Androgens have recently been recognized to play a major role in female fertility, both under normal and pathophysiological conditions. Traditionally, androgens are considered detrimental to ovarian function and are often associated with infertility. However, through generation of global and granulosa cell (GC)-specific androgen receptor (AR) knockout (ARKO) mouse models, others and we have pioneered a new concept that critical androgen actions through ARs are absolutely essential for normal ovarian function and female fertility. Our studies indicate that ARs expressed in GCs control pre-antral follicle growth and development to antral follicles, while preventing follicular atresia. However, to date, the underlying mechanism of AR actions in the ovary is poorly understood. Androgen functions are mediated by both “genomic/nuclear” and “non- genomic/extra-nuclear” actions of ARs. This RO1 proposal will study the physiological role and underlying mechanisms of membrane-initiated androgen actions during follicular development. Our studies show that androgen signaling via extra-nuclear ARs is critical for genomic intra-nuclear signaling and thus, the physiological effects of androgens in GCs involve a synergistic action between these two AR signaling pathways. We find that androgens promote follicular development and attenuate follicular atresia through both nuclear and extra-nuclear signaling pathways. The first portion of this grant focuses on further elucidating this “outside-inside” cross talk between ARs, and its role in ovarian physiology. We have found that androgens through membrane-initiated AR signaling promote epigenetic changes in the genome by modifying histone methylation in GCs. Interestingly, epigenetic changes are now proposed to be a possible underlying cause of certain hyper-androgenic pathophysiological conditions in women, such as Polycystic Ovary Syndrome. Therefore, we propose to determine the mechanism(s) by which androgens cause histone modifications, identify genes that are epigenetically regulated by androgens in GCs and determine its physiological significance with respect to follicular development and female fertility. In the second portion of this grant we concentrate our efforts on understanding the underlying mechanism of non-genomic, transcription independent effects of androgens in regulating follicular development. We have found two proteins; follicle stimulating hormone receptor and hypoxia-inducible factor 1 alpha that are regulated by androgens by a translation dependent pathway in GCs. We propose to use these two biologically relevant proteins as endpoints to elucidate how androgens promote translation in GCs. These proposed studies will provide novel insights about androgen signaling in general, with a specific focus on androgen actions in female reproduction. We believe that these studies will help us develop unique ways to control follicular development and thus female fertility, as well as identify potential b...