Effects of Radioactive Iodine Therapy on Ovarian Reserve: A Prospective Pilot Study

Abstract

Background:

Thyroid carcinoma is the most common endocrine malignancy. Surgery is the standard therapeutic approach for patients with differentiated thyroid carcinoma (DTC), followed by radioiodine (RAI) therapy if indicated. For women with DTC, the effects of RAI therapy on gonadal and reproductive function are an important consideration. This study aimed to evaluate the effects of RAI therapy on ovarian function.

Methods:

A total of 33 premenopausal women were enrolled in this study. Serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, and anti-Müllerian hormone (AMH) levels during the early follicular phase were measured before and 3, 6, and 12 months after RAI therapy. The Friedman and Wilcoxon tests were used to detect changes in FSH, AMH, LH, and estradiol levels induced by RAI therapy over time.

Results:

The patients' ages ranged from 21 to 38 years, with a mean age of 31.15 ± 4.83 years. The median follow-up was 19 months (range 4–26 months). The median AMH levels were 3.25 ng/mL (range 0.32–17.42 ng/mL), 1 ng/mL (range 0.01–3.93 ng/mL), 1.13 ng/mL (range 0.08–6.12 ng/mL), and 1.37 ng/mL (range 0.09–6.1 ng/mL) before and at 3, 6, and 12 months after RAI therapy, respectively. The median FSH levels were 6.6 mIU/mL (range 3.78–15.5 mIU/mL), 5.83 mIU/mL (range 4.19–35.36 mIU/mL), 7.71 mIU/mL (range 4.24–16.25 mIU/mL), and 7.04 mIU/mL (range 4.93–19.96 mIU/mL) before and at 3, 6, and 12 months after RAI therapy, respectively. The AMH levels were higher before than after RAI therapy (p = 0.001). The AMH levels did not differ significantly between the three time points (p > 0.05). The FSH, LH, and estradiol levels were similar before and after RAI therapy (p > 0.05).

Conclusion:

AMH is considered an important marker of ovarian reserve. Ovarian reserve decreased after RAI therapy. More attention may be needed when considering RAI therapy for patients with reduced ovarian reserve.

Introduction

Thyroid carcinoma (TC) is the most common endocrine malignancy with the most rapidly increasing incidence in both men and women. The yearly incidence has nearly tripled from 4.9 per 100,000 in 1975 to 14.3 per 100,000 in 2009 (1). In contrast, the mortality rate from TC is stable, suggesting that the increased incidence is the result of the discovery of subclinical, indolent tumors. The overall survival rate of patients with TC is high. Differentiated TC (DTC), including papillary and follicular cancer, comprises the vast majority (>90%) of all thyroid cancers (2).

Surgery is the standard therapeutic approach for patients with DTC, followed by radioiodine (RAI) therapy, if indicated, and thyroid hormone suppression therapy. RAI therapy using ¹³¹I has been used since 1946 for the management of DTC to ablate residual thyroid cancer or treat metastases.

Acute and chronic complications of RAI therapy can limit the usefulness of this treatment. In the short term, radiation thyroiditis, painless neck edema, sialadenitis, and tumor hemorrhage or edema occur in 10–30% of patients, particularly when higher doses are given (3). An increased risk of secondary malignancies has been reported after RAI therapy for thyroid cancer (4,5). Transient oligospermia and decreased ovarian function may occur, but subsequent infertility is rare except after high doses (6,7). Men receiving cumulative RAI activities ≥400 mCi should be counseled on potential infertility risks (8). Temporary amenorrhea/oligomenorrhea lasting 4–10 months occurs in 20–27% of menstruating women after RAI therapy for thyroid cancer. Although the sample sizes in studies have been small, the long-term rates of infertility, miscarriage, and fetal malformation do not appear to be elevated in women after RAI therapy (7,9).

Anti-Müllerian hormone (AMH) is a member of the transforming growth factor beta family and is expressed by the small (<8 mm) preantral and early antral follicles. The AMH level reflects the size of the primordial follicle pool and may be the best biochemical marker of ovarian function across an array of clinical situations (10). In adult women, AMH levels gradually decline as the primordial follicle pool declines with age (11), and AMH is undetectable at menopause (12). AMH is a reliable predictor of ovarian reserve because it does not fluctuate during the menstrual cycle, is unaffected by hormones, and is affected earlier than sex hormones.

Women with good ovarian reserve have sufficient production of ovarian hormones from small follicles early in the menstrual cycle to maintain follicle-stimulating hormone (FSH) at low levels. In contrast, women with a reduced pool of follicles and oocytes have insufficient production of ovarian hormones for the normal inhibition of pituitary FSH secretion. Thus, FSH increases early during the cycle (13).

This study also determined estradiol (E₂) levels on day 3 of the menstrual cycle, although there are conflicting data as to whether this marker is predictive of ovarian reserve and the response to ovarian stimulation (14). An E₂ level <80 pg/mL suggests adequate ovarian reserve, but other cutoffs are also utilized.

The study evaluated changes in the markers of ovarian reserve before and after RAI therapy in DTC patients.

Methods

This study was conducted in the Department of Endocrinology at Yildirim Beyazit University hospital. Premenopausal DTC patients admitted to the endocrinology outpatient clinic between December 2015 and November 2017 were evaluated. Total thyroidectomy was performed in all patients. Patients planning to undergo RAI therapy were enrolled in the study. Informed written consent was obtained from all subjects prior to their enrollment, and the local ethics committee approved the study protocol.

Thirty-three premenopausal women >18 years of age who were not on hormonal contraceptives were enrolled in this study. None of these patients had previously received RAI or any form of radiation or ovarian surgery. RAI treatment was applied within three months after the operation. The time interval between surgery and RAI treatment was variable, ranging from 15 to 90 days. The patients were started on levothyroxine (LT4) treatment immediately after surgery unless they were not going to take RAI within 30 days after surgery. The thyrotropin (TSH) level had risen to >30 μIU/mL in all patients prior to RAI therapy. All patients underwent high-dose (75–150 mCi) RAI therapy. The preparation for RAI therapy was performed with thyroid hormone withdrawal. Patients were evaluated before and after RAI therapy, and blood samples were collected for analysis. AMH, FSH, luteinizing hormone (LH), TSH, and E₂ levels were analyzed at the follicular phase of the last menstrual cycle before RAI therapy after thyroidectomy and were compared to levels at 3, 6, and 12 months after RAI therapy, designated as the first, second, third, and fourth measurements, respectively.

An early-morning (between 8:00am and 9:00am) fasting blood sample was obtained during the follicular phase (days 3–5). This blood sample was used for measuring AMH, gonadotropins, and E₂. Gonadotropins and E₂ were measured as described previously (15,16). TSH levels had been measured by immunoassay (Immulite 2000; DPC Diagnostics, Los Angeles, CA; and UniCel DxI 800; Beckman Coulter, Brea, CA) using commercial kits in venous blood samples. Serum AMH was assayed using an enzyme-linked immunosorbent assay kit (CUSABIO; Cosmo Bio, Carlsbad, CA). The assay sensitivity for AMH was 0.375 ng/mL, and the intra- and inter-assay coefficients of variation were 7.1% and 9.8%, respectively. Serum AMH levels ≤0.17 ng/mL were considered to be in the menopausal range (12). The fertility status of the patients was evaluated during the follow-up period.

Statistics

Continuous data are given as means ± standard deviation or medians (minimum–maximum). The normality of the variable distributions was assessed using the Kolmogorov–Smirnov test. Statistical analysis was performed using IBM SPSS Statistics for Windows v21.0 (IBM Corp., Armonk, NY). When parametric test assumptions were met, one-way repeated-measures analysis of variance (ANOVA) was used. If the assumptions for parametric tests were not met, the Friedman and Wilcoxon tests were used. One-way ANOVA or the Kruskal–Wallis test was used to determine significant differences among the means of three or more independent groups. Spearman's correlation was used in univariate analysis. The significance level was set as p < 0.05.

Results

A total of 33 premenopausal women were enrolled in this study. The patients ranged in age from 21 to 38 years, with a mean age of 31.15 ± 4.83 years; 21 (63.6%) patients were ≥30 years, whereas 12 (36.4%) were <30 years (Table 1).

Table 1.

Demographic and Clinical Baseline Characteristics of Patients

	DTC patients (n = 33)
Age	31.15 ± 4.83
Range	21–38
≥30 years	21 (63.6%) patients
RAI activity, mCi	111.36 ± 27.3
RAI activity 75/100/150 mCi	5/18/10 patients
Baseline AMH, ng/mL	3.25 (0.32–17.42)
Previous pregnancy, n/N (%)	24/33 (72.7%)

DTC, differentiated thyroid carcinoma; RAI, radioactive iodine; AMH, anti-Müllerian hormone.

The median AMH levels were 3.25 ng/mL (range 0.32–17.42 ng/mL), 1 ng/mL (range 0.01–3.93 ng/mL), 1.13 ng/mL (range 0.08–6.12 ng/mL), and 1.37 ng/mL (range 0.09–6.1 ng/mL) at the first, second, third, and fourth measurements, respectively. The median FSH levels were 6.6 mIU/mL (range 3.78–15.5 mIU/mL), 5.83 mIU/mL (range 4.19–35.36 mIU/mL), 7.71 mIU/mL (range 4.24–16.25 mIU/mL), and 7.04 (4.93–19.96 mIU/mL) at the first, second, third, and fourth measurements, respectively. The AMH, FSH, LH, and E₂ levels before and after RAI therapy are listed in Table 2. The AMH levels were significantly higher before than after RAI therapy. Thus, the AMH level measured at the first time point was significantly higher than those at the second, third, and fourth time points (p = 0.001, 0.009, and 0.011, respectively), but there were no significant differences among the levels at the second, third, and fourth time points (p > 0.05). The levels of FSH, LH, and E₂ did not differ between the measurement time points (p > 0.05). There was no correlation between age and AMH levels (p > 0.05). In subgroup analysis, AMH levels were not different for patients aged ≥30 years or <30 years at baseline, third measurements, and fourth measurements (p > 0.05). AMH levels were higher in patients <30 years old at second measurements (2.60 ± 1.34 and 1.04 ± 0.97; p = 0.003). The extent of AMH reduction ([AMH after RAI – baseline AMH]/baseline AMH) at three months were different in the groups. It was higher in the older group (73 ± 15% and 21 ± 18.2%; p = 0.004).

Table 2.

Assessment of Ovarian Reserve Before and After RAI Ablative Therapy

	Before RAI	3 months after RAI	6 months after RAI	12 months after RAI	p
AMH, ng/mL	3.25 (0.32–17.42)	1 (0.01–3.93)	1.13 (0.08–6.12)	1.37 (0.09–6.1)	0.001
Interquartile range	2.01–4.87	0.27–2.92	0.62–2.19	0.42–2.45
FSH, mIU/mL	6.6 (3.78–15.5)	5.83 (4.19–35.36)	7.71 (4.24–16.25)	7.04 (4.93–19.96)	0.32
LH, mIU/mL	5.09 (2.71–11.63)	7.19 (1.79–35.37)	5.18 (2.04–20.21)	5.5 (1.77–28.57)	0.26
Estradiol, pg/mL	45.86 (28.73–115.4)	65.3 (25.8–210.3)	48.45 (26.46–162)	46.7 (5–158.8)	0.68

Statistically significant values are shown in bold.

FSH, follicle-stimulating hormone; LH, luteinizing hormone.

All patients were treated with RAI ablative therapy; 5, 18, and 10 of the patients received 75, 100, and 150 mCi doses of RAI, respectively. There were no significant differences in AMH levels between patients receiving different RAI doses (p > 0.05). Median TSH in the follicular phase of the last menstrual cycle before RAI therapy after thyroidectomy (not to be confounded with the TSH level just before RAI) was 9 μIU/mL and was similar to the TSH levels after RAI therapy (p = 0.175).

The median follow-up period was 19 months (range 4–26 months). Twenty patients completed at least one year of follow-up. Twenty-six patients completed either the third- or sixth-month control periods, 19 of whom completed both. During the follow-up period, disease recurrence or persistence was detected in two patients who required additional RAI therapy. These patients were removed from subsequent analyses after the third measurements. Three patients became pregnant. One was an unplanned pregnancy that occurred just six months after RAI therapy. This pregnancy was terminated per the patient's choice. The other pregnancies continued without complications. In this study, nine of the patients desired to become pregnant whereas 19 did not. There were no significant differences between the AMH levels at all time points among the patients who became pregnant, desired to become pregnant, or did not want to become pregnant (p > 0.05). The fertility status of the patients during the follow-up period is shown in Figure 1.

FIG. 1.

Plot of the fertility status of patients during the follow-up period.

Discussion

In this study, patient AMH levels decreased after high-dose RAI therapy and stabilized after three months. Gonadotropin and E₂ levels did not differ before and after RAI therapy. Since 1949, there have been anecdotal reports of precocious menopause following large courses of RAI therapy (17). Ceccarelli et al. (18) reported an earlier age of menopause in women treated for thyroid cancer with RAI therapy and LT4 suppressive therapy compared to a control group of women treated with LT4 for goiter. Howell et al. estimated the radiation dose delivered to the ovaries to be 140 mGy for an administered activity of 100 mCi, and this exposure could impair ovarian function (19). In contrast to these studies, another study found no difference in the menopausal age of 34 women treated with RAI (average activity 133 mCi; range 100–460 mCi) compared to the menopausal age of their sisters and mothers (20). In a meta-analysis by Sawka et al. (7), RAI-treated women experienced menopause at a slightly younger age than did women who had not received RAI treatment. Earlier menopause may have been the result of RAI-induced ovarian damage. This harm may contribute to the expected decline in ovarian function and expedite the process of follicular atresia in premenopausal women with a reduced pool of viable follicles. It was estimated that ovarian damage after RAI therapy led to menopause onset approximately one year earlier than that in the overall population.

Acibucu et al. found lower AMH levels in a group of women who had received RAI therapy for thyroid cancer ablation compared to healthy age- and body mass index–matched controls (21). No differences were found between the patient group and the control group in terms of LH and E₂ levels, while FSH was found to be higher in the control group. Giusti et al. compared the AMH levels of 34 premenopausal women treated with RAI therapy for thyroid cancer with 23 control thyroid cancer patients who did not receive RAI therapy (22). The AMH levels were only slightly, and not significantly, lower when ablative RAI therapy was performed after thyroidectomy. FSH and E₂ levels were not different between the groups. A recent study by Yaish et al. supports the present results (23). Their study design was highly similar, and they showed a significant decrease in AMH levels three months after RAI therapy. The number of patients followed in the current study is about 30% higher than in the study by Yaish et al., with a longer follow-up duration; while their longest follow-up duration was 12 months, it was 26 months in the study presented here.

FSH levels vary during the menstrual cycle and between consecutive cycles. Therefore, repeated FSH measurements are necessary. AMH levels are more stable. FSH, E₂, and inhibin B indirectly reflect ovarian reserve, but cyclic variation renders the correlation with ovarian reserve more difficult. The variability found in FSH and E₂ levels and the relative stability of AMH levels observed in this study and other studies may indicate that AMH is a better marker of ovarian reserve (24). Measuring the AMH level for the evaluation of age-related gonadal reserve in premenopausal women with thyroid cancer is recommended.

In this study, there was no correlation between age and AMH levels in the whole study population (p > 0.05). Acibucu et al. (21) reported similar results, whereas Giusti et al. (22) did not. The data from Giusti et al. showed strong age-related changes in AMH levels in women with thyroid cancer. In a study by Lee et al. (25) of healthy women aged 38–43 years, an average AMH level of 2.3 ng/mL (16.4 pmol/L) was found in women aged 38–40 years and 1.4 ng/mL (10.0 pmol/L) in those aged 41–43 years. These values were similar to those reported by Giusti et al. The patients in the current study were younger than the patients in those two studies, which may explain the contrasting results. In subgroup analysis of the present study, AMH levels were higher in patients <30 years old when compared to women >30 years at the second measurement. The extent of AMH reduction at three months was higher in older patients. Although the patients in the current studies were younger, these findings are similar to those obtained by Yaish et al. (23). The patients in the present study received a single dose of 75, 100, or 150 mCi. There were no significant differences in AMH levels between the different RAI activities at any of the time points analyzed. The study by Giusti et al. (22) supports these results, as they found that AMH levels were not correlated with cumulative RAI activity. A recently published study showed that RAI activity levels (30, 50, 100, and 150 mCi; >100 mCi or <100 mCi; or 30 mCi vs. all the other activities) did not affect the rate of AMH level decrease after RAI therapy. The RAI activities administered in the present study were relatively high, and the results might have differed if lower doses had been used.

During the follow-up period, three patients became pregnant, another nine wanted to become pregnant, and 19 did not want to become pregnant. Despite the reduction in AMH levels, it is not possible to speculate about fertility. The follow-up period was short, and thus the fertility of those patients who desired pregnancy cannot be predicted. Three of the patients who wanted to become pregnant were in their first year after RAI therapy, when pregnancy should be avoided. The AMH levels after RAI therapy did not differ among patients wanting to become pregnant, patients not wanting to become pregnant, and pregnant patients. It is not thought that there was a significant decline in fertility according to these results and limitations. In a study by Steiner et al., biomarkers indicating diminished compared to normal ovarian reserve were not associated with reduced fertility (26). Wu et al. showed that RAI ablation did not affect birth-rate among women treated for DTC. However, in subgroup analyses, birth rate among women aged 35–39 years was significantly decreased in those who received RAI versus those who did not (27). Several studies have reported no significant effects on fertility or parity after RAI treatment for thyroid cancer (28 –31).

This study was a prospective pilot study of single high-dose RAI-treated thyroid cancer patients. Ovarian reserve as evaluated by AMH levels decreased after RAI therapy. During the follow-up period, this effect appeared to be irreversible. Larger prospective studies with longer follow-up periods are needed to observe whether this effect is permanent or transient. These data should be considered preliminary, as prospective data collection is still ongoing.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

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