Androgen-Estrogen Balance in CVD Risk

描述（由申请人提供）：心血管疾病（CVD）预计仍将是本世纪全球的头号杀手。关键的心血管疾病危险因素，如2型糖尿病和肥胖，已经达到流行病的程度，甚至在年轻人中也是如此。性激素（如雌激素和睾酮）在男性和女性的心血管疾病进展中都起着核心作用。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增加3倍，男性心血管疾病死亡率的变化比女性早5-10年。对不同心血管疾病风险的标准解释涉及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（男性雌激素和女性雄激素）在成人一生中与葡萄糖失调有关的心血管疾病发展中的作用。为了实现这一目标，我们建议将内源性性激素、葡萄糖失调和老年人心血管疾病联系起来，并将内源性性激素与年轻人动脉粥样硬化和心功能障碍联系起来。我们的方法以两个新兴概念为中心：与女性相比，内源性性激素可能对男性产生相反（或性别二态）的影响；内源性性激素的时间变化（而不仅仅是水平）影响心血管疾病的风险。我们建议采取一种有效的内分泌流行病学方法。我们将使用现有的数据，并测量在两项正在进行的纵向研究中反复收集的美国原住民男性和女性血液中的内源性性激素，这两项研究是“强心脏研究”和“强心脏家庭研究”。美洲原住民是心血管疾病和糖尿病高发的少数群体。我们的具体目标是：1)区分循环内源性雌激素、雄激素和SHBG的变化是否与男性和女性糖尿病患者随后的CVD事件相关；2)确定循环内源性雌激素、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；3)在男性和女性的整个成年寿命中，表征内源性雄激素和雌激素的动态及其与颈动脉粥样硬化、心功能障碍和相关危险因素（特别是葡萄糖调节异常和肥胖）的关系。更好地了解性激素与心血管疾病的相互作用及其在衰老过程中的危险因素将广泛影响公共卫生策略、风险分层和心血管疾病的治疗。

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.