Pathomechanism and novel treatments for Polycystic Ovary Syndrome (PCOS)

PCOS is characterized by hyperandrogenism, disrupted menstrual cyclicity (oligo- or anovulation), and polycystic ovarian morphology. Central to the pathomechanism of PCOS is the increased pulse generator activity of mediobasal hypothalamic kisspeptin (KP) neurons, causing dysregulated gonadotropin-releasing hormone (GnRH) secretion, elevated serum luteinizing hormone (LH) pulsatility and excessive ovarian androgen production. Affecting 8–13% of women of reproductive age, PCOS is often complicated by metabolic side effects such as insulin resistance and obesity. Available therapies focus on symptom management (e.g.: infertility, hirsutism, insulin resistance, obesity, endometrial hyperplasia…), rather than curing the underlying condition. In this research program we will use murine PCOS models to address changes in the gene expression profiles of KP and GnRH neurons, using high-throughput bulk sequencing methods (LCM-Seq and IHC/LCM-Seq) developed in our laboratory. Molecular mechanisms responsible for the increased pulse generator activity are uncovered by comparing the gene expression landscapes of KP and GnRH neurons from PCOS mice (with an estrous cycle arrested in diestrus) and its normal cycling controls (in diestrus) and receptors upregulated in PCOS states are investigated to identify drug targets for novel treatments.