Hyperthyroidism Potentially Linked to Increased Ovarian Cancer Risk

Patients with hyperthyroidism may be at an increased risk of ovarian cancer (OC), according to a study published in BMC Cancer that aimed to investigate the potential causal impact of thyroid dysfunction on OC risk.¹

According to the National Cancer Institute, the annual incidence of OC is about 11.6 cases per 100,000 US women, with 60% diagnosed at an advanced stage.² Also, the researchers noted that OC has become a global health issue for women as survival rates have not improved despite clinical surgery advancements.¹

Additionally, OC’s pathogenesis is poorly understood, but reported risk factors include genetic and endocrine factors. As the body’s principal endocrine gland, the thyroid synthesizes and secretes hormones crucial for regulating various functions, such as metabolism and growth. The researchers noted that thyroid hormones possess cancer-promoting effects by stimulating cell differentiation and proliferation. Therefore, thyroid dysfunction is considered a potential risk factor for cancer development and prevention.

However, data regarding the impact of thyroid hormones on ovary function remain unclear. Similarly, the existing evidence on the association between OC and thyroid function is contradictory, making it difficult to establish a causal relationship between them.

Because of this, the researchers aimed to investigate the causal impact of thyroid dysfunction on OC through a Mendelian randomization (MR) study; MR uses genetic information to explore causal exposure-outcome links.³ More specifically, they explored the causal relationships among hypothyroidism, hyperthyroidism, free thyroxine (FT4), thyrotropin (TSH), and OC risk. The researchers explained that the study would help examine OC’s origin and offer new clinical prevention and treatment methods.¹

The researchers found a causal relationship between hyperthyroidism and ovarian cancer (OC) risk. | Image Credit: Vitalii Vodolazskyi - stock.adobe.com

They used summary data from genome-wide association studies (GWASs) of European ancestry cohorts, namely the Integrative Epidemiology Unit (IEU) OpenGWAS database and the ThyroidOmics Consortium database. Overall, the researchers analyzed 410,141 hypothyroidism samples, 484,598 hyperthyroidism samples, 199,741 OC samples, and 72,167 combined TSH and FT4 samples.

From GWAS summary statistics, they extracted prominent single nucleotide polymorphisms (SNPs) to serve as genetic instrumental variables (IVs) for thyroid dysfunction and OC. After a series of quality evaluations, the researchers selected 17, 66, 26, and 11 SNPs as effective IVs for hyperthyroidism, hypothyroidism, TSH, and FT4, respectively.

The researchers used the inverse variance-weighted (IVW) method to assess the potential causal effect of thyroid dysfunction on OC. They further assessed the causal effect through complementary approaches, like simple mode, MR-Egger, weighted mode, and weighted median. Additionally, the researchers conducted various sensitivity analyses, including Cochran’s Q test and the leave-one-out test, to assess the robustness of their findings.

Through the IVW analysis, the researchers discovered a significant correlation between hyperthyroidism levels and an elevated OC risk (OR, 1.094; 95% CI, 1.029-1.164; P = .004). These results were also reflected through the MR-Egger (OR, 1.174; 95% CI, 1.054-1.308; P = .011), weighted mode (OR, 1.133; 95% CI, 1.044-1.229; P .011), and weighted median (OR, 1.148; 95% CI, 1.057-1.245; P = .001) methods. However, the researchers did not find a statistically significant causal relationship between TSH, FT4, hypothyroidism, and OC risk.

The sensitivity analyses demonstrated reliable, consistent results, with no significant heterogeneity estimates. More specifically, when hyperthyroidism was used as the exposure, no heterogeneity was noted among SNPs (Cochran’s Q value, 12.773; P = .689). Heterogeneity was also not found in hypothyroidism (P = .279), FT4 (P = .473), or TSH (P = .561).

The stability of their results was further confirmed by the leave-one-out test, along with the scatter and funnel plots. Therefore, the results obtained through their IVW analysis are considered reliable.

The researchers acknowledged some limitations, one being that all participants were of European descent; this limits the generalizability of their findings to other races and ethnicities. Also, the researchers could not distinguish between different OC types. Despite these limitations, the researchers used their findings to suggest areas for future research.

“This study suggests a causal relationship between hyperthyroidism and OC, underscoring the importance of thyroid hormones in the prevention and treatment of the female reproductive system. However, the mechanism by which the hypothalamic-pituitary-thyroid axis promotes OC development remains incompletely understood and requires further study.,” the authors concluded.

References

1. Wang T, Wang X, Wu J, Li X. Causal relationship between thyroid dysfunction and ovarian cancer: a two-sample Mendelian randomization study. BMC Cancer. 2024;24(1):629. Published 2024 May 23. doi:10.1186/s12885-024-12385-5
2. National Cancer Institute. Cancer of the ovary - cancer stat facts. SEER. Published 2018. https://seer.cancer.gov/statfacts/html/ovary.html
3. Davey Smith G, Hemani G. Mendelian randomization: genetic anchors for causal inference in epidemiological studies. Hum Mol Genet. 2014;23(R1):R89-R98. doi:10.1093/hmg/ddu328