A novel model of reproductive and metabolic features of polycystic ovary syndrome

描述（由申请人提供）：多囊卵巢综合征（PCOS）是人类最常见的生殖内分泌疾病之一。多囊卵巢综合征（PCOS）不仅是一种以多毛、不孕、反复流产、子宫内膜癌等为主要症状的妇科疾病，而且是一种伴有多种代谢紊乱的综合征。最近认识到胰岛素抵抗在PCOS中的突出作用，强调了该疾病的代谢方面，并强调了II型糖尿病（DM）和心血管疾病（CVD）的相关风险。PCOS的生殖和代谢发病率使其成为一个重要的女性健康问题，在受影响个体的整个生命周期中都会产生医疗后果。然而，其病因和发病机制尚不清楚，目前尚无有效的治疗方法。目前，还没有一种比较性的PCOS动物模型能够充分体现该综合征的复杂性。本申请的目的是表征和验证雌性Ossabaw猪作为PCOS模型，其体现了综合征的代谢和生殖方面。我们假设Ossabaw猪是PCOS代谢和生殖机制的良好比较动物模型，基于我们强有力的初步研究结果，这表明雌性Ossabaw猪在过量喂养时自然发展出代谢综合征（MS）的许多特征，并且它们发展出PCOS与MS的特征，即高雄激素血症，卵巢增大和卵泡生长改变。我们计划通过追求一个单一的特定目标来实现我们的目标：在Ossabaw女性中评估诱导代谢综合征的饮食中PCOS的特定生殖和代谢病因。生殖方面，包括高雄激素血症、卵泡膜细胞雄激素产生异常、LH：FSH比值改变、卵巢囊肿和无排卵。代谢参数包括血脂异常、葡萄糖耐受不良、高胰岛素血症和胰岛素受体信号传导的特定改变。该团队为开展拟议的研究做好了特别充分的准备，因为他们结合了生殖、内分泌、心血管疾病和肥胖等领域的专业知识。这项研究具有创新性，因为它将首次描述PCOS的模型，其中可以整体研究综合征的复杂异常。拟议研究的基本原理是，将Ossabaw小型猪作为PCOS模型的特征将允许该领域的重大进展。研究人员将能够阐明该疾病的病理生理学，从而为PCOS的直接症状制定管理策略，如不孕症，雄激素过多和代谢综合征，以及其长期健康影响，包括子宫内膜癌，糖尿病和心血管疾病。多囊卵巢综合征（PCOS）是育龄妇女最常见的内分泌疾病之一。目前，还没有一个完整的动物模型，代表了生殖和代谢的复杂性综合征。Ossabaw小型猪作为PCOS模型的特征将允许该领域的重大进展。研究人员将能够阐明该疾病的病理生理学，从而为PCOS的直接症状制定管理策略，如不孕症，雄激素过多和代谢综合征，以及其长期健康影响，包括子宫内膜癌，糖尿病和心血管疾病。

DESCRIPTION (provided by applicant): Polycystic ovary syndrome (PCOS) is one of the most common human reproductive endocrine disorders. PCOS is not only a gynecological condition presenting with symptoms such as hirsutism, infertility, recurrent pregnancy loss and endometrial carcinoma, but a comprehensive syndrome with a variety of associated metabolic disorders. Recent recognition of the prominent role of insulin resistance in PCOS has emphasized the metabolic aspects of the disorder and highlighted the associated risks of type II diabetes mellitus (DM) and cardiovascular disease (CVD). The reproductive and metabolic morbidities of PCOS make it an important women's health issue, with medical consequences across the lifespan of affected individuals. However, the etiology and pathogenesis of the syndrome are unclear, and there is no effective cure. Currently, no comparative animal model of PCOS exists that fully embodies the complexity of the syndrome. The objective of this application is to characterize and validate the female Ossabaw pig as a model of PCOS that embodies both the metabolic and reproductive aspects of the syndrome. We hypothesize that the Ossabaw pig is a good comparative animal model of both the metabolic and reproductive mechanisms of PCOS based upon our strong preliminary findings, which demonstrate that female Ossabaw swine naturally develop many characteristics of metabolic syndrome (MS) when fed in excess, and that they develop features of PCOS with MS, namely hyperandrogenemia, enlarged ovaries and altered follicular growth. We plan to accomplish our objective by pursuing a single Specific Aim: Evaluate specific reproductive and metabolic etiologies of PCOS in Ossabaw females fed a diet that induces metabolic syndrome. Reproductively, these include hyperandrogenemia, abnormal theca cell androgen production, altered LH:FSH ratios, cystic ovaries and anovulation. Metabolic parameters include dyslipidemia, glucose intolerance, hyperinsulinemia, and specific alterations in insulin receptor signaling. This team is particularly well prepared to undertake the proposed research, as they have combined expertise in the areas of reproduction, endocrinology, cardiovascular disease and adiposity. The proposed research is innovative in that it will characterize, for the first time, a model for PCOS in which the complex abnormalities of the syndrome can be studied as a whole. The rationale for the proposed research is that characterization of the Ossabaw mini-pig as a model of PCOS will permit significant advances in the field. Researchers will be able to elucidate the pathophysiology of the disease and thus develop management strategies for the immediate symptoms of PCOS, such as infertility, androgen excess and metabolic syndrome, as well as its long term health implications, including endometrial cancer, diabetes and cardiovascular disease. PUBLIC HEALTH RELEVANCE: Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in reproductive aged women. Currently, there is no complete animal model that represents both the reproductive and metabolic complexities of the syndrome. Characterization of the Ossabaw mini-pig as a model of PCOS will permit significant advances in the field. Researchers will be able to elucidate the pathophysiology of the disease and thus develop management strategies for the immediate symptoms of PCOS, such as infertility, androgen excess and metabolic syndrome, as well as its long term health implications, including endometrial cancer, diabetes and cardiovascular disease.