Menopause is associated with dyslipidemia and an increased risk of cardio-cerebrovascular disease. The classic view assumes that the underlying mechanism of dyslipidemia is attributed to an insufficiency of estrogen. In addition to a decrease in estrogen, circulating follicle-stimulating hormone (FSH) levels become elevated at menopause. In this study, we find that blocking FSH reduces serum cholesterol via inhibiting hepatic cholesterol biosynthesis. First, epidemiological results show that the serum FSH levels are positively correlated with the serum total cholesterol levels, even after adjustment by considering the effects of serum estrogen. In addition, the prevalence of hypercholesterolemia is significantly higher in peri-menopausal women than that in pre-menopausal women. Furthermore, we generated a mouse model of FSH elevation by intraperitoneally injecting exogenous FSH into ovariectomized (OVX) mice, in which a normal level of estrogen (E2) was maintained by exogenous supplementation. Consistently, the results indicate that FSH, independent of estrogen, increases the serum cholesterol level in this mouse model. Moreover, blocking FSH signaling by anti-FSHβ antibody or ablating the FSH receptor (FSHR) gene could effectively prevent hypercholesterolemia induced by FSH injection or high-cholesterol diet feeding. Mechanistically, FSH, via binding to hepatic FSHRs, activates the Gi2α/β-arrestin-2/Akt pathway and subsequently inhibits the binding of FoxO1 with the SREBP-2 promoter, thus preventing FoxO1 from repressing SREBP-2 gene transcription. This effect, in turn, results in the upregulation of SREBP-2, which drives HMGCR nascent transcription and de novo cholesterol biosynthesis, leading to the increase of cholesterol accumulation. This study uncovers that blocking FSH signaling might be a new strategy for treating hypercholesterolemia during menopause, particularly for women in peri-menopause characterized by FSH elevation only.

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We thank Prof. Yingli Lu (Shanghai JiaoTong University School of Medicine, China) for the assistance in the measurement of de novo cholesterol biosynthesis. Great thanks to Prof. Jinpeng Sun and Prof. Xiao Yu (Shandong University School of Medicine, China) for their technical assistance referring to G proteins and β-arrestins in this project. We thank Shengfeng Wang (Department of Epidemiology and Biostatistics, Peking University Health Science Center, China) for providing professional instructions in statistical analyses. We are grateful to Prof. Yongsheng Chang (Chinese Academy of Medical Sciences and Peking Union Medical College) for his suggestions in writing the manuscript. And great thanks to Prof. Shucun Qin and his team (Taishan Medical University, China). This work was supported by grants from the National Natural Science Foundation (81870607, 81670796, 81430020, 81230018, 81300644 and 31640020) and National Key R&D Program (SQ2017YFSF090203) of China.

Author information


  1. Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong University, 250021, Jinan, Shandong, China

    • Yanjing Guo
    • , Meng Zhao
    • , Shizhan Ma
    • , Lu Liu
    • , Yujie Li
    • , Chunxiao Yu
    • , Xiaoyi Qi
    • , Qian Wang
    • , Haiqing Zhang
    • , Qingbo Guan
    • , Lifang Zhao
    • , Shimeng Xuan
    • , Huili Yan
    • , Qihang Li
    • , Yongfeng Song
    •  & Jiajun Zhao
  2. Shandong Key Laboratory of Endocrinology and Lipid Metabolism, 250021, Jinan, Shandong, China

    • Yanjing Guo
    • , Meng Zhao
    • , Shizhan Ma
    • , Zhao He
    • , Lu Liu
    • , Yujie Li
    • , Chunxiao Yu
    • , Xiaoyi Qi
    • , Qian Wang
    • , Haiqing Zhang
    • , Qingbo Guan
    • , Lifang Zhao
    • , Shimeng Xuan
    • , Huili Yan
    • , Qihang Li
    • , Yongfeng Song
    •  & Jiajun Zhao
  3. Institute of Endocrinology and metabolism, Shandong Academy of Clinical Medicine, 250021, Jinan, Shandong, China

    • Yanjing Guo
    • , Meng Zhao
    • , Shizhan Ma
    • , Zhao He
    • , Lu Liu
    • , Yujie Li
    • , Chunxiao Yu
    • , Xiaoyi Qi
    • , Qian Wang
    • , Haiqing Zhang
    • , Qingbo Guan
    • , Lifang Zhao
    • , Shimeng Xuan
    • , Huili Yan
    • , Qihang Li
    • , Yongfeng Song
    • , Ling Gao
    •  & Jiajun Zhao
  4. Scientific Center, Shandong Provincial Hospital Affiliated to Shandong University, 250021, Jinan, Shandong, China

    • Tao Bo
    • , Wenbin Chen
    • , Xu Hou
    • , Yanliang Lin
    •  & Ling Gao
  5. Department of Biostatistics, School of Public Health, Shandong University, 250012, Jinan, Shandong, China

    • Zhongshang Yuan
  6. Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong University, 250021, Jinan, Shandong, China

    • Jun Liu
    •  & Zhenhai Zhang
  7. Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong University, 250021, Jinan, Shandong, China

    • Qiang Zhu
  8. Department of Pathology, Shandong Provincial Hospital Affiliated to Shandong University, 250021, Jinan, Shandong, China

    • Qiangxiu Wang
    •  & Xiaoyan Lin
  9. Department of Gynecology, Shandong Provincial Hospital Affiliated to Shandong University, 250021, Jinan, Shandong, China

    • Zhongli Yang
    •  & Min Cui
  10. Department of Physiology and Neurobiology, and Institute for Systems Genomics, University of Connecticut, Storrs, CT, 06269, USA

    • Li Wang
    •  & Yongfeng Song


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Y.J.G. and Y.F.S. performed most of the experiments, analyzed and interpreted data and wrote the manuscript. T.B. helped to construct the Fshr-/- mouse model and design some primers. H.Q.Z., M.Z., Z.S.Y., and L.L. conducted and analyzed the epidemiological data. M.S.Z. and W.B.C. performed the bioinformatic analysis. J.L. and Z.H.Z. provided the human liver samples. Z.L.Y. and M.C. provided the human ovarian samples. Q.X.W. and X.Y.L. helped to analyze the pathology results. M.X.S. and Q.H.L. helped to maintain the animal models. H.L.Y., and L.F.Z., performed some of the in vitro experiments. Q.W., C.X.Y., X.Y.Q., Y.L.L., and Y.J.L. helped with some of the in vivo experiments. Z.H., X.H., and L.W. helped to write the manuscript. L.G. and J.J.Z supervised the project and wrote the manuscript.

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The authors declare no competing interests.

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Correspondence to Yongfeng Song or Ling Gao or Jiajun Zhao.

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