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

描述(申请人提供)：在十年内，每七个美国人中就有一个是绝经后的女性。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与骨质疏松症相关的骨折，十分之一的人将患上乳腺癌。生殖生命阶段和这些绝经相关疾病的发病之间的关系尚未得到充分的探讨，这在很大程度上是因为缺乏适合妇女自然更年期的动物模型。我们建议将一项在小鼠身上开发的技术扩展到食蟹猴(猕猴)，该技术利用暴露于4-乙烯基环己烯二环氧化物(VCD)来选择性地靶向原始和初级卵泡，从而导致卵巢衰竭并模拟女性发生的更年期。我们假设，荷尔蒙分泌、卵泡耗尽的猴子(我们称之为“剩余卵巢更年期”)将模仿自然绝经后妇女的疾病易感性。总体目标是使用ROM和卵巢切除(OVX)猴子来确定与绝经后相比，在围绝经期过渡期间慢性疾病的发展过程。目标是： 具体目的1.比较卵巢去卵泡猴子和去卵巢猕猴的激素特征。 具体目的2.确定围绝经期过渡期间动脉粥样硬化的易感性增加的程度，以及在ROM和OVX治疗条件下观察到的动物心血管危险因素或卵巢激素的变化与这种易感性增加的关系。 具体目标3.确定围绝经期过渡期间骨丢失易感性增加的程度，以及这种增加与在ROM和OVX动物中观察到的垂体和卵巢激素变化之间的关系。 具体目的4.确定血浆雄激素浓度是否以及在多大程度上调节雌激素刺激的ROM猴乳腺细胞增殖，并与其OVX猴子进行比较。相关性：据推测，围绝经期明显影响绝经后妇女的疾病，特别是心血管疾病和骨质疏松症的易感性增加；这种增加(拟议的研究旨在检测到这种增加)意味着需要积极的早期干预。此外，据推测，自然更年期妇女的卵巢间质会产生大量的--尽管是可变的--睾酮，这反过来可能会减缓骨质丢失、动脉粥样硬化的进展，甚至可能减缓乳腺癌的发生。通过确定围绝经期和绝经后妇女的残留激素对这些疾病过程的影响程度，拟议的研究将促进为改善绝经后生活质量而开发有针对性的个性化治疗。

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.