The Functional and Clinical Significance of the 24-Hour Rhythm of Circulating Glucocorticoids
Open accessAbstract
Adrenal glucocorticoids are major modulators of multiple functions, including energy metabolism, stress responses, immunity, and cognition. The endogenous secretion of glucocorticoids is normally characterized by a prominent and robust circadian (around 24 hours) oscillation, with a daily peak around the time of the habitual sleep-wake transition and minimal levels in the evening and early part of the night. It has long been recognized that this 24-hour rhythm partly reflects the activity of a master circadian pacemaker located in the suprachiasmatic nucleus of the hypothalamus. In the past decade, secondary circadian clocks based on the same molecular machinery as the central master pacemaker were found in other brain areas as well as in most peripheral tissues, including the adrenal glands. Evidence is rapidly accumulating to indicate that misalignment between central and peripheral clocks has a host of adverse effects. The robust rhythm in circulating glucocorticoid levels has been recognized as a major internal synchronizer of the circadian system. The present review examines the scientific foundation of these novel advances and their implications for health and disease prevention and treatment.
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Cortisol, not melatonin, is the key metabolic central synchronizing signal.
“This rhythm is important for its action because cortisol, not melatonin, is recognized to be the key metabolic central synchronizing signal [60–62].”
From Sleep, testosterone and cortisol balance, and ageing men (2022) · cites this paper as [60]
The Introduction (section I.B; page unavailable) calls the glucocorticoid rhythm a major internal synchronizing signal. But section II.D identifies both glucocorticoids and melatonin as key endocrine rhythms and describes melatonin as an internal synchronizer. The source therefore does not support the claim’s exclusion of melatonin or establish cortisol as the sole key metabolic synchronizing signal. (LLM, conf=0.88)
Experimental — accuracy not yet measuredExperimental administration of glucocorticoid synchronizes peripheral clocks in liver, muscle, adipose tissue, pancreas, and gut.
“Experimental administration of glucocorticoid synchronizes the peripheral clocks located in liver, muscle, and adipose tissue which are the major storage sites for glycogen, protein, and fat, respectively, as well as other metabolically relevant organs such as pancreas and gut [60–63].”
From Sleep, testosterone and cortisol balance, and ageing men (2022) · cites this paper as [60]
Section IV.B (page not provided) says dexamethasone synchronizes the liver clock in mice and describes glucocorticoid effects on clock-gene rhythms in skeletal muscle and adipose tissue. Its pancreas and gut subsections do not report synchronization by administered glucocorticoids; Section II.C instead identifies restricted feeding as a synchronizer of clocks in all five organs. (LLM, conf=0.88)
Experimental — accuracy not yet measuredHypercortisolemia during the late-afternoon and early-evening is harmful, and is believed to cause insulin resistance observed with advanced age, impair physical performance, and trigger neurocognitive deficits.
“These findings are highly relevant because hypercortisolemia during the late-afternoon and early-evening is harmful, and is believed to cause the insulin resistance observed with advanced age [60, 69, 70], impair physical performance [71] and trigger neurocognitive deficits [72].”
From Sleep, testosterone and cortisol balance, and ageing men (2022) · cites this paper as [60]
In VI.A (Aging; page unavailable), the paper says elevated cortisol in older adults could facilitate insulin resistance and memory deficits. It also reports an association between flatter cortisol rhythms and impaired physical functioning, but does not establish that late-day hypercortisolemia causes the physical or neurocognitive deficits as the claim suggests. (LLM, conf=0.84)
Experimental — accuracy not yet measuredDisruption of glucocorticoid rhythms often leads to disease.
“Disruption of these hormone rhythms often leads to disease ( 2 ),”
From Dynamic modulation of glucose utilisation by glucocorticoid rhythms in health and disease (2020) · cites this paper as [2]
The Introduction (section I.B) says altered glucocorticoid rhythms may promote circadian misalignment and adverse health consequences. Section VI.D also links nonphysiological cortisol profiles during replacement therapy with increased morbidity. The paper does not establish that rhythm disruption often leads to disease; its general causal statement is more cautious. (LLM, conf=0.83)
Experimental — accuracy not yet measuredIn hypercortisolism, cortisol levels are higher than normal and in some cases display abnormal rhythmicity, varying by underlying condition.
“in hypercortisolism, it is not only that CORT levels are higher than normal, but in some cases, they also display abnormal rhythmicity. This varies depending on whether the underlying condition is associated with Cushing's syndrome, depression, PTSD, acute inflammation following major surgery, or chronic inflammatory diseases (e.g., rheumatoid arthritis) ( 2, 5-13, 57-60 ).”
From Dynamic modulation of glucose utilisation by glucocorticoid rhythms in health and disease (2020) · cites this paper as [2]
Section VI.D reports elevated cortisol and dampened or absent circadian variation in Cushing’s syndrome; VI.E reports high cortisol with altered secretion patterns in many severely depressed patients. But VI.E reports lower, not higher, basal morning cortisol in PTSD, and the passages found do not establish the claimed patterns following major surgery or in rheumatoid arthritis. The sentence therefore overextends what this source supports across the listed conditions. (LLM, conf=0.85)
Experimental — accuracy not yet measured
Many conditions associated with hypercortisolism are accompanied by disruption of normal glucose metabolism while preserving some degree of cortisol rhythmicity.
“many of these conditions are accompanied by a disruption of normal glucose metabolism while preserving some degree of CORT rhythmicity.”
From Dynamic modulation of glucose utilisation by glucocorticoid rhythms in health and disease (2020) · cites this paper as [2]
Section VI.D links Cushing’s syndrome to glucose intolerance and says some patients with pituitary-dependent disease retain low-amplitude cortisol variation. But it also says circadian modulation is generally absent in Cushing’s disease and that persistent rhythmicity is rare in adrenal Cushing’s syndrome. Section VI.E describes persistent rhythmicity in severe depression with hypercortisolism, but does not establish disrupted glucose metabolism in those patients; the broader claim about many conditions is therefore not fully supported. (LLM, conf=0.84)
Experimental — accuracy not yet measuredMounting evidence suggests that circadian clock genes within the brain, skeletal muscle, adipose tissue, gut, liver and pancreas may play a major role in regulating insulin sensitivity, possibly cooperating with glucocorticoids in controlling circadian variability.
“Similarly, mounting evidence suggests that circadian clock genes within the brain, skeletal muscle, adipose tissue, gut, liver and pancreas (to name a few) may play a major role in regulating insulin sensitivity, possibly cooperating with glucocorticoids in controlling circadian variability ( 2, 73, 74 ).”
From Dynamic modulation of glucose utilisation by glucocorticoid rhythms in health and disease (2020) · cites this paper as [2]
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- Authors
- Oster, H., Challet, E., Ott, V., Arvat, E., de Kloet, E. R., Dijk, D.-J., Lightman, S., Vgontzas, A., & Van Cauter, E.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Medical Department I (H.O., V.O.), University of Lübeck, 23562 Lübeck, Germany; Institute for Cellular and Integrative Neuroscience (E.C.), Centre National de la Recherche Scientifique (CNRS) UPR 3212, University of Strasbourg, 67084 Strasbourg, France; Division of Endocrinology, Diabetology and Metabolism (E.A.), Department of Internal Medicine, University of Turin, 10043 Turin, Italy; Departmen
- Venue
- Endocrine Reviews
- Publisher
- The Endocrine Society
- Published
- 2016-10-17
- Volume
- 38
- Issue
- 1
- Pages
- 3-45
- ISSN
- 0163-769X (ISSN-L)
- 1945-7189
- PMC
- PMC5563520
- OpenAlex
- W2535896286
- Cited by
- 548
- References
- 440
- Citations by year
- 2026: 64 · 2025: 77 · 2024: 47 · 2023: 61 · 2022: 57 · 2021: 72 · 2020: 77 · 2019: 35 · 2018: 31 · 2017: 24 · 2016: 1 · 2014: 2
- FWCI
- 3.21
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Endocrine Reviews (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Explore Bristol Research (publishedVersion, cc-by)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- HAL (submittedVersion, other-oa)
- Leiden Repository (Leiden University) (submittedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion)
- Bristol Research (University of Bristol) (submittedVersion, cc-by)
- Funders
- Medical Research Council (MR/J008893/1, MR/J012548/1)
- Biotechnology and Biological Sciences Research Council (BB/L007622/1)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- glucocorticoids, circadian rhythm, circadian clock, suprachiasmatic nucleus, adrenal gland, peripheral circadian clock, sleep-wake transition, circadian misalignment, adrenal steroid secretion
- MeSH terms
- Animals, Circadian Rhythm, Glucocorticoids, Humans, Circadian Clocks
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