Xian-Hua Lin1, Miao-E Liu1, Hai-Yan Xu1, Xue-Jun Chen2, Hui Wang3, Shen Tian1, Jian-Zhong Sheng4, He-Feng Huang5. 1. Key Laboratory of Reproductive Genetics, Ministry of Education, Zhejiang University, Hangzhou, People's Republic of China; Department of Reproductive Endocrinology, Women's Hospital, Zhejiang University, Hangzhou, People's Republic of China. 2. Medical Reproductive Center, Enze Maternity Hospital, Taizhou, Zhejiang, People's Republic of China. 3. Medical Reproductive Center, Hangzhou First People's Hospital, Hangzhou, People's Republic of China. 4. Key Laboratory of Reproductive Genetics, Ministry of Education, Zhejiang University, Hangzhou, People's Republic of China; Department of Pathology and Pathophysiology, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China. 5. Key Laboratory of Reproductive Genetics, Ministry of Education, Zhejiang University, Hangzhou, People's Republic of China; International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People's Republic of China; Department of Reproductive Endocrinology, Women's Hospital, Zhejiang University, Hangzhou, People's Republic of China. Electronic address: huanghefg@hotmail.com.
Abstract
OBJECTIVE: To examine epithelial Na(+) channel (ENaC) expression in endometrium of overweight/obese women with polycystic ovary syndrome (PCOS) during the window of implantation, and to explore the mechanism linking leptin-mediated reduction of γ-ENaC to low endometrial receptivity. DESIGN: Controlled, prospective, clinical, experimental study. SETTING: University-based infertility center. PATIENT(S): Blood and endometrium samples were collected from 12 control women and 12 overweight/obese PCOS patients. Pregnancy outcomes were obtained from 245 women with male-factor infertility (533 cycles) and 57 infertile women with PCOS (120 cycles) who underwent intrauterine insemination. INTERVENTION(S): Human endometrial biopsies. MAIN OUTCOME MEASURE(S): Expression of ENaC mRNA and protein in endometrium. RESULT(S): The expression of γ-ENaC decreased in the secretory phase endometrium of PCOS patients who showed increased serum leptin levels. In cultured endometrial cells (Ishikawa cells), leptin dose-dependently down-regulated the expression of γ-ENaC and reduced the JAr spheroid attachment rate, which could be blocked by knockdown of STAT3, a signal in the pathway of leptin receptor activation. The overweight/obese PCOS patients with increased serum leptin levels showed a significantly increased biochemical pregnancy rate, suggesting that high leptin might attenuate endometrial receptivity and increase very early pregnancy loss. CONCLUSION(S): High serum leptin may reduce endometrial receptivity by activating the STAT3 signal pathway and down-regulating γ-ENaC expression in the endometrium. These results provide valuable new insights into the molecular mechanisms linking abnormal ENaC gene expression to early pregnancy loss in overweight/obese PCOS patients.
OBJECTIVE: To examine epithelial Na(+) channel (ENaC) expression in endometrium of overweight/obesewomen with polycystic ovary syndrome (PCOS) during the window of implantation, and to explore the mechanism linking leptin-mediated reduction of γ-ENaC to low endometrial receptivity. DESIGN: Controlled, prospective, clinical, experimental study. SETTING: University-based infertility center. PATIENT(S): Blood and endometrium samples were collected from 12 control women and 12 overweight/obese PCOSpatients. Pregnancy outcomes were obtained from 245 women with male-factor infertility (533 cycles) and 57 infertile women with PCOS (120 cycles) who underwent intrauterine insemination. INTERVENTION(S): Human endometrial biopsies. MAIN OUTCOME MEASURE(S): Expression of ENaC mRNA and protein in endometrium. RESULT(S): The expression of γ-ENaC decreased in the secretory phase endometrium of PCOSpatients who showed increased serum leptin levels. In cultured endometrial cells (Ishikawa cells), leptin dose-dependently down-regulated the expression of γ-ENaC and reduced the JAr spheroid attachment rate, which could be blocked by knockdown of STAT3, a signal in the pathway of leptin receptor activation. The overweight/obese PCOSpatients with increased serum leptin levels showed a significantly increased biochemical pregnancy rate, suggesting that high leptin might attenuate endometrial receptivity and increase very early pregnancy loss. CONCLUSION(S): High serum leptin may reduce endometrial receptivity by activating the STAT3 signal pathway and down-regulating γ-ENaC expression in the endometrium. These results provide valuable new insights into the molecular mechanisms linking abnormal ENaC gene expression to early pregnancy loss in overweight/obese PCOSpatients.
Authors: Torie C Plowden; Shvetha M Zarek; Saima Rafique; Lindsey A Sjaarda; Enrique F Schisterman; Robert M Silver; Edwina H Yeung; Rose Radin; Stefanie N Hinkle; Noya Galai; Sunni L Mumford Journal: Obes Sci Pract Date: 2020-01-07