PROJECT SUMMARY Nonalcoholic steatohepatitis (NASH), or fat-related liver inflammation and scarring is projected to be the leading cause of cirrhosis, primary liver cancer, and the leading indication for liver transplantation in the United States (U.S.) within the next few years. Women are at disproportionate risk for NASH, with approximately 15 million U.S. women affected, and therapeutic options in NASH are limited. There is an urgent need to understand risk factors for NASH and its progression in women, and sex hormones may provide a missing link. While estrogens have been shown to protect against NASH progression, emerging data support the detrimental role of androgens in this disease. Our preliminary data demonstrate a strong and independent association of testosterone levels with risk of imaging-confirmed NAFLD in women, as well as a strong association between a clinical marker of hyperandrogenism and advanced NASH fibrosis on biopsy. No studies to date have characterized comprehensive sex hormone levels in women to investigate the association of androgen levels, or interplay between androgens and estrogens, on the natural history of NASH in women. To address this knowledge gap I will leverage the NIDDK-funded multicenter NASH Clinical Research Network (NASH CRN cohort) to perform sex hormone measures on banked serum to investigate their association with histologic measures of NASH severity and progression. I will then conduct a pilot randomized controlled trial to assess the feasibility, safety and preliminary efficacy of androgen receptor antagonist therapy on NASH progression in women. I hypothesize that higher androgen levels will be associated with worse NASH severity and progression, and these associations will be stronger in women with lower estrogen. My long-term goal is to lead multidisciplinary research merging reproductive endocrinology, women's health, and liver disease, with specific expertise in the influence of sex hormones and hormone modifying therapy on liver disease in women. I have a strong background in hepatitis C virus (HCV) in women, including recent research on the role of sex hormones in HCV fibrosis. I am now expanding my research to study androgens in NASH given the profound public health implications of NASH, the disproportionate risk of NASH in women, and emerging data linking androgens to fat-related liver injury in women. This study may help to identify women at risk for NASH progression while elucidating a novel mechanism for therapeutic intervention. I have assembled an extraordinary multidisciplinary mentorship team including my primary mentor in NASH, Dr. Terrault, my reproductive endocrinology mentor, Dr. Cedars, and Dr. Bacchetti as my biostatistical mentor. With a detailed five-year research and training plan I will develop content expertise in clinical trials, reproductive endocrinology and NASH pathobiology, while obtaining preliminary data for a larger, R01 trial investigating anti-androgen therapy in women with NASH. With this foundation I will launch my multidisciplinary career as an expert in sex hormones, and sex hormone modifying therapy, on liver disease in women.