Apoptotic Effects of High Estradiol Concentrations on Endometrial Glandular Cells

作者：Chen Shee Uan; Chou Chia Hung; Chen Mei Jou; Chen Tzu Hsin; Yang Yu Shih; Yang John Hsiahn^*

来源：Journal of Clinical Endocrinology & Metabolism, 2014, 99(6): E971-E980.

DOI：10.1210/jc.2013-3794

Context: High serum estradiol (E-2) concentrations result in adverse reproductive outcome in in vitro fertilization cycles, and the detrimental effects are probably due to impaired endometrial receptivity.
Objective: Endometrial glandular cells (EGCs) are the cells that embryos first interact with during implantation. Our objective is to examine the in vitro EGC alterations after high E-2 treatment.
Design: This was a prospective study.
Setting: The study was conducted at a tertiary university hospital.
Patients: Six women in the follicular phase participated in the study.
Interventions: EGCs were purified from human endometrium and cultured with different concentrations (0, 10(-9), 10(-8), 10(-7), 10(-5), 10(-4) M) of E-2.
Main Outcome Measure(s): EGC apoptosis and its underlying mechanism were measured.
Results: In vitro BeWo spheroid-EGC implantation assay demonstrated that the stimulation with 10(-5) and 10(-4) M E-2 for 2 days decreased embryo implantation potentials. Presence of apoptotic bodies and DNA fragmentation and an increased percentage of sub-G(1) phase were found in EGCs treated with high E-2 concentrations. The high E-2-treated EGCs could be rescued from apoptosis after the addition of estrogen receptor antagonist ICI 182 780. Western blot revealed increased inhibitory-kappa B (I kappa B)-alpha expression and decreased nuclear factor-kappa B (NF-kappa B) expression in high E-2-treated EGCs, and NF-kappa B binding site-driven luciferase activity was decreased as well. When EGCs were pretreated with I kappa B-alpha small interfering RNA, high E-2-induced B cell lymphoma 2 (Bcl-2) down-regulation did not occur and EGCs apoptosis was reduced. Bcl-2 overexpression also rescued high E-2-induced EGCs from apoptosis.
Conclusions: High E-2 concentrations induced EGCs apoptosis through enhancing I kappa B-alpha expression, which in turn suppressed NF-kappa B expression. The decreased nuclear NF-kappa B subsequently inhibited Bcl-2 expression and accordingly enhanced EGC apoptosis.

• 出版日期2014-6