Leptin downregulates γENaC expression A novel mechanism involved in low endometrial receptivity

Polycystic ovary syndrome patients who are overweight or obese showed increased serum leptin levels. High leptin levels may reduce g-epithelial Naþ channel expression in human endometrium via activating the STAT3 pathway, resulting in attenuated endometrial receptivity.

Xian-Hua Lin, M.D., Miao-E. Liu, M.B., Hai-Yan Xu, M.B., Xue-Jun Chen, M.D., Hui Wang, M.B., Shen Tian, M.D., Jian-Zhong Sheng, Ph.D., He-Feng Huang, M.D.

Volume 103, Issue 1, Pages 228-235


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.

Controlled, prospective, clinical, experimental study.

University-based infertility center.

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.

Human endometrial biopsies.

Main Outcome Measure(s):
Expression of ENaC mRNA and protein in endometrium.

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.

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.

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