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CLINICAL INVESTIGATION
Age-Related Changes in Slow Wave Sleep
and REM Sleep and Relationship
With Growth Hormone and
Cortisol Levels in Healthy Men
Eve Van Cauter, PhD
Rachel Leproult, MS
Laurence Plat, MD
D
ECREASED SUBJECTIVE SLEEP
quality is one of the most
common health complaints
of older adults.
1
The most
consistent alterations associated with
normal aging include increased num-
ber and duration of awakenings and
decreased amounts of deep slow wave
(SW) sleep (ie, stages 3 and 4 of non–
rapid eye movement (non-REM)
sleep).
2-4
REM sleep appears to be rela-
tively better preserved during aging.
3-7
The age at which changes in amount
and distribution of sleep stages appear
is unclear because the majority of
studies have been based on compari-
sons of young vs older adults. Several
investigators have noticed that there
are marked decreases in SW sleep in
early adulthood in men but not in
women.
8-11
Sleep is a major modulator of endo-
crine function, particularly of pituitary-
dependent hormonal release. Growth
hormone (GH) secretion is stimulated
during sleep and, in men, 60% to 70%
of daily GH secretion occurs during
early sleep, in association with SW
sleep.
12
Whether decrements in SW
sleep contribute to the well-known de-
crease in GH secretion in normal ag-
ing is not known.
13-15
In contrast to the enhanced activity
of the GH axis during sleep, the hypo-
thalamic-pituitary-adrenal (HPA) axis is
acutely inhibited during early SW
Author Affiliations: Department of Medicine, Uni-
versity of Chicago, Chicago, Ill.
Corresponding Author and Reprints: Eve Van Cauter,
PhD, Department of Medicine, MC 1027, University of
Chicago, 5841 S Maryland Ave, Chicago, IL 60637
(e-mail: evcauter@medicine.bsd.uchicago.edu).
Context In young adults, sleep affects the regulation of growth hormone (GH) and
cortisol. The relationship between decreased sleep quality in older adults and age-
related changes in the regulation of GH and cortisol is unknown.
Objective To determine the chronology of age-related changes in sleep duration
and quality (sleep stages) in healthy men and whether concomitant alterations occur
in GH and cortisol levels.
Design and Setting Data combined from a series of studies conducted between
1985 and 1999 at 4 laboratories.
Subjects A total of 149 healthy men, aged 16 to 83 years, with a mean (SD) body
mass index of 24.1 (2.3) kg/m
2
, without sleep complaints or histories of endocrine,
psychiatric, or sleep disorders.
Main Outcome Measures Twenty-four–hour profiles of plasma GH and cortisol
levels and polygraphic sleep recordings.
Results The mean (SEM) percentage of deep slow wave sleep decreased from
18.9% (1.3%) during early adulthood (age 16-25 years) to 3.4% (1.0%) during
midlife (age 36-50 years) and was replaced by lighter sleep (stages 1 and 2) with-
out significant increases in sleep fragmentation or decreases in rapid eye movement
(REM) sleep. The transition from midlife to late life (age 71-83 years) involved no
further significant decrease in slow wave sleep but an increase in time awake of 28
minutes per decade at the expense of decreases in both light non-REM sleep (−24
minutes per decade; P,.001) and REM sleep (−10 minutes per decade; P,.001).
The decline in slow wave sleep from early adulthood to midlife was paralleled by a
major decline in GH secretion (−372 µg per decade; P,.001). From midlife to late
life, GH secretion further declined at a slower rate (−43 µg per decade; P,.02).
Independently of age, the amount of GH secretion was significantly associated with
slow wave sleep (P,.001). Increasing age was associated with an elevation of
evening cortisol levels (+19.3 nmol/L per decade; P,.001) that became significant
only after age 50 years, when sleep became more fragmented and REM sleep
declined. A trend for an association between lower amounts of REM sleep and
higher evening cortisol concentrations independent of age was detected (P,.10).
Conclusions In men, age-related changes in slow wave sleep and REM sleep occur
with markedly different chronologies and are each associated with specific hormonal
alterations. Future studies should evaluate whether strategies to enhance sleep qual-
ity may have beneficial hormonal effects.
JAMA. 2000;284:861-868 www.jama.com
For editorial comment see p 879.
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sleep.
16-20
Furthermore, even partial sleep
deprivation results in an elevation of cor-
tisol levels the following evening.
21
Thus,
both decreased SW sleep and sleep loss
resulting from increased sleep fragmen-
tation could contribute to elevating cor-
tisol levels. An elevation of evening cor-
tisol levels is a hallmark of aging
14,15,22
that is thought to reflect an impair-
ment of the negative feedback control
of the HPA axis and could underlie a
constellation of metabolic and cogni-
tive alterations.
23-25
The present study defines the chro-
nology of age-related changes in sleep
duration and quality (ie, amounts of
sleep stages), GH secretion, and corti-
sol levels in healthy men and exam-
ines whether decrements in sleep qual-
ity are associated with alterations of GH
and cortisol levels.
METHODS
Subjects
Data from a total of 149 healthy men,
aged 16 to 83 years, are presented. Mean
(SD) body mass index (BMI) of the sub-
jects was 24.1 (2.3) kg/m
2
. All sub-
jects were of normal weight (BMI,18-28
kg/m
2
).
The data were collected between 1985
and 1999 in a series of studies from our
group (109 out of 149 individual data
sets
14,26-32
) and 3 other laboratories using
similar assay procedures, recording pro-
cedures, or both (University of Pitts-
burgh, Pittsburgh, Pa, 14 subjects
33,34
;
University of California, Los Angeles, 8
subjects
35,36
; and Pennsylvania State Uni-
versity, Hershey, 18 subjects
37
). Except
for data from 29 subjects studied in our
laboratory, all other data were included
in previously published reports that did
not address the chronology of age effects.
The raw data from all 149 subjects were
submitted to a new analysis designed to
quantitatively define sleep and hor-
monal parameters across adulthood.
The subjects were paid volunteers
who had no sleep complaints, did not
take any drugs, were in good health
based on a physical examination, and
had no history of endocrine, psychiat-
ric, or sleep disorders. Shift workers, sub-
jects recently having traveled across time
zones, and competitive athletes were ex-
cluded. The young subjects had reached
Tanner stage 5 of sexual maturity and
full body height. The older men were
self-sufficient and had no cognitive im-
pairment. All subjects gave written in-
formed consent. The experimental pro-
tocol was approved by the ethics review
board at each institution.
Experimental Protocol
Prior to the study, the subjects spent 1
to 3 habituation nights in the sleep labo-
ratory. In studies including hormonal
measurements (133 of 149 studies), a
catheter was inserted into a forearm vein
and blood samples were collected at 15-
to 30-minute intervals for 24 to 25 hours.
During the night, the catheter was con-
nected to tubing extending to an adja-
cent room to avoid disturbing the sub-
ject. All-night polygraphic sleep
recordings were obtained. The subjects
remained recumbent in bed in dark-
ness for at least 8 hours. Daytime naps
were not allowed.
Sleep, cortisol, and GH profiles were
obtained in 132, 124, and 114 sub-
jects, respectively. Concomitant sleep,
cortisol, and GH profiles were ob-
tained in 94 subjects.
Sleep Recording and Analysis
Polygraphic sleep recordings were visu-
ally scored at 20- or 30-second inter-
vals in stages wake, 1, 2, 3, and 4, and
REM using standardized criteria.
38
Sleep
onset and morning awakening were de-
fined, respectively, as the times of oc-
currence of the first and last interval
scored as stage 2, 3, 4, or REM. The sleep
period was defined as the interval sepa-
rating sleep onset from morning awak-
ening. The total sleep time was calcu-
lated as the sleep period minus the total
duration of awakenings. The total dura-
tion of each stage was expressed in min-
utes as well as a percentage of the sleep
period. Slow wave sleep was defined as
the sum of stages 3 and 4.
Hormonal Assays
In all studies, cortisol levels were mea-
sured by a standard radioimmunoassay
(RIA). The limit of sensitivity averaged
27.6 nmol/L and intra-assay coeffi-
cients of variation (CV) were 5% to 10%.
In 89 profiles, GH concentrations were
measured by an RIA with a sensitivity
of 0.4 µg/L.
39
Intra-assay CV ranged from
5% to 9%. The interassay CV averaged
15%. In 25 studies, GH concentrations
were measured by a chemilumines-
cence method (8 studies: Nichols Insti-
tute Diagnostics, San Juan Capistrano,
Calif; and 17 studies: Diagnostic Prod-
uct Corporation, Los Angeles, Calif)
with a limit of sensitivity of 0.002 to
0.003 µg/L, an intra-assay CV ranging
from 4.8% to 9.9%, and an interassay CV
less than 8%. Baseline, ie, nonpulsatile,
concentrations of GH less than 1 µg/L
by chemiluminescence correspond to
concentrations less than the limit of sen-
sitivity (0.4 µg/L) by RIA. Estimations
of pulsatile GH secretion greater than
baseline levels derived from GH pro-
files measured by chemiluminescence do
not differ significantly from those mea-
sured by RIA.
40
Analysis of Individual
Cortisol Profiles
The circadian variation of plasma cor-
tisol was quantified using a best-fit
curve based on periodogram calcula-
tions.
41
The acrophase and nadir were
defined, respectively, as the times of oc-
currence of the maximum and mini-
mum of the best-fit curve. The value of
the acrophase or nadir was defined as
the level attained by the best-fit curve
at the acrophase or nadir.
Analysis of Individual GH Profiles
Significant pulses of GH secretion greater
than baseline levels were identified us-
ing a computerized algorithm.
42
The
threshold for significance was set at 2
times the intra-assay CV. For each sig-
nificant pulse, the amount of GH se-
creted above baseline level was esti-
mated by mathematical deconvolution
based on a 1-compartment model for GH
clearance and variable individual half-
lives.
43
The total amount of GH se-
creted over a given time interval was de-
termined by summing the amounts
secreted in each of the pulses occur-
ring during that time interval.
SLEEP AND HORMONAL PARAMETERS FROM EARLY TO LATE ADULTHOOD
862 JAMA, August 16, 2000—Vol 284, No. 7 (Reprinted) ©2000 American Medical Association. All rights reserved.
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Statistical Analysis
Each of the parameters used to quan-
tify sleep, GH secretion, and the 24-
hour cortisol profile was used in 2 analy-
ses. First, the parameter was considered
as a dependent variable in an analysis of
variance (ANOVA) including age, BMI,
and the interaction age 3 BMI as inde-
pendent variables. When the interac-
tion age 3 BMI had P..05 based on type
III sums of squares, the analysis was re-
peated with only age and BMI as inde-
pendent variables. To verify that signifi-
cant interactions did not reflect the
impact of a single subject, the calcula-
tions were repeated after excluding data
from the most outlying subject for the
variables in the analysis. The interac-
tion was maintained in the analysis only
if the statistical significance was not criti-
cally dependent on a single subject. Sec-
ond, the data were grouped by age ranges
(aged 16-25 years, 42 subjects; aged
26-35 years, 28 subjects; aged 36-50
years: 26 subjects; aged 51-60 years, 23
subjects; aged 61-70 years, 18 subjects;
and aged 71-83 years, 12 subjects). For
each parameter, simple linear regres-
sions with age as an independent vari-
able were calculated separately for sub-
jects from early adulthood (aged 16-25
years) to 43 years, ie, the midpoint of the
midlife range (aged 36-50 years), and for
subjects from midlife to late life (aged
44-83 years). Unless otherwise indi-
cated, all group values are expressed as
mean (SEM).
RESULTS
Sleep
Consistent with previous reports,
3-5
the
sleep period was not significantly af-
fected by age. In contrast, total sleep
time decreased markedly with aging
(P,.001), but significant reductions in
total sleep time did not occur until af-
ter midlife. From midlife until the
eighth decade, total sleep time de-
creased, on average, by 27 minute per
decade (T
ABLE, next page).
Aging had a differential impact on
sleep parameters (F
IGURE 1). From
early adulthood to midlife (age 16-25
to 36-50 years), the percentage of SW
sleep decreased from 18.9% (1.3%) to
3.4% (1.0%), and this decrease in deep
non-REM sleep was compensated by an
increase in light non-REM sleep (ie,
stages 1 and 2) from 51.2% (1.4 %) to
67.3% (1.6 %) without significant
change in time spent awake. There were
no changes in REM sleep from early
Figure 1. Percentages of Sleep Period Spent in Wake, Stages 1 and 2, SW Sleep, and REM
Sleep as a Function of Age
26-3516-25 71-8351-60 61-7036-50
% of Sleep Period
60
Wake Time
0
20
40
60
Effect of Age: P<.001
Effect of BMI: P
=
.17
Interaction: P
=
.07
0
20
40
% of Sleep Period
25
20
10
Slow Wave Sleep
0
5
15
40
Effect of Age: P<.001
Effect of BMI: P<.001
Interaction: P<.002
0
30
20
10
% of Sleep Period
25
20
10
REM Sleep
0
5
15
Age Range, y
25
40
Effect of Age: P<.001
Effect of BMI: P
=
.35
Interaction: P
=
.06
0
20
30
10
Age, y
15 8545 55 65 7535
% of Sleep Period
70
60
40
Stage 1 and 2 Sleep
0
30
20
10
50
90
20
50
70
80
40
30
60
Effect of Age: P<.004
Effect of BMI: P<.001
Interaction: P<.005
Mean (SEM) for each age group shown in the left panels. Individual data are plotted in the right panels. SW
indicates slow wave; REM, rapid eye movement; and BMI, body mass index. Probability levels refer to the
effects of age, BMI, and their interaction in an analysis of variance (ANOVA) model using type III sums of
squares. When the level of interaction was not significant (P..05), the interaction was removed from the ANOVA.
P values for age and BMI are then reported for ANOVA without interaction. The multiple correlations were
r=0.636 for percentage of wake time, r= 0.324 for percentage of stages 1 and 2, r= 0.672 for percentages of
SW sleep, and r 0.499 for percentage of REM.
SLEEP AND HORMONAL PARAMETERS FROM EARLY TO LATE ADULTHOOD
©2000 American Medical Association. All rights reserved. (Reprinted) JAMA, August 16, 2000—Vol 284, No. 7 863
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adulthood to midlife. Increases in wake
time and decreases in REM sleep be-
came significant starting at midlife, and
stages 1 and 2 decreased from 60.5%
(2.5%) for subjects aged 51 to 60 years
to 50.6% (4.6%) for subjects older than
70 years. Changes in SW sleep after age
50 years were not significant.
Effects of BMI and of the interaction
age 3 BMI were significant for stages 1
and 2 and SW sleep, but not for other
sleep parameters (Figure 1). In young
to middle-aged subjects (aged 16-43
years), but not in older adults (aged
44-83 years), higher BMI was associ-
ated with shallower, non-REM sleep (less
SW sleep, more stages 1 and 2 sleep).
Growth Hormone
Mean 24-hour GH profiles from 8 older
men and 8 young men who were
matched for BMI illustrate the tempo-
ral coincidence of the major GH pulse
with early sleep and the marked reduc-
tion in GH levels in old age (F
IGURE 2).
The impact of age on GH secretion
during the 24-hour cycle, wake time,
and sleep, is illustrated in F
IGURE 3. Sig-
nificant effects of age independent of
BMI were evident. From young adult-
hood to midlife, GH secretion de-
creased by nearly 75%. Further smaller
decreases occurred between midlife and
late adulthood (Table).
A significant negative association of
BMI with 24-hour GH secretion and GH
secretion during waking, but not dur-
ing sleep, was detected independently
of age.
Cortisol
Mean 24-hour cortisol profiles in young
and older men are shown in the lower
panels of Figure 2. In both groups, cor-
tisol levels show an early morning eleva-
tion, declining levels throughout the day-
time, and a nocturnal quiescent period.
Age differences are mostly apparent in
the evening and early part of the night.
F
IGURE 4 illustrates the changes in
24-hour mean cortisol level, morning
acrophase, and evening nadir across
adulthood. A modest effect of aging on
the 24-hour mean cortisol level was de-
tected. Aging was associated with an el-
Table. Chronology of Age-Related Changes in Sleep Parameters, Growth Hormone Secretion,
and Cortisol Levels
*
Variable
Age Group
P
Value
Early Adulthood to Midlife
(Age 16 to 43 Years)†
P
Value
Midlife to Late Life
(Age 44 to 83 Years)‡
Duration, min/decade§
Sleep period −10 .21 −2 .69
Total sleep time −1 .94 −27 ,.001
Wake time −7 .28 +28 ,.001
REM sleep +3 .52 −10 ,.001
SW sleep −38 ,.001 −4 .13
Stages 1 and 2 +34 ,.001 −24 ,.001
Growth Hormone, µg/decade
24-Hour GH secretion −372 ,.001 −43 ,.02
Waking GH secretion −150 .002 −27 .05
Sleeping GH secretion −221 ,.001 −16 ,.06
Cortisol, nmol/L per decade\
24-Hour mean level +0.6 .99 +11.0 ,.07
Morning acrophase level −8.8 .66 +10.2 .32
Evening nadir level −1.7 .81 +19.3 ,.001
*
REM indicates rapid eye movement; SW, slow wave; and GH, growth hormone.
†Data from 74 men was analyzed for “Sleep,” from 66 for “Growth Hormone,” and from 71 for “Cortisol.”
‡Data from 58 men was analyzed for “Sleep,” from 48 for “Growth Hormone,” and from 53 for “Cortisol.”
§Sleep period was defined as the interval separating sleep onset from morning awakening. Total sleep time was cal-
culated as the sleep period minus the total duration of awakenings.
\To convert nmol/L to ng/mL, divide by 2.759.
Figure 2. Mean 24-Hour Profiles of Plasma Growth Hormone (GH) and Plasma Cortisol From
Young and Older Men Matched for BMI
Plasma GH, µg/L
12
8
Growth Hormone Secretion Profiles
Age 17-24 Years Age 70-83 Years
0
4
12
0
8
4
Plasma Cortisol, nmol/L
500
400
200
Cortisol Secretion Profiles
0
100
300
12
500
400
0
200
300
100
Clock Time
08 0820 00 041612
Clock Time
08 0820 00 0416
BMI indicates body mass index. The mean (SD) BMI in the older men was 24.1 (0.8) kg/m
2
and in young men,
24.1 (0.6) kg/m
2
. Dashed line indicates SEM.
SLEEP AND HORMONAL PARAMETERS FROM EARLY TO LATE ADULTHOOD
864 JAMA, August 16, 2000—Vol 284, No. 7 (Reprinted) ©2000 American Medical Association. All rights reserved.
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evation of the evening nadir, but morn-
ing maximum values remained stable
across all age ranges. Increases in
evening cortisol levels became appar-
ent after midlife (Table).
There were no effects of BMI or of the
interaction BMI 3 age on any of the pa-
rameters characterizing the 24-hour
cortisol profile.
Relationships Between Sleep
and Hormonal Alterations
Age-related decreases in GH secretion
and SW sleep followed a similar chro-
nology, with the majority of the dec-
rements occurring in young adult-
hood, whereas age-related increases in
evening cortisol did not occur until the
fifth decade, when decreases in REM
sleep and increases in amount of wake
time became apparent (Table). We thus
sought to determine whether the con-
comitant sleep alteration and its inter-
action with age contributed to the hor-
monal changes.
Analysis of variance of GH secre-
tion during sleep in relation to age, SW
sleep, and their interaction indicated
that SW sleep (P,.001) and the inter-
action age 3 SW sleep (P =.008) ac-
counted for the majority of the vari-
ance and that effects of age per se were
nonsignificant (P..50). Similar find-
ings were obtained when total 24-
hour GH secretion was analyzed (age,
P..50; SW sleep, <.001; age 3 SW
sleep, P =.003). In young to middle-
aged subjects, but not in older men, in-
creased amounts of SW sleep were as-
sociated with higher levels of GH
secretion. The left panels of F
IGURE 5
compare GH levels during sleep in sub-
jects who had large amounts of SW
sleep and in age- and BMI-matched sub-
jects who had small amounts of SW
sleep.
The variance of evening cortisol lev-
els was analyzed in relation to age, REM
sleep, wake time, and their interac-
tions. The contributions of all interac-
tions and of wake time were not sig-
nificant. Age (P,.001) and, to a lesser
extent, REM sleep (P,.10) were both
negatively related to evening cortisol
concentrations. To illustrate the in-
verse relationship between amounts of
REM sleep and evening cortisol levels,
the right panels of Figure 5 show the
mean cortisol nadir in subjects with
large amounts of REM sleep and in age-
and BMI-matched subjects with small
amounts of REM sleep.
COMMENT
The present analysis demonstrates that,
in healthy men, aging affects SW sleep
and GH release with a similar chronol-
ogy characterized by major decrements
from early adulthood to midlife. In con-
trast, the impact of age on REM sleep,
sleep fragmentation, and HPA function
does not become apparent until later in
life. The analysis further suggests that
age-related alterations in the somato-
tropic and corticotropic axes may par-
tially reflect decreased sleep quality.
Human sleep is under the dual con-
trol of circadian rhythmicity and of a
homeostatic process relating the depth
of sleep to the duration of prior wake-
fulness.
44
This homeostatic process in-
volves a putative neural sleep factor that
increases during waking and decays ex-
Figure 3. Amount of Growth Hormone (GH) Secreted During the 24-Hour Cycle, Wake
Time, and Sleep as a Function of Age
Amount of GH Secreted, µg
800
24-h Secretion
0
400
200
600
1500
Effect of Age: P<.02
Effect of BMI: P<.02
Interaction: P<.04
0
500
1000
26-3516-25 71-8351-60 61-7036-50
Amount of GH Secreted, µg
400
300
100
Secretion During Sleep Time
0
200
Age Range, y
25
1000
Effect of Age: P<.001
Effect of BMI: P
=
.47
Interaction: P
=
.25
0
600
800
400
200
Age, y
15 8545 55 65 7535
Amount of GH Secreted, µg
300
200
Secretion During Wake Time
0
100
1000
0
200
600
800
400
Effect of Age: P<.02
Effect of BMI: P<.008
Interaction: P<.04
Mean (SEM) for each age group shown in the left panels. Individual data are plotted in the right panels. BMI
indicates body mass index. Probability levels refer to the effect of age, BMI, and their interaction in an analysis
of variance (ANOVA) model using type III sums of squares. When level of interaction was not significant (P..05),
the interaction was removed from the ANOVA. P values for age and BMI are then reported for ANOVA with-
out interaction. The multiple correlations were r=0.565 for 24-hour growth hormone secretion, r=0.405 for
waking growth hormone secretion, and r= 0.551 for sleeping growth hormone secretion. Similar results are
obtained when only growth hormone data measured by radioimmunoassay are analyzed.
SLEEP AND HORMONAL PARAMETERS FROM EARLY TO LATE ADULTHOOD
©2000 American Medical Association. All rights reserved. (Reprinted) JAMA, August 16, 2000—Vol 284, No. 7 865
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ponentially during sleep. Slow wave
sleep is primarily controlled by the ho-
meostatic process. Circadian rhythmic-
ity is an oscillation with a near 24-
hour period generated by a pacemaker
located in the hypothalamic suprachi-
asmatic nucleus. Circadian rhythmic-
ity plays an important role in sleep tim-
ing, sleep consolidation, and the
distribution of REM sleep.
45
The pres-
ent data indicate that an alteration in
sleep-wake homeostasis is an early bio-
logical marker of aging in adult men.
In contrast, components of sleep that
are under the control of the circadian
pacemaker appear to be relatively well
preserved until late in life.
The chronology of aging of GH se-
cretion follows a pattern remarkably
similar to that of SW sleep. Thus, in
men, the so-called “somatopause” oc-
curs early in adulthood, between age 25
and 35 years, an age range that corre-
sponds to the human life expectancy be-
fore the development of modern civi-
lization and is essentially completed by
the end of the fourth decade. Our analy-
ses further indicate that reduced
amounts of SW sleep, independent of
age, are partly responsible for reduced
GH secretion in midlife and late life.
That this correlative evidence reflects
a common mechanism underlying SW
sleep generation and GH release rather
than an indirect association is sup-
ported by 2 studies that have shown that
pharmacological enhancement of SW
sleep results in increased GH re-
lease.
46,47
Also supporting a causal re-
lationship between decreased sleep
quality and reduced nocturnal GH se-
cretion are studies in patients with sleep
apnea showing a marked increase in GH
release following treatment with posi-
tive airway pressure.
48,49
The reverse in-
teraction between sleep and GH, ie, a
deleterious impact of reduced somato-
tropic function on sleep, is also pos-
sible since studies in both normal and
pathological conditions have shown
that GH-releasing factor and GH influ-
ence sleep quality.
12,50
In the present
study of nonobese men, the finding of
a negative impact of BMI on both GH
secretion during waking and amount of
SW sleep is consistent with the hypoth-
esis that inhibition of the GH axis may
adversely affect sleep regulation.
While the clinical implications of de-
creased SW sleep are still unclear, the
relative GH deficiency of the elderly is
associated with increased fat tissue and
abdominal obesity, reduced muscle mass
and strength, and reduced exercise ca-
pacity.
51-53
Multiple trials are currently
examining the clinical usefulness and
safety of replacement therapy with re-
combinant GH, the other hormones of
the GH axis, and synthetic GH secreta-
gogues in elderly adults without patho-
logical GH deficiency. While the ben-
efits of such interventions are still
unproven, the present findings suggest
that they should target a younger age
range than currently envisioned, ie, in-
dividuals in early midlife rather than
those older than 65 years, when periph-
eral tissues have been continuously ex-
posed to very low levels of GH for at least
2 decades. Furthermore, since pharma-
cological enhancement of SW sleep in
young adults has been shown to result
in a simultaneous and proportional in-
crease in GH release
46,47
and ongoing
studies in our laboratory indicate that
Figure 4. 24-Hour Mean Level and Levels of Morning Acrophase and Evening Nadir of
Plasma Cortisol as a Function of Age
Plasma Cortisol, nmol/L
300
24-h Mean Level
0
200
100
380
Effect of Age: P<.02
Effect of BMI: P
=
.65
Interaction: P
=
.06
80
180
280
26-3516-25 71-8351-60 61-7036-50
Plasma Cortisol, nmol/L
200
150
50
Evening Nadir
0
100
Age Range, y
25
200
Effect of Age: P<.001
Effect of BMI: P
=
.18
Interaction: P
=
.87
0
100
150
50
Age, y
15 8545 55 65 7535
Plasma Cortisol, nmol/L
500
300
200
100
400
Morning Acrophase
0
750
150
350
550
Effect of Age: P
=
.80
Effect of BMI: P
=
.36
Interaction: P
=
.16
Mean (SEM) for each age group shown in the left panels. Individual data are plotted in the right panels. BMI
indicates body mass index. Probability levels refer to the effect of age, BMI, and their interaction in an analysis
of variance (ANOVA) model using type III sums of squares. When level of interaction was not significant (P..05),
the interaction was removed from the ANOVA. P values for age and BMI are then reported for ANOVA with-
out interaction. The multiple correlations were r =0.243 for 24-hour mean level, r=0.089 for level of morning
acrophase, and r= 0.544 for level of evening nadir.
SLEEP AND HORMONAL PARAMETERS FROM EARLY TO LATE ADULTHOOD
866 JAMA, August 16, 2000—Vol 284, No. 7 (Reprinted) ©2000 American Medical Association. All rights reserved.
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similar effects can be obtained in older
subjects, drugs that reliably stimulate SW
sleep may represent a novel class of GH
secretagogues.
The present data demonstrate that
the amount of REM sleep is reduced by
approximately 50% in late life vs young
adulthood. However, reduced amounts
of REM sleep and significant sleep frag-
mentation do not occur until after age
50 years. The impact of aging on cor-
tisol levels followed the same chronol-
ogy. Aging was associated with an el-
evation of evening cortisol levels,
reflecting an impaired ability to achieve
evening quiescence following morn-
ing stimulation. Studies in both ani-
mals and humans have indicated that
deleterious effects of HPA hyperactiv-
ity are more pronounced at the time of
the trough of the rhythm than at the
time of the peak.
25,54
Thus, modest el-
evations in evening cortisol levels could
facilitate the development of central and
peripheral disturbances associated with
glucocorticoid excess, such as memory
deficits and insulin resistance,
24,25
and
further promote sleep fragmentation.
Indeed, elevated cortisol levels may pro-
mote awakenings.
55,56
Elevated evening cortisol levels in late
life probably reflect an impairment of
the negative feedback control of the
HPA axis in aging. Our analyses sug-
gest that there is a relationship be-
tween this alteration of HPA function
and decreased amounts of REM sleep
that is independent of age. The data
generally support the concept that de-
creased sleep quality contributes to the
allostatic load, ie, the wear and tear re-
sulting from overactivity of stress-
responsive systems.
57
The present study focused on the ef-
fects of aging on the relationship be-
tween sleep and the somatotopic and
corticotropic axes in men because the
predominant GH secretion occurs dur-
ing sleep in men but not in women
11
and because there is evidence to sug-
gest that the marked decreases in SW
sleep in early adulthood occur in men
but not in women.
8-11
Whether conclu-
sions similar to those obtained for men
hold for women will require a sepa-
rate evaluation as sex differences in
sleep quality as well as 24-hour pro-
files of GH and cortisol secretion have
been well documented in both young
and older adults.
11,12,22
In conclusion, in healthy men, the
distinct changes in sleep quality that
characterize the transitions from early
adulthood to midlife, on the one hand,
and from midlife to old age, on the other
hand, are each associated with spe-
cific alterations in hormonal systems
that are essential for metabolic regula-
tion. Strategies to prevent or limit dec-
rements of sleep quality in midlife and
late life may therefore represent an in-
direct form of hormonal therapy with
possible beneficial health conse-
quences.
Funding/Support: This work was supported in part
by grants AG-11412 from the National Institute on
Aging, DK-41814 from the National Institute of Dia-
betes and Digestive and Kidney Diseases, and by the
Mind-Body Network of the MacArthur Foundation
(Chicago, Ill). During the performance of this re-
search, Dr Plat was supported by the Suzanne and Jean
Pirart Fellowship from the Association Belge du Dia-
be` te (Brussels, Belgium).
Acknowledgment: We thank R. T. Rubin, MD (Al-
legheny-Singer Research Institute, Pittsburgh, Pa),
D. J. Kupfer (Western Psychiatric Institute and Clin-
ics, University of Pittsburgh), and A. N. Vgontzas, MD
(Department of Psychiatry, Pennsylvania State Uni-
versity, Hershey) for contributing previously pub-
lished data sets to the present analysis.
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868 JAMA, August 16, 2000—Vol 284, No. 7 (Reprinted) ©2000 American Medical Association. All rights reserved.
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