Obesity associated advanced glycation end products within the human uterine cavity adversely impact endometrial...

Do obese levels of advanced glycation end products (AGEs) within the uterine cavity detrimentally alter tissue function in embryo implantation and placental development?

Obese levels of AGEs activate inflammatory signaling (p65 NFκB) within endometrial epithelial cells and alter their function, cause endoplasmic reticulum (ER) stress in endometrial stromal cells and impair decidualization, compromise implantation of blastocyst mimics and inhibit trophoblast invasion.

Obese women experience a higher incidence of infertility, recurrent miscarriage and pregnancy complications compared with lean women. Oocyte donation cycles suggest a detrimental uterine environment plays a role in these outcomes.

Uterine lavage and tissues from lean (BMI 19.5-24.9, n = 17) and obese (BMI > 30, n = 16) women examined. Cell culture experiments utilizing human endometrial epithelial, trophectoderm and trophoblast cell lines and primary human stromal cells used to examine the functional impact of obese levels of AGEs.

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 endometrial tissues obtained from lean and obese women determined by immunohistochemistry. Endometrial epithelial cells (ECC-1), primary human stromal cells and trophoblast cells (HTR8-SVneo) treated with lean (2000 nmol/mol lysine) or obese (8000 nmol/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 release), ER stress (western immunoblot for p-PERK) determined. Co-cultures of endometrial epithelial cells and blastocyst mimics (trophectoderm spheroids) similarly treated with lean or obese uterine levels of AGEs to determine their impact on embryo implantation.

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 increased immunostaining for AGEs, RAGE and NFkB within obese endometrial tissues during the proliferative phase of the menstrual cycle. Obese uterine levels of AGEs inhibited adhesion and proliferation of endometrial epithelial (ECC-1) cells compared to treatment with lean uterine levels of AGEs. Obese uterine AGE levels impacted primary human endometrial stromal cell decidualization and activated ER 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.

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Mechanistic studies are performed in vitro and may not completely recapitulate cell function in vivo.

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. Uterine AGE assessment in infertility work up may prove useful in determining underlying causes of infertility. AGEs can be targeted pharmacologically and such treatments may prove effective in improving reproductive complications experience by obese women.

Supported by NHMRC Fellowship (#1002028 to L.A.S.), and the Victorian Government's Operational Infrastructure Support Program. MTC is supported by a JDRF Australia Clinical Research Network Career Development Award. The authors have declared that no conflict of interest exists.