Gonadotropin action in the polycystic ovary

促性腺激素在多囊卵巢中的作用

• 批准号: MR/S025235/1
• 负责人: Stephen Franks
• 金额: $ 62.12万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FS025235%2F1
• 关键词: Gonadotropin; action; polycystic; ovary

Polycystic ovary syndrome (PCOS) is the commonest hormone disorder in women, affecting between 5-10% of women of reproductive age, and typically first manifests itself during adolescence. It is a major cause of infertility and causes distressing skin problems (acne and unwanted body hair) that contribute to a negative impact on quality of life and often, overt depression. PCOS is also associated with risks to long-term health, and, in particular there is a 3-fold increase in the risk of developing type 2 diabetes (late onset, or non insulin-dependent diabetes) in later life. Infertility in women with PCOS is due to infrequent or absent ovulation (monthly release of an egg) and can usually be corrected by appropriate choice of treatment but many women remain involuntarily infertile and/or have persistent skin problems. Genetic factors play a major role in the development of PCOS but we still do not fully understand the cause or causes of the syndrome. Nevertheless, recent data from the genetic studies have provided some new clues about the key factors that might be involved in abnormal function of the ovaries and those data complement previous work in our lab that has demonstrated the importance of disordered hormone signals that control the ovary. The two most important reproductive hormones that control the ovary are luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which are produced by the pituitary gland in the brain. These hormones bind to specific proteins (receptors) on the surface of cells that nurture the growing eggs, ensuring that they behave in a way that supports healthy egg growth and ovulation. In PCOS, it is thought that these receptors might behave abnormally, resulting in the egg stopping growing and failing to ovulate. The purpose of the proposed research project is to study in detail how LH and FSH act on these cells from normal and polycystic ovaries. We shall focus, in particular, on the function of the receptors in the ovary that recognize LH and FSH and the way in which these hormones, once bound to their receptors, signal within the cell both in normal women and those with PCOS. We will use granulosa-lutein (GL) cells that are obtained at the time of egg collection for IVF and are normally discarded because they are not needed otherwise. GL cells will be collected from individual patients and transported to the lab for our research protocol. We have ethical approval for these studies and the patients each give informed consent. Once in the laboratory we shall prepare the cells in various ways, including culturing them for up to 72h. Using techniques including analysis of hormones produced by the cells (and the genes and proteins that are involved in regulation of hormone production) as well as high-resolution microscopy, we will examine the key steps involved in the action of LH and FSH on GL cells and how these differ between normal and PCOS ovaries. We anticipate that in future the information generated can be directly applied to improve the quality of life of women with PCOS. We expect to uncover specific biochemical "fingerprints" of PCOS that will be applicable to making an early diagnosis (e.g. in adolescent girls with early signs of PCOS but who do not have a firm diagnosis) and, in particular, to identify those most at risk of problems with fertility or long-term complications. Importantly, once we have identified the biochemical pathways that are dysfunctional in PCOS, it will be possible, in future, to design and test drugs with potential to target key points in these pathways to improve function. Our results will be presented at scientific meetings and prepared for publication in the leading scientific journals in the field. The applicants have extensive experience in talking about their research to fund-raising bodies, to patient groups and to broadcast and written media.

多囊卵巢综合征(PCOS)是女性最常见的激素紊乱，影响5%-10%的育龄妇女，通常在青春期首发。它是不孕不育的主要原因，并导致令人痛苦的皮肤问题(粉刺和多余的体毛)，对生活质量造成负面影响，通常还会导致明显的抑郁症。多囊卵巢综合征还与长期健康的风险有关，尤其是在晚年患2型糖尿病(晚发或非胰岛素依赖型糖尿病)的风险增加了3倍。患有多囊卵巢综合征的妇女的不孕症是由于不频繁或不排卵(每月排卵)，通常可以通过适当的治疗选择来纠正，但许多妇女仍然不由自主地不孕和/或有持续性的皮肤问题。遗传因素在多囊卵巢综合征的发生发展中起着重要作用，但目前对该综合征的病因尚不完全清楚。然而，最近来自遗传学研究的数据为可能涉及卵巢功能异常的关键因素提供了一些新的线索，这些数据补充了我们实验室之前的工作，这些工作证明了控制卵巢的紊乱激素信号的重要性。控制卵巢的两种最重要的生殖激素是黄体生成素(LH)和卵泡刺激素(FSH)，这两种激素是由大脑中的脑下垂体产生的。这些荷尔蒙结合在细胞表面的特定蛋白质(受体)上，培养发育中的卵子，确保它们的行为方式支持卵子的健康生长和排卵。在多囊卵巢综合征中，人们认为这些受体可能行为异常，导致卵子停止生长和无法排卵。这项拟议的研究项目的目的是详细研究黄体生成素和卵泡刺激素如何作用于正常卵巢和多囊卵巢的这些细胞。我们将特别关注卵巢中识别黄体生成素和卵泡刺激素的受体的功能，以及这些激素一旦与其受体结合，在正常女性和多囊卵巢综合征患者的细胞内发出信号的方式。我们将使用颗粒-叶黄素(GL)细胞，这些细胞是在采集卵子进行体外受精时获得的，通常会被丢弃，因为其他方面不需要它们。GL细胞将从个别患者身上收集，并被运送到实验室进行我们的研究方案。我们对这些研究有伦理上的批准，每个患者都给予知情同意。一旦进入实验室，我们将以各种方式准备细胞，包括培养长达72小时。使用包括分析细胞产生的激素(以及参与调节激素产生的基因和蛋白质)以及高分辨率显微镜在内的技术，我们将研究黄体生成素和卵泡刺激素对GL细胞作用的关键步骤，以及这些步骤在正常卵巢和多囊卵巢综合征之间的差异。我们预计，在未来，所产生的信息可以直接应用于改善多囊卵巢综合征妇女的生活质量。我们希望发现适用于早期诊断的多囊卵巢综合征的特定生化“指纹”(例如，在有多囊卵巢综合征早期症状但没有确诊的青春期女孩中)，特别是识别那些最有可能出现生育问题或长期并发症的人。重要的是，一旦我们确定了多囊卵巢综合征中功能失调的生化途径，未来就有可能设计和测试有潜力针对这些途径中的关键点来改善功能的药物。我们的成果将在科学会议上公布，并准备在该领域的领先科学期刊上发表。申请者在向筹款机构、患者团体以及广播和书面媒体谈论他们的研究方面拥有丰富的经验。

项目成果

Androgen Reduces Mitochondrial Respiration in Mouse Brown Adipocytes: A Model for Disordered Energy Balance in Polycystic Ovary Syndrome.

• DOI: 10.3390/ijms22010243
• 发表时间: 2020-12-29
• 期刊: International journal of molecular sciences
• 影响因子: 5.6
• 作者: Lerner A;Kewada D;Ahmed A;Hardy K;Christian M;Franks S
• 通讯作者: Franks S

Intrafollicular Concentrations of the Oocyte-secreted Factors GDF9 and BMP15 Vary Inversely in Polycystic Ovaries.

• DOI: 10.1210/clinem/dgac272
• 发表时间: 2022-07-14
• 期刊: The Journal of clinical endocrinology and metabolism