Rapid Glucocorticoid Receptor-Mediated Inhibition of Hypothalamic–Pituitary–Adrenal Ultradian Activity in Healthy Males

Abstract

A complex dynamic ultradian rhythm underlies the hypothalamic-pituitary-adrenal (HPA) circadian rhythm. We have investigated in normal human male subjects the importance, site of action, and receptor-mediated processes involved in rapid basal corticosteroid feedback and its interaction with corticotrophin releasing hormone (CRH) drive. Pro-opiomelanocortin (POMC), ACTH, and cortisol were measured every 10 min from healthy males during the awakening period or late afternoon using an automated blood sampling system. Mathematical modeling into discrete pulses of activity revealed that intravenous infusion of the synthetic mixed glucocorticoid/ mineralocorticoid agonist prednisolone produced rapid inhibition of ACTH and cortisol pulsatility within 30 min in the morning and afternoon. Any pulse that had commenced at the time of injection was unaffected, and subsequent pulsatility was inhibited. Prednisolone also inhibited ACTH and cortisol secretion in response to exogenous CRH stimulation, inferring rapid feedback inhibition at the anterior pituitary. Circulating POMC peptide concentrations were unaffected, suggesting that the rapid corticosteroid inhibitory effect specifically targeted ACTH secretion from pituitary corticotrophs. Prednisolone fast feedback was only reduced by glucocorticoid receptor antagonist pretreatment and not by mineralocorticoid receptor antagonism, suggesting a glucocorticoid receptor-mediated pathway. The intravenous prednisolone suppression test provides a powerful new tool to investigate HPA abnormalities underlying metabolic and psychiatric disease states.

60 YEARS OF NEUROENDOCRINOLOGY: Glucocorticoid dynamics: insights from mathematical, experimental and clinical studies

“…This time delay of a few minutes is presumably due to the time needed by the adrenal for de novo synthesis CORT in response to ACTH, since in contrast to peptides hormones (e.g., CRH and ACTH), CORT cannot be pre-synthesized and stored within adrenal steroidogenic cells due to its lipophilic nature. Once released into the general circulation, CORT activates a fast (presumably non-genomic) negative feedback mechanism at the level of the pituitary that still remains to be fully characterized (Jones et al 1972, 1974, Rotsztejn et al 1975a,b, Mahmoud et al 1984, Widmaier & Dallman 1984, Hinz & Hirschelmann 2000, Russell et al 2010.…”

Predictive modeling of the hypothalamic-pituitary-adrenal (HPA) axis response to acute and chronic stress

“…acteristic frequencies: ultradian oscillations, with a period of 20-120 min [4][5][6] superimposed on circadian oscillations, with a period of about 24 h. The importance of circadian rhythms for adequate functioning of the HPA axis has been recognized for years [7,8]; in addition, new experimental [9][10][11][12][13][14][15] and theoretical [16][17][18][19][20][21][22][23][24][25][26][27] results offer enough evidence to support the indispensable roles of ultradian oscillatory dynamics of HPA hormones levels for normal physiology. Since ultradian and circadian oscillations operate on different time scales, their effects are manifested in different biological realms.…”

Temporal control of glucocorticoid neurodynamics and its relevance for brain homeostasis, neuropathology and glucocorticoid-based therapeutics

“…These pulses vary in amplitude and duration throughout the day, but their origin seems to be the result of a selfsustaining feedforward and GR-dependent feedback oscillatory activity between the anterior pituitary (AP) and AGs -a sub-hypothalamic oscillatory mechanism (Waite et al, 2012;Walker et al, 2010;Russell et al, 2010). This results in a 24 h profile of circulating endogenous GCs, where pulses of adrenal GC secretion of varying amplitude and duration occur periodically, approximately every 60-145 min Gavrila et al, 2003), in anticipation of cortisol's estimated half-life (around 90 min) (Rai et al, 2004;Depue et al, 1985).…”

“…These states result in prolonged high GC levels and thus the elimination of the recovery periods / self-limiting control of GR activation during the descending phase of the ultradian pulse cycles, leading to brain GC resistance (Meijer et al, 2003) followed by GR down-regulation and inductively reduced GR-dependent regulatory influences (Makino et al, 1995). For instance, rapid GR-dependent negative feedback regulation of ACTH release under basal conditions or acute stress (Russell et al, 2010) is reduced in major depression, a condition accompanied with an overactive HPA axis (Young et al, 1991). Other examples involve the reduction of immune system's sensitivity to GCs' immunosuppressive effects during chronic psychological stress (Miller et al, 2002), or the selective down-regulation of hippocampal GRs under sustained stress in rodents and non-human primates (Brooke et al, 1994) or after the experimental induction of viral encephalitis in rats (Bener et al, 2007).…”