Abnormally enhanced cystic fibrosis transmembrane conductance regulator-mediated apoptosis in endometrial cells contributes to impaired embryo implantation in controlled ovarian hyperstimulation

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• 作者：Jian Zhi Yang ; Xiaohua Jiang ; JianDa Dong ; JingHui Guo ; Hui Chen ; Lai Ling Tsang ; Yiu Wa Chung ; XiaoHu Zhang ; Hsiao Chang Chan
• 关键词：Controlled ovarian hyperstimulation (COH) ; cystic fibrosis transmembrane conductance regulator (CFTR) ; apoptosis ; implantation
• 刊名：Fertility and Sterility
• 出版年：2011
• 出版时间：May 2011
• 年：2011
• 卷：95
• 期：6
• 页码：2100-2106.e2
• 全文大小：768 K

文摘

Objective

To investigate the effects and underlying mechanism of controlled ovarian hyperstimulation (COH)-induced supraphysiologic concentration of E₂ on the endometrium and outcome of embryo implantation.

Design

Prospective experimental study.

Setting

University-based laboratory.

Animal(s)

Imprinting control region female mice, 8–10 weeks old with regular estrous cycles.

Intervention(s)

Intraperitoneal injection of 10 IU of pregnant mare serum gonadotropin (PMSG) at noon followed by an additional injection of 10 IU hCG 48 hours later.

Main Outcome Measure(s)

Uteri were collected from either superovulated or control mice (natural cycle) the morning after hCG administration on day 4 to evaluate and count blastocysts. A mouse blastocyst-endometrium coculture model was used to evaluate blastocyst adhesion to control or COH-treated endometrium. The cystic fibrosis transmembrane conductance regulator (CFTR) expression was determined by immunofluorescence, Western blot, and apoptosis determined by terminal deoxynucleotidyl transferase dUTP nick end labeling assay in both natural cycle and COH cycle endometrium. Primary culture of mouse endometrial epithelial cells was established to further determine the effects of various concentrations of E₂ on apoptosis.

Result(s)

We demonstrated that COH had adverse effects on blastocyst adhesion. In addition, COH endometrium exhibited an aberrant up-regulation of CFTR expression and a higher apoptotic rate compared with normal endometrium during the implantation period. Administration of exogenous supraphysiologic concentration of E₂ to primary mouse endometrial epithelial cells mimicked the COH-induced up-regulation of CFTR and apoptosis observed in vivo. Furthermore, inhibition of CFTR activity abrogated E₂-induced apoptosis.

Conclusion(s)

The COH-induced supraphysiologic concentration of E₂ aberrantly up-regulates CFTR, which leads to increased apoptosis in endometrial epithelial cells, resulting in impaired embryo implantation.