The Origin of Glucocorticoid Hormone Oscillations

Abstract

Characterization of a peripheral hormonal system identifies the origin and mechanisms of regulation of glucocorticoid hormone oscillations in rats.

Abstract

Oscillating levels of adrenal glucocorticoid hormones are essential for optimal gene expression, and for maintaining physiological and behavioural responsiveness to stress. The biological basis for these oscillations is not known, but a neuronal “pulse generator” within the hypothalamus has remained a popular hypothesis. We demonstrate that pulsatile hypothalamic activity is not required for generating ultradian glucocorticoid oscillations. We show that a constant level of corticotrophin-releasing hormone (CRH) can activate a dynamic pituitary-adrenal peripheral network to produce ultradian adrenocorticotrophic hormone and glucocorticoid oscillations with a physiological frequency. This oscillatory response to CRH is dose dependent and becomes disrupted for higher levels of CRH. These data suggest that glucocorticoid oscillations result from a sub-hypothalamic pituitary-adrenal system, which functions as a deterministic peripheral hormone oscillator with a characteristic ultradian frequency. This constitutes a novel mechanism by which the level, rather than the pattern, of CRH determines the dynamics of glucocorticoid hormone secretion.

Author Summary

Glucocorticoid steroid hormones, such as cortisol and corticosterone, provide a rapid response to both physical and psychological stress, and act on areas of the brain that influence learning, memory, and behaviour. Glucocorticoids are released from the adrenal glands in near-hourly pulses, which results in oscillating glucocorticoid levels in the blood and in target organs. These hormone oscillations can become disrupted during ageing and in stress-related disease (e.g., major depression), so it is important to identify the underlying mechanisms that govern their dynamics. Although the origin of the oscillations is not known, it is assumed that they are generated by a neuronal “pulse generator” within the brain. In this study, we present data that challenge this hypothesis. We characterize a peripheral hormonal system and show that constant levels of corticotrophin-releasing hormone can induce and regulate hormone oscillations independent of the brain. We also describe mechanisms that can disrupt these oscillations. These findings have important implications for our understanding of glucocorticoid signalling in both health and disease, and will be important for the design of novel treatment strategies that take into account timing of hormone administration to patients undergoing steroid therapy for inflammatory or malignant disease.