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（由申请人提供）：在本次更新中，我们假设绝经类型和相关激素变化与对激素治疗（HT）的认知反应有关。最初的研究使用大鼠评估手术绝经（Ovx）和使用4-乙烯基环己烯二环氧化物（VCD）的过渡性绝经的HT变化。VCD处理的大鼠发生卵巢衰竭;卵泡和雌激素耗尽，雄激素变得无抵抗力，促性腺激素增加，类似于过渡性绝经妇女的概况。来自最初拨款的数据为测试关于过渡性绝经与手术绝经的新假设奠定了基础。在女性中，过渡期和手术绝经都与记忆变化有关。然而，大多数啮齿动物研究都测试了Ovx后的认知影响。尽管洞察大鼠模型产生关于手术激素损失，手术绝经模型<13%的妇女。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。本研究提出了四个目的：目的1）我们发现雄烯二酮（Andro）与记忆障碍有关。由于Andro直接转化为雌酮，我们已经证明雌酮诱导的记忆障碍，我们假设Andro转化为雌酮损害记忆。目的1测试是否安德罗的转换为雌激素，或雄激素受体刺激，其认知功能的基础。目的2）临床研究支持HT有益于认知的关键窗口。大鼠研究支持这一点;然而，这些研究使用了Ovx大鼠，并且仅给予17 <$-雌二醇（E2）。E2是天然存在于女性和大鼠中，但仅以痕量存在于结合型马雌激素（CEE）HT中。在大鼠中，我们发现CEE增强了手术绝经后的记忆力，但在卵泡耗竭后给予过渡性绝经后的记忆力受损。目的2测试不同类型的更年期期间和之后的认知变化，以及与E2相比，在卵泡耗竭之前或期间给予CEE是否会损害记忆。目的3）发现羟色胺（HT）抑制剂醋酸甲羟孕酮（MPA）可使Ovx大鼠的认知功能受损，并使海马谷氨酸脱羧酶（GAD）蛋白表达减少，可能是对GABAA受体（GABAAR）刺激的补偿作用。另一种维生素E，醋酸炔诺酮（NETA），增强了Ovx大鼠的记忆力。我们假设NETA拮抗GABAAR，减少GABAAR介导的抑制，增强记忆。目的3将确定GABA能系统是否是MPA和NETA诱导的记忆变化的基础。目标4）。 这个目标测试MPA或NETA是否影响CEE或E2的效果。为此目的选择MPA来测试HT Prempro（CEE+MPA）;选择NETA是因为其可能成为新型组合HT的一部分，因为它用于避孕药并增强大鼠认知。在每项研究中，我们将量化GAD和胆碱能标记物，每一个先前被证明与认知有关，在认知特征大鼠的大脑中。多元回归和生长建模将测试两种更年期模型中GABA能系统、胆碱能系统、激素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影响，更年期类型和HT的变化以及相关机制。