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Cited by 884Sleep and related disordersStress Responses and CortisolSleep and Wakefulness Research

Chronic insomnia is associated with nyctohemeral activation of the hypothalamic-pituitary-adrenal axis: clinical implications

Vgontzas, Alexandros N., Bixler, Edward O., Lin, Hung-Mo, Prolo, Paolo, Mastorakos, George, Vela-Bueno, Antonio, Kales, Anthony, Chrousos, George P.·2001·The Journal of Clinical Endocrinology & Metabolism
DOI 10.1210/jcem.86.8.7778
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Abstract

Although insomnia is, by far, the most commonly encountered sleep disorder in medical practice, our knowledge in regard to its neurobiology and medical significance is limited. Activation of the hypothalamic-pituitary-adrenal axis leads to arousal and sleeplessness in animals and humans; however, there is a paucity of data regarding the activity of the hypothalamic-pituitary-adrenal axis in insomniacs. We hypothesized that chronic insomnia is associated with increased plasma levels of ACTH and cortisol. Eleven young insomniacs (6 men and 5 women) and 13 healthy controls (9 men and 4 women) without sleep disturbances, matched for age and body mass index, were monitored in the sleep laboratory for 4 consecutive nights, whereas serial 24-h plasma measures of ACTH and cortisol were obtained during the fourth day. Insomniacs, compared with controls, slept poorly (significantly higher sleep latency and wake during baseline nights). The 24-h ACTH and cortisol secretions were significantly higher in insomniacs, compared with normal controls (4.2 +/- 0.3 vs. 3.3 +/- 0.3 pM, P = 0.04; and 218.0 +/- 11.0 vs. 190.4 +/- 8.3 nM, P = 0.07). Within the 24-h period, the greatest elevations were observed in the evening and first half of the night. Also, insomniacs with a high degree of objective sleep disturbance (% sleep time < 70), compared with those with a low degree of sleep disturbance, secreted a higher amount of cortisol. Pulsatile analysis revealed a significantly higher number of peaks per 24 h in insomniacs than in controls (P < 0.05), whereas cosinor analysis showed no differences in the temporal pattern of ACTH or cortisol secretion between insomniacs and controls. We conclude that insomnia is associated with an overall increase of ACTH and cortisol secretion, which, however, retains a normal circadian pattern. These findings are consistent with a disorder of central nervous system hyperarousal rather than one of sleep loss, which is usually associated with no change or decrease in cortisol secretion or a circadian disturbance. Chronic activation of the hypothalamic-pituitary-adrenal axis in insomnia suggests that insomniacs are at risk not only for mental disorders, i.e. chronic anxiety and depression, but also for significant medical morbidity associated with such activation. The therapeutic goal in insomnia should be to decrease the overall level of physiologic and emotional arousal, and not just to improve the nighttime sleep.

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  • Safety behaviors maintain insomnia by preventing disconfirmation of exaggerated worries about sleep and often disrupt sleep drive and circadian rhythms.

    “Although these behaviors are intended to reduce distress or promote sleep, they maintain insomnia by preventing disconfirmation of exaggerated worries about sleep and often disrupt sleep drive and circadian rhythms [18].”

    From Pre-Sleep Anxiety: Mechanisms and Therapeutic Approaches in Clinical Practice. (2026) · cites this paper as [18]

  • Perceived utility of safety behaviors, rather than just their frequency, predicts insomnia severity.

    “Importantly, research indicates that the perceived utility (i.e., the belief that 3 of 21 these behaviors are necessary) rather than just the frequency of safety behaviors, predicts insomnia severity, suggesting that functional relationship individuals have with these behaviors is critical to understanding their maintaining role [18].”

    From Pre-Sleep Anxiety: Mechanisms and Therapeutic Approaches in Clinical Practice. (2026) · cites this paper as [18]

  • Multiple studies have observed that sleep loss, either from acute partial or total sleep deprivation or from recurrent sleep curtailment or insomnia, results in elevated evening cortisol levels.

    “Multiple studies have observed that sleep loss, either from acute partial or total sleep deprivation or from recurrent sleep curtailment or insomnia, results in elevated evening cortisol levels (12–19).”

    From Adverse effects of two nights of sleep restriction on the hypothalamic-pituitary-adrenal axis in healthy men (2014) · cites this paper as [14]

  • Later studies found that 24-h urinary free cortisol, norepinephrine, and catecholamine metabolites levels were increased in patients with insomnia or were correlated with PSG indices of sleep disturbance in insomnia patients.

    “later studies found that 24-h urinary free cortisol, norepinephrine, and catecholamine metabolites levels were increased in patients with insomnia or were correlated with PSG indices of sleep disturbance in insomnia patients(148-151).”

    From Sleep: important considerations for the prevention of cardiovascular disease (2016) · cites this paper as [149]

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Authors
Vgontzas, A. N., Bixler, E. O., Lin, H.-M., Prolo, P., Mastorakos, G., Vela-Bueno, A., Kales, A., & Chrousos, G. P.
Affiliations
  • Pennsylvania State University (US)
  • University of California, Los Angeles (US)
  • National and Kapodistrian University of Athens (GR)
  • Department of Psychiatry (A.V.-B.), Autonomous University, Madrid, Spain 28003
  • National Institutes of Health (US)
Corresponding author
Vgontzas, Alexandros N.
ORCID
Venue
The Journal of Clinical Endocrinology & Metabolism
Publisher
The Endocrine Society
Published
2001-08-01
Volume
86
Issue
8
Pages
3787-3794
ISSN
  • 0021-972X (ISSN-L)
  • 1945-7197
DOI
10.1210/jcem.86.8.7778
OpenAlex
W1999790218
Cited by
884
References
48
Citations by year
2026: 43 · 2025: 38 · 2024: 35 · 2023: 37 · 2022: 53 · 2021: 38 · 2020: 37 · 2019: 38 · 2018: 36 · 2017: 40 · 2016: 44 · 2015: 43 · 2014: 36 · 2013: 49 · 2012: 31
FWCI
26.48
Type
journal article
Language
en
Open access
closed
Locations
  • The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
  • PubMed (publishedVersion)
Funders
NIH Clinical Center
Topics
  • Social Sciences › Psychology › Experimental and Cognitive Psychology › Sleep and related disorders
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
Keywords
chronic insomnia, hypothalamic-pituitary-adrenal axis, ACTH, cortisol, circadian rhythm, hyperarousal, sleep disorders, sleep latency, anxiety, depression, neuroendocrine activation, neurodegeneration, neuroinflammation
MeSH terms
Adrenocorticotropic Hormone, Adult, Circadian Rhythm, Female, Humans, Hydrocortisone, Hypothalamo-Hypophyseal System, Sleep Initiation and Maintenance Disorders, Male, Pituitary-Adrenal System, Reference Values, Sleep Stages, Sleep, REM, Body Mass Index, Area Under Curve, Sleep Disorders, Circadian Rhythm

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