The Negative Impact of Obesity Associated Advanced Glycation End Products on Female Fertility

Background: The incidence of overweight and obesity is growing worldwide. Around 60% of reproductive aged women in developed countries are overweight/obese before conception and these women experience a higher incidence of infertility and placental associated pregnancy complications. The pre-conception uterine environment is key in achieving embryo implantation and a healthy pregnancy. Therefore, we aimed to quantify levels of advanced glycation end products (known to be elevated systemically in obese subjects) within the obese in-fertile versus lean fertile uterine environment and determine if obese levels of advanced glycation end products (AGEs) within the uterine cavity detrimentally alter tissue function in embryo implantation and placental development.Materials and Methods: Levels of AGEs examined within uterine lavage assessed by ELISA to determine differences between lean and obese women. Expression and localization of AGEs, receptor for AGEs (RAGE) and NFκB within endo-metrial tissues obtained from lean and obese women deter-mined by immunohistochemistry. Endometrial epithelial cells (ECC-1), primary human stromal cells and trophoblast cells (HTR8-SVneo) treated with lean (2000nmol/mol lysine) or obese (8000nmol/mol lysine) uterine levels of AGEs and p65-NFκB (western immunoblot), real time adhesion, proliferation migration and invasion (xCelligence real time cell function analysis), decidualization (cell morphology and prolactin re-lease), endoplasmic reticulum stress (western immunoblot for p-PERK) determined. Co-cultures of endometrial epithelial cells and blastocyst mimics (trophectoderm spheroids) simi-larly treated with lean or obese uterine levels of AGEs to de-termine their impact on embryo implantation.Results: AGEs were significantly elevated (P=0.004) within the obese (6503.59 µmol/mol lysine) versus lean (2165.88 µmol/mol lysine) uterine cavity (uterine lavage) with in-creased immunostaining for AGEs, RAGE and NFkB within obese endometrial tissues during the proliferative phase of the menstrual cycle. Obese uterine levels of AGEs demonstrated a trend to activate NFκB signaling within endometrial epithelial (ECC-1) cells and inhibited their adhesion and proliferation versus treatment with lean uterine levels of AGEs. Obese uter-ine AGE levels impacted primary human endometrial stromal cell decidualization and activated endoplasmic reticulum stress within these cells. Obese uterine levels of AGEs also inhibited trophectodermal spheroid adhesion to hormonally primed endometrial epithelial cells and trophoblast cell line HTR8/SV-neo invasion.Conclusion: These data corroborate clinical data suggesting the presence of an altered uterine environment in obese women and demonstrate that elevated uterine levels of AGEs within these women may detrimentally impact endometrial function, embryo implantation and placental development.

کلیدواژه ها:

Obesity ، Infertility ، Endometrial Receptivity ، Advanced Glycation End Products ، Inflammation