SLEEP PHYSIOLOGY
Sex Differences in Nocturnal Growth Hormone and Prolactin Secretion in Healthy
Older Adults: Relationships With Sleep EEG Variables
Federica Latta, PhD1; Rachel Leproult, PhD1,2; Esra Tasali, MD1; Elisa Hofmann, MD1; Mireille L’Hermite-Balériaux, MS2; Georges Copinschi, MD, PhD2; Eve Van
Cauter, PhD1
Department of Medicine, University of Chicago, Chicago, IL; 2Laboratoire de Physiologie and Centre d’Etude des Rythmes Biologiques, Université
Libre de Bruxelles, Belgium
1
mone release correlated with delta activity. In women, presleep growth
hormone release appeared to inhibit both postsleep growth hormone release and sleep consolidation. Prolactin release was related to rapid eye
movement sleep and was lower in men than in women. Women with poor
sleep maintenance had a lower prolactin acrophase.
Conclusions: Major sex differences in the nocturnal profiles of growth
hormone and prolactin and their relationship to sleep electroencephalogram variables are present in healthy older adults. Our analyses suggest
that lower sleep-onset release of growth hormone in women as compared
with men could be related to lower levels of delta activity. Improvements
in the homeostatic control of sleep could have hormonal benefits in older
adults.
Keywords: Aging, sex differences, delta activity, growth hormone, prolactin.
Citation: Latta F; Leproult R; Tasali E et al. Sex differences in nocturnal
growth hormone and prolactin secretion in healthy older adults: relationships with sleep EEG variables. SLEEP 2005;28(12): 1519-1524.
Study Objectives: To examine sex differences in nocturnal growth hormone and prolactin release in older adults.
Design: Sleep was polygraphically recorded for 2 consecutive nights, and
blood was sampled at frequent intervals during the last 24 hours.
Setting: The University of Chicago Clinical Research Center.
Participants: Two groups of healthy nonobese older subjects: 10 men
(59 ± 2 years, mean ± SEM), and 10 postmenopausal women (63 ± 2
years).
Interventions: N/A.
Measurements and Results: A spectral analysis of the electroencephalogram was performed in the delta and alpha bands. When delta activity
was normalized for the activity in rapid eye movement sleep, women had
lower delta activity than men. Growth hormone secretion was estimated
by deconvolution. The prolactin profile was quantified by a best-fit curve.
In both sexes, growth hormone was released both before and after sleep
onset. In men, there was no relationship between presleep growth hormone release and subsequent sleep quality and postsleep growth hor-
delta activity and GH release is paradoxically less robust than in
men, despite the fact that women generally have more SWS and
delta activity then men.4-7
Prolactin is also preferentially released during SWS,8 but a
“dose-response” relationship between prolactin and SWS/slowwave activity has not been reported. Awakenings that interrupt
sleep result in an inhibition of prolactin release, similar to the
inhibition of GH.8 In young adults, prolactin levels are higher in
women than in men both during wake and during sleep.9
Pronounced decreases in circulating daytime and nighttime
GH concentrations occur with aging in both older men and women.10,11 Studies examining the impact of GH replacement therapy
in older adults have demonstrated that this relative GH deficiency
of the elderly is partly responsible for increased adiposity and
decreased muscle mass and strength.12,13 Sex differences in the
24-hour profile of GH release in older adults have not been well
characterized. In a study of sleep quality and alterations in GH
secretion in 149 normal men between the age of 16 and 83 years,
we found that, independent of age, the amount of SWS was a
significant predictor of the amount of nocturnal GH secretion.11
Delta activity was not analyzed. Whether the relationship of reduced GH secretion to SWS and delta activity is similar in postmenopausal women as compared with men is not known.
An age-related decline also occurs for sleep-related prolactin release, and elderly adults have a nearly 50% dampening of
the nocturnal prolactin elevation when compared with young
adults.9,14-16 While sex differences are clearly apparent in young
adults, with women releasing more prolactin than men during
both the daytime and the nighttime,9 it is not known whether this
sex difference persists in older age.
Aging is associated with consistent alterations in sleep archi-
INTRODUCTION
SLEEP IS A MAJOR MODULATOR OF ENDOCRINE FUNCTION. THE RELEASE OF GROWTH HORMONE (GH) AND
PROLACTIN BY THE PITUITARY GLAND IS particularly dependent on sleep. Indeed, in normal adults, sleep onset is consistently associated with a large increase in the release of both hormones, and acute total sleep deprivation results in a suppression
of nighttime GH and prolactin levels.1
The secretion of GH during sleep occurs during slow-wave
sleep (SWS) and is interrupted during awakenings. In young men,
sleep-related GH release is quantitatively correlated with delta activity and can be stimulated by pharmacological compounds that
promote SWS and delta activity.2,3 The sleep-onset GH pulse is
generally the largest secretory episode of the 24-hour cycle and
represents the majority of the daily output of this important metabolic hormone. In young women, the association between SWS/
Disclosure Statement
This was not an industry supported study. Dr. Van Cauter has received research support from Pharmacia; and is the CSO of Slowave Inc. Dr. Hofmann has received research support from Genentech. Drs. Latta, Leproult,
Tasali, L’Hermite-Baleriaux, and Copinschi have indicated no financial conflicts of interest.
Submitted for publication May 2005
Accepted for publication August 2005
Address correspondence to: Eve Van Cauter, PhD, Department of Medicine – MC 1027 University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637; Tel: (773) 702-0169; Fax: (773) 702-7686; E-mail:
[email protected]
SLEEP, Vol. 28, No. 12, 2005
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GH, PRL and Sleep in Aging—Latta et al
fects related to venipuncture had subsided. At night, the indwelling catheter was connected to a plastic tube extending to an adjacent room to collect blood samples without disturbing the subject.
The total amount of blood withdrawn was in conformity with the
regulations of the Institutional Review Board. Each blood sample
was immediately centrifuged at 4°C. Plasma samples were frozen
at -20°C until assay.
tecture, including decreased SWS and delta activity, and increased
sleep fragmentation.7,11,17-19 While most studies have concluded
that sleep quality is better preserved in women than in men, we
report, in a companion paper,20 a novel analysis of delta and alpha
activities in older adults that suggests that the sex difference could
in fact be in the opposite direction. Indeed, when delta activity in
non-rapid eye movement (NREM) sleep (which decreased, as expected, across successive sleep cycles) was normalized for delta
activity in rapid eye movement (REM) sleep (which remained
constant across successive sleep cycles), women had lower levels
of delta activity than men, consistent with the higher prevalence
of sleep complaints in women than in men. Furthermore, in women, but not in men, delta activity in NREM sleep was associated
with alpha activity. Whether these sex differences in delta activity
in the sleep electroencephalogram of older adults are associated
with differences in hormones that are preferentially released during SWS is not known.
The present study was, therefore, designed to analyze sex differences in sleep-related GH and prolactin releases in healthy older adults and to characterize the relationship between sleep and
hormone variables.
Hormonal Assays and Analysis
Determination of plasma GH and prolactin levels were performed using a chemiluminescent enzyme immunoassay (Immulite, Diagnostic Products, Los Angeles, CA). For GH, the lower
limit of sensitivity of the assay was 0.05 µg/L, and the intraassay
coefficient of variation averaged 6%. For prolactin, the limit of
sensitivity was 0.5 µg/L, and the intraassay coefficient of variation averaged 5.5%. All samples collected in the same individual
were analyzed in the same assay run in order to avoid inter assay
variations.
Analysis of Hormone Profiles
The wave shape of the plasma prolactin profiles was quantified by a best-fit curve obtained using a robust locally weighted
regression procedure with a regression window of 4 hours.21 The
acrophases and the nadirs were defined as the respective maxima
and minima of the best-fit curves. The nocturnal acrophase was
defined as the highest acrophase occurring during the sleep period. In analyses of the relationships between hormone and sleep
variables, the nocturnal acrophase was used as a summary measure for prolactin.
Because the 24-hour profile of plasma GH levels normally
consists of a series of secretory pulses interrupting low GH concentrations, these profiles were quantified by pulse analysis rather
than by variables derived from a best-fit curve. GH secretory rates
were first derived from the corresponding plasma GH concentrations by mathematical deconvolution using a 1-compartment
model for GH clearance and subject-adjusted half-lives (in the
range 13 to 21 minutes) as previously described.22 The distribution volume was assumed to be 7% of the body weight.23 Significant GH secretory pulses were identified using a modification of
the pulse-detection program ULTRA, as previously described.24
The total amount of GH secreted over a given time interval was
determined by summing the amounts secreted in each of the significant pulses occurring during that time interval. If a pulse overlapped 2 time intervals, the amount of GH secreted was divided
proportionally. In analyses of the relationships between hormone
and sleep variables, the amount of GH secreted in the 3-hour interval preceding sleep onset i.e., GH secretion before sleep onset )
and the amount of GH released during the first 3 hours after sleep
onset i.e., GH secretion after sleep onset ) were used as summary
measures for GH.
METHODS
Subjects
Twenty healthy fully self-sufficient older adults participated in
the study: 10 men (59 ± 2 years, body mass index of 25 ± 0.7 kg/
m2, mean ± SEM), and 10 women (63 ± 2 years, 24 ± 0.7 kg/m2).
The study protocol was approved by the Institutional Review
Board of the University of Chicago, and all volunteers gave informed written consent.
Only healthy subjects with regular life habits who did not take
any drugs were included. Only women who were at least 1 year
past menopause and did not suffer from hot flashes were included. None of the women was on hormone replacement therapy.
Screening procedures included a clinical interview, routine laboratory blood tests, evaluation of mood and cognition, a physical
examination, and an oral glucose tolerance test. All participants
had normal findings on clinical examination, normal results in
laboratory tests (including thyroid function tests, biochemistry,
complete blood count, and lipid panel), and no history of psychiatric or endocrine illness, sleep disorders, or neurologic disorders.
Other details of the inclusion criteria are given in the companion
paper.20
Experimental Protocol
For 1 week before the study, the subjects were required to
maintain regular rest-activity cycles and to adhere to a fixed mutually agreed upon bedtimes and wake-up times (± 30 minutes).
The bedtime schedule was individually designed for each subject,
taking into account the usual life habits. After 1 night of habituation, 2 consecutive nights were recorded, 1 without and 1 with
blood sampling, as described in the companion manuscript.20
At noon of the second day of the study, a catheter for blood
sampling was placed in the nondominant arm, and blood was collected at 20-minute intervals for 24 hours for the measurement of
hormone profiles. The intravenous line was kept patent by a slow
drip of saline. A 2-hour delay between insertion of the sampling
catheter and beginning of sample collection ensured that stress efSLEEP, Vol. 28, No. 12, 2005
Sleep Recording and Analysis
Polygraphic sleep recordings were visually scored using standardized criteria.25 A spectral analysis on the central electroencephalogram lead was performed (PRANA, PhiTools, Strasbourg,
France), and power spectra were obtained in the delta and alpha
bands. All the details are given in the companion paper.20
1520
GH, PRL and Sleep in Aging—Latta et al
Table 1—Impact of Sex on Growth Hormone Secretion and Prolactin
Levels.
Hormone
Sex
P level
Growth hormone secretion Men (n=10) Women (n=10)
Level, µg
24-h
355 ± 67
248 ± 32
.1664
During sleep
118 ± 17
51 ± 13
.0058
During wake
238 ± 55
197 ± 33
.5313
Before sleep onset
97 ± 19
59 ± 18
.1629
After sleep onset
98 ± 15
35 ± 14
.0072
Percentage of 24-h total, %
During sleep
39.3 ± 5.2
23.7 ± 5.6 .0558
After sleep onset
31.5 ± 4.0
16.0 ± 5.8 .0409
Before sleep onset
25.1 ± 3.7
21.1 ± 5.1 .5392
Prolactin
Level, µg/L
24-h
7.8 ± 0.6
10 ± 0.5
.0129
During daytime
194 ± 13
225 ± 15
.1283
During nighttime
220 ± 17
337 ± 18
.0002
Acrophase
11.7 ± 1.0
16.0 ± 1.2 .0105
Figure 1—Upper panels: Mean (+ SEM) profiles of absolute delta
activity in men (left panel) and women (right panel) for the first 4
non-rapid eye movement (NREM)/rapid eye movement (REM) sleep
cycles in the night of blood sampling. Lower panels: Mean profiles
of delta activity in men (left panel) and women (right panel) for the
first 4 NREM/REM sleep cycles in the night of blood sampling when,
in each epoch and for each subject, delta activity is expressed as a
percentage of the mean delta activity in REM sleep. Dashed vertical
lines delimit REM sleep episodes.
Data are presented as mean ± SEM.
Growth Hormone
Figure 2 shows mean profiles of plasma GH levels. The top
panels show the mean profiles aligned to clock time (the dark bars
representing the sleep periods), while the bottom panels show the
mean profiles aligned to sleep onset. The Table summarizes the
quantitative analysis of the GH profiles.
Confirming previous reports,26,27 there was no significant sex
difference in the 24-hour GH secretion between older men and
age- and weight-matched postmenopausal women. During the
sleep period, however, GH secretion was lower in women than in
men, whether expressed in absolute value (µg) or as a percentage
of the 24-hour secretion (Table). This sex difference in sleep-related GH secretion was already apparent during the first 3 hours
of sleep.
Both men and women showed elevations of GH levels in the
late evening, prior to sleep onset. In the present group of healthy
older adults, a negative correlation between the percentage of
24-hour GH secreted before sleep onset and the percentage of
24-hour GH secreted after sleep onset was present in women (r=0.6313, P = .0503). This finding is consistent with the well-documented negative feedback regulation of GH on its own release.28,29
In contrast, in men, GH secretion before sleep onset did not seem
to influence GH release after sleep onset (r=0.1786, P = .6215).
We conducted exploratory analyses to detect a putative impact
of GH secretion before sleep onset on subsequent sleep quality
(characterized by sleep stages as well as electroencephalogram
delta and alpha activities). In women, there was a robust positive
association between GH secretion before sleep onset and subsequent sleep fragmentation, as quantified by the amount of time
spent in wake (r=0.8362, P = .0026, right upper panel of Figure 3)
whereas, in men, no such association was present (r=0.0070, P =
.9848, upper left panel of Figure 3). In women, similar significant
correlations between GH secretion before sleep onset and subsequent sleep quality were found for sleep maintenance (r=-0.8345
P = .0027), and time spent in REM sleep (r=-0.7863, P = .007).
While such associations cannot determine the direction of causality, it is noteworthy that no correlations were present in either sex
Statistical Analysis
All group values are expressed as mean ± SEM. An unpaired
t test was used to examine sex differences in hormone variables.
Associations between hormone variables, sex, and sleep variables
were explored using analyses of covariance (ANCOVA). When
significant interactions between sex and sleep variables were detected, sex-specific correlations were calculated. For GH, we first
examined associations between GH secretion before sleep onset
and sleep variables and then associations between GH secretion
after sleep onset and sleep variables. For prolactin, we examined
associations between the nocturnal acrophase and sleep variables.
All statistical calculations were performed using the StatViewSE+
and SuperAnova software packages for Macintosh (Abacus Concepts Inc., Berkeley, CA).
RESULTS
Sleep
A detailed analysis of sleep stages and power spectra in both
men and women has been reported in the companion manuscript.20
In the present report, we focus on delta activity during NREM
sleep because of its known temporal association with the release
of both GH and prolactin.
Figure 1 shows the mean profiles of absolute (upper panels)
delta activity in men and women for the first 4 NREM/REM sleep
cycles of the night with blood sampling. Women appear to have
higher absolute delta activity than men. When delta activity in
NREM sleep was normalized for delta activity in REM sleep, the
sex difference was reversed, i.e., women had lower delta activity
than men (bottom panels).
SLEEP, Vol. 28, No. 12, 2005
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GH, PRL and Sleep in Aging—Latta et al
Figure 3—Upper panels: Relationship between amount of growth
hormone (GH) secreted in the 3 hours before sleep onset and minutes
of wakefulness in men (left panel) and women (right panel). Lower
panels: Relationship between amount of GH secreted during sleep
and absolute delta activity during non-rapid eye movement (NREM)
sleep in men (left panel) and women (right panel).
Figure 2—Mean (+ SEM) profiles of plasma growth hormone (GH) in
men (left) and women (right) referenced to the clock time (top panels)
and to the sleep onset (bottom panels). The black bars represent the
sleep periods.
between measures of sleep fragmentation in the previous night
(without blood sampling) and GH release before sleep onset on
the following day.
Analysis of covariance with GH secretion during sleep as dependent variable, sex as factor and min of SWS and REM sleep as
regressors revealed that the amount of GH released during sleep
was predicted by sex (P = .0024), the amount of REM sleep (P =
.0398) but was not significantly associated with the time spent in
stages III and IV (P = .1506).
When the relationship of GH released during sleep and absolute
delta activity during NREM sleep was examined, sex differences
were clearly apparent. As illustrated in the lower panels of Figure
3, in women, there were no significant associations between absolute delta activity and GH release (r=0.0587, P = .8808) whereas a
robust correlation was found in men (r=0.7431, P = .0218). Similar findings were obtained when delta activity in NREM sleep
was normalized for delta activity in REM (men: r=0.6943, P =
.038; women: r=0.0849, P = .8280).
There were no associations between absolute or normalized alpha activity and nocturnal GH release in either sex group.
sleep (P = .0084), but not of the amount of SWS (P = .6395), were
found for the prolactin acrophase. There were no significant interactions, suggesting that the impact of REM sleep on the nocturnal
prolactin acrophase was similar in both men and women. Figure
5 illustrates the positive relationship between the nocturnal prolactin acrophase and the amount of REM sleep in all subjects.
In women but not in men, the prolactin acrophase was negatively correlated with intrasleep awakenings (r=-0.6639, P = .0363)
and positively correlated with sleep maintenance (r=0.6487, P =
.0424).
There were no associations between measures of prolactin
release during sleep and measures of delta or alpha activities
(whether absolute or normalized) in either sex group.
DISCUSSION
The present study demonstrates important sex differences in
the nocturnal release of GH and prolactin in healthy nonobese
older men and postmenopausal women who did not take any
medication. The findings also suggest that sleep quality may be
an important determinant of the secretion of these 2 hormones in
normal aging.
Aging appears to be associated not only with an overall decrease in the secretion of GH, but also with a different temporal
organization of the release of this “antiaging” hormone. Indeed,
in both sex groups, a significant amount of GH secretion occurred
in the late evening, before habitual bedtime, at a time when GH
secretion is usually quiescent in young men. Such GH pulses before sleep onset may, however, appear in young subjects when
studied in a state of sleep debt resulting from experimental bedtime restriction.30 Since total sleep time is consistently lower in
older adults, it is possible that this secretion before sleep onset
might reflect an accumulation of sleep loss resulting from an inability to achieve sufficient sleep in older adults. Sleep need or
sleep capacity in older adults remains, however, to be defined.
In older men, there was no relationship between GH release
Prolactin
Mean profiles of plasma prolactin are shown in Figure 4, and
the variables quantifying the prolactin profiles are summarized in
the Table. Men had significantly lower 24-hour mean prolactin
levels than women. While daytime levels were essentially similar in both groups, the nighttime levels were markedly blunted in
men.
A clear rise in prolactin release following bedtime could be
identified in both men and women. The timing of the nocturnal
prolactin acrophase was similar in men and women and occurred
3 to 4 hours after sleep onset. The value of the acrophase was
significantly lower in men than in women.
Associations between nocturnal prolactin release, sex, and
amounts of SWS and REM sleep were explored by ANCOVA,
with the nocturnal prolactin acrophase as the dependent variable.
Significant effects of sex (P = .0025) and of the amount of REM
SLEEP, Vol. 28, No. 12, 2005
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GH, PRL and Sleep in Aging—Latta et al
Figure 5—Relationship between prolactin acrophase and minutes of
rapid eye movement (REM) sleep in the night of blood sampling in
men (filled symbols) and women (open symbols).
Figure 4—Mean (+ SEM) profiles of plasma prolactin in men and
women referenced to the clock time (top panels) and to the sleep onset
(bottom panels). The black bars represent the sleep periods.
bust relationship between the nocturnal prolactin elevation and
the amount of REM sleep emerged from our analysis. There is
increasing evidence, demonstrated in animal studies, for a link
between prolactin and REM sleep. Rodents exposed to stressors
that elicit prolactin release show significant increases in REM
sleep for several hours.32,33 Short-term administration of prolactin
promotes REM sleep in rats, cats, and rabbits, and long-term hyperprolactinemia and hypoprolactinemia increase and decrease,
respectively REM sleep in rodents.34 While these animal studies support a role for prolactin in sleep regulation, there is also
evidence for the reverse direction of causality, i.e., that nocturnal prolactin release is dependent on sleep quality. In particular,
awakenings interrupting sleep inhibit human prolactin release in
young subjects,35 and our finding of a negative correlation between the prolactin acrophase and measures of sleep fragmentation in older women suggests the persistence of this effect in older
adults.
The positive relationships between nocturnal GH and prolactin
release and amounts of REM sleep detected in the present study
of older adults have not been found in studies of younger adults
and may reflect a relationship between the preservation of overall sleep quality and of sleep-related endocrine release, although
the direction of causality cannot be inferred from our data. The
amount of REM sleep is inversely related to the presence of a
sleep debt, as both experimental sleep restriction and sleep loss
due to pathologic conditions such as sleep-disordered breathing
are associated with reduced amounts of REM sleep.36-38 While the
clinical implications of decreased SWS and REM sleep have not
been well investigated, multiple studies have shown that the relative GH deficiency of the elderly is associated with increased fat
tissue and abdominal obesity, reduced muscle mass and strength,
and reduced exercise capacity.12,13,39 Reduced prolactin levels may
be involved in compromised immune function in older adulthood.40 It remains to be determined whether the correction of
age-related sleep disturbances could be associated with multiple
health benefits.
In conclusion, the present findings in a small sample of healthy
nonobese drug-free older men and women suggest the presence
of important sex differences in the associations between sleep
variables and the nocturnal profiles of GH and prolactin.
before sleep onset and subsequent sleep fragmentation. Furthermore, the robust quantitative relationship between SWS/delta activity and GH release after sleep onset, which is well documented
in young men, was still present. In contrast, in older women, GH
release before sleep onset appeared to negatively impact both the
amount of GH secreted during sleep and sleep consolidation. Indeed, robust negative correlations were found between GH secretion before and after sleep onset, as well as between GH secretion before sleep onset and sleep maintenance. In contrast to men,
no significant correlation between GH release after sleep onset
and measures of delta activity could be detected in women. The
persistence of an association between GH release during sleep
and delta activity in older women is, however, supported by preliminary findings from our laboratory that indicate that pharmacologic enhancement of delta activity in older women results in
increased GH release.31 One possible explanation for the lack of
correlation between GH release and delta activity in the women
included in the present study is that the variable influence of GH
release before sleep onset prevented the detection of this association in a relatively small number of subjects. Another possible
reason is suggested by our analysis of delta and alpha activities
described in detail in the companion paper.20 This analysis reveals
that, when normalized for delta activity in REM sleep, delta activity in NREM sleep is actually lower in women than in men and
is associated with concomitant alpha activity. The combination
of lower normalized delta activity with concomitant alpha activity during NREM sleep could be involved in limiting GH release
after sleep onset in postmenopausal women.
The present study demonstrates for the first time the existence
of a robust sex difference in prolactin levels in older adults, with
clearly lower nighttime release in men than in postmenopausal
women. Daytime levels were comparable in both sex groups,
contrasting with findings in young adults, in which women have
higher prolactin levels than men throughout the 24-hour cycle.9
While prolactin release is concomitant with delta activity in
young adults,8 a quantitative relationship between amounts of
delta activity and amount of prolactin levels was not reported
and was also not detected in our older volunteers. Instead, a roSLEEP, Vol. 28, No. 12, 2005
1523
GH, PRL and Sleep in Aging—Latta et al
scatterplots. J Am Stat Assoc 1979;74:829-36.
22. Van Cauter E, Kerkhofs M, Caufriez A, Van Onderbergen A, Thorner MO, Copinschi G. A quantitative estimation of GH secretion in
normal man: reproducibility and relation to sleep and time of day. J
Clin Endocrinol Metab 1992;74:1441-50.
23. Refetoff S, Sonksen PH. Disappearance rate of endogenous and exogenous human growth hormone in man. J Clin Endocrinol Metab
1970;30:386-92.
24. Van Cauter E. Estimating false-positive and false-negative errors in
analyses of hormonal pulsatility. Am J Physiol Endocrinol Metab
1988;254:E786-94.
25. Rechtschaffen A, Kales A. A manual of standardized terminology,
techniques and scoring system for sleep stages of human subjects.
Washington, DC: Government Printing Office; 1968.
26. Guldner J, Schier T, Friess E, Colla M, Holsboer F, Steiger A. Reduced efficacy of growth hormone-releasing hormone in modulating sleep endocrine activity in the elderly. Neurobiol Aging
1997;18:491-5.
27. Antonijevic IA, Murck H, Frieboes RM, Steiger A. Sexually dimorphic effects of GHRH on sleep-endocrine activity in patients with
depression and normal controls - part II: hormone secretion. Sleep
Res Online 2000;3:15-21.
28. Mendelson WB, Jacobs LS, Gillin JC. Negative feedback secretion of sleep-related growth hormone secretion. J Clin Endocrinol
Metab 1983;56:486-8.
29. Lanzi R, Tannenbaum GS. Time course and mechanism of growth
hormone’s negative feedback effect on its own spontaneous release.
Endocrinology 1992;130:780-8.
30. Spiegel K, Leproult R, Colecchia EF, et al. Adaptation of the 24-h
growth hormone profile to a state of sleep debt. Am J Physiol Regul
Integr Comp Physiol 2000;279:R874-83.
31. Latta F, Hofmann E, Leproult R, et al. Restoration of slow-wave
sleep and nocturnal growth hormone secretion in older adults by
gamma hydroxybutyrate administration. Sleep 2000;23:A214.
32. Bodosi B, Obal FJ, Gardi J, Komlodi J, Fang J, Krueger JM. An
ether stressor increases REM sleep in rats: possible role of prolactin. Am J Physiol Regul Integr Comp Physiol 2000;279:R1590-8.
33. Meerlo P, Easton A, Bergmann BM, Turek FW. Restraint increases
prolactin and REM sleep in C57BL/6J mice but not in BALB/cJ
mice. Am J Physiol Regul Integr Comp Physiol 2001;281:R84654.
34. Roky R, Obal FJ, Valatx JL, et al. Prolactin and rapid eye movement
sleep regulation. Sleep. 1995;18:536-2.
35. Van Cauter E. Endocrine Physiology. In: Kryger MH, Roth T, Dement WC, eds. Principles and Practice of Sleep Medicine. 4th ed.
Philadelphia: Elsevier Saunders Company; 2005:266-82.
36. Spiegel K, Leproult R, Van Cauter E. Impact of sleep debt on metabolic and endocrine function. Lancet 1999;354:1435-9.
37. Van Dongen HP, Maislin G, Mullington JM, Dinges DF. The cumulative cost of additional wakefulness: dose-response effects on
neurobehavioral functions and sleep physiology from chronic sleep
restriction and total sleep deprivation. Sleep 2003;26:117-26.
38. Carskadon M, Dement W. Normal human sleep: An overview. In:
Kryger M, Roth T, Dement W, eds. Principles and Practice of Sleep
Medicine. 4th ed. Philadelphia: Elsevier Saunders; 2005:13-23.
39. Bjorntorp P. The regulation of adipose tissue distribution in humans.
Int J Obes Relat Metab Disord 1996;20:291-302.
40. Horseman ND. Prolactin. In: Degroot LG, Jameson JL, eds. Endocrinology. 4th ed. Vol. 1. Philadelphia: WB Saunders; 2001:209-20.
REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
Van Cauter E. Endocrine Rhythms. In: Becker KL, ed. Principles
and Practice of Endocrinology and Metabolism. 3rd ed. Vol. 1. Philadelphia: Lippincott Williams Wilkins; 2001:57-68.
Gronfier C, Luthringer R, Follenius M, et al. A quantitative evaluation of the relationships between growth hormone secretion and
delta wave electroencephalographic activity during normal sleep
and after enrichment in delta waves. Sleep 1996;19:817-24.
Van Cauter E, Plat L, Scharf M, et al. Simultaneous stimulation
of slow-wave sleep and growth hormone secretion by gamma-hydroxybutyrate in normal young men. J Clin Invest. 1997;100:74553.
Dijk D, Beersma DGM, Bloem GM. Sex differences in the sleep
EEG of young adults: visual scoring and spectral analysis. Sleep
1989;12:500-7.
Van Cauter E, Copinschi G. Interactions between growth hormone
secretion and sleep. In: Smith RG, Thorner MO, eds. Human Growth
Hormone: Research and Clinical Practice. Vol. 19. Totowa, NJ: Humana Press, Inc; 1999:261-83.
Carrier J, Land S, Buysse DJ, Kupfer DJ, Monk TH. The effects of
age and gender on sleep EEG power spectral density in the middle
years of life (ages 20-60 years old). Psychophysiology 2001;38:23242.
Redline S, Kirchner L, Quan SF, Gottlieb DJ, Kapur V, Newman A.
The effects of age, sex, ethnicity, and sleep-disordered breathing on
sleep architecture. Arch Intern Med. 2004;164:406-18.
Spiegel K, Luthringer R, Follenius M, et al. Temporal relationship
between prolactin secretion and slow-wave electroencephalic activity during sleep. Sleep. 1995;18:543-8.
Katznelson L, Riskind PN, Saxe VC, Klibanski A. Prolactin pulsatile characteristics in postmenopausal women. J Clin Endocrinol
Metab 1998;83:761-4.
Ho KY, Evans WS, Blizzard RM, et al. Effects of sex and age on the
24-hour profile of growth hormone secretion in man: importance
of endogenous estradiol concentrations. J Clin Endocrinol Metab
1987;64:51-8.
Van Cauter E, Leproult R, Plat L. Age-related changes in slow wave
sleep and REM sleep and relationship with growth hormone and
cortisol levels in healthy men. JAMA 2000;284:861-8.
Rudman D, Feller AG, Nagraj HS, et al. Effects of human growth
hormone in men over 60 years old. N Engl J Med 1990;323:1-6.
Corpas E, Harman SM, Blackman MR. Human growth hormone
and human aging. Endocrinol Rev 1993;14:20-39.
Greenspan SL, Klibanski A, Rowe JW, Elahi D. Age alters pulsatile prolactin release: influence of dopaminergic inhibition. Am J
Physiol 1990;258:E799-804.
Van Coevorden A, Mockel J, Laurent E, et al. Neuroendocrine
rhythms and sleep in aging men. Am J Physiol 1991;260:E651-61.
Iranmanesh A, Mulligan T, Veldhuis JD. Mechanisms subserving
the physiological nocturnal relative hypoprolactinemia of healthy
older men: dual decline in prolactin secretory burst mass and basal
release with preservation of pulse duration, frequency, and interpulse interval—a General Clinical Research Center study. J Clin
Endocrinol Metab 1999;84:1083-90.
Bliwise DL. Sleep in normal aging and dementia. Sleep 1993;16:4081.
Prinz PN. Sleep and sleep disorders in older adults. J Clin Neurophysiol 1995;12:139-46.
Vitiello MV, Larsen LH, Moe KE. Age-related sleep change gender and estrogen effects on the subjective-objective sleep quality
relationships of healthy, noncomplaining older men and women. J
Psychosom Res. 2004;56:503-10.
Latta F, Leproult R, Tasali E, et al. Sex differences in delta and alpha
EEG activities in healthy older adults. Sleep. 2005;28(12):15251534.
Cleveland WS. Robust locally weighted regression and smoothing
SLEEP, Vol. 28, No. 12, 2005
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GH, PRL and Sleep in Aging—Latta et al