Glucocorticoid dysregulations and their clinical correlates. From receptors to therapeutics.
Glucocorticoid dysregulations and their clinical correlates. From receptors to therapeutics.
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DOI：
10.1111/j.1749-6632.2009.04987.x
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发表时间：
2009-10
影响因子：
5.2
通讯作者：
Sternberg EM
中科院分区：
文献类型：
--
作者：
Marques AH;Silverman MN;Sternberg EM
临床医生早就知道，大剂量糖皮质激素治疗的患者中有相当一部分会出现各种严重的副作用，包括代谢综合征、骨质流失和情绪变化，如抑郁症、躁狂或轻躁狂症状，甚至自杀。这些副作用的表达或严重程度个体差异的原因尚不清楚。然而，最近出现的文献开始阐明这些影响的可能机制。作为本卷的介绍，本章将回顾糖皮质激素释放的基本生物学和糖皮质激素受体功能的分子机制，并将讨论糖皮质激素作用在各个层面的失调如何导致这种副作用。在分子水平上，糖皮质激素受体多态性可能与受体功能减退或功能亢进相关，因此可能导致个体对糖皮质激素治疗效果的敏感性差异。许多因素调节下丘脑-垂体-肾上腺（HPA）轴的反应性，这也可能导致糖皮质激素副作用的个体差异。其中之一是性激素状态以及雌激素和孕激素对HPA轴功能和情绪的影响。另一个是免疫系统活动，其中免疫分子，如白细胞介素和细胞因子，激活HPA轴并改变大脑功能，包括记忆，认知和情绪。细胞因子在诱导疾病行为中的作用，与抑郁性精神病学重叠，也可能导致这种精神病学的个体差异。总的来说，这些知识将具有重要的相关性，以确定风险患者，以避免或尽量减少这些副作用时，他们与糖皮质激素治疗。提出了一个评估患者的框架，包括功能，生理和分子生物标志物，以确定与糖皮质激素治疗相关的抑郁症的风险患者亚组，并预防副作用，在许多情况下可能危及生命。
Clinicians have long known that a substantial proportion of patients treated with high-dose glucocorticoids experience a variety of serious side effects, including metabolic syndrome, bone loss, and mood shifts, such as depressive symptomatology, manic or hypomanic symptoms, and even suicide. The reason for individual variability in expression or severity of these side effects is not clear. However, recent emerging literature is beginning to shed light on possible mechanisms of these effects. As an introduction to this volume, this chapter will review the basic biology of glucocorticoid release and molecular mechanisms of glucocorticoid receptor function, and will discuss how dysregulation of glucocorticoid action at all levels could contribute to such side effects. At the molecular level, glucocorticoid receptor polymorphisms may be associated either with receptor hypofunction or hyperfunction and could thus contribute to differential individual sensitivity to the effects of glucocorticoid treatment. Numerous factors regulate hypothalamic-pituitary-adrenal (HPA) axis responsiveness, which could also contribute to individual differences in glucocorticoid side effects. One of these is sex hormone status and the influence of estrogen and progesterone on HPA axis function and mood. Another is immune system activity, in which immune molecules, such as interleukins and cytokines, activate the HPA axis and alter brain function, including memory, cognition, and mood. The effects of cytokines in inducing sickness behaviors, which overlap with depressive symptomatology, could also contribute to individual differences in such symptomatology. Taken together, this knowledge will have important relevance for identifying at-risk patients to avoid or minimize such side effects when they are treated with glucocorticoids. A framework for assessment of patients is proposed that incorporates functional, physiological, and molecular biomarkers to identify subgroups of patients at risk for depressive symptomatology associated with glucocorticoid treatment, and for prevention of side effects, which in many cases can be life-threatening.
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影响因子：
17.7
作者：
Daly, RC;Danaceau, MA;Schmidt, PJ
通讯作者：
Schmidt, PJ
影响因子：
15.1
作者：
Capuron, L;Hauser, P;Neveu, PJ
通讯作者：
Neveu, PJ
影响因子：
6.7
作者：
Carroll, B. J.;Cassidy, F.;Veldhuis, J. D.
通讯作者：
Veldhuis, J. D.
影响因子：
11
作者：
Anisman, H;Ravindran, AV;Merali, Z
通讯作者：
Merali, Z
影响因子：
10.6
作者：
Bremmer, Marijke A.;Deeg, Dorly J. H.;Hoogendijk, Witte J. G.
通讯作者：
Hoogendijk, Witte J. G.