Research Article: ETA-mediated anti-TNF-α therapy ameliorates the phenotype of PCOS model induced by letrozole

Date Published: June 6, 2019

Publisher: Public Library of Science

Author(s): Qin Lang, Xie Yidong, Zhang Xueguang, Wu Sixian, Xu Wenming, Zuo Tao, Yang Yu.


Chronic inflammation is a typical characteristic of polycystic ovary syndrome (PCOS), in which, tumor necrosis factor (TNF)-α plays an important role. We investigated whether anti-TNF-α therapy can alleviate the core phenotypes of PCOS. In pubertal female Wistar rats, release pellets of letrozole (LET) were administered continuously for 90 days to induce PCOS-like phenotypes, followed by treatment with etanercept (ETA), a TNF-α inhibitor. ETA significantly inhibited increases in body weight and androgen, TNF-α, and MCP-1 levels, excessive recruitment of lipid droplets, altered levels of pre-adipose differentiation markers, and abnormal development of follicles. In addition, TNF-α and testosterone (T) levels in the rat sera were significantly positively correlated. Further experiments were performed to investigate the relationship between TNF-α and androgen. Persistent exposure of the RAW 264.7 cell line to low doses of testosterone significantly enhanced TNF-α expression and activated the NF-κB signaling pathway, which were blocked by ETA. Furthermore, treatment with TNF-α promoted the production of testosterone in KGN granulosa cells by reducing CYP19A1 expression, whereas ETA treatment blocked this process. In conclusion, anti-TNF-α therapy with ETA may be an efficient method to alleviate PCOS, whose underlying mechanism may be associated with its ability to reduce excessive androgen levels.

Partial Text

Polycystic ovary syndrome (PCOS) is a common endocrine disease that affects 6–21% women of reproductive age, approximately 75% of whom experience infertility due to anovulation [1,2]. Its pathological characteristics present diversity and heterogeneity, and include menstrual sparse or amenorrhea, chronic ovulation problem, infertility, increased hair growth, and acne, along with complications such as obesity, hyperandrogenism, hyperinsulinism, and chronic inflammation [3,4]. Although androgen plays an important role in the growth and development of follicles [5,6], excess androgen leads to a polycystic morphology of the ovary [7,8]. Furthermore, in previous epidemiological analyses, androgen levels were found to be associated with levels of other PCOS-related biomarkers, which reflected the characteristics of PCOS [9,10]. Hyperandrogenism has been regarded as a key causative factor of PCOS, and is widely accepted as one of the three core features of “Rotterdam Consensus Criteria,” which was the first international diagnostic standard of PCOS established in 2003 [11].

Although chronic inflammation plays a key role in the pathogenesis of polycystic ovary syndrome (PCOS), few investigations on the underlying mechanisms, or on the detailed roles of inflammatory factors in PCOS progression, have been made. TNF-α, a key Th-1 related inflammatory factor, has attracted a lot of attention in a variety of diseases, and numerous studies have confirmed its roles in physiological activities [30–32], which prompted us to investigate the use of TNF-α as a therapeutic agent against the pathogenesis of PCOS.