The Menopause Transition: Estrogen Variability, HPA axis and Affective Symptoms

项目摘要 容易受到生殖激素正常变化的有害情绪影响， 导致生殖情绪障碍绝经过渡期（MT）与明显的 激素变异性（在相对E2缺乏的背景下）和临床风险大幅增加 削弱焦虑和快感缺乏。焦虑的特点是认知偏见，解释模糊的刺激， 与威胁有关的方式。快感缺失可以定义为接近奖励的动机降低。的 基于神经生物学的“威胁反应性”和“接近动机”的结构提供了一个框架， 研究MT中25%的妇女所经历的临床损伤的病理生理学。虽然 在MT情感症状的原因仍然未知，严重的生活压力接近MT是一个强大的 预测器本研究的主要目的是在一个素质-压力模型的框架内，确定 雌二醇（E2）在临床焦虑症和快感缺乏症中的病理生理机制。 具体而言，E2变异性或E2水平是否可预测下丘脑-垂体-肾上腺（HPA）轴过度 反应性和受损的恢复压力，反过来，赤字的行为指数的威胁反应， 接近动机和焦虑和快感缺乏的症状。研究的第二个目的是 使用激素操作作为机械探针，以稳定绝经前范围内的E2变异性， a）HPA轴反应性/恢复是否代表对以下的行为和症状反应的生物标志物： E2稳定; B）近期严重的生活压力是否预测HPA轴对激素稳定的反应。 总共有170名妇女在早期或晚期MT谁是合格的激素探针将被招募，以反映 基于状态-特质焦虑量表自我报告的焦虑和快感缺乏症状的完整连续体 和Snaith-Hamilton快乐量表。然而，我们会过度表现临床上的损害， 焦虑和快感缺乏表型的结束（75%的样本）。超过8周的基线，焦虑和 通过液相色谱-串联质谱法（LC-MS）测量快感缺乏症状和血清E2。 MS/MS）将每周进行评估。基线8周时，HPA轴（血浆皮质醇和ACTH） 对特里尔社会压力测试的反应和威胁反应的行为测量（通过点探针任务） 和接近动机（奖励任务的努力支出“EEfRT”）。使用透皮 E2作为药理学探针，以稳定绝经前E2范围内的变异性， 随机分配至经皮E2（0.10 mg）或安慰剂组16周。这不是一项临床疗效试验。我们将 使用一项激素调控的RCT设计，以研究E2的病理生理作用 HPA轴失调的变异性（或E2水平），以及威胁反应性和接近动机。 在第9-16周期间，每周评估血清E2，并评估HPA轴对应激和行为的反应性。 在16周的探测期间，每四周评估对点探测和EEfRT任务的响应。

PROJECT SUMMARY Vulnerability to the deleterious mood effects of normal changes in reproductive hormones is a likely underpinning to reproductive mood disorders. The menopause transition (MT) is associated with pronounced hormonal variability (within the context of relative E2 deprivation) and substantially increased risk for clinically impairing anxiety and anhedonia. Anxiety is characterized by cognitive bias to interpret ambiguous stimuli in a threat-related manner. Anhedonia can be defined by decreased motivation to approach rewards. The neurobiologically-based constructs of ‘threat reactivity’ and ‘approach motivation’ provide a framework for studying the pathophysiology of the clinical impairment experienced by 25% of women in the MT. Although the causes of affective symptoms in the MT remain unknown, severe life stress proximate to the MT is a strong predictor. Framed within a diathesis-stress model, the primary objective of this research is to determine the pathophysiological mechanisms of estradiol (E2) in the clinical anxiety and anhedonia seen in the MT. Specifically whether E2 variability or E2 levels predict exaggerated hypothalamic-pituitary-adrenal (HPA) axis reactivity and impaired recovery to stress and, in turn, deficits in behavioral indices of threat responsivity and approach motivation and symptoms of anxiety and anhedonia. The secondary objective of the research is to use a hormonal manipulation as a mechanistic probe to stabilize E2 variability in premenopausal ranges and determine if: a) HPA axis reactivity/recovery represents a biomarker of behavioral and symptom responses to E2 stabilization; b) whether recent severe life stress predicts the HPA axis response to hormone stabilization. A total of 170 women in the early or late MT who are eligible for the hormonal probe will be recruited to reflect the full continuum of anxiety and anhedonia symptoms based on self-report to the State-Trait Anxiety Inventory and the Snaith-Hamilton Pleasure Scale, respectively. However, we will over-represent the clinically impairing end of the anxious and anhedonic phenotype (75% of the sample). Over an 8-week baseline, anxiety and anhedonia symptoms and serum E2 measured by liquid chromatography-tandem mass spectrometry (LC- MS/MS) will be assessed on a weekly basis. At baseline week 8, HPA axis (plasma cortisol and ACTH) response to the Trier Social Stress Test and behavioral measures of threat responsivity (via Dot-Probe task) and approach motivation (Effort Expenditure for Rewards Task ‘EEfRT’) will be determined. Using transdermal E2 as a pharmacological probe to stabilize variability of E2 in premenopausal ranges, women will then be randomized to transdermal E2 (0.10 mg) or placebo for 16 weeks. This is not a clinical efficacy trial. We will use an RCT design with a hormonal manipulation in order to investigate the pathophysiologic role of E2 variability (or E2 levels) in HPA axis dysregulation and, in turn, threat responsivity and approach motivation. Serum E2 will be assessed weekly during weeks 9-16, and HPA axis reactivity to stress and behavioral responses to the Dot-Probe and EEfRT tasks will be assessed every four weeks during the 16 week probe.