Ultradian hormone stimulation induces glucocorticoid receptor-mediated pulses of gene transcription
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Studies on glucocorticoid receptor (GR) action typically assess gene responses by long-term stimulation with synthetic hormones. As corticosteroids are released from adrenal glands in a circadian and high-frequency (ultradian) mode, such treatments may not provide an accurate assessment of physiological hormone action. Here we demonstrate that ultradian hormone stimulation induces cyclic GR-mediated transcriptional regulation, or gene pulsing, both in cultured cells and in animal models. Equilibrium receptor-occupancy of regulatory elements precisely tracks the ligand pulses. Nascent RNA transcripts from GR-regulated genes are released in distinct quanta, demonstrating a profound difference between the transcriptional programs induced by ultradian and constant stimulation. Gene pulsing is driven by rapid GR exchange with response elements and by GR recycling through the chaperone machinery, which promotes GR activation and reactivation in response to the ultradian hormone release, thus coupling promoter activity to the naturally occurring fluctuations in hormone levels. The GR signalling pathway has been optimized for a prompt and timely response to fluctuations in hormone levels, indicating that biologically accurate regulation of gene targets by GR requires an ultradian mode of hormone stimulation.
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A high proportion of patients on conventional corticosteroid replacement therapy for adrenal insufficiency are overtreated or on inappropriate replacement regimens.
“A high proportion of patients on “conventional” corticosteroid replacement therapy for AI are over treated or on inappropriate replacement regimens (120).”
From Hormonal Replacement in Hypopituitarism in Adults: An Endocrine Society Clinical Practice Guideline (2016) · cites this paper as [120]
The Discussion says corticosteroid replacement regimens for patients with hypocortisolaemia lack effective ultradian rhythmicity, which supports a concern about how replacement is administered. It does not say that a high proportion of patients are overtreated or quantify how many receive inappropriate regimens. (LLM, conf=0.84)
Experimental — accuracy not yet measuredUltradian hormone stimulation induces glucocorticoid receptor-mediated pulses of gene transcription.
“For instance, ultradian hormone stimulation is known to induce glucocorticoid receptor-mediated pulses of gene transcription [78], and there exists a growing realisation that understanding how the dynamics of glucocorticoid signalling affects gene regulation is key to the design of effective chronotherapies 79, 80.”
From Mathematical Modelling of Endocrine Systems (2019) · cites this paper as [78]
Glucocorticoid responsive genes respond to rapid fluctuations in glucocorticoid levels in a biologically meaningful way.
“it is now clear that glucocorticoid responsive genes respond to these rapid fluctuations in a biologically meaningful way.”
From Origin of ultradian pulsatility in the hypothalamic–pituitary–adrenal axis (2010) · cites this paper as Stavreva et al. 2009
The physiological response to "clamped" cortisol levels may differ from ultradian rhythm.
“This suggests that acute diurnal variation in cortisol concentrations may not substantially alter lipolysis during normal physiology, although the physiological response to “clamped” cortisol levels may differ from ultradian rhythm.34”
From Acute physiological effects of glucocorticoids on fuel metabolism in humans are permissive but not direct (2017) · cites this paper as [34]
Very few studies have assessed the impact of glucocorticoid dose optimization on markers of bone formation and resorption.
“Very few studies have assessed the impact of GC dose optimization on markers of bone formation and resorption (120).”
From Hormonal Replacement in Hypopituitarism in Adults: An Endocrine Society Clinical Practice Guideline (2016) · cites this paper as [120]
The Discussion addresses glucocorticoid treatment timing and its possible side effects, but not how many studies have assessed dose optimization. Searches for bone formation, bone resorption, and dose optimization found no passage about bone-turnover markers in our copy. (LLM, conf=0.76)
Experimental — accuracy not yet measured
New experimental and theoretical results offer enough evidence to support the indispensable roles of ultradian oscillatory dynamics of HPA hormones levels for normal physiology.
“new experimental [9-15] and theoretical [16-27] results offer enough evidence to support the indispensable roles of ultradian oscillatory dynamics of HPA hormones levels for normal physiology.”
From Predictive modeling of the hypothalamic-pituitary-adrenal (HPA) axis response to acute and chronic stress (2011) · cites this paper as [12]
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Self-citation
- Authors
- Stavreva, D. A., Wiench, M., John, S., Conway-Campbell, B. L., McKenna, M. A., Pooley, J. R., Johnson, T. A., Voss, T. C., Lightman, S. L., & Hager, G. L.
- Affiliations
- National Institutes of Health (US)
- University of Bristol (GB)
- Corresponding author
- Hager, Gordon L.
- ORCID
- Venue
- Nature Cell Biology
- Published
- 2009-08-16
- Volume
- 11
- Issue
- 9
- Pages
- 1093-1102
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- PMC
- PMC6711162
- OpenAlex
- W2054146939
- Semantic Scholar
- 46653d7803e0e8cf6f38faadae4485e29aa794b8
- Cited by
- 375
- References
- 42
- Citations by year
- 2026: 12 · 2025: 8 · 2024: 14 · 2023: 14 · 2022: 12 · 2021: 20 · 2020: 12 · 2019: 18 · 2018: 16 · 2017: 19 · 2016: 29 · 2015: 24 · 2014: 42 · 2013: 27 · 2012: 25
- FWCI
- 20.55
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- Explore Bristol Research (submittedVersion)
- Funders
- Wellcome Trust (074112, 075548)
- National Institutes of Health
- Biotechnology and Biological Sciences Research Council (BB/C51297X/1)
- National Cancer Institute (ZIABC010027)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
- Keywords
- glucocorticoid receptor, transcriptional regulation, chaperone machinery, receptor recycling, receptor occupancy, glucocorticoid signaling
- MeSH terms
- Adrenal Cortex Hormones, Adrenalectomy, Animals, Cell Line, Circadian Rhythm, Gene Expression Regulation, Humans, Models, Biological, Receptors, Glucocorticoid, RNA Polymerase II, Time Factors, Transcription, Genetic, Rats, Sprague-Dawley, Molecular Chaperones, Response Elements, Protein Transport, Green Fluorescent Proteins, Mice, Rats
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