{"paper_id":"3519fc38-29a1-4c04-9f3b-7b8c1987658b","body_text":"Abstract\nAndrogen excess drives metabolic and reproductive complications in polycystic ovary syndrome (PCOS), affecting 10-15% of women globally. Aldo-keto reductase 1C3 (AKR1C3) converts inactive precursors from both the classic and the recently identified 11-oxygenated androgen pathways, generating testosterone and 11-ketotestosterone, respectively, which exert comparable androgen receptor activation. Both circulate in similar concentrations in premenopausal women while 11-ketotestosterone is predominant after menopause and in PCOS. Here, we show that adipocytes are a major site of AKR1C3 and androgen receptor expression, with increased expression in women and individuals with obesity. Using human female adipose tissue explants, we find a much higher activation of 11-oxygenated over classic androgens, observing a decrease in 11-oxygenated but not classic androgen activation by AKR1C3 inhibition. Correspondingly, we demonstrate that AKR1C3 inhibitor treatment in premenopausal women selectively disrupts the activation of 11-oxygenated androgens. Pharmacological targeting of AKR1C3 provides a novel strategy to alleviate systemic and intra-adipose 11-oxygenated androgen excess.\nOne Sentence Summary Inhibition of the androgen-activating enzyme AKR1C3 results in a major decrease in 11-oxygenated but not classic androgens in women.\nCompeting Interest Statement\nMichaele Peters, Andrea Wagenfeld, Jan-Peter Ingwersen, and Jan Hilpert are employees of Bayer AG, Berlin, Germany. Laura B.L. Wittemans is currently employed by Novo Nordisk Research Centre Oxford but, while she conducted the research described in this manuscript, was only affiliated to the University of Oxford.","source_license":"CC-BY-4.0","license_restricted":false}