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

更年期过渡：雌激素变异、HPA 轴和情感症状

基本信息

批准号：
9349605
负责人：
SUSAN S. GIRDLER
金额：
$ 64.67万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-08 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9349605
关键词：
Adrenal Glands Affect Affective Affective Symptoms Anhedonia Antidepressive Agents Anxiety Anxiety Disorders Behavior Behavioral Behavioral Symptoms Biological Biological Markers Cessation of life Clinical Cognitive Corticotropin Data Disease susceptibility Divorce Eligibility Determination Equipment and supply inventories Estradiol Estrogens Etiology Exhibits Expenditure Female Functional disorder Hormonal Hormones Hydrocortisone Hypothalamic structure Impairment Life Stress Link Liquid Chromatography Longevity Major Depressive Disorder Measures Mediating Mediation Menopause Menstruation Mental Depression Modeling Mood Disorders Moods Motivation Neurobiology Pathogenesis Patient Self-Report Perimenopause Pharmacology Phenotype Pituitary Gland Placebos Plasma Play Postpartum Depression Postpartum Period Predisposition Premenopause Psychopathology Randomized Recovery Recruitment Activity Research Rewards Risk Role Sampling Serum Severities Stimulus Stress Stressful Event Symptoms Testing Trier Social Stress Test Woman anxiety symptoms anxious base behavior measurement behavioral response biological adaptation to stress clinical anxiety clinical efficacy clinical predictors clinical risk clinically relevant clinically significant common symptom depressive symptoms deprivation design dysphoria efficacy trial experience hypothalamic-pituitary-adrenal axis indexing insight interest loved ones mood symptom novel marker pleasure psychobiologic reproductive reproductive hormone response stem stress reactivity stressor symptomatology tandem mass spectrometry trait

项目摘要

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.

项目摘要复制激素正常变化的有害情绪影响的脆弱性很可能是一种为生殖情绪障碍而言。更年期过渡（MT）与明显激素变异性（在相对E2剥夺的背景下），并大大增加了临床上的风险损害焦虑和痛苦。焦虑的特征是认知偏见来解释一个与威胁有关的方式。 Anhedonia可以通过改进的动力来获得奖励来定义。这基于神经生物学的“威胁反应性”和“方法动机”的结构为框架提供了一个框架研究MT中25％的女性经历的临床障碍的病理生理学。虽然 MT中造成情感症状的原因仍然未知，紧邻MT的严重生命压力很强预测指标。在素质变应学模型中构建，这项研究的主要目的是确定雌二醇（E2）在临床动画和MT中看到的Anhedonia的病理生理机制。具体而言，E2变异性还是E2水平是否预测夸张的下丘脑 - 垂体 - 肾上腺（HPA）轴反应性和减轻压力的恢复受损，进而定义了威胁反应性和动画和阿尼多尼亚的动机和症状。该研究的次要目标是使用荷尔蒙操纵作为机械探针，以稳定绝经前的E2变异性和确定是否：a）HPA轴反应性/恢复表示行为和症状反应的生物标志物 E2稳定； b）最近的严重生命应力是否预测HPA轴对马-Mon稳定的反应。在符合荷尔蒙调查的早期或晚期，总共有170名女性将被招募以反映基于自我报告的国家特征焦虑清单的焦虑和抗痛符号的完整连续性和Snaith-Hamilton愉悦量表。但是，我们将过度代表临床障碍焦虑和厌恶表型的末端（占样本的75％）。超过8周的基线，焦虑和通过液相色谱串联质谱法测量的Anhedonia符号和血清E2（LC- MS/MS）将每周评估。在基线第8周，HPA轴（血浆皮质醇和ACTH）对Trier社会压力测试和威胁响应的行为度量的反应（通过DOT-PROBE任务）将确定动力（奖励任务'eefrt'的努力支出）。使用透皮 E2作为稳定E2在绝经前范围内变异性的药物探针，然后女性将是随机分配至翻译E2（0.10 mg）或安慰剂16周。这不是临床效率试验。我们将使用具有激素操纵的RCT设计，以研究E2的病理生理作用 HPA轴失调中的变异性（或E2水平），反过来又威胁响应和进近动机。血清E2每周在第9-16周进行评估，HPA轴对压力和行为的反应性在16周探测期间，将每四个星期评估对DOT探针和EEFRT任务的响应。