Effects of Supraphysiologic Levels of Estradiol on Endometrial Decidualization, sFlt1, and HOXA10 Expression

Supraphysiologic estradiol (E₂) levels associated with controlled ovarian hyperstimulation in high in vitro fertilization (IVF) responders may alter implantation and placentation and increase the risk of preeclampsia. Our hypothesis is that elevated E₂ levels in vitro significantly alter endometrial decidualization, sFlt1, and HOXA10 expression.

Human endometrial stromal cells were treated with a decidualization cocktail of medroxyprogesterone, cyclic adenosine monophosphate, and 3 concentrations of E₂ 10 nM (standard), 100 nM (intermediate), or 1000 nM E₂ (high). Effects on sFlt1, prolactin (PRL), insulin-like growth factor binding protein 1 (IGFBP-1), vascular endothelial growth factor (VEGF), and HOXA10 were studied.

Prolactin, IGFBP-1, and VEGF significantly increased at all 3 E₂ concentrations. While IGFBP-1 and VEGF did not change with increasing E₂, PRL was less with high E₂ (6.0 ng/mL ± 1.4 standard error of the mean) compared to standard (21.4 ± 3.2) and intermediate (19.8 ± 3.8). sFlt1 decrease was similar at all E₂ concentrations. HOXA10 was lower at standard (10%) and intermediate (30%) as expected, but did not change with high E₂.

Supraphysiologic E₂ levels associated with high IVF responders that exceed in vivo levels may impair in vitro endometrial decidualization. Although PRL did increase with high E₂, the levels were, however, attenuated and 3.4-fold lower than standard and intermediate E₂. sFlt1 was decreased under all 3 conditions with no differences between concentrations. Reduced HOXA10 was not observed with high E₂. These findings suggest that elevated E₂ levels in vitro may alter endometrial decidualization and subsequently affect implantation and placentation.