Too much of a good thing? Experimental evidence suggests prolonged exposure to hCG is detrimental to endometrial receptivity

Does prolonged exposure of the endometrium to hCG, as experienced after ovulation induction in an assisted reproduction technology (ART) cycle, affect functional measures of endometrial receptivity? Prolonged endometrial hCG exposure detrimentally affects the manner in which the endometrium can respond to hCG secreted by the blastocyst. Prolonged hCG exposure down-regulates endometrial LHCG receptor (LHCGR) expression in a baboon model. HCG exposure during the proliferative phase of oocyte-donation cycles and frozen embryo transfer cycles is associated with a lower pregnancy rate. LHCGR was examined in endometria of women undergoing ART cycles (GnRH agonist/antagonist) and across the menstrual cycle in normally cycling fertile women. To determine whether prolonged hCG exposure affects the subsequent endometrial response to hCG, endometrial epithelial cells (HES cell line and primary cultures of human endometrial epithelial cells) were exposed to a low dose of hCG (0.55 IU) for up to 5 days, to mimic the chronic exposure during an ART cycle, and subsequently exposed to an acute blastocyst mimic dose of hCG (20 IU). Endometrial tissues were collected at hCG 2 (n 37) from women undergoing ART between August 2006 and August 2008, and across the cycle from women with known fertility (n 40). LHCGR localization and staining intensity were determined by immunohistochemistry and semi-quantitative scoring. HES cells were treated with hCG as above and analyzed for LHCGR localization (immunocytochemistry), phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 (western immunoblotting), adhesion to trophoblast-like matrices (adhesion assays) and tight junction integrity (trans-epithelial resistance assessment). Endometrial epithelial LHCGR staining was significantly lower in women stimulated with a GnRH agonist protocol who did not become pregnant in that cycle versus the natural menstrual cycle (P 0.05). Chronic low-dose hCG exposure in vitro mediated a down-regulation and internalization of the LHCGR in endometrial epithelial cells. Prolonged exposure to chronic low-dose hCG (35 days) abrogated ERK 1/2 phosphorylation, adhesion to extracellular matrices and changes in tight junction integrity in response to a subsequent acute high dose (20 IU) of hCG. Studies using cell lines and primary cultures of cells in vitro are not fully representative of the complex endometrial milieu in vivo. These data reinforce the clinical observations that precocious or prolonged hCG exposure may detrimentally affect endometrial receptivity and provide a mechanistic basis for these clinical findings. The data appear to support the notion that in women for whom ART has not succeeded, a different, minimally stimulated approach without exposure to exogenous hCG may improve outcomes. The authors have no competing interests. This work was supported by a Lalor postdoctoral fellowship (J.E.), NHMRC of Australia, Fellowship No. 1002028 (L.A.S.), Program grant (No. 494802) and by the Victorian Governments Operational Infrastructure Funding. N/A.