Role of growth factors of the TGFbeta superfamily in aberrant follicle development in polycystic ovary syndrome

多囊卵巢综合征（PCOS）影响超过5%的育龄妇女，对生育能力和长期健康都有重大影响。它会导致月经不调，是排卵相关不孕的主要原因，而且由于其相关的代谢异常，患糖尿病的风险很高。然而，我们仍然对其病因知之甚少，这使得诊断不准确，也意味着我们正在治疗由此产生的症状，而不是根本原因。我们在这个应用中试图解决的主要问题是了解PCOS女性排卵很少或根本不排卵的原因。一个女人出生时就有卵子供应，这些卵子必须持续到她的整个生殖周期。这些卵子被一层支持细胞（颗粒）包围，储存在卵巢的小卵泡中。这个静止的卵泡池被称为原始池。促使原始卵泡开始生长的过程尚不清楚，但有证据表明，局部产生的生长因子起着重要作用，特别是那些所谓的转化生长因子β (tgfβ)家族。这些证据大部分来自我们实验室对小鼠卵泡发育的研究。tgf - β生长因子是由各种大小的卵泡产生并起作用的蛋白质，包括最小的原始卵泡。在我们对患有多囊卵巢综合征的女性卵巢样本的早期研究中，我们已经表明，导致排卵不频繁的问题可能存在于卵巢卵泡生命的最初阶段，我们已经表明，在患有多囊卵巢综合征的女性的非常小的卵泡中，至少有一种TGFbeta家族成员（抗<s:1>勒氏激素或AMH）产生异常。对于目前的提议，我们将有独特的途径从患有和不患有多囊卵巢综合征的女性获得卵巢组织，其中大部分将来自一个以研究为导向的项目，该项目旨在保护即将接受癌症治疗的年轻女性的卵巢组织。我们获得的每个样本都是通常会被丢弃的“备用”组织样本。我们还将收集有多囊卵巢综合征（PCOS）和没有PCOS的女性的小活检，这些女性正在接受常规腹腔镜检查（以观察卵巢和输卵管），或者正在进行卵巢“钻孔”以刺激排卵。我们将确定tgf - β生长因子（及其受体靶点）何时何地产生（根据发育阶段），它们如何在卵巢细胞内发出信号，它们如何与其他生长因子网络相互作用，以及这些过程在正常卵巢和多囊卵巢之间是否不同。我们还将在培养卵巢组织的小样本中检查添加tgf - β生长因子的影响。我们希望这些研究将提供重要的线索，不仅了解多囊卵巢综合征妇女的生育问题，而且了解它们与代谢性疾病的发展之间的关系，包括这些妇女易患的糖尿病。

Polycystic Ovary Syndrome (PCOS) affects more than 5% of women of reproductive age and has a major impact both on fertility and on long-term health. It results in irregular menstruation, is the main reason for ovulation-related infertility and, because of its associated metabolic abnormalities, carries a high risk of developing diabetes. However we still know very little about its cause or causes, which makes diagnosis imprecise and means that we are treating the resulting symptoms rather than the underlying causes. The main problem that we are attempting to address in this application is to understand the reasons why women with PCOS ovulate infrequently or not at all. A woman is born with a supply of eggs that must last throughout her reproductive lifespan. These eggs are surrounded by a single layer of supporting (granulosa) cells and stored in tiny follicles in the ovary. This resting pool of follicles is termed the primordial pool. The processes that prompt primordial follicles to start growing remain unclear but there is evidence that locally produced growth factors play an important part, particularly those of the so-called transforming growth factor beta (TGFbeta) family. Much of this evidence comes from studies of mouse follicle development in our own laboratory. TGFbeta growth factors are proteins that are produced by and act in follicles of all sizes, including the very smallest, primordial, follicles. In our earlier studies of ovarian samples from women with PCOS, we have shown that the problems that lead to infrequent ovulation may lie in the very earliest stages of the life of the ovarian follicle and we have already shown that at least one of the TGFbeta family members (anti-Müllerian Hormone or AMH) is produced abnormally in very small follicles of women with PCOS. For the current proposal we will have unique access to ovarian tissue from women with and without PCOS, much of which will come from a research-orientated programme for conservation of ovary tissue in young women about to undergo treatment for cancer. Every sample that we obtain will be "spare" tissue samples that would normally be discarded. We will also be able to collect small biopsies of women with and without PCOS who are undergoing routine laparoscopy (to visualise the ovaries and Fallopian tubes) or who are having ovarian "drilling" as a procedure to stimulate ovulation.We will determine where and when (according to developmental stage) TGFbeta growth factors (and their receptor targets) are produced, how they signal within ovarian cells, how they may interact other growth factor networks, and whether these processes differ between normal and polycystic ovaries. We will also examine the effects of added TGFbeta growth factors in small samples of cultured ovarian tissue. We expect these studies will provide important clues not only to understanding fertility problems in women with PCOS but also how they may relate to the development of metabolic disorders, including diabetes, to which these women are predisposed.