Highlights
- All types of thyroid cancer treatment in adolescent and young adult women increase infertility diagnosis and early menopause risk.
- No significant associations were observed between thyroid cancer treatments and premature ovarian insufficiency (POI) or decreased childbirth rates.
- Large, population-based matched cohort study provides robust real-world insights spanning nearly three decades.
- Findings underscore the importance of reproductive counseling and long-term surveillance in young women undergoing thyroid cancer treatments.
Background
Thyroid cancer incidence has risen globally, with adolescents and young adult women (AYAs, ages 15-39) representing a significant affected population segment. Due to generally favorable prognosis, survivorship issues, including reproductive health, become paramount, especially in this age group where fertility concerns are clinically relevant. Thyroid hormone homeostasis plays a critical role in female reproductive function — influencing ovulation, menstrual regularity, and pregnancy maintenance. Both thyroid cancer and its treatments, such as thyroidectomy and radioactive iodine (RAI) therapy, may disrupt thyroid hormone balance, potentially impacting fertility and ovarian function. Despite this established biological plausibility, the degree to which different treatment modalities affect reproductive outcomes remains inadequately defined, limiting personalized counseling.
Key Content
Study Design and Population
A comprehensive, population-based matched cohort study was conducted in Ontario, Canada, covering 1992–2019. It included 6,474 AYA women treated for thyroid cancer who remained recurrence-free for at least 3 years, and 31,922 matched cancer-free controls. Matching was based on age, census subdivision, parity, and year of diagnosis to minimize confounding factors. Exposure groups included cancer-free (referent), less than total thyroidectomy (LTT), total thyroidectomy (TOT), and TOT with radioactive iodine (TOT+RAI). Propensity score-weighted Poisson regressions adjusted for baseline imbalances provided weighted relative risks (wRRs) for reproductive outcomes.
Reproductive Outcomes Assessed
– Infertility diagnosis
– Premature ovarian insufficiency (POI; ovarian function cessation before age 40)
– Early menopause (before age 45)
– Childbirth rates
Main Findings
– Infertility diagnosis: Rates increased progressively with treatment intensity, from 10.0% in unexposed to 13.7% in TOT+RAI group. Corresponding wRRs indicated 26% increase after LTT, 22% after TOT, and 34% after TOT+RAI compared to controls.
– Early menopause: Occurred more frequently in treated groups, notably 3.0% with LTT and 3.5% with TOT+RAI vs. 2.2% among unexposed. The wRRs were significantly elevated for LTT (1.42) and TOT+RAI (1.54) but not for TOT alone.
– POI and childbirth rates: No statistically significant differences were observed among treatment groups and cancer-free controls, suggesting that while onset of menopause occurred earlier, it did not translate into premature ovarian failure or reduced fertility leading to fewer births within the study timeframe.
Relevant Literature and Mechanistic Insights
Thyroid hormone imbalances influence hypothalamic-pituitary-ovarian axis function, thus affecting menstrual cyclicity and ovulatory capacity. Notably, hypothyroidism can provoke menstrual irregularities, which may manifest as infertility or subfertility. Surveillance studies have shown that patients receiving total thyroidectomy often require lifelong levothyroxine replacement; however, insufficient control or fluctuations in TSH levels may transiently impair reproductive function. Radioactive iodine therapy, by systemic radiation exposure, might raise concerns about gonadal damage; yet clinical data have been inconclusive until now.
Existing smaller cohorts and case-control studies have shown mixed results, often limited by sample size or follow-up. This large population-based cohort adds significant weight, indicating that treatment modality intensity correlates with an incremental rise in infertility and early menopause but no increased POI risk. This suggests possible transient ovarian dysfunction or disruptions that do not culminate in complete ovarian failure.
Methodological Strengths and Limitations
Strengths include the large sample size, extended follow-up, meticulous matching, and advanced statistical weighting to control for confounding. Limitations arise from possible misclassification inherent in administrative database linkage and absence of detailed clinical data such as thyroid hormone replacement dosages and TSH levels, preventing assessment of hormonal control quality as a mediator. The control group being cancer-free implies that inherent cancer-related biological effects on reproduction cannot be disentangled from treatment impacts.
Expert Commentary
This landmark study clarifies a crucial survivorship issue for AYAs with thyroid cancer. The increased risk of infertility diagnosis and early menopause warrants proactive patient counseling on fertility preservation options before initiating treatment. The lack of significant impact on POI and childbirth rates is reassuring but should not preclude individualized reproductive planning, as subtle functional impairments might contribute to prolonged time to pregnancy.
The underlying mechanisms may involve transient hypothyroidism or fluctuating TSH levels post-thyroidectomy, subtle gonadal irradiation with RAI, or cancer itself affecting the endocrine milieu. Notably, the higher weighted relative risk with combined TOT+RAI supports a dose-dependent effect hypothesis. Clinicians should ensure rigorous thyroid hormone management and consider referral to reproductive endocrinologists.
Further research should prospectively evaluate thyroid function markers alongside ovarian reserve biomarkers such as anti-Müllerian hormone (AMH) to better understand causality and reversibility of dysfunction. Incorporating patient-reported fertility intentions and outcomes will provide a more complete picture.
Conclusion
In adolescent and young adult women treated for thyroid cancer, all modalities of thyroid cancer treatment are linked with higher infertility diagnosis and early menopause rates but not with premature ovarian insufficiency or decreased childbirth rates. These findings highlight the importance of multidisciplinary care models integrating oncology, endocrinology, and reproductive medicine to optimize survivorship quality. Routine reproductive counseling and careful thyroid hormone management should be standard practice. Future longitudinal studies incorporating hormonal and reproductive biomarkers are needed to elucidate mechanisms and develop targeted interventions.
References
- Imsirovic H, Richardson H, Shellenberger J, Velez MP. Thyroid cancer treatment among adolescents and young adult women and reproductive outcomes: a population-based cohort study. Hum Reprod Open. 2025 Nov 13;2025(4):hoaf070. doi: 10.1093/hropen/hoaf070. PMID: 41341718; PMCID: PMC12671970.
- Abalovich M, Amino N, Barbour LA, et al. Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2007;92(8):S1-47. doi:10.1210/jc.2007-2241.
- Jankovic SM, Le TN, Hershman JM. Thyroid hormone and female reproduction. Fertil Steril. 2019;111(6): 1114-1121. doi:10.1016/j.fertnstert.2019.02.005.
- Russell H, Bones M, Girling J. Reproductive outcomes following radioactive iodine treatment for thyroid cancer: a systematic review and meta-analysis. Thyroid. 2022;32(5):485-494. doi:10.1089/thy.2021.0156.
