Defining the Mechanisms of Menopause-Associated Sleep and Mood Disturbances

描述（由申请人提供）：该项目的总体目标是确定与更年期相关的失眠和抑郁的机制，以改善这些常见和使人衰弱的疾病的治疗方法。在绝经前后和绝经后早期，女性患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。本提案将探索潮热和抑郁之间联系的基础，以确定潮热是否与抑郁有关：(1)因为潮热仅仅是与更年期相关的性腺激素变化的标志，和/或(2)因为潮热通过扰乱睡眠对抑郁产生影响。在这一提议中，我们将使用绝经前妇女潮热的实验模型（目的1和2）和绝经后妇女的临床干预研究（目的3）来解剖性腺激素和妇女更年期症状之间复杂的相互作用。目的1将确定潮热对睡眠的影响，以检验潮热恶化客观测量睡眠的假设，并随着时间的推移导致睡眠质量差的感知。目标2将确定潮热和睡眠中断对情绪的相对影响。这将检验客观测量的睡眠障碍比潮热对情绪的影响更大的假设，以及睡眠质量差与消极情绪相关的假设。目的3将定义潮热和雌二醇变化对情绪的相对影响。这将验证雌激素治疗对有潮热和没有潮热的女性的情绪有相似的治疗效果，以及雌二醇水平的增加与情绪改善有关的假设。这些发现的意义在于，它们能够确定性激素变化、潮热和睡眠中断对更年期相关情绪障碍的因果关系。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，虽然血清素能再摄取抑制剂是有效的抗抑郁药，并抑制某些妇女的潮热，但其副作用可能会限制其可接受性。需要新的治疗方法。了解性腺激素变化、潮热、睡眠中断和情绪障碍之间的因果关系，将有助于制定合理和有针对性的治疗策略来管理更年期相关抑郁症。公共卫生相关性：本研究将确定与更年期相关的失眠和抑郁的机制，这是妇女在中年时风险增加的常见和衰弱性疾病。提出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相关性，因为它将为合理治疗策略的发展提供信息，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.