Androgen-Estrogen Balance in CVD Risk

描述(申请人提供)：心血管疾病(CVD)预计仍将是本世纪全球头号杀手。关键的心血管疾病风险因素，如2型糖尿病和肥胖症，已经达到流行的比例，即使在年轻人中也是如此。性激素(如雌激素和睾丸素)在男性和女性发展为脑血管病的过程中起着核心作用。男性患心血管疾病的风险特别高：男性患心血管疾病的风险是女性的3倍，而且男性的心血管疾病死亡率比女性早5-10年。对不同的心血管疾病风险的标准解释是不同数量的内源性雌激素：相对于男性，女性体内更多的内源性雌激素可以在绝经前提供心血管保护。然而，越来越多的证据表明，雌激素的解释过于简单化了。我们的总体目标是确定“其他”内源性性激素(男性中的雌激素和女性中的雄激素)与血糖失调有关的作用，在成人一生中发生心血管疾病的过程中。为了达到这一目标，我们建议将老年人的内源性性激素、葡萄糖调节失调和心血管疾病联系起来，并将年轻人的动脉粥样硬化和心功能不全与内源性性激素联系起来。我们的方法集中在两个新兴概念上：内源性性激素可能会对男性产生与女性相反的(或性别二态)效应，内源性性激素的时间变化，而不仅仅是水平，会影响心血管疾病的风险。我们建议采取有效的内分泌流行病学方法。我们将使用现有的数据，并在两项正在进行的纵向研究--强心脏研究和强心脏家族研究--中，测量已经反复从美洲原住民男性和女性那里收集的库血中的内源性性激素。美洲原住民是心血管疾病和糖尿病发病率较高的少数群体。我们的具体目标是：1)区分男性和女性糖尿病患者循环中内源性雌激素、雄激素和SHBG的变化是否与随后的心血管事件有关；2)确定循环中的内源性雌激素、雄激素和性激素结合球蛋白(SHBG)水平是否与随后的糖尿病前期和糖尿病相关；以及3)在成年后的男性和女性中，表征内源性雄激素和雌激素的动态变化及其与颈动脉粥样硬化、心脏功能障碍和相关危险因素，特别是糖调节失调和肥胖的关系。更好地了解性激素和心血管疾病的相互作用及其在老龄化过程中的危险因素将广泛影响公共卫生战略、风险分层和心血管疾病的治疗。 公共卫生相关性：心血管疾病(CVD)是全球头号杀手。老年人的心血管疾病负担最大，但动脉粥样硬化和心血管功能障碍在年轻人中迅速上升，特别是在美洲原住民中。这项研究试图显著提高我们对性激素(如雌激素和睾酮)如何影响从年轻到年长的男性和女性的血糖失调和心血管疾病风险的理解。数以百万计的男性和女性正在接受性激素治疗，以治疗各种健康问题。这项研究试图确定谁可能从这种疗法中受益(以及谁可能受到伤害)，并制定旨在降低心血管疾病发病率和严重性的性激素改变疗法。

DESCRIPTION (provided by applicant): Cardiovascular disease (CVD) is projected to remain the #1 killer this century worldwide. Key CVD risk factors, such as type 2 diabetes and obesity, have reached epidemic proportions, even among younger adults. Sex hormones (such as estrogen and testosterone) are centrally involved in progression to CVD in both men and women. Men are at especially high risk for CVD: male gender confers a 3-fold increased risk of CVD and CVD death rates are shifted 5-10 years earlier in men than in women. The standard explanation for the differing CVD risk invokes differing amounts of endogenous estrogen: greater endogenous estrogen in women, relative to men, provides CV protection until menopause. However, evidence is accumulating that the estrogen explanation is an over-simplification. Our general objective is to identify the roles of the "other" endogenous sex hormones (estrogen in men and androgen in women), in relation to glucose dysregulation, in the development CVD across the adult lifespan. Towards this goal, we propose to relate endogenous sex hormones, glucose dysregulation, and CVD in older adults and relate endogenous sex hormones to atherosclerosis and cardiac dysfunction in younger adults. Our approach centers on two emerging concepts: endogenous sex hormones may assert opposite (or gender-dimorphic) effects in men compared with women and temporal changes, not just levels, of endogenous sex hormones influence CVD risk. We propose to take an efficient, endocrine epidemiological approach. We will use existing data and measure endogenous sex hormones in banked blood already collected repeatedly from Native American men and women within two ongoing longitudinal studies, the Strong Heart Study and the Strong Heart Family Study. Native Americans are a minority group with high rates of CVD and diabetes. Our specific aims are: 1) to differentiate if change in circulating endogenous estrogen, androgen, and SHBG are associated with subsequent CVD events in men and women with diabetes; 2) to determine if levels of circulating endogenous estrogen, androgen, and sex hormone binding globulin (SHBG) levels are associated with subsequent pre-diabetes and diabetes; and 3) across the adult lifespan in men and women, to characterize endogenous androgen and estrogen dynamics and their relationships to carotid atherosclerosis, cardiac dysfunction, and related risk factors, particularly glucose dysregulation and obesity. A better understanding of the interplay of sex hormones and CVD and its risk factors during aging would broadly impact public health strategies, risk stratification, and treatment of CVD. PUBLIC HEALTH RELEVANCE: Cardiovascular disease (CVD) is the #1 killer worldwide. Elders carry the greatest CVD burden, but atherosclerosis and CV dysfunction is rising rapidly in younger adults, especially among Native Americans. This study seeks to enhance significantly our understanding of how sex hormones (such as estrogen and testosterone) influence glucose dysregulation and CVD risk, in young to elder men and women. Millions of men and women are taking sex hormone therapies for a variety of health problems. The study seeks to identify who might benefit (and who might be harmed) from such therapies and to formulate sex hormone-altering therapies seeking to reduce CVD incidence and severity.