Estrogens protect uterine against oxidative stress induced by hyperglycemia and obesit

Abstract

Obesity and diabetes prompt oxidative stress and an inflammatory environment that alter the homeostasis of several tissues, including uterine tissue. Estrogens are the main regulators of the endometrial function through the interaction with estrogen receptors. In this work we studied the effect of estradiol (E2) and estrone (E1) on the uterine oxidative stress induced by hyperglycemia; inflammation or obesity. To that end uterine slices isolated from female bilaterally ovariectomized (OVX) obese (Ob) and non-obese (nOb) Wistar rats were in vitro incubated with E2 or E1 in the presence of high glucose (25mM) or the pro-inflammatory agent LPS (5µg/mL). Oxidative-non oxidative stress was determined measuring the release to the incubation medium of the reactive oxygen species (ROS) hydrogen peroxide (H2O2, fluorescence assay) or nitric oxide (NO, Griess technique) respectively. Short interval treatment (10-20 min) with E2 or E1 (0.1-10 nM) increased NO production (2.20 ±0.22; 4.3 ± 0.64; 3.2 ±0.45 nmolNO/mg prot E2; E1; control, p< 0.01); effect detected either in young and adult OVX rats (3-14 month old age). The stimulatory action of both estrogens on NO synthesis was also evidenced in Ob rats (38; 33% a/c E2; E1 p< 0.05). H2O2 measurements showed that diabetic rats exhibited a 0.6 fold increase in ROS production respect to control group. Similar results were obtained in Ob rats (2656 ±632 vs 1595±287 nmol H2O2/mg prot, Ob vs nOb, p< 0.02). When uterine slices were exposed to E2 in the presence of LPS, a markedly reduction in ROS synthesis induced by LPS was observed (50 vs 12 % a/c, LPS vs LPS+E2, p< 0.05). Indeed, the steroid completely blunted the enhancement of H2O2 production induced by high glucose. Interestingly, E1 elicited similar action than E2. The results presented suggest that estrogens counteracted uterine oxidative stress induced by diabetes or obesity. A point to highlight is that the forgotten estrone exhibits comparable action than estradiol.