COGNITIVE AGING: EFFECTS OF ESTRADIOL AND RALOXIFENE

雌激素对各种系统有多种影响，更年期缺乏这些激素会增加患上与年龄有关的问题的风险，如骨质疏松症、心血管疾病、记忆障碍和痴呆症。 雌激素替代疗法（ERT）通常用于绝经期妇女，以防止雌激素缺乏的不良后果。 然而，雌激素替代疗法与更大的患乳腺癌和肾癌的风险有关。非甾体雌激素已被开发用于模拟雌激素对特定系统的有益作用，但最大限度地减少其对乳腺和子宫内膜组织的增殖作用。 这些被称为选择性雌激素受体调节剂（SERM）的化合物在外周靶组织中具有良好的疗效，但其对认知功能的影响尚不清楚。 显然，SERM对认知的影响，必须先表征这些代理商可以被认为是一个有用的替代ERT。 我们将使用人类绝经期的恒河猴模型来研究雌二醇和SERM雷洛昔芬对女性认知的影响。 一项在老年卵巢切除（OVX）雌性恒河猴中进行的初步研究表明，长期剥夺雌激素可能会加剧视觉识别记忆缺陷，但可以防止随着年龄的增长而出现空间记忆缺陷。 该项目将确定在相同的OVX猴中，炔雌醇（EE 2）是否能够逆转这种认知表现模式，以及SERM雷洛昔芬是否具有类似的作用。 在有和没有激素治疗的时期，猴子将被重复测试三个记忆任务的电池。具体目标1将确定EE 2是否增强老年OVX雌性恒河猴的视觉识别记忆和工作记忆，同时损害空间记忆;具体目标2将确定SERM雷洛昔芬是否作为EE 2激动剂对记忆功能起作用。 恒河猴的这些数据将提供有关EE 2和雷洛昔芬对女性认知的疗效的有价值的信息，并将有助于评估在低雌激素女性中使用这些化合物的风险和益处，特别是在绝经后。

Estrogens have a multiplicity of effects on a variety of systems and deficiency of these hormones at menopause can increase the risk of developing age-related problems such as osteoporosis, cardiovascular diseases, memory impairments and dementia. Estrogen Replacement Therapy (ERT) is often prescribed to menopausal women to protect against such adverse consequences of estrogen deficiency. ERT, however is associated with a grater risk of developing breast and urine cancers. Non-steroidal estrogens have been developed to mimic the beneficial effects of estrogens on specific systems, yet minimize their proliferative effects on breast and endometrial tissues. These compounds called selective Estrogen Receptor Modulators(SERMs), have a well-documented efficacy in peripheral target tissues, but their effects on cognitive function are not known. Clearly, the effects of SERMs on cognition must be characterized before these agents can be considered as a useful alternative to ERT. We will use a rhesus monkey model of human menopause to examine the effects of estradiol and the SERM raloxifene on female cognition. A preliminary study in aged ovariectomized (OVX) female rhesus monkeys suggested that long-term deprivation of estrogens may exaggerate visual recognition memory deficits, but protect against the development with aging of spatial memory deficits. This project will determine in the same OVX monkeys whether ethinyl estradiol (EE2) is able to reverse this pattern of cognitive performance and whether the SERM raloxifene has similar effects. Monkeys will be repeatedly tested on a battery of three memory tasks, during periods with and without hormonal treatment. Specific Aim 1 will determine whether EE2 enhances visual recognition memory and working memory, while impairing spatial memory in aged OVX female rhesus monkeys; Specific Aim 2 will determine whether the SERM raloxifene acts as an EE2 agonist on memory functions. These data in the rhesus monkey will provide valuable information on the efficacy of EE2 and raloxifene on female cognition and will help evaluating the risks and benefits of using these compounds in hypoestrogenic women, especially after menopause.