Hyperandrogenism drives ovarian inflammation and pyroptosis: A possible pathogenesis of PCOS follicular dysplasia

• Published in: International immunopharmacology 2023-12, Vol.125 (Pt A), p.111141-111141, Article 111141
• Main Authors: Xiang, Yu, Wang, Hua, Ding, Huimin, Xu, Tianyue, Liu, Xiu, Huang, Zichao, Wu, Honghui, Ge, Hongshan
• Format: Article
• Language: English
• Subjects: Animals; Dehydroepiandrosterone; Endoplasmic reticulum stress; Female; Humans; Hyperandrogenism; Inflammation; Inflammatory; Mice; Polycystic ovary syndrome; Polycystic Ovary Syndrome - metabolism; Polycystic Ovary Syndrome - pathology; Pyroptosis; Testosterone; Tumor Microenvironment
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2023.111141

[Display omitted] •Hyperandrogenic-induced pyrolysis in PCOS is mediated by inflammatory factors activation.•Exposure to hyperandrogenic induces ER stress activation in granulosa cells.•The hyperandrogenic treatment induces ER stress activation and promotes inflammation.•Activation of inflammation promotes granulosa cell pyrolysis. Hyperandrogenemia and persistent chronic inflammation, two main striking features of polycystic ovary syndrome (PCOS), have been proven involved in follicular dysgenesis in PCOS. However, the association between hyperandrogenism and inflammation activation in PCOS is not fully understood. Excess testosterone（T） induces inflammation and pyroptosis activation in a mouse model of PCOS, leading to ovarian dysfunction and fibrosis. Excessive endoplasmic reticulum (ER) stress is present in ovarian granulosa cells (GCs), testosterone-induced PCOS mouse and cellular models. This study found higher levels of interleukin (IL)-1β, IL-8, IL-17, and IL-18 in the follicular fluid of PCOS patients with hyperandrogenemia undergoing IVF treatment. In addition, pyroptosis in GCs was demonstrated, which was significantly elevated in PCOS patients. To clarify the association of hyperandrogenism, inflammation, and pyroptosis activation in PCOS, dehydroepiandrosterone(DHEA)-treated mouse PCOS model and T-treated KGN cell line were explored for PCOS mechanism. Markers of inflammatory activation and pyroptosis were significantly increased after DHEA treatment in mice and T treatment in KGN cells. In addition, ER stress sensor proteins were increased simultaneously. However, suppression of inflammation by genipin(GP) led to decreased pyroptosis in KGN cells but no variation in ER stress sensor proteins. In contrast, when treated with tauroursodeoxycholic acid(TUDCA) to attenuate ER stress, the markers of inflammatory factors were significantly reduced, accompanied by a reduction in pyroptosis. Our results suggest that persistent hyperandrogenemia of PCOS promotes local inflammatory activation of the ovary, and the imbalanced inflammatory microenvironment leads to pyroptosis of GCs, which is mediated by ER stress activation.