MELATONIN FOR AGE-RELATED SLEEP DISTURBANCE IN WOMEN

描述(申请人提供)：在经历更年期过渡的女性中，睡眠抱怨急剧增加，而且这些抱怨在绝经后并未停止。在60岁以上的健康女性中，多达一半的人也报告睡眠受到干扰，主要表现为睡眠维持性失眠。在多大程度上影响睡眠质量的生理变化，如昼夜节律性、体温调节和性激素重新调节的变化，在中年女性中出现，并随着年龄的增长而加剧，仍然知之甚少。很明显，需要进一步了解这些生理变化与老年女性睡眠问题的关系，以及研究治疗睡眠障碍的替代方法。最初的项目期是这项提议的竞争性延续，试图在绝经后几年的妇女中检查性激素谱和体温变量是否与客观测量的睡眠质量有关，正如已报道的围绝经期妇女的情况。在这些年长的绝经后女性中，性激素谱被证实在年龄增长过程中仍有显著变化，低雌二醇和高黄体生成素水平都与睡眠质量差有关。此外，与年轻的绝经前女性相比，老年女性在睡眠中有更多的黄体生成素脉冲，而且这些黄体生成素脉冲中的大部分都与从睡眠中醒来有时间上的联系。睡眠质量较差的绝经后女性在夜间睡眠之前和期间的核心体温水平都较高，在清醒和睡眠之间核心体温下降幅度较小。最后，另一项对缺乏睡眠的性激素昼夜节律的研究发现，老年人的黄体生成素脉搏幅度的节律出现了相位提前，这与一天中睡眠通常最受干扰的时间相对应。我们目前的目标是验证这一假设，即在围绝经期和老年绝经后妇女中使用外源性褪黑素可以改善睡眠质量。褪黑素可能是唯一适合治疗老年女性睡眠障碍的药物，因为它具有降温、安眠和抗促性腺激素的特性。在迄今为止最大规模的褪黑素治疗年龄相关睡眠障碍的系统临床试验中，这项研究将评估缓释褪黑素与安慰剂对性激素水平、体温、昼夜节律幅度和睡眠质量的影响，这些女性有高促性腺激素水平、潮热和睡眠维持性失眠。这项研究将增加我们对导致睡眠障碍的几个生理因素的了解，并被视为开发一种安全有效的治疗更年期和衰老所致睡眠问题的第一步。

DESCRIPTION (provided by applicant): Sleep complaints increase dramatically among women experiencing the menopause transition, and these complaints do not cease post-menopause. Up to half of otherwise healthy women over age 60 report disrupted sleep as well, primarily in the form of sleep maintenance insomnia. To what extent physiological changes that influence sleep quality, such as alterations in circadian rhythmicity, thermoregulation, and reregulation of sex hormones that emerge in middle-aged women and are exacerbated with increasing age, remain poorly understood. It has become clear that further understanding of how these physiological changes relate to sleep problems in older women is needed, as are investigations of alternative approaches to treating the sleep disturbance. The initial project period for which this proposal is a COMPETING CONTINUATION sought to examine, in women several years beyond menopause, whether sex hormone profiles and body temperature variables were associated with objectively measured sleep quality, as had been reported for perimenopausal women. In these older postmenopausal women, it was confirmed that sex hormone profiles remained significantly altered in aging, and that both low estradiol and high LH levels were associated with poor sleep quality. Also, older women had more LH pulses during sleep than did young, premenopausal women, and are large majority of these LH pulses were temporally associated with awakenings from sleep. Postmenopausal women with poorer sleep quality had higher body core temperature levels both prior to and during nocturnal sleep, and a blunted drop in core temperature between wakefulness and sleep. Finally, a separate study examining circadian rhythms of sex hormone profiles in the absence of sleep revealed that older individuals exhibit a phase advance in the rhythm of LH pulse amplitudes, which corresponds to the time of day that sleep is typically most disrupted. Our current aim is to test the hypothesis that sleep quality can be improved using exogenous melatonin in perimenopausal as well as older, postmenopausal women. Melatonin may be uniquely appropriate for treating sleep disturbance in aging women, because of its hypothermic, soporific, and antigonadotropic properties. In the largest systematic clinical trial to date of melatonin for age-related sleep disturbance, the study will evaluate the effects of slow release melatonin versus placebo on sex hormone levels, body temperature, circadian rhythm amplitude, and sleep quality in women who have high gonadotropin levels, hot flashes, and sleep maintenance insomnia. The study will increase our understanding of several physiological factors that contribute to sleep disturbance, and is viewed as an initial step toward developing a safe and effective treatment for sleep problems that accompany both menopause and aging.