Cardio‐metabolic consequences of glucocorticoid replacement: relevance of ultradian signalling

Abstract

Summary Chronic exposure to elevated glucocorticoid levels is associated with obesity, insulin resistance, impaired glucose tolerance, hypertension and dyslipidaemia, manifest classically in Cushing's syndrome and with high‐dose glucocorticoid therapy. However, cardiovascular events are also reportedly higher in patients with primary and secondary hypoadrenalism receiving ‘replacement’ glucocorticoid doses. This has been attributed to an inability to mimic accurately the diurnal rhythm of cortisol with current oral replacement therapy and subsequent glucocorticoid excess. Although development of delayed release oral preparations has sought to overcome this problem, there has been little attention on the ultradian rhythm of glucocorticoids and its relevance for replacement therapy and associated cardio‐metabolic comorbidity. Endogenous glucocorticoids are released in a pulsatile manner, and this ultradian rhythm is important in maintaining homeostatic control through glucocorticoid‐receptor (GR)‐dependent transcription regulation that rapidly responds to circulating hormone levels. Constant glucocorticoid exposure can result in continuous transcription, aberrant mRNA accumulation and abnormal protein levels. GR regulation of transcription programmes is highly cell and tissue specific, binding to distinct genomic loci in different cellular contexts. GR also interacts with a large cohort of DNA‐binding factors with cell‐specific interactions. The relevance of kinetic patterns of GR‐dependent gene expression in vivo is not yet fully elucidated. However, given that GR gene variants are associated with cardiovascular disease, it is possible that ultradian delivery of glucocorticoid replacement may become important, at least in selected patients.

Subcutaneous pulsatile glucocorticoid replacement therapy

“…Indeed, the pattern of glucocorticoid exposure – and even the phase of the pulse – results in differential effects on behaviour and the c‐fos response of the brain – particularly the amygdala – to a stressor. This is also likely to lead to metabolic and cardiovascular dysfunction . Current replacement regimes with their relatively constant glucocorticoid receptor occupancy and consequent abnormal glucocorticoid‐dependent gene transcription undoubtedly contribute to glucocorticoid side effects and may even be a causal factor for the excessive morbidity and mortality of patients on glucocorticoid replacement.…”

“…This is also likely to lead to metabolic and cardiovascular dysfunction. [21][22][23] Current replacement regimes with their relatively constant glucocorticoid receptor occupancy and consequent abnormal glucocorticoid-dependent gene transcription undoubtedly contribute to glucocorticoid side effects and may even be a causal factor for the excessive morbidity and mortality of patients on glucocorticoid replacement. The current report shows that it is possible to reproduce near physiological patterns of both circadian and ultradian rhythmicity using a specialized pump and simple subcutaneous infusion techniques.…”

Renal and Blood Pressure Response to a High-Salt Diet in Mice With Reduced Global Expression of the Glucocorticoid Receptor

“…More subtly, clamping corticosterone in the mid-physiological range ablates the normal diurnal rhythmicity, activates NCC and induces non-dipping BP in mice ( Ivy et al, 2016 ). Interestingly, adrenalectomy also induces non-dipping BP in mice ( Sei et al, 2008 ) and in humans such circadian abnormalities have a detrimental impact on cardiovascular health ( Henley and Lightman, 2014 ).…”

Beta-2 Adrenergic and Glucocorticoid Receptor Agonists Modulate Ozone-Induced Pulmonary Protein Leakage and Inflammation in Healthy and Adrenalectomized Rats

“…The activation of neural SAM-and HPA-mediated stress responses increases the release of epinephrine and corticosterone/cortisol, respectively, from adrenal glands, which in turn, produces tissue-specific homeostatic changes in metabolic and immune processes associated with the fight-or-flight response (Gorman, 2013). Chronic elevations of stress hormones have been associated with neurological abnormalities including psychosocial disorders and systemic inflammatory conditions (Barr, 2017;Henley and Lightman, 2014). We have previously shown that acute ozone-and acrolein-induced respiratory injury and inflammation are associated with the activation of neuroendocrine stress pathways in both healthy and diabetic rat models (Bass et al, 2013;Miller et al, 2015;Snow et al, 2017) and in healthy humans (Miller et al, 2016a).…”