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

我们继续研究计划的广泛目标是破译过渡期的认知和大脑影响。 以及绝经期的手术变体，包括通过发现有效的激素来优化认知老化， 治疗（HT）的选择，在妇女更年期的变化。这包括确定 记忆和大脑的变化作为过渡性更年期englomerate时，卵巢正在经历卵泡耗竭， 以及过渡期和手术绝经期变异后干预的最佳参数。 更年期与认知能力下降和痴呆风险增加有关。然而，驱动因素 这些结果，以及HT参数改变效果，是不确定的。重要性得到强调， 大多数女性至少有三分之一的生命处于更年期状态， 变异（有或没有子宫、卵泡耗竭卵巢或HT）。在目前的赠款期间，我们有23个 出版物;使用大鼠模型，我们表明，过渡性更年期对记忆力有影响， 在围绝经期，当卵泡经历早期耗竭时， 雄烯二酮水平与较差的记忆结果相关，短期子宫切除术（子宫 移除）单独损害记忆。我们发现孕酮损害记忆，这些影响是 由GABA能系统调节。我们还发现，几种临床使用的合成孕激素损害了 记忆，并确定了一个增强记忆：左炔诺孕酮（左）。服用口服避孕药或 HT，一个有子宫的女人必须包括一个沿着雌激素，以抵消雌激素诱导的增生。 因此，我们进行了一项单独与联合研究，并显示17β-雌二醇（E2）和左旋 单独使用时记忆力增强，但联合使用时记忆力受损。我们还发现E2- 诱导的认知益处与胆碱能完整性相关，建立在文献显示雌激素- 胆碱能相互作用这一更新解决了这些集体调查结果所产生的关键问题。目的 1测试不同的E2方案是否减轻与围绝经期相关的记忆障碍。 过渡，并评估抗雄激素或具有最小雄激素性的新型孕激素，目标是 找到不会逆转E2对认知和大脑有益影响的选择。目标2决定了变化 在更年期类型，包括子宫切除术，影响认知和大脑，测试影响的时间窗口， 年龄和卵泡耗竭状态。目的3定义了更年期变异和临床使用的HT如何与 候选神经递质系统的机制细节，系统地检查GABA能信号， 胆碱能回路我们将联合收割机的行为，生理和神经生物学方法结合在一起， 一项盲法和随机动物模型研究计划，以解开更年期变异的复杂性 和HT神经认知增强的机会，从临床明确推断指令。

The broad goal of our continued program of research is to decipher the cognitive and brain effects of transitional and surgical variants of menopause, including optimizing cognitive aging by discovering efficacious hormone therapy (HT) options in the context of menopause variations seen in women. This incorporates determining memory and brain changes as transitional menopause ensues when ovaries are undergoing follicular depletion, as well as the optimal parameters for interventions subsequent to transitional and surgical menopause variants. Menopause has been associated with cognitive decline and increased dementia risk. However, factors driving these outcomes, and which HT parameters alter effects, are undetermined. Importance is underscored given that most women are living at least one-third of their lives in a menopausal state encompassed by numerous variations (with or without a uterus, follicular deplete ovaries, or HT). In the current grant period, we had 23 publications; using the rat model, we showed that transitional menopause detrimentally impacted memory, that effects were most pronounced during perimenopause when follicles were undergoing early depletion, that higher androstenedione levels were associated with worse memory outcomes, and that short-term hysterectomy (uterus removal) alone impaired memory. We found that progesterone impaired memory, and that these effects were modulated by the GABAergic system. We also showed that several clinically-used synthetic progestins impaired memory, and identified one that enhanced memory: Levonorgestrel (Levo). When taking oral contraceptives or HT, a woman with a uterus must include a progestin along with estrogens to offset estrogen-induced hyperplasia. Thus, we performed an individual versus combination study, and showed that 17β-estradiol (E2) and Levo each enhanced memory when given alone, but impaired memory when given in combination. We also found that E2- induced cognitive benefits were associated with cholinergic integrity, building on literature showing estrogen- cholinergic interactions. This renewal addresses critical questions stemming from these collective findings. Aim 1 tests whether varied E2 regimens attenuate memory impairments associated with the perimenopausal transition, and assesses novel progestins that are anti-androgenic or have minimal androgenicity, with a goal to find options that do not reverse beneficial E2 effects on cognition and the brain. Aim 2 determines how variations in menopause type, including hysterectomy, impact cognition and the brain, testing effects of a temporal window, age, and follicular depletion state. Aim 3 defines how menopause variants and clinically-used HTs interact with candidate neurotransmitter systems in mechanistic detail, systematically examining GABAergic signaling and cholinergic circuitry. We combine behavioral, physiological, and neurobiological approaches in the framework of a blinded and randomized animal model research program to disentangle the complexity of menopause variants and HT opportunities for neurocognitive enhancement, extrapolating directives explicitly from the clinic.