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Endocrine Care |
Departments of Endocrinology and Internal Medicine (W.B.), University of Pisa, 56122 Pisa, Italy
Address all correspondence and requests for reprints to: Dr. Claudia Ceccarelli, Dipartimento di Endocrinologia, University of Pisa, Ospedale Cisanello, Via Paradisa 2, 56122 Pisa, Italy. E-mail: claudiac{at}endoc.med.unipi.it
Abstract
Treatment with 131I for differentiated thyroid cancer may give a follicle-damaging radiation dose to the ovaries. This damage to the ovarian function could shorten the fertile life span and advance the natural menopause. To address this issue, we studied retrospectively the menopausal age of 130 women treated with 131I for differentiated thyroid cancer in our institution from 1974–1993. The menopausal age of women treated with 131I for differentiated thyroid cancer after total thyroidectomy and subjected to suppressive L-T4 therapy was compared with the menopausal age of a control group including 127 goitrous women who were treated with suppressive L-T4 for a comparable period of time. The cumulative therapeutic 131I dose to cancer patients ranged from 1,110–40,700 MBq (mean ± SD, 5,308 ± 5,483 MBq; median, 3700 MBq). All patients chosen for the study were younger than 45 yr when first treated (i.e. first administration of 131I and L-T4 for cancer patients, and institution of L-T4therapy for goitrous patients), and older than 45 yr at the end of the study period. The menopausal status of both groups was assessed from the clinical records and compared using Kaplan-Meier survival analysis. The menopausal age of cancer women treated with 131I and suppressive L-T4 therapy was less than that of goitrous patients treated with suppressive L-T4 therapy (P < 0.001). We could not detect any relationship between menopausal age and the age at the first or last 131I dose or to the cumulative 131I dose received. These data indicate that 131I treatment is probably associated with an earlier ovarian failure in thyroid cancer patients. Conceivably, the ovarian irradiation by 131I might contribute to the process of the follicular atresia, thus inducing earlier menopause.
RADIOIODINE 131 (131I) IS routinely used in differentiated thyroid cancer (DTC) for ablation of thyroid remnants and for treatment of metastases. The 131I activity administered in a single dose ranges from 1110–5500 MBq and may be given repeatedly when metastatic disease is present.
When appropriately treated, DTC is often associated with a normal life expectancy, and the effect of ionizing radiation on reproductive function is often a cause of concern for younger patients. In males repeated radioiodine administration is associated with an impairment of spermatogenesis and increased levels of FSH (1, 2, 3). In females no significant effect on fertility (4) or on offspring (5, 6) has been found after 131I treatment for DTC.
However, after very large doses of 131I (up to 12,100 MBq), given for ablation of thyroid remnants, Raymond et al. reported temporary ovarian failure, mainly in older premenopausal women (7). This finding confirms the anecdotal reports by Trunnel et al. (8) and Dobyns and Maloof (9) of cases of precocious menopause after large doses of 131I. To our knowledge no other data are available about a possible effect of irradiation from 131I on menopausal age.
It is virtually impossible to design a prospective study on the ovarian effect of 131I therapy due to the long time span involved. In this context retrospective studies based on the available clinical records are of particular relevance, as they are the sole source of information.
The aim of the present work was to investigate a possible difference in the age at menopause between women with DTC treated during their fertile life with 131I for thyroid residues or metastases and women of similar age affected by nodular goiter. This control group was selected as the closest possible control group available; with the exception of the limited periods of hypothyroidism due to 131I examination and therapy in patients with DTC, both groups were subjected to suppressive L-T4 therapy and had a similar follow-up schedule. To this end, we have examined retrospectively the records of all female patients treated in our center for DTC over a period of 10 yr and followed up for 23 yr, and a control group of goitrous female patients.
Subjects and Methods
Patients
We have examined all the records of patients admitted for treatment of DTC at the Institute of Endocrinology (now Department of Endocrinology) from 1974 to 1993. After surgery, thyroid cancer patients received an ablative dose of 131I (1100–3700 MBq). Six to 18 months later, a whole body scan (WBS) was performed, using 185 MBq 131I, to ascertain the persistence of remnant tissue and the presence of functioning metastases. If required, further 131I ablative doses were administered every 6–12 months. Since 1985 a detectable level of serum Tg was regarded as evidence of disease activity regardless of the results of the WBS. After a negative scan (and undetectable Tg while not receiving L-T4 therapy), no additional WBS examination was performed. Follow-up was continued based on clinical examination, neck ultrasound, and blood tests for thyroid hormones, TSH, Tg, and anti-Tg and antithyroperoxidase antibodies.
The interviews were conducted by trained residents or the senior medical staff, and clinical data about the patient’s health status, including nonthyroid disease and gynecological condition, were reported in the patient’s file.
Similarly, goitrous patients receiving suppressive L-T4 therapy were examined every year with interview and blood tests, including thyroid hormones, TSH, and, at least once, antithyroid antibody determination. This control group is the closest possible group, with data updated yearly and with the same methodology. It is important to note that no group of euthyroid normal women is available with data collected in the same way over the same period of time.
Inclusion criteria
For this study we selected all of the female thyroid cancer patients who were younger than 45 yr at the time of the first ablative dose (i.e. immediately after surgery), and older than 45 yr at the time of the study. The same criteria were applied to select a similar group of goitrous female patients. Care was taken to ensure that the two groups had a similar age distribution. The inclusion criteria were 1) the presence of menses at the time of entering into the study, and 2) undetectable TSH levels (<0.1 µU/ml) at each follow-up visit during L-T4 therapy. For cancer patients, the transient elevation of TSH at the time of whole body scans, due to the withdrawal of L-T4 therapy, was not considered an exclusion criterion. There were many more patients with goiter than cancer patients, but many of them were excluded from the study because of insufficient compliance with the L-T4 therapy and the periodic regular controls.
One hundred and thirty cancer patients fulfilling the inclusion criteria were studied. They were treated with 131I; the cumulative dose ranged from 1,110–40,700 MBq (mean ± SD, 5,308 ± 5,483 MBq; median, 3700 MBq). One hundred and twenty-seven goitrous patients fulfilling the inclusion criteria were selected for the control group. Of this 127 patients, 32 (25.2%) had been given partial thyroidectomy.
Because gonadotropin levels were not routinely determined, the age at menopause was defined as lack of menses, persisting for at least 6 consecutive months (10). This information is systematically recorded in the clinical records, and it is collected at least once at year, thus ruling out the possibility of a significant memory effect when women are interviewed on this issue several years later (11).
Statistical analysis
Menopause is a unique, irreversible event in the life of a woman. For this reason, age at menopause was studied by survival analysis (11). Of the 130 women with thyroid cancer, 14 (10.7%) experienced surgical menopause after inclusion in the study; 1 had chemical castration for breast cancer and for the purpose of the present analysis was considered as having surgical menopause. Ten patients (6.9%) underwent estro-progestinic (E-P) therapy (for contraception or replacement). Of the 127 women with nodular goiter, 11 had surgical menopause (8.7%), and 8 (6.3%) underwent E-P therapy. Patients who underwent surgical menopause or E-P therapy were excluded, as their menopausal status was uncertain. Data relative to these women were treated as censored observations and withdrawn from the analysis at the date of surgery or E-P therapy, respectively. The survival curves were compared using the log-rank.
Results
The ages of cancer and goitrous patients at presentation (initial
age) and at the time of the study (final age) as well as the length of
the follow-up are reported in Table 1
. No
significant difference between the two groups was found for any of the
three parameters.
|
.
Cancer patients experienced menopause significantly earlier than
goitrous patients (
2 = 11.79;
P < 0.001). The curves are similar up to the age of 47
yr, but subsequently show a different pattern. At the age of 51 yr
(median age of menopause in the general population, 12), only 29% of
the cancer women were still cycling vs. 49% of the goitrous
patients. The median age of the menopause was 49.5 yr for cancer
patients and 51 yr for goitrous patients.
|
Early menopause can be associated with antiovary autoimmunity and to antithyroid autoimmunity (12). For this reason we compared the frequency of antithyroid antibodies in the two groups, and their presence was found in 21.3% of the cancer patients and 29.8% of the goitrous patients (P = 0.2, NS).
Discussion
We compared the menopausal age of women treated with 131I and suppressive L-T4 therapy for thyroid cancer and the menopausal age of women treated with suppressive L-T4 therapy alone for nodular goiter. It should be emphasized that this is a retrospective study using a database not specifically designed for this protocol. The data available to us were not ideal and were deficient in some respects. For example, a hormonal assay for menopause had not been performed in the vast majority of our patients. For this reason we decided to use a clinical definition of menopause as lack of menses for at least 6 consecutive months. This definition, although normally accepted in gynecological studies (10), is not ideal. However, the definition is unlikely to have played a greater role in one group compared with the other.
An earlier onset of menopause was observed in the cancer group, whereas the median age of menopause in the goiter group was almost identical to that reported for the normal population (i.e. 49% of women were still cycling at 51 yr of age) (13).
Radiation is recognized as a cause of sterility. In males, a transient increase in FSH and reduction of normokinetic sperm may follow 131I therapy (1, 2, 3). Large cumulative doses cause permanent impairment of male reproductive capability, as assessed by a permanent increase in FSH levels (2).
Precocious menopause was observed in females subjected to external radiotherapy in the pelvic region (14). It is commonly accepted that a radiation dose of 1.5 Gy delivered to the ovaries may result in transient sterility, whereas a radiation dose of 3.2 Gy or more may induce permanent sterility (15). The effects of 131I therapy on ovarian function were addressed by Maxon (16). Based on data derived from external radiation and atomic fallout studies (assuming a dose to the ovaries of 14 x 10-2 mGy/MBq), Maxon inferred that no permanent sterility may be predicted in women receiving up to 11,100 MBq, whereas sterility may be expected in 60% of those receiving very large cumulative amounts of 131I, such as 29,600 MBq or more.
In women with differentiated thyroid cancer, subjected to 131I therapy in very large amounts (11,100 ± 500 MBq) for the ablation of the thyroid remnant, Izembart et al. estimated that the radiation dose delivered to the ovaries was 1.140 ± 0.340 Gy (17). The value of this dose is of the same order of magnitude as the dose of external irradiation inducing transient sterility. In 18 of 66 women subjected to 131I therapy, transient primary amenorrhea was observed by the same researchers from the 2nd to the 14th month after 131I administration (7).
To our knowledge no other adverse effect on female fertility after 131I therapy has been reported. The epidemiological studies on fertility of women treated with 131I for thyroid cancer focused on the child-bearing capability of the subjects and the health status of their offspring (4, 5, 6). As a consequence, the patient sample was biased toward a younger age, when patients are not only capable of having, but also willing to have, children. On the contrary, the present work uses a different end point for the evaluation of gonadal damage, focusing on a cohort of premenopausal women. As our mean observation time is 9 yr (range, 1–23), most of the subjects treated at a younger age were still cycling at the time of this study. For these subjects it seems that their apparent fertility was unaffected by the treatment. This, in turn, raises the question of whether radiation damage might be greater in older patients, as commonly believed for radiation damage in general (18). When we subdivided our DTC patients into two groups according to the age at first and last doses, we failed to demonstrate a difference. This, however, might be due to the insufficient power of our test, leaving the question basically unanswered.
A highly significant difference in the menopausal age was observed between the 131I-treated women and the controls. Earlier menopause could well be due to ovarian damage induced by 131I therapy. This damage could contribute to the natural decline of ovarian function and hasten the process of follicular atresia in premenopausal women who have a reduced pool of viable follicles (19).
Other cancer-mediated effects might induce earlier menopause, such as hypothalamic stress or thyroid autoimmunity. Patients who know that they have cancer may experience hypothalamic stress, and this factor cannot be ruled out even if such stress normally is assumed to induce short-term consequences (20). On the contrary, median follow-up between the diagnosis of cancer and the time of the study for still cycling patients and menopause for the others was approximately 9 yr, ranging from 1–23 yr.
Thyroid autoimmunity has been associated with precocious menopause (13). In this study antithyroid antibodies were present in 22% of the cancer patients and in 28% of the goitrous patients. The difference was not significant. Thyroid autoimmunity, therefore, does not seem to explain the difference in the menopausal age of the two groups.
If the anticipation of menopause observed in this study is due to 131I treatment, we must conclude that even in females, as in males, 131I therapy affects reproductive function. However, in males the effects of radiation are not age related. On the contrary, in women the radiation damage becomes evident at the end of the fertile life span.
Acknowledgments
The authors are grateful to Dave Coder (Washington University, Seattle, WA) for carefully reviewing the manuscript.
Footnotes
Abbreviations: DTC, Differentiated thyroid cancer; E-P, estroprogestinic; WBS, whole body scan.
Received February 1, 2001.
Accepted April 12, 2001.
References
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F. Pacini, M. Schlumberger, C. Harmer, G. G Berg, O. Cohen, L. Duntas, F. Jamar, B. Jarzab, E. Limbert, P. Lind, et al. Post-surgical use of radioiodine (131I) in patients with papillary and follicular thyroid cancer and the issue of remnant ablation: a consensus report Eur. J. Endocrinol., November 1, 2005; 153(5): 651 - 659. [Abstract] [Full Text] [PDF]
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R. J. Robbins and M. J. Schlumberger The Evolving Role of 131I for the Treatment of Differentiated Thyroid Carcinoma J. Nucl. Med., January 1, 2005; 46(1_suppl): 28S - 37S. [Abstract] [Full Text] [PDF]
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