Fixing the broken clock in adrenal disorders: focus on glucocorticoids and chronotherapy

Abstract

<jats:p>The circadian rhythm derives from the integration of many signals that shape the expression of clock-related genes in a 24-h cycle. Biological tasks, including cell proliferation, differentiation, energy storage, and immune regulation, are preferentially confined to specific periods. A gating system, supervised by the central and peripheral clocks, coordinates the endogenous and exogenous signals and prepares for transition to activities confined to periods of light or darkness. The fluctuations of cortisol and its receptor are crucial in modulating these signals. Glucocorticoids and the autonomous nervous system act as a bridge between the suprachiasmatic master clock and almost all peripheral clocks. Additional peripheral synchronizing mechanisms including metabolic fluxes and cytokines stabilize the network. The pacemaker is amplified by peaks and troughs in cortisol and their response to food, activity, and inflammation. However, when the glucocorticoid exposure pattern becomes chronically flattened at high- (as in Cushing’s syndrome) or low (as in adrenal insufficiency) levels, the system fails. While endocrinologists are well aware of cortisol rhythm, too little attention has been given to interventions aimed at restoring physiological cortisol fluctuations in adrenal disorders. However, acting on glucocorticoid levels may not be the only way to restore clock-related activities. First, a counterregulatory mechanism on the glucocorticoid receptor itself controls signal transduction, and second, melatonin and/or metabolically active drugs and nutrients could also be used to modulate the clock. All these aspects are described herein, providing some insights into the emerging role of chronopharmacology, focusing on glucocorticoid excess and deficiency disorders.</jats:p>

The Lack of Light-Dark and Feeding-Fasting Cycles Alters Temporal Events in the Goldfish (Carassius auratus) Stress Axis

“…It is well established that mean plasma cortisol levels are not the only parameter to be considered when studying the HPI function in mammals; temporal events in the HPI axis are also important [ 5 , 59 ]. Thus, the relevance of a robust rhythm of cortisol, with high nocturnal levels (as occurs in randomly fed fish) versus a dampened rhythm with lower cortisol levels (in LD-2 and DD-2 groups) should be investigated.…”

Early Metabolic Benefits of Switching Hydrocortisone to Modified Release Hydrocortisone in Adult Adrenal Insufficiency

“…One potential explanation for the metabolic benefits conferred by MR-HC vs standard HC therapy in our study relates to improved regulation of circadian clock mechanisms. Glucocorticoids mediate interactions between central and peripheral clocks in humans ( 26 ). Adrenal disorders such as AI associate with dysregulation of clock synchronization through disrupted circadian rhythms of cortisol ( 26 ).…”

“…Glucocorticoids mediate interactions between central and peripheral clocks in humans ( 26 ). Adrenal disorders such as AI associate with dysregulation of clock synchronization through disrupted circadian rhythms of cortisol ( 26 ). Furthermore, evidence suggests that replicating a more physiological cortisol rhythm through once-daily MR-HC rather than multiple daily doses of HC confers additional benefits that include restoration of immune function and improved inflammatory profile ( 16 ).…”

“…These benefits correlate with improved circadian gene expression profile ( 19 ). Switching from multiple daily HC administration to once-daily MR-HC associates with improved synchronization of clock gene expression ( 26 ). Furthermore, improved glucocorticoid exposure during the night with MR-HC may result in improved synchronization of nocturnal autonomic pathways ( 27 ), and optimized entrainment of hypothalamic and melanocortinergic activities ( 26 ).…”

“…Switching from multiple daily HC administration to once-daily MR-HC associates with improved synchronization of clock gene expression ( 26 ). Furthermore, improved glucocorticoid exposure during the night with MR-HC may result in improved synchronization of nocturnal autonomic pathways ( 27 ), and optimized entrainment of hypothalamic and melanocortinergic activities ( 26 ). We hypothesize that such nocturnal re-synchronization of key neuro-autonomic and endocrine pathways underlies, at least in part, the increase in SMR observed following switch from HC to MR-HC therapy.…”