Protective effect of eicosapentaenoic acid against estradiol valerate-induced endometrial hyperplasia via modulation of NF-κB/HIF-1α/VEGF signaling pathway in rats

Early diagnosis and treatment of endometrial hyperplasia (EH) remains mandatory for endometrial cancer (EC) prevention. To study the possible protective effect of eicosapentaenoic acid (EPA) in EH - induced by estradiol valerate (EV) in rats. Adult female Wistar rats were given EV with or without EPA for 10 days. The uterine changes were evaluated by both physical (weight index) and histopathological methods. The markers of oxidative stress (Uterine malondialdehyde (MDA) and serum total antioxidant capacity (TAC) as well as serum estradiol and progesterone levels, and apoptosis (uterine caspase-3) were determined. Immunohistochemical estimations of nuclear factor kappa B (NF-κB) and vascular endothelial growth factor (VEGF) in addition to hypoxia-inducible factor 1 alpha (HIF-1α) immunoblotting were measured in uterine tissue. EV showed significant increase in uterine weight index that is accompanied with histopatholigical evidences of EH. Such changes were associated with significant alterations in oxidative stress markers, modulation of estradiol and progesterone serum levels, an increase in HIF-1α, NF-κB and VEGF immuno-expressions and a significant decrease in caspase-3. EPA, in either dose, showed significant amelioration in uterine weight index as well as in histopathological changes. Such effect was accompanied with significant improvement in the measured hormonal levels, oxidative stress, apoptosis, and inflammatory parameters. EPA in the used doses provided biochemical and histopathological improvement in EV-induced EH via modulation of NF-κB/HIF-1α/VEGF signaling pathway.