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Polycystic ovary syndrome (PCOS) is the leading cause of female infertility and linked to type-2 diabetes and endometrial cancer. Progress in managing the disorder is hindered by a lack of insight into the underlying mechanisms. We know that male hormones play a key role and that PCOS runs in families. Recently we made the discovery that prenatal androgen-induced PCOS-like traits in female and male mice are passed down across multiple generations. Thus, growing evidence suggests that genetic and epigenetic mechanisms act in concert in complex traits as PCOS.Yet fundamental questions remain:What are the cell-type-specific epigenetic and transcriptomic disease signatures and signaling pathways in PCOS endometrium and adipose tissue? Can such perturbations be reversed?What are the key triggers and molecular pathways that drive transmission of PCOS in the absence of PCOS-associated gene variants?Can germ cells drive transmission in the absence of direct intrauterine effects? If so, can PCOS be transmitted to future generations also by sons?We will integrate human and mouse studies with state-of-the-art molecular techniques to answer these questions. The fundamental novel insights that the proposed projects will yield into PCOS etiology and pathophysiology will have several important translational implications that could shape how PCOS, and associated comorbidities is managed. The long-term goal is to give targeted treatment and to predict response to treatment.

Polycystic ovary syndrome (PCOS) is the leading cause of female infertility and linked to type-2 diabetes and cancer. Progress in managing the disorder is hindered by lack of insight into the underlying mechanisms. We know that male hormones plays a key role and that PCOS runs in families. Recently we made the discovery that PCOS-like symptoms, induced by exposing pregnant mice to male hormone, are passed down from mothers to great-granddaughters. Moreover, we have indications that sons can transmit the disease as well. _x000D_ _x000D_ I will take a multidisciplinary approach to get better insights into how PCOS is passed on in families. We will use human and mouse studies as well as state-of-the-art molecular techniques to dissect the key mechanisms that influence how the syndrome is passed on across generations both by women and men. My vision is to open new horizons for prevention strategies rather than managing symptoms, thereby markedly reducing the burden of the disease in both women and men._x000D_