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

摘要 非酒精性脂肪性肝病（NAFLD）发病率上升幅度最大的是年轻人，而 女性被认为具有更大的纤维化进展风险。非酒精性脂肪肝炎 NASH现在是女性肝移植的主要适应症，尽管治疗选择 NASH是有限的。迫切需要确定新的治疗目标和可改变的风险因素 对于女性NASH，性激素可能提供了缺失的一环。我们之前已经证明， 睾酮水平增加女性肝脂肪变性的风险，尽管在我的K23之前，没有研究表明 其特征在于雄激素与NASH组织学的关联，或高雄激素血症的关联， 女性NASH组织学。因此，我的K23利用了多中心NASH临床研究 网络中，我们进行了全面的性激素措施，发现更高的 睾酮水平与绝经前妇女NASH严重程度独立相关， 男性的研究结果则相反。我们进一步表明，患有高雄激素血症的女性 多囊卵巢综合征（PCOS）的内分泌疾病比非PCOS的NASH更严重 对照组，以及在年轻时的晚期纤维化。这些综合调查结果支持以下理由： 我的K23 Aim 3试点随机对照试验，以评估雄激素的可行性和安全性， 受体拮抗剂治疗NASH的年轻女性。由于新冠肺炎期间试点试验招募停止， 现在，K23计划被要求延长一年，以支持完成Aim 3计划的努力和直接的研究费用 研究入组以及安全性和可行性结局分析。从目标3获得的试验数据将 为R01级资助提供必要的基础，以评估NASH的雄激素调节 治疗年轻女性。 我的长期目标是领导多学科研究， 女性健康和肝脏疾病，在性激素和激素的影响方面拥有特定专业知识 女性肝病的改良疗法。在我的K23过程中，我完成了正式的临床试验 培训并获得了开发和启动临床试验的关键经验，为我的 计划在NAFLD女性中进行雄激素受体调节的R01，同时还完成 生殖内分泌学培训与激素对代谢疾病的影响有关。在此 同时，我还扩大了我对肝病生殖健康研究的广度， 在这个领域发表了19篇第一篇或高级作者的文章，包括那些与我的K23直接相关的文章。我 在国家一级，这项工作得到了认可，并被选为就职典礼的第一作者。 代表AASLD的肝病生殖健康指导文件。这样我就 最大限度地利用了K23提供的培训和资源，并实现了我的总体职业目标， 成为生殖健康和肝病领域的领导者。

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.