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。雌激素替代疗法（ERT）通常用于更年期妇女，以防止雌激素缺乏的不良后果。然而，ERT与患乳腺癌和尿癌的风险增加有关。非甾体雌激素已被开发出来，以模仿雌激素对特定系统的有益作用，但最大限度地减少其对乳房和子宫内膜组织的增殖作用。这些化合物被称为选择性雌激素受体调节剂（SERMs），在外周靶组织中有很好的疗效，但它们对认知功能的影响尚不清楚。显然，SERMs对认知的影响必须在这些药物被认为是ERT的有用替代品之前进行表征。我们将使用人类更年期的恒河猴模型来检查雌二醇和SERM雷洛昔芬对女性认知的影响。一项对老年去卵巢雌性恒河猴的初步研究表明，长期剥夺雌激素可能会加重视觉识别记忆缺陷，但对空间记忆缺陷的发展有保护作用。该项目将在同样的OVX猴子中确定乙炔雌二醇（EE2）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效果。在接受和不接受激素治疗期间，研究人员将对猴子进行三组记忆任务的反复测试。特异性目的1将确定EE2是否增强视觉识别记忆和工作记忆，同时损害老年OVX雌性恒河猴的空间记忆；特异性目标2将确定SERM雷洛昔芬是否作为EE2激动剂对记忆功能起作用。恒河猴的这些数据将为EE2和雷洛昔芬对女性认知的功效提供有价值的信息，并将有助于评估在雌激素水平低下的女性，特别是绝经后使用这些化合物的风险和益处。

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.