Pulsatile cortisol feedback on ACTH secretion is mediated by the glucocorticoid receptor and modulated by gender

Ferdinand Roelfsema, Paul Aoun, Johannes D. Veldhuis

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


Context: Factors that regulate physiological feedback by pulses of glucocorticoids on the hypothalamic-pituitary unit are sparsely defined in humans in relation to gluco-or mineralocorticoid receptor pathways, gender, age, and the sex steroid milieu. Objective: The objective of the study was to test (the clinical hypothesis) that glucocorticoid (GR) and mineralocorticoid (MR) receptor-selective mechanisms differentially govern pulsatile cortisol-dependent negative feedback on ACTH output ( by the hypothalamo-pituitary unit) in men and women studied under experimentally defined T and estradiol depletion and repletion, respectively. Setting: The study was conducted at the Mayo Center for Translational Science Activities. Subjects: Healthy middle-aged men (n = 16) and women (n = 25) participated in the study. Interventions: This was a randomized, prospective, double-blind, placebo-and saline-controlled study of pulsatile cortisol infusions in low cortisol-clamped volunteers with and without eplerenone (MR blocker) and mifepristone (GR blocker) administration under a low and normal T and estradiol clamp. During frequent sampling, a bolus of CRH-arginine vasopressin was infused to assess corticotrope responsiveness. Analytical Methods and Outcomes: Deconvolution and approximate entropy of ACTH profiles were measured. Results: Infusion of cortisol (but not saline) pulses diminished ACTH secretion. The GR antagonist, mifepristone, interfered with negative feedbackonbothACTHburst massandsecretion regularity. Eplerenone, an MR antagonist, exerted no detectable effect on the same parameters. Despite feedback imposition, CRH-arginine vasopressin-stimulated ACTH secretion was also increased by mifepristone and not by eplerenone. Withdrawal vs addback of sex steroids had no effect on ACTH secretion parameters. Nonetheless, ACTH secretion was greater (P = .006) and more regular (P = .004) in men than women. Conclusion: Pulsatile cortisol feedback on ACTH secretion in this paradigm is mediated by the glucocorticoid receptor, in part acting at the level of the pituitary, and influenced by sex. (J Clin Endocrinol Metab 101: 4094-4102, 2016).

Original languageEnglish (US)
Pages (from-to)4094-4102
Number of pages9
JournalJournal of Clinical Endocrinology and Metabolism
Issue number11
StatePublished - Nov 2016


  • Florida
  • Palm Beach Diabetes and Endocrine Specialists
  • West Palm Beach

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical


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