{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T12:25:03Z","timestamp":1784809503309,"version":"3.55.0"},"reference-count":52,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T00:00:00Z","timestamp":1766016000000},"content-version":"vor","delay-in-days":351,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Human Mutation"],"published-print":{"date-parts":[[2025,1]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Periods and pregnancy may affect the development of endometrial cancer by affecting the secretion of sex hormones, but the causal relationship is not clear, and its mediating factors need to be explored.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In this study, multivariable Mendelian randomization was used to analyze summary statistics of genome\u2010wide association studies of European ancestry, to evaluate the effect of 10 period\u2010 or pregnancy\u2010related factors on endometrial cancer. In addition, we performed the heterogeneity test and pleiotropy test to analyze the sensitivity. Because of the effect of sex hormones on body metabolism and the relationship between metabolism\u2010related traits and cancer, we explored the mediating effect of metabolism\u2010related traits by two\u2010step Mendelian randomization.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      This study showed that age at menarche (\n                      <jats:italic>p<\/jats:italic>\n                      = 1.21e \u2212 05; OR = 0.6852; 95% CI: 0.5784\u20130.8116), age at menopause (\n                      <jats:italic>p<\/jats:italic>\n                      = 0.00098; OR = 1.242; 95% CI: 1.0919\u20131.4127), and sex hormone\u2013binding globulin (SHBG) levels (\n                      <jats:italic>p<\/jats:italic>\n                      = 7.4e \u2212 07; OR = 0.5914; 95% CI: 0.4804\u20130.7281) have an independent causal relationship with the incidence of endometrial cancer. Moreover, several obesity\u2010related traits play a mediating role in the causal relationship between age at menarche and endometrial cancer. The mediators and their mediating effects are BMI (55.54%), obesity (30.37%), waist circumference preference (27.67%), body fat percentage (17.61%), and waist\u2010to\u2010hip ratio (14.82%). These results are robust to sensitivity analysis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study demonstrated the independent effect of pregnancy\u2010 and period\u2010related factors on endometrial cancer and suggested that avoiding obesity may be an effective method to prevent endometrial cancer for patients with premature menarche.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1155\/humu\/3401957","type":"journal-article","created":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T10:39:27Z","timestamp":1766054367000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Causal Relationships Between Pregnancy, Menstrual History, and Endometrial Cancer With Mediating Effects of Metabolism\u2010Related 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