Identification of Cellular Damage in Uteri From Hyperinsulinemic Mice Treated With Unopposed Estradiol

Abstract Unopposed estradiol and obesity are known risk factors for endometrial adenocarcinoma (EC). Endometrium from women with was found to have an increase in mutations relative tissue normal weight women, indicating DNA damage may be accelerated the setting of obesity. Since is associated high levels insulin anovulatory cycles, we sought mimic these conditions a mouse model. We previously that hyperinsulinemic MKR mice, without confounder obesity, increased incidence nuclear atypia glands. hypothesized hyperinsulinemia unopposed synergistic effect on inducing abnormal architecture endometrium, than either alone. At 8-10 weeks old, cohorts (n=20) WT mice underwent ovariectomy placement (E2) or placebo (P) pellet. Metabolic profiling included tolerance testing MR body composition. 3 months post-implantation, received partial hysterectomy second pellet replacement. 6 months, remaining uterus bisected into pieces. A blinded histological analysis conducted by gynecology pathologist. marker due oxidative stress, 8-oxoguanine-DNA-glycosylase (8-OHdG), quantified ELISA. Data analyzed using Kruskal-Wallis test multiple correction, Fischer’s exact test. By MKR-E2 treated had 27% lower MKR-P (p<0.05), 31% WT-E2 (p<0.01). WT-P similar weight, were (p=ns). Percent fat across all 4 placebo-treated small, atrophied uteri minimal gland formation, E2 failure determined presence occurred at months. All other enlarged uteri. The frequency dilation (p=ns), but moderate-severe dilation, whereas 50% mild (p=0.07). Focal hyperplasia present one mouse, mouse. 7-fold higher mean 8-OHdG (5.0±3.7 vs 0.7±1.6, p<0.002). (1.6±0.8 1.8±0.6, p=ns), as did Our findings show exacerbates cystic induced chronic estradiol, synergy promoting glandular growth endometrium. Surprisingly, uterine highest alone, hormonal state mimicking post-menopause. Further work needed understand intrauterine stress-induced damage.