Endometrial cancer is the sixth most common female cancer, and the incidence rate has been rising rapidly in the past several decades worldwide (1). The incidence of endometrial cancer is higher in developed countries than in developing countries (2). From 2012 to 2020, the incidence of endometrial cancer has doubled in the United States; it increased from 32,000 cases to 65,620 cases (3, 4). In Korea, the incidence of endometrial cancer gradually increased between 1999 and 2020 (5, 6). The western lifestyle, increase in the obese population, and low fertility rate are all presumed to be possible contributors to the increasing incidence of endometrial cancer (7, 8).

Metabolic syndrome, a pathologic condition characterized by abdominal obesity, insulin resistance, dyslipidemia, hypertension, and hyperglycemia, has emerged as one of the most pressing public health issues worldwide (9, 10). With the growing population of obese adults, the frequency of metabolic syndrome has increased dramatically in recent decades (11). In Korea, the prevalence of metabolic syndrome increased from 21.6% in 2007 to 22.9% in 2018 (12).

Obesity is one of the most essential features of metabolic syndrome and is closely related to cancer incidence and high mortality (13, 14). Several studies had demonstrated that metabolic syndrome was associated with the development of various malignancies, including liver, colorectal, ovarian, breast, and thyroid cancers (15–19). A positive relationship was also reported between metabolic syndrome and the risk of endometrial cancer (20–23). However, despite the recent trend of increasing obesity and metabolic syndrome rates among young women worldwide (24–27), most studies related to endometrial cancer and metabolic syndrome had been conducted mainly on post-menopausal women. Only limited evidence is available on the risk of endometrial cancer according to the combination of metabolic syndrome and menopause status.

Therefore, we aimed to investigate the association between metabolic syndrome and the risk of endometrial cancer according to the menopausal status using the Korean nationwide population-based cohort.

To our knowledge, this nationwide population-based cohort study was the first evaluating the risk of developing endometrial cancer in women with metabolic syndrome or each metabolic syndrome component according to the menopausal status. In this study, endometrial cancer risk was considerably higher in individuals who had metabolic syndrome components than those who did not. The impact of metabolic syndrome on the risk of endometrial cancer varied depending on the menopausal status: the risk of endometrial cancer from metabolic syndrome was higher in the pre-menopausal subgroup than post-menopausal subgroup.

Endometrial cancer predominantly occurs in post-menopause women. Moreover, the incidence of endometrial cancer is increasing in most countries, mainly due to the increasing incidence in pre-menopausal women. While the incidence of endometrial cancer among pre-menopausal women has decreased in European nations, including Denmark, the Czech Republic, and the Netherlands, it has gradually increased in Asian nations, including China, Japan, and Singapore (1). Especially, in Korea, the incidence of endometrial cancer between 1999 and 2017 increased most rapidly in the young women under 30 years and 30–39 years age group (annual percent change (APC), 8.7% and 7.4%, respectively). On the other hand, the 40–49 years and 50–59 years age groups, showed relatively slow increase during the same period (APC, 5.1% and 5.7% respectively) (6). Similarly, the incidence rate of endometrial cancer has increased most rapidly in women under 50 years in New Zealand (31). Nonetheless, these studies have limitations on comprehensively demonstrating the reasons why pre-menopausal women have a higher risk of endometrial cancer. Guo et al. reported that the significantly increased incidence of endometrial cancer in the 20–39 years age group was related with the concurrent increasing prevalence of obesity in young women in the United States (32). However, this study used only a group of pre-menopausal women and did not confirm the association between obesity-induced metabolic syndrome and endometrial cancer. Previous researchers reported positive associations between metabolic syndrome and obesity and the incidence of female cancers, including endometrial cancer (33–35). As the prevalence of metabolic syndrome has markedly increased affecting one quarter of the global population (10), the prevalence of endometrial cancer is predicted to further rise in the future.

The positive correlation between metabolic syndrome and the risk of endometrial cancer in our study is supported by previous studies. An Italian case-control study including 454 endometrial cancer cases and 798 controls showed a significant association between metabolic syndrome and risk of endometrial cancer. Among components of metabolic syndrome, obesity appeared to be a critical factor for developing endometrial cancer (23). Another case-control study in the United States investigated the effect of metabolic syndrome on the incidence of endometrial cancer using the large population data from 1993 to 2007 (16,323 cases of endometrial cancer and 100,751 controls) which included women aged 65 and older. Among patients diagnosed with metabolic syndrome, the risk of endometrial cancer was doubled in obese patients compared to that of non-obese patients (36). Although only post-menopausal women were included, Rhonda et al. found that endometrial cancer risk was doubled in women who had metabolic syndrome and WC > 88cm (21). To date, most previous studies did not examine the relationship between metabolic syndrome and endometrial cancer according to the menopausal status, and they only discussed the relationship in post-menopausal women. In addition, the association between metabolic syndrome and endometrial cancer in recent studies is limited to Western women (37). Considering that incidence and mortality rates of endometrial cancer have ethnic and geographic variations (38), large cohort studies are also required in Asian women. Therefore, we performed a comprehensive national population-based cohort study of Korean females.

We showed that there was a higher incidence of endometrial cancer in pre-menopausal women with metabolic syndrome than post-menopausal counterparts. Similarly, Friedenreich et al. found that metabolic syndrome was highly linked to the occurrence of endometrial cancer and the risk of endometrial cancer was higher in pre-menopausal women than in post-menopausal women in the presence of the metabolic syndrome (22). Furthermore, we discovered that abdominal obesity was a major determinant in the development of endometrial cancer among the components of metabolic syndrome. Pre-menopausal women were shown to be 69% more likely to develop endometrial cancer when they have a higher WC (≥85cm), while post-menopausal women with a WC of ≥85cm had a 40% increased risk. When pre-menopausal women have abdominal obesity, their risk of endometrial cancer rises considerably. Recently, our research team reported on the female-specific cancer risk according to obesity and menopausal status using a nationwide cohort in Korea. In the pre-menopausal women, a WC of <75cm was related with a protective effect against the risk of endometrial cancer, but a WC of ≥95cm was substantially linked with an elevated risk of endometrial cancer (39). Soliman et al. have shown that most patients diagnosed with endometrial cancer at a young age were obese (40). Considering that estrogen is a well-known endometrial growth factor, excessive estrogen produced by redundant adipocytes of obese seems to be responsible for continuous stimulation of the endometrium, endometrial hyperplasia and endometrial cancer (41, 42).

Other studies have reported that metabolic syndrome components other than WC are not associated with the development of endometrial cancer (21). However, our findings suggested that other metabolic syndrome components (BP, TG, HDL-C and fasting blood glucose) could be additional risk factors for developing endometrial cancer. For example, high BP increased the risk of endometrial cancer by 20% in the total population. Like WC, pre-menopausal women with high BP also showed a higher risk than post-menopausal counterparts. Other metabolic syndrome components also significantly increased the incidence of endometrial cancer, suggesting that it might potentially be a useful criterion for predicting the risk of endometrial cancer. This finding is important because metabolic syndrome and obesity can be managed and prevented with exercise and diet control (43).

Our study has several limitations. First, we only used Korean data and ethnicity differences were not discussed here. Second, we did not differentiate the histologic subtypes or stages of endometrial cancer due to the lack of accessibility to the specific clinicopathologic data. Third, dietary habits and lifestyles that could potentially modulate the metabolic syndrome were not included. Fourth, smoking data were not detailed in the analysis because the data we used did not include the duration of smoking and the cessation data. Fifth, we did not analyze the duration of the metabolic syndrome, which may also affect the development of endometrial cancer. Finally, as this study is a large-scale retrospective study, the differences in health examinations and laboratory measurements (etc., different assays for blood tests, time of fasting for those blood tests, how WC was measured) performed to determine metabolic syndrome should be considered. Nevertheless, this study covered more than 2.8 million South Korean women and had a long follow-up period (median, 8.37 years), providing sufficient time for monitoring endometrial cancer development. Also, we eliminated individuals with less than a year of follow-up to establish a causal link and minimize detection bias. To the best of our knowledge, this is the largest cohort to examine the effects of metabolic syndrome on the development of endometrial cancer according to menopause status.

In conclusion, this large, nationwide population cohort study provides evidence of the effect of metabolic syndrome on the development of endometrial cancer according to the menopausal status. To summarize our findings, women with metabolic syndrome, especially pre-menopausal women with abdominal obesity, were at high risk of developing endometrial cancer. For pre-menopausal women as well as post-menopausal women with metabolic syndrome, frequent endometrial cancer surveillance and risk modulation by supervised exercise in combination with nutrition programs might be necessary.

The datasets presented in this article are not readily available because according to Korean law, we are not allowed to transfer any data files to a third party. However, data are available from the Korea National Health Insurance Sharing Service Institutional Data Access/Ethics Committee (https://nhiss.nhis.or.kr/bd/ay/bdaya001iv.do) for researchers who meet the criteria for access to confidential data. Researchers can apply for the National Health Insurance data sharing service upon approval of the institutional review board of their institution. Requests to access the datasets should be directed to Korea National Health Insurance Sharing Service Institutional Data Access/Ethics Committee (https://nhiss.nhis.or.kr/bd/ay/bdaya001iv.do).

The studies involving human participants were reviewed and approved by The Institutional Review Board of Seoul National University Hospital (No. 1811-048-983). Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

HJ contributed to the study design, data interpretation, and writing of the first draft of the manuscript. SK contributed to data interpretation and review of the manuscript. WW, AS, YH, JK, IP, and JL were involved in data interpretation. JY was involved in data analysis. K-DH contributed to the study design, analysis of the data, and advice on the study conception. YS supervised the entire project. All authors reviewed or revised the manuscript and approved the final manuscript for submission.

This work was supported by BK21 Plus Program of the Department of Agricultural Biotechnology, Seoul National University (Seoul, Korea).

Author YH was employed by the company SK Biopharmaceuticals Co., Ltd.

The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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