Pulsed Glucocorticoid Replacement Therapy

脉冲式糖皮质激素替代疗法

• 批准号: MR/J012548/1
• 负责人: Stafford Lightman
• 金额: $ 94.13万
• 依托单位: University of Bristol
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FJ012548%2F1
• 关键词: Pulsed; Glucocorticoid; Replacement; Therapy

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.

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。它是以每日(昼夜)节律产生的，早上第一件事就是高水平，晚上下降到非常低的水平。有许多疾病，如爱迪生病、先天性肾上腺增生症和脑垂体疾病，患者无法产生足够的这种激素，因此需要替代治疗。目前，我们给患者提供标准的片剂替代疗法，试图模仿正常的荷尔蒙特征。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)，患者通常会感到身体不适，伴有严重的疲劳。现在已经知道，皮质醇以大约每小时一次的脉冲释放到血流中，这种脉冲模式对身体的正常反应至关重要。不幸的是，这种脉动模式并不是我们目前为患者提供的替代模式，这很可能导致这些患者的过度死亡率和糟糕的生活质量。我们建议开发一种量身定做的治疗方法，允许我们以一种接近模拟自然激素释放的方式将氢化可的松脉冲输送到皮肤下。我们将首先在正常的健康志愿者身上测试这一点，以确保我们提供的输液速度与正常个体的输液速度相同。一旦我们确定了最佳方案，我们将在Addison病和先天性肾上腺增生症患者中使用这种输液模式。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。

项目成果

Glucocorticoid ultradian rhythmicity differentially regulates mood and resting state networks in the human brain: A randomised controlled clinical trial.

• DOI: 10.1016/j.psyneuen.2020.105096
• 发表时间: 2021-03
• 期刊: Psychoneuroendocrinology
• 影响因子: 3.7
• 作者: Kalafatakis K;Russell GM;Ferguson SG;Grabski M;Harmer CJ;Munafò MR;Marchant N;Wilson A;Brooks JC;Thakrar J;Murphy P;Thai NJ;Lightman SL
• 通讯作者: Lightman SL

Effects of the pattern of glucocorticoid replacement on neural processing, emotional reactivity and well-being in healthy male individuals: study protocol for a randomised controlled trial.

• DOI: 10.1186/s13063-016-1159-x
• 发表时间: 2016-01-22
• 期刊: Trials
• 影响因子: 2.5
• 作者: Kalafatakis K;Russell GM;Harmer CJ;Munafo MR;Marchant N;Wilson A;Brooks JC;Thai NJ;Ferguson SG;Stevenson K;Durant C;Schmidt K;Lightman SL
• 通讯作者: Lightman SL

A Time for Metabolism and Hormones

• DOI: 10.1007/978-3-319-27069-2
• 发表时间: 2016
• 作者: P. Sassone-Corsi;Y. Christen