Atherosclerosis, Immune Mediated Inflammation and Hypoestrogenemia in Young Women

 描述（由申请人提供）：早发心血管疾病（CVD）是年轻女性死亡的主要原因。虽然所有其他年龄组的心血管疾病死亡率都有所下降，但35至44岁的女性死亡率仍在继续上升，传统的心血管疾病风险因素并没有捕捉到这种风险，留下了许多无法解释的原因。先前的研究表明，年轻女性不规则的月经周期会使CVD风险增加50%。特纳综合征是一种遗传缺陷，从出生起就导致长期的低雌激素血症（HypoE），患有这种综合征的妇女由于加速的CVD而过早死亡。此外，下丘脑起源的hypoE与绝经前阻塞性冠状动脉疾病的妇女缺血的体征和症状有关。总之，这些数据表明绝经前妇女的HypoE与加速的CVD相关;这些相关性的机制尚不清楚。已确定免疫介导的炎症在动脉粥样硬化中起作用，并且雌激素具有免疫调节作用，导致促炎细胞因子的抑制，同时增加抗炎细胞因子。此外，有大量文献表明绝经后雌激素丢失期间促炎细胞因子增加。我们假设绝经前妇女的HypoE与临床前CVD相关，雌激素介导的免疫介导的炎症增加是一种机制途径。我们计划：1）研究HypoE、血管功能和临床前CVD之间的关系; 2）研究HypoE和免疫介导的炎症之间的关系; 3）在一项随机、双盲、安慰剂对照试验中评估4周经皮雌二醇和2周雌激素加孕酮对HypoE女性血管功能和免疫介导的炎症的影响。 我们的研究很重要，因为它有可能在年轻女性中发现一种新的CVD风险因素以及相关的免疫介导途径。据估计，高达34%的绝经前妇女有继发性闭经，导致HypoE，即162万18至44岁的美国妇女，使其成为月经周期中断比多囊卵巢综合征更常见的病因。美国儿科学会和美国妇产科学院主张，由于雌激素对全身组织的重要性，月经周期应被视为“生命体征”。例如，已经确定绝经前妇女的HypoE导致早发性骨质疏松症，并且与这种骨质疏松症相关的免疫应答改变。 该K23应用程序还解决了培训合格的临床研究人员的重要需求，这些研究人员具有与血管生物学，动脉粥样硬化，免疫学和临床试验设计相关的专家合作的技能。目标是建立在申请人的生物统计学，妇女健康和内源性和外源性雌激素的经验，通过获得成功的独立临床研究生涯所需的额外技能。

 DESCRIPTION (provided by applicant): Premature cardiovascular disease (CVD) is the leading cause of death in young women. While death rates from CVD have declined in all other age groups, they are continuing to increase in women between the ages of 35 and 44 years and traditional CVD risk factors are not capturing this risk, leaving much unexplained. Prior research has demonstrated that irregular menstrual cycling in young women poses up to a 50% increased CVD risk. Women with Turner's syndrome, a genetic defect resulting in prolonged hypoestrogenemia (HypoE) from birth, have premature deaths due to accelerated CVD. Additionally, HypoE of hypothalamic origin has been associated with premenopausal obstructive coronary artery disease in women with signs and symptoms of ischemia. Taken together these data indicate that HypoE in premenopausal women is associated with accelerated CVD; and the mechanism(s) for these associations are unknown. It is established that immune- mediated inflammation plays a role in atherosclerosis, and estrogen has immunomodulatory effects resulting in suppression of pro-inflammatory cytokines while increasing anti-inflammatory cytokines. Furthermore, there is a large body of literature that demonstrates increased proinflammatory cytokines during estrogen loss after menopause. We hypothesize that HypoE in premenopausal women is associated with pre-clinical CVD, and that estrogen-mediated increases immune-mediated inflammation is a mechanistic pathway. We plan to: 1) investigate the relationship between HypoE, vascular function and preclinical CVD; 2) investigate the relationship between HypoE and immune-mediated inflammation; 3) evaluate in a randomized, double-blinded, placebo-controlled trial the impact of 4 weeks of transdermal estradiol followed by 2 weeks of estrogen plus progesterone in women with HypoE on vascular function and immune-mediated inflammation. Our study is important because it has the potential to identify a novel CVD risk factor in young women as well as an associated immune-mediated pathway. It is estimated that up to 34% of premenopausal women have secondary amenorrhea resulting in HypoE, that is 1.62 million US women between the ages of 18 and 44 years, making it more common etiology for menstrual cycle disruption than polycystic ovary syndrome. The American Academy of Pediatrics and the American College of Obstetrics and Gynecology have advocated that the menstrual cycle should be considered a "vital sign" due to the importance of estrogen on tissues throughout the body. For example, it has already well-established that HypoE in premenopausal women results in early-onset osteoporosis and that the immune response related to this osteoporosis is altered. This K23 application also addresses the important need to train qualified clinical investigators with the skills to work with experts related to vascular biology, atherosclerosis, immunology, and clinical trial design. The goal is to build on the applicant's experience in biostatistics, women's health and endogenous and exogenous estrogen by acquiring additional skills required for a successful independent clinical research career.