2005 © Oxford University Press
Maintenance of Ovarian Function and Risk of Premature Menopause Related to Cancer Treatment
Correspondence to: Charles Sklar, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10021 (e-mail: sklarc{at}mskcc.org).
 |
ABSTRACT |
|---|
 Top Abstract IntroductionNORMAL REPRODUCTIVE PHYSIOLOGYTREATMENT-INDUCED ACUTE OVARIAN...CHEMOTHERAPY-INDUCED ACUTE...RADIATION-INDUCED ACUTE OVARIAN...TREATMENT-INDUCED PREMATURE...References |
|---|
Ovarian damage following cancer therapy is dependent on age at treatment as well as the type of therapeutic exposures. Older age and exposure to higher doses of alkylating agents and higher doses of radiation to the ovary are associated with a greater likelihood of ovarian failure. Acute loss of ovarian function during or shortly following treatment is relatively uncommon in females treated during childhood and adolescence but can be seen following myeloablative, alkylator-based cytoreduction (e.g., busulfan and cyclophosphamide) for stem cell transplant and following direct ovarian radiation with doses >10 Gy. For survivors who retain normal ovarian function after cancer therapy, there is an increased risk of premature menopause later in life. The risk factors associated with an early menopause include exposure to high doses of alkylating agents and abdomino-pelvic radiation.
|
INTRODUCTION |
|---|
|
TopAbstractIntroductionNORMAL REPRODUCTIVE PHYSIOLOGYTREATMENT-INDUCED ACUTE OVARIAN...CHEMOTHERAPY-INDUCED ACUTE...RADIATION-INDUCED ACUTE OVARIAN...TREATMENT-INDUCED PREMATURE...References |
|---|
Advances in the treatment of childhood cancer have resulted in markedly improved survival rates. However, with these advancements cancer survivors now face the long-term consequences of treatment with intensive, multimodality therapies. Women exposed to various forms of cancer therapy, particularly high-dose chemotherapy and gonadal irradiation, can potentially suffer the loss of reproductive function. The following will provide an overview of the risks of acute ovarian failure and premature menopause in female survivors of childhood cancer.
|
NORMAL REPRODUCTIVE PHYSIOLOGY |
|---|
|
TopAbstractIntroductionNORMAL REPRODUCTIVE PHYSIOLOGYTREATMENT-INDUCED ACUTE OVARIAN...CHEMOTHERAPY-INDUCED ACUTE...RADIATION-INDUCED ACUTE OVARIAN...TREATMENT-INDUCED PREMATURE...References |
|---|
The follicle, the functional unit within the ovary, consists of the sex steroid–producing cells (i.e., granulosa and thecal cells) and the germ cells that ultimately become ova. Due to the structural and functional interdependence within the follicle between the sex hormone–producing cells and the oocyte, insults that cause disruption and damage to the germ cells lead to loss of both endocrine function as well germ cell failure and infertility (1). Likewise, toxic injury to granulosa cells results in estrogen insufficiency as well as oocyte death.
Conventional wisdom indicates that the number of germ cells in the female is fixed at birth and steadily decreases with advancing age. Because of the progressive decline in the number of primordial follicles with increasing age, susceptibility to chemotherapy- and radiation-induced damage is very age-dependent in females. Recent data suggest, however, that there may be proliferating germ cells present in the postnatal mammalian ovary, which are capable of replenishing the pool of follicles (2).
Regular ovulatory menstrual cycles come about via the coordination between the hypothalamus, pituitary, ovary, and lower reproductive tract. Normal female reproductive function requires an intact hypothalamic–pituitary unit, functional ovaries, and a normally responsive uterus.
|
TREATMENT-INDUCED ACUTE OVARIAN FAILURE |
|---|
|
TopAbstractIntroductionNORMAL REPRODUCTIVE PHYSIOLOGYTREATMENT-INDUCED ACUTE OVARIAN...CHEMOTHERAPY-INDUCED ACUTE...RADIATION-INDUCED ACUTE OVARIAN...TREATMENT-INDUCED PREMATURE...References |
|---|
The term acute ovarian failure refers to the loss of ovarian function that arises during or shortly after the completion of cancer therapy. By contrast, the term premature menopause refers to the loss of ovarian function that occurs years after completion of cancer therapy following a window of normal functioning.
|
CHEMOTHERAPY-INDUCED ACUTE OVARIAN FAILURE |
|---|
|
TopAbstractIntroductionNORMAL REPRODUCTIVE PHYSIOLOGYTREATMENT-INDUCED ACUTE OVARIAN...CHEMOTHERAPY-INDUCED ACUTE...RADIATION-INDUCED ACUTE OVARIAN...TREATMENT-INDUCED PREMATURE...References |
|---|
The ovaries of prepubertal children and adolescents, with their greater complement of follicles, are relatively resistant to chemotherapy-induced damage compared to the ovary of the adult (3). Nonetheless, certain chemotherapeutic agents when given at high doses are toxic even to young ovaries, particularly alkylating agents, cisplatinum, and the nitrosoureas (BCNU and CCNU) (1). Increased plasma concentrations of FSH have been noted in young women treated with alkylating agents for acute leukemia (4), brain tumors (5), and Hodgkin disease (6). Fortunately, many of these young women demonstrate normalization of FSH levels over time and only a minority appear to experience irreversible ovarian failure requiring long-term hormone replacement therapy. Of note, recovery may not occur for many years following completion of therapy.
Females who receive high-dose, myeloablative therapy with alkylating agents in the context of allogeneic or autologous stem cell transplantation, are at high risk of developing acute ovarian failure (7,8). The agents most commonly utilized in this setting include busulfan, melphalan, and thiotepa.
|
RADIATION-INDUCED ACUTE OVARIAN FAILURE |
|---|
|
TopAbstractIntroductionNORMAL REPRODUCTIVE PHYSIOLOGYTREATMENT-INDUCED ACUTE OVARIAN...CHEMOTHERAPY-INDUCED ACUTE...RADIATION-INDUCED ACUTE OVARIAN...TREATMENT-INDUCED PREMATURE...References |
|---|
Individuals who receive abdominal, pelvic, or spinal irradiation are at increased risk of developing acute ovarian failure, especially if both ovaries are within the treatment field (1,9). Recent studies suggest that the LD50 (i.e., the radiation dose required to kill 50% of oocytes) of the human oocyte is <2 Gy (10). The data suggest that the ovary of younger individuals is more resistant to damage from irradiation than is the ovary of older individuals (11,12). Thus, while radiation doses of 6 Gy may be sufficient to produce irreversible ovarian damage in women >40 years of age , doses in the range of 10–20 Gy are needed to induce permanent ovarian failure in the majority of females treated during childhood (13,14).
Administration of spinal radiation for the treatment of acute lymphoblastic leukemia and brain tumors appears to result in clinically significant ovarian damage in some young women (5,15). Girls treated with whole abdominal and/or pelvic irradiation for Hodgkin disease, a Wilms tumor, or other solid tumors (e.g., rhabdomyosarcoma, neuroblastoma) are at high risk of acute ovarian failure (6,16). When ovarian transposition is performed prior to radiotherapy, however, ovarian function is retained in the majority of young girls and adolescent females (13).
Patients who receive a stem cell transplant with total body irradiation (TBI) are at the greatest risk of developing acute ovarian failure. Virtually 100% of patients who undergo a marrow transplant with TBI after age 10 years will develop acute ovarian failure, whereas approximately 50% of girls who received a transplant before age 10 years will suffer acute loss of ovarian function (17).
The risk of gonadotropin deficiency appears to increase following doses >30 Gy to the hypothalamic–pituitary unit (18). Moreover, the risk increases with increasing follow-up time.
|
TREATMENT-INDUCED PREMATURE MENOPAUSE |
|---|
|
TopAbstractIntroductionNORMAL REPRODUCTIVE PHYSIOLOGYTREATMENT-INDUCED ACUTE OVARIAN...CHEMOTHERAPY-INDUCED ACUTE...RADIATION-INDUCED ACUTE OVARIAN...TREATMENT-INDUCED PREMATURE...References |
|---|
The majority of prepubertal girls and adolescent females who receive standard combination chemotherapy and/or low-dose radiotherapy to the ovaries will retain or recover ovarian function during the immediate post-treatment period. However, histologic examination of ovarian tissue and ultrasound studies performed after cancer therapy have revealed a decreased number of ovarian follicles and inhibition of follicular growth compared with age-matched controls (19,20). As menopause appears to be triggered when the number of ovarian follicles drops below a threshold number, one would predict that a reduction in the population of follicles as a result of cancer therapy would result in an earlier timing of menopause (21).
Byrne et al. have assessed the risk of early menopause in a cohort of 1067 childhood cancer patients diagnosed between 1945 and 1976 (22). Survivors were on average 32.2 years of age at follow-up. Despite exposure to therapies that would be considered "mild" by current standards, young women who were diagnosed and treated for cancer between ages 13 and 19 years, and who were still menstruating at age 21, had a fourfold increased risk of menopause occurring during ages 21–25. The relative risk of early menopause was 9.2 for those treated with alkylating agents alone and 27 for women who received a combination of radiation below the diaphragm and alkylating agents. Limitations of this study include the inability to separate surgical from nonsurgical causes of menopause and a lack of detailed information on therapeutic exposures (e.g., cumulative doses of chemotherapy, ovarian doses of radiation).
A more recent study examined risk of early menopause among 719 survivors of childhood cancer who were treated in Ontario, Canada from 1964–1988 (23). The investigators identified 65 menopausal cases, including 36 nonsurgical cases. For nonsurgical menopause, the risk of menopause was elevated for those treated after puberty but only for those women treated with alkylating agents plus abdominal–pelvic radiation (RR 5.96, 95% CI: 1.86, 19.1). The risk also increased with increasing dose of abdominal–pelvic irradiation and alkylating-agent score. It is important to note that this study did not use non-cancer controls and the details of cancer treatment (e.g., cumulative doses of chemotherapy, ovarian doses of radiation) were not known. None of the prior studies has attempted to exclude women with CNS disease or potential central causes for cessation of menses (e.g., gonadotropin deficiency).
We are currently analyzing data on the incidence of and risk factors for a premature menopause in a large cohort of female survivors who are participants of the Childhood Cancer Survivor Study (CCSS). The CCSS is a retrospective cohort study of 5-year survivors of childhood cancer who were treated at 25 pediatric cancer centers throughout North America during the period 1970–1986 (24). After excluding survivors who experienced acute ovarian failure, received >30 Gy hypothalamic–pituitary irradiation, or had incomplete data, there were 2823 survivors, all 18 years or older, eligible for this study. The median age at cancer diagnosis was 7 years (0–20 years) and median age at follow-up was 29 years (18–50 years). Data on menstrual status, cause of menopause (i.e., surgical versus nonsurgical), and age at last menstruation were available on all participants. Additionally, a comprehensive questionnaire addressing psychosexual adjustment has been completed by some 85% of eligible participants. Comparison data are available on 1074 sibling controls. Results of this study are likely to provide important new data on the incidence and risk factors for premature menopause in this population.
Although we have learned much about the impact of cancer treatment on ovarian function, many questions remain unanswered. Data are needed to increase our understanding of the health risks associated with premature loss of ovarian function and the optimal approach to the management of various conditions such as osteoporosis. Future studies will hopefully refine our ability to predict which subgroups of survivors are at highest risk for a premature menopause and establish which methods of fertility preservation are most appropriate (25).
|
REFERENCES |
|---|
|
TopAbstractIntroductionNORMAL REPRODUCTIVE PHYSIOLOGYTREATMENT-INDUCED ACUTE OVARIAN...CHEMOTHERAPY-INDUCED ACUTE...RADIATION-INDUCED ACUTE OVARIAN...TREATMENT-INDUCED PREMATURE...References |
|---|
(1) Sklar C. Reproductive physiology and treatment-related loss of sex hormone production. Med Pediatr Oncol 1999;33:2–8.[CrossRef][Web of Science][Medline]
(2) Johnson J, Canning J, Kaneko T, Pru JK, Tilly JL. Germline stem cells and follicular renewal in the postnatal mammalian ovary. Nature 2004;428:145–50.[CrossRef][Medline]
(3) Meistrich ML, Vassilopoulou-Sellin R, Lipshultz LI. Gonadal dysfunction. In: DeVita VT, Jr., Hellman S, Rosenberg SA, editors. Cancer: principles and practice of oncology. Philadelphia (PA): Lippincott-Raven; 1997.
(4) Wallace WIHB, Shalet SM, Tetlow LJ, Morris-Jones PH. Ovarian function following the treatment of childhood acute lymphoblastic leukemia. Med Pediatr Oncol 1993;21:333–9.[Web of Science][Medline]
(5) Livesey EA, Brook CGD. Gonadal dysfunction after treatment of intracranial tumours. Arch Dis Childh 1988;63:495–500.
(6) Papadakis V, Vlachopapadopoulou E, Van Syckle K, et al. Gonadal function in young patients successfully treated for Hodgkin disease. Med Pediatr Oncol 1999;32:366–72.[CrossRef][Web of Science][Medline]
(7) Michel G, Socié MG, Gebhard F, Bernaudin F, Thuret I, Vannier JP, et al. Late effects of allogeneic bone marrow transplantation for children with acute myeloblastic leukemia in first complete remission: the impact of conditioning regimen without total-body irradiation–a report from the Société Française de Greffe de Moelle. J Clin Oncol 1997;15:2238–46.
(8) Thibaud E, Rodriguez-Macias K, Trivin C, Espérou H, Michon J, Brauner R. Ovarian function after bone marrow transplantation during childhood. Bone Marrow Transplant 1998;21:287–90.[CrossRef][Web of Science][Medline]
(9) Stillman RJ, Schinfeld JS, Schiff I, Gelber RD, Greenberger J, Larson M, et al. Ovarian failure in long-term survivors of childhood malignancy. Am J Obstet Gynecol 1981;139:62–6.[Web of Science][Medline]
(10) Wallace WHB, Thomson AB, Kelsey TW. Radiosensitivity of the human oocyte. Hum Reprod 2003;18:117–21.
(11) Horning SJ, Hoppe RT, Kaplan HS, Rosenberg SA. Female reproductive potential after treatment for Hodgkin's disease. N Engl J Med 1981;304:1377–82.[Abstract]
(12) Lushbaugh CC, Casarett GW. The effects of gonadal irradiation in clinical radiation therapy: a review. Cancer 1976;37:1111–20.[CrossRef][Web of Science][Medline]
(13) Thibaud E, Ramirez M, Brauner R, Flamant F, Zucker JM, Fekete C, et al. Preservation of ovarian function by ovarian transposition performed before pelvic irradiation during childhood. J Pediatr 1992;121:880–4.[CrossRef][Web of Science][Medline]
(14) Sarafoglou K, Boulad F, Gillio A, Sklar C. Gonadal function after bone marrow transplantation for acute leukemia during childhood. J Pediatr 1997;130:210–6.[CrossRef][Web of Science][Medline]
(15) Hamre MR, Robison LL, Nesbit ME, Sather HN, Meadows AT, Ortega JA, et al. Effects of radiation on ovarian function in long-term survivors of childhood acute lymphoblastic leukemia: a report from the Childrens Cancer Study Group. J Clin Oncol 1987;5:1759–65.
(16) Wallace WHB, Shalet SM, Hendry JH, Morris-Jones PH, Gattamaneni HR. Ovarian failure following abdominal irradiation in childhood: the radiosensitivity of the human oocyte. Br J Radiol 1989;62:995–8.
(17) Sklar C. Growth and endocrine disturbances after bone marrow transplantation in childhood. Acta Paediatr 1995;411(suppl):57–61.
(18) Sklar CA, Constine LS. Chronic neuroendocrinological sequelae of radiation therapy. Int J Radiat Oncol Biol Phys 1995;31:1113–21.[CrossRef][Web of Science][Medline]
(19) Himelstein-Braw R, Peters H, Faber M. Influence of irradiation and chemotherapy on the ovaries of children with abdominal tumors. Br J Cancer 1977;36:269–75.[Web of Science][Medline]
(20) Larsen EC, Müller J, Schmiegelow K, Rechnitzer C, Andersen AN. Reduced ovarian function in long-term survivors of radiation- and chemotherapy-treated childhood cancer. J Clin Endocrinol Metab 2003;88:5307–14.
(21) Faddy MJ, Gosden RG. A model conforming the decline in follicle numbers to the age of menopause in women. Hum Reprod 1996;11:1484–6.
(22) Byrne J, Fears TR, Gail MH, Pee D, Connelly RR, Austin DF, et al. Early menopause in long-term survivors of cancer during adolescence. Am J Obstet Gynecol 1992;166:788–93.[Web of Science][Medline]
(23) Chiarelli AM, Marrett LD, Darlington G. Early menopause and infertility in females after treatment for childhood cancer diagnosed in 1964–1988 Am J Epidemiol 1999;150:245–54.
(24) Robison LL, Mertens AC, Boice JD, Breslow NE, Donaldson SS, Green DM, et al. Study design and cohort characteristics of the Childhood Cancer Survivor Study: a multi-institutional collaborative project. Med Pediatr Oncol 2002;38:229–39.[CrossRef][Web of Science][Medline]
(25) Oktay K, Sonmezer M. Ovarian tissue banking for cancer patients. Fertility preservation, not just ovarian cryopreservation. Hum Reprod 2004;19:477–80.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  P. D. Inskip, L. L. Robison, M. Stovall, S. A. Smith, S. Hammond, A. C. Mertens, J. A. Whitton, L. Diller, L. Kenney, S. S. Donaldson, et al. Radiation Dose and Breast Cancer Risk in the Childhood Cancer Survivor Study J. Clin. Oncol., August 20, 2009; 27(24): 3901 - 3907. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. M. Green, C. A. Sklar, J. D. Boice Jr, J. J. Mulvihill, J. A. Whitton, M. Stovall, and Y. Yasui Ovarian Failure and Reproductive Outcomes After Childhood Cancer Treatment: Results From the Childhood Cancer Survivor Study J. Clin. Oncol., May 10, 2009; 27(14): 2374 - 2381. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Lie Fong, J.S.E. Laven, F.G.A.J. Hakvoort-Cammel, I. Schipper, J.A. Visser, A.P.N. Themmen, F.H. de Jong, and M.M. van den Heuvel-Eibrink Assessment of ovarian reserve in adult childhood cancer survivors using anti-Mullerian hormone Hum. Reprod., April 1, 2009; 24(4): 982 - 990. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. L. Friedman, A. Rovo, W. Leisenring, A. Locasciulli, M. E. D. Flowers, A. Tichelli, J. E. Sanders, H. J. Deeg, and G. Socie Increased risk of breast cancer among survivors of allogeneic hematopoietic cell transplantation: a report from the FHCRC and the EBMT-Late Effect Working Party Blood, January 15, 2008; 111(2): 939 - 944. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. L. De Bruin, J. Huisbrink, M. Hauptmann, M. A. Kuenen, G. M. Ouwens, M. B. van't Veer, B. M. P. Aleman, and F. E. van Leeuwen Treatment-related risk factors for premature menopause following Hodgkin lymphoma Blood, January 1, 2008; 111(1): 101 - 108. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||