Understanding endometrial tissue field defects in obesity-related endometrial hyperplasia

Obesity incidence continues to rise in the U.S. Obesity is more common in women, and women are at higher risk for developing obesity-related co-morbidities. Currently, more than 1 in 3 women are obese, and more than 1 in 4 women are overweight. By 2030, 1 in 2 women are predicted to be obese. Obesity is risk factor for various gynecologic conditions, including endometrial hyperplasia. Endometrial hyperplasia risk increases as a woman’s body mass index increases. Obese women are 4-6 times more likely to develop endometrial hyperplasia compared to non-obese women. Endometrial hyperplasia is characterized by the benign overgrowth of uterine endometrial glands and abnormal uterine bleeding. Abnormal uterine bleeding can negatively impact a woman’s quality of life. Complex atypical endometrial hyperplasia is associated with malignant transformation and progression to endometrial cancer. Obese women show increased extragonadal aromatization of androgens into estrogen and increased estrogen bioavailability. ‘Unopposed’ estrogen is defined as increased circulating estrogen relative to progesterone. In addition to reproductive tract pathologies, the hormone imbalances associated with obesity can lead to menstrual irregularities, pregnancy complications, and infertility. Younger women develop endometrial hyperplasia secondary to conditions leading to ‘unopposed’ estrogen from anovulatory cycles, such as polycystic ovary syndrome or PCOS. In pre- menopausal women with abnormal uterine bleeding, endometrial hyperplasia incidence is as high as 10%, and, in women with PCOS, endometrial hyperplasia incidence is greater than 20%. Public awareness of the associations between obesity and disease susceptibility in women remains low, and research on the adverse health effects of obesity in women remains underfunded relative to its societal burden. Intentional weight loss can lower endometrial hyperplasia risk in obese women, but certain barriers prevent obese, at-risk women from losing weight or maintaining healthy lifestyles while living in obesogenic environments. Our overarching idea is that endometrial hyperplasia risk factors impact different cell types across the endometrial microenvironment, creating a ‘tissue field of susceptibility,’ which affects the cellular and molecular crosstalk necessary for normal endometrial function and the prevention of endometrial hyperplasia. We will use genetically engineered mouse models of endometrial hyperplasia, mouse models of high fat diet-induced obesity, histopathological assessments of mouse and human endometrial hyperplasia, adoptive bone marrow transfers, and ‘omics approaches to determine the mechanisms underlying endometrial hyperplasia development and progression within the susceptible endometrial tissue field. Our aspirational goals are to inform new early detection and prevention strategies by identifying early biomarkers within the uterine microenvironment that predict endometrial hyperplasia pathogenesis and severity in at-risk obese women. Project Number: 1R56HD116739-01A1 | Fiscal Year: 2025 | NIH Institute/Center: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) | Principal Investigator: Ronald Chandler | Institution: HENRY FORD HEALTH + MICHIGAN STATE UNIVERSITY HEALTH SCIENCES, EAST LANSING, MI | Award Amount: $1,394,304 | Activity Code: R56 | Study Section: Integrative and Clinical Endocrinology and Reproduction Study Section[ICER] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R56HD11673901A1