Effects on Female Fertility

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In normally menstruating women, ovarian function depends on pituitary production of follicle-stimulating hormone (FSH), which stimulates the ovarian follicular granulosa cells to develop and produce estradiol. This causes feedback inhibition of the pituitary maintaining FSH at a low level. At puberty approximately 200 000 ovarian follicles are present and functioning in the ovary. This number progressively declines with age to approximately 400 at the time of menopause. Fertility in women can be assessed from the menstrual history and by measuring FSH levels. Persisting amenorrhea with FSH levels more than 30IU/L implies the onset of menopause.

Radiation produces dose-related gonadal damage to both the germ cell and the endocrine component of ovarian tissue. Experience with external beam radiotherapy suggests that the probability of infertility for a given dose of radiation increases with age; treatment with 4Gy will produce infertility in only 30% of young women but in 100% of those over the age of 40. In addition, resumption of menstruation has been seen in adolescents irradiated to doses as high as 20 Gy [4]. The same age effect is recognized following exposure to chemotherapy drugs.

Following administration of high activities of 131I, menstrual irregularities have been reported in 20-30% of premenopausal female patients

[5]. Amenorrhea has been reported to occur within 6 months after treatment but lasted only for a short time (less than 6 months in most patients). In our retrospective analysis of 409 female patients under the age of 40 years, 8% developed amenorrhea lasting 4-10 months and 12% reported menstrual changes such as lighter menses and shorter or longer cycle but these reverted to normal within 6 months [6].Patients who developed temporary amenorrhea were older (median age 36, range 29-40) compared with those who either had mild menstrual changes (median age 28 years) or no changes (median age 31 years). In our study only women under the age of 40 were included; however, we noticed four older patients (age 44-46 years) who became menopausal following radioiodine therapy. These observations possibly indicate a higher ovarian sensitivity to irradiation with older age.

High serum FSH/luteinizing hormone (LH) values in women with temporary amenorrhea following radioiodine therapy indicate temporary ovarian failure [5]. Contributing factors are not known. Both psychological stress leading to hypothalamic amenorrhea and hypothyroidism have been implicated. However, in most cases amenorrhea appears 1-3 months after treatment when the patient is on thyroxine replacement. This interval also excludes an action of radioactivity on the maturing follicle, possibly suggesting an effect on the oocytes involved in future cycles.

After radioiodine administration, sources of radiation to the ovaries are the blood, bladder, gut, and functioning metastases close to the ovaries. Based on the Medical Internal Radiation Dose (MIRD) estimate, the dose received by each ovary is 0.14cGy/37MBq (1 mCi) [7]. However, the "ideal MIRD model" subject is morphologically bigger than the average patient and the kinetic model used applies to euthyroid patients; iodine-treated patients are severely hypothyroid at the time of administration and renal clearance of iodine is decreased, resulting in a more prolonged gonadal exposure. Mathematical models taking into account individual patient morphology lead to ovarian dose estimates approximately threefold higher (0.4cGy/37MBq (1mCi). Applying this model to a group of 50 patients with metastases treated with a dose of 1011.1 GBq (300 mCi) 131I, no difference was found between the calculated dose to the ovary in 12 patients who developed amenorrhea (1.29 ± 0.33 Gy) and 33 who did not (1.08 ± 0.33 Gy) [8].

Despite the documented ovarian dysfunction following radioiodine therapy, there is no indication that this is correlated with lasting infertility. Several large studies have reported that exposure to radioiodine does not affect the outcome of subsequent pregnancy or offspring [6,9-12]. An early study in children and adolescents treated with a mean total dose of 196mCi of radioiodine reported a 12% incidence of infertility, 1.4% incidence of miscarriage, 8% incidence of prematurity, and 1% incidence of congenital anomaly; these rates were not significantly different from those of the general population [11]. In our series, a total of 427 children were born to 276 women. Seven patients were advised against conception and 125 had no wish to have children. Four premature deaths and 14 spontaneous abortions were reported but no malformations [6]. In the Gustave-Roussy series an increased incidence of miscarriage (20%) was seen especially within the first year after 131I administration. However, whether and to what extent this is related to gonadal irradiation rather than to suboptimal control of thyroid status could not be established. With the exception of miscarriages, there was no evidence that exposure to radioiodine affects the outcome of subsequent pregnancies and offspring [12]. ARSAC (Administration of Radioactive Substances Advisory Committee) recommends a minimum period of 4 months before conception as the dose to the fetus should not exceed 1mGy [13]. Suppressive thyroxine therapy should continue during pregnancy and thyroid function tests should be monitored regularly to ensure that thyroid-stimulating hormone (TSH) remains suppressed as thy-roxine requirements may increase during pregnancy.

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