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From the Clinical Research Centers |
Sleep Research and Treatment Center, Department of Psychiatry (A.N.V., E.O.B., A.M.W., A.K.), and Department of Health Evaluation Sciences (H.-M.L.), Pennsylvania State University, Hershey, Pennsylvania 17033; Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health (K.Z., G.P.C.), Bethesda, Maryland 20892; and Department of Psychiatry, Autonomous University (A.V.-B.), Madrid, Spain
Address all correspondence and requests for reprints to: Alexandros N. Vgontzas, M.D., Sleep Research and Treatment Center, Department of Psychiatry, Pennsylvania State University College of Medicine, 500 University Drive, Hershey, Pennsylvania 17033. E-mail: axv3{at}psu.edu
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Abstract |
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We studied 12 healthy middle-aged (45.1 ± 4.9) and 12 healthy young (22.7 ± 2.8) men by monitoring their sleep by polysomnography for 4 consecutive nights, including in tandem 1 adaptation and 2 baseline nights and a night during which we administered equipotent doses of ovine CRH (1 µg/kg, iv bolus) 10 min after sleep onset. Analyses included comparisons within and between groups using multiple ANOVA and regression analysis.
Although both middle-aged and young men responded to CRH with similar elevations of ACTH and cortisol, the former had significantly more wakefulness and suppression of slow wave sleep compared with baseline sleep; in contrast, the latter showed no change. Also, comparison of the change in sleep patterns from baseline to the CRH night in the young men to the respective change observed in middle-aged men showed that middle-age was associated with significantly higher wakefulness and significantly greater decrease in slow wave sleep than in young age.
We conclude that middle-aged men show increased vulnerability of sleep to stress hormones, possibly resulting in impairments in the quality of sleep during periods of stress. We suggest that changes in sleep physiology associated with middle-age play a significant role in the marked increase of prevalence of insomnia in middle-age.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Middle-age is associated with increased prevalence of insomnia, and reported emotional stress is the most frequent underlying cause of insomnia complaints (7). Indeed, up to 40% of the general population report difficulties in falling or staying asleep in middle-age in contrast to about 20% of young subjects (7). It has been suggested that the increased prevalence of insomnia in middle-age is due to increased life stress during this period of life. Another, as yet unexplored possibility is that it is due to increased sensitivity of sleep to the arousal-producing effects of stress.
The administration of CRH has been used widely as a sensitive means to evaluate the activity of the HPA axis in many physiological and pathological conditions (8). The effect of CRH, which is a potent arousal-promoting agent, on human sleep has been assessed in a few studies, only in young individuals, with inconclusive results (9, 10). On the other hand, even though glucocorticoids have arousal- promoting properties at pharmacological doses, little is known about the actions of endogenous cortisol elevations around the time of sleep onset. The goal of our study was to assess whether middle-aged, healthy men are different from young men in terms of response to CRH administration during sleep. We hypothesized that middle-aged men’s sleep would be more vulnerable to the arousing effects of CRH and/or cortisol.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Twelve young healthy men, 20–28 yr of age (mean ± SD, 22.7 ± 2.8), and 12 middle-aged healthy men, 37–54 yr of age (45.1 ± 4.9), were recruited from the community and from the medical and technical staff and students of the Milton S. Hershey Medical Center (Hershey, PA). A thorough medical assessment, including physical history and examination, and a detailed sleep history were completed for each subject. The subjects were in good general health, had no sleep complaints or circadian abnormalities, were not under any stress, were not taking any medications, and were screened in the Sleep Laboratory for sleep disordered breathing, nocturnal myoclonus, or other primary sleep disorders. Also, a battery of clinical tests, including full blood count, urinalysis, thyroid indexes, and electrocardiogram, were negative for abnormal findings. The two groups were not different in terms of body mass index (26.2 ± 2.8 vs. 25.3 ± 2.2 for middle-aged and young subjects, respectively; P = NS). The study was approved by the institutional review board, and each subject signed a written informed consent.
Protocol
Each subject spent 4 consecutive nights in the Sleep Laboratory
(1 adaptation night, 2 baseline nights, followed by the night of CRH
administration). During the fourth night an indwelling catheter was
inserted in the antecubital vein about 60 min before the start of the
sleep recording. The catheter was kept patent with small amounts of
heparin. During the sleep-recording period, blood collection and CRH
administration took place outside the subjects’ rooms through a
perforation in the wall via 12-ft tubing, to decrease sleep disturbance
from the blood-drawing technique. A standard dose of ovine CRH (1
µg/kg) was administered by iv bolus during the first sleep cycle
(
10 min after sleep onset, as determined by standard
polysomnographic criteria) (11). ACTH and cortisol were
sampled at -10 min (time of sleep onset), 0 min (time of CRH
administration), 5 min, 15 min, and 30 min post-CRH and every 30 min
for the remainder of the night. Also, urinary free cortisol was
measured in two consecutive (baseline days 2 and 3) 24-h complete urine
collections. The 24-h urine collections were completed the morning
before the nighttime administration of CRH.
Sleep recordings
Sleep laboratory recording was carried out in a sound-attenuated, light- and temperature-controlled room that had a comfortable bedroom-like atmosphere. During this evaluation, each subject was monitored continuously for 8 h by electroencephalogram (EEG), electromyogram, and electrooculogram according to standard methods. The 8-h period in bed was based on individual subject’s habitual times of onset of sleep, which ranged between 2200–2300 h. The average start and stop times of sleep recordings for middle-aged and young men were 2201 ± 13 vs. 2200 ± 2 min and 0559 ± 13 vs. 0601 ± 3 min, respectively. The sleep records were scored independently of any knowledge of the experimental condition according to standardized criteria (11). Each night in the laboratory, the participants completed a single seven-point subjective questionnaire assessing levels of anxiety and stress during the day.
Sleep parameters assessed from the sleep recordings were grouped into three categories: sleep efficiency measures, amount of sleep stages, and additional rapid eye movement (REM) variables. Sleep efficiency measures included sleep induction (sleep latency), sleep maintenance [wake time after sleep onset (WTASO), total wake time (sum of sleep latency and WTASO), and percentage of sleep time (total sleep time as percentage of time in bed). The duration of sleep stages [REM, 1, 2, SWS (3 and 4 combined)] was expressed as absolute minutes or as percentage of total sleep time, which is calculated as the minutes in each stage as the percentage of total sleep time. The additional REM variables included REM latency (the interval from sleep onset to the first REM period), REM interval (average time lapsing between two consecutive REM periods), and REM density (calculated by counting the number of eye movements in a 40-s epoch divided by the number of epochs within this REM period). The onset of sleep was established by the presence of any sleep stage for 1 min or longer. However, if the initial stage of sleep was stage 1, it had to be followed without any intervening wakefulness by at least 60 s of stage 2, 3, 4, or REM. The distribution of wakefulness, SWS, and REM sleep through the night was examined by halves of the night. One half of the night was established by subtracting sleep latency from the total amount of laboratory time and then dividing the remaining time into equal halves. Data from nights 2 and 3 were averaged (baseline).
Hormone assays
Blood collected from the indwelling catheter was transferred to an ethylenediamine tetraacetate-containing tube and refrigerated until centrifugation (within 3 h). The supernatant was frozen at -20 C until hormone assay. ACTH and cortisol levels were measured by specific immunoassay techniques as previously described (12). The lower limit of detection was 5 pg/mL for ACTH and 0.7 µg/dL for cortisol. The intra- and interassay coefficients were, respectively, 4.6% and 6.0% for cortisol and 10.0% and 12.0% for ACTH.
Statistical analysis
The basal plasma ACTH and cortisol concentrations for each individual were taken as the mean value at -10 and 0 min. The average times of blood collection for the two basal hormonal measures were 2228 ± 16 and 2238 ± 16 min for middle-aged men and 2227 ± 16 and 2237 ± 16 min for young men, respectively. The total and net amount of time-integrated ACTH and cortisol secretion after the administration of CRH were calculated by the trapezoid method [integrated area under the curve (AUC)]. The total time-integrated ACTH and cortisol responses were expressed as the area beneath the concentration-time curve from 0–450 min. The net integrated ACTH and cortisol responses were expressed as the area beneath the concentration-time curve from 0–450 min minus the area corresponding to the mean of the two baseline values multiplied by 450 min. The peak ACTH and cortisol responses corresponded to the highest levels of ACTH and cortisol achieved after CRH administration. Serial nighttime plasma ACTH and cortisol levels were analyzed simultaneously using multiple ANOVA (MANOVA) for repeated measures over time (mixed effects model, with fixed effects being time and the two groups, and random effects being the subjects), followed by the Dunnett post-hoc test. Differences in terms of sleep values between baseline (the average across nights 2 and 3 in the sleep laboratory) and night 4 within each group were examined using paired two-tailed Student’s t test. To assess differences between young and middle-aged men in terms of their responses to CRH, we compared the change from baseline to night 4 (CRH night) of the young men to the change from baseline to night 4 of the middle-aged men using regression analysis, where the outcome is the change in score, and the main predictor is the age group. In this analysis we also covaried the respective baseline sleep measures to control for possible differences in the baseline. In this part of the analysis, data are presented as the least square mean ± SE. The remainder of the data are expressed as the mean ± SE, except for age, body mass index, and time, which are expressed as the mean ± SD.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The middle-aged compared with the young men demonstrated markedly
and significantly lower amounts of slow wave sleep during the 2
baseline nights (3.7 ± 1.0% vs. 11.4 ± 1.8%;
P < 0.01; Table 1
).
There were no differences between the two groups in terms of overall
sleep efficiency measures, i.e. percentage of sleep time or
total wake time. However, middle-aged men compared with young men
demonstrated a shorter sleep latency (10.1 ± 1.4 vs.
23.3 ± 5.1 min; P < 0.05), whereas they had more
wake time after sleep onset (46.5 ± 8.6 vs. 25.9
± 5.0 min; P < 0.05). There were no differences in
terms of daytime anxiety/stress levels within the groups (baseline
vs. CRH night, 1.9 vs. 1.5 in the middle-aged and
1.9 vs. 2.0 in the young) or between groups during baseline
(1.9 vs. 1.9) or CRH (1.5 vs. 2.0) nights.
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There were no differences between the two groups in terms of
average 2-day 24-h urinary free cortisol excretion (222.5 ± 18.1
nmol/24 h in the middle-aged vs. 245.6 ± 26.9 nmol/24
h in the young; P = NS). The baseline mean plasma ACTH
and cortisol values were similar in the middle-aged and young men
[2.1 ± 0.5 vs. 1.7 ± 0.2 pmol/L
(P = NS) and 151.4 ± 44.3 vs.
94.5 ± 22.6 nmol/L (P = NS) for the middle-aged
and young, respectively; Fig. 1].
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The mean post-CRH level of cortisol was significantly, albeit
slightly, lower in the middle-aged than in the young men (350.4 ±
22.1 vs. 375.2 ± 24.8 nmol/L; P <
0.05, by MANOVA). Also, the net amount of time-integrated (AUC)
cortisol for the entire night was significantly lower in the
middle-aged than in the young men (90,894.7 ± 17,897.8
vs. 138,974.9 ± 14,448.5 nmol/L·min;
P < 0.05; Fig. 1
). However, the total AUCs of cortisol
were similar in the middle-aged and young men (150,720.7 ±
9,345.1 vs. 180,115.0 ± 12,250.1 nmol/L·min;
P = NS). The net and total AUC of ACTH were also
similar in the middle-aged and young men [1,644.2 ± 273.5
vs. 2,159.9 ± 344.5 pmol/L·min (P =
NS); 2,509.8 ± 2,79.4 vs. 2,913.6 ± 391.9
(P = NS), respectively; Fig. 1].
Effect of oCRH administration on sleep EEG in young and middle-aged men
The administration of CRH in middle-aged men was associated with a
significant increase in wakefulness compared with the baseline (wake
time after sleep onset and total wake time were increased, whereas
percent sleep time was decreased; all P < 0.05; Table 1 and Fig. 2A). In contrast, CRH was not
associated with a significant change in wakefulness compared with
baseline in young men (wake time after sleep onset, total wake time,
and percent sleep time; Table 1 and Fig. 2B). The major impact in terms
of wakefulness in middle-aged men occurred during the first half of the
night, when CRH-stimulated ACTH and cortisol secretion peaked
[42.9 ± 11.1 vs. 19.0 ± 3.1 min in middle-aged
men (P < 0.05); 11.9 ± 2.4 min vs.
11.1 ± 3.7 min in young men (P = NS)]. Also, the
amount of SWS in middle-aged men tended to decrease during the first
half of the night (7.5 ± 3.0 vs. 14.4 ± 4.0 min;
P < 0.09), whereas there was no change in the amount
of SWS in young men.
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). Comparison of the effect of oCRH administration on sleep EEG between young and middle-aged men
A comparison of the change from baseline to the CRH night in the
young men to the respective change observed in middle-aged men after
adjusting for baseline differences showed that middle-age was
associated with significantly higher wakefulness compared with youth
(Fig. 3). Specifically, middle-age was
associated with a significantly higher increase in WTASO (47.1 ±
17.2 vs. 8.7 ± 8.4 min; P < 0.05) and
total wake time (54.2 ± 16.4 vs. 12.2 ± 9.3 min;
P < 0.05) and a decrease in percentage of sleep time
(-11.2 ± 3.4% vs. -2.5 ± 1.9%;
P < 0.05). Also, the effect on wakefulness was
stronger in the first half of the night, as indicated by the
significant increase in WTASO during the first half of the night
(26.6 ± 11.1 vs. -1.9 ± 2.4 min;
P < 0.05), but not during the second half of the
night. Furthermore, middle-aged men demonstrated a significantly higher
decrease in SWS during the first half of the night (-10.7 ± 4.0
vs. 10.0 ± 5.0 min; P < 0.05).
No differences were found between the groups in terms of the effects of
CRH on the remaining sleep stages, including amount of REM sleep and
REM variables.
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Correlations between indexes of sleep disturbance, i.e.
change in SWS (baseline minus CRH night) and peak concentrations of
cortisol after CRH administration, showed a significant correlation
between change in SWS and peak cortisol levels in middle-aged men
(rxy = 0.6; P < 0.05), but not
in young men (rxy = 0.1; P = 0.7;
Fig. 4). Correlations between WTASO and
cortisol peaks were in the same direction. No correlations were
observed between sleep disturbance and peak ACTH levels.
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Discussion |
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Our observations of the effect of CRH on sleep are consistent with the
sleep disturbances (decreased SWS, increased wakefulness) observed in
hypercortisolemic patients with melancholic depression (16, 17) and in patients with Cushing syndrome (18) and
with an early report that decreased adrenal corticosteroids in normal
subjects or patients with Addison’s disease were associated with a
significant increase in 
(deep) sleep (19). In humans
the nighttime administration of human CRH either in a pulsatile mode
(four injections of 50 µg or hourly injection of 10 µg through the
night) or as a constant infusion (30 µg/h) in young healthy men
either resulted in a small decrease in SWS (9) or had no
effect on any sleep parameters (10, 20). Two recent
studies showed either no significant effect on sleep (50 µg oCRH, iv
bolus) (21) or a significant decrease in SWS and sleep
efficiency in young males (100 µg hCRH, iv bolus) (22).
Thus, the majority of the studies, including ours, despite the
differences in type of CRH used (ovine vs. human), dose,
timing, and type of administration (bolus vs. constant
infusion) suggest that the sleep of young individuals is rather
resistant to the arousing effects of CRH.
Blood-drawing procedures may have a mild disturbing effect on healthy subjects’ sleep (23) (our unpublished data). Thus, it is possible that in this study the presence of the catheter and the awareness of iv injection of CRH might have had an impact on the subjects’ sleep. This impact was more apparent in the middle-aged group, who showed an increase in sleep latency. However, the facts that 1) there was a positive correlation between sleep disturbance and elevation of cortisol in the middle-aged, but not in the young, and 2) sleep disturbances were more pronounced in the middle-aged men, although the cortisol elevation was smaller than that in young men support our conclusion that middle-aged men showed increased vulnerability to stress hormones.
CRH administration was associated with a suppression of the amount of REM sleep, which was significant in young men, whereas REM density was unaffected. These findings are consistent with previous reports that showed a reduction in the amount of REM sleep, but not REM density, induced by exogenously administered CRH (9), prednisone (24), or hydrocortisone (25). We have previously demonstrated that 24-h urinary free cortisol excretion correlated significantly and positively with the amount of REM sleep and not with REM density in normal volunteers, suggesting that REM sleep is associated with an endogenous activation of the HPA axis (26). The reduction of REM sleep after CRH administration may be the result of elevated cortisol levels on REM sleep as previously described (24, 25), possibly through a negative feedback regulation loop. An alternative explanation is that the REM reduction may reflect the fact that in young men a small increase in wakefulness occurred primarily during the second half of the sleep period when REM is more prevalent.
Our findings have several clinical implications. First, the increased prevalence of insomnia in middle-age may, in fact, be the result of deteriorating sleep mechanisms associated with increased sensitivity to arousal-producing stress hormones, such as CRH and cortisol. This suggests that a middle-aged individual compared with a young individual is at a significantly higher risk of developing insomnia when faced with equivalent stressors. Second, our findings may explain at least partially why major depression, a condition of increased production of CRH and cortisol, is associated in middle-age with insomnia, whereas in the young it is frequently associated with sleepiness (16, 17). Third, our study explains the common experience that widely used stimulants, i.e. caffeinated beverages, have a stronger sleep- disturbing effect in middle-age than in the young.
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Acknowledgments |
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Received September 13, 2000.
Revised November 29, 2000.
Accepted December 9, 2000.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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-sleep and plasma delta-sleep-inducing
peptide in patients with Cushing syndrome. Neuroendocrinology. 60:626–634.[Medline]
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) and middle-aged (
) healthy men. Inset, Net
integrated nighttime AUC in young (
