on determining the gonadotoxicity of specific chemotherapeutic regimens rather than single agents. Irradiation of the ovaries (in total body radiation; direct pelvic, abdominal, or spinal irradiation; or scatter irradiation) of 1–2 Gy in girls and 4–6 Gy in adults depletes the follicle population and permanently impacts ovarian function. Posttreatment, reproductive capacity should be monitored through the measurement of gonadotropins and markers of follicle health, such as anti-Müllerian hormone (AMH).
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References
National Cancer Institute Surveillance Epidemiology and End Results. Fast stats. 2011. http://seer.cancer.gov/faststats/selections.php?run=runit%26output=2%26data=1%26statistic=1%26cancer=1%26year=201103%26race=1%26sex=3%26series=age%26age=9. Accessed 16 Nov 2011.
Canada AL, Schover LR. The psychosocial impact of interrupted childbearing in long-term female cancer survivors. Psychooncology. 2010. doi:10.1002/pon.1875.
Tschudin S, Bitzer J. Psychological aspects of fertility preservation in men and women affected by cancer and other life-threatening diseases. Hum Reprod Update. 2009;15:587–97.
Schover LR, et al. Having children after cancer. A pilot survey of survivors’ attitudes and experiences. Cancer. 1999;86:697–709.
Tschudin S, et al. Correlates of fertility issues in an internet survey of cancer survivors. J Psychosom Obstet Gynaecol. 2010;31:150–7.
Goodwin T, et al. Attitudes and practices of pediatric oncology providers regarding fertility issues. Pediatr Blood Cancer. 2007;48:80–5.
Quinn GP, et al. Physician referral for fertility preservation in oncology patients: a national study of practice behaviors. J Clin Oncol. 2009;27:5952–7.
Johnson J, et al. Germline stem cells and follicular renewal in the postnatal mammalian ovary. Nature. 2004;428:145–50.
SteadyHealth.com. How to count your menstrual cycle. 2011. http://ic.steadyhealth.com/how_to_count_your_menstrual_cycle.html. Accessed 12 Nov 2011.
te Velde ER, et al. Developmental and endocrine aspects of normal ovarian aging. Mol Cell Endocrinol. 1998;145:67–73.
Johnston RJ, Wallace WH. Normal ovarian function and assessment of ovarian reserve in the survivor of childhood cancer. Pediatr Blood Cancer. 2009;53:296–302.
Yu B, et al. Changes in markers of ovarian reserve and endocrine function in young women with breast cancer undergoing adjuvant chemotherapy. Cancer. 2010;116:2099–105.
Epstein RJ. Drug-induced DNA damage and tumor chemosensitivity. J Clin Oncol. 1990;8:2062–84.
Meirow D, et al. Cortical fibrosis and blood-vessels damage in human ovaries exposed to chemotherapy. Potential mechanisms of ovarian injury. Hum Reprod. 2007;22:1626–33.
Green DM, et al. Ovarian failure and reproductive outcomes after childhood cancer treatment: results from the Childhood Cancer Survivor Study. J Clin Oncol. 2009;27:2374–81.
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.
Maltaris T, et al. The effect of cancer treatment on female fertility and strategies for preserving fertility. Eur J Obstet Gynecol Reprod Biol. 2007;130:148–55.
Soleimani R, et al. Mechanisms of chemotherapy-induced human ovarian aging: double strand DNA breaks and microvascular compromise. Aging. 2011;3:782–93.
De Bruin ML, et al. Treatment-related risk factors for premature menopause following Hodgkin lymphoma. Blood. 2008;111:101–8.
Falcone T. Preservation of fertility in the cancer patient. MedGenMed. 2005;7:65.
Fertile Hope. Women: risk of amenorrhea from chemotherapy and radiation treatments for cancer. 2007. http://www.fertilehope.org/healthcare-professionals/clinical-tools/RiskAmenorrhea_v3.pdf. Accessed 16 Nov 2011.
Whitehead E, et al. The effect of combination chemotherapy on ovarian function in women treated for Hodgkin’s disease. Cancer. 1983;52:988–93.
Schilsky RL, et al. Long-term follow up of ovarian function in women treated with MOPP chemotherapy for Hodgkin’s disease. Am J Med. 1981;71:552–6.
Kreuser ED, et al. Long-term gonadal dysfunction and its impact on bone mineralization in patients following COPP/ABVD chemotherapy for Hodgkin’s disease. Ann Oncol. 1992;3:105–10.
Behringer K, et al. Secondary amenorrhea after Hodgkin’s lymphoma is influenced by age at treatment, stage of disease, chemotherapy regimen, and the use of oral contraceptives during therapy: a report from the German Hodgkin’s Lymphoma Study Group. J Clin Oncol. 2005;23:7555–64.
Brusamolino E, et al. Treatment of early-stage Hodgkin’s disease with four cycles of ABVD followed by adjuvant radio-therapy: analysis of efficacy and long-term toxicity. Haematologica. 2000;85:1032–9.
Minton SE, Munster PN. Chemotherapy-induced amenorrhea and fertility in women undergoing adjuvant treatment for breast cancer. Cancer Control. 2002;9:466–72.
Bines J, Oleske DM, Cobleigh MA. Ovarian function in premenopausal women treated with adjuvant chemotherapy for breast cancer. J Clin Oncol. 1996;14:1718–29.
Tham YL, et al. The rates of chemotherapy-induced amenorrhea in patients treated with adjuvant doxorubicin and cyclophosphamide followed by a taxane. Am J Clin Oncol. 2007;30:126–32.
Sanders JE, et al. Pregnancies following high-dose cyclophosphamide with or without high-dose busulfan or total-body irradiation and bone marrow transplantation. Blood. 1996;87:3045–52.
Wallace WH, Thomson AB, Kelsey TW. The radiosensitivity of the human oocyte. Hum Reprod. 2003;18:117–21.
Lushbaugh CC, Casarett GW. The effects of gonadal irradiation in clinical radiation therapy: a review. Cancer. 1976;37:1111–25.
Wallace WH, et al. Predicting age of ovarian failure after radiation to a field that includes the ovaries. Int J Radiat Oncol Biol Phys. 2005;62:738–44.
Thomson AB, et al. Late reproductive sequelae following treatment of childhood cancer and options for fertility preservation. Best Pract Res Clin Endocrinol Metab. 2002;16:311–34.
Bath LE, et al. Ovarian and uterine characteristics after total body irradiation in childhood and adolescence: response to sex steroid replacement. Br J Obstet Gynaecol. 1999;106:1265–72.
Wallace WH, et al. Ovarian failure following abdominal irradiation in childhood: the radiosensitivity of the human oocyte. Br J Radiol. 1989;62:995–8.
Bath LE, et al. Hypothalamic-pituitary-ovarian dysfunction after prepubertal chemotherapy and cranial irradiation for acute leukaemia. Hum Reprod. 2001;16:1838–44.
Shepherd JH, et al. Radical vaginal trachelectomy as a fertility-sparing procedure in women with early-stage cervical cancer-cumulative pregnancy rate in a series of 123 women. BJOG. 2006;113:719–24.
Children’s Oncology Group. HealthLink: healthy living after treatment for childhood cancer. 2008. http://survivorshipguidelines.org/pdf/HeartHealth.pdf. Accessed 11 Nov 2011.
Green DM, et al. Fertility of female survivors of childhood cancer: a report from the childhood cancer survivor study. J Clin Oncol. 2009;27:2677–85.
Letourneau JM, et al. Acute ovarian failure underestimates age-specific reproductive impairment for young women undergoing chemotherapy for cancer. Cancer. 2011. doi:10.1002/cncr.26403.
Anderson RA, et al. The effects of chemotherapy and long-term gonadotrophin suppression on the ovarian reserve in premenopausal women with breast cancer. Hum Reprod. 2006;21:2583–92.
Lutchman Singh K, Davies M, Chatterjee R. Fertility in female cancer survivors: pathophysiology, preservation and the role of ovarian reserve testing. Hum Reprod Update. 2005;11:69–89.
de Vet A, et al. Antimullerian hormone serum levels: a putative marker for ovarian aging. Fertil Steril. 2002;77:357–62.
Anderson RA, Cameron DA. Pretreament serum anti-Mullerian hormone predicts long-term ovarian function and bone mass after chemotherapy for early breast cancer. J Clin Endocrinol Metab. 2011;96:1336–43.
Rosendahl M, et al. Dynamics and mechanisms of chemotherapy-induced ovarian follicular depletion in women of fertile age. Fertil Steril. 2010;94(1):156–66.
Larsen EC, et al. Diminished ovarian reserve in female childhood cancer survivors with regular menstrual cycles and basal FSH <10 IU/l. Hum Reprod. 2003;18(2):417–22.
Bath LE, et al. Depletion of ovarian reserve in young women after treatment for cancer in childhood: detection by anti-Mullerian hormone, inhibin B and ovarian ultrasound. Hum Reprod. 2003;18(11):2368–74.
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This work was supported by the Oncofertility Consortium NIH/NICHD 5UL1DE019587.
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Levine, J. (2012). Gonadotoxicity of Cancer Therapies in Pediatric and Reproductive-Age Females. In: Gracia, C., Woodruff, T. (eds) Oncofertility Medical Practice. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-9425-7_1
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