Effects of Estradiol & Phytoestrogens on Stress Responsivity

描述(申请人提供)：焦虑是中年女性常见但未被研究的主诉，并在更年期过渡期间增加。在更年期过渡期间，雌激素的变化是戏剧性的，间接数据表明雌激素，特别是雌激素受体β，在调节焦虑方面具有潜在的作用。雌激素受体的两个亚型，α和β(ER-α和ER-β)，似乎与女性焦虑的表达密切相关。优先靶向ER-β的化合物，包括植物来源的雌激素(植物雌激素)，降低了实验动物的焦虑行为和对包括社会应激在内的离散应激源的反应。这项应用的主要目的是开展第一项研究，通过比较和对比植物雌激素、雌二醇和安慰剂对日常焦虑和实验室中适度心理社会压力的反应的影响，将这些临床前研究转化为人类。另一个主要关注点是情绪认知和非情绪认知。这一焦点源于雌激素可以影响糖皮质激素对记忆的负面影响的证据。这些目标将通过一项为期12周的随机安慰剂对照临床试验来实现，该试验比较了三种治疗方法：1)广泛使用的植物雌激素补充剂(Novasoy(R)400，每天两次55毫克片剂)；2)口服雌二醇(每天1毫克)；以及3)安慰剂(每天两次相同的片剂)，对120名处于更年期过渡的健康妇女(每组40人)进行比较。为了测量焦虑程度，女性将在基线和整个治疗期间完成每日情绪日记。为了测量对心理社会压力的反应性，特里尔社会压力测试的平行形式将被用来在治疗前后诱导适度的心理社会压力。特里尔社会压力测试是一种广泛使用的实验室诱导方法，涉及意外的公开演讲和社会评估性恐惧。在这两个实验室阶段，在控制条件和心理社会压力条件下，将获得主观压力、皮质醇和情绪记忆表现的测量。这项临床试验的结果将增加关于中年雌激素变化作为中年女性焦虑和压力症状的一个促成因素的重要性的关键信息。阳性发现将为随后研究ER-β激动剂治疗女性焦虑症状和障碍提供理论依据。 公共卫生相关性：与男性相比，女性焦虑症的患病率更高，而且在中年(45岁以后)女性中显著增加，但男性没有。非临床样本中的焦虑特征在女性中也比男性更常见，在荷尔蒙过渡期，包括更年期过渡期，焦虑特征会恶化。为了进一步了解更年期焦虑妇女的治疗方案，本研究旨在测试两种广泛使用的绝经疗法--雌二醇和植物雌激素--对日常焦虑和应激反应的影响，以及日常和引发应激的认知影响。

DESCRIPTION (provided by applicant): Anxiety is a common, but understudied complaint in midlife women, and increases during the menopausal transition. Changes in estrogen are dramatic during the menopausal transition, and indirect data suggest a potential role for estrogen, particularly estrogen receptor beta, in mediating anxiety. Two subtypes of the estrogen receptor, alpha and beta (ER-alpha and ER-beta), appear to be critically involved in the expression of anxiety in females. Compounds that preferentially target ER-beta, including plant-derived estrogens (phytoestrogens), lower both anxiety behaviors and responsivity to discrete stressors, including social stress, in laboratory animals. The primary aim of this application is to carry out the first study to translate these preclinical studies to humans by comparing and contrasting of the effects of phytoestrogens, estradiol, and placebo on daily anxiety and responses to moderate psychosocial stress in the laboratory. Another major focus is emotional and non-emotional cognition. This focus stems from evidence that estrogen can affect the negative impact of glucocorticoids on memory. These aims will be accomplished in a 12-week randomized placebo- controlled, clinical trial comparing three treatments: 1) a widely used phytoestrogen supplement (Novasoy(R) 400, 55 mg tablet twice daily); 2) oral estradiol (1 mg/daily); and 3) placebo (identical appearing tablets twice daily) in 120 healthy women in the menopausal transition (40 per group). To measure anxiety, women will complete daily mood diaries at baseline and throughout the treatment period. To measure responsivity to psychosocial stress, parallel forms of the Trier Social Stress Test, a widely used laboratory induction that involves unanticipated public speaking and social evaluative fear, will be used to induce moderate psychosocial stress before and after treatment. At both laboratory sessions, measures of subjective stress, cortisol, and emotional memory performance will be obtained during a control condition and during the psychosocial stress condition. The results from this clinical trial will add critical information about the importance of estrogen changes at midlife as a contributing factor for anxiety and stress symptoms in midlife women. Positive findings would provide a rationale for subsequent investigations of ER-beta agonists in the treatment of anxiety symptoms and disorders in women. PUBLIC HEALTH RELEVANCE: The prevalence of anxiety disorders is higher in women compared to men, and increases significantly in women at midlife (after age 45) but not men. Anxiety traits in non-clinical samples are also more common in women than men and worsen during hormonal transitional states, including the menopausal transition. To further our understanding of treatment options for women with anxiety during the menopausal transition, this study aims to test the effects of two widely used menopausal therapies, estradiol and phytoestrogens, on daily anxiety and stress responsivity, and the cognitive effects of daily and provoked stress.