Investigating hypothalamic kisspeptin neuronal dysfunction as a key mediator of the pathophysiology of PCOS and HA

研究下丘脑 Kisspeptin 神经元功能障碍作为 PCOS 和 HA 病理生理学的关键介质

• 批准号: MR/W024144/1
• 负责人: Bijal Patel
• 金额: $ 40.68万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW024144%2F1
• 关键词: Investigating; hypothalamic; kisspeptin; neuronal; dysfunction

Problem: Polycystic Ovary Syndrome (PCOS) and Hypothalamic Amenorrhoea (HA) are the two commonest reproductive disorders affecting young women, being found in 2-13% and 1-2% of pre-menopausal women, respectively. PCOS is characterised by menstrual irregularity, hyperandrogenism and polycystic ovarian morphology on ultrasound (PCOM), whereas HA by low body-weight, excessive exercise and psychological stress. A key abnormality in both of these reproductive disorders is the alteration in hypothalamic gonadotrophin releasing hormone (GnRH) pulsatility. Specifically, women with PCOS have increased GnRH pulsatility, whereas women with HA have reduced GnRH pulsatility. Kisspeptin (KP) neurons in the arcuate (ARC) nucleus of the hypothalamus (infundibular nucleus in humans) are thought to be the 'GnRH pulse generator'. Although ARC kisspeptin expression is increased in most PCOS-like models eg prenatal androgenised model, it is not known whether this alteration is causal in the aetiology of the reproductive phenotype. Furthermore, it is not known whether attenuating kisspeptin neuronal overactivity in an established model of PCOS (ie prenatal androgenised model) can attenuate the PCOS-like phenotype. Conversely, although ARC kisspeptin expression is reduced in HA-like models, it is not known whether increasing ARC kisspeptin neuronal activation can rescue reproductive health in the face of undernutrition.Furthermore, the diagnosis of both conditions can be challenging. Whilst the diagnosis of both conditions is supported by guidelines, both conditions are diagnoses of exclusion and up to 86% of women diagnosed as HA also meet diagnostic criteria for PCOS. Thus, even clinicians with specialist expertise may be faced with diagnostic uncertainty in women presenting with oligo/amenorrhoea. As the alteration in hypothalamic function is a key but divergent abnormality in these conditions, I will evaluate whether assessment of hypothalamic dysfunction using a KP test could represent an objective method to classify the cause of menstrual disturbance in women presenting with oligo/amenorrhoea.Aims:1. Determine whether restoring ARC kisspeptin-neuronal activation can rescue estrus cyclicity in a mouse model of HA.2. Determine whether increased ARC kisspeptin-neuronal activity is responsible for PCOS 2a: Establish whether reducing ARC kisspeptin-neuronal overactivity in an established mouse model of PCOS (prenatal androgenised) can resolve the reproductive phenotype. 2b: Determine whether increasing ARC kisspeptin-neuronal activation in healthy adult female mice induces a PCOS-like phenotype.3. Evaluate the discriminatory performance of the endocrine response to an intravenous bolus of KP as a diagnostic test to differentiate PCOS and HA in oligo/amenorrhoeic women.Applications and Benefits: This proposal will establish the extent to which alterations in the activity of ARC kisspeptin neurons are directly responsible for the phenotype observed in PCOS and HA. Moreover, these data will establish the therapeutic relevance of targeting these neurons by determining whether attenuating their overactivity in a prenatal androgenised PCOS-like model, or increasing it in a HA model, can resolve the disturbance in reproductive health.KP is a potent stimulator of hypothalamic GnRH secretion, and thus can be used to assess hypothalamic function. My pilot data demonstrates that the luteinising hormone (LH) response is exaggerated in women with HA, compared to those with PCOS. Thus, a KP test of hypothalamic function could be developed into an objective test to identify the cause in women presenting with oligo/amenorrhoea.Summary:The overall aim of this proposal is to investigate the role of hypothalamic arcuate kisspeptin neuronal activity in the aetiology of PCOS and HA, and to determine the utility of KP as a diagnostic test in women presenting with menstrual disturbance.

问题：多囊卵巢综合征（PCOS）和下丘脑闭经（HA）是影响年轻妇女的两种最常见的生殖疾病，分别在2-13％和1-2％的绝经前妇女中发现。 PCOS的特征在于超声（PCOM）上的月经不规则性，超雄激素和多囊卵巢形态，而HA则通过低体重，过度运动和心理压力。这两种生殖疾病的关键异常是下丘脑性促性腺营养蛋白释放激素（GNRH）脉动的改变。具体而言，患有PCOS的女性具有GNRH搏动性的增加，而HA的女性具有GNRH搏动性降低。下丘脑（人类的不可核核）的弧形（ARC）核中的Kisspeptin（KP）神经元被认为是“ GnRH脉冲发生器”。尽管大多数PCOS样模型，例如产前雄激素化模型，弧吻蛋白的表达增加了，但尚不清楚这种改变在生殖表型的病因中是否是因果关系。此外，尚不清楚在已建立的PCOS模型（即产前雄激素化模型）中衰减Kisspeptin神经元过度活跃是否可以减弱PCOS样表型。相反，尽管在类似HA的模型中弧吻蛋白的表达降低，但面对营养不良，尚不清楚增加弧肽神经元激活是否可以挽救生殖健康。尽管这两种情况的诊断都由指南支持，但两种情况都是排除的诊断，而被诊断为HA的妇女中最多可满足PCOS的诊断标准。因此，即使是具有专业专业知识的临床医生，也可能面临着与寡核酸/闭经乳腺癌的妇女的诊断不确定性。由于下丘脑功能的改变是在这些条件下的关键但异常，因此我将评估使用KP检验对下丘脑功能障碍的评估是否可以代表一种客观方法，以分类具有Oligo/anyorrhoea.aim的女性的男性扰动原因。确定恢复弧肽 - 神经元激活是否可以在HA.2的小鼠模型中挽救发情环节。确定增加的ARC亲吻肽 - 神经元活性是否负责PCOS 2A：确定在已建立的PCOS小鼠模型（产前雄激素化）中，降低ARC Kisspeptin-神经元过度活跃是否可以解决生殖表型。 2B：确定健康成年雌性小鼠中增加的ARC亲吻肽 - 神经元激活是否会诱导PCOS样表型3。评估内分泌对KP静脉推注的反应的歧视性能，作为诊断测试，以区分PCOS和HA中的PCOS和HA中的HA。应用和好处：该建议将确定在PCOS和HA中对ARC Kisspeptin Neurons活性直接负责的ARC Kisspeptin Neurons活性的变化的程度。此外，这些数据将通过确定在产前雄激素化的PCOS模型中减弱其过度活动的靶向这些神经元的治疗相关性，或者在HA模型中增加该神经元可以解决生殖健康中的干扰。KP是一种有效的gnrh gnrH刺激剂，因此可以评估下种的刺激剂，并可以评估HypothAmic的功能。我的试点数据表明，与患有PCOS的女性相比，HA女性的黄体素激素（LH）反应被夸大了。因此，可以将下丘脑功能的KP检验发展为客观测试，以识别妇女的原因。

项目成果

Kisspeptin in the Prediction of Pregnancy Complications.

• DOI: 10.3389/fendo.2022.942664
• 发表时间: 2022
• 期刊: Frontiers in endocrinology
• 影响因子: 5.2