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

节奏在自然界中无处不在，我们体内几乎所有的荷尔蒙系统都遵循一个每日周期。一个很好的例子是下丘脑-垂体-肾上腺（HPA）轴，它调节重要激素皮质醇的分泌，是哺乳动物中提供快速反应和抵御压力的主要激素系统。皮质醇水平在休息（睡眠）期间较低，并在清晨上升，为个体的日常活动做好准备。然而，我们现在知道，这种激素实际上是以脉冲或短脉冲的方式分泌的，每天大约每小时一次，早晨的脉冲较大，构成了一般的昼夜节律趋势。现在有重要的证据表明，为了使体内组织的功能“最佳”，皮质醇的振荡水平是必不可少的。尽管如此，接受激素替代和类固醇治疗的炎症或恶性疾病的患者通常暴露于恒定水平的长效合成类固醇。这种输送模式是在我们理解皮质醇脉动性的重要性之前开发的，并且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，皮质醇节律在不同的生理和病理条件下会被打乱。这方面的一个很好的例子是与衰老和长期压力有关的节奏中断，考虑到与压力有关的疾病是我们社会的一个迅速增加的特征，而衰老是认知能力下降、免疫反应下降和虚弱的一个主要危险因素，我们理解控制人体内源性皮质醇产生的生物机制是非常重要的;以及这些激素的循环水平如何帮助优化身体对环境影响的反应，并维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，以适当地确定这些生物机制。通过使用这种方法，我们最近发现了体内调节皮质醇脉动分泌的潜在网络。这是特别令人兴奋的，因为现在我们了解了这种节奏的来源，我们可以开始系统地探索维持“正常”节奏的关键机制。反过来，这将有助于我们了解衰老和疾病的节奏如何以及为什么会发生变化，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.