Drug-induced Endometrial Cancer: A Pharmacovigilance Study Based on Real-World Data from the FAERS Database

Drug-induced Endometrial Cancer: A Pharmacovigilance Study Based on Real-World Data from the FAERS Database | 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 Article Drug-induced Endometrial Cancer: A Pharmacovigilance Study Based on Real-World Data from the FAERS Database Huiping Zhang, Juan Wang, Yu Wang, Yingying Ma, Yulu Gou, Zhuo Zhou This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6733006/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 5 You are reading this latest preprint version Abstract This study aims to identify and evaluate drugs associated with the risk of endometrial cancer using the FDA Adverse Event Reporting System (FAERS) database. We retrieved adverse drug events (ADEs) related to drug-induced endometrial cancer from the FAERS database (Q1 2004–Q4 2024). A disproportionality analysis was conducted to identify drugs significantly associated with endometrial cancer risk, and time-to-onset (TTO) analyses were performed to assess the timing and risk profiles of adverse reactions related to endometrial cancer. Our study identified 2,352 ADEs linked to endometrial cancer. Disproportionality analysis identified 32 drugs associated with endometrial cancer risk, including 11 hormone medications, 9 cancer drugs, 2 antihypertensive drugs, 1 antiviral drug, 4 immunosuppressants, 1 mineral supplement, 1 gastrointestinal drug, and 3 osteoporosis drugs. Through a comprehensive analysis of the FAERS database, our study identified drugs strongly associated with endometrial carcinogenesis. Preventing drug-related endometrial cancer requires careful drug selection and monitoring. This study provides evidence-based insights for clinical management, aiming to optimize clinical care and mitigate risks. Biological sciences/Cancer Biological sciences/Drug discovery Health sciences/Diseases Health sciences/Risk factors Endometrial cancer FAERS Adverse drug events Disproportionality analysis Pharmacovigilance Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 1 Introduction Endometrial cancer (EC) is one of the most common malignant tumors of the female reproductive system. In 2020, there were 417,000 new cases diagnosed globally, and the overall incidence rate has been rising annually [ 1 ] . It has been reported that the lifetime risk for women to develop endometrial cancer is approximately 3%, with increased risks associated with obesity, family history, and polycystic ovary syndrome [ 2 ] . The etiology of endometrial cancer is complex, but factors such as hormonal imbalances, genetic susceptibility, obesity, diabetes, and long-term use of estrogen-based drugs have been proven to be closely related to its occurrence [ 3 – 5 ] . However, specific studies identifying which drugs or drug categories may lead to endometrial cancer are still lacking. Therefore, identifying these drugs is crucial for preventing drug-induced EC. During a normal menstrual cycle, estrogen stimulates the proliferation of the endometrium, while periodic progesterone and regular menstrual shedding maintain the health of the endometrium. The lack of natural progesterone leads to an excess of unopposed estrogen driven by obesity, which is the main pathological process for the occurrence of endometrial cancer [ 6 ] . Increased lifelong exposure to unopposed estrogen is a reproductive risk factor, including early menarche (<12 years), late menopause (≥ 55 years), anovulation (such as polycystic ovary syndrome), and infertility, which also increases the risk of endometrial cancer [ 7 ] . In clinical practice, drug-induced endometrial cancer has gradually become a focus of attention. Common drugs associated with endometrial cancer include estrogen-based medications, tamoxifen, and certain chemotherapy drugs [ 8 , 9 ] . Tamoxifen, a selective estrogen receptor modulator, increases the risk of endometrial cancer when used long-term for the prevention or treatment of hormone-sensitive breast cancer [ 10 ] . However, there is currently a lack of real-world data studies on drug-related endometrial cancer. The FAERS (FDA Adverse Event Reporting System) database is one of the largest adverse drug event reporting databases globally, containing information on adverse drug reactions, drug-drug interactions, and drug-induced diseases, which is of significant importance for drug safety research [ 11 ] . This study aims to explore drug-related adverse reactions to endometrial cancer using real-world data from the FAERS database and assess the relationship between drug use and the occurrence of endometrial cancer. By analyzing a large number of clinical reports, this study seeks to identify drugs that may induce endometrial cancer, providing scientific evidence for clinicians in drug selection and management. 2 Materials and Methods 2.1 Data Source The data for this study was sourced from the FAERS database, which is available for download from the official FDA website (https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html). The database is updated quarterly and provides two data formats for download: ASCII and XML. For this study, the raw ASCII data files from the first quarter of 2004 to the fourth quarter of 2024 were downloaded for statistical analysis. 2.2 Adverse Reaction Identification In this study, the MedDRA dictionary (MedDRA 27.1) was used to code the adverse event names in the FAERS database using preferred terms (PTs). A standardized query was applied to identify PTs related to "Drug-induced endometrial cancer," and this term was selected for analysis. Cases related to this PT were extracted from the DEMO file using their PRIMARYID, and duplicate reports were excluded to ensure accurate case statistics. Additional information, such as the patient's age, weight, reporter's identity, and reporting country, was also obtained. For drug-related analysis, only cases marked as "primary suspect drug" were included. Entries marked as "secondary suspect drug," "concomitant drug," or "interaction drug" were excluded to reduce uncertainty in the results. 2.3 Statistical Analysis This study used R 4.4.2 and SPSS 29.0 for statistical analysis. This study employed four methods to identify potential drug-event associations: Reporting Odds Ratio (ROR) [12] , Proportional Reporting Ratio (PRR) [13] , Bayesian Confidence Propagation Neural Network (BCPNN) [14] , and Multi-item Gamma Poisson Shrinker (MGPS) [14] . These methods evaluate the statistical relationship between a specific drug and an adverse event (AE) by calculating the relative frequency of target adverse reactions caused by the target drug in the database over a given period. "a" refers to the number of reports that include both the target drug and target adverse reaction."b" refers to the number of reports with other drug adverse reactions that include the target drug. "c" refers to the number of reports with target drug adverse reactions that include other drugs. "d" refers to the number of reports that include both other drugs and other drug adverse reactions (as shown in Table 1).The formulas for the four methods are presented in Table 2. Drugs that passed the screening criteria of all four methods were included in the study, indicating a significant association with drug-induced endometrial cancer. Additionally, the duration of drug use leading to drug-induced endometrial cancer was also analyzed. 3 Results 3.1 Data Acquisition Results From Q1 2004 to Q4 2024, a total of 2,353 drug-associated endometrial cancer reports were retrieved from the FDA Adverse Event Reporting System (FAERS) database. These reports included patient demographic information (e.g., age, weight), time-to-onset of adverse events (AEs), and clinical outcomes (e.g., hospitalization, death). The data acquisition workflow is illustrated in Figure 1. 3.2 Basic Information on Drug-Related Endometrial Cancer Reports Drug-related endometrial cancer reports come from 69 countries or regions, with the highest number reported by the United States (53.29%), followed by Canada (5.65%), the United Kingdom (3.44%), and others (as shown in Figure 2). The number of reports shows an upward trend, reaching a peak in 2021. The majority of reporters are Medical Doctors (39.57%), followed by Consumers (29.15%), Healthcare Professionals (10.92%), and others. The age group most represented is 45-65 years (34.38%), followed by 65-74 years (15.81%), and ≥75 years (7.56%). In terms of weight, the majority fall within the ≥80kg category (11.90%), followed by 50-64.9kg (7.05%) and 65-79.9kg (6.59%). The main outcomes of drug-related endometrial cancer are Hospitalization (26.31%), followed by Death (8.84%), Life-threatening (3.91%), and others (as shown in Figure 3). 3.3 Drug Risks and Classification of Drug-Related Endometrial Cancer Based on four methods: ROR, PRR, BCPNN, and MGPS, 32 potential drugs that could induce endometrial cancer were identified. According to the ROR values, the highest-risk drug is Toremifene (ROR = 307.8), followed by Raloxifene (ROR = 130.85), Tamoxifen (ROR = 105.81), Dostarlimab (ROR = 87.04), Drospirenone; Estradiol (ROR = 69.88), Bazedoxifene; Estrogens Conjugated (ROR = 60.16), Ulipristal (ROR = 44.2), Progesterone (ROR = 30.73), Ospemifene (ROR = 27.75), Estrogens Conjugated; Medroxyprogesterone (ROR = 27.64), Estradiol; Norethisterone (ROR = 27.1), Zinc (ROR = 26.5), Estrogens Conjugated (ROR = 18.05), Medroxyprogesterone (ROR = 14.03), Estradiol (ROR = 10.81), Amlodipine; Hydrochlorothiazide; Valsartan (ROR = 8.73), Exemestane (ROR = 8.49), Anastrozole (ROR = 8.23), Carboplatin (ROR = 7.75), Testosterone (ROR = 7.57), Letrozole (ROR = 6.75), Doxorubicin (ROR = 6.64), Valsartan (ROR = 5.49), Trastuzumab (ROR = 4.99), Interferon Beta-1A (ROR = 4.28), Ranitidine (ROR = 4.13), Alendronic Acid (ROR = 4.04), Guselkumab (ROR = 3.86), Levonorgestrel (ROR = 3.64), Everolimus (ROR = 3.41), Risankizumab (ROR = 3.1), Infliximab (ROR = 2.93) (as shown in Table 3). The selected high-risk drugs are classified as follows: Hormone medications include 11 types, Cancer drugs include 9 types, Antihypertensive drugs include 2 types, Antiviral drugs include 1 type, Immunosuppressants include 4 types, Mineral supplements include 1 type, Gastrointestinal drugs include 1 type, and Osteoporosis drugs include 3 types (as shown in Figure 4). 3.5 Drug-Induced Onset Time of Drug-Related Endometrial Cancer In studies on drug-related endometrial cancer, some reports recorded the onset time. The median onset time for Interferon Beta-1A is 1778.88 days, for Tamoxifen is 2113.32 days, for Levonorgestrel is 1039.73 days, for Infliximab is 1622.57 days, for Raloxifene is 1662.98 days, for Doxorubicin is 726.42 days, for Letrozole is 495.25 days, and for Conjugated Estrogens; Medroxyprogesterone Acetate is 1275.86 days. The median onset time for Risankizumab is 286.5 days, and for Alendronic acid is 532.7 days (as shown in Table 4 and Figure 5). 4 Discussion The incidence of endometrial cancer has shown a yearly increasing trend, and drug-related endometrial cancer is gradually receiving more attention in clinical practice. However, there is still a lack of research based on real-world data regarding drug-related endometrial cancer. Therefore, this study identified 32 drugs associated with endometrial cancer incidence through the FAERS database. This not only provides a new perspective for drug safety evaluation but also offers crucial data support for further understanding the potential impact of drugs on endometrial cancer. It also provides a scientific basis for formulating reasonable drug use guidelines. Endometrial cancer originates from the endometrium and typically occurs in postmenopausal women, with obesity also being a risk factor for endometrial cancer [1] . In this study, the most common age range was 45-65 years, and the most frequent weight was ≥80 kg, which is consistent with previous findings. Based on the four methods—ROR, PRR, BCPNN, and MGPS—32 potential drugs inducing endometrial cancer were identified. These drugs include hormonal drugs, cancer treatment drugs, osteoporosis medications, mineral supplements, immunosuppressants, antiviral drugs, and antihypertensive drugs. Hormonal drugs are commonly used in the treatment of conditions such as contraception, menstrual disorders, polycystic ovary syndrome, and endometriosis [17, 18] . Estrogen promotes endometrial hyperplasia, and long-term estrogen exposure increases the risk of gene mutations, leading to the development of endometrial cancer [19, 20] . Progesterone can inhibit estrogen-induced endometrial hyperplasia, and the combined use of estrogen and progesterone can effectively prevent excessive endometrial growth and reduce the risk of endometrial cancer. However, long-term or improper use of these drugs may increase the risk of endometrial cancer [21] . Estrogen exposure has been clearly identified as a cause of endometrial cancer [22] . The results of this study show that among hormonal drugs, Drospirenone and Estradiol (ROR=69.88) are the drugs with the highest risk, which is consistent with previous conclusions. Additionally, this study reports that the median onset time for Conjugated Estrogens and Medroxyprogesterone Acetate was approximately 1275.86 days. Therefore, when using hormonal drugs, the patient's health status, medical history, and endometrial condition should be thoroughly assessed, and a reasonable treatment plan should be selected with regular monitoring. In this study, 10 oncology treatment drugs were screened, with the two drugs having the highest risk being Toremifene and Tamoxifen (ROR=105.81). Both of these drugs are selective estrogen receptor modulators (SERMs) used in the treatment of breast cancer [22] . Tamoxifen works by binding to estrogen receptors, blocking the action of estrogen, and thus inhibiting the growth of estrogen-dependent breast cancer cells [25] . Although Tamoxifen acts as an anti-estrogen in breast tissue, it exhibits estrogen-like effects in the endometrium and some other tissues, activating estrogen receptors and leading to endometrial hyperplasia, thereby increasing the risk of endometrial cancer [26] . Endometrial cancer caused by Tamoxifen is usually type I endometrial cancer [27] , and in this study, the median onset time for Toremifene-induced endometrial cancer was 2113.32 days. Toremifene has similar side effects to Tamoxifen, but previous studies have shown that Toremifene has a weaker stimulating effect on the endometrium compared to Tamoxifen, making it a more suitable choice for some patients, particularly those at risk for endometrial diseases. However, this risk is generally lower than the benefits gained from breast cancer treatment [28] . In clinical practice, the overall health status of the patient, cancer type, and risk factors should be considered to balance treatment benefits and side effects when developing personalized treatment plans. Letrozole, Anastrozole, and Exemestane are aromatase inhibitors mainly used to treat hormone receptor-positive breast cancer in postmenopausal women. These drugs reduce the synthesis of estrogen and may reduce the incidence of endometrial cancer to some extent [30] . The results of this study indicate that these three drugs may be associated with the occurrence of endometrial cancer, but this contradiction may be caused by limitations of the database, the specificity of the patient population, differences in drug usage, or other complex biological mechanisms. Carboplatin and Doxorubicin are commonly used chemotherapy drugs, but there is currently no evidence that they increase the risk of endometrial cancer, and further research is needed on their relationship with endometrial cancer. Trastuzumab and Everolimus are mainly used in the treatment of HER2-positive breast cancer and gastric cancer [31-33] , but there is no clear evidence regarding their relationship with endometrial cancer. Valsartan, Amlodipine, Hydrochlorothiazide, and Valsartans are antihypertensive drugs, including angiotensin II receptor antagonists and calcium channel blockers [34] . Previous studies have shown that angiotensin II receptors promote the survival of endometrial cancer cells [35] , but there is no evidence linking calcium channel blockers to the occurrence and development of endometrial cancer, which warrants further exploration. Interferon Beta-1A is a recombinant protein that reduces inflammation in the central nervous system by regulating immune responses [36] , but there is no evidence linking it to endometrial cancer. Ranitidine is commonly used to treat conditions caused by excess stomach acid [37] , but there is no evidence showing its association with endometrial cancer. Raloxifene, Alendronic Acid, and Ospemifene are currently used in the treatment of osteoporosis [38] , and both Ospemifene and Raloxifene are selective estrogen receptor modulators. Previous studies have shown that long-term use of Ospemifene may increase the risk of endometrial cancer [39] , while Raloxifene may reduce the risk of endometrial cancer [40] . In this study, Ospemifene and Raloxifene were found to potentially be associated with the occurrence of endometrial cancer, and further research is needed. Zinc is an important trace element in the body, and its deficiency can lead to various diseases [41] . The relationship between zinc and endometrial cancer is currently unclear. However, this study has several limitations. The FAERS database relies on voluntarily submitted adverse event reports, which may lead to underreporting of data. Some adverse events may not be reported, especially mild or unnoticed events. Many reports lack sufficient evidence to establish a causal relationship between drug exposure and adverse events. Confirming such causal relationships is a common issue in drug safety monitoring, particularly in observational studies. Since reports primarily come from healthcare professionals and drug users, data may be subject to selection bias, where only certain types of events or those occurring in specific populations are reported, affecting the generalizability and representativeness of the results. Therefore, the results of our data mining should be interpreted cautiously, and conclusions should be drawn through comprehensive, evidence-based evaluations. 5 Conclusion This study explored the potential association between drug exposure and the incidence of endometrial cancer using the FAERS database, helping to quickly identify drugs that may lead to endometrial cancer and proposing strategies for further research. Management of drug-induced endometrial cancer requires a patient-centered approach to treatment, which may be restricted by treatment adjustments, while other patient populations may have more flexibility in drug management. Future research should combine real-world data with experimental validation to develop a comprehensive safety profile for drugs potentially associated with macular edema, supporting safer treatment methods. Abbreviations ROR Reporting Odds Ratio CI Confidence Interval. Declarations Data availability statement The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found below: FAERS Public Dashboard (https://www.fda.gov/drugs/questions-and-answers-fdas-adverse-event-reporting-system-faers/fda-adverse-event-reporting-system-faers-public-dashboard). Ethics statement The data used in this study are from publicly available public databases, thus not requiring informed consent and ethical statements. Author contributions The study was conceptualized and designed by Huiping Zhang and Zhuo Zhou. The data analysis and result interpretation were carried out by Huiping Zhang, Juan Wang, Yu Wang, Yingying Ma, Yulu Gou, Zhuo Zhou. Data acquisition was undertaken by Huiping Zhang, Zhuo zhou and Juan Wang. Software support was contributed by Yu Wang, Yingying Ma and Yulu Gou. 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Tables Tables 1 to 4 are available in the Supplementary Files section Additional Declarations No competing interests reported. Supplementary Files Tables.docx PT.xlsx Cite Share Download PDF Status: Under Review Version 1 posted Reviewers invited by journal 11 Jul, 2025 Editor assigned by journal 11 Jul, 2025 Editor invited by journal 11 Jun, 2025 Submission checks completed at journal 03 Jun, 2025 First submitted to journal 03 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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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-6733006","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":484751143,"identity":"9ebe88a7-a08c-4248-bd89-93ed749d7f66","order_by":0,"name":"Huiping Zhang","email":"","orcid":"","institution":"Northwest University First Hospital","correspondingAuthor":false,"prefix":"","firstName":"Huiping","middleName":"","lastName":"Zhang","suffix":""},{"id":484751146,"identity":"46b6feed-24cf-49b3-bc89-34025d24c846","order_by":1,"name":"Juan Wang","email":"","orcid":"","institution":"Northwest University First Hospital","correspondingAuthor":false,"prefix":"","firstName":"Juan","middleName":"","lastName":"Wang","suffix":""},{"id":484751149,"identity":"06267957-987c-4fdf-bc4a-9578f7a9919e","order_by":2,"name":"Yu Wang","email":"","orcid":"","institution":"Affiliated Hospital of Yan'an University","correspondingAuthor":false,"prefix":"","firstName":"Yu","middleName":"","lastName":"Wang","suffix":""},{"id":484751151,"identity":"5933458b-aafc-4d04-813a-8badfcda9509","order_by":3,"name":"Yingying Ma","email":"","orcid":"","institution":"Affiliated Hospital of Yan'an University","correspondingAuthor":false,"prefix":"","firstName":"Yingying","middleName":"","lastName":"Ma","suffix":""},{"id":484751152,"identity":"743abcfe-3cb7-4524-a83d-528e9f168030","order_by":4,"name":"Yulu Gou","email":"","orcid":"","institution":"Affiliated Hospital of Yan'an University","correspondingAuthor":false,"prefix":"","firstName":"Yulu","middleName":"","lastName":"Gou","suffix":""},{"id":484751153,"identity":"3d73a887-e89a-4265-bfe5-58ab2f6eb90d","order_by":5,"name":"Zhuo Zhou","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAyklEQVRIiWNgGAWjYBAC+/kHGx///SfBzMbeQKQWAwnmwwY8bBbs/DwHiNbClibAw1bBLzkjgUgt5tI9ZgwSPBLSBjcfb7zBUGMTTVCL5ZwzZg8MJCSMDW6nFVswHEvLbSCo50COuUGCgUSywe0cMwnGhsNEaTGTOJAgUb/h5hkitRjcSEuTbDggwSw5g4dILZI9hw8bMzZIMPPzAP2SQIxf+NkbGx8zNtQBo/LwxhsfamyI8AuyIyUSSFEO0UKqjlEwCkbBKBgZAADUlzyIC6bxwwAAAABJRU5ErkJggg==","orcid":"","institution":"Northwest University First Hospital","correspondingAuthor":true,"prefix":"","firstName":"Zhuo","middleName":"","lastName":"Zhou","suffix":""}],"badges":[],"createdAt":"2025-05-23 12:53:13","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6733006/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6733006/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":86775342,"identity":"deaef7ee-9ae3-46f6-acbe-f96f378a39e4","added_by":"auto","created_at":"2025-07-15 12:31:17","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":170080,"visible":true,"origin":"","legend":"\u003cp\u003eThe flow diagram of screening reports containing drug-related endometrial cancer from the FAERS database.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6733006/v1/633482aac5a9dc9f9c588a20.png"},{"id":86776253,"identity":"f79128e0-12a4-45dd-a35d-da31b60b9c04","added_by":"auto","created_at":"2025-07-15 12:39:17","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":110002,"visible":true,"origin":"","legend":"\u003cp\u003eDistribution of Reported Countries for Drug-Related Endometrial Cancer Reports\u003c/p\u003e\n\u003cp\u003eA. Map of Reported Countries Distribution; B. Pie Chart of Reported Countries Distribution\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6733006/v1/26cbe9ae64f26898ce245541.png"},{"id":86776255,"identity":"a3ffb69d-addf-41bb-921e-1e7ebd5b5f23","added_by":"auto","created_at":"2025-07-15 12:39:17","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":141735,"visible":true,"origin":"","legend":"\u003cp\u003eBasic Information on Drug-Related Endometrial Cancer\u003c/p\u003e\n\u003cp\u003eA. Distribution of Drug-Related Endometrial Cancer Outcomes; B. Distribution of Reported Years for Drug-Related Endometrial Cancer; C. Age Distribution of Drug-Related Endometrial Cancer; D. Weight Distribution of Drug-Related Endometrial Cancer; E. Distribution of Reporters' Identities for Drug-Related Endometrial Cancer\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-6733006/v1/32a2a4b3556c307160ed2689.png"},{"id":86775345,"identity":"024c7aaa-1881-4cfc-a723-0893412c1da0","added_by":"auto","created_at":"2025-07-15 12:31:17","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":183909,"visible":true,"origin":"","legend":"\u003cp\u003eForest Plot of Drug-Induced Endometrial Cancer under ROR Classification\u003c/p\u003e\n\u003cp\u003eAbbreviation: ROR, Reporting Odds Ratio; CI, Confidence Interval.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-6733006/v1/ad7b816473d25e98e364484e.png"},{"id":86775339,"identity":"9dccc92c-78f4-4ea5-ac38-01bb8a9a07f0","added_by":"auto","created_at":"2025-07-15 12:31:17","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":95644,"visible":true,"origin":"","legend":"\u003cp\u003eCumulative Risk Timeline of Drug-Induced Endometrial Cancer by Different Medications\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-6733006/v1/699878dc6b89d524ba2be407.png"},{"id":86778446,"identity":"f252efdd-2499-45fb-836f-16f1e7876903","added_by":"auto","created_at":"2025-07-15 12:55:22","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":944289,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6733006/v1/01b4a68c-3a00-4f8b-837d-c40fd050f95f.pdf"},{"id":86775337,"identity":"a98da71e-776c-4951-b102-983fa0aab198","added_by":"auto","created_at":"2025-07-15 12:31:17","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":35122,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-6733006/v1/51c2c8f6e2d97d4f03487218.docx"},{"id":86775344,"identity":"b39044eb-9f94-44a3-8fca-7d068f97f90b","added_by":"auto","created_at":"2025-07-15 12:31:17","extension":"xlsx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":88932,"visible":true,"origin":"","legend":"","description":"","filename":"PT.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-6733006/v1/780f4fbc3051e2ffee488354.xlsx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Drug-induced Endometrial Cancer: A Pharmacovigilance Study Based on Real-World Data from the FAERS Database","fulltext":[{"header":"1 Introduction","content":"\u003cp\u003eEndometrial cancer (EC) is one of the most common malignant tumors of the female reproductive system. In 2020, there were 417,000 new cases diagnosed globally, and the overall incidence rate has been rising annually\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e. It has been reported that the lifetime risk for women to develop endometrial cancer is approximately 3%, with increased risks associated with obesity, family history, and polycystic ovary syndrome\u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. The etiology of endometrial cancer is complex, but factors such as hormonal imbalances, genetic susceptibility, obesity, diabetes, and long-term use of estrogen-based drugs have been proven to be closely related to its occurrence\u003csup\u003e[\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e. However, specific studies identifying which drugs or drug categories may lead to endometrial cancer are still lacking. Therefore, identifying these drugs is crucial for preventing drug-induced EC.\u003c/p\u003e\u003cp\u003eDuring a normal menstrual cycle, estrogen stimulates the proliferation of the endometrium, while periodic progesterone and regular menstrual shedding maintain the health of the endometrium. The lack of natural progesterone leads to an excess of unopposed estrogen driven by obesity, which is the main pathological process for the occurrence of endometrial cancer\u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e. Increased lifelong exposure to unopposed estrogen is a reproductive risk factor, including early menarche (\u0026amp;lt;12 years), late menopause (\u0026ge;\u0026thinsp;55 years), anovulation (such as polycystic ovary syndrome), and infertility, which also increases the risk of endometrial cancer\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e. In clinical practice, drug-induced endometrial cancer has gradually become a focus of attention. Common drugs associated with endometrial cancer include estrogen-based medications, tamoxifen, and certain chemotherapy drugs\u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e. Tamoxifen, a selective estrogen receptor modulator, increases the risk of endometrial cancer when used long-term for the prevention or treatment of hormone-sensitive breast cancer\u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e. However, there is currently a lack of real-world data studies on drug-related endometrial cancer. The FAERS (FDA Adverse Event Reporting System) database is one of the largest adverse drug event reporting databases globally, containing information on adverse drug reactions, drug-drug interactions, and drug-induced diseases, which is of significant importance for drug safety research\u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e. This study aims to explore drug-related adverse reactions to endometrial cancer using real-world data from the FAERS database and assess the relationship between drug use and the occurrence of endometrial cancer. By analyzing a large number of clinical reports, this study seeks to identify drugs that may induce endometrial cancer, providing scientific evidence for clinicians in drug selection and management.\u003c/p\u003e"},{"header":"2 Materials and Methods","content":"\u003cp\u003e2.1 Data Source\u003c/p\u003e\n\u003cp\u003eThe data for this study was sourced from the FAERS database, which is available for download from the official FDA website (https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html). The database is updated quarterly and provides two data formats for download: ASCII and XML. For this study, the raw ASCII data files from the first quarter of 2004 to the fourth quarter of 2024 were downloaded for statistical analysis. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e2.2 Adverse Reaction Identification\u003c/p\u003e\n\u003cp\u003eIn this study, the MedDRA dictionary (MedDRA 27.1) was used to code the adverse event names in the FAERS database using preferred terms (PTs). A standardized query was applied to identify PTs related to \u0026quot;Drug-induced endometrial cancer,\u0026quot; and this term was selected for analysis. Cases related to this PT were extracted from the DEMO file using their PRIMARYID, and duplicate reports were excluded to ensure accurate case statistics. Additional information, such as the patient\u0026apos;s age, weight, reporter\u0026apos;s identity, and reporting country, was also obtained. For drug-related analysis, only cases marked as \u0026quot;primary suspect drug\u0026quot; were included. Entries marked as \u0026quot;secondary suspect drug,\u0026quot; \u0026quot;concomitant drug,\u0026quot; or \u0026quot;interaction drug\u0026quot; were excluded to reduce uncertainty in the results. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e2.3 Statistical Analysis\u003c/p\u003e\n\u003cp\u003eThis study used R 4.4.2 and SPSS 29.0 for statistical analysis. This study employed four methods to identify potential drug-event associations: Reporting Odds Ratio (ROR)\u003csup\u003e[12]\u003c/sup\u003e, Proportional Reporting Ratio (PRR)\u003csup\u003e[13]\u003c/sup\u003e, Bayesian Confidence Propagation Neural Network (BCPNN)\u0026nbsp;\u003csup\u003e[14]\u003c/sup\u003e, and Multi-item Gamma Poisson Shrinker (MGPS)\u003csup\u003e[14]\u003c/sup\u003e. These methods evaluate the statistical relationship between a specific drug and an adverse event (AE) by calculating the relative frequency of target adverse reactions caused by the target drug in the database over a given period. \u0026quot;a\u0026quot; refers to the number of reports that include both the target drug and target adverse reaction.\u0026quot;b\u0026quot; refers to the number of reports with other drug adverse reactions that include the target drug. \u0026quot;c\u0026quot; refers to the number of reports with target drug adverse reactions that include other drugs. \u0026quot;d\u0026quot; refers to the number of reports that include both other drugs and other drug adverse reactions (as shown in Table 1).The formulas for the four methods are presented in Table 2. Drugs that passed the screening criteria of all four methods were included in the study, indicating a significant association with drug-induced endometrial cancer. Additionally, the duration of drug use leading to drug-induced endometrial cancer was also analyzed.\u003c/p\u003e"},{"header":"3 Results","content":"\u003cp\u003e3.1 Data Acquisition Results\u003c/p\u003e\n\u003cp\u003eFrom Q1 2004 to Q4 2024, a total of 2,353 drug-associated endometrial cancer reports were retrieved from the FDA Adverse Event Reporting System (FAERS) database. These reports included patient demographic information (e.g., age, weight), time-to-onset of adverse events (AEs), and clinical outcomes (e.g., hospitalization, death). The data acquisition workflow is illustrated in Figure 1.\u003c/p\u003e\n\u003cp\u003e3.2 Basic Information on Drug-Related Endometrial Cancer Reports\u003c/p\u003e\n\u003cp\u003eDrug-related endometrial cancer reports come from 69 countries or regions, with the highest number reported by the United States (53.29%), followed by Canada (5.65%), the United Kingdom (3.44%), and others (as shown in Figure 2). The number of reports shows an upward trend, reaching a peak in 2021. The majority of reporters are Medical Doctors (39.57%), followed by Consumers (29.15%), Healthcare Professionals (10.92%), and others. The age group most represented is 45-65 years (34.38%), followed by 65-74 years (15.81%), and \u0026ge;75 years (7.56%). In terms of weight, the majority fall within the \u0026ge;80kg category (11.90%), followed by 50-64.9kg (7.05%) and 65-79.9kg (6.59%). The main outcomes of drug-related endometrial cancer are Hospitalization (26.31%), followed by Death (8.84%), Life-threatening (3.91%), and others (as shown in Figure 3).\u003c/p\u003e\n\u003cp\u003e3.3 Drug Risks and Classification of Drug-Related Endometrial Cancer\u003c/p\u003e\n\u003cp\u003eBased on four methods: ROR, PRR, BCPNN, and MGPS, 32 potential drugs that could induce endometrial cancer were identified. According to the ROR values, the highest-risk drug is Toremifene (ROR = 307.8), followed by Raloxifene (ROR = 130.85), Tamoxifen (ROR = 105.81), Dostarlimab (ROR = 87.04), Drospirenone; Estradiol (ROR = 69.88), Bazedoxifene; Estrogens Conjugated (ROR = 60.16), Ulipristal (ROR = 44.2), Progesterone (ROR = 30.73), Ospemifene (ROR = 27.75), Estrogens Conjugated; Medroxyprogesterone (ROR = 27.64), Estradiol; Norethisterone (ROR = 27.1), Zinc (ROR = 26.5), Estrogens Conjugated (ROR = 18.05), Medroxyprogesterone (ROR = 14.03), Estradiol (ROR = 10.81), Amlodipine; Hydrochlorothiazide; Valsartan (ROR = 8.73), Exemestane (ROR = 8.49), Anastrozole (ROR = 8.23), Carboplatin (ROR = 7.75), Testosterone (ROR = 7.57), Letrozole (ROR = 6.75), Doxorubicin (ROR = 6.64), Valsartan (ROR = 5.49), Trastuzumab (ROR = 4.99), Interferon Beta-1A (ROR = 4.28), Ranitidine (ROR = 4.13), Alendronic Acid (ROR = 4.04), Guselkumab (ROR = 3.86), Levonorgestrel (ROR = 3.64), Everolimus (ROR = 3.41), Risankizumab (ROR = 3.1), Infliximab (ROR = 2.93) (as shown in Table 3).\u003c/p\u003e\n\u003cp\u003eThe selected high-risk drugs are classified as follows: Hormone medications include 11 types, Cancer drugs include 9 types, Antihypertensive drugs include 2 types, Antiviral drugs include 1 type, Immunosuppressants include 4 types, Mineral supplements include 1 type, Gastrointestinal drugs include 1 type, and Osteoporosis drugs include 3 types (as shown in Figure 4).\u003c/p\u003e\n\u003cp\u003e3.5 Drug-Induced Onset Time of Drug-Related Endometrial Cancer\u003c/p\u003e\n\u003cp\u003eIn studies on drug-related endometrial cancer, some reports recorded the onset time. The median onset time for Interferon Beta-1A is 1778.88 days, for Tamoxifen is 2113.32 days, for Levonorgestrel is 1039.73 days, for Infliximab is 1622.57 days, for Raloxifene is 1662.98 days, for Doxorubicin is 726.42 days, for Letrozole is 495.25 days, and for Conjugated Estrogens; Medroxyprogesterone Acetate is 1275.86 days. The median onset time for Risankizumab is 286.5 days, and for Alendronic acid is 532.7 days (as shown in Table 4 and Figure 5).\u003c/p\u003e"},{"header":"4 Discussion","content":"\u003cp\u003eThe incidence of endometrial cancer has shown a yearly increasing trend, and drug-related endometrial cancer is gradually receiving more attention in clinical practice. However, there is still a lack of research based on real-world data regarding drug-related endometrial cancer. Therefore, this study identified 32 drugs associated with endometrial cancer incidence through the FAERS database. This not only provides a new perspective for drug safety evaluation but also offers crucial data support for further understanding the potential impact of drugs on endometrial cancer. It also provides a scientific basis for formulating reasonable drug use guidelines.\u003c/p\u003e\n\u003cp\u003eEndometrial cancer originates from the endometrium and typically occurs in postmenopausal women, with obesity also being a risk factor for endometrial cancer\u003csup\u003e[1]\u003c/sup\u003e. In this study, the most common age range was 45-65 years, and the most frequent weight was\u0026nbsp;≥80 kg, which is consistent with previous findings. Based on the four methods—ROR, PRR, BCPNN, and MGPS—32 potential drugs inducing endometrial cancer were identified. These drugs include hormonal drugs, cancer treatment drugs, osteoporosis medications, mineral supplements, immunosuppressants, antiviral drugs, and antihypertensive drugs. Hormonal drugs are commonly used in the treatment of conditions such as contraception, menstrual disorders, polycystic ovary syndrome, and endometriosis\u003csup\u003e[17, 18]\u003c/sup\u003e. Estrogen promotes endometrial hyperplasia, and long-term estrogen exposure increases the risk of gene mutations, leading to the development of endometrial cancer\u003csup\u003e[19, 20]\u003c/sup\u003e. Progesterone can inhibit estrogen-induced endometrial hyperplasia, and the combined use of estrogen and progesterone can effectively prevent excessive endometrial growth and reduce the risk of endometrial cancer. However, long-term or improper use of these drugs may increase the risk of endometrial cancer\u003csup\u003e[21]\u003c/sup\u003e. Estrogen exposure has been clearly identified as a cause of endometrial cancer\u003csup\u003e[22]\u003c/sup\u003e. The results of this study show that among hormonal drugs, Drospirenone and Estradiol (ROR=69.88) are the drugs with the highest risk, which is consistent with previous conclusions. Additionally, this study reports that the median onset time for Conjugated Estrogens and Medroxyprogesterone Acetate was approximately 1275.86 days. Therefore, when using hormonal drugs, the patient's health status, medical history, and endometrial condition should be thoroughly assessed, and a reasonable treatment plan should be selected with regular monitoring.\u003c/p\u003e\n\u003cp\u003eIn this study, 10 oncology treatment drugs were screened, with the two drugs having the highest risk being Toremifene and Tamoxifen (ROR=105.81). Both of these drugs are selective estrogen receptor modulators (SERMs) used in the treatment of breast cancer\u003csup\u003e[22]\u003c/sup\u003e. Tamoxifen works by binding to estrogen receptors, blocking the action of estrogen, and thus inhibiting the growth of estrogen-dependent breast cancer cells\u003csup\u003e[25]\u003c/sup\u003e. Although Tamoxifen acts as an anti-estrogen in breast tissue, it exhibits estrogen-like effects in the endometrium and some other tissues, activating estrogen receptors and leading to endometrial hyperplasia, thereby increasing the risk of endometrial cancer\u003csup\u003e[26]\u003c/sup\u003e. Endometrial cancer caused by Tamoxifen is usually type I endometrial cancer\u003csup\u003e[27]\u003c/sup\u003e, and in this study, the median onset time for Toremifene-induced endometrial cancer was 2113.32 days. Toremifene has similar side effects to Tamoxifen, but previous studies have shown that Toremifene has a weaker stimulating effect on the endometrium compared to Tamoxifen, making it a more suitable choice for some patients, particularly those at risk for endometrial diseases. However, this risk is generally lower than the benefits gained from breast cancer treatment\u003csup\u003e[28]\u003c/sup\u003e. In clinical practice, the overall health status of the patient, cancer type, and risk factors should be considered to balance treatment benefits and side effects when developing personalized treatment plans. Letrozole, Anastrozole, and Exemestane are aromatase inhibitors mainly used to treat hormone receptor-positive breast cancer in postmenopausal women. These drugs reduce the synthesis of estrogen and may reduce the incidence of endometrial cancer to some extent\u003csup\u003e[30]\u003c/sup\u003e. The results of this study indicate that these three drugs may be associated with the occurrence of endometrial cancer, but this contradiction may be caused by limitations of the database, the specificity of the patient population, differences in drug usage, or other complex biological mechanisms. Carboplatin and Doxorubicin are commonly used chemotherapy drugs, but there is currently no evidence that they increase the risk of endometrial cancer, and further research is needed on their relationship with endometrial cancer. Trastuzumab and Everolimus are mainly used in the treatment of HER2-positive breast cancer and gastric cancer\u003csup\u003e[31-33]\u003c/sup\u003e, but there is no clear evidence regarding their relationship with endometrial cancer. Valsartan, Amlodipine, Hydrochlorothiazide, and Valsartans are antihypertensive drugs, including angiotensin II receptor antagonists and calcium channel blockers\u003csup\u003e[34]\u003c/sup\u003e. Previous studies have shown that angiotensin II receptors promote the survival of endometrial cancer cells\u003csup\u003e[35]\u003c/sup\u003e, but there is no evidence linking calcium channel blockers to the occurrence and development of endometrial cancer, which warrants further exploration. Interferon Beta-1A is a recombinant protein that reduces inflammation in the central nervous system by regulating immune responses\u003csup\u003e[36]\u003c/sup\u003e, but there is no evidence linking it to endometrial cancer. Ranitidine is commonly used to treat conditions caused by excess stomach acid\u003csup\u003e[37]\u003c/sup\u003e, but there is no evidence showing its association with endometrial cancer. Raloxifene, Alendronic Acid, and Ospemifene are currently used in the treatment of osteoporosis\u003csup\u003e[38]\u003c/sup\u003e, and both Ospemifene and Raloxifene are selective estrogen receptor modulators. Previous studies have shown that long-term use of Ospemifene may increase the risk of endometrial cancer\u003csup\u003e[39]\u003c/sup\u003e, while Raloxifene may reduce the risk of endometrial cancer\u003csup\u003e[40]\u003c/sup\u003e. In this study, Ospemifene and Raloxifene were found to potentially be associated with the occurrence of endometrial cancer, and further research is needed. Zinc is an important trace element in the body, and its deficiency can lead to various diseases\u003csup\u003e[41]\u003c/sup\u003e. The relationship between zinc and endometrial cancer is currently unclear.\u003c/p\u003e\n\u003cp\u003eHowever, this study has several limitations. The FAERS database relies on voluntarily submitted adverse event reports, which may lead to underreporting of data. Some adverse events may not be reported, especially mild or unnoticed events. Many reports lack sufficient evidence to establish a causal relationship between drug exposure and adverse events. Confirming such causal relationships is a common issue in drug safety monitoring, particularly in observational studies. Since reports primarily come from healthcare professionals and drug users, data may be subject to selection bias, where only certain types of events or those occurring in specific populations are reported, affecting the generalizability and representativeness of the results. Therefore, the results of our data mining should be interpreted cautiously, and conclusions should be drawn through comprehensive, evidence-based evaluations.\u003c/p\u003e"},{"header":"5 Conclusion","content":"\u003cp\u003eThis study explored the potential association between drug exposure and the incidence of endometrial cancer using the FAERS database, helping to quickly identify drugs that may lead to endometrial cancer and proposing strategies for further research. Management of drug-induced endometrial cancer requires a patient-centered approach to treatment, which may be restricted by treatment adjustments, while other patient populations may have more flexibility in drug management. Future research should combine real-world data with experimental validation to develop a comprehensive safety profile for drugs potentially associated with macular edema, supporting safer treatment methods.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eROR\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eReporting Odds Ratio\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCI\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eConfidence Interval.\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003eData availability statement\u003c/p\u003e\n\u003cp\u003eThe datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found below: FAERS Public Dashboard (https://www.fda.gov/drugs/questions-and-answers-fdas-adverse-event-reporting-system-faers/fda-adverse-event-reporting-system-faers-public-dashboard).\u003c/p\u003e\n\u003cp\u003eEthics statement\u003c/p\u003e\n\u003cp\u003eThe data used in this study are from publicly available public databases, thus not requiring informed consent and ethical statements.\u003c/p\u003e\n\u003cp\u003eAuthor contributions\u003c/p\u003e\n\u003cp\u003eThe study was conceptualized and designed by Huiping Zhang and Zhuo Zhou. The data analysis and result interpretation were carried out by\u0026nbsp;Huiping Zhang, Juan Wang, Yu Wang, Yingying Ma, Yulu Gou, Zhuo Zhou.\u0026nbsp;Data acquisition was undertaken by Huiping Zhang, Zhuo zhou and Juan Wang. Software support was contributed by\u0026nbsp;Yu Wang, Yingying Ma and Yulu Gou. The composition and refinement of the manuscript were primarily the responsibility of Huiping Zhang and Zhuo Zhou. All authors have read and approved the final work.\u003c/p\u003e\n\u003cp\u003eFunding\u003c/p\u003e\n\u003cp\u003eNone\u003c/p\u003e\n\u003cp\u003eConflict of interest\u003c/p\u003e\n\u003cp\u003eThe 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. \u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eCrosbie E J, Kitson S J, McAlpine J N, et al. Endometrial cancer[J]. Lancet, 2022,399(10333):1412-1428.\u003c/li\u003e\n\u003cli\u003eRaglan O, Kalliala I, Markozannes G, et al. Risk factors for endometrial cancer: An umbrella review of the literature[J]. Int J Cancer, 2019,145(7):1719-1730.\u003c/li\u003e\n\u003cli\u003eSjogren L L, Morch L S, Lokkegaard E. 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Clin Interv Aging, 2014,9:1939-1950.\u003c/li\u003e\n\u003cli\u003eNeven P, Lunde T, Benedetti-Panici P, et al. A multicentre randomised trial to compare uterine safety of raloxifene with a continuous combined hormone replacement therapy containing oestradiol and norethisterone acetate[J]. BJOG, 2003,110(2):157-167.\u003c/li\u003e\n\u003cli\u003eAhmad R, Shaju R, Atfi A, et al. Zinc and Diabetes: A Connection between Micronutrient and Metabolism[J]. Cells, 2024,13(16).\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 4 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":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Endometrial cancer, FAERS, Adverse drug events, Disproportionality analysis, Pharmacovigilance","lastPublishedDoi":"10.21203/rs.3.rs-6733006/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6733006/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThis study aims to identify and evaluate drugs associated with the risk of endometrial cancer using the FDA Adverse Event Reporting System (FAERS) database. We retrieved adverse drug events (ADEs) related to drug-induced endometrial cancer from the FAERS database (Q1 2004–Q4 2024). A disproportionality analysis was conducted to identify drugs significantly associated with endometrial cancer risk, and time-to-onset (TTO) analyses were performed to assess the timing and risk profiles of adverse reactions related to endometrial cancer. Our study identified 2,352 ADEs linked to endometrial cancer. Disproportionality analysis identified 32 drugs associated with endometrial cancer risk, including 11 hormone medications, 9 cancer drugs, 2 antihypertensive drugs, 1 antiviral drug, 4 immunosuppressants, 1 mineral supplement, 1 gastrointestinal drug, and 3 osteoporosis drugs. Through a comprehensive analysis of the FAERS database, our study identified drugs strongly associated with endometrial carcinogenesis. Preventing drug-related endometrial cancer requires careful drug selection and monitoring. This study provides evidence-based insights for clinical management, aiming to optimize clinical care and mitigate risks.\u003c/p\u003e","manuscriptTitle":"Drug-induced Endometrial Cancer: A Pharmacovigilance Study Based on Real-World Data from the FAERS Database","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-15 12:31:12","doi":"10.21203/rs.3.rs-6733006/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewersInvited","content":"","date":"2025-07-11T05:50:27+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-07-11T05:45:46+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-06-11T10:46:38+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-06-03T15:28:35+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2025-06-03T15:24:16+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"57c61627-d366-453a-8e57-fb2215f74374","owner":[],"postedDate":"July 15th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":51458712,"name":"Biological sciences/Cancer"},{"id":51458713,"name":"Biological sciences/Drug discovery"},{"id":51458714,"name":"Health sciences/Diseases"},{"id":51458715,"name":"Health sciences/Risk factors"}],"tags":[],"updatedAt":"2025-07-15T12:31:13+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-15 12:31:12","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6733006","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6733006","identity":"rs-6733006","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}