Pilot study on the risks of testosterone replacement to the brain

 描述（由申请人提供）：目前对美国人群的估计表明，超过20%的45岁以上男性可能患有性腺功能减退症（总睾酮<300 pg/dL），超过30%的70岁以上美国男性被认为患有性腺功能减退症。在过去的十年中，睾酮替代疗法（TRT）的处方增加了3倍。然而，最近的研究表明，TRT可增加心脑血管疾病的发病率和死亡率。这些风险背后的原因尚不清楚。了解T对脑血管系统和大脑的作用机制，不仅可以优化TRT的治疗时机，还可以优化TRT的剂量、途径和制剂。最近的证据表明，绝经后妇女的激素治疗有一个“关键窗口”，超过这个窗口，雌激素就会失去其有益的作用，甚至可能对认知和大脑衰老产生不利影响。由于T在大脑中的许多作用涉及转化为雌激素和类似于雌激素的抗氧化作用，我们假设T在大脑中的有益作用也可能在男性中具有疗效的“关键窗口”。此外，氧化应激水平可能介导这一“关键窗口”。“我们最近发现，只有在高氧化应激条件下， 在男人身上。这个试点补助金旨在调查TRT对认知，大脑老化和氧化损伤反应的“关键窗口”概念。形态学和行为学研究将用于确定剂量和时间依赖性类固醇替代方案在大鼠模型中的作用。总体目标是建立一个成功的和难治性TRT模型，然后可以用来生成机制假说，为后续的壁外赠款提交使用自然老化和共病条件下的TRT。目的1将检验TRT对认知和氧化应激的有益作用在长期睾酮剥夺（LTTD）后减弱的假设。去势中年大鼠将经历短期（1d）或长期（10周）睾酮剥夺，然后再恢复到生理水平。将认知功能以及外周和中枢氧化应激与用溶剂处理的完整和去势大鼠进行比较。目的二：验证长期睾酮剥夺（LTTD）抑制TRT对实验性脑卒中的神经保护作用。去势雄性中年大鼠在恢复到生理水平之前将经历短期（1d）或长期（10周）睾酮剥夺。大鼠将通过在大脑中动脉附近实质内注射内皮素-1经历实验性中风。感觉运动功能、认知功能以及外周和中枢氧化应激将与完整的 和用载体处理的去势大鼠。这些PILOT研究的结果不仅将为额外的机制性校外资助提案提供关键的初步数据，而且还将为那些考虑TRT的男性提供重要信息。

 DESCRIPTION (provided by applicant): Current estimates of the US population suggest greater than 20% of men over 45 years of age may be hypogonadal (total Testosterone <300 pg/dL), and more than 30% of US men over 70 are considered hypogonadal. Over the last decade prescriptions for testosterone replacement therapy (TRT) have increased 3-fold. However, recent studies suggest that TRT can increase cardiovascular and cerebrovascular morbidity and mortality. The reasons underlying these risks are unknown. An understanding of the mechanism of action of T's effects on the cerebrovasculature and brain could lead to optimized therapies with respect not just to timing, but also dose, route, and formulation for TRT. Recent evidence indicates that there is a "critical window" for hormone therapy in postmenopausal women, beyond which estrogens lose their beneficial effects, and may even have detrimental effects on cognition and brain aging. Because many of T's effects in the brain involve conversion to estrogen and antioxidant effects similar to estrogen, we hypothesize that the beneficial effects of T in the brain may also have a "critical window" of efficacy in males. Further, oxidative stress levels may mediate this "critical window." We have recently found that T levels are inversely related to cognitive function only under conditions of high oxidative stress in men. This PILOT grant seeks to investigate the concept of a "critical window" for TRT on cognition, brain aging, and response to oxidative injury. Morphological and behavioral studies will be used to define the role of dose and time-dependent steroid replacement regimens in a rat model. The overall goal is to establish a model of successful and refractory TRT that can then be used to generate mechanistic hypotheses for subsequent extramural grant submissions using natural aging and comorbid conditions in the context of TRT. Aim 1 will test the hypothesis that the beneficial effects of TRT on cognition and oxidative stress are diminished following long-term testosterone deprivation (LTTD). Castrate middle-aged rats will undergo short (1d) or long-term (10 wk) testosterone deprivation before replacement to physiological levels. Cognitive function and peripheral and central oxidative stress will be compared to intact and castrate rats treated with vehicle. Aim 2 will test the hypothesis that long-term testosterone deprivation (LTTD) inhibits the neuroprotective effects of TRT in experimental stroke. Castrate male middle-aged rats will undergo short (1d) or long-term (10 wk) testosterone deprivation before replacement to physiological levels. Rats will undergo experimental stroke using intraparenchymal injection of endothelin-1 adjacent to the middle cerebral artery. Sensory-motor function, cognitive function and peripheral and central oxidative stress will be compared to intact and castrate rats treated with vehicle. Results of these PILOT studies not only will provide critical preliminary data for additional mechanistic extramural grant proposals, but also will provide important information for those men considering TRT.