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: 8304221
• 负责人: Susan E Appt
• 金额: $ 54.2万
• 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 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8304221
• 关键词: Affect; 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; Vascular System; Woman; aged; base; bone; bone loss; design; experience; improved; inflammatory marker; mouse model; mullerian-inhibiting hormone; nonhuman primate; older women; 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）：绝经后妇女的全球人口正在增加（预计到2025年为11亿），这些妇女的生存时间比其前任更长。冠心病（CHD），骨质疏松症和代谢综合征构成了影响这一人群的大部分健康负担。然而，尽管流行病学和临床研究相当大，但这些慢性和退化性疾病的起始和轨迹尚不清楚。知识的两个具体差距是：1）围绝经期是否或在多大程度上是加速疾病进展的时期； 2）在更年期时期积累的病理生物学变化是否建立了绝经后疾病结局的轨迹。因此，本申请寻求支持继续对杂期和绝经后猴子进行研究。这项正在进行的研究利用了最近在我们机构开发的绝经过渡的非人类灵长类动物模型。该模型改编自使用化学（4-乙烯基环己烯二氧化碳-VCD）的小鼠模型通过细胞凋亡和闭锁来破坏原始卵泡。该模型概括了妇女在围绝经期转变期间妇女所经历的生理变化，包括原始卵泡的数量减少和最终消耗以及随后的抗炎性激素（AMH）降低。此外，所产生的卵泡卵巢的基质具有与绝经后妇女相似的生物学活性（例如雄激素产生）。据总结，该模型比卵巢切除动物具有多个优势，该研究平台不会产生与在绝经后妇女中观察到的那些相当的激素特征或危险因素（例如，血清脂质）。围绕末期过渡和绝经后的知识差距的现有差距促使我们提出以下四个具体目的：1）确定饮食诱导的动脉粥样硬化进展的程度，直接通过活检进行测量，在卵巢肌肉切除术（OVX）之间，以及莫尼氏菌（VCD）（vcd predepaimed）（vcd predepaimed），是否有差异。动脉粥样硬化的程度决定了绝经后动脉粥样硬化发展的程度，最后，在绝经后和绝经后阶段，动脉粥样硬化进展的轨迹是否有所不同； 2）确定骨质流失是否发生在上绝经期间的过渡过程中，并比较在绝经后相观察到的任何骨质流失的幅度； 3）确定在围绝经内部过渡期间，代谢综合征的元素以及在多大程度上出现的元素，以及在绝经后或绝经后的增加是否更大；和4）在骨周围和绝经后与VCD处理的猴子的荷尔蒙特征与在其OVX和绝经前对应物中观察到的激素特征，并确定这些生殖阶段的卵巢激素的变化是否与这些生殖阶段的卵巢阶段的变化有关，是否与动脉粥样硬化的风险范围和心脏病患者相关。公共卫生相关性：通过这项调查获得的信息将为妇女及其医生迫切需要证据，以基于有关绝经后治疗方案的决定。此外，这项研究中观察到的结果很可能超越血管和肌肉骨骼系统，包括对卵巢激素（例如大脑）敏感的其他组织。

项目成果

Endocrine profile of an ovariectomized cynomolgus monkey (Macaca fascicularis) with a supernumerary ovary.

具有多余卵巢的切除卵巢食蟹猴（Macaca fasciculis）的内分泌特征。

• 发表时间: 2011
• 期刊: Comparative medicine
• 影响因子: 0.8
• 作者: Ethun,KellyF;Cline,JMark;Appt,SusanE
• 通讯作者: Appt,SusanE

Effects of bazedoxifene alone and with conjugated equine estrogens on coronary and peripheral artery atherosclerosis in postmenopausal monkeys.

• DOI: 10.1097/gme.0b013e318271e59b
• 发表时间: 2013-03
• 期刊: Menopause (New York, N.Y.)
• 作者: Clarkson TB;Ethun KF;Chen H;Golden D;Floyd E;Appt SE
• 通讯作者: Appt SE

Effects of bazedoxifene, conjugated equine estrogens, and a tissue-selective estrogen complex containing both bazedoxifene and conjugated equine estrogens on cerebral artery atherosclerosis in postmenopausal monkeys.

• DOI: 10.1097/gme.0b013e31829370e5
• 发表时间: 2014-01
• 期刊: Menopause (New York, N.Y.)
• 作者: Clarkson TB;Ethun KF;Pajewski NM;Golden D;Floyd E;Appt SE
• 通讯作者: Appt SE

Response to an adequate dietary intake of vitamin D3 modulates the effect of estrogen therapy on bone density.

饮食中摄入足够的维生素 D3 可以调节雌激素治疗对骨密度的影响。

• DOI: 10.1089/jwh.2011.3244
• 发表时间: 2012
• 期刊: Journal of women's health (2002)
• 作者: Schnatz,PeterF;Marakovits,KimberlyA;O'Sullivan,DavidM;Ethun,Kelly;Clarkson,ThomasB;Appt,SusanE
• 通讯作者: Appt,SusanE