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，我们研究了与激素治疗（HT）认知反应相关的更年期类型和相关激素变化。最初的资助使用大鼠来评估手术绝经（Ovx）的 HT 变化，以及使用 4-乙烯基环己烯二环氧化物 (VCD) 治疗的过渡性更年期大鼠会出现卵巢衰竭和雌激素耗尽，雄激素变得不受抑制；和促性腺激素的增加，重新组合了过渡性更年期女性的数据，为测试关于女性过渡性更年期和手术性更年期的新假设奠定了基础。然而，大多数啮齿动物研究都表明。 Ovx 后测试了认知效果。尽管大鼠模型对手术激素损失有一定的了解，但手术绝经模型的女性比例低于 13%。在此，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。使用大鼠提出了绝经过渡和 HT 的最佳参数： 目标 1) 我们发现雄烯二酮 (Andro) 与记忆受损有关，因为 Andro 直接转化为雌酮，并且我们已经证明雌酮引起的记忆障碍，我们研究Andro向雌激素或雄激素受体刺激的转变是其认知损害的基础。目标1测试Andro向雌激素或雄激素受体刺激的转变是否是其认知损害的根源。 2) 临床研究支持了 HT 有益于认知的关键窗口期，但是，这些研究使用了 Ovx 大鼠，并且只给出了 17¿ -雌二醇 (E2)。E2 在女性和大鼠中天然存在，但仅在结合马雌激素 (CEE) HT 中存在微量，我们发现 CEE 可以增强手术绝经后的记忆力，但会损害过渡性绝经后的记忆力。目标 2 测试不同类型的绝经期间和之后的认知变化，以及相比之下，在卵泡耗尽之前或期间给予 CEE 是否会损害记忆。目标 3) 我们发现 HT 孕激素醋酸甲羟孕酮 (MPA) 会损害 Ovx 大鼠的认知能力，并减少海马谷氨酸脱羧酶 (GAD) 蛋白，可能是对另一种孕激素醋酸炔诺酮 (GABAAR) 的刺激进行补偿。 NETA），增强了 Ovx 大鼠的记忆力，我们努力发现 NETA 具有拮抗作用。 GABAAR，减少 GABAAR 介导的抑制，增强记忆，目标 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）测试 MPA 或 NETA 是否影响 CEE 或 MPA。被选中用于测试 HT Prempro (CEE+MPA)，因为它有可能成为新型组合 HT 的一部分，因为它用于避孕药具和药物中；在每项研究中，我们都将量化具有认知特征的大鼠大脑中的 GAD 和胆碱能标记物，这些标记物先前已被证明与认知有关。多元回归和生长模型将测试 GABA 能系统、胆碱能系统和激素水平之间的关系。以及两种更年期模型中的认知。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。