International Journal of Radiation Oncology*Biology*Physics
Clinical investigationOvaryPredicting age of ovarian failure after radiation to a field that includes the ovaries
Introduction
As survival rates for children and adolescents treated for cancer continue to improve, a population of young women of reproductive age emerges for whom issues of fertile potential are paramount. Impaired fecundity and premature ovarian failure are recognized potential late sequelae of radiotherapy to the ovaries.
The human ovary contains a fixed pool of primordial oocytes, maximal at 5 months of gestational age, which declines with increasing age in a biexponential fashion, culminating in the menopause at an average age of 50–51 years. For any given age, the size of the oocyte pool can be estimated based on a mathematical model of decline (1, 2). The rate of oocyte decline represents an instantaneous rate of temporal change determined by the remaining population pool, which increases around age 37 years when approximately 25,000 primordial oocytes remain, and precedes the menopause by 12–14 years (3). Reproductive aging in women is due to ovarian oocyte depletion with approximately 1,000 oocytes remaining at the menopause (4). Assessment of ovarian reserve and reproductive age in healthy women remains a challenge, but the recent application of our solution to the Faddy-Gosden model of ovarian primordial oocyte decline may allow an accurate assessment of ovarian reserve by measurement of ovarian volume (5).
Radiotherapy may be used either alone or in combination with surgery and chemotherapy to provide local disease control for solid tumors. Because of its established late sequelae on immature and developing tissues, irradiation is used cautiously, especially in children and adolescents. Total body, craniospinal axis, whole abdominal, or pelvic irradiation potentially expose the ovaries to irradiation, and may cause premature ovarian failure. The degree of impairment is related to the volume treated, total radiation dose, fractionation schedule, and age at time of treatment (2, 6, 7, 8). The number of primordial oocytes present at the time of treatment, together with the biologic dose of radiotherapy received by the ovaries, will determine the fertile “window” and influence the age at premature ovarian failure.
Assessing the extent of radiation-induced damage of the primordial oocytes and predicting the impact on fertile potential has been challenging. An understanding of ovarian follicle dynamics has allowed us to determine the radiosensitivity of the human oocyte to be <2 Gy (2). Application of this estimate has made it possible to determine the surviving fraction of the primordial oocyte pool for a given dose of radiotherapy and therefore predict the age (with confidence intervals) of premature ovarian failure by applying a mathematical model of decay.
Section snippets
Radiosensitivity of the human oocyte
Faddy and Gosden provide a model for natural follicle decline in healthy women (1). The model is obtained by incorporating age at menopause data into a least squares analysis of four histologic studies, (3, 9, 10, 11) and a large study of ages at menopause (12). The result is the differential equation: where x denotes age, y(x) is population at age x, and with initial value y (0) = 701,200. The initial value denotes population at birth.
We consider this to be
Results
Using this method, the age at which premature ovarian failure supervenes for individual patients treated from birth to 50 years for any given dose of radiotherapy can be predicted. For illustration, we have selected a range of radiation doses from 3 Gy to 12 Gy and predicted the age (range) of ovarian failure following treatment from birth to 30 years (Table 1). If we take into consideration the wide variation of primordial follicles at any given age, the upper and lower age limits for the
Discussion
This is the first model to reliably predict the age at which ovarian failure will supervene for any patient after treatment with a known dose of radiotherapy received by the ovaries. Based on our previous determination of the radiosensitivity of the human oocyte to be <2 Gy, we were able to calculate the surviving fraction of the follicle pool for any given dose of radiotherapy (2). From this, it was possible to predict the age of menopause by applying a mathematical model of decay. With no
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