Effects of Estradiol & Phytoestrogens on Stress Responsivity

描述（由申请人提供）：焦虑是一种常见的，但在中年妇女中尚未充分研究的抱怨，并在更年期过渡期间增加。在绝经过渡期，雌激素的变化是巨大的，间接数据表明雌激素，特别是雌激素受体β，在调节焦虑方面有潜在的作用。雌激素受体的两种亚型，α和β (er - α和er - β)，似乎在女性焦虑的表达中起关键作用。在实验动物中，优先靶向er - β的化合物，包括植物性雌激素（植物雌激素），可以降低焦虑行为和对离散压力源（包括社会压力）的反应。本申请的主要目的是通过比较和对比植物雌激素、雌二醇和安慰剂在实验室中对日常焦虑和对中度社会心理压力的反应的影响，开展第一个将这些临床前研究转化为人类的研究。另一个重点是情绪认知和非情绪认知。这种关注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。这些目标将在一项为期12周的随机安慰剂对照临床试验中实现，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, 55毫克片剂，每日两次）；2)口服雌二醇（1毫克/天）；3)在120名处于绝经期的健康妇女（每组40人）中使用安慰剂（相同的药片，每天两次）。为了测量焦虑，女性将在基线和整个治疗期间完成每日情绪日记。为了测量对社会心理压力的反应，将使用特里尔社会压力测试（Trier Social stress Test）的平行形式来诱导治疗前后的中度社会心理压力。特里尔社会压力测试是一种广泛使用的实验室诱导，涉及意想不到的公开演讲和社会评价性恐惧。在两个实验阶段，将在对照条件和社会心理压力条件下获得主观压力、皮质醇和情绪记忆表现的测量。这项临床试验的结果将为中年女性雌激素变化作为焦虑和压力症状的促成因素的重要性提供重要信息。阳性结果将为er - β受体激动剂治疗女性焦虑症状和障碍的后续研究提供依据。

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.