Medical Consequences of Long-Term Anabolic-Androgenic Steroid Abuse

描述（由申请人提供）：合成代谢雄激素类固醇（AAS）是一个激素家族，包括睾酮及其合成衍生物。几十年来，精英运动员一直在使用AAS来提高成绩，但直到20世纪80年代，非法使用AAS才从精英运动员中扩散到普通人群中。现在，大约有200万美国人使用AAS，有时累积多年的高超生理剂量的总暴露。初步证据表明，长期使用AAS可能导致严重的医疗后果，特别是心血管影响。然而，人们对这些仍然知之甚少，部分原因是直到最近，大多数AAS用户还太年轻，没有进入风险年龄。现在，随着第一批非法使用AAS的人进入中年，这种情况即将发生变化。这些人是在20世纪80年代的年轻人中首次使用AAS的。在一项初步研究中，我们的研究小组使用心电图和超声心动图来比较12名年龄在32-46岁之间的长期AAS使用者和7名年龄匹配的举重运动员，他们报告了相似的运动水平，但没有使用AAS。与非服用者相比，AAS服用者表现出明显的心肌去极化延迟，同时心脏收缩和舒张功能（收缩和舒张功能）出现显著和高度显著的损伤，与已确定类型的心肌病相似。虽然我们没有在初步研究中评估动脉粥样硬化疾病，但我们小组和其他人之前的工作表明，这也可能是使用AAS的结果。为了进一步评估长期使用AAS的影响，我们建议对80名长期使用AAS的人、55名无AAS使用史的举重运动员和55名非举重运动员进行详细的医学和心脏评估。将使用PI在过去10年中开发的经过验证的方法招募和筛选男性，旨在在研究非法药物使用者时最大限度地减少选择和信息偏差。我们的主要具体目的是验证长期使用AAS会导致心脏电传导异常的假设：1)以心肌去极化延迟为特征，增加心律紊乱的风险；2)心肌功能受损，以左室舒张和收缩功能不全为特征，增加心力衰竭的风险；3)加速动脉粥样硬化，增加心肌梗死和其他动脉粥样硬化疾病的风险。我们的第二个具体目标是通过比较3组，特别是使用医学和实验室测试来评估其他可能的AAS影响，特别是1)肝脏和肾脏以及2)下丘脑-垂体-性腺轴。在所有主要的药物滥用形式中，长期滥用AAS的医疗影响可能是最不为人所知的；迄今为止，没有比较研究对一大群慢性AAS使用者进行了全面的医学评估。这代表了科学知识的严重不足，因为即使按照保守的估计，也有数十万美国人经历了长期的AAS暴露，而这一群体中的老年人刚刚步入中年。因此，拟议的研究将对公共卫生产生重大影响。

DESCRIPTION (provided by applicant): The anabolic-androgenic steroids (AAS) are a family of hormones that includes testosterone and its synthetic derivatives. For decades, elite athletes have used AAS to improve performance, but it was not until the 1980s that illicit AAS use spread out of elite athletics and into the general population. Now, some 2 million Americans have used AAS, sometimes accumulating years of total exposure to highly supraphysiologic doses. Preliminary evidence suggests that long-term AAS use may cause serious medical consequences, including especially cardiovascular effects. However, these remain poorly understood, in part because until recently, most AAS users were still too young to have entered the age of risk. Now, this situation is poised to change, as the first large wave of illicit AAS users - those who first used AAS as youths in the 1980s - enters middle age. In a pilot study, now in press, our group used electrocardiography and echocardiography to compare 12 long- term AAS users, aged 32-46 years, and 7 age-matched weightlifters reporting similar exercise levels but no AAS use. Compared with nonusers, the AAS users showed significantly delayed myocardial depolarization, together with striking and highly significant impairments of cardiac contraction and relaxation (systolic and diastolic function), similar to those seen in established types of cardiomyopathy. Although we did not assess atherosclerotic disease in the pilot study, prior work by our group and others suggests that this too may be a consequence of AAS use. To further assess the effects of long-term AAS use, we propose to perform detailed medical and cardiac assessments in 80 long-term AAS users, 55 weightlifters reporting no history of AAS use, and 55 non-weightlifting men. Men will be recruited and screened using proven methods, developed by the PI over the last 10 years, designed to minimize selection and information bias to the maximum extent possible when studying illicit substance users. Our primary specific aim is to test the hypothesis that long-term AAS use causes 1) abnormalities of cardiac electrical conduction, characterized by delayed myocardial depolarization, increasing the risk for cardiac rhythm disturbances; 2) impaired myocardial function, characterized particularly by left ventricular diastolic and systolic dysfunction, increasing the risk for heart failure; and 3) accelerated atherogenesis, increasing the risk for myocardial infarction and other atherosclerotic disease. Our secondary specific aim is to assess other possible AAS effects by comparing the 3 groups using medical and laboratory tests focused especially on 1) the liver and kidney and 2) the hypothalamic-pituitary-gonadal axis. The medical effects of long-term AAS abuse are probably the least understood of any major form of drug abuse; no comparative study to date has performed full medical evaluations on a large group of chronic AAS users. This represents a serious deficit in scientific knowledge since, even by conservative estimates, hundreds of thousands of Americans have experienced long-term AAS exposure, and the older members of this group are just now reaching middle age. Thus the proposed study will have major public health impact. PUBLIC HEALTH RELEVANCE: At least 2 million Americans have used illicit anabolic-androgenic steroids (AAS; drugs such as testosterone and its relatives), either for athletic purposes or simply to enhance personal appearance - and growing evidence now suggests that these individuals may be at risk for serious medical consequences, especially on the cardiovascular system. A recent pilot study from our laboratory, now in press, adds to this evidence by showing striking impairments of cardiac contraction and relaxation in 12 long-term AAS users as compared to 7 age-matched weightlifters reporting comparable exercise history but no AAS use. Based on these ominous preliminary findings, we propose to perform detailed medical evaluations, including a comprehensive battery of cardiac tests, in 80 long-term illicit AAS users, 55 matched weightlifters reporting no history of AAS use, and 55 non-weightlifting comparison men; to our knowledge, this the first large study of its kind, and it addresses a major deficit in our current knowledge of the dangers of substance abuse.