Follicle-Stimulating Hormone Induces Postmenopausal Dyslipidemia Through Inhibiting Hepatic Cholesterol Metabolism

Context: The elevated low-density-lipoprotein cholesterol (LDL-C) in menopausal women is associated with higher risks of cardiovascular diseases. Objective: The aim of this study is to investigate the influence and mechanism by which high postmenopausal FSH levels affect lipid profiles. Methods: The serum FSH and lipid levels were examined in 400 Chinese postmenopausal women. The FSH receptor (FSHR) expression was identified in liver and HepG2 cells by PCR and Western blotting. The effects of FSH on lipid metabolism were confirmed in an ovariectomized mouse model by using GnRH agonist with or without additional FSH to mimic different FSH status. LDL receptor (LDLR), a necessary factor for clearance of LDL-C through endocytosis, was examined by PCR and Western blotting. Results: The postmenopausal women with higher serum FSH (>= 78.3 IU/L at baseline) had higher serum total cholesterol and LDL-C levels than those women with FSH levels of 40-78.3 IU/L (P < .01). The improvements of total cholesterol and LDL-C levels were more significant in higher FSH women group after treatment with hormone replacement therapy. It was only in the women whose FSH levels were reduced more than 30% after hormone replacement therapy who showed significant improvement of lipid levels. Ovariectomized mice had high serum FSH and lipids levels and reduced hepatic LDLR expression. In HepG2 cells, FSH inhibited the LDLR in a dose-and time-dependent manner, and the FSHR knockdown with specific siRNA reversed the lower LDLR induced by FSH. Conclusions: FSH may interact with its receptors in hepatocytes and reduce LDLR levels, which subsequently attenuates the endocytosis of LDL-C, resulting in an elevated circulating LDL-C level.