The pituitary corticotroph: an organizing centre for oscillatory activity of the HPA axis?

自然界中的节律无处不在，我们体内几乎所有的荷尔蒙系统都遵循着一个每日的周期。下丘脑-垂体-肾上腺(HPA)轴就是一个很好的例子，它调节着至关重要的激素皮质醇的分泌，是哺乳动物的主要荷尔蒙系统，提供快速反应和防御压力。皮质醇水平在休息(睡眠)期间很低，并在清晨上升，为个人的日常活动做准备。然而，我们现在知道，这种荷尔蒙实际上是以脉冲或短脉冲的形式分泌的，在一天中每小时左右分泌一次，早上的脉冲更大，构成了一般的昼夜趋势。现在有重要的证据表明，为了让身体组织发挥最佳功能，皮质醇水平的波动是必不可少的。尽管如此，接受激素替代和类固醇治疗的炎症性或恶性疾病患者通常会接触到持续水平的长效合成类固醇。这种给药模式是在我们了解皮质醇脉动性的重要性之前开发出来的，可能会限制治疗效果，并导致与长期使用合成类固醇相关的非常高水平的副作用。此外，我们现在还知道，在不同的生理和病理条件下，皮质醇的节律会被打乱。与衰老和长期压力相关的节律紊乱就是很好的例子。鉴于与压力相关的疾病在我们的社会中迅速增加，衰老是认知能力下降、免疫反应下降和虚弱的主要风险因素，我们非常重要的是了解控制身体内源性皮质醇产生的生物机制；以及这些荷尔蒙的循环水平如何帮助优化身体对环境影响的反应，并保持正常的内部调节过程。鉴于HPA轴的复杂性，数学模型提供了一个强大的工具来适当地识别这些生物学机制。通过使用这种方法，我们最近发现了体内一个潜在的网络，它调节皮质醇的脉动性分泌。这特别令人兴奋，因为既然我们了解了这种节奏的起源，我们就可以开始系统地探索对保持正常节奏至关重要的关键机制。这反过来将帮助我们理解衰老和疾病的节奏如何以及为什么发生变化，以及这些变化如何导致或保护我们免受病理后果的影响。

Rhythms are everywhere in nature, and nearly all hormonal systems in our bodies follow a daily cycle. A good example of this is the hypothalamic-pituitary-adrenal (HPA) axis, which regulates the secretion of the vital hormone cortisol, and is the major hormonal system in mammals that provides a rapid response and defence against stress. Cortisol levels are low during periods of resting (sleep) and rise early in the morning to prepare an individual for daily activity.However, we now know that this hormone is actually secreted in pulses, or short bursts, every hour or so throughout the day, with larger pulses during the morning, making up the general circadian trend. There is now significant evidence that in order for tissues in the body to function 'optimally', oscillating levels of cortisol are essential.Despite this, patients undergoing both hormone replacement and steroid therapy for inflammatory or malignant disease are typically exposed to constant levels of long-acting synthetic steroids. This pattern of delivery was developed before we understood the importance of cortisol pulsatility, and may well limit efficacy of treatment as well as contribute to the very high levels of side effects associated with the long-term use of synthetic steroids. Moreover, we also now know that the cortisol rhythm becomes disrupted in different physiological and pathological conditions. Good examples of this are the disruptions to the rhythm that are associated with ageing and prolonged stress.Given that stress-related illness is a rapidly increasing feature of our society, and that aging is a major risk factor for cognitive decline, decreased immune response and frailty, it is very important that we understand the biological mechanisms that govern the body's endogenous production of cortisol; and also how these cycling levels of hormone help to optimise the body's response to environmental influences and to maintain normal internal regulatory processes. Given the complexity of the HPA axis, mathematical models provide a powerful tool with which to appropriately identify these biological mechanisms. By using this approach, we have recently identified a potential network in the body that regulates the pulsatile secretion of cortisol. This is particularly exciting because, now that we understand where this rhythm originates from, we can begin to systematically probe the key mechanisms that are important for maintaining a 'normal' rhythm. This, in turn, will help us to understand how and why the rhythm changes in ageing and disease, and how these changes cause, or protect us from pathological consequences.