Male Hormonal Contraception and Metabolic Health

项目总结(见说明)： 全球人口继续以惊人的速度增长。调查显示，男性和女性都希望有更多的男性避孕选择。由雄激素和孕激素组成的男性激素避孕方案很有吸引力，因为它们有很高的有效率，是完全可逆的，而且是新型男性避孕药中临床开发最先进的。然而，人们担心外源性激素对男性的性腺外影响，特别是对心血管疾病(CVD)的长期风险。关于雄激素和孕激素对心血管疾病危险因素的影响的数据喜忧参半。一方面，男性激素避孕药会降低高密度脂蛋白(高密度脂蛋白)，这是一种保护心脏的脂蛋白，并且会导致体重增加，随着时间的推移，这可能会增加胰岛素抵抗。相反，血清睾酮水平低与心血管疾病、胰岛素抵抗和死亡率的风险增加相关，这对外源性雄激素必然以剂量依赖的方式增加心血管风险的观点提出了质疑。这项建议的总体目标是阐明男性激素避孕药对体内CVD的三个重要危险因素的影响。我们将集中讨论雄激素和孕激素对1)高密度脂蛋白介导的胆固醇外流的影响，这是高密度脂蛋白的关键心脏保护功能，2)高密度脂蛋白相关的蛋白质组成，以及3)脂肪组织炎症，胰岛素抵抗的关键介质。新出现的数据表明，其中每一种都与心血管疾病的发病机制有关，而且每一种都可能被外源性类固醇所改变。 我们将在健康男性中进行一项安慰剂对照试验，以直接量化单独增加血清睾酮水平或与有效的避孕药孕酮-去甲孕酮(DMPA)联合使用对人类高密度脂蛋白和脂肪组织的影响。为了补充我们的人类研究，我们将使用转基因小鼠来确定雄激素是否通过对脂肪组织巨噬细胞的影响来降低心血管疾病风险，脂肪组织巨噬细胞是协调脂肪组织炎症和胰岛素抵抗的一种中心细胞类型。拟议的研究将提供有关雄激素和孕激素对男性新陈代谢和心血管疾病风险的影响的临床和机制数据。

PROJECT SUMMARY (See Instructions): Global population continues to grow at an astonishing rate. Surveys suggest that both genders desire more male contraceptive options. Male hormonal contraceptive regimens that consist of androgens plus a progestin are attractive as they have high efficacy rates, are fully reversible, and, among novel male contraceptives, are the most advanced in clinical development. There are concerns, however, regarding the extra-gonadal effects of exogenous hormone administration in men, particularly surrounding long-term risk for cardiovascular disease (CVD). Data regarding the impact of androgens and progestins on risk factors for CVD are mixed. On the one hand, male hormonal contraceptives lower high-density lipoprotein (HDL), a cardioprotective lipoprotein, and can cause weight gain that might increase insulin resistance over time. In contrast, low levels of serum testosterone are associated with elevated risk for CVD, insulin resistance, and mortality, calling into question the notion that exogenous androgens necessarily increase CVD risk in a dose dependent manner. The overall objective of this proposal is to clarify the impact of male hormonal contraceptives on three important risk factors for CVD in vivo. We will focus on the effects of androgens and progestins on 1) HDL-mediated cholesterol efflux, a key cardioprotective function of HDL, 2) HDL-associated protein composition, and 3) adipose tissue inflammation, a critical mediator of insulin resistance. Emerging data implicates each of these in the pathogenesis of CVD and each is likely modified by exogenous steroids. We will conduct a placebo-controlled trial in healthy men to directly quantify the effects of increasing levels of serum testosterone alone or combine with an effective contraceptive progestin, depomedroxyprogessterone acetatate (DMPA), on human HDL and adipose tissue. To compliment our human study, we will use genetically modified mice to determine whether androgens reduce CVD risk via effects on adipose tissue macrophages, a central cell type in orchestrating adipose tissue inflammation and insulin resistance. The proposed studies will provide both clinical and mechanistic data regarding the impact of androgens and progestins on male metabolism and CVD risk.