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)是影响年轻女性的两种最常见的生殖障碍，分别出现在2-13%和1-2%的绝经前女性。PCOS的特点是月经不规律、高雄激素血症和多囊卵巢超声(PCOM)，而HA的特点是低体重、过度运动和心理应激。这两种生殖障碍的一个关键异常是下丘脑促性腺激素释放激素(GnRH)搏动性的改变。具体地说，患有多囊卵巢综合征的妇女GnRH搏动性增加，而患有HA的妇女GnRH搏动性降低。位于下丘脑弓状核(ARC)(人类漏斗核)的Kis speptin(KP)神经元被认为是“GnRH脉冲发生器”。虽然在大多数PCOS样模型中，如产前雄激素化模型中，ARC kispeptin的表达增加，但尚不清楚这种变化是否与生殖表型的病因学有关。此外，目前尚不清楚在已建立的PCOS模型(即产前雄激素模型)中，减轻Kispeptin神经元过度活动是否可以减弱PCOS样表型。相反，尽管在类HA模型中ARC Kisspeptin的表达减少，但增加ARC Kisspeptin神经元的激活是否能在营养不良的情况下拯救生殖健康尚不清楚。此外，这两种疾病的诊断都可能具有挑战性。虽然这两种情况的诊断都得到了指南的支持，但这两种情况都是排除诊断，高达86%的被诊断为HA的妇女也符合多囊卵巢综合征的诊断标准。因此，即使是具有专业知识的临床医生也可能面临对出现少经/闭经的妇女的诊断不确定性。由于下丘脑功能的改变是这些情况下的关键但不同的异常，我将评估使用KP试验评估下丘脑功能障碍是否可以代表一种客观的方法来对出现月经少/闭经的妇女的月经紊乱原因进行分类。目的：1.确定恢复ARC Kispeptin-神经元激活是否可以挽救HA型小鼠模型的动情周期。确定ARC Kispeptin神经元活性增加是否与PCOS 2a有关：确定在已建立的PCOS(产前雄激素治疗)小鼠模型中，减少ARC Kispeptin神经元过度活动是否可以解决生殖表型问题。2B：确定在健康的成年雌性小鼠中增加ARC kispeptin神经元的激活是否会诱导PCOS样表型。评估静脉推注KP的内分泌反应的鉴别性能，以此作为鉴别少经/闭经妇女多囊卵巢综合征和透明质酸的诊断试验。应用和益处：这项建议将建立ARC Kisspeptin神经元活性变化直接导致多囊卵巢综合征和透明质酸表型的程度。此外，这些数据将通过确定在产前雄激素样多囊卵巢综合征模型中减弱这些神经元的过度活动，还是在HA模型中增加它们的过度活动，来建立针对这些神经元的治疗相关性，以解决生殖健康方面的障碍。KP是下丘脑GnRH分泌的有力刺激因子，因此可用于评估下丘脑功能。我的试验数据显示，与多囊卵巢综合征患者相比，HA患者的促黄体生成素(LH)反应被夸大了。因此，下丘脑功能的KP测试可以发展成为一种客观的测试，以确定女性出现月经过少/闭经的原因。总结：本研究的总体目标是探讨下丘脑弓状基底膜蛋白神经元活动在PCOS和HA病因中的作用，并确定KP作为月经紊乱女性的诊断测试的价值。

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