用于解释HPA轴适应状态和糖皮质激素反馈动力学的ACTH刺激试验的机制建模框架
A mechanistic modeling framework to interpret ACTH stimulation tests across HPA axis adaptation states and glucocorticoid feedback dynamics
浏览论文内容
中文总结 AI 辅助
本研究提出整合激素动力学等的机制建模框架，模拟HPA轴180天的三个阶段，评估高低剂量ACTH试验，揭示静态试验局限，为应激相关肾上腺疾病的诊断提供依据。
中文摘要 AI 辅助
下丘脑-垂体-肾上腺（HPA）轴是协调内分泌响应生理与心理应激的关键调节系统。尽管ACTH刺激试验仍是肾上腺功能评估的核心手段，但其解释因慢性应激暴露下HPA轴的动态适应性而复杂化：长期应激会诱导腺体重塑、糖皮质激素受体（GR）抵抗及延迟反馈恢复，所有这些都可能改变试验结果却不提示原发性肾上腺功能衰竭。本研究提出一种机制建模框架，整合了激素动力学、反馈抑制及促肾上腺皮质细胞与肾上腺区室的功能质量适应。我们模拟了HPA轴在180天内的三个阶段——基线、慢性应激和恢复，同时引入随时间变化的GR抵抗函数以模拟反馈脱敏及其恢复。利用该框架，我们在三个生理阶段评估了低剂量（1μg）和高剂量（250μg）ACTH刺激试验。我们的模拟显示，皮质醇响应对应激暴露的强度和时间高度敏感，ACTH响应性具有阶段依赖性，且在恢复阶段常因持续的反馈抵抗而减弱；低剂量ACTH试验更可靠地反映部分肾上腺适应，而高剂量试验因超生理驱动存在掩盖功能障碍的风险。这些结果凸显了静态试验范式的局限性，表明考虑腺体可塑性和GR反馈动力学对有效内分泌诊断至关重要，尤其针对应激相关或治疗诱导的肾上腺疾病。
英文摘要
The hypothalamic pituitary adrenal (HPA) axis is a key regulatory system coordinating endocrine responses to physiological and psychological stress. While the ACTH stimulation test remains a cornerstone of adrenal function assessment, its interpretation is complicated by the dynamic and adaptive nature of the HPA axis under chronic stress exposure. In particular, prolonged stress induces glandular remodeling, glucocorticoid receptor (GR) resistance and delayed feedback recovery, all of which may alter test outcomes without indicating primary adrenal failure. In this study, we present a mechanistic modeling framework that integrates hormonal kinetics, feedback inhibition and functional mass adaptation of the corticotroph and adrenal compartments. We simulate the HPA axis over $180$ days encompassing three phases - baseline, chronic stress and recovery, while introducing a time varying GR resistance function to mimic feedback desensitization and its resolution. Using this framework, we evaluate both low dose ($1 μg)$ and high dose ($250 μg)$ ACTH stimulation tests across physiological phases. Our simulations show that cortisol responses are highly sensitive to both the magnitude and timing of stress exposure and that ACTH responsiveness is phase dependent and often blunted during recovery due to persistent feedback resistance. Low dose ACTH testing more reliably reflects partial adrenal adaptation, while high dose tests risks masking dysfunction due to supraphysiological drive. These results highlight the limitations of static testing paradigms and suggest that accounting for glandular plasticity and GR feedback dynamics is essential for effective endocrine diagnosis particularly in stress related or treatment induced adrenal disorders.
发表机构
- Central University of Haryana（哈里亚纳中央大学）
机构由 AI 辅助整理，请以论文原文为准。
