Mice endometrium receptivity in early pregnancy is impaired by maternal hyperinsulinemia

Abstract

Previous studies have investigated the lower embryo implantation rates in women with polycystic ovary syndrome, obesity and type 2 diabetes, and specifically the association between the abnormal oocyte and embryo and hyperinsulinemia. The importance of hyperinsulinemia on maternal endometrium receptivity remains to be elucidated. The present study used a hyperinsulinemic mouse model to determine whether hyperinsulinemia may affect endometrial receptivity. An insulin intervention mouse model was first established. The serum levels of insulin, progesterone and estradiol were subsequently detected by ELISA assay analysis. The number of implantation sites was recorded using Trypan blue dye and the morphology of mice uteri was investigated using hematoxylin and eosin staining. The expression levels of molecular markers associated with endometrial receptivity were detected by reverse transcription-quantitative polymerase chain reaction, western blotting and immunohistochemistry analyses. Finally, the importance of mechanistic target of rapamycin (mTOR) expression following insulin treatment was determined. Mice treated with insulin developed insulin resistance and hyperinsulinemia. The number of implantation sites following insulin treatment did not differ between the control and insulin-treated groups. Additionally, no significant morphological alterations in mice uteri between control and insulin-treated groups were observed. However, the expression levels of estrogen receptor (Esr) 1, Esr2, progesterone receptor and homeobox A10 associated with endometrial receptivity, were imbalanced during endometrium receptivity when maternal hyperinsulinemia was induced. Western blot analysis revealed that expression levels of endometrial phosphorylated (p)-mTOR and p-ribosomal protein S6 kinase β-1 were significantly greater in the insulin-treated group. These results demonstrated that although an embryo may implant into endometrium, mice endometrium receptivity in early pregnancy may be impaired by maternal hyperinsulinemia. In addition, mTOR signaling may be involved in this process. The present study provides preliminary results demonstrating that female reproduction may be compromised during hyperinsulinemia, which requires further investigation in future studies.

Hyperinsulinemia restrains endometrial angiogenesis during decidualization in early pregnancy

“…However, little has been reported on the regulatory effects of high-level insulin on the endometrium. Our previous study found that high levels of insulin could result in impaired endometrial receptivity and further affect endometrial decidualization in early pregnant mice (Li et al 2017).…”

Selective Survival of Embryos Can Explain DNA Methylation Signatures of Adverse Prenatal Environments

“…Indeed, in humans more than half of all embryos may fail to implant or abort soon after implantation (Wilcox et al, 1999). This number can be substantially higher under maternal adversity (Bellver et al, 2013;Dechanet et al, 2011;Li et al, 2017b). We therefore expect that maternal adversity could generate intense selection on gene expression and the associated epigenomic profiles, in particular during implantation.…”

Consistent Role of Insulin Resistance in Recurrent Pregnancy Loss and Recurrent Implantation Failure: A Case-control Study

“…The hypothesized reasons of IR on ART failure in both RIF and RPL were that IR may be related to the decreased oocyte quality [30,31], poor embryonic development [32,33] and decreased endometrial receptivity [34][35][36].…”

“…That may be an important cause of incomplete embryo implantation and miscarriages [40]. IR and hyperinsulinemia may in uence decidualization by multiple factors like prokineticin 1, forkhead-O1 [41], insulin-like growth factor binding protein-1 [42], hox gene A10 [34] and endometrial protein PP14 [43]. A study conducted by Hu et al on pregnant rats demonstrated that insulin resistance induced damage mediated by mitochondria as well as the subsequent imbalance of oxidative stress responses in the gravid uterus [44].…”