Impact of hypothyroidism and hyperthyroidism on endometrial cancer incidence: Results from a large population-based cohort study

Impact of hypothyroidism and hyperthyroidism on endometrial cancer incidence: Results from a large population-based cohort study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Impact of hypothyroidism and hyperthyroidism on endometrial cancer incidence: Results from a large population-based cohort study Allan Jensen, Bugge Nøhr, Jane Christensen, Mathilde Gottschau, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6974955/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 25 Mar, 2026 Read the published version in European Journal of Epidemiology → Version 1 posted 5 You are reading this latest preprint version Abstract The limited number of studies examining the association between thyroid diseases and endometrial cancer have yielded inconsistent findings. The study aimed to examine the association between hypothyroidism and hyperthyroidism and the risk of endometrial cancer using comprehensive nationwide register data from Denmark. We conducted a population-based cohort study including 1,057,937 women born in Denmark between 1960 and 1997. Information on thyroid disease diagnoses, cancer diagnoses, covariates, migration, and vital status was obtained from nationwide Danish health and administrative registers. Cox proportional hazards models were used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for endometrial cancer overall and for type I tumors. A landmark analysis examined risks associated with exposures before age 40, and pseudo-observation methods estimated absolute risk differences. During a median follow-up of 17.5 years, 1,159 women were diagnosed with endometrial cancer. Women with hypothyroidism had a higher rate of overall endometrial cancer (HR: 1.54, 95% CI: 1.22–1.94) and type I tumors (HR: 1.65, 95% CI: 1.29–2.11). These associations were consistent across subgroups defined by menopausal status and time since diagnosis. No association was observed for hyperthyroidism (HR: 1.13, 95% CI: 0.80–1.61). In the landmark analysis, hypothyroidism remained associated with an increased endometrial cancer rate, but the absolute risk difference by age 60 was modest and not statistically significant. In conclusion, hypothyroidism was associated with a modestly increased rate of endometrial cancer, while no association was observed for hyperthyroidism. These findings support further investigation into thyroid function and endometrial carcinogenesis. Endometrial cancer hypothyroidism hyperthyroidism population-based cohort study Denmark Figures Figure 1 INTRODUCTION Thyroid disorders encompass a range of conditions including hypothyroidism (characterized by insufficient levels of triiodothyronine [T3] and thyroxine [T4]), hyperthyroidism (elevated T3 and T4 levels), goiter, thyroiditis, and thyroid nodules. Among thyroid disorders, hypothyroidism and hyperthyroidism are the most common, with both conditions showing a higher prevalence in women [ 1 , 2 ]. While thyroid dysfunction has been associated with a number of chronic conditions, including type 1 diabetes, cardiovascular disease, cognitive impairment and dementia [ 3 – 5 ], its potential role in the development of hormone-sensitive cancers remains less studied [ 6 ]. Endometrial cancer is the sixth most common cancer among women globally, with 417,367 new cases and 97,370 deaths reported in 2020 [ 7 ]. Unlike several other cancer types showing declining incidence trends, the incidence of endometrial cancer continues to rise, particularly in countries undergoing rapid socioeconomic transitions [ 7 ]. Endometrial cancer is classified into two main subtypes based on etiology and histopathology. Type I tumors, which constitute approximately 80% of cases, are estrogen-dependent and generally associated with a favorable prognosis. Established risk factors for type I include unopposed estrogen therapy, obesity, early menarche, late menopause, and nulliparity, whereas combined hormonal contraceptives, hormone therapy, and multiparity are protective. Type II tumors are less influenced by estrogen, are more aggressive, and have a less clearly defined risk profile, although low parity and diabetes have been suggested as possible contributors [ 8 ]. While early-stage endometrial cancer has a favorable prognosis with five-year survival nearing 95%, 10–15% of patients are diagnosed at an advanced stage, where survival can drop to 10–20% [ 9 , 10 ]. Alterations in thyroid function may contribute to endometrial carcinogenesis through both direct and indirect mechanisms. Thyroid hormones can bind to nuclear thyroid hormone receptors expressed in endometrial tissue, thereby potentially regulating the expression of genes involved in proliferation, differentiation, and apoptosis [ 11 , 12 ]. Thyroid dysfunction also influences estrogen bioavailability through its effect on sex hormone-binding globulin (SHBG): hyperthyroidism increases SHBG levels, thereby reducing the concentration of free (bioavailable) estrogen, while hypothyroidism decreases SHBG, leading to higher levels of bioavailable estrogen, which may promote endometrial proliferation [ 9 , 13 ]. In addition, hypothyroidism is associated with obesity, insulin resistance and chronic inflammation, all of which are implicated in endometrial cancer development [ 14 , 15 ]. It may also disrupt menstrual cycles, ovulation, and fertility, further contributing to prolonged unopposed estrogen exposure [ 16 ]. Finally, thyroid dysfunction may affect the hypothalamic-pituitary-gonadal axis and hepatic hormone metabolism, thereby altering the uterine hormonal milieu in ways relevant to endometrial carcinogenesis [ 6 , 11 , 16 ]. Despite this biological plausibility, few epidemiological studies have examined associations between thyroid disorders and endometrial cancer [ 17 – 26 ]. To date, no studies have reported a convincing association between hyperthyroidism and endometrial cancer [ 18 , 19 , 22 , 24 , 25 ]. In contrast, findings for hypothyroidism have been inconsistent as four studies reported null associations [ 20 , 22 , 25 , 26 ], while two studies found an increased rate of endometrial cancer [ 21 , 23 ]. One additional study observed an elevated rate among women with broadly defined thyroid disease, without distinguishing between hypo- and hyperthyroidism [ 17 ]. Discrepancies across studies may reflect differences in study design and methodological limitations, including reliance on self-reported thyroid diagnoses, inconsistent diagnostic criteria, small sample sizes, incomplete follow-up, and inadequate adjustment for confounders, particularly obesity, which is a well-established risk factor for endometrial cancer and is associated with hypothyroidism [ 27 , 28 ], Provided the limited and inconsistent findings to date, we conducted a large nationwide cohort study in Denmark to investigate the association between hypothyroidism and hyperthyroidism and the risk of endometrial cancer. Using data from the Danish national health registers, we followed more than one million women born between 1960 and 1997 to assess these associations, overall and for type I endometrial cancer. METHODS Data Sources and Linkage All Danish residents are assigned a unique personal identification number, enabling individual-level linkage across national health and population registers. For this study, we integrated data from multiple registers using these unique identifiers. Detailed information on data sources and coding is provided in the Supplementary Material. Study population The study population included all women born in Denmark between January 1, 1960, and December 31, 1997 (n = 1,252,479), as identified in the Danish Civil Registration System. Through linkage to nationwide registers, we obtained data on thyroid disorders, cancer diagnoses, potential confounders, and vital/emigration status. Exposure Assessment Exposure to hypothyroidism and hyperthyroidism was identified using nationwide Danish health registers. Women aged 25 years or older were classified as exposed if they had either a physician-confirmed diagnosis of hypothyroidism or hyperthyroidism recorded in the Danish National Patient Register, or if they had redeemed a relevant prescription recorded in the Danish National Prescription Register. Diagnostic information was based on the International Classification of Diseases, 8th Revision (ICD-8) from 1977 to 1993 and 10th Revision (ICD-10) from 1994 onward. The Danish National Prescription Register has captured all redeemed prescriptions, coded using the Anatomical Therapeutic Chemical (ATC) system, since 1995. The date of thyroid disease onset was defined as the earliest occurrence of either a hospital diagnosis or prescription redemption for thyroid medication. For women diagnosed with both hyperthyroidism and hypothyroidism during follow-up, we applied mutually exclusive classification rules. Women initially diagnosed with hyperthyroidism and later developing hypothyroidism remained classified as hyperthyroid, using the date of first hyperthyroidism diagnosis as the exposure start. Conversely, women with an initial hypothyroidism diagnosis who were subsequently diagnosed with hyperthyroidism were reclassified as hyperthyroid, but with the start date anchored at their initial hypothyroidism diagnosis. This approach reflects the clinical trajectory of conditions such as Graves’ disease, where thyroid function may transition due to shifts in thyrotropin receptor antibody activity [ 29 ]. An exception was made for women assigned the diagnostic code DO992B (hypothyroidism complicating pregnancy, childbirth, or the postpartum period). These individuals were not considered hyperthyroid, as this condition is typically associated with transient postpartum thyroiditis in women with thyroid peroxidase (TPO) antibody positivity, which often includes a short-lived hyperthyroid phase that is self-limiting [ 30 ]. Outcome assessment Incident cases of endometrial cancer were identified through the Danish Cancer Register using the International Classification of Diseases, 7th revision (ICD-7) up to 1977, and the 10th revision (ICD-10) from 1978 onwards. Tumors were classified using the International Classification of Diseases for Oncology, 3rd edition (ICD-O-3) morphology codes into type I (endometrioid, mucinous), type II (serous, clear cell, mixed), and other/unspecified subtypes, following Bokhman’s dualistic model [ 31 ]. Only tumors with a morphology code ending in ‘3’ were included. Follow-up To ensure accurate assessment of baseline characteristics and capture physician-confirmed diagnoses of hypothyroidism or hyperthyroidism from the Danish National Patient Register, as well as relevant prescriptions from the Danish National Prescription Register, follow-up began at the later of age 25 or January 1, 1996. The start year of 1996 was selected to reduce misclassification of current medication use, as comprehensive data in the Danish National Prescription Register have been available only since 1995. Women were excluded if, prior to follow-up, they had died, emigrated, received a cancer diagnosis other than non-melanoma skin cancer, or had missing data on highest level of education. Participants were followed until the first occurrence of endometrial cancer, another cancer diagnosis (excluding non-melanoma skin cancer), hysterectomy, death, emigration, or the end of follow-up on December 31, 2022. Statistical analysis Median follow-up time was estimated using the reverse Kaplan-Meier curve. Cause-specific Cox proportional hazards models were applied to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for endometrial cancer (overall and type I tumors) among women with hypothyroidism or hyperthyroidism compared to those without thyroid disease. Due to a limited number of exposed cases, analyses for type II tumors and other histological subtypes were not feasible. Age was used as the underlying time scale, with delayed entry at age 25 or on January 1, 1996, whichever occurred last. Thyroid disease was modeled as a time-varying categorical variable (no thyroid disease, hypothyroidism, hyperthyroidism), with exposure status updated during follow-up. Analyses were additionally performed by time since thyroid disease diagnosis (< 10 years, ≥ 10 years) and by menopausal status, both treated as time-varying covariates. As individual-level data on age at menopause were unavailable, we assigned a fixed value of 51 years, which is the median age at menopause in Denmark, as a proxy [ 32 ]. Confounders were selected based on prior knowledge and data availability from Danish national registers. These included birth year (categorized into six intervals for the 1960–1997 period), highest obtained level of education (basic, medium, higher), and pre-existing diagnoses of smoking-related diseases, type I diabetes, and obesity. All covariates except birth year were identified at age 25. Two Cox models were constructed: an unadjusted model and a model adjusted for the above-mentioned confounders. We also performed landmark analyses [ 33 , 34 ] with age 40 as the landmark, allowing for covariate updates beyond baseline while remaining prior to the median age at endometrial cancer diagnosis in Denmark [ 35 ]. This analysis included only women alive and cancer-free at age 40. Educational level was fixed at age 25, while smoking-related diseases, type 1 diabetes, and obesity were updated and fixed at age 40. For all study participants, a 20-year prediction window was applied with artificial censoring at age 60. The Aalen-Johansen estimator was used to calculate unadjusted absolute risks (cumulative incidences) for endometrial cancer across thyroid disease categories. Cox proportional hazard regression models were used to assess associations between exposure and cause-specific hazard of endometrial cancer, adjusting for both time-fixed and updated covariates at age 40. To estimate the adjusted absolute risk difference of endometrial cancer at age 60, while accounting for the above-mentioned potential confounders, we applied a pseudo-observation approach that accounted for competing risks (other cancers and death without prior cancer) [ 36 ]. Linear regression models with robust variance estimation were used to obtain risk differences. The proportional hazard assumption was evaluated using Schoenfeld residuals. All analyses were conducted in R version 4.2.2 ( https://www.r-project.org/ ), with two-sided p-values of 0.05 considered statistically significant. RESULTS From the initial cohort of 1,252,479 women born in Denmark between January 1, 1960, and December 31, 1997, a total of 194,542 were excluded based on predefined criteria, yielding a final analytic cohort of 1,057,937 women (Figure 1). The median follow-up time was 17.5 years and the median age at end of follow-up was 43.3 years (inter quartile range [IQR]: 33.0-52.8). By the end of follow-up, 47,309 women had been diagnosed with hypothyroidism and 26,072 with hyperthyroidism. The median age at first hypothyroidism diagnosis was 37.5 years (IQR: 29.8-46.1) and the median year of hyperthyroidism diagnosis was 35.7 years (IQR: 29.0-44.4). A total of 1,159 women were diagnosed with endometrial cancer during follow-up, of which 79.1% (n = 917) were classified as type I and 20.9% (n = 242) as type II, other, or unspecified histology. The median age at endometrial cancer diagnosis was 51.2 years (IQR: 45.4–55.0) among women without thyroid disease, 53.3 years (IQR: 47.8–56.4) among those with hypothyroidism, and 53.7 years (IQR: 50.3–56.5) among those with hyperthyroidism. In the sensitivity analysis using a landmark analytic approach, the cohort included 611,277 women with a median follow-up of 10.3 years. Baseline characteristics of the main study population are presented in Table 1. Compared to women without thyroid disease, those with thyroid disorders more frequently had a basic educational level and a higher prevalence of smoking-related diseases, type I diabetes, and obesity. Comparable patterns were observed in the landmark analysis cohort (Supplementary Table 1). Hypothyroidism and endometrial cancer The associations between hypothyroidism and endometrial cancer are presented in Tables 2 and 3. Overall, both unadjusted and adjusted hazard ratios (HRs) showed consistent trends; however, direct comparison is limited by the non-collapsibility of the Cox proportional hazards model. After adjustment for birth year, highest obtained level of education, type I diabetes, smoking-related diseases, and obesity, women diagnosed with hypothyroidism had a higher rate of endometrial cancer compared with women without thyroid disease (adjusted HR: 1.54, 95% CI: 1.22–1.94). A similar association was observed for type I endometrial cancer (HR: 1.65, 95% CI: 1.29–2.11). Time since hypothyroidism diagnosis had little influence on the magnitude of the association for either overall or type I endometrial cancer (Table 2). Also menopausal status had minimal impact on the strength of the association, with similar HRs observed for both premenopausal (HR: 1.44, 95% CI: 0.96–2.16) and postmenopausal women (HR: 1.59, 95% CI: 1.20–2.11); however, the association reached statistical significance only in postmenopausal women. These patterns were consistent in the analysis of type I endometrial cancer (HRs: 1.73, 95% CI: 1.29–2.32 for postmenopausal women; and 1.48, 95% CI: 0.93–2.35 for premenopausal women) (Table 3). In the landmark analysis, the elevated rate of endometrial cancer associated with hypothyroidism persisted (HR: 1.68, 95% CI: 1.13–2.48). The adjusted absolute risk of developing endometrial cancer by age 60 was higher among women diagnosed with hypothyroidism (0.62%, 95% CI: 0.29%–0.95%) than among those without thyroid disease (0.39%, 95% CI: 0.36%–0.41%), although the difference in absolute risk was not statistically significant (risk difference: 0.15 percentage points, 95% CI: -0.02% to 0.33%). Hyperthyroidism and endometrial cancer In Table 2 and 3, the associations between hyperthyroidism and endometrial cancer are shown. No association was found between a diagnosis of hyperthyroidism and endometrial cancer (adjusted HR: 1.13, 95% CI: 0.80–1.61), with similar results observed for type I endometrial cancer (adjusted HR: 1.13, 95% CI: 0.77–1.68). Time since hyperthyroidism diagnosis had little influence on the magnitude of the association for either overall or type I endometrial cancer (Table 2). Also, menopausal status did not materially alter the associations as the HRs were 0.97 (95% CI: 0.52–1.81) among premenopausal women and 1.23 (95% CI: 0.80–1.89) among postmenopausal women, with similar estimates observed for type I endometrial cancer (Table 3). In the landmark analysis, also no association was found between hyperthyroidism and endometrial cancer (HR: 1.00, 95% CI: 0.56–1.76). The adjusted absolute risk of endometrial cancer by age 60 among women with hyperthyroidism (0.48%, 95% CI: 0.13%–0.83%) was comparable to that among women without thyroid disease (0.39%, 95% CI: 0.36%–0.41%), with no statistically significant difference in absolute risk (risk difference: 0.07 percentage points, 95% CI: -0.17% to 0.30%). DISCUSSION In this large nationwide cohort study comprising over one million Danish women, we observed no association between hyperthyroidism and endometrial cancer. In contrast, hypothyroidism was linked to a 54% higher overall rate of endometrial cancer and a 65% higher rate for type I tumors compared to no thyroid disease. These associations were consistent across subgroups defined by menopausal status and time since diagnosis, and they persisted in landmark analyses limited to hypothyroidism diagnoses occurring before age 40. However, the landmark analyses demonstrated that the absolute difference in endometrial cancer risk at age 60 between women with and without hypothyroidism was small and not statistically significant, indicating that while a possible association exists, its clinical relevance may be modest. Our findings regarding hyperthyroidism align with all previous epidemiological studies on this topic [ 18 , 19 , 22 , 24 , 25 ]. Most recently, Leung et al. [ 25 ] conducted a large population-based retrospective cohort study utilizing data from the Taiwan National Health Insurance Research Database, which included 296,872 women diagnosed with hyperthyroidism, among whom 484 developed endometrial cancer and observed no increase in this malignancy among women with hyperthyroidism. Together with our results, these findings suggest that hyperthyroidism is unlikely to have a major role in endometrial carcinogenesis. Nonetheless, due to plausible biological mechanisms, including estrogen bioavailability, altered SHBG levels, and reproductive hormone dynamics [ 11 , 13 , 16 ], this association warrants further investigation, especially in subgroups with different hyperthyroidism etiologies or treatment history. Our findings for hypothyroidism are consistent with two previous studies reporting an elevated risk of endometrial cancer [ 21 , 23 ]. A large population-based study by Krashin et al. [ 23 ] used data from 375,635 Israeli women who had a blood test for TSH levels and found that TSH levels in the hypothyroid range was associated with an elevated risk of endometrial cancer. Similarly, Kurnit et al. [ 21 ] used data from a large case-control study nested in the US University HealthSystem Consortium database and reported a higher rate of hypothyroidism among women with uterine cancer compared to women who served as controls. Brinton et al. [ 17 ] also observed an increased risk of endometrial cancer among women with broadly defined thyroid disease, although the study did not differentiate between hypothyroidism and hyperthyroidism. However, the literature remains inconsistent, with several studies reporting no marked associations [ 20 , 22 , 25 , 26 ], underscoring the need for additional investigations. The observed increased risk of endometrial cancer among women diagnosed with hypothyroidism may be explained by several interrelated biological mechanisms. Hypothyroidism is frequently accompanied by metabolic alterations including obesity, insulin resistance, dyslipidemia, and chronic low-grade systemic inflammation; all of which are established risk factors for endometrial cancer [ 11 , 13 – 16 , 27 , 37 , 38 ]. Thyroid hormones influence lipid metabolism and glucose homeostasis; reduced levels of triiodothyronine (T3) and thyroxine (T4) can impair insulin signaling, increase adiposity, and elevate circulating inflammatory cytokines, thereby creating a pro-tumorigenic environment [ 6 , 37 , 39 ]. In addition, low thyroid hormone levels suppress hepatic production of SHBG, leading to elevated levels of bioavailable estradiol. This enhances estrogenic stimulation of the endometrium, particularly relevant for type I tumors, which are estrogen-dependent [ 6 , 9 , 13 , 27 ]. Hypothyroidism also affects the hypothalamic–pituitary–gonadal axis and can disrupt gonadotropin-releasing hormone (GnRH) pulsatility, leading to menstrual disturbances, anovulation, oligomenorrhea, and ultimately infertility or nulliparity which are all recognized risk factors for endometrial cancer [ 6 , 11 , 16 ]. These reproductive effects are particularly pertinent when thyroid dysfunction occurs during a woman’s reproductive years, potentially prolonging exposure to unopposed endogenous estrogen. Although these pathways are biologically plausible, it remains uncertain whether hypothyroidism independently contributes to the risk of endometrial cancer or primarily exerts its effect through shared metabolic and hormonal intermediates. Consequently, intrinsic factors associated with the development of hypothyroidism in women may also play a significant role. [ 6 , 16 ]. Although our analyses adjusted for comorbid obesity and diabetes, we lacked data on BMI, exogenous hormone use, and lifestyle factors. Further studies incorporating these factors as well as estrogen levels and markers of metabolic dysfunction are needed to disentangle these effects and determine whether hypothyroidism represents a modifiable risk factor for endometrial cancer. Differences in study design, sample size, baseline population characteristics, and the extent to which confounding (particularly obesity) has been addressed may help explain the inconsistencies observed across previous studies. Whereas our study utilized both physician-verified diagnoses and prescription register data to enhance exposure classification, other investigations have relied on self-reported or medical record-based data, potentially increasing the risk of misclassification. Furthermore, most population-based studies, including ours, could not distinguish between autoimmune and non-autoimmune hypothyroidism, which may have divergent implications for endometrial carcinogenesis. Although our findings of an increased risk of endometrial cancer among women with hypothyroidism are consistent with two previous epidemiological studies [ 21 , 23 ], this is not a universal finding as most studies found no association [ 20 , 22 , 25 , 26 ]. Thus, the conflicting evidence underscores the need for further research, ideally integrating biochemical thyroid function measures and data on treatment and disease severity to clarify the nature and strength of this potential association. To our knowledge, no previous studies have examined the association between thyroid disorders and endometrial cancer according to menopausal status. In our study, menopausal status did virtually not modify the associations for either hypothyroidism or hyperthyroidism. This may reflect the predominance of type I endometrial cancer in our cohort, which is hormone-driven and influenced by estrogen exposure both before and after menopause. Additionally, the use of a fixed age cutoff (51 years) to define menopause may have introduced misclassification, potentially attenuating true effect differences. However, our consistent findings across strata suggest that thyroid dysfunction may influence endometrial cancer risk through mechanisms that operate independently of menopausal status. Still, more precise measurement of menopausal transition and hormone levels would be valuable in future studies. The main strengths of this study include its large, population-based design with comprehensive data from the Danish health and administrative registers, long follow-up duration, and access to detailed information on key confounders. The use of high-quality register data minimizes recall bias and virtually eliminates loss to follow-up. Exposure and outcome ascertainment were enhanced using physician-certified, guideline-based diagnoses for thyroid disorders and histologically verified endometrial cancer cases, reducing misclassification compared with studies relying on self-reported data. A notable strength is the incorporation of prescription records from the Danish National Prescription Register, which enabled the identification of thyroid disease cases managed exclusively in primary care and not captured in the Danish National Patient Register. This approach improved case ascertainment and reduced the risk of differential misclassification. While some women with undiagnosed or subclinical thyroid dysfunction may have gone unrecognized, potentially leading to an underestimation of the associations, this could have introduced some bias. Our study includes the largest cohort of women with thyroid disease and the highest number of endometrial cancer cases reported to date, providing high statistical precision for most overall risk estimates and allowing for detailed subgroup analyses by menopausal status and histologic subtype, including type I endometrial cancer, which have rarely been explored in previous research. However, limited statistical power in some subgroups may have contributed to wide confidence intervals. To assess the robustness of our findings, we conducted a landmark analysis restricted to exposures occurring before age 40, accounting for time-varying confounding and competing risks such as mortality and other cancers. The results were consistent with our primary analyses, reinforcing the validity of our findings. Finally, although we adjusted for several key confounders identified a priori based on existing evidence and register data availability, residual or unmeasured confounding cannot be entirely excluded. Several limitations should be acknowledged. Although we relied on high-quality, register-based diagnoses of thyroid disease, validation through clinical chart review or biochemical measurements was not possible due to ethical and data protection constraints. Variability in diagnostic practices and evolving clinical guidelines over time may have introduced some misclassification of thyroid disease diagnoses [ 40 ]. In addition, clinical details such as thyroid hormone levels, TSH concentrations, disease duration, and treatment-specific information, including the use of radioactive iodine or surgical interventions, were not available. As a result, we could not evaluate the influence of disease severity, treatment modality, or duration of thyroid dysfunction on endometrial cancer risk. Surveillance bias is another potential concern, as women with thyroid disorders may have increased healthcare contact, potentially leading to higher likelihood of cancer detection. While endometrial cancer is usually diagnosed symptomatically rather than through screening, heightened medical attention could modestly affect diagnostic rates. Lastly, we used age 51 as a proxy for menopausal transition based on national averages. Although this approach is common in epidemiologic studies, it may have resulted in non-differential misclassification and attenuation of risk estimates across menopausal strata. In conclusion, we found no evidence of an association between hyperthyroidism and endometrial cancer, which is in concordance with previous research. In contrast, our results suggest that hypothyroidism is associated with an increased rate of endometrial cancer. Although absolute risk differences were small and not statistically significant, the consistency of associations across analyses underscores the need for further research to clarify the biological basis and clinical relevance of this association. Declarations Competing interest All authors have no relevant financial or non-financial interests to disclose. Ethics approval As this study utilized data from Danish health registers and did not include any direct contact with study participants, an ethical approval was not required. Necessary permissions for the use of register data that were compiled in a project-specific database at Statistics Denmark (project number 708651) were granted by the Danish Health Data Authority (reference number FSEID-00006179). The Danish Cancer Society holds responsibility for data stored in the Danish Cancer Institute’s database at Statistics Denmark. In accordance with the General Data Protection Regulation (GDPR), the project has been registered in the Danish Cancer Society’s internal register of projects involving personal data (Journal number 2022-DCRC-0008). Funding The study was supported by research grants from the Danish Cancer Society’s Scientific Committee (Rp21772-A17580) and the Jascha Foundation (2023 − 0408). Authors contribution All authors contributed to the study conception and design. Mathilde Gottschau performed data extraction and data management. Jane Christensen performed the statistical analysis. Allan Jensen conducted the literature review and wrote the first draft of the manuscript. All authors commented on previous versions of the manuscript, approved the final manuscript and were accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. References Carlé A, Pedersen IB, Knudsen N, et al. 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Chen YK, Lin CL, Cheng FT, Sung FC, Kao CH. Cancer risk in patients with Hashimoto's thyroiditis: a nationwide cohort study. Br J Cancer. 2013;109(9):2496–501. 10.1038/bjc.2013.597 . https:// . Kurnit KC, Ward KK, McHale MT, Saenz CC, Plaxe SC. Increased prevalence of comorbid conditions in women with uterine cancer. Gynecol Oncol. 2015;138(3):731–4. https://doi:10.1016/j.ygyno.2015.07.004 . Kang JH, Kueck AS, Stevens R, et al. A large cohort study of hypothyroidism and hyperthyroidism in relation to gynecologic cancers. Obstet Gynecol Int. 2013;2013:743721. https://doi:10.1155/2013/743721 . Krashin E, Silverman B, Steinberg DM, et al. Opposing effects of thyroid hormones on cancer risk: a population-based study. Eur J Endocrinol. 2021;184(3):477–86. 10.1530/eje-20-1123 . https://doi . Lee JY, Lee MK, Lee JH, Kim K, Bae K, Sohn SY. Cancer Risks of Patients with Graves' Disease Who Received Antithyroid Drugs as Initial Treatment: A Nationwide Population-Based Analysis. Thyroid. 2024;34(10):1271–9. https://doi:10.1089/thy.2024.0178 . Leung JH, Wang SY, Leung HWC, Yu TS, Chan ALF. Hypothyroidism and hyperthyroidism related to gynecologic cancers: a nationwide population-based cohort study. Sci Rep. 2024;14(1):1892. https://doi:10.1038/s41598-023-50439-z . Wang B, Luo Y, Liu T, et al. Assessment of bidirectional relationships between hypothyroidism and endometrial cancer: a two-sample Mendelian randomization study. Front Endocrinol. 2024;15:1308208. https://doi:10.3389/fendo.2024.1308208 . Fader AN, Arriba LN, Frasure HE, von Gruenigen VE. Endometrial cancer and obesity: epidemiology, biomarkers, prevention and survivorship. Gynecol Oncol. 2009;114(1):121–7. https://doi:10.1016/j.ygyno.2009.03.039 . Song RH, Wang B, Yao QM, Li Q, Jia X, Zhang JA. The Impact of Obesity on Thyroid Autoimmunity and Dysfunction: A Systematic Review and Meta-Analysis. Front Immunol. 2019;10:2349. https://doi:10.3389/fimmu.2019.02349 . Takasu N, Matsushita M. Changes of TSH-Stimulation Blocking Antibody (TSBAb) and Thyroid Stimulating Antibody (TSAb) Over 10 Years in 34 TSBAb-Positive Patients with Hypothyroidism and in 98 TSAb-Positive Graves' Patients with Hyperthyroidism: Reevaluation of TSBAb and TSAb in TSH-Receptor-Antibody (TRAb)-Positive Patients. J thyroid Res. 2012;2012:182176. https://doi:10.1155/2012/182176 . Lazarus JH, Parkes AB, Premawardhana LD. Postpartum thyroiditis. Autoimmunity. 2002;35(3):169–73. 10.1080/08916930290031667 . https:// . Bokhman JV. Two pathogenetic types of endometrial carcinoma. Gynecol Oncol. 1983;15(1):10–7. 10.1016/0090-8258(83)90111-7 . https:// . McKinlay SM, Brambilla DJ, Posner JG. The normal menopause transition. Maturitas. 2008;61(1–2):4–16. https://doi:10.1016/j.maturitas.2008.09.005 . Anderson JR, Cain KC, Gelber RD. Analysis of survival by tumor response. J Clin oncology: official J Am Soc Clin Oncol. 1983;1(11):710–9. https://doi:10.1200/jco.1983.1.11.710 . H vHHP. Dynamic Prediction in Clinical Survival Analysis. Boca Ranton, Florida, USA: Taylor and Francis Group, LLC; 2012. Gottschau M, Mellemkjaer L, Hannibal CG, Kjaer SK. Ovarian and tubal cancer in Denmark: an update on incidence and survival. Acta Obstet Gynecol Scand. 2016;95(10):1181–9. https://doi:10.1111/aogs.12948 . Andersen PK, Klein JP, Rosthøj S. Generalised linear models for correlated pseudo-observations, with applications to multi‐state models. Biometrika. 2003;90(1):15–27. https://doi.org/10.1093/biomet/90.1.15 . Duntas LH. Thyroid disease and lipids. Thyroid. 2002;12(4):287–93. 10.1089/10507250252949405 . https:// . Reinehr T. Obesity and thyroid function. Mol Cell Endocrinol. 2010;316(2):165–71. 10.1016/j.mce.2009.06.005 . https://doi . Duntas LH, Brenta G. The effect of thyroid disorders on lipid levels and metabolism. Med Clin North Am. 2012;96(2):269–. https://doi:10.1016/j.mcna.2012.01.012 . 81. Medici BB, Nygaard B, la Cour JL, et al. Changes in Prescription Routines for Treating Hypothyroidism Between 2001 and 2015: An Observational Study of 929,684 Primary Care Patients in Copenhagen. Thyroid. 2019;29(7):910–9. https://doi:10.1089/thy.2018.0539 . Tables Tables 1 to 3 are available in the Supplementary Files section. Supplementary Files Tables.docx SupplementaryMaterial.pdf Cite Share Download PDF Status: Published Journal Publication published 25 Mar, 2026 Read the published version in European Journal of Epidemiology → Version 1 posted Reviewers agreed at journal 06 Jul, 2025 Reviewers invited by journal 06 Jul, 2025 Editor invited by journal 30 Jun, 2025 Editor assigned by journal 26 Jun, 2025 First submitted to journal 25 Jun, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6974955","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":481229020,"identity":"12fa1701-6c2f-4d31-a40d-2109d9705e6d","order_by":0,"name":"Allan Jensen","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAt0lEQVRIiWNgGAWjYDACduYGBoYKGI8tgQgtzIxALWdI1sLYRooW/mbGxs+F8+zkzdkPH/vAUJZGWIvEYcZm6Znbkg139qQlz2A4l0OEww4zNkjzbjvAuOEGjzHQhRWEdcgDbfnNO+eA/YYb/J+J02JwmLFNmrfhQCLQFmagFiIcZgjUYs1zLDl5w5k0Y4aEc0R4X+548+HbPDV2thuOH37M8KEsmbAWVJBAqoZRMApGwSgYBdgBAGdTNiEwVatuAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0001-8124-4880","institution":"Danish Cancer Society: Kraeftens Bekaempelse","correspondingAuthor":true,"prefix":"","firstName":"Allan","middleName":"","lastName":"Jensen","suffix":""},{"id":481229021,"identity":"4e174559-72c8-40f1-b88e-7f95e96f1b36","order_by":1,"name":"Bugge Nøhr","email":"","orcid":"","institution":"Herlev Sygehus: Herlev Hospital","correspondingAuthor":false,"prefix":"","firstName":"Bugge","middleName":"","lastName":"Nøhr","suffix":""},{"id":481229022,"identity":"1ca3d940-e640-4c95-b6f8-766a292ae3fb","order_by":2,"name":"Jane 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Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jens","middleName":"","lastName":"Pedersen","suffix":""},{"id":481229026,"identity":"def287dd-0d0b-4dc6-9ada-d243f28d97ea","order_by":6,"name":"Susanne Krüger Kjær","email":"","orcid":"","institution":"Danish Cancer Society: Kraeftens Bekaempelse","correspondingAuthor":false,"prefix":"","firstName":"Susanne","middleName":"Krüger","lastName":"Kjær","suffix":""}],"badges":[],"createdAt":"2025-06-25 12:53:49","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6974955/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6974955/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s10654-026-01391-5","type":"published","date":"2026-03-25T16:11:23+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":86538613,"identity":"624f436e-fb4d-473c-8b34-372e8fde5046","added_by":"auto","created_at":"2025-07-11 19:26:06","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":411596,"visible":true,"origin":"","legend":"\u003cp\u003eFlow diagram describing the study cohort included for analysis.\u003c/p\u003e","description":"","filename":"Fig1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6974955/v1/402391a78eca2ebf00416d6d.jpg"},{"id":105755985,"identity":"029e7af7-ce50-42d6-948c-523fe1f6b3f5","added_by":"auto","created_at":"2026-03-30 16:33:53","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":932117,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6974955/v1/5465ada0-a5f0-413c-b7ff-25e850e86d65.pdf"},{"id":86537396,"identity":"24982641-c3db-4ed8-a888-4dba529a00c8","added_by":"auto","created_at":"2025-07-11 19:02:05","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":32233,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-6974955/v1/16ea4e2e4c7c85d1426663dc.docx"},{"id":86537851,"identity":"6fbddfbd-c480-423a-8dce-d9249f187ef7","added_by":"auto","created_at":"2025-07-11 19:10:06","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":256460,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryMaterial.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6974955/v1/977eb9a67f4f4dbe7a6ce163.pdf"}],"financialInterests":"","formattedTitle":"Impact of hypothyroidism and hyperthyroidism on endometrial cancer incidence: Results from a large population-based cohort study","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eThyroid disorders encompass a range of conditions including hypothyroidism (characterized by insufficient levels of triiodothyronine [T3] and thyroxine [T4]), hyperthyroidism (elevated T3 and T4 levels), goiter, thyroiditis, and thyroid nodules. Among thyroid disorders, hypothyroidism and hyperthyroidism are the most common, with both conditions showing a higher prevalence in women [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. While thyroid dysfunction has been associated with a number of chronic conditions, including type 1 diabetes, cardiovascular disease, cognitive impairment and dementia [\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], its potential role in the development of hormone-sensitive cancers remains less studied [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Endometrial cancer is the sixth most common cancer among women globally, with 417,367 new cases and 97,370 deaths reported in 2020 [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Unlike several other cancer types showing declining incidence trends, the incidence of endometrial cancer continues to rise, particularly in countries undergoing rapid socioeconomic transitions [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Endometrial cancer is classified into two main subtypes based on etiology and histopathology. Type I tumors, which constitute approximately 80% of cases, are estrogen-dependent and generally associated with a favorable prognosis. Established risk factors for type I include unopposed estrogen therapy, obesity, early menarche, late menopause, and nulliparity, whereas combined hormonal contraceptives, hormone therapy, and multiparity are protective. Type II tumors are less influenced by estrogen, are more aggressive, and have a less clearly defined risk profile, although low parity and diabetes have been suggested as possible contributors [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. While early-stage endometrial cancer has a favorable prognosis with five-year survival nearing 95%, 10\u0026ndash;15% of patients are diagnosed at an advanced stage, where survival can drop to 10\u0026ndash;20% [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eAlterations in thyroid function may contribute to endometrial carcinogenesis through both direct and indirect mechanisms. Thyroid hormones can bind to nuclear thyroid hormone receptors expressed in endometrial tissue, thereby potentially regulating the expression of genes involved in proliferation, differentiation, and apoptosis [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Thyroid dysfunction also influences estrogen bioavailability through its effect on sex hormone-binding globulin (SHBG): hyperthyroidism increases SHBG levels, thereby reducing the concentration of free (bioavailable) estrogen, while hypothyroidism decreases SHBG, leading to higher levels of bioavailable estrogen, which may promote endometrial proliferation [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. In addition, hypothyroidism is associated with obesity, insulin resistance and chronic inflammation, all of which are implicated in endometrial cancer development [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. It may also disrupt menstrual cycles, ovulation, and fertility, further contributing to prolonged unopposed estrogen exposure [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Finally, thyroid dysfunction may affect the hypothalamic-pituitary-gonadal axis and hepatic hormone metabolism, thereby altering the uterine hormonal milieu in ways relevant to endometrial carcinogenesis [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eDespite this biological plausibility, few epidemiological studies have examined associations between thyroid disorders and endometrial cancer [\u003cspan additionalcitationids=\"CR18 CR19 CR20 CR21 CR22 CR23 CR24 CR25\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. To date, no studies have reported a convincing association between hyperthyroidism and endometrial cancer [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. In contrast, findings for hypothyroidism have been inconsistent as four studies reported null associations [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e], while two studies found an increased rate of endometrial cancer [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. One additional study observed an elevated rate among women with broadly defined thyroid disease, without distinguishing between hypo- and hyperthyroidism [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Discrepancies across studies may reflect differences in study design and methodological limitations, including reliance on self-reported thyroid diagnoses, inconsistent diagnostic criteria, small sample sizes, incomplete follow-up, and inadequate adjustment for confounders, particularly obesity, which is a well-established risk factor for endometrial cancer and is associated with hypothyroidism [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e],\u003c/p\u003e\u003cp\u003e Provided the limited and inconsistent findings to date, we conducted a large nationwide cohort study in Denmark to investigate the association between hypothyroidism and hyperthyroidism and the risk of endometrial cancer. Using data from the Danish national health registers, we followed more than one million women born between 1960 and 1997 to assess these associations, overall and for type I endometrial cancer.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eData Sources and Linkage\u003c/h2\u003e\u003cp\u003eAll Danish residents are assigned a unique personal identification number, enabling individual-level linkage across national health and population registers. For this study, we integrated data from multiple registers using these unique identifiers. Detailed information on data sources and coding is provided in the Supplementary Material.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eStudy population\u003c/h3\u003e\n\u003cp\u003eThe study population included all women born in Denmark between January 1, 1960, and December 31, 1997 (n\u0026thinsp;=\u0026thinsp;1,252,479), as identified in the Danish Civil Registration System. Through linkage to nationwide registers, we obtained data on thyroid disorders, cancer diagnoses, potential confounders, and vital/emigration status.\u003c/p\u003e\n\u003ch3\u003eExposure Assessment\u003c/h3\u003e\n\u003cp\u003eExposure to hypothyroidism and hyperthyroidism was identified using nationwide Danish health registers. Women aged 25 years or older were classified as exposed if they had either a physician-confirmed diagnosis of hypothyroidism or hyperthyroidism recorded in the Danish National Patient Register, or if they had redeemed a relevant prescription recorded in the Danish National Prescription Register. Diagnostic information was based on the International Classification of Diseases, 8th Revision (ICD-8) from 1977 to 1993 and 10th Revision (ICD-10) from 1994 onward. The Danish National Prescription Register has captured all redeemed prescriptions, coded using the Anatomical Therapeutic Chemical (ATC) system, since 1995.\u003c/p\u003e\u003cp\u003eThe date of thyroid disease onset was defined as the earliest occurrence of either a hospital diagnosis or prescription redemption for thyroid medication. For women diagnosed with both hyperthyroidism and hypothyroidism during follow-up, we applied mutually exclusive classification rules. Women initially diagnosed with hyperthyroidism and later developing hypothyroidism remained classified as hyperthyroid, using the date of first hyperthyroidism diagnosis as the exposure start. Conversely, women with an initial hypothyroidism diagnosis who were subsequently diagnosed with hyperthyroidism were reclassified as hyperthyroid, but with the start date anchored at their initial hypothyroidism diagnosis. This approach reflects the clinical trajectory of conditions such as Graves\u0026rsquo; disease, where thyroid function may transition due to shifts in thyrotropin receptor antibody activity [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. An exception was made for women assigned the diagnostic code DO992B (hypothyroidism complicating pregnancy, childbirth, or the postpartum period). These individuals were not considered hyperthyroid, as this condition is typically associated with transient postpartum thyroiditis in women with thyroid peroxidase (TPO) antibody positivity, which often includes a short-lived hyperthyroid phase that is self-limiting [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e].\u003c/p\u003e\n\u003ch3\u003eOutcome assessment\u003c/h3\u003e\n\u003cp\u003eIncident cases of endometrial cancer were identified through the Danish Cancer Register using the International Classification of Diseases, 7th revision (ICD-7) up to 1977, and the 10th revision (ICD-10) from 1978 onwards. Tumors were classified using the International Classification of Diseases for Oncology, 3rd edition (ICD-O-3) morphology codes into type I (endometrioid, mucinous), type II (serous, clear cell, mixed), and other/unspecified subtypes, following Bokhman\u0026rsquo;s dualistic model [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Only tumors with a morphology code ending in \u0026lsquo;3\u0026rsquo; were included.\u003c/p\u003e\n\u003ch3\u003eFollow-up\u003c/h3\u003e\n\u003cp\u003eTo ensure accurate assessment of baseline characteristics and capture physician-confirmed diagnoses of hypothyroidism or hyperthyroidism from the Danish National Patient Register, as well as relevant prescriptions from the Danish National Prescription Register, follow-up began at the later of age 25 or January 1, 1996. The start year of 1996 was selected to reduce misclassification of current medication use, as comprehensive data in the Danish National Prescription Register have been available only since 1995. Women were excluded if, prior to follow-up, they had died, emigrated, received a cancer diagnosis other than non-melanoma skin cancer, or had missing data on highest level of education. Participants were followed until the first occurrence of endometrial cancer, another cancer diagnosis (excluding non-melanoma skin cancer), hysterectomy, death, emigration, or the end of follow-up on December 31, 2022.\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eMedian follow-up time was estimated using the reverse Kaplan-Meier curve. Cause-specific Cox proportional hazards models were applied to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for endometrial cancer (overall and type I tumors) among women with hypothyroidism or hyperthyroidism compared to those without thyroid disease. Due to a limited number of exposed cases, analyses for type II tumors and other histological subtypes were not feasible. Age was used as the underlying time scale, with delayed entry at age 25 or on January 1, 1996, whichever occurred last. Thyroid disease was modeled as a time-varying categorical variable (no thyroid disease, hypothyroidism, hyperthyroidism), with exposure status updated during follow-up. Analyses were additionally performed by time since thyroid disease diagnosis (\u0026lt;\u0026thinsp;10 years, \u0026ge;\u0026thinsp;10 years) and by menopausal status, both treated as time-varying covariates. As individual-level data on age at menopause were unavailable, we assigned a fixed value of 51 years, which is the median age at menopause in Denmark, as a proxy [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Confounders were selected based on prior knowledge and data availability from Danish national registers. These included birth year (categorized into six intervals for the 1960\u0026ndash;1997 period), highest obtained level of education (basic, medium, higher), and pre-existing diagnoses of smoking-related diseases, type I diabetes, and obesity. All covariates except birth year were identified at age 25. Two Cox models were constructed: an unadjusted model and a model adjusted for the above-mentioned confounders.\u003c/p\u003e\u003cp\u003eWe also performed landmark analyses [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e] with age 40 as the landmark, allowing for covariate updates beyond baseline while remaining prior to the median age at endometrial cancer diagnosis in Denmark [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. This analysis included only women alive and cancer-free at age 40. Educational level was fixed at age 25, while smoking-related diseases, type 1 diabetes, and obesity were updated and fixed at age 40. For all study participants, a 20-year prediction window was applied with artificial censoring at age 60. The Aalen-Johansen estimator was used to calculate unadjusted absolute risks (cumulative incidences) for endometrial cancer across thyroid disease categories. Cox proportional hazard regression models were used to assess associations between exposure and cause-specific hazard of endometrial cancer, adjusting for both time-fixed and updated covariates at age 40. To estimate the adjusted absolute risk difference of endometrial cancer at age 60, while accounting for the above-mentioned potential confounders, we applied a pseudo-observation approach that accounted for competing risks (other cancers and death without prior cancer) [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. Linear regression models with robust variance estimation were used to obtain risk differences. The proportional hazard assumption was evaluated using Schoenfeld residuals. All analyses were conducted in R version 4.2.2 (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.r-project.org/\u003c/span\u003e\u003cspan address=\"https://www.r-project.org/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e), with two-sided p-values of 0.05 considered statistically significant.\u003c/p\u003e\u003c/div\u003e"},{"header":"RESULTS","content":"\u003cp\u003eFrom the initial cohort of 1,252,479 women born in Denmark between January 1, 1960, and December 31, 1997, a total of 194,542 were excluded based on predefined criteria, yielding a final analytic cohort of 1,057,937 women (Figure 1). The median follow-up time was 17.5 years\u0026nbsp;and the median age at end of follow-up was 43.3 years (inter quartile range [IQR]: 33.0-52.8). By the end of follow-up, 47,309 women had been diagnosed with hypothyroidism and 26,072 with hyperthyroidism. The median age at first hypothyroidism diagnosis was 37.5 years (IQR: 29.8-46.1) and the median year of hyperthyroidism diagnosis was 35.7 years (IQR: 29.0-44.4). A total of 1,159 women were diagnosed with endometrial cancer during follow-up, of which 79.1% (n = 917) were classified as type I and 20.9% (n = 242) as type II, other, or unspecified histology. The median age at endometrial cancer diagnosis was 51.2 years (IQR: 45.4–55.0) among women without thyroid disease, 53.3 years (IQR: 47.8–56.4) among those with hypothyroidism, and 53.7 years (IQR: 50.3–56.5) among those with hyperthyroidism. In the sensitivity analysis using a landmark analytic approach, the cohort included 611,277 women with a median follow-up of 10.3 years. Baseline characteristics of the main study population are presented in Table 1. Compared to women without thyroid disease, those with thyroid disorders more frequently had a basic educational level and a higher prevalence of smoking-related diseases, type I diabetes, and obesity. Comparable patterns were observed in the landmark analysis cohort (Supplementary Table 1).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHypothyroidism and endometrial cancer\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe associations between hypothyroidism and endometrial cancer are presented in Tables 2 and 3. Overall, both unadjusted and adjusted hazard ratios (HRs) showed consistent trends; however, direct comparison is limited by the non-collapsibility of the Cox proportional hazards model. After adjustment for birth year, highest obtained level of education, type I diabetes, smoking-related diseases, and obesity, women diagnosed with hypothyroidism had a higher rate of endometrial cancer compared with women without thyroid disease (adjusted HR: 1.54, 95% CI: 1.22–1.94). A similar association was observed for type I endometrial cancer (HR: 1.65, 95% CI: 1.29–2.11). Time since hypothyroidism diagnosis had little influence on the magnitude of the association for either overall or type I endometrial cancer (Table 2). Also menopausal status had minimal impact on the strength of the association, with similar HRs observed for both premenopausal (HR: 1.44, 95% CI: 0.96–2.16) and postmenopausal women (HR: 1.59, 95% CI: 1.20–2.11); however, the association reached statistical significance only in postmenopausal women. These patterns were consistent in the analysis of type I endometrial cancer (HRs: 1.73, 95% CI: 1.29–2.32 for postmenopausal women; and 1.48, 95% CI: 0.93–2.35 for premenopausal women) (Table 3).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn the landmark analysis, the elevated rate of endometrial cancer associated with hypothyroidism persisted (HR: 1.68, 95% CI: 1.13–2.48). The adjusted absolute risk of developing endometrial cancer by age 60 was higher among women diagnosed with hypothyroidism (0.62%, 95% CI: 0.29%–0.95%) than among those without thyroid disease (0.39%, 95% CI: 0.36%–0.41%), although the difference in absolute risk was not statistically significant (risk difference: 0.15 percentage points, 95% CI: -0.02% to 0.33%).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHyperthyroidism and endometrial cancer\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn Table 2 and 3, the associations between hyperthyroidism and endometrial cancer are shown. No association was found between a diagnosis of hyperthyroidism and endometrial cancer (adjusted HR: 1.13, 95% CI: 0.80–1.61), with similar results observed for type I endometrial cancer (adjusted HR: 1.13, 95% CI: 0.77–1.68). Time since hyperthyroidism diagnosis had little influence on the magnitude of the association for either overall or type I endometrial cancer (Table 2). Also, menopausal status did not materially alter the associations as the HRs were 0.97 (95% CI: 0.52–1.81) among premenopausal women and 1.23 (95% CI: 0.80–1.89) among postmenopausal women, with similar estimates observed for type I endometrial cancer (Table 3). In the landmark analysis, also no association was found between hyperthyroidism and endometrial cancer (HR: 1.00, 95% CI: 0.56–1.76). The adjusted absolute risk of endometrial cancer by age 60 among women with hyperthyroidism (0.48%, 95% CI: 0.13%–0.83%) was comparable to that among women without thyroid disease (0.39%, 95% CI: 0.36%–0.41%), with no statistically significant difference in absolute risk (risk difference: 0.07 percentage points, 95% CI: -0.17% to 0.30%).\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eIn this large nationwide cohort study comprising over one million Danish women, we observed no association between hyperthyroidism and endometrial cancer. In contrast, hypothyroidism was linked to a 54% higher overall rate of endometrial cancer and a 65% higher rate for type I tumors compared to no thyroid disease. These associations were consistent across subgroups defined by menopausal status and time since diagnosis, and they persisted in landmark analyses limited to hypothyroidism diagnoses occurring before age 40. However, the landmark analyses demonstrated that the absolute difference in endometrial cancer risk at age 60 between women with and without hypothyroidism was small and not statistically significant, indicating that while a possible association exists, its clinical relevance may be modest.\u003c/p\u003e\u003cp\u003eOur findings regarding hyperthyroidism align with all previous epidemiological studies on this topic [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Most recently, Leung et al. [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e] conducted a large population-based retrospective cohort study utilizing data from the Taiwan National Health Insurance Research Database, which included 296,872 women diagnosed with hyperthyroidism, among whom 484 developed endometrial cancer and observed no increase in this malignancy among women with hyperthyroidism. Together with our results, these findings suggest that hyperthyroidism is unlikely to have a major role in endometrial carcinogenesis. Nonetheless, due to plausible biological mechanisms, including estrogen bioavailability, altered SHBG levels, and reproductive hormone dynamics [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], this association warrants further investigation, especially in subgroups with different hyperthyroidism etiologies or treatment history.\u003c/p\u003e\u003cp\u003eOur findings for hypothyroidism are consistent with two previous studies reporting an elevated risk of endometrial cancer [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. A large population-based study by Krashin et al. [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e] used data from 375,635 Israeli women who had a blood test for TSH levels and found that TSH levels in the hypothyroid range was associated with an elevated risk of endometrial cancer. Similarly, Kurnit et al. [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] used data from a large case-control study nested in the US University HealthSystem Consortium database and reported a higher rate of hypothyroidism among women with uterine cancer compared to women who served as controls. Brinton et al. [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] also observed an increased risk of endometrial cancer among women with broadly defined thyroid disease, although the study did not differentiate between hypothyroidism and hyperthyroidism. However, the literature remains inconsistent, with several studies reporting no marked associations [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e], underscoring the need for additional investigations.\u003c/p\u003e\u003cp\u003eThe observed increased risk of endometrial cancer among women diagnosed with hypothyroidism may be explained by several interrelated biological mechanisms. Hypothyroidism is frequently accompanied by metabolic alterations including obesity, insulin resistance, dyslipidemia, and chronic low-grade systemic inflammation; all of which are established risk factors for endometrial cancer [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan additionalcitationids=\"CR14 CR15\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. Thyroid hormones influence lipid metabolism and glucose homeostasis; reduced levels of triiodothyronine (T3) and thyroxine (T4) can impair insulin signaling, increase adiposity, and elevate circulating inflammatory cytokines, thereby creating a pro-tumorigenic environment [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. In addition, low thyroid hormone levels suppress hepatic production of SHBG, leading to elevated levels of bioavailable estradiol. This enhances estrogenic stimulation of the endometrium, particularly relevant for type I tumors, which are estrogen-dependent [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Hypothyroidism also affects the hypothalamic\u0026ndash;pituitary\u0026ndash;gonadal axis and can disrupt gonadotropin-releasing hormone (GnRH) pulsatility, leading to menstrual disturbances, anovulation, oligomenorrhea, and ultimately infertility or nulliparity which are all recognized risk factors for endometrial cancer [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. These reproductive effects are particularly pertinent when thyroid dysfunction occurs during a woman\u0026rsquo;s reproductive years, potentially prolonging exposure to unopposed endogenous estrogen.\u003c/p\u003e\u003cp\u003eAlthough these pathways are biologically plausible, it remains uncertain whether hypothyroidism independently contributes to the risk of endometrial cancer or primarily exerts its effect through shared metabolic and hormonal intermediates. Consequently, intrinsic factors associated with the development of hypothyroidism in women may also play a significant role. [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Although our analyses adjusted for comorbid obesity and diabetes, we lacked data on BMI, exogenous hormone use, and lifestyle factors. Further studies incorporating these factors as well as estrogen levels and markers of metabolic dysfunction are needed to disentangle these effects and determine whether hypothyroidism represents a modifiable risk factor for endometrial cancer.\u003c/p\u003e\u003cp\u003eDifferences in study design, sample size, baseline population characteristics, and the extent to which confounding (particularly obesity) has been addressed may help explain the inconsistencies observed across previous studies. Whereas our study utilized both physician-verified diagnoses and prescription register data to enhance exposure classification, other investigations have relied on self-reported or medical record-based data, potentially increasing the risk of misclassification. Furthermore, most population-based studies, including ours, could not distinguish between autoimmune and non-autoimmune hypothyroidism, which may have divergent implications for endometrial carcinogenesis. Although our findings of an increased risk of endometrial cancer among women with hypothyroidism are consistent with two previous epidemiological studies [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e], this is not a universal finding as most studies found no association [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Thus, the conflicting evidence underscores the need for further research, ideally integrating biochemical thyroid function measures and data on treatment and disease severity to clarify the nature and strength of this potential association.\u003c/p\u003e\u003cp\u003eTo our knowledge, no previous studies have examined the association between thyroid disorders and endometrial cancer according to menopausal status. In our study, menopausal status did virtually not modify the associations for either hypothyroidism or hyperthyroidism. This may reflect the predominance of type I endometrial cancer in our cohort, which is hormone-driven and influenced by estrogen exposure both before and after menopause. Additionally, the use of a fixed age cutoff (51 years) to define menopause may have introduced misclassification, potentially attenuating true effect differences. However, our consistent findings across strata suggest that thyroid dysfunction may influence endometrial cancer risk through mechanisms that operate independently of menopausal status. Still, more precise measurement of menopausal transition and hormone levels would be valuable in future studies.\u003c/p\u003e\u003cp\u003eThe main strengths of this study include its large, population-based design with comprehensive data from the Danish health and administrative registers, long follow-up duration, and access to detailed information on key confounders. The use of high-quality register data minimizes recall bias and virtually eliminates loss to follow-up. Exposure and outcome ascertainment were enhanced using physician-certified, guideline-based diagnoses for thyroid disorders and histologically verified endometrial cancer cases, reducing misclassification compared with studies relying on self-reported data. A notable strength is the incorporation of prescription records from the Danish National Prescription Register, which enabled the identification of thyroid disease cases managed exclusively in primary care and not captured in the Danish National Patient Register. This approach improved case ascertainment and reduced the risk of differential misclassification. While some women with undiagnosed or subclinical thyroid dysfunction may have gone unrecognized, potentially leading to an underestimation of the associations, this could have introduced some bias. Our study includes the largest cohort of women with thyroid disease and the highest number of endometrial cancer cases reported to date, providing high statistical precision for most overall risk estimates and allowing for detailed subgroup analyses by menopausal status and histologic subtype, including type I endometrial cancer, which have rarely been explored in previous research. However, limited statistical power in some subgroups may have contributed to wide confidence intervals. To assess the robustness of our findings, we conducted a landmark analysis restricted to exposures occurring before age 40, accounting for time-varying confounding and competing risks such as mortality and other cancers. The results were consistent with our primary analyses, reinforcing the validity of our findings. Finally, although we adjusted for several key confounders identified a priori based on existing evidence and register data availability, residual or unmeasured confounding cannot be entirely excluded.\u003c/p\u003e\u003cp\u003eSeveral limitations should be acknowledged. Although we relied on high-quality, register-based diagnoses of thyroid disease, validation through clinical chart review or biochemical measurements was not possible due to ethical and data protection constraints. Variability in diagnostic practices and evolving clinical guidelines over time may have introduced some misclassification of thyroid disease diagnoses [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. In addition, clinical details such as thyroid hormone levels, TSH concentrations, disease duration, and treatment-specific information, including the use of radioactive iodine or surgical interventions, were not available. As a result, we could not evaluate the influence of disease severity, treatment modality, or duration of thyroid dysfunction on endometrial cancer risk. Surveillance bias is another potential concern, as women with thyroid disorders may have increased healthcare contact, potentially leading to higher likelihood of cancer detection. While endometrial cancer is usually diagnosed symptomatically rather than through screening, heightened medical attention could modestly affect diagnostic rates. Lastly, we used age 51 as a proxy for menopausal transition based on national averages. Although this approach is common in epidemiologic studies, it may have resulted in non-differential misclassification and attenuation of risk estimates across menopausal strata.\u003c/p\u003e\u003cp\u003eIn conclusion, we found no evidence of an association between hyperthyroidism and endometrial cancer, which is in concordance with previous research. In contrast, our results suggest that hypothyroidism is associated with an increased rate of endometrial cancer. Although absolute risk differences were small and not statistically significant, the consistency of associations across analyses underscores the need for further research to clarify the biological basis and clinical relevance of this association.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003ch2\u003eCompeting interest\u003c/h2\u003e\u003cp\u003eAll authors have no relevant financial or non-financial interests to disclose.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003ch2\u003eEthics approval\u003c/h2\u003e\u003cp\u003eAs this study utilized data from Danish health registers and did not include any direct contact with study participants, an ethical approval was not required. Necessary permissions for the use of register data that were compiled in a project-specific database at Statistics Denmark (project number 708651) were granted by the Danish Health Data Authority (reference number FSEID-00006179). The Danish Cancer Society holds responsibility for data stored in the Danish Cancer Institute\u0026rsquo;s database at Statistics Denmark. In accordance with the General Data Protection Regulation (GDPR), the project has been registered in the Danish Cancer Society\u0026rsquo;s internal register of projects involving personal data (Journal number 2022-DCRC-0008).\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e\u003cp\u003e The study was supported by research grants from the Danish Cancer Society\u0026rsquo;s Scientific Committee (Rp21772-A17580) and the Jascha Foundation (2023\u0026thinsp;\u0026minus;\u0026thinsp;0408).\u003c/p\u003e\u003ch2\u003eAuthors contribution\u003c/h2\u003e\u003cp\u003eAll authors contributed to the study conception and design. Mathilde Gottschau performed data extraction and data management. Jane Christensen performed the statistical analysis. Allan Jensen conducted the literature review and wrote the first draft of the manuscript. All authors commented on previous versions of the manuscript, approved the final manuscript and were accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eCarl\u0026eacute; A, Pedersen IB, Knudsen N, et al. Epidemiology of subtypes of hyperthyroidism in Denmark: a population-based study. Eur J Endocrinol. 2011;164(5):801\u0026ndash;9. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi:10.1530/eje-10-1155\u003c/span\u003e\u003cspan address=\"https://doi:10.1530/eje-10-1155\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTaylor PN, Albrecht D, Scholz A, et al. Global epidemiology of hyperthyroidism and hypothyroidism. 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Thyroid. 2019;29(7):910\u0026ndash;9. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi:10.1089/thy.2018.0539\u003c/span\u003e\u003cspan address=\"https://doi:10.1089/thy.2018.0539\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 3 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-epidemiology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejep","sideBox":"Learn more about [European Journal of Epidemiology](https://www.springer.com/journal/10654)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ejep/default.aspx","title":"European Journal of Epidemiology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Endometrial cancer, hypothyroidism, hyperthyroidism, population-based cohort study, Denmark","lastPublishedDoi":"10.21203/rs.3.rs-6974955/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6974955/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe limited number of studies examining the association between thyroid diseases and endometrial cancer have yielded inconsistent findings. The study aimed to examine the association between hypothyroidism and hyperthyroidism and the risk of endometrial cancer using comprehensive nationwide register data from Denmark. We conducted a population-based cohort study including 1,057,937 women born in Denmark between 1960 and 1997. Information on thyroid disease diagnoses, cancer diagnoses, covariates, migration, and vital status was obtained from nationwide Danish health and administrative registers. Cox proportional hazards models were used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for endometrial cancer overall and for type I tumors. A landmark analysis examined risks associated with exposures before age 40, and pseudo-observation methods estimated absolute risk differences. During a median follow-up of 17.5 years, 1,159 women were diagnosed with endometrial cancer. Women with hypothyroidism had a higher rate of overall endometrial cancer (HR: 1.54, 95% CI: 1.22\u0026ndash;1.94) and type I tumors (HR: 1.65, 95% CI: 1.29\u0026ndash;2.11). These associations were consistent across subgroups defined by menopausal status and time since diagnosis. No association was observed for hyperthyroidism (HR: 1.13, 95% CI: 0.80\u0026ndash;1.61). In the landmark analysis, hypothyroidism remained associated with an increased endometrial cancer rate, but the absolute risk difference by age 60 was modest and not statistically significant. In conclusion, hypothyroidism was associated with a modestly increased rate of endometrial cancer, while no association was observed for hyperthyroidism. These findings support further investigation into thyroid function and endometrial carcinogenesis.\u003c/p\u003e","manuscriptTitle":"Impact of hypothyroidism and hyperthyroidism on endometrial cancer incidence: Results from a large population-based cohort study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-11 19:02:01","doi":"10.21203/rs.3.rs-6974955/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2025-07-06T11:06:10+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-07-06T08:45:35+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"European Journal of Epidemiology","date":"2025-06-30T13:36:31+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-06-26T17:12:46+00:00","index":"","fulltext":""},{"type":"submitted","content":"European Journal of Epidemiology","date":"2025-06-25T08:51:09+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-epidemiology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejep","sideBox":"Learn more about [European Journal of Epidemiology](https://www.springer.com/journal/10654)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ejep/default.aspx","title":"European Journal of Epidemiology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"88e8193b-25c0-4a63-8dd6-69a45ad9731f","owner":[],"postedDate":"July 11th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-03-30T16:27:31+00:00","versionOfRecord":{"articleIdentity":"rs-6974955","link":"https://doi.org/10.1007/s10654-026-01391-5","journal":{"identity":"european-journal-of-epidemiology","isVorOnly":false,"title":"European Journal of Epidemiology"},"publishedOn":"2026-03-25 16:11:23","publishedOnDateReadable":"March 25th, 2026"},"versionCreatedAt":"2025-07-11 19:02:01","video":"","vorDoi":"10.1007/s10654-026-01391-5","vorDoiUrl":"https://doi.org/10.1007/s10654-026-01391-5","workflowStages":[]},"version":"v1","identity":"rs-6974955","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6974955","identity":"rs-6974955","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}