Pulsed Glucocorticoid Replacement Therapy

皮质醇（也称为氢化可的松）是一种由肾上腺产生的激素，对生命至关重要。它是按每日（昼夜）节律产生的，早晨第一件事是高水平，晚上下降到非常低的水平。有许多疾病，如阿狄森氏病、先天性肾上腺增生症和垂体疾病，患者无法产生足够的这种激素，因此需要替代治疗。目前，我们给患者标准的替代治疗药片，试图模仿正常的激素水平。然而，尽管如此，他们的死亡率仍然是背景人群的两倍（类似于吸烟增加的风险），患者通常感到严重疲劳，身体不适。现在我们知道，皮质醇以大约每小时一次的脉冲释放到血液中，这种脉冲模式对身体的正常反应至关重要。不幸的是，这种搏动模式并不是我们目前给病人的替代模式，这可能会导致这些病人的高死亡率和低质量的生活。我们建议开发一种量身定制的治疗方法，使我们能够在皮肤下以一种密切模仿自然激素释放的方式输送氢化可的松脉冲。我们将首先在正常的健康志愿者中进行测试，以确保我们提供的输注速率与正常个体的输注速率相同。一旦我们建立了最佳方案，我们将在Addison病和先天性肾上腺增生患者中使用这种输注模式。我们将通过测量他们的激素水平来评估治疗的有效性，并使用专门针对患者症状的心理测试来评估他们的生活质量和情绪健康的改善情况。

Cortisol (also called hydrocortisone) is a hormone produced by the adrenal glands that is essential for life. It is produced in a daily (circadian) rhythm with high levels first thing in the morning, falling to very low levels at night time. There are many medical conditions such as Addison's disease, congenital adrenal hyperplasia and pituitary disease where patients cannot produce enough of this hormone and therefore require replacement therapy. At present we give patients standard replacement therapy with tablets in an attempt to mimic a normal hormonal profile. However despite this their death rates remain twice that of the background population (similar to the increased risk from smoking) and patients often feel generally unwell with severe fatigue. It is now known that cortisol is released into the blood stream in approximately hourly pulses, and that this pattern of pulses is vital for the body's normal responses. Unfortunately this pulsatile pattern is not the pattern of replacement that we currently give patients and this could well contribute to the excess death rate and the poor quality of life of these patients. We propose to develop a tailor made treatment that allows us to deliver pulses of hydrocortisone under the skin in a way that closely mimics natural hormone release. We shall initially test this in normal healthy volunteers to ensure we provide infusion rates that are equivalent to those produced in a normal individual. Once we have established the best protocol for this, we will use this infusion pattern in patients with Addison's disease and congenital adrenal hyperplasia. We shall assess the effectiveness of the treatment by measuring their hormone levels and evaluating the improvement in their quality of life and emotional well being using psychological tests that are specifically tailored to the symptoms of our patients.