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

项目摘要 非酒精性脂肪性肝炎（NASH），或脂肪相关的肝脏炎症和瘢痕形成预计将是 肝硬化的主要原因，原发性肝癌，以及美国肝移植的主要指征 州（美国）在未来几年内。女性患NASH的风险不成比例，约15 目前，NASH的患病人数约为100万，NASH的治疗选择有限。迫切需要 了解NASH的风险因素及其在女性中的进展，性激素可能提供缺失的环节。 虽然雌激素已被证明可以防止NASH进展，但新出现的数据支持有害的 雄激素在这种疾病中的作用我们的初步数据表明， 睾酮水平与女性影像学证实的NAFLD风险之间存在密切联系， 高雄激素血症和晚期NASH纤维化的临床标志物。迄今为止， 表征女性的全面性激素水平，以研究雄激素水平的相关性，或 雄激素和雌激素之间的相互作用，关于女性NASH的自然史。为了解决这个 我将利用NIDDK资助的多中心NASH临床研究网络（NASH CRN 队列）对库存血清进行性激素测量，以研究其与组织学 NASH严重程度和进展的测量。然后，我将进行一项试点随机对照试验，以评估 雄激素受体拮抗剂治疗NASH进展的可行性、安全性和初步疗效 妇女我假设雄激素水平越高，NASH的严重程度越严重， 进展，并且这些关联在雌激素较低的女性中更强。 我的长期目标是领导多学科研究，将生殖内分泌学、女性生殖学和生殖医学结合起来， 健康和肝病，在性激素和激素调节的影响方面具有特定的专业知识 女性肝病的治疗。我在女性丙型肝炎病毒（HCV）方面有很强的背景，包括 性激素在HCV纤维化中作用的最新研究。我现在正在扩大我的研究， 考虑到NASH对公共卫生的深远影响，NASH的不成比例风险 在女性中，以及将雄激素与女性脂肪相关肝损伤联系起来的新数据。这项研究可能有助于 确定有NASH进展风险的女性，同时阐明治疗干预的新机制。我 我组建了一个非凡的多学科导师团队，其中包括我在NASH的主要导师， Terrault，我的生殖内分泌学导师，Cedars博士和Bacchetti博士作为我的生物统计学导师。 通过一个详细的五年研究和培训计划，我将开发临床试验的内容专业知识， 生殖内分泌学和NASH病理生物学，同时获得更大R01试验的初步数据 研究NASH女性患者的抗雄激素治疗。有了这个基础，我将启动我的多学科 作为性激素和性激素调节疗法的专家，在女性肝病方面。

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.