Defining the Mechanisms of Menopause-Associated Sleep and Mood Disturbances

描述(由申请人提供)：这个项目的主要目标是确定更年期相关失眠和抑郁的机制，以便改进这些常见和衰弱疾病的治疗方法。女性在围绝经期和绝经后早期失眠和抑郁的风险增加。潮热与更年期相关的失眠和抑郁有关，但这些联系的生物学基础尚不清楚。这项建议将探索潮热和抑郁之间的联系的基础，以确定潮热是否与抑郁症有关：(1)潮热只是更年期性腺激素变化的标志，和/或(2)潮热通过其扰乱睡眠的作用对抑郁症产生影响。在这项建议中，我们将使用绝经前妇女潮热的实验模型(目标1和2)和绝经后妇女的临床干预研究(目标3)，剖析妇女性腺激素和更年期症状之间的复杂相互作用。目的1将确定潮热对睡眠的影响，以检验潮热会恶化客观测量的睡眠并导致人们随着时间的推移而感觉睡眠质量不佳的假设。目标2将确定潮热和睡眠中断对情绪的相对影响。这将检验这样的假设，即客观测量的睡眠障碍对情绪的影响比潮热更大，以及睡眠质量差的感觉与负面情绪相关。目标3将确定潮热和雌二醇变化对情绪的相对影响。这将检验这样的假设，即雌激素治疗对有潮热和无潮热的女性的情绪有类似的治疗效果，以及雌激素水平的增加与情绪的改善相关。这些发现的意义在于，他们能够确定性腺激素变化、潮热和睡眠中断对更年期相关情绪障碍的因果贡献。由于妇女健康倡议的结果描述了激素治疗的重要风险，因此接受激素治疗的妇女越来越少。同样，尽管5-羟色胺能再摄取抑制剂是有效的抗抑郁药物，可以抑制一些女性的潮热，但它们的副作用可能会限制它们的接受度。需要新的治疗方法。了解性腺激素变化、潮热、睡眠障碍和情绪障碍之间的因果关系，将有助于开发合理和有针对性的治疗策略来管理更年期相关的抑郁症。公共卫生相关性：这项研究将确定更年期相关失眠和抑郁的机制，这是一种常见的、使人衰弱的疾病，女性在中年患上这些疾病的风险更高。拟议的机制研究将确定潮热对睡眠的影响，以及性腺激素、潮热和睡眠中断对情绪障碍的相对影响。这项工作具有重要的公共卫生意义，因为它将为开发合理的治疗策略提供信息，并导致更年期相关抑郁症的新治疗范例。

DESCRIPTION (provided by applicant): The broad goal of this project is to define the mechanisms of menopause-associated insomnia and depression in order to improve therapeutic approaches to these common and debilitating disorders. Women are at increased risk for insomnia and depression during the perimenopause and early postmenopause. Hot flashes have been linked to menopause-associated insomnia and depression, but the biological basis of these associations is poorly understood. This proposal will explore the basis for the association between hot flashes and depression to determine if hot flashes are associated with depression: (1) because hot flashes are merely a marker for menopause-associated alterations in gonadal hormones, and/or (2) because hot flashes exert their effects on depression through their sleep-disrupting effects. In this proposal, we will dissect the complex interactions among gonadal hormones and menopausal symptoms in women using an experimental model of hot flashes in premenopausal women (Aims 1 and 2) and a clinical intervention study in postmenopausal women (Aim 3). Aim 1 will determine the effect of hot flashes on sleep to test the hypotheses that hot flashes worsen objectively measured sleep and lead to the perception of poor sleep quality over time. Aim 2 will identify the relative effects of hot flashes and sleep disruption on mood. This will test the hypotheses that objectively measured sleep disturbance has a greater effect than hot flashes on mood and that perception of poor sleep correlates with negative mood. Aim 3 will define the relative effects of hot flashes and changes in estradiol on mood. This will test the hypotheses that estrogen treatment has a similar therapeutic effect on mood in women with and without hot flashes and that increasing levels of estradiol correlate with improvement in mood. The significance of these findings lies in their ability to define the causal contributions of gonadal hormone changes, hot flashes and sleep disruption to menopause-associated mood disturbance. Since the results of the Women's Health Initiative described important risks of hormone therapy, fewer women are being treated with hormone therapy. Similarly, although serotonergic reuptake inhibitors are effective antidepressants and suppress hot flashes in some women, their side effect profiles may limit their acceptability. Novel treatment approaches are needed. Understanding the causal pathways between alterations in gonadal hormones, hot flashes, sleep disruption, and mood disturbance will inform the development of rational and targeted therapeutic strategies for management of menopause-associated depression. PUBLIC HEALTH RELEVANCE: This study will identify the mechanisms of menopause-associated insomnia and depression, common and debilitating disorders for which women are at increased risk during midlife. The proposed mechanistic studies will define the impact of hot flashes on sleep and the relative effects of gonadal hormones, hot flashes, and sleep disruption on mood disturbance. This work has important public health relevance because it will inform the development of rational therapeutic strategies and lead to novel treatment paradigms for menopause- associated depression.