Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in Australia, affecting 12-21% of the female population. Typical clinical features of PCOS include hyperandrogenism, polycystic ovaries and oligo- or anovulation. Reduced fertility is a cardinal feature of PCOS, which arises due to the hyperandrogenic endocrine environment accompanying PCOS. Several lines of evidence have shown that androgens signal through the mammalian target of rapamycin complex 1 (mTORC1) signalling pathway. However, the functional role of the mTORC1 signalling pathway within the PCOS ovary is unknown.
To determine if hyperandrogenism stimulates ovarian mTORC1 signalling, we performed immunohistochemical (IHC) localisation of known markers of mTORC1 activity in ovaries of DHT treated mice, a well-established preclinical model of PCOS. IHC analysis demonstrated increased mTORC1 activity in DHT treated ovaries compared to controls. To ascertain whether mTOR hyperactivation is sufficient for development of the PCOS phenotype, we devised a mouse model with ovarian specific deletion of Liver Kinase B1, a major negative regulator of mTORC1 signalling. The conditional deletion of the LKB1 gene using Amhr2-cre was confirmed by examining LKB1 protein expression in control and mutant ovaries. Histological examination of LKB1 mutant ovaries revealed massive expansion of antral follicle population, which progressively develop into the polycystic ovarian phenotype. Immunostaining for AMH and inhibinα confirmed that mTORC1 hyperactivation causes antral follicle expansion without any obvious changes in the preantral follicle population. Examination of mTORC1 activity revealed hyperactivation of mTOR signalling in mutant ovaries compared to controls. To understand why mutant ovaries develop the PCOS phenotype, we examined the expression of markers of cell proliferation and cell death respectively. This analysis demonstrated the concurrent increase in cell proliferation and apoptosis within the granulosa cells of mutant antral follicles. Overall these results suggest that hyperandrogenism upregulates ovarian mTORC1 activity and thereby induces the ovarian phenotype of PCOS.