TSH SECRETION--ROLE OF GLUCOCORTICOIDS

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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.