Rapid glucocorticoid receptor-mediated inhibition of hypothalamic- pituitary-adrenal ultradian activity in healthy males

Georgina M. Russell, David E. Henley, Jack Leendertz, Jennie A. Douthwaite, Susan A. Wood, Adam Stevens, Wolfram W. Woltersdorf, Bernard W.M.M. Peeters, Ge S.F. Ruigt, Anne White, Johannes D. Veldhuis, Stafford L. Lightman

Research output: Contribution to journalArticle

77 Scopus citations

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. CirculatingPOMCpeptide 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.

Original languageEnglish (US)
Pages (from-to)6106-6115
Number of pages10
JournalJournal of Neuroscience
Volume30
Issue number17
DOIs
StatePublished - Apr 28 2010

ASJC Scopus subject areas

  • Neuroscience(all)

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    Russell, G. M., Henley, D. E., Leendertz, J., Douthwaite, J. A., Wood, S. A., Stevens, A., Woltersdorf, W. W., Peeters, B. W. M. M., Ruigt, G. S. F., White, A., Veldhuis, J. D., & Lightman, S. L. (2010). Rapid glucocorticoid receptor-mediated inhibition of hypothalamic- pituitary-adrenal ultradian activity in healthy males. Journal of Neuroscience, 30(17), 6106-6115. https://doi.org/10.1523/JNEUROSCI.5332-09.2010