title: Abnormally enhanced cystic fibrosis transmembrane conductance regulator-mediated apoptosis in endometrial cells contributes to impaired embryo implantation in controlled ovarian hyperstimulation.
abstract: 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.
  
  
  METHODS
  Prospective experimental study.
  
  
  METHODS
  University-based laboratory.
  
  
  METHODS
  Imprinting control region female mice, 8-10 weeks old with regular estrous cycles.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Jian Zhi
authors.initials: JZ
authors.lastname: Yang
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Jiang
authors.forename: JianDa
authors.initials: J
authors.lastname: Dong
authors.forename: JingHui
authors.initials: J
authors.lastname: Guo
authors.forename: Hui
authors.initials: H
authors.lastname: Chen
authors.forename: Lai Ling
authors.initials: LL
authors.lastname: Tsang
authors.forename: Yiu Wa
authors.initials: YW
authors.lastname: Chung
authors.forename: XiaoHu
authors.initials: X
authors.lastname: Zhang
authors.forename: Hsiao Chang
authors.initials: HC
authors.lastname: Chan
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D010064:Embryo Implantation / Q000187:drug effects / Q000502:physiology; D004717:Endometrium / Q000378:metabolism* / Q000473:pathology / Q000502:physiology; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D005300:Fertility Agents, Female / Q000494:pharmacology; D008297:Male; D049990:Membrane Transport Modulators / Q000494:pharmacology; D051379:Mice; D010062:Ovulation Induction / Q000379:methods; D011247:Pregnancy; D015854:Up-Regulation / Q000502:physiology
chemical_list: D005300:Fertility Agents, Female; D049990:Membrane Transport Modulators; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D004958:Estradiol