Pulsatile cortisol feedback on ACTH secretion is mediated by the glucocorticoid receptor and modulated by gender
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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 feedback on both ACTH burst mass and secretion 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.
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In healthy subjects ACTH ApEn is age, body mass index, and sex independent, unless the glucocorticoid receptor is blocked experimentally.
“Indeed, in healthy subjects ACTH ApEn is age, body mass index, and sex independent, unless the glucocorticoid receptor is blocked experimentally (31).”
From Regulation of Pulsatile and Entropic ACTH Secretion Under Fixed Exogenous Secretagogue Clamps (2017) · cites this paper as [31]
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- Authors
- Roelfsema, F., Aoun, P., & Veldhuis, J. D.
- Affiliations
- Leiden University Medical Center (NL)
- Mayo Clinic (US)
- Corresponding author
- Veldhuis, Johannes D.
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2016-08-22
- Volume
- 101
- Issue
- 11
- Pages
- 4094-4102
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- PMC
- PMC5095237
- OpenAlex
- W2513598173
- Semantic Scholar
- c7e0cd1a803f331fc586b0cef3042f7e135674af
- Cited by
- 23
- References
- 42
- Citations by year
- 2026: 3 · 2023: 1 · 2022: 2 · 2021: 1 · 2020: 1 · 2019: 6 · 2018: 6 · 2017: 3
- FWCI
- 5.02
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- Funders
- National Institutes of Health (UL1TR000135, TR000135, DK050456)
- National Institute of Standards and Technology (60NANB10D005Z)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK050456, R01DK073148)
- National Center for Advancing Translational Sciences (60NANB10D005Z, TR000135)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal Regulation and Hypertension
- Keywords
- ACTH secretion, glucocorticoid receptor, mineralocorticoid receptor, negative feedback, hypothalamic-pituitary-adrenal axis, sex differences, mifepristone, eplerenone, estradiol, testosterone, vasopressin, corticotropin-releasing factor
- MeSH terms
- Eplerenone, Adrenocorticotropic Hormone, Adult, Mineralocorticoid Receptor Antagonists, Double-Blind Method, Female, Hormone Antagonists, Humans, Hydrocortisone, Male, Middle Aged, Prospective Studies, Receptors, Glucocorticoid, Sex Factors, Spironolactone, Mifepristone
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