SUN-116 - Estradiol and Progesterone Regulate Glucose Metabolism in the Uterine Epithelium of Mice

Glucose is critically important during early pregnancy. Previous studies have shown that glucose levels must be tightly regulated as both low and high glucose concentrations impair embryo development. One way for the uterus to precisely regulate the amount of glucose secreted into the uterine lumen is via glycogen metabolism. It has been suggested that estradiol (E2) and progesterone (P4) play roles in regulating changes in the uterine epithelial glycogen pool during the preimplantation period. Mice (24) were ovariectomized and divided into 4 groups of control, E2 (100 ng/day), P4 (1 mg/day), and E2+P4 followed by 4-days daily subcutaneous injections. Diastase labile Periodic Acid-Schiff (PAS) staining showed that glycogen was increased by E2 treatment. P4 had no effect and was able to block the effects of E2 when given in combination. There was no difference in the immunostaining levels of hexokinase (HK1, the enzyme that phosphorylates glucose) among treatments. E2-treated mice had higher levels of glycogen synthase 1 (GYS1) immunostaining in both luminal (LE) and glandular epithelium (GE). We have previously suggested that the epithelial effect of E2 is mediated by insulin-like growth factor 1 (IGF1). Immunostaining levels in the stroma for IGF1 were higher in E2 and E2+P4 treated groups compared to P4 and control. These results indicate that E2 has glycogenic effects on both LE and GE that might be mediated by increased IGF1 . Immunostaining levels of glucose-6-phosphatase (G6PC, the enzyme that dephosphorylates glucose-6-phosphate) were higher in both P4 and E2+P4 groups. Immunostaining levels of pyruvate kinase (PKM2, a rate-limiting enzyme in glycolysis) were also higher in both P4 and E2+P4 groups. The levels of glycogen phosphorylase (PYGM, the enzyme that breaks down glycogen) did not differ among groups. These results show that P4 stimulates glycogenolysis in both LE and GE. G6P from glycogen could be dephosphorylated and secreted into the luminal epithelium or metabolized via glycolysis to produce ATP in the uterine epithelium. To compare the effects of insulin and IGF1 on glycogen synthesis in the uterine epithelium, 18 mice were ovariectomized and divided into 3 groups of control, IGF1 or insulin (both 1.5 mg/Kg/day) which received intraperitoneal injections for 2 days. PAS staining showed that the IGF1-treated group had higher levels of uterine epithelial glycogen compared to insulin and control. Immunostaining levels of HK1, GYS1 and PYGM were all higher in the uterine epithelium of IGF1-treated mice. These results suggest that IGF1 predominantly regulates glycogen metabolism in the uterine epithelium . Overall, our results suggest that E2 and P4 play important roles in regulating uterine epithelial glucose metabolism. E2 promotes glycogenesis primarily through IGF1-mediated stimulation while P4 stimulates glycogenolysis and glycolysis to support the uterine environment

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