Obesity is a global epidemic; obese women experience a higher degree of infertility versus lean women. Even when ‘lean gametes’ are used (utilizing sperm and oocytes from lean parents in donor oocyte/surrogate cycles), obese women exhibit decreased fertility and fecundity. These clinical data implicate an altered uterine environment in detrimental fertility outcomes for obese women.
We demonstrate elevated levels of highly inflammatory advanced glycation end products (AGEs, determined by AGE ELISA) within the uterine microenvironment (uterine lavage) and uterine tissues of obese women; with upregulation of the AGE receptor, RAGE, within obese endometrial tissues (AGE/RAGE in tissues examined by immunohistochemistry). Inflammatory chemokines, cytokines (determined by multiplex analysis) and signalling factors (NFκB, determined by immunohistochemistry) are similarly elevated within the obese uterine milieu, with ‘obese’ levels of AGEs mediating nuclear NFκB activation within endometrial epithelial cells (determined by Western immunoblot). Functionally, ‘obese’ levels of AGEs (8umol) inhibit endometrial epithelial cell adhesion and proliferation (determined by xCelligence real time cell function analysis); alter endometrial stromal cell decidualization (determined by prolactin release) via induction of endoplasmic-reticulum stress (determined by western immunoblot); inhibit ‘embryo’ (trophectodermal spheroid) adhesion to endometrial luminal epithelial cells (determined by in vitro 'embryo' adhesion assay) and inhibit extravillous trophoblast invasion (determined by xCelligence real time cell function analysis) .
Together these data suggest AGEs detrimentally impact endometrial receptivity, embryo implantation and placental development in obese women reflecting the reduced fertility, increased early pregnancy loss and incidence of pregnancy complications associated with deficient placentation (e.g. preeclampsia) commonly observed in these women. AGEs may therefore be targeted in obese women to improve reproductive outcomes.