Testosterone Dose-Response on Cardiometabolic Outcomes in Surgically Menopausal W

描述（由申请人提供）：本提案的总体目标是评估不同剂量睾酮治疗对手术绝经妇女心血管风险的潜在不良影响。睾酮对女性体脂分布和代谢结果变化的剂量-反应关系此前尚未建立。在患有多囊卵巢综合征的女性中，睾丸激素水平与脂肪量、血脂异常和胰岛素抵抗呈正相关。目前正在研制治疗绝经后妇女性功能障碍的睾酮制剂。然而，来自多囊卵巢综合征（PCOS）女性的数据显示，睾酮水平升高与脂肪量、致动脉粥样硬化性血脂异常和胰岛素抵抗有关，这表明外源性雄激素可能会加重女性的代谢和心血管风险结果。因此，医学界对性功能障碍女性补充雄激素的长期安全性一直存在重大争议。我们提出了一项研究：1)我们将比较低血清睾酮水平的手术绝经妇女在6个月的时间内接受一系列睾酮剂量的腹部脂肪分布，胰岛素抵抗，脂质谱和炎症标志物的变化；2)我们将评估这些各种代谢和炎症标志物与睾酮给药后腹部脂肪分布变化的关系。剂量-反应分析将帮助我们确定睾酮浓度的治疗范围，该范围既能对性功能产生有益影响，又不会对心血管风险产生重大不利影响。这项拟议的研究，除了促进我们对生理和超生理剂量睾酮对心血管标志物影响的机制的理解外，还可能为未来评估女性雄激素治疗心血管安全性的长期干预试验奠定基础。

DESCRIPTION (provided by applicant): The overall goal of this proposal is to evaluate the potential adverse effects of testosterone therapy at varying doses on cardiovascular risk profile in surgically menopausal women. Testosterone dose-response relationships on changes in body fat distribution and metabolic outcomes in women have not been established previously. In women with PCOS, testosterone levels have been positively associated with fat mass, dyslipidemia and insulin resistance. Testosterone formulations are being developed for the treatment of sexual dysfunction in post-menopausal women. However, the data from PCOS women demonstrating the association of higher testosterone levels with fat mass, proatherogenic dyslipidemia, and insulin resistance suggest that exogenous androgens may worsen metabolic and cardiovascular risk outcomes in women. As a result, there has been significant controversy in the medical community about the long term safety of androgen supplementation in women with sexual dysfunction. We propose a study in which: 1) we will compare changes in abdominal fat distribution, insulin resistance, lipid profile and inflammatory markers in surgically menopausal women with low serum testosterone levels receiving a range of testosterone doses over a 6-month time period, and 2) we will assess the associations of these various metabolic and inflammatory markers with changes in abdominal fat distribution in response to testosterone administration. A dose-response analysis will help us identify a therapeutic range of testosterone concentrations that can achieve beneficial effects on sexual function without having significant adverse effects on cardiovascular risk profile. This proposed study, in addition to advancing our understanding of mechanisms underlying effects of physiologic and supraphysiologic doses of testosterone on cardiovascular markers, is likely to lay the groundwork for future long-term intervention trials assessing cardiovascular safety of androgen therapy in women.