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The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 11 4201-4206
Copyright © 2000 by The Endocrine Society

Original Studies

Glucocorticoid Replacement Is Permissive for Rapid Eye Movement Sleep and Sleep Consolidation in Patients with Adrenal Insufficiency1

Diego GarcÍa-Borreguero, Thomas A. Wehr, Oscar Larrosa, Juan J. Granizo, Donna Hardwick, George P. Chrousos and Theodore C. Friedman2

Clinical Psychobiology Branch (D.G.B., T.A.W.), National Institute of Mental Health; and Laboratory of Developmental Neurobiology (T.C.F.) and Pediatric and Reproductive Endocrinology Branch (T.C.F., D.H., G.P.C.), National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892; Sleep Disorders Unit, Department of Neurology, Fundacion Jiménez Díaz (D.G.B., O.L.), 28040 Madrid, Spain; Research and Epidemiology Unit (J.J.G.) and Division of Endocrinology, Department of Medicine, Cedars-Sinai Research Institute-University of California School of Medicine (T.C.F.), Los Angeles, California 90048; and Division of Endocrinology, Department of Medicine, Charles R. Drew University of Medicine and Sciences-University of California School of Medicine (T.C.F.), Los Angeles, California 90059

Address all correspondence and requests for reprints to: Theodore C. Friedman, M.D., Ph.D., Division of Endocrinology, Charles R. Drew University of Medicine and Sciences, 1721 East 120th Street, Los Angeles, California 90059. E-mail: friedmant{at}hotmail.com


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
There is a well described temporal relation between hormonal secretion and sleep phase, with hormones of the hypothalamic-pituitary-adrenal (HPA) axis possibly playing a role in determining entry into and duration of different sleep stages. In this study sleep features were studied in primary Addison’s patients with undetectable levels of cortisol treated in a double blind, randomized, cross-over fashion with either hydrocortisone or placebo supplementation. We found that REM latency was significantly decreased in Addison’s patients when receiving hydrocortisone at bedtime, whereas REM sleep time was increased. There was a trend toward an increase in the percentage of time in REM sleep and the number of REM sleep episodes. Waking time after sleep onset was increased, whereas no differences were observed between the two conditions when total sleep time or specific non-REM sleep parameters were evaluated. Our results suggest that in Addison’s patients, cortisol plays a positive, permissive role in REM sleep regulation and may help to consolidate sleep. These effects may be mediated either directly by the central effects of glucocorticoids and/or indirectly through CRH and/or ACTH.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
RAPID EYE MOVEMENT (REM) sleep is characterized by a relative activation of the central nervous system (including increased mental activity associated with dreaming and reduced arousal threshold) as well as by episodic bursts of rapid eye movements and muscle atonia (1). Episodes of REM sleep occur approximately every 90 min during the night, with the greatest portion of REM sleep in the second part of the night. Several lines of evidence suggest that the hypothalamic-pituitary-adrenal (HPA) axis is related to and may modulate REM sleep in humans. Like REM sleep, the HPA axis is most active in the second half of the night, with as much as 70% of the total nighttime cortisol secretion occurring during that time. A positive correlation between 24-h urinary free cortisol excretion and REM sleep has been shown in normal volunteers (2). Furthermore, studies in experimental animals have shown that the central administration of CRH induces cortical activation analogous to that seen in wakefulness or REM sleep (3, 4, 5).

Patients with primary adrenal insufficiency (Addison’s disease), because of their lack of endogenous glucocorticoid production, offer researchers a unique opportunity to study the effects of manipulation of the HPA axis on sleep parameters. Prior studies administering exogenous glucocorticoids to normal volunteers were hindered by the difficulty in interpreting the effect of exogenous steroids vs. suppression of the endogenous HPA axis. Additionally, different exogenous steroids exert different effects on sleep (6). In this study we used two paradigms of HPA axis manipulation to study sleep parameters in patients with adrenal insufficiency. In one condition, glucocorticoid replacement was withheld for 1.5 days, thus providing undetectable cortisol, high plasma ACTH, and, presumably, high hypothalamic CRH levels. In the second condition, hydrocortisone replacement was given before bedtime, so that a state of relatively high (for that time of day) cortisol and lower ACTH and CRH was produced. Mineralocorticoid replacement was continued in both situations. A randomized, double blind, cross-over paradigm was used to compare the two situations to each other.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

The protocol was approved by the NIH clinical review board, and all subjects gave written informed consent before participating in the study. Ten patients [6 females and 4 males; 10 Caucasians; aged 34.8 ± 9.0 yr (mean ± SD); age range, 23–49 yr] with primary adrenal insufficiency (Addison’s disease) completed the sleep studies. Seven of those patients completed the hormonal sampling protocol. All patients had undetectable cortisol levels and were replaced with proper amounts of fludrocortisone and hydrocortisone. Daily fludrocortisone replacement varied from 0.05–0.5 mg daily and was monitored by an upright PRA measurement in the normal range. Daily hydrocortisone (HC) replacement dosage ranged between 20–30 mg/day and was monitored by 24-h urinary free cortisol and 17-hydroxysteroid excretion within the normal range. Although most patients received their HC replacement in 2 divided doses, for the purposes of the study they received a single morning replacement dose comprised of their total daily dose. Five of 10 patients were receiving thyroid hormone replacement, which continued throughout the study. For comparison of cortisol and ACTH values, 7 age- and sex-matched normal volunteers underwent hormonal sampling every 60 min for the same time period. This control group was taken from our controls previously described (7) and age and sex matched to the current subjects.

Study design

After admission to an in-patient ward at the NIH Clinical Center, an adaptation night (night 0) to the sleep laboratory was carried out. During that night and all subsequent nights, lights were turned off at 2200 h and turned on at 0600 h. On the following day (day 1), medications were administered as usual [including the daily replacement dose of HC (20–30 mg), fludrocortisone, and other medications], and a baseline sleep study was carried out, but was not analyzed, to acclimate the subjects to the procedure (adaptation night 1). So as not to exceed the permitted blood volume, no blood was drawn during that night. On day 2, the dose of HC was withheld, whereas fludrocortisone and other medications were administered without interruption. On night 2, at 2200 h, after randomization for the order of treatments, HC or placebo was administered under double blind conditions. After drug intake, lights were turned off, and a sleep study was carried out until 0600 h. On day 3 at 1100 h, administration of the alternative drug condition took place (i.e. the patients who had received HC at 2200 h received placebo at 1100 h, and vice versa). The arm of the study is thus labeled either HC deprived (placebo at bedtime) or HC at bedtime. Because of the short duration of HC deprivation, none of the HC-deprived patients exhibited any signs or symptoms of adrenal insufficiency. One week later, the same patients underwent the study protocol with a reversed order of treatments (i.e. those patients who received HC at 2200 h and placebo at 1100 h during the first week received placebo at 2200 h and HC at 1100 h during the second week).

Sleep stages were identified by means of a continuous recording of the electroencephalogram, vertical and horizontal electrooculogram, and electromyogram. The records were scored off-line according to the criteria of Rechtschaffen and Kales (8). Sleep stages were scored under conditions blind to the order of medication.

Sleep parameters were defined as following: total sleep time, total time asleep; sleep latency, time between lights off and sleep onset (first epoch of stage 2, 3, 4, or REM); wakefulness after sleep onset, time of wakefulness between sleep onset and sleep offset (last epoch of sleep); early morning awakening, time between sleep offset and lights on; sleep efficiency, total sleep time x 100/total recording period; and total recording period, sum of sleep latency, wakefulness after sleep onset, early morning awakening, movement time, disconnecting time, and total sleep time. In addition, REM sleep latency was defined as the time between sleep onset and first epoch of REM sleep, and REM density was defined as the number of rapid eye movements per min of REM sleep.

Hormonal analyses

On night 2, blood was drawn every 30 min between 1700 h (day 2) and 1300 h (day 3) from a separate room by means of an iv line extended through the wall. Blood was transferred to a prechilled ethylenediamine tetraacetate tube and refrigerated until centrifugation. The supernatant was frozen at -20 C until it was assayed for delta sleep-inducing peptide-like immunoreactivity (DSIP-LI), GH, cortisol, and ACTH. DSIP-LI was measured by RIA as previously described (9), using antiserum K-7914, which recognizes the nonapeptide and its phosphorylated and precursor forms. Cortisol (10) and GH (11) were measured by RIA, and ACTH was determined by immunoradiometric assay (12) as previously described. Hormone levels are expressed as the mean ± SD.

Statistical analyses

Sleep parameters for both arms of the study were compared using paired t tests. As hormone levels were not normally distributed, differences in hormone levels between HC at bedtime and HC-deprived conditions were statistically assessed by the Wilcoxon signed ranked nonparametric test for comparison of paired samples.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
As expected, nighttime plasma cortisol levels were undetectable in the HC-deprived condition of the Addison’s patients (Fig. 1AGo). Patients who received HC at bedtime, on the other hand, had an appropriate increase in plasma cortisol levels, with a peak at 0100 h (Fig. 1AGo). ACTH levels in the Addison’s patients (both groups) were elevated compared with those in normal volunteers. They were significantly suppressed in the arm of the study in which patients received HC at bedtime compared with the HC-deprived arm (Fig. 1BGo).



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  		Figure 1. Diurnal rhythms of plasma cortisol (A), ACTH (B), DSIP-LI (C), and GH (D) in patients with Addison’s disease who received HC at bedtime or were HC deprived. Blood was drawn every 30 min from 1700–1300 h on the following day. Values for cortisol and ACTH from seven age- and sex-matched normal volunteers is also shown. Data represent the mean ± SD at each time point.

 
Sleep parameters of the HC-deprived and HC at bedtime arms of the study are depicted in Table 1Go. REM latency was decreased, whereas total REM sleep time was increased when HC was administered at bedtime. There was a trend (P < 0.1) toward an increase in the number of episodes of REM sleep and the percentage of time in REM sleep. REM density and all non-REM parameters were not affected by the time of administration of HC. Wakefulness after sleep onset was decreased and movement time increased when HC was administered at bedtime. Sleep latency, total sleep time, early morning awakening, and sleep efficiency were similar in both conditions. A representative sleep profile of an Addison’s patient showing sleep stages during the HC at bedtime and HC-deprived arms is shown in Fig. 2Go.


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  		Table 1. Effects of the time of administration of hydrocortisone on sleep parameters

 


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  		Figure 2. Representative sleep profile of an Addison’s patient, showing sleep stages during the HC at bedtime and HC-deprived arms. *, Number of REM episodes per min of REM sleep.

 
No differences were seen in plasma levels of DSIP-LI (Fig. 1CGo) and GH (Fig. 1DGo) between the two conditions in the Addison’s patients.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The most important finding of this study is that REM latency was increased and the amount of time in REM sleep was diminished in the HC-deprived Addison’s patients. Although a matched comparison with normal volunteers was not made in this study, a previous study from our group using similar methods found that normal volunteers had a mean REM latency of 103 min, a value that is intermediate between those found in the HC-deprived (145 min) and HC at bedtime (70.7 min) conditions in this study (13). These results suggest that cortisol secretion may be needed to facilitate both the initiation and maintenance of REM sleep, and this facilitation is absent in glucocorticoid-deprived Addison’s patients. Our results are supported by those of Vgontzas et al., who found that normal volunteers with an increase in cortisol and catecholamine secretion had increased amounts of REM sleep (2). In addition, the absence of HC results in a decrease in sleep continuity, as measured by the waking time after sleep onset. This is especially evident when the sleep cycle of a sample Addison’s patient is examined with and without HC replacement (Fig. 2Go). Thus, in Addison’s patients, HC replacement results in a more consolidated sleep pattern.

The major difference between the two experimental conditions (HC deprived and HC at bedtime) was the amount of circulating nighttime cortisol. Bedtime administration of HC also reduced plasma ACTH levels and, most likely, CRH levels. However, after acute administration of one dose of HC, plasma ACTH levels were still elevated compared with those in age- and sex-matched normal volunteers (Fig. 1BGo). Thus, either an absolute level of cortisol is permissive for the initiation and maintenance of REM sleep or, alternatively, in a nonmutually exclusive manner, declining levels of CRH or ACTH are permissive for REM sleep. We do not attribute the changes in sleep parameters to a nonspecific effect of glucocorticoid withdrawal, as the HC-deprived (for <2 days) patients did not exhibit any symptoms or signs of adrenal insufficiency.

We also found that plasma levels of two putative sleep hormones, GH and DSIP, were similar throughout the night in the HC-deprived and HC at bedtime conditions, suggesting that the change in sleep parameters was not mediated by either of these two hormones.

Sleep patterns of Addison’s patients on and off replacement steroids were previously studied by Gillin et al. (14). In their study of four patients (only three with primary Addison’s disease), delta sleep increased during the replacement period. REM parameters, including REM latency, were not different between the two groups. In fact, the REM latency both on replacement (71 min) and off replacement (70 min) was very similar to the REM latency that we observed in HC at bedtime patients (71 min), whereas our sleep latency of 145 min in patients with HC deprivation was quite different from that reported by Gillin et al. (14). The discrepancy in the results of the two studies may be due to differences in the dose, type, and time of replacement therapy or to the small number of patients examined in the previous study.

In normal individuals, exogenous glucocorticoids have been found to reduce REM sleep, whereas continuous administration of iv hydrocortisone may increase non-REM sleep (6, 14, 15, 16, 17). However, there is no unanimity for the latter finding, as clinical and experimental studies have indicated that glucocorticoids are associated with sleep disturbance (18, 19, 20) and non-REM sleep drives the inhibition of pituitary-adrenal secretion in humans (21, 22). We interpret the inhibitory role of glucocorticoids on REM sleep in normal subjects along with the permissive role in Addison’s patients as demonstrating that some cortisol is needed for REM sleep, with excess cortisol inhibiting REM sleep. An alternative interpretation is that the decrease in REM sleep in normal subjects receiving exogenous glucocorticoids is caused by CRH and/or ACTH suppression. In Addison’s patients, on the other hand, high ACTH and CRH levels are still present despite HC administration, so that CRH and/or ACTH may still signal the entry into REM sleep. 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.

Some earlier studies have reported decreasing levels in plasma cortisol during episodes of REM sleep, whereas increasing levels of cortisol were found during slow wave sleep (24, 25). The researchers concluded that REM sleep had an inhibitory effect on adrenal secretion. It is important to realize, however, that cortisol secretion is delayed compared with CRH and ACTH by approximately 30 and 15 min, respectively. Thus, a decline in cortisol during REM sleep may represent a peak in ACTH or CRH secretion 15–30 min previously. Born and colleagues showed an increase in plasma cortisol during slow wave sleep before entry into REM sleep (15). This increase in cortisol might represent a preparatory function of each cortisol peak before entry into REM sleep and could be accompanied by declining plasma levels of cortisol once REM sleep started.

In our study hydrocortisone-deprived patients had excess sleep fragmentation, which was reduced by administration of HC at bedtime. Similarly, administration of the glucocorticoid antagonist, mifepristone, increased sleep fragmentation (26). On the other extreme, excessive activity of the HPA axis in conditions such as insomnia (27) or depression (28) is associated with sleep fragmentation. Therefore, it is likely that both extremes of HPA activity might lead to sleep fragmentation.

Finally, untreated or undertreated Addison’s patients have excessive daytime fatigue (29). Our results suggest that the decrease in REM sleep and increased awake time after sleep onset in the HC-deprived Addison’s patient might contribute to the daytime fatigue of these patients.


   Acknowledgments
 
We thank Mr. Nick Barker and Ms. Pat Reeves, NIH, for assistance with operation of the polysomnograph; Mr. Curtis Lyons and Ms. Barbara Filmore, NIH, for centrifuging the blood samples; and Drs. Anders Bjartell and Rolf Ekman, University of Lund (Lund, Sweden), for supplying the DSIP antiserum.


   Footnotes
 
1 Presented in part at the 15th Congress of the European Sleep Research Society, Madrid, Spain, September 1998. Back

2 Supported by Center of Clinical Research Excellence Grant U54-RR-14616–01( to Charles R. Drew University of Medicine and Sciences) and a Culpeper Fellow. Back

Received April 3, 2000.

Revised July 18, 2000.

Accepted August 4, 2000.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Feinberg I. 1974 Changes in sleep cycle with age. J Psychiatry Res. 10:283–306.[CrossRef][Medline]
  2. Vgontzas AN, Bixler EO, Papanicolaou DA, et al. 1997 Rapid eye movement sleep correlates with the overall activities of the hypothalamic-pituitary-adrenal axis and sympathetic system in healthy humans. J Clin Endocrinol Metab. 82:3278–3280.[Abstract/Free Full Text]
  3. Shibasaki T, Yamauchi N, Hotta M, et al. 1991 Brain corticotropin-releasing hormone increases arousal in stress. Brain Res. 554:352–354.[CrossRef][Medline]
  4. Gonzalez MM, Valatx JL. 1997 Effect of intracerebroventricular administration of alpha-helical CRH (9–41) on the sleep/waking cycle in rats under normal conditions or after subjection to an acute stressful stimulus. J Sleep Res. 6:164–170.[CrossRef][Medline]
  5. Ehlers CL, Reed TK, Henriksen SJ. 1986 Effects of corticotropin-releasing factor and growth hormone-releasing factor on sleep and activity in rats. Neuroendocrinology. 42:467–474.[Medline]
  6. Born J, Zwick A, Roth G, Fehm-Wolfsdorf G, Fehm HL. 1987 Differential effects of hydrocortisone, fluocortolone, and aldosterone on nocturnal sleep in humans. Acta Endocrinol (Copenh). 116:129–137.[Medline]
  7. Friedman TC, Garcia-Borreguero D, Hardwick D, et al. 1994 Diurnal rhythm of plasma {delta} sleep-inducing peptide in humans: evidence for positive correlation with body temperature and negative correlation with REM and slow wave sleep. J Clin Endocrinol Metab. 78:1085–1089.[Abstract]
  8. Rechtschaffen A, Kales A. 1968 A manual for tthe standardized terminology, techniques, and scoring system for sleep stages of human subjects. Washington DC: U.S. Government Printing Office; NIH Publication 204.
  9. Ekman R, Larsson I, Malmquist M, Thorell JI. 1983 Radioimmunoassay of delta sleep-inducing peptide using an iodinated p-hydroxyphenylpropionic acid derivative as tracer. Regul Pept. 6:371–378.[CrossRef][Medline]
  10. Foster LB, Dunn RT. 1974 Single-antibody technique for radioimmunoassay of cortisol in unextracted serum or plasma. Clin Chem. 20:365–368.[Abstract]
  11. Odell WD, Rayford PL, Ross GT. 1967 Simplified, partially automated method for radioimmunoassay of human thyroid-stimulating, growth, luteinizing, and follicle stimulating hormones. J Lab Clin Med. 70:973–980.[Medline]
  12. White A, Smith H, Hoadley M, Dobson SH, Ratcliffe JG. 1987 Clinical evaluation of a two-site immunoradiometric assay for adrenocorticotropin in unextracted human plasma using monoclonal antibodies. Clin Endocrinol (Oxf). 26:41–51.[Medline]
  13. Friedman TC, Garcia-Borreguero D, Hardwick D, et al. 1994 Decreased delta-sleep and plasma delta-sleep-inducing peptide in patients with Cushing syndrome. Neuroendocrinology. 60:626–634.[Medline]
  14. Gillin JC, Jacobs LS, Snyder F, Henkin RI. 1974 Effects of decreased adrenal corticosteroids: changes in sleep in normal subjects and patients with adrenal cortical insufficiency. Electroencephalogr Clin Neurophysiol. 36:283–289.[CrossRef][Medline]
  15. Born J, Spath-Schwalbe E, Schwakenhofer H, Kern W, Fehm HL. 1989 Influences of corticotropin-releasing hormone, adrenocorticotropin, and cortisol on sleep in normal man. J Clin Endocrinol Metab. 68:904–911.[Abstract]
  16. Gillin JC, Jacobs LS, Fram DH, Snyder F. 1972 Acute effect of a glucocorticoid on normal human sleep. Nature. 237:398–399.[CrossRef][Medline]
  17. Fehm HL, Benkowitsch R, Kern W, Fehm-Wolfsdorf G, Pauschinger P, Born J. 1986 Influences of corticosteroids, dexamethasone and hydrocortisone on sleep in humans. Neuropsychobiology. 16:198–204.[Medline]
  18. Steiger A, Holsboer F. 1997 Neuropeptides and human sleep. Sleep. 20:1038–1052.[Medline]
  19. Chrousos GP, Gold PW. 1992 The concepts of stress and stress system disorders. Overview of physical and behavioral homeostasis. JAMA. 267:1244–1252.[Abstract]
  20. Spath-Schwalbe E, Uthgenannt D, Korting N, Fehm HL, Born J. 1994 Sleep and wakefulness affect the responsiveness of the pituitary-adrenocortical axis to arginine vasopressin in humans. Neuroendocrinology. 60:544–548.[Medline]
  21. Vgontzas AN, Mastorakos G, Bixler EO, Kales A, Gold PW, Chrousos GP. 1999 Sleep deprivation effects on the activity of the hypothalamic-pituitary-adrenal and growth axes: potential clinical implications. Clin Endocrinol (Oxf). 51:205–215.[CrossRef][Medline]
  22. Bierwolf C, Struve K, Marshall L, Born J, Fehm HL. 1997 Slow wave sleep drives inhibition of pituitary-adrenal secretion in humans. J Neuroendocrinol. 9:479–484.[CrossRef][Medline]
  23. Holsboer F, von Bardeleben U, Steiger A. 1988 Effects of intravenous corticotropin-releasing hormone upon sleep-related growth hormone surge and sleep EEG in man. Neuroendocrinology. 48:32–38.[Medline]
  24. Follenius M, Brandenberger G, Bandesapt JJ, Libert JP, Ehrhart J. 1992 Nocturnal cortisol release in relation to sleep structure. Sleep. 15:21–27.[Medline]
  25. Born J, Kern W, Bieber K, Fehm-Wolfsdorf G, Schiebe M, Fehm HL. 1986 Night-time plasma cortisol secretion is associated with specific sleep stages. Biol Psychiatry. 21:1415–1424.[CrossRef][Medline]
  26. Wiedemann K, Lauer C, Pollmacher T, Holsboer F. 1994 Sleep endocrine effects of antigluco- and antimineralocorticoids in healthy males. Am J Physiol. 267:E109—E114.
  27. Vgontzas AN, Tsigos C, Bixler EO, et al. 1998 Chronic insomnia and activity of the stress system: a preliminary study. J Psychosom Res. 45:21–31.[CrossRef][Medline]
  28. Steiger A, von Bardeleben U, Herth T, Holsboer F. 1989 Sleep EEG and nocturnal secretion of cortisol and growth hormone in male patients with endogenous depression before treatment and after recovery. J Affect Disord. 16:189–195.[CrossRef][Medline]
  29. Friedman TC. 1997 Adrenal gland. In: Andreoli TE, eds. Cecil essentials of medicine. Philadelphia: Saunders; 497–508.



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