PHYSIOLOGY OF ESTROGEN'S MOOD EFFECT IN MENOPAUSAL WOMEN

描述（由申请人提供）：这个以患者为导向的职业发展奖专注于发展围绝经期抑郁症跨学科领域的专业知识。更年期在女性中是普遍存在的，10%的围绝经期女性患有抑郁症。本项目将剖析雌激素替代疗法（ERT）治疗绝经期妇女抑郁症的机制。我们假设ERT通过直接的中枢神经系统作用来改善情绪，而不是简单地治疗潮热和睡眠中断。一项生理干预研究将比较ERT和催眠剂对围绝经期抑郁妇女的情绪影响。通过控制ERT对睡眠的影响，可以揭示ERT对情绪的直接神经调节作用。多导睡眠图（PSG）研究将用于探索ERT和催眠剂唑吡坦对睡眠结构的影响。本研究将：(1)确定雌激素抗抑郁作用的关键因素；(2)确定围绝经期妇女的亚群特征，这些妇女的抑郁症可以用非激素治疗和需要ERT治疗；(3)确定围绝经期妇女抑郁症的最佳管理方法。通过研究潮热对睡眠、情绪和生活质量的影响，了解ERT对情绪影响的组成部分也将推动潮热研究领域的发展。这对于开发新的雌激素替代品和假定的潮热疗法至关重要，这些疗法越来越多地用于乳腺癌妇女和其他不能或不愿接受ERT的妇女。

DESCRIPTION (provided by applicant): This Mentored Patient-Oriented Career Development Award focuses on developing expertise in the interdisciplinary field of perimenopausal depression. Menopause is universal in women, and depressive disorders occur in 10% of perimenopausal women. This project will dissect the mechanisms by which estrogen replacement therapy (ERT) treats depression in menopausal women. We hypothesize that ERT improves mood by a direct CNS effect, rather than by simply treating hot flushes and sleep disruption. A physiologic intervention study will compare the mood effect of ERT with that of a hypnotic agent in depressed perimenopausal women. The direct neuromodulatory effect of ERT on mood will be unmasked by controlling for ERT's effect on sleep. Polysomnographic (PSG) studies will be used to explore changes in sleep architecture that occur with ERT and the hypnotic agent zolpidem. This study will: (1) identify the elements critical to estrogen's antidepressant benefit; (2) characterize subpopulations of perimenopausal women whose depression can be treated with non-hormonal therapies and those who require treatment with ERT; and (3) define optimal management of depression in perimenopausal women. Understanding the components of ERT's effect on mood will also advance the field of hot-flush research by examining the impact of hot flushes on sleep, mood, and quality-of-life. This is critical for the development of novel estrogen alternatives and putative hot-flush therapies increasingly used in women with breast cancer and others unable or unwilling to take ERT. ENVIRONMENT: The proposed study will be based at Massachusetts General Hospital (MGH), with outstanding interdisciplinary sponsorship and consultant input. PSG studies will be performed at McLean Hospital. I will receive mentorship from Lee Cohen, M.D., in the Department of Psychiatry, and Janet Hall, M.D., in the Reproductive Endocrinology Unit of the Department of Medicine at MGH. Both sponsors are internationally recognized in their respective fields and have exceptional track records as effective research mentors. Their combined expertise will shape my career development in this interdisciplinary field. CAREER DEVELOPMENT PLAN: Physiologic investigation of mood disturbance in menopausal women requires that I acquire knowledge of (1) sleep medicine; and (2) research methods for healthoutcomes assessment and clinical intervention studies using physiologic measures. I will receive formal training in each of these specific research areas under the supervision of expert consultants. Such training will lay the foundation for a career of clinical investigation into the physiology of perimenopausal depression and the impact of hot flushes on sleep, mood, and quality-of-life.