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

卵泡耗尽的卵巢在慢性疾病发病机制中的作用

• 批准号: 7730857
• 负责人: Susan E Appt
• 金额: $ 58.14万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7730857
• 关键词: Affect; Age; Androgens; Animals; Apoptosis; Atherosclerosis; Biological Markers; Biopsy; Blood Pressure; Blood Vessels; Brain; Cardiovascular system; Central obesity; Characteristics; Chemicals; Chronic; Chronic Disease; Clinical Research; Control Groups; Coronary heart disease; Data; Degenerative Disorder; Development; Diet; Disease; Disease Outcome; Disease Progression; Dyslipidemias; Elements; Epidemiology; Estrogens; Event; Exhibits; Experimental Designs; Failure; Fiber; Follicle Stimulating Hormone; Follicular Atresia; Grant; Health; Hormonal; Hormones; Hyperglycemia; Indium; Individual; Institution; Intervention; Intraperitoneal Injections; Investigation; Knowledge; Lipids; Long-Term Effects; Measures; Menopause; Metabolic; Metabolic syndrome; Modeling; Monkeys; Mus; Musculoskeletal System; Osteoporosis; Outcome; Ovarian; Ovarian hormone; Ovary; Pathogenesis; Perimenopause; Phase; Physicians; Physiological; Pilot Projects; Population; Positioning Attribute; Postmenopause; Premenopause; Primordial Follicle; Process; Production; Quality of life; Research; Research Design; Residual state; Risk; Risk Factors; Role; Serum; Staging; Suggestion; Techniques; Testosterone; Time; Tissues; Transition Elements; Uncertainty; Woman; aged; base; bone; bone loss; design; experience; improved; inflammatory marker; mouse model; mullerian-inhibiting hormone; nonhuman primate; older women; public health relevance; reproductive; skeletal

DESCRIPTION (provided by applicant): The worldwide population of postmenopausal women is increasing (expected to be 1.1 billion by 2025) and these women are surviving longer than their predecessors. Coronary heart disease (CHD), osteoporosis, and the metabolic syndrome comprise a substantial part of the health burden affecting this population. However, despite considerable epidemiological and clinical research, the initiation and trajectory of these chronic and degenerative conditions remain unclear. Two specific gaps in knowledge are: 1) whether or to what extent the perimenopause is a time of accelerated disease progression; and 2) whether the pathobiological changes that have accumulated by the time of menopause establish the trajectory of postmenopausal disease outcomes. Accordingly, this application seeks support to continue a study of peri- and post-menopausal monkeys. The study in progress takes advantage of a nonhuman primate model of the menopausal transition developed recently at our institution. This model was adapted from a mouse model of perimenopause which uses a chemical (4-vinylcyclohexene diepoxide -VCD) to destroy primordial follicles via apoptosis and atresia. The model recapitulates the physiological changes experienced by women during the perimenopausal transition, including decreased numbers and ultimate depletion of primordial follicles and subsequent decreases in antimullerian hormone (AMH). Further, the stroma of the resulting follicle-depleted ovary has similar biologic activity (e.g. androgen production) to that of naturally postmenopausal women. As summarized, this model has several advantages over ovariectomized animals, a research platform that does not yield hormonal characteristics or risk factors (e.g., serum lipids) comparable to those observed in naturally postmenopausal women. The existing gaps in knowledge surrounding the perimenopausal transition and postmenopause prompted us to propose the following four Specific Aims: 1) Determine the extent to which diet induced atherosclerosis progression, as measured directly through biopsy, differs among ovariectomized (OVX), perimenopausal (VCD treated) and premenopausal monkeys, whether perimenopausal atherosclerosis extent determines the extent of postmenopausal atherosclerosis development, and finally, whether the trajectories of atherosclerosis progression differ between the peri and postmenopausal phases; 2) Determine whether bone loss occurs during the perimenopausal transition and to compare the magnitude of any bone loss that does occur with that observed during the postmenopausal phase; 3) Determine if and to what extent, elements of the metabolic syndrome appear during the perimenopausal transition, and whether the increases are greater in peri or postmenopausal phase; and 4) To compare and contrast the hormonal characteristics of VCD-treated monkeys both peri- and postmenopausally, with those observed in their OVX and premenopausal counterparts, and to determine whether changes in ovarian hormones in these reproductive phases are associated with changes in atherosclerosis extent and cardiovascular, skeletal, and metabolic risk biomarkers. PUBLIC HEALTH RELEVANCE: The information gained through this investigation will provide women and their physicians with urgently required evidence on which to base decisions concerning peri- and postmenopausal treatment options. In addition, the outcomes observed in this study might well extend beyond the vascular and musculoskeletal systems to include other tissues that are sensitive to the effects of ovarian hormones, such as the brain.

描述（由申请人提供）：全球绝经后妇女人口正在增加（预计到 2025 年将达到 11 亿），并且这些妇女的寿命比她们的前辈更长。冠心病（CHD）、骨质疏松症和代谢综合征是影响该人群的健康负担的很大一部分。然而，尽管进行了大量的流行病学和临床研究，这些慢性和退行性疾病的发生和轨迹仍不清楚。两个具体的知识差距是：1）围绝经期是否或在多大程度上是疾病加速进展的时期； 2）绝经前积累的病理变化是否确定了绝经后疾病结果的轨迹。因此，本申请寻求支持以继续对绝经期和绝经后猴子进行研究。正在进行的研究利用了我们机构最近开发的非人类灵长类动物绝经过渡模型。该模型改编自围绝经期小鼠模型，该模型使用化学物质（4-乙烯基环己烯二环氧化合物-VCD）通过细胞凋亡和闭锁破坏原始卵泡。该模型概括了女性在围绝经期过渡期间经历的生理变化，包括原始卵泡数量减少和最终耗尽，以及随后抗苗勒管激素 (AMH) 的减少。此外，由此产生的卵泡耗尽的卵巢的基质具有与自然绝经后妇女相似的生物活性（例如雄激素的产生）。综上所述，该模型比卵巢切除动物有几个优点，这是一个研究平台，不会产生与自然绝经后妇女中观察到的激素特征或危险因素（例如血脂）相当的结果。围绕围绝经期过渡和绝经后的现有知识差距促使我们提出以下四个具体目标：1）确定饮食诱导动脉粥样硬化进展的程度（通过活检直接测量）在卵巢切除（OVX）、围绝经期（VCD 治疗）和绝经前猴之间存在差异，无论是否围绝经期 动脉粥样硬化程度决定绝经后动脉粥样硬化发展的程度，最后决定围绝经期和绝经后动脉粥样硬化进展轨迹是否不同； 2) 确定围绝经期过渡期间是否发生骨质流失，并将确实发生的骨质流失程度与绝经后阶段观察到的骨质流失程度进行比较； 3) 确定在围绝经期过渡期间是否出现代谢综合征的要素以及出现的程度，以及围绝经期或绝经后阶段的增加是否更大； 4) 将 VCD 治疗的猴子在围绝经期和绝经后的激素特征与在 OVX 和绝经前的猴子中观察到的激素特征进行比较和对比，并确定这些生殖阶段卵巢激素的变化是否与动脉粥样硬化程度以及心血管、骨骼和代谢风险生物标志物的变化相关。公共健康相关性：通过这项调查获得的信息将为妇女及其医生提供迫切需要的证据，以此作为有关绝经期和绝经后治疗方案决策的基础。此外，这项研究中观察到的结果很可能不仅限于血管和肌肉骨骼系统，还包括对卵巢激素影响敏感的其他组织，例如大脑。