RT Journal Article
SR Electronic
T1 Rapid Glucocorticoid Receptor-Mediated Inhibition of Hypothalamic–Pituitary–Adrenal Ultradian Activity in Healthy Males
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 6106
OP 6115
DO 10.1523/JNEUROSCI.5332-09.2010
VO 30
IS 17
A1 Georgina M. Russell
A1 David E. Henley
A1 Jack Leendertz
A1 Jennie A. Douthwaite
A1 Susan A. Wood
A1 Adam Stevens
A1 Wolfram W. Woltersdorf
A1 Bernard W. M. M. Peeters
A1 Ge S. F. Ruigt
A1 Anne White
A1 Johannes D. Veldhuis
A1 Stafford L. Lightman
YR 2010
UL http://www.jneurosci.org/content/30/17/6106.abstract
AB 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.