Int J Biol Sci 2021; 17(9):2338-2347. doi:10.7150/ijbs.60332

Research Paper

High ovarian GDF-8 levels contribute to elevated estradiol production in ovarian hyperstimulation syndrome by stimulating aromatase expression

Lanlan Fang1#, Yang Yan1#, Sijia Wang1,2#, Yanjie Guo1, Yiran Li1,2, Qiongqiong Jia1, Xiaoyu Han1, Boqun Liu1, Jung-Chien Cheng1✉, Ying-Pu Sun1✉

1. Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
2. Department of Obstetrics & Gynaecology, The Chinese University of Hong Kong, New Territories, Hong Kong, China.
#These authors contributed equally to this work.

This is an open access article distributed under the terms of the Creative Commons Attribution License ( See for full terms and conditions.
Fang L, Yan Y, Wang S, Guo Y, Li Y, Jia Q, Han X, Liu B, Cheng JC, Sun YP. High ovarian GDF-8 levels contribute to elevated estradiol production in ovarian hyperstimulation syndrome by stimulating aromatase expression. Int J Biol Sci 2021; 17(9):2338-2347. doi:10.7150/ijbs.60332. Available from

File import instruction


Rationale: Growth differentiation factor-8 (GDF-8), also known as myostatin, belongs to the transforming growth factor-beta (TGF-β) superfamily. GDF-8 is expressed in the ovary and regulates various ovarian functions. Ovarian hyperstimulation syndrome (OHSS) is one of the most serious disorders during in vitro fertilization treatment. Aromatase, encoded by the CYP19A1 gene, is the enzyme that catalyzes the final step in estradiol (E2) biosynthesis. It has been demonstrated that high serum E2 levels are associated with the development of OHSS. However, the effects of GDF-8 on aromatase expression and its roles in the pathogenesis of OHSS remain unclear.

Methods: The effect of GDF-8 on aromatase expression and the underlying mechanisms were explored by a series of in vitro experiments in primary human granulosa-lutein (hGL) and KGN cells. Rat OHSS model and human follicular fluid samples were used to examine the roles of the GDF-8 system in the pathogenesis of OHSS.

Results: We demonstrate that GDF-8 stimulates aromatase expression and E2 production in hGL and KGN cells. In addition, TGF-β type I receptor ALK5-mediated SMAD2/3 signaling is required for GDF-8-induced aromatase expression and E2 production. Using a rat OHSS model, we show that the aromatase and GDF-8 levels are upregulated in the ovaries of OHSS rats. Blocking the function of ALK5 by the administration of its inhibitor, SB431542, alleviates OHSS symptoms and the upregulation of aromatase. Clinical results reveal that the protein levels of GDF-8 are upregulated in the follicular fluid of OHSS patients. Moreover, the expression of GDF-8 is increased in hGL cells of OHSS patients.

Conclusions: This study helps to elucidate the mechanisms mediating the expression of aromatase in human granulosa cells, which may lead to the development of alternative therapeutic approaches for OHSS.

Keywords: GDF-8, Aromatase, Estradiol, OHSS, Granulosa cells