Role of the Follicle-Depleted Ovary in the Pathogenesis of Chronic Diseases

描述（由申请人提供）：在十年内，每七个美国人中就有一个将是绝经后妇女。心血管疾病将是这一群体中最大的单一死亡原因，多达一半的人将遭受骨质疏松相关的骨折，十分之一的人将患上乳腺癌。在很大程度上，由于缺乏适当的妇女自然绝经动物模型，生殖阶段与这些与更年期有关的疾病的发病之间的关系尚未得到充分探讨。我们建议将在小鼠中开发的一项技术扩展到食环猴（Macaca fascicularis），该技术使用暴露于4-乙烯基环己烯二氧化二（VCD）来选择性地靶向原始和初级卵泡，从而诱导卵巢衰竭并模拟女性更年期的发生。我们假设，具有产生激素、卵泡减少的卵巢的猴子（我们称之为“残留卵巢更年期”[ROM]）将模仿自然绝经后妇女的疾病脆弱性。总体目标是使用ROM和卵巢切除（OVX）猴子来确定围绝经期过渡期间与绝经后时期相比慢性疾病过程的发展。目标是：

DESCRIPTION (provided by applicant): Within a decade one of every seven Americans will be a postmenopausal woman. Cardiovascular disease will be the largest single cause of death within this group, up to half will suffer an osteoporosis-related fracture, and one in ten will develop breast cancer. The relationship between stage of reproductive life and the onset of these menopause-associated diseases has not been explored adequately, in large part, because of the lack of a suitable animal model of natural menopause in women. We propose to extend to cynomolgus monkeys (Macaca fascicularis) a technique developed in mice that uses exposure to 4-vinylcyclohexene diepoxide (VCD) to selectively target primordial and primary follicles, thereby inducing ovarian failure and modeling the menopause as it occurs in women. We hypothesize that monkeys with a hormone-producing, follicle-depleted ovary (a condition that we refer to as "residual ovary menopause" [ROM]) will mimic the disease vulnerability of naturally postmenopausal women. The overall objective is to use ROM and ovariectomized (OVX) monkeys to determine the development of chronic disease processes during the perimenopausal transition compared to the postmenopausal period. The aims are: Specific Aim 1. To compare and contrast the hormonal characteristics of monkeys with follicle-depleted ovaries with those observed in their ovariectomized counterparts. Specific Aim 2. To determine the extent to which vulnerability to atherosclerosis is increased during the perimenopausal transition and how any such increase in vulnerability is related to changes in cardiovascular risk factors or ovarian hormones observed among animals in the ROM and OVX treatment conditions. Specific Aim 3. To determine the extent to which vulnerability to bone loss is increased during the perimenopausal transition and how any such increase is related to the pituitary and ovarian hormonal changes observed among ROM and OVX animals. Specific Aim 4. To determine if and to what extent plasma androgen concentrations modulate estradiol-stimulated breast cell proliferation in ROM monkeys in comparison to their OVX counterparts. Relevance: It has been speculated that there is a perimenopausal increase in vulnerability to the diseases that prominently affect postmenopausal women, especially cardiovascular disease and osteoporosis; such an increase (which the proposed research is designed to detect) implies the need for vigorous early intervention. Further, it has been speculated that the ovarian stroma of naturally menopausal women produces a significant -though variable- amount of testosterone, which in turn may moderate the progression of bone loss, atherosclerosis, and perhaps the occurrence of breast cancer. By determining the extent to which the residual hormones of peri- and postmenopausal women influence these disease processes, the proposed research will facilitate the development of targeted, individualized therapies for improving the postmenopausal quality of life.