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：多囊卵巢综合症 (PCOS) 和下丘脑闭经 (HA) 是影响年轻女性的两种最常见的生殖疾病，分别占绝经前女性的 2-13% 和 1-2%。 PCOS 的特点是月经不调、雄激素过多和超声多囊卵巢形态 (PCOM)，而 HA 的特点是低体重、过度运动和心理压力。这两种生殖疾病的一个关键异常是下丘脑促性腺激素释放激素 (GnRH) 脉动的改变。具体来说，患有 PCOS 的女性 GnRH 搏动性增加，而患有 HA 的女性 GnRH 搏动性降低。下丘脑弓状 (ARC) 核（人类漏斗核）中的 Kisspeptin (KP) 神经元被认为是“GnRH 脉冲发生器”。尽管 ARC Kisspeptin 表达在大多数 PCOS 样模型（例如产前雄激素化模型）中增加，但尚不清楚这种改变是否与生殖表型的病因有关。此外，尚不清楚在已建立的 PCOS 模型（即产前雄激素化模型）中减弱 Kisspeptin 神经元过度活动是否可以减弱 PCOS 样表型。相反，尽管 ARC Kisspeptin 表达在 HA 样模型中减少，但尚不清楚增加 ARC Kisspeptin 神经元激活是否可以在营养不良的情况下挽救生殖健康。此外，这两种情况的诊断可能具有挑战性。虽然这两种疾病的诊断都有指南支持，但这两种疾病都是排除性诊断，高达 86% 被诊断为 HA 的女性也符合 PCOS 的诊断标准。因此，即使具有专业知识的临床医生也可能面临少经/闭经女性的诊断不确定性。由于下丘脑功能的改变是这些情况下的一个关键但不同的异常，我将评估使用 KP 测试评估下丘脑功能障碍是否可以代表一种客观方法，对患有少经/闭经的女性月经失调的原因进行分类。目的：1。确定恢复 ARC Kisspeptin 神经元激活是否可以挽救 HA.2 小鼠模型的动情周期。确定 ARC Kisspeptin 神经元活性增加是否与 PCOS 2a 相关：确定在已建立的 PCOS（产前雄激素化）小鼠模型中减少 ARC Kisspeptin 神经元过度活动是否可以解决生殖表型。 2b：确定健康成年雌性小鼠中增加 ARC Kisspeptin 神经元激活是否会诱导 PCOS 样表型。3。评估内分泌反应对静脉推注 KP 的区分性能，作为区分少经/闭经女性中 PCOS 和 HA 的诊断测试。 应用和益处：该提案将确定 ARC Kisspeptin 神经元活性的改变在多大程度上直接导致 PCOS 和 HA 中观察到的表型。此外，这些数据将确定靶向这些神经元的治疗相关性，确定在产前雄激素化 PCOS 样模型中减弱这些神经元的过度活动，或在 HA 模型中增加其过度活动是否可以解决生殖健康的干扰。KP 是下丘脑 GnRH 分泌的有效刺激剂，因此可用于评估下丘脑功能。我的试验数据表明，与 PCOS 患者相比，患有 HA 的女性的黄体生成素 (LH) 反应更为夸张。因此，下丘脑功能的 KP 测试可以发展成为一项客观测试，以确定女性月经稀少/闭经的原因。摘要：本提案的总体目的是研究下丘脑弓状 Kisspeptin 神经元活动在 PCOS 和 HA 病因学中的作用，并确定 KP 作为月经失调女性诊断测试的实用性。

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