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: 9033389
• 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/9033389
• 关键词: Academy; Address; Advocate; Age; Amenorrhea; American; Anti-Inflammatory Agents; 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; Estradiol; Estrogens; Etiology; Event; Future; Goals; Gynecology; Hormonal; Hypothalamic structure; Immune; Immune response; Immunology; Inflammation; Inflammatory; Investigation; Ischemia; Left; 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; Qualifying; 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; immune function; improved; 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（由申请人提供）： 早发性心血管疾病 (CVD) 是年轻女性死亡的主要原因，虽然所有其他年龄组的 CVD 死亡率均有所下降，但 35 岁至 44 岁女性的死亡率却持续上升。多年来，传统的 CVD 风险因素并没有捕捉到这种风险，因此之前的研究表明，年轻女性的月经周期不规则会使患有特纳氏病的女性增加 50% 的 CVD 风险。综合征是一种导致出生后长期低雌激素血症 (HypoE) 的遗传缺陷，会因加速 CVD 而导致过早死亡。此外，下丘脑来源的 HypoE 与具有缺血体征和症状的女性绝经前阻塞性冠状动脉疾病有关。数据表明，绝经前女性的 HypoE 与加速 CVD 相关；并且这些关联的机制尚不清楚，免疫介导的炎症在其中发挥着作用。动脉粥样硬化，雌激素具有免疫调节作用，可抑制促炎细胞因子，同时增加抗炎细胞因子。此外，大量文献表明绝经前女性雌激素减少期间促炎细胞因子增加。与临床前 CVD 相关，并且雌激素介导的增加免疫介导的炎症是一种机制途径，我们计划：1）研究 HypoE、血管功能和临床前之间的关系。 CVD；2) 研究 HypoE 与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 周透皮雌二醇随后 2 周雌激素加孕激素对 HypoE 女性的影响我们的研究很重要，因为它有可能确定年轻女性的一种新的 CVD 危险因素以及相关的免疫介导途径。美国儿科学会和美国学院称，34% 的绝经前女性患有继发性闭经，导致 HypoE，即 162 万名年龄在 18 岁至 44 岁之间的美国女性，这使得月经周期紊乱比多囊卵巢综合症更为常见。妇产科主张，由于雌激素对整个组织的重要性，月经周期应被视为“生命体征”例如，已经明确绝经前女性的 HypoE 会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反应会发生改变。该 K23 应用还解决了培训合格临床研究人员的重要需求。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通过获取申请人在生物统计学、妇女健康以及内源性和外源性雌激素方面的经验。成功的独立临床研究职业所需的额外技能。