Dissecting Androgen excess and metabolic dysfunction – an Integrated SYstems approach to PolyCystic Ovary Syndrome (DAISY-PCOS) (360G-Wellcome-209492_Z_17_Z)

Polycystic ovary syndrome (PCOS) affects 5-10% of all women; androgen excess is one of its major diagnostic features. While often perceived as a reproductive disorder, PCOS is now emerging as a lifelong, complex metabolic disorder, with increased risk of type 2 diabetes, hypertension, cardiovascular disease, and, as recently documented, non-alcoholic fatty liver disease (NAFLD). However, there has been no recent breakthrough regarding risk stratification or therapeutic intervention in PCOS. Our work has provided evidence for a key role of androgens in the development of PCOS-related metabolic complications. We will combine cutting edge in vivo physiology techniques, state-of-the-art metabolomics and machine learning-based computational approaches to address our overarching hypothesis that androgens are major drivers of metabolic risk in PCOS. We will use an integrated set of in vitro, ex vivo and in vivo experimental medicine studies to test this hypothesis and answer our specific questions: Does the control of androgen excess improve metabolic function? What is the role of different androgen pathways in conveying metabolic risk? Can we integrate phenome and metabolome data by machine learning to predict metabolic risk in PCOS? Our overall aim is the identification of novel personalized approaches and therapeutic targets for patients with PCOS.