Atherosclerosis, Immune Mediated Inflammation and Hypoestrogenemia in Young Women

年轻女性的动脉粥样硬化、免疫介导的炎症和低雌激素血症

• 批准号: 9766355
• 负责人: Chrisandra Lee Shufelt
• 金额: $ 19.77万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9766355
• 关键词: Academy; Address; Advocate; Age; Amenorrhea; American; Anti-inflammatory; Atherosclerosis; Biology; Biometry; Birth; Blood Vessels; Cardiovascular Diseases; Cause of Death; Cessation of life; Clinical Investigator; Clinical Research; Clinical Trials Design; Coronary Arteriosclerosis; Data; Death Rate; Development Plans; Discipline of obstetrics; Dose; Endothelium; Estradiol; Estrogens; Etiology; Event; Future; Goals; Gynecology; Hormonal; Hypothalamic structure; Immune; Immune response; Immunology; Inflammation; Inflammatory; Investigation; Ischemia; Link; Literature; Measures; Medial; Mediating; Menopause; Menstrual cycle; Mentors; Modality; Mutation; Natural Immunity; Osteoporosis; Pathway interactions; Patients; Pediatrics; Peripheral; Phenotype; Placebos; Play; Polycystic Ovary Syndrome; Premenopause; Progesterone; Randomized; Research; Research Project Grants; Risk; Risk Factors; Role; Route; Signs and Symptoms; T-Lymphocyte; Testing; Thick; Tissues; Training; Translating; Turner' s Syndrome; Woman; Women' s Health; Work; adaptive immunity; age group; arterial tonometry; cardiovascular disorder risk; career; career development; clinical care; college; cytokine; design; double-blind placebo controlled trial; early onset; experience; functional hypothalamic amenorrhea; hormone therapy; immunoregulation; improved; multidisciplinary; novel; novel strategies; older men; older women; patient oriented research; pre-clinical; premature; prevent; public health relevance; research and development; response; skills; young man; young woman

 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.

 描述（由适用提供）：早产心血管疾病（CVD）是年轻女性死亡的主要原因。尽管CVD的死亡率在所有其他年龄段的人数都下降了，但她们35至44岁的女性仍在继续增加，传统的CVD危险因素并未捕获这种风险，这留下了太多意外。先前的研究表明，年轻女性的月经循环不规则构成高达50％的CVD风险。特纳综合征的女性是一种遗传缺陷，导致长期发育不良（Hypoe）出生时，由于CVD加速而导致过早死亡。此外，下丘脑起源的大麻与脑缺血体征和症状的女性中绝经前阻塞性冠状动脉疾病有关。将这些数据综合在一起，表明绝经前妇女的HypoE与加速的CVD有关；这些关联的机制尚不清楚。已经确定，免疫介导的炎症性在动脉粥样硬化中起作用，雌激素具有免疫调节作用，导致抑制促炎性细胞因子，同时增加抗炎细胞因子。此外，有大量文献表明在更年期后雌激素丧失期间促炎性细胞因子增加。我们假设绝经前女性的HypoE与临床前CVD有关，并且雌激素介导的增加会增加免疫介导的感染是机械途径。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与免疫介导的感染之间的关系； 3）在一项随机，双盲的安慰剂对照试验中评估4周的雌激素雌激素加2周的雌激素加孕激素对血管功能和免疫介导的感染的影响。我们的研究很重要，因为它有可能识别年轻女性的新型CVD风险因素以及相关的免疫介导的途径。据估计，多达34％的绝经前妇女患有继发性闭经，导致催眠，即18至44岁之间的162万美国妇女，使得比多囊性卵巢综合征更常见于月经周期。美国儿科学会和美国妇产科学院提倡月经周期应视为“生命体征”，因为雌激素对整个身体的组织的重要性。例如，已经良好地表明，绝经前女性的高hye会导致早期骨质疏松症，并且与这种骨质疏松症相关的免疫反应改变了。该K23应用程序还解决了培训合格的临床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有关的技能的重要需求。目的是基于该应用程序在生物统计学，妇女健康以及内源性和外源性雌激素方面的经验，通过获得成功的独立临床研究生涯所需的其他技能。