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 女性被认为有更大的纤维化进展风险。非酒精性脂肪性肝炎 (NASH)现在是女性肝移植的主要适应症，尽管治疗方案 纳什是有限的。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来说，性激素可能提供了缺失的一环。我们之前已经表明， 睾丸激素水平会增加女性患肝脏脂肪变性的风险，尽管在我的K23之前，没有研究表明 以雄激素与NASH组织学或高雄激素血症的关联为特征 对女性进行纳什组织学检查。因此，我的K23利用了多中心纳什临床研究 我们在网络中进行了全面的性激素测量，发现 睾丸激素水平与绝经前妇女的NASH严重程度独立相关，而 相反的发现在男性身上很明显。我们进一步表明，患有高雄激素的女性 称为多囊卵巢综合征(PCOS)的内分泌疾病比非PCOS患者有更严重的NASH 对照组，以及较年轻时的晚期纤维化。这些综合发现支持了这一理论基础 我的K23 Aim 3试点随机对照试验的一部分，以评估雄激素的可行性和安全性 NASH年轻女性的受体拮抗剂。由于飞行员试训在COVID期间暂停， 现在要求将K23延期一年，以支持完成目标3的努力和直接研究成本 研究招生以及安全性和可行性结果分析。从AIM 3获得的试点数据将 为评估NASH雄激素调节的R01水平拨款提供必要的基础 年轻女性的治疗。 我的长期目标是领导融合生殖内分泌学的多学科研究， 妇女健康和肝病，在性激素和激素的影响方面具有专门知识 女性肝病的改良疗法。在我学习K23的过程中，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R01关于NAFLD女性雄激素受体调节，同时也完成 与激素对代谢性疾病影响有关的生殖内分泌学培训。在此期间 时间，我还扩大了我对肝病生殖健康的研究广度，有 在这一领域发表了19篇第一或高级作者的文章，包括那些与我的K23直接相关的文章。我 因这项工作在国家一级获得认可，并被选为第一作者 代表AASLD的肝病生殖健康指导文件。通过这种方式，我有了 最大限度地利用我的K23提供的培训和资源，并实现了我的首要职业目标 成为生殖健康和肝病领域的领先者。

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.