Understanding endometrial tissue field defects in obesity-related endometrial hyperplasia

PROJECT SUMMARY
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.

Grant Number: 1R56HD116739-01A1
NIH Institute/Center: NIH
Principal Investigator: Ronald Chandler