Integrative Network View of PCOS: Organ Crosstalk Driven by the Hyperandrogenemia–Insulin Resistance–Inflammation Triad

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Zhaoyue Luo,1,* Wei Ji,2,* Jiajia An,3,* Miaolong He,4,* Huijun Wang,1 Jingxia Li,1 Yixuan Ma,1 Dawei Zhu,5 Kexin Lu,4 Lei Han11Department of Reproductive Medicine, Shandong Medical and Pharmaceutical University Hospital, Shandong Medical and Pharmaceutical University, Binzhou, Shandong, People’s Republic of China; 2Department of Gynecology and Obstetrics, The First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan, People’s Republic of China; 3Department of Clinical Laboratory, Shandong Medical and Pharmaceutical University Hospital, Shandong Medical and Pharmaceutical University, Binzhou, Shandong, People’s Republic of China; 4Department of Obstetrics and Gynecology, Shandong Medical and Pharmaceutical University Hospital, Shandong Medical and Pharmaceutical University, Binzhou, Shandong, People’s Republic of China; 5Heart Center, Women and Children’s Hospital, Qingdao University, Qingdao, People’s Republic of China*These authors contributed equally to this workCorrespondence: Kexin Lu, Department of Obstetrics and Gynecology, Shandong Medical and Pharmaceutical University Hospital, Shandong Medical and Pharmaceutical University, Binzhou, Shandong, People’s Republic of China, Email 907676191@qq.com Lei Han, Department of Reproductive Medicine, Shandong Medical and Pharmaceutical University Hospital, Shandong Medical and Pharmaceutical University, Binzhou, Shandong, People’s Republic of China, Email hanleimm@126.comAbstract: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder affecting women of reproductive age, traditionally attributed to neuroendocrine dysregulation of the hypothalamic-pituitary-ovarian (HPO) axis. However, growing evidence suggests that PCOS is a systemic network disease driven by multi-organ crosstalk. Beyond the HPO axis, adipose tissue, gut microbiota, pancreas, skeletal muscle, thyroid, adrenal glands, and immune organs interact with the ovary through secretion of hormones, metabolites, and inflammatory mediators, forming a complex bidirectional regulatory network. Herein, we propose that the "triad” of hyperandrogenemia, insulin resistance, and chronic inflammation serves as the core pathological axis permeating this network. This multi-organ positive-feedback loop explains the marked phenotypic heterogeneity of PCOS and its propensity to evolve into metabolic syndrome. Accordingly, precision management of PCOS should be redirected toward individualized stratification based on organ-network features. A deeper understanding of these inter-organ crosstalk mechanisms will provide a rationale for developing multi-targeted therapies aimed at the "hyperandrogenemia–IR–inflammation” triad, ultimately improving reproductive and metabolic health throughout women’s lives.Keywords: polycystic ovary syndrome, crosstalk, metabolism, ovary, multiple organs

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