Variations in Hormones During Menopause: Effects on Cognitive and Brain Aging

更年期激素的变化：对认知和大脑衰老的影响

• 批准号: 8504875
• 负责人: HEATHER A. BIMONTE-NELSON
• 金额: $ 32.03万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8504875
• 关键词: Age; Alzheimer' s disease risk; Androgen Receptor; Androgens; Androstenedione; Attenuated; Award; Basic Science; Brain; Clinical Research; Clinical Trials; Cognition; Cognitive; Cognitive aging; Conjugated Equine Estrogens; Contraceptive Agents; Data; Endometrial Hyperplasia; Enzymes; Estradiol; Estrogens; Estrone; Etiology; Foundations; Glutamate Decarboxylase; Goals; Gonadotropins; Grant; Growth; Hippocampus (Brain); Hormonal; Hormonal Change; Hormones; Impaired cognition; Impairment; Ions; Link; Mediating; Medroxyprogesterone 17-Acetate; Memory; Memory impairment; Menopause; Modeling; Norethisterone Acetate; Operative Surgical Procedures; Ovarian; Ovarian hormone; Ovary; Paper; Prempro; Progestins; Proteins; Publications; Rattus; Research; Risk; Risk Factors; Rodent; Rodent Model; Series; Suggestion; System; Testing; Time; Uterus; Variant; Woman; Work; age related cognitive change; aging brain; birth control; cholinergic; cognitive change; cognitive enhancement; follow-up; gamma-Aminobutyric Acid; hormone therapy; insight; middle age; novel; ovarian failure; programs; prohormone; public health relevance; receptor

DESCRIPTION (provided by applicant): In this renewal, we hypothesize that type of menopause and associated hormone changes relate to cognitive responsiveness to hormone therapy (HT). The initial grant used rats to assess variations in HTs with surgical menopause (Ovx), and transitional menopause using 4-vinylcyclohexene diepoxide (VCD). VCD-treated rats undergo ovarian failure; follicles and estrogens deplete, androgens become unopposed, and gonadotropins increase, a profile resembling transitionally menopausal women. Data from the initial grant lay the foundation for testing new hypotheses regarding transitional versus surgical menopause. In women, both transitional and surgical menopause have been related to memory changes. However, most rodent studies have tested cognitive effects after Ovx. Despite insight rat models yield regarding surgical hormone loss, surgical menopause models <13% of women. Here, we examine how different menopause types impact cognitive and brain aging, and aim to determine optimal parameters for the menopause transition and HT. Four aims are proposed, using rats: Aim 1) We found that androstenedione (Andro) relates to impaired memory. Since Andro is directly converted to estrone, and we have shown estrone-induced memory impairments, we hypothesize that Andro's conversion to estrone impairs memory. Aim 1 tests whether Andro's conversion to estrogens, or androgen receptor stimulation, underlies its cognitive detriments. Aim 2) Clinical studies support a critical window during which HT benefits cognition. Rat studies support this; however, these studies used Ovx rats, and gave only 17¿-estradiol (E2). E2 is naturally-occurring in women and rats, but is present only in trace amounts in conjugated equine estrogens (CEE) HT. In rats, we found that CEE enhanced memory after surgical menopause, but impaired memory after transitional menopause when given after follicle depletion. Aim 2 tests cognitive change during and after different types of menopause, and whether giving CEE before or during follicular depletion impairs memory, as compared to E2. Aim 3) We found that the HT progestin medroxyprogesterone acetate (MPA) impaired cognition in Ovx rats, and decreased hippocampal glutamic acid decarboxylase (GAD) protein, possibly compensating for GABAA receptor (GABAAR) stimulation. Another progestin, norethindrone acetate (NETA), enhanced memory in Ovx rats. We hypothesize that NETA antagonizes the GABAAR, reducing GABAAR-mediated inhibition, enhancing memory. Aim 3 will determine whether the GABAergic system underlies MPA- and NETA-induced memory changes. Aim 4). This aim tests whether MPA or NETA impacts the effects of CEE or E2. MPA was chosen for this aim to test the HT Prempro (CEE+MPA); NETA was chosen due to its potential to be part of a novel combination HT, as it is used in contraceptives and it enhanced rat cognition. In each study, we will quantify GAD and cholinergic markers, each previously shown to relate to cognition, in brains of cognitively characterized rats. Multiple regression and growth modeling will test relations between the GABAergic system, cholinergic system, hormone levels, and cognition in both menopause models. This work will yield insight into cognitive effects of the menopause transition, variations in menopause type and HTs, and related mechanisms.

描述（由适用提供）：在此续签中，我们假设这种更年期和相关的马酮变化与马酮治疗（HT）的认知反应性有关。最初的赠款使用大鼠评估了使用4-乙烯基环己烯（VCD）的HTS的HTS变异和过渡更年期的变化。 VCD处理的大鼠发生卵巢衰竭；卵泡和雌激素耗尽，雄激素无反应，促性腺激素增加，这是类似于过渡绝经的妇女的特征。最初赠款的数据为测试有关过渡性与手术更年期的新假设的基础。在女性中，过渡和手术更年期都与记忆变化有关。但是，大多数啮齿动物研究已经测试了OVX后的认知效应。尽管洞察大鼠模型在手术激素丧失方面产生了产量，但手术绝经模型<13％的女性。在这里，我们研究了不同的更年期类型如何影响认知和大脑衰老，并旨在确定更年期过渡和HT的最佳参数。提出了四个目的，使用大鼠：目标1）我们发现雄激素（Andro）与记忆受损有关。由于Andro直接转换为雌酮，并且我们显示了雌酮诱导的记忆力障碍，因此我们假设Andro的转化为雌狮会损害记忆。 AIM 1测试Andro的转化为进化或雄激素受体刺激是其认知损害的基础。目的2）临床研究支持HT受益认知的关键窗口。大鼠研究支持这一点；但是，这些研究使用了OVX大鼠，仅分别给出17° - 雌二醇（E2）。 E2在女性和大鼠中是天然存在的，但仅在共轭等效性（CEE）HT中以痕量存在。在大鼠中，我们发现外科绝经后的CEE增强了记忆力，但在卵泡消耗后给予过渡更年期后的记忆力受损。 AIM 2测试在不同类型的更年期期间和之后的认知变化，以及与E2相比，是否在卵泡耗尽之前或期间给予CEE会损害记忆。目的3）我们发现，OVX大鼠的认知障碍乙酸盐孕激素（MPA），降低了海马谷氨酸脱羧酶（GAD）蛋白，可能会补偿GABAA受体（GABAAR）刺激的补偿。另一个孕激素乙酸盐（Neta）增强了OVX大鼠的记忆。我们假设Neta会拮抗Gabaar，从而减少了Gabaar介导的抑制作用，从而增强了记忆力。 AIM 3将确定GABA能系统是否是MPA和NETA诱导的内存变化的基础。目标4）。此目的测试MPA或Neta是否影响CEE或E2的影响。选择了MPA以测试HT PremPro（CEE+MPA）；选择Neta是因为它可能成为新型组合HT的潜力，因为它用于避孕药并增强了大鼠认知。在每项研究中，我们将在认知表征大鼠的大脑中量化GAD和胆碱能标记物，该标记与认知有关。多重回归和增长模型将在两个更年期模型中测试GABA能系统，胆碱能系统，胆碱能水平和认知之间的关系。这项工作将深入了解更年期过渡的认知作用，更年期类型和HTS的变化以及相关机制。