TSH SECRETION--ROLE OF GLUCOCORTICOIDS

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 在急性或慢性病期间减少。然而，决定因素 生理性(非应激)TSH分泌以及TSH抑制 压力，都是未知的。这项提议的总体假设是，在 人的糖皮质激素含有生理水平的TSH分泌， 并在高水平介导应激诱导的TSH抑制。 为了验证这一假设，我们将探讨三个具体目标： 1)生理性(非应激)糖皮质激素水平对 将测定促甲状腺激素的分泌。 2)糖皮质激素水平升高对促甲状腺激素的影响 分泌物将会被确定。 3)生理或应激状态下糖皮质激素抑制TSH的部位 级别将得到澄清。 为实现这些目标，将利用下列实验工具： 1)动态TSH分泌的测定。促甲状腺激素通常分泌在 具有昼夜节律变化的一系列脉冲，并由 下丘脑促甲状腺激素释放激素(TRH)。测量 搏动性、昼夜节律和TRH刺激的TSH水平是一种敏感的方法 发现基础状态下不明显的TSH分泌异常 水平是经过测量的。反褶积分析的数学技巧 将用于获得基础和搏动性TSH的精确估计 测量的TSH时间序列中的分泌物。 2)应用米非司酮。健康的受试者将获得 米非司酮，一种竞争性糖皮质激素拮抗剂，将允许 应激、内源性皮质醇水平和促甲状腺激素之间的分离 分泌物。 3)招募原发性肾上腺功能不全或合并肾上腺功能不全患者 TRH和皮质醇缺乏。在这些受试者中，血清皮质醇或TSH 水平可以通过注射氢化可的松或 真的。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 压力，皮质醇水平，下丘脑对脑下垂体的输入，以及 促甲状腺激素分泌。 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。为了绕过这一点 问题是，短期禁食已经发展成为一种压力模型- 在人体内诱导TSH抑制。 从这些研究中获得的见解将促进我们对 糖皮质激素相关疾病中的甲状腺功能障碍 立面。这样的结果可能有助于继续努力尽量减少 应激和糖皮质激素对人体新陈代谢的不利影响。

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.