Androgen dysregulates the follicular extracellular matrix and increases pro-fibrotic gene expression in the mouse ovary

The extracellular matrix (ECM) defines the biomechanical and biochemical microenvironment of tissues, directing cell behaviour and phenotype. In the ovary, ECM must dynamically remodel in each cycle under hormonal regulation to control follicle development and produce fertilizable oocytes. Dysregulation of this process may result in aberrant formation of ECM as seen in polycystic ovary syndrome (PCOS) whose pathology includes fibrosis of the ovary and which is a major cause of infertility. PCOS is characterised by hyperandrogenism and, here, we investigate the impact of androgens on fibrosis, cell-ECM interactions and mechanosensing. We report an altered network of gene expression related to the genesis of fibrosis. Preantral follicles from C57BL/6 mice (14-15 days postpartum) were stimulated with dihydrotestosterone (DHT, 10nM) in 24/72 hours culture. Expression of fibrosis-associated genes (Eln; Ctgf; Acta2; Plod2; Hpse) significantly increased with androgen (72 h), as did TGF-β signalling (Tgfb1; Tgfb3). We show a direct connection between androgen and mechanosensing within the ovary, with androgen upregulating the mechanosensitive Hippo pathway (Yap1; Lats1; Lats2; Stk3; Stk4; Frmd6) and downstream targets (Ctgf; Axl; Cyr61). Our results highlight hyperandrogenism as a probable driver of the fibrosis in the polycystic ovary, and emphasise the importance of ECM regulation in follicle development and fertility.