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TSH SECRETION--ROLE OF GLUCOCORTICOIDS

TSH 分泌——糖皮质激素的作用

基本信息

批准号：
2905642
负责人：
MARY H SAMUELS
金额：
$ 11.26万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1995
资助国家：
美国
起止时间：
1995-08-15 至 2002-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2905642
关键词：
Addison's disease circadian rhythms cortisol fasting hormone regulation /control mechanism human subject hyperadrenalism hypoadrenalism hypothalamic pituitary adrenal axis mifepristone secretion stress thyrotropin thyrotropin releasing hormone

项目摘要

Past studies in humans have shown that elevated cortisol levels suppress thyroid stimulating hormone (TSH) secretion, and that TSH secretion is decreased during acute or chronic illnesses. However, the determinants of physiologic (nonstressed) TSH secretion, as well as TSH suppression during stress, are unknown. The overall hypothesis of this proposal is that, in the human, glucocorticoids contain TSH secretion at physiologic levels, and mediate stress-induced TSH suppression at elevated levels. To test this hypothesis, three specific aims will be addressed: 1) The effect of physiologic (nonstressed) levels of glucocorticoids on TSH secretion will be determined. 2) The effect of elevated (stress) levels of glucocorticoids on TSH secretion will be determined. 3) The site of TSH suppression by glucocorticoids at physiologic or stress levels will be clarified. To address these aims, the following experimental tools will be utilized: 1) Measurement of dynamic TSH secretion. TSH is normally secreted in a series of pulses with a circadian variation, and is stimulated by hypothalamic thyrotropin-releasing hormone (TRH). Measurement of pulsatile, circadian, and TRH-stimulated TSH levels is a sensitive way to uncover abnormalities in TSH secretion that are not evident when basal levels are measured. The mathematical technique of deconvolution analysis will be used to obtain precise estimates of basal and pulsatile TSH secretion from measured TSH time series. 2) Administration of mifepristone. Healthy subjects will receive mifepristone, a competitive glucocorticoid antagonist, which will permit a dissociation between stress, endogenous cortisol levels, and TSH secretion. 3) Recruitment of subjects with primary adrenal insufficiency or combined TRH and cortisol deficiency. In these subjects, serum cortisol or TSH levels can be manipulated independently by infusions of hydrocortisone or TRH. These subjects will receive hydrocortisone infusion regimens that reproduce endogenous physiologic or stress patterns of cortisol secretion. Subjects with TRH deficiency will also receive TRH infusions that normalize endogenous TSH levels. This will permit a dissociation between stress, cortisol levels, hypothalamic input to the pituitary gland, and TSH secretion. 4) Fasting model. The stress of illness is difficult to study, since experimental conditions cannot be standardized. To circumvent this problem, short-term fasting has been developed as a model of stress- induced TSH suppression in the human. Insights gained from these studies will advance our understanding of thyroid dysfunction in conditions associated with glucocorticoid elevations. Such results may contribute to continuing efforts to minimize adverse effects of stress and glucocorticoids on human metabolism.

过去对人类的研究表明，皮质醇水平升高会抑制促甲状腺激素（TSH）分泌，TSH分泌是在急性或慢性疾病期间减少。然而，生理（非应激）TSH分泌，以及TSH抑制，压力，是未知的。该提案的总体假设是，人类糖皮质激素含有生理水平的TSH分泌，并介导应激诱导的高水平TSH抑制。为了检验这一假设，将讨论三个具体目标： 1)生理（非应激）水平的糖皮质激素对将测定TSH分泌。 2)糖皮质激素水平升高对TSH的影响将确定分泌。 3)生理或应激状态下糖皮质激素抑制TSH的部位水平将得到澄清。为实现这些目标，将利用以下实验工具： 1)动态TSH分泌的测量。促甲状腺激素通常分泌在具有昼夜变化的一系列脉冲，并且由下丘脑促甲状腺激素释放激素（TRH）。测量脉动，昼夜节律和TRH刺激的TSH水平是一种敏感的方式，发现TSH分泌异常，当基础水平是衡量的。反褶积分析的数学技术将用于获得基础和脉动TSH的精确估计值从测量的TSH时间序列分泌。 2)服用米非司酮。健康受试者将接受米非司酮是一种竞争性糖皮质激素拮抗剂，压力、内源性皮质醇水平和TSH之间的分离分泌物 3)招募原发性肾上腺功能不全或合并 TRH和皮质醇缺乏。在这些受试者中，水平可以通过注射氢化可的松或 TRH。这些受试者将接受氢化可的松输注方案，复制皮质醇分泌的内源性生理或应激模式。 TRH缺乏的受试者也将接受TRH输注，使内源性TSH水平正常化。这将允许分离压力、皮质醇水平、下丘脑对脑垂体的输入，以及 TSH分泌。 4)禁食模型。疾病的压力很难研究，因为实验条件不能标准化。为了规避这个问题，短期禁食已被开发为压力模型- 在人体内引起TSH抑制。从这些研究中获得的见解将促进我们对糖皮质激素相关性甲状腺功能障碍海拔这些结果可能有助于继续努力，应激和糖皮质激素对人体代谢的不利影响。