Raison Charles L, Miller Andrew H
Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, 1639 Pierce Drive, Atlanta, GA 30322, USA.
Am J Psychiatry. 2003 Sep;160(9):1554-65. doi: 10.1176/appi.ajp.160.9.1554.
Previous theories have emphasized the role of excessive glucocorticoid activity in the pathology of chronic stress. Nevertheless, insufficient glucocorticoid signaling (resulting from decreased hormone bioavailability or reduced hormone sensitivity) may have equally devastating effects on bodily function. Such effects may be related in part to the role of glucocorticoids in restraining activation of the immune system and other components of the stress response, including the sympathetic nervous system (SNS) and corticotropin-releasing hormone (CRH).
The literature on neuroendocrine function and glucocorticoid-relevant pathologies in stress-related neuropsychiatric disorders, including posttraumatic stress disorder and major depression, was reviewed.
Although not occurring together, both hypocortisolism and reduced responsiveness to glucocorticoids (as determined by dexamethasone challenge tests) were reliably found. Stress-related neuropsychiatric disorders were also associated with immune system activation/inflammation, high SNS tone, and CRH hypersecretion, which are all consistent with insufficient glucocorticoid-mediated regulation of stress hyperresponsiveness. Finally, antidepressants, a mainstay in the treatment of stress-related disorders, were regularly associated with evidence of enhanced glucocorticoid signaling.
Neuroendocrine data provide evidence of insufficient glucocorticoid signaling in stress-related neuropsychiatric disorders. Impaired feedback regulation of relevant stress responses, especially immune activation/inflammation, may, in turn, contribute to stress-related pathology, including alterations in behavior, insulin sensitivity, bone metabolism, and acquired immune responses. From an evolutionary perspective, reduced glucocorticoid signaling, whether achieved at the level of the hormone or its receptor, may foster immune readiness and increase arousal. Emphasis on insufficient glucocorticoid signaling in stress-related pathology encourages development of therapeutic strategies to enhance glucocorticoid signaling pathways.
以往的理论强调了糖皮质激素活性过高在慢性应激病理过程中的作用。然而，糖皮质激素信号不足（由激素生物利用度降低或激素敏感性降低所致）可能对身体功能产生同样严重的影响。这些影响可能部分与糖皮质激素在抑制免疫系统激活以及应激反应的其他组成部分（包括交感神经系统（SNS）和促肾上腺皮质激素释放激素（CRH））方面的作用有关。
对有关应激相关神经精神疾病（包括创伤后应激障碍和重度抑郁症）中神经内分泌功能和糖皮质激素相关病理的文献进行了综述。
虽然低皮质醇血症和对糖皮质激素反应性降低（通过地塞米松激发试验确定）并非同时出现，但均被可靠地发现。应激相关神经精神疾病还与免疫系统激活/炎症、高交感神经系统张力和CRH分泌过多有关，这些均与糖皮质激素介导的应激反应过度调节不足相一致。最后，抗抑郁药作为应激相关疾病治疗的主要药物，经常与糖皮质激素信号增强的证据相关联。
神经内分泌数据为应激相关神经精神疾病中糖皮质激素信号不足提供了证据。相关应激反应的反馈调节受损，尤其是免疫激活/炎症，可能反过来导致应激相关的病理变化，包括行为、胰岛素敏感性、骨代谢和获得性免疫反应的改变。从进化的角度来看，糖皮质激素信号降低，无论在激素水平还是其受体水平实现，都可能促进免疫准备并增加觉醒。强调应激相关病理中糖皮质激素信号不足，鼓励开发增强糖皮质激素信号通路的治疗策略。
