Androgens and Nonalcoholic Steatohepatitis: The Role of Male Sex Hormones in Women with NASH

摘要

ABSTRACT The greatest rise in incident nonalcoholic fatty liver disease (NAFLD) is seen among young adults, while women are recognized as having greater risk for fibrosis progression. Nonalcoholic steatohepatitis (NASH) is now the leading indication for liver transplantation in women, though therapeutic options for NASH are limited. There is an urgent need to identify novel treatment targets and modifiable risk factors for NASH in women, and sex hormones may provide a missing link. We have previously shown that testosterone levels increase risk for hepatic steatosis in women, though prior to my K23, no studies had characterized the association of androgens with NASH histology, or the association of hyperandrogenism with NASH histology in women. My K23 therefore leveraged the multicenter NASH Clinical Research Network in which we performed comprehensive sex hormone measures and found that higher testosterone levels were independently associated with NASH severity in pre-menopausal women, while opposite findings were apparent in men. We further showed that women with the hyperandrogenic endocrinopathy known as Polycystic Ovary Syndrome (PCOS) had more severe NASH than non-PCOS controls, as well as advanced fibrosis at a younger age. These composite findings support the rationale of my K23 Aim 3 pilot randomized controlled trial to assess the feasibility and safety of an androgen receptor antagonist in young women with NASH. Because pilot trial enrollment was halted during COVID, a one-year K23 extension is now requested to support effort and direct research costs to complete Aim 3 study enrollment and analysis of safety and feasibility outcomes. The pilot data obtained from Aim 3 will provide the requisite foundation for an R01-level grant to evaluate androgen modulation for NASH treatment in young women. 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. During the course of my K23 I completed formal clinical trial training and obtained key experience in developing and launching a clinical trial in preparation for my planned R01 on androgen receptor modulation in women with NAFLD, while also completing reproductive endocrinology training related to hormonal influences on metabolic disease. During this time, I also expanded the breadth of my research on reproductive health in liver disease, having published 19 first- or senior-authored articles in this area, including those directly related to my K23. I have been recognized for this work on a national level, and selected to be first author of the inaugural Reproductive Health in Liver Disease Guidance Document on behalf of the AASLD. In this way I have maximized the training and resources provided by my K23, and met my overarching career goal of emerging as a leader in reproductive health and liver disease.