Radioactive Iodine and Female Fertility: Are We Underestimating the Risk?

Dear Editor:

We read with great interest the recent American Thyroid Association (ATA) guidelines for the management of adult patients with differentiated thyroid cancer (DTC). ¹ With regard to the impact of radioactive iodine (RAI) therapy on female fertility, the guidelines state that “such therapy has not been shown to impact future fertility,” despite acknowledging a post-treatment reduction in ovarian reserve. ¹

Several points merit further consideration. First, recommendation 42D is largely based on a systematic review published in 2008, which reported no significant differences in pregnancy rates, but identified a modest reduction in anti-Müllerian hormone (AMH) concentrations one year after RAI treatment, as well as an association with earlier age at menopause. ² Second, clinical outcomes, such as menstrual irregularities, miscarriage rates, clinical pregnancy, and age at menopause, are not reliable surrogate markers of ovarian reserve, as they may be influenced by multiple confounding factors independent of RAI exposure. These include female age, chromosomal and other genetic abnormalities, male-related factors, environmental exposures (e.g., smoking), and prior gynecological surgery. ³

Currently, AMH levels and antral follicle count (AFC) are regarded as the most accurate and reproducible markers of ovarian reserve. ⁴ In this context, a recent meta-analysis demonstrated that a single RAI dose (50–150 mCi) is associated with a significant and sustained reduction in AMH concentrations at three, six, and 12 months following treatment in women with DTC (weighted mean difference at 12 months: −1.62 ng/mL; 95% confidence interval: −2.02 to −1.22). ⁵ No corresponding changes in follicle-stimulating hormone levels were observed. ⁵ Notably, in one of the included prospective studies, AMH concentrations remained persistently reduced up to four years after RAI therapy, following an initial decline of approximately 55% at 12 months. ⁶ These findings were further corroborated by a subsequent study published after the meta-analysis, which also demonstrated a significant reduction in AFC following RAI treatment. ⁷

Taken together, the available evidence indicates that RAI therapy exerts a clinically meaningful adverse effect on ovarian reserve.^5,8 This potential harm should be carefully weighed when considering RAI treatment in women seeking fertility counseling, particularly those of advanced reproductive age (>35 years) and those with low-risk DTC, for whom the benefit of RAI may be limited.