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

项目总结 容易受到生殖荷尔蒙正常变化的有害情绪影响的可能是 导致生殖情绪障碍。更年期过渡(MT)与明显的 激素变异性(在相对缺乏E2的情况下)和显著增加的临床风险 削弱焦虑和快感缺失。焦虑症的特征是认知偏向，不愿解释不明确的刺激。 与威胁相关的方式。快感缺乏症可以定义为追求回报的动力减弱。这个 基于神经生物学的“威胁反应性”和“接近动机”概念提供了一个框架 研究MT中25%的女性的临床损害的病理生理学。尽管 MT的情感症状的原因尚不清楚，MT附近的严重生活应激是一种强烈的 预言者。在素质-压力模型的框架内，本研究的主要目标是确定 雌激素(E2)在MT临床焦虑和快感减退中的病理生理机制。 具体地说，E2变异性或E2水平是否预示下丘脑-垂体-肾上腺(HPA)轴的夸大 对压力的反应性和受损的恢复，进而导致威胁反应性和行为指数的缺陷 接近焦虑和快感缺乏的动机和症状。这项研究的次要目标是 使用荷尔蒙操作作为一种机械探针来稳定绝经前和 确定：a)HPA轴反应/恢复是否代表行为和症状反应的生物标记物 E2稳定；b)最近严重的生活压力是否预示着HPA轴对激素稳定的反应。 在MT早期或晚期，共有170名有资格参加荷尔蒙调查的女性将被招募来反映 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 和斯奈思-汉密尔顿快乐量表。然而，我们将过度代表临床上受损的人 焦虑和无快感表型的结束(样本的75%)。在8周的基线上，焦虑和 液-质联用法测定快感乏力症状和血清雌二醇 MS/MS)将按周进行评估。在基线第8周，HPA轴(血浆皮质醇和ACTH) 对Trier社会压力测试的反应和威胁反应的行为测量(通过Dot-Probe任务) 方法动机(奖励任务的努力支出‘EEFRT’)将被确定。使用透皮贴剂 作为一种药理探针，将E2的变异性稳定在绝经前的范围内，届时女性将被 随机服用E2透皮贴剂(0.10毫克)或安慰剂，疗程16周。这不是一项临床疗效试验。我们会 采用随机对照试验设计，结合激素调节，研究雌二醇的病理生理作用 HPA轴的可变性(或E2水平)失调，进而影响威胁反应和接近动机。 在第9-16周每周评估一次血清雌二醇，HPA轴对压力和行为的反应性 在16周的探测期间，对Dot-Probe和EEFRT任务的反应将每四周进行一次评估。

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.