Testosterone Dose-Response on Cardiometabolic Outcomes in Surgically Menopausal W

睾酮剂量反应对手术绝经 W 患者心脏代谢结果的影响

• 批准号: 8596189
• 负责人: Grace Huang
• 金额: $ 6.76万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8596189
• 关键词: Abdomen; Adverse effects; Advocate; Androgen Therapy; Androgens; Blood specimen; Body fat; Cardiovascular system; Communities; Data; Dialysis procedure; Dose; Double-Blind Method; Drug Formulations; Dyslipidemias; Equilibrium; Estrogens; Fasting; Fatty acid glycerol esters; Future; Goals; Inflammatory; Injection of therapeutic agent; Insulin Resistance; Interleukin-6; Intervention Trial; Lipids; Measures; Medical; Menopause; Metabolic; Metabolic Marker; Outcome; Personal Satisfaction; Physiological; Placebos; Postmenopause; Randomized; Regimen; Risk Marker; Running; Safety; Serum; Sex Functioning; Sexual Dysfunction; Supplementation; Symptoms; TNF gene; Testosterone; Testosterone Enanthate; Therapeutic; Time; Uncertainty; Visceral; Woman; abdominal fat; cardiovascular risk factor; improved; inflammatory marker; public health relevance; randomized placebo controlled trial; response; subcutaneous; testosterone replacement therapy; treatment duration

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.

描述（由申请方提供）：本提案的总体目标是评价不同剂量睾酮治疗对手术绝经女性心血管风险特征的潜在不良影响。先前尚未建立女性体内脂肪分布和代谢结果变化的替吉奥剂量-反应关系。在患有PCOS的女性中，睾酮水平与脂肪量、血脂异常和胰岛素抵抗呈正相关。正在开发替西泮制剂用于治疗绝经后妇女的性功能障碍。然而，来自PCOS女性的数据表明，较高的睾酮水平与脂肪量、致动脉粥样硬化性血脂异常和胰岛素抵抗相关，这表明外源性雄激素可能会恶化女性的代谢和心血管风险结局。因此，医学界对性功能障碍妇女补充雄激素的长期安全性存在重大争议。我们建议进行一项研究，其中：1）我们将比较在6个月的时间段内接受一系列睾酮剂量的低血清睾酮水平的手术绝经妇女的腹部脂肪分布、胰岛素抵抗、脂质谱和炎症标志物的变化，和2）我们将评估这些不同的代谢和炎症标志物与睾丸激素引起的腹部脂肪分布变化之间的关系局剂量反应分析将帮助我们确定一个治疗范围的睾酮浓度，可以实现对性功能的有益影响，而不会对心血管风险状况产生显着的不利影响。这项拟议的研究，除了推进我们的生理和超生理剂量的睾酮对心血管标志物的影响的机制的理解，可能为未来的长期干预试验评估雄激素治疗的女性心血管安全性奠定基础。