PHYSIOLOGY OF STRESS AND CLINICAL APPLICATIONS OF CORTICOTROPIN RELEASING HORMONE

在这个项目中，我们寻求推进内分泌的理解， 应激机制和促肾上腺皮质激素释放激素的作用 (CRH)在正常和应激生理学中以及在 下丘脑-垂体-肾上腺功能 这一领域的快速进展， 最近发现的化学结构使其成为可能， 首先是绵羊CRH（oCRH），最近是人CRH（hCRH）。 我们 目的是确定绵羊的剂量-反应关系 和人类CRH在非人类灵长类动物和人类，研究代谢 这些肽的清除率，以开发测量CRH的方法 准确地在患者的组织和生物液体中， 下丘脑-垂体-肾上腺轴异常，发展为 临床CRH试验，并评估其在肾上腺功能不全， 库欣综合征和假库欣状态。 迄今为止，我们的研究 表明绵羊和人CRH在非人灵长类动物中均具有活性， 伙计 确定了人体适宜的剂量和检测方式 药理学参数已经在两种灵长类动物中测定 还有男人 CRH刺激似乎是一个有用的测试，在区分 肾上腺功能不全、库欣综合征和 伪库欣状态 生理实验表明，库欣氏症 疾病是垂体的，而抑郁症中的皮质醇增多症是 起源于下丘脑 应用免疫球蛋白治疗库欣病 手术之后是CRH刺激试验的正常化。 人类 CRH导致人类受试者血浆ACTH和皮质醇短暂升高， 是脉冲状的，模拟自发发生的生理ACTH， 皮质醇分泌期 这可以通过简短的血浆来解释 这种肽的半衰期和高MCR。 hCRH的这些特性使得 它是研究植物生理学的重要手段， 下丘脑垂体肾上腺轴 以脉冲式给药hCRH 时尚恢复了皮质醇的分泌模式， 下丘脑肾上腺功能不全

In this project we seek to advance understanding of the endocrine mechanisms of stress and of the role of corticotropin releasing hormone (CRH) in normal and stress physiology and in disorders of hypothalamic-pituitary-adrenal function. Rapid progress in this area has been made prossible by the recent discovery of the chemical structures of, first, ovine CRH (oCRH) and, more recently, of human CRH (hCRH). Our objectives have been to determine the dose-response relationships for ovine and human CRH in nonhuman primates and in man, to study the metabolic clearance rates of these peptides, to develop methods to measure CRH accurately in tissues and in biological fluids of patients with abnormalities of the hypothalamic-pituitary-adrenal axis, to develop a clinical CRH test, and to evaluate its usefulness in adrenal insufficiency, Cushing's syndrome, and pseudo-Cushing's states. Our studies to date have shown that both ovine and human CRH are active in non-human primates and man. The appropriate dose and mode of testing man have been established and the pharmacological parameters have been determined in both primates and men. CRH stimulation appears to be a useful test in the differential diagnoisis of adrenal insufficiency, Cushing's syndrome and pseudo-Cushing's states. Physiological experiments suggest that Cushing's disease is pituitary, whereas hypercortisolism in depression is hypothalamic in orgin. Succuessful treatment of Cushing's disease with surgery is followed by normalization of the CRH stimulation test. Human CRH causes brief plasma ACTH and cortisol elevations in human subjects that are pulselike and mimic the spontaneously occurring physiologic ACTH and cortisol secretory episodes. This is explained by the brief plasma half-life and the high MCR of this peptide. These properties of hCRH make it an important means for the study of the physiology of the hypothalamic-pituitary-adreanl axis. Administration of hCRH in a pulsatile fashion restores the secretory pattern of cortisol in patients with hypothalamic adrenal insufficiency.