Ovarian failure due to anticancer drugs and radiation
- Corrine K Welt, MD
Corrine K Welt, MD
- Professor of Medicine
- University of Utah School of Medicine
- Charles L Shapiro, MD
Charles L Shapiro, MD
- Professor of Medicine
- Co-Director of Dubin Breast Center
- Director of Translational Breast Cancer Research
- Director of Cancer Survivorship, Tisch Cancer Institute
- Section Editors
- Robert L Barbieri, MD
Robert L Barbieri, MD
- Editor-in-Chief — Obstetrics, Gynecology and Women's Health
- Section Editor — General Gynecology and Female Reproductive Endocrinology
- Kate Macy Ladd Professor of Obstetrics, Gynecology and Reproductive Biology
- Harvard Medical School
- William F Crowley, Jr, MD
William F Crowley, Jr, MD
- Section Editor — Female Reproductive Endocrinology
- Daniel K Podolsky Professor of Medicine
- Harvard Medical School
Several toxins can cause primary hypogonadism. Some are lifesaving therapies, such as anticancer drugs and radiation therapy. Others include cigarette smoke, chemicals, pesticides, viruses, and radioactivity. Anticancer drugs and radiation therapy are the most common of the known ovarian toxins, and will become an increasingly frequent cause of ovarian failure. It is estimated that up to 1 in 1000 persons under age 20 years will have been cured of cancer by these treatments by the year 2000, and many of them will have forgotten their treatment by the time they seek care for reproductive dysfunction. As an example, in a survey of 1928 adult survivors of childhood cancer, 14 percent denied having had cancer and 18 percent misclassified their treatment . Ovarian failure due to anticancer drugs and radiation will be reviewed here. Other causes of premature ovarian failure, an overview of fertility in cancer survivors, and options for fertility preservation in patients undergoing gonadotoxic therapy are discussed elsewhere. (See "Pathogenesis and causes of spontaneous primary ovarian insufficiency (premature ovarian failure)" and "Overview of infertility and pregnancy outcome in cancer survivors" and "Fertility preservation in patients undergoing gonadotoxic treatment or gonadal resection".)
Ovarian effects — Most anticancer drugs affect dividing cells and, therefore, would be expected to affect the granulosa and theca cells of the ovary more than the nondividing oocytes. However, the effect of these drugs on ovarian function varies widely, some having no effect and others causing permanent hypogonadism (table 1). Typically, the ovaries of women who received chemotherapy have normal to mildly decreased numbers of primordial follicles and a greater decrease in the numbers of larger maturing follicles [2,3], indicating a greater effect on follicular development than on oocytes.
Consistent with these histology findings are the clinical observations that many women, especially under 40 years of age, develop amenorrhea during chemotherapy, often with high serum gonadotropin concentrations, but menstrual function and, in some cases, fertility, may return several months to years after the cessation of therapy [4-6].
Individual agents — Alkylating drugs, such as cyclophosphamide, are the best documented and most potent at inducing ovarian failure. They alter base pairs, leading to DNA cross-links, and introduce single-strand DNA breaks . As a result, they can theoretically affect both resting cells, such as oocytes, and dividing cells. The effects are age, dose, and drug-dependent. Younger women are affected less often than older women, presumably because they have more remaining oocytes. In one study, as an example, all women over age 40 years had amenorrhea after receiving more than 5.2 g of cyclophosphamide, whereas the dose required to cause amenorrhea in younger women was 9.5 g .
Variable susceptibility to ovarian dysfunction — However, there is considerable variation in susceptibility, with some women having normal ovarian function but others of the same age having permanent primary hypogonadism after high doses of a single drug. (See "Acute side effects of adjuvant chemotherapy for early stage breast cancer" and "Patterns of relapse and long-term complications of therapy in breast cancer survivors" and "General toxicity of cyclophosphamide in rheumatic diseases".)
- Byrne J, Lewis S, Halamek L, et al. Childhood cancer survivors' knowledge of their diagnosis and treatment. Ann Intern Med 1989; 110:400.
- Warne GL, Fairley KF, Hobbs JB, Martin FI. Cyclophosphamide-induced ovarian failure. N Engl J Med 1973; 289:1159.
- Nicosia SV, Matus-Ridley M, Meadows AT. Gonadal effects of cancer therapy in girls. Cancer 1985; 55:2364.
- Siris ES, Leventhal BG, Vaitukaitis JL. Effects of childhood leukemia and chemotherapy on puberty and reproductive function in girls. N Engl J Med 1976; 294:1143.
- Bakri YN, Pedersen P, Nassar M. Normal pregnancy after curative multiagent chemotherapy for choriocarcinoma with brain metastases. Acta Obstet Gynecol Scand 1991; 70:611.
- Hershlag A, Schuster MW. Return of fertility after autologous stem cell transplantation. Fertil Steril 2002; 77:419.
- Epstein RJ. Drug-induced DNA damage and tumor chemosensitivity. J Clin Oncol 1990; 8:2062.
- Koyama H, Wada T, Nishizawa Y, et al. Cyclophosphamide-induced ovarian failure and its therapeutic significance in patients with breast cancer. Cancer 1977; 39:1403.
- Anderson RA, Cameron DA. Pretreatment serum anti-müllerian hormone predicts long-term ovarian function and bone mass after chemotherapy for early breast cancer. J Clin Endocrinol Metab 2011; 96:1336.
- Gracia CR, Sammel MD, Freeman E, et al. Impact of cancer therapies on ovarian reserve. Fertil Steril 2012; 97:134.
- Dunlop CE, Anderson RA. Uses of anti-Müllerian hormone (AMH) measurement before and after cancer treatment in women. Maturitas 2015; 80:245.
- Stillman RJ, Schinfeld JS, Schiff I, et al. Ovarian failure in long-term survivors of childhood malignancy. Am J Obstet Gynecol 1981; 139:62.
- Schilsky RL, Sherins RJ, Hubbard SM, 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.
- Bines J, Oleske DM, Cobleigh MA. Ovarian function in premenopausal women treated with adjuvant chemotherapy for breast cancer. J Clin Oncol 1996; 14:1718.
- Quigley C, Cowell C, Jimenez M, et al. Normal or early development of puberty despite gonadal damage in children treated for acute lymphoblastic leukemia. N Engl J Med 1989; 321:143.
- Baker TG. Radiosensitivity of mammalian oocytes with particular reference to the human female. Am J Obstet Gynecol 1971; 110:746.
- Raymond JP, Izembart M, Marliac V, et al. Temporary ovarian failure in thyroid cancer patients after thyroid remnant ablation with radioactive iodine. J Clin Endocrinol Metab 1989; 69:186.
- Ash P. The influence of radiation on fertility in man. Br J Radiol 1980; 53:271.
- GANS B, BAHARY C, LEVIE B. OVARIAN REGENERATION AND PREGNANCY FOLLOWING MASSIVE RADIOTHERAPY FOR DYSGERMINOMA. REPORT OF A CASE. Obstet Gynecol 1963; 22:596.
- Horning SJ, Hoppe RT, Kaplan HS, Rosenberg SA. Female reproductive potential after treatment for Hodgkin's disease. N Engl J Med 1981; 304:1377.
- Green DM, Yakar D, Brecher ML, et al. Ovarian function in adolescent women following successful treatment for non-Hodgkin's lymphoma. Am J Pediatr Hematol Oncol 1983; 5:27.
- Wallace WH, Thomson AB, Kelsey TW. The radiosensitivity of the human oocyte. Hum Reprod 2003; 18:117.
- Wallace WH, Thomson AB, Saran F, Kelsey TW. Predicting age of ovarian failure after radiation to a field that includes the ovaries. Int J Radiat Oncol Biol Phys 2005; 62:738.
- Averette HE, Boike GM, Jarrell MA. Effects of cancer chemotherapy on gonadal function and reproductive capacity. CA Cancer J Clin 1990; 40:199.
- Green DM, Sklar CA, Boice JD Jr, et al. Ovarian failure and reproductive outcomes after childhood cancer treatment: results from the Childhood Cancer Survivor Study. J Clin Oncol 2009; 27:2374.
- Sklar CA, Mertens AC, Mitby P, et al. Premature menopause in survivors of childhood cancer: a report from the childhood cancer survivor study. J Natl Cancer Inst 2006; 98:890.
- ACOG: Committee Opinion No. 584: oocyte cryopreservation. Obstet Gynecol 2014; 123:221.
- ACOG Committee Opinion No. 405: ovarian tissue and oocyte cryopreservation. Obstet Gynecol 2008; 111:1255.
- CHEMOTHERAPEUTIC DRUGS
- Ovarian effects
- Individual agents
- - Variable susceptibility to ovarian dysfunction
- Biochemical markers of ovarian reserve
- Multiple drug regimens
- RADIATION THERAPY
- CHILDHOOD CANCER SURVIVORS
- FERTILITY PRESERVATION
- Prevention of ovarian failure
- - Ovarian suppression
- - Oophoropexy
- Cryopreservation techniques
- - Embryos
- - Oocytes
- - Ovarian tissue
- INFORMATION FOR PATIENTS