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Effects of Intravenous Corticotropin-Releasing Hormone upon Sleep-Related Growth Hormone Surge and Sleep EEG in Man
Abstract
Corticotropin-releasing hormone (CRH) plays a key role in coordinating neuroendocrine, metabolic and behavioral responses in stress and affective disorders. To further investigate the effects of enhanced pituitary-adrenocortical activity upon sleep-related phenomena we administered four intravenous injections of 50 µg human (h)-CRH or saline to 11 normal males at 10 p.m., 11 p.m., 12 p.m. and 1 a.m. and measured plasma levels of cortisol and growth hormone (GH) as well as sleep EEG recordings throughout the night. Treatment with h-CRH resulted in a significant increase of mean (± SEM) cortisol secretion between 11 p.m. and 3 a.m. (h-CRH: 100.6 + 9.5 ng/ml; saline: 39.0 ± 1.5 ng/ml; p < 0.01). This initial cortisol increase after repeated h-CRH stimulations was followed by a period of attenuated plasma cortisol between 3 and 7 a.m. (h-CRH: 70.3 + 7.0 ng/ml; saline: 115.5 ± 8.0 ng/ml; p < 0.01). Cortisol surges after h-CRH were associated with a significant blunting of sleep-related GH release expressed as areas under concentration curves (h-CRH: 1.245 ± 0.32 ng/ml/min · 103; saline: 2.462 + 0.92 ng/ml/min· 103, p < O.01). In addition to these hormonal effects, h-CRH induced a decrease of REM and slow wave sleep (stages III and IV) while the amount of more shallow sleep (stages I and II)increased. These effects upon sleep structure were more pronounced during the second part of the night. We conclude that h-CRH induces effects in healthy humans (GH blunting and SWS reduction) which resemble those seen among hypercortisolemic depressives and surmise that CRH plays a role to mediate endocrine as well as behavioral phenomena in the affective disorders.
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“there is in turn strong evidence that elevated CRH tone increases sleep EEG frequency, thereby decreasing SWS, and increasing light sleep and wakefulness [94].”
From Impact of Sleep and Its Disturbances on Hypothalamo-Pituitary-Adrenal Axis Activity (2010) · cites this paper as [94]
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Self-citationMechanisms of Cancer-Related Fatigue
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InfluentialStress Hormone Regulation: Biological Role and Translation into Therapy
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“In humans as well as in rats, CRH administration reduces the amount of slow wave sleep and enhances REM sleep (Ehlers et al. 1986, Holsboer et al. 1988), a pattern that is also observed in depression.”
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“While sleep loss and sleep disruption are generally thought of as activating the HPA axis, there is in turn strong evidence that elevated CRH tone increases sleep EEG frequency, thereby decreasing SWS, and increasing light sleep and wakefulness [94].”
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“This notion is supported by earlier reports indicating that intravenous administration of CRH influences sleep electroencephalo-grams in humans 39 and that blockage of central CRH receptors reduces spontaneous waking.”
ResultGhrelin promotes slow-wave sleep in humans
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“A similar course of cortisol secretion was found after pulsatile intravenous administration of CRH in young males (20).”
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“In women, however, sleep was impaired after GHRH and cortisol and ACTH was enhanced [83,84], which is similar to the effects of CRH [73].”
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“From the study in normal humans the influence of endogenous CRH on REMS is uncertain, however, since CRH suppresses REMS (Holsboer et al., 1988).”
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“Thus, CRH disturbs sleep continuity, promotes EEG activity in the higher frequency range and reduces slow wave sleep (Ehlers et al., 1986, 1997; Holsboer et al., 1988; Opp, 1995; Chang and Opp, 2001; Steiger, 2002).”
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“Indeed, preliminary clinical evidence in adults suggests that interventions targeted at suppressing CRH activity may be effective in treating insomnia (34–36).”
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Self-citationMagnesium and Affective Disorders
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“This is in line with the finding that CRH administered intravenously (i.v.) to healthy subjects leads to an increase of more shallow sleep (Holsboer et al., 1988).”
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“healthy men either resulted in a small decrease in SWS (9) or”
BackgroundResultTreatment with the CRH1-receptor-antagonist R121919 improves sleep-EEG in patients with depression
Held, K., Kunzel, H. E., Ising, M., Schmid, D. A., Zobel, A. W., Murck, H., Holsboer, F., & Steiger, A. (2003) · Journal of Psychiatric Research · doi:10.1016/s0022-3956(03)00076-1 · Cited by 123
“In healthy young male controls after repetitive hourly intravenous (iv) boluses of 4 50 mg CRH during sleep onset slow-wave-sleep (SWS) decreased (Holsboer et al., 1988), probably to due a central action of CRH.”
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“Although one study found that iv administration of CRH reduced REM sleep (23), this is probably an indirect effect of CRH, as iv administration of this hormone is unlikely to cross the blood-brain barrier.”
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“…is dominated by light sleep and frequently occurring brief arousals together with increased blood pressure and heart rate as well as a surge of cortisol and norepinephrine levels (Davies et al., 1993; 521 F.M usso et al./ N euroIm age 58 (2011) 508 –525 Holsboer et al., 1988; Redwine et al., 2000).”
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“It is beyond the scope of this study to reveal whether the decreased amounts of NREM sleep can be attributed to attenuated levels of SWA, but this would implicate that reduced SWA is an intrinsic sleepphysiological feature of the HR mouse line, which might be brought about by a chronic activation of the CRH system [6,…”
BackgroundSelf-citationDelta Sleep Response to Metyrapone in Post-Traumatic Stress Disorder
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“In addition, given the known inhibitory effect of CRF on the somatotropic axis (Holsboer et al, 1988; Steiger et al, 1992) and the known relation between delta sleep and growth hormone release (Van Cauter et al, 2000), it will be necessary to measure growth hormone responses in order to understand…”
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“…studies have shown that CRH has similar effects on sleep and neuroendocrine measures as SP as demonstrated here, i.e. decrease of REM and increase of stage 1 and 2 sleep as well as increase of cortisol secretion and blunting of sleep-related GH release (Born et al. 1989; Holsboer et al. 1988).”
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“…cortisol secretion. nu For example REM sleep is enhanced in CRH-overexpressing mice compared to the wildtype (Kimura et al., 2010). r When CRH was co-administered with ghrelin it promoted sleep, in contrast to its sleep-impairing effect after having been administered alone (Holsboer et al., 1988).”
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“Holsboer et al. (1988) have found that following hourly boluses of 50 pg hCRH between 10.00pm and 1.00 am there was a marked decrease in slow wave sleep (SWS) and REM sleep which became significant in the second half of the night.”
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“These data strengthen themselves since with the use of CRH antagonist, R121919, in depressed patients, there is an increase in the slow wave sleep.”
InfluentialDifferent Neuronal Phenotypes in the Lateral Hypothalamus and Their Role in Sleep and Wakefulness
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Sleep-disordered breathing and hormones
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Cortisol Enhances non-REM Sleep and Growth Hormone Secretion in Elderly Subjects
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“In young male healthy volunteers repetitive hourly iv injection from 2200 to 0100 h decrease SWS and the GH surge whereas cortisol levels increase during the first half of the night (Holsboer et al., 1988).”
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“CRH was shown to increase wakefulness (Vgontzas et al., 2001) and to decrease SWS and REM sleep in men (Holsboer et al., 1988) and to decrease sleep 3 stage in women (Schüssler et al., 2008a).”
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Self-citationListening to mutant mice: a spotlight on the role of CRF/CRF receptor systems in affective disorders
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“It is well known that corticotropin-releasing hormone and cortisol have adverse effects on sleep quality [24,25].”
BackgroundEnhanced Slow Wave Sleep in Patients with Prolactinoma
Frieboes, R.-M., Murck, H., Stalla, G. K., Antonijevic, I. A., & Steiger, A. (1998) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.83.8.5016 · Cited by 66
Self-citationCorticotropin releasing factor receptor antagonists for major depressive disorder
Páez-Pereda, M., Hausch, F., & Holsboer, F. (2011) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.2011.565330 · Cited by 59
“These results are in line with the effects on sleep EEG produced by the overexpression of CRF in mice and the intravenous injection of CRF in men [105,106].”
ResultSelf-citationKluge, M., SCHÜSSLER, P., Bleninger, P., Kleyer, S., Uhr, M., Weikel, J. C., Yassouridis, A., Zuber, V., & Steiger, A. (2008) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2008.01.008 · Cited by 56
“The latter finding is in accordance with a significant reduction of REM sleep after CRH administration during spontaneous sleep (Holsboer et al., 1988; Vgontzas et al., 2001).”
BackgroundResultInfluentialSelf-citationSleep disturbances in patients with Addison's disease
Løvås, K., Husebye, E., Holsten, F., & Bjorvatn, B. (2003) · European Journal of Endocrinology · doi:10.1530/eje.0.1480449 · Cited by 54
Cholinergic REM sleep induction test in subjects at high risk for psychiatric disorders
Schreiber, W., Lauer, C. J., Krumrey, K., Holsboer, F., & Krieg, J.-C. (1992) · Biological Psychiatry · doi:10.1016/0006-3223(92)90144-o · Cited by 55
Self-citationThe stress hormone system in various sleep disorders
Lattova, Z., Keckeis, M., Maurovich-Horvat, E., Wetter, T. C., Wilde-Frenz, J., Schuld, A., & Pollmächer, T. (2011) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2011.03.013 · Cited by 54
“Exogenous CRHhas been shown to increase EEG frequency, light sleep and wakefulness (Ehlers et al., 1986; Chang and Opp, 2001) to enhance REM sleep (Kimura et al., 2010) and to decrease the amount of slowwave sleep (SWS;Holsboer et al.,1988).”
BackgroundEndotoxin Enhances EEG Alpha and Beta Power in Human Sleep
Trachsel, L., Schreiber, W., Holsboer, F., & Pollmächer, T. (1994) · SLEEP · doi:10.1093/sleep/17.2.132 · Cited by 54
Self-citationRestless legs syndrome: Evidence for nocturnal hypothalamic‐pituitary‐adrenal system activation
Schilling, C., Schredl, M., Strobl, P., & Deuschle, M. (2010) · Movement Disorders · doi:10.1002/mds.23026 · Cited by 53
Sleep disturbances in highly stress reactive mice: Modeling endophenotypes of major depression
Fenzl, T., Touma, C., Romanowski, C. P. N., Ruschel, J., Holsboer, F., Landgraf, R., Kimura, M., & Yassouridis, A. (2011) · BMC Neuroscience · doi:10.1186/1471-2202-12-29 · Cited by 54
“The locus coeruleus (LC), as part of the reticular activating system projects to the thalamus (additionally to the forebrain, cortex and hypothalamus) and activation through CRH leads to an increase in EEG frequency, decreased SWS (0.5-4.5 Hz) and increased wakefulness [71,72].”
BackgroundInfluentialSelf-citationFrieboes, R.-M., Müller, U., Murck, H., von Cramon, D. Y., Holsboer, F., & Steiger, A. (1999) · Journal of Neuropsychiatry · doi:10.1176/jnp.11.3.354 · Cited by 52
Self-citationHori, H., Teraishi, T., Sasayama, D., Ozeki, Y., Matsuo, J., Kawamoto, Y., Kinoshita, Y., Hattori, K., Higuchi, T., & Kunugi, H. (2011) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2011.04.001 · Cited by 52
Lancel, M., Müller-Preuss, P., Wigger, A., Landgraf, R., & Holsboer, F. (2002) · Journal of Psychiatric Research · doi:10.1016/s0022-3956(02)00009-2 · Cited by 50
Self-citation
Metadata
- Authors
- Holsboer, F., von Bardeleben, U., & Steiger, A.
- Affiliations
- Johannes Gutenberg University Mainz (DE)
- Venue
- Neuroendocrinology
- Publisher
- S. Karger AG
- Published
- 2008-04-02
- Volume
- 48
- Issue
- 1
- Pages
- 32-38
- ISSN
- 0028-3835 (ISSN-L)
- 1423-0194
- OpenAlex
- W2040727780
- Cited by
- 255
- References
- 0
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 7 · 2023: 2 · 2022: 6 · 2021: 11 · 2020: 3 · 2019: 3 · 2018: 1 · 2017: 3 · 2016: 3 · 2015: 6 · 2014: 7 · 2013: 6 · 2012: 2
- FWCI
- 5.66
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neuroendocrinology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
- Keywords
- corticotropin-releasing factor, cortisol secretion, sleep EEG, REM sleep, slow-wave sleep, sleep architecture, growth hormone secretion, circadian rhythm
- MeSH terms
- Adult, Corticotropin-Releasing Hormone, Electroencephalography, Humans, Injections, Intravenous, Male, Pituitary-Adrenal System, Sleep, Growth Hormone
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