Follicle-stimulating hormone promotes age-related endometrial atrophy through cross-talk with transforming growth factor beta signal transduction pathway.

Dan Zhang,Jingyi Li,Xinmei Liu,Chengliang Zhou,Bo Zhu,Yifeng Liu,Yeqing Qian,Hefeng Huang,Luting Chen,Runjv Zhang,Gufeng Xu,Fan Qu,Shuai Shi,Xiaoqun Ye,Weijun Yang,Jianzhong Sheng

doi:10.1111/acel.12278

Abstract

It is widely believed that endometrial atrophy in postmenopausal women is due to an age-related reduction in estrogen level. But the role of high circulating follicle-stimulating hormone (FSH) in postmenopausal syndrome is not clear. Here, we explored the role of high circulating FSH in physiological endometrial atrophy. We found that FSH exacerbated post-OVX endometrial atrophy in mice, and this effect was ameliorated by lowering FSH with Gonadotrophin-releasing hormone agonist (GnRHa). In vitro, FSH inhibited endometrial proliferation and promoted the apoptosis of primary cultured endometrial cells in a dose-dependent manner. In addition, upregulation of caspase3, caspase8, caspase9, autophagy-related proteins (ATG3, ATG5, ATG7, ATG12 and LC3) and downregulation of c-Jun were also observed in endometrial adenocytes. Furthermore, smad2 and smad3 showed a time-dependent activation in endometrial cells which can be partly inhibited by blocking the transforming growth factor beta receptor II (TβRII). In conclusion, FSH regulated endometrial atrophy by affecting the proliferation, autophagy and apoptosis of endometrial cells partly through activation of the transforming growth factor beta (TGFβ) pathway.

Highlights

Researchers indicated the uterus of follicle-stimulating hormone (FSH) receptors (FSHR) knocked out mice weighted twofolds more than that of wild-type mice (Danilovich et al, 2002; Abel et al, 2003)
The OVX-induced decreased uterine size and weight was suppressed by administration of gonadotropin-releasing hormone agonist (GnRHa) (0.5 lg dayÀ1) (Fig. 1A,B), which inhibited the release of FSH and LH from the pituitary (Hsueh & Erickson, 1979)
Administration of recombinant FSH (0.15 IU dayÀ1) in Gonadotrophin-releasing hormone agonist (GnRHa) (0.5 lg dayÀ1) pretreated OVX animal model led to decreases in uterine size and weight (Fig 1A,B), which may be attributed to the elevation of FSH level

Summary

Introduction

We hypothesized that high circulating FSH plays a key role in endometrial atrophy in postmenopausal women. We built a high FSH mice model by performing ovariectomy (OVX) (Fig. 1A). The OVX-induced decreased uterine size and weight was suppressed by administration of gonadotropin-releasing hormone agonist (GnRHa) (0.5 lg dayÀ1) (Fig. 1A,B), which inhibited the release of FSH and LH from the pituitary (Hsueh & Erickson, 1979).

Results

Conclusion