1 Center for the Study of
Biological Rhythms (CERB), A complex interrelationship exists between sleep
and somatotropic activity. In humans, intravenous injections of growth
hormone-releasing hormone (GHRH) given during sleep consistently
stimulate slow-wave (SW) sleep, particularly when given in the latter
part of the night. In the present study, the possible somnogenic
effects induced under similar conditions by GH-releasing peptide (GHRP)
were investigated in seven young healthy men. Bolus intravenous
injections of GHRP-2 (1 µg/kg body wt) or saline, in randomized
order, were given after 60 s of the third rapid-eye-movement period.
All GHRP injections were immediately followed by transient prolactin
elevations and by GH pulses of a magnitude within or around the upper
limit of the physiological range. Except for a nonsignificant tendency to increased amounts of wakefulness during the 1st h after the injection, no effects of GHRP-2 administration on sleep were detected. There was in particular no enhancement of SW sleep. Thus, in contrast to GHRH, late-night single injections of GHRP-2 at a dosage resulting in similar GH elevations have no stimulatory effects on SW sleep. The
present data provide evidence against the involvement of the GHRP axis
in human SW sleep regulation.
prolactin; rapid-eye-movement sleep
NUMEROUS STUDIES have documented a complex
interrelationship between sleep and somatotropic activity in animals as
well as in humans. In animals, elevated growth hormone (GH) circulating levels are found during sleep (17, 22, 24). In normal young men, a
consistent temporal association between slow-wave (SW) sleep (SW:
stages III and IV) and GH nocturnal secretion has been demonstrated. On
a daily basis, the major GH secretory episode is a sleep
onset-associated pulse occurring during the first phase of SW sleep
(15, 36, 39). A close relationship between the amount of GH secreted
during sleep and the duration of SW stages has been evidenced in a
pulse-by-pulse analysis of GH secretory profiles (39). Pharmacological
stimulation of deep sleep by ritanserin or by Conversely, there is also good evidence to indicate that somatotropic
activity is involved in the quality and the maintenance of sleep (20).
In particular, the role of GHRH has been evidenced in humans as well as
in laboratory animals. In rodents, intracerebral as well as systemic
injections of GHRH stimulate non-rapid-eye-movement (non-REM) sleep,
even in hypophysectomized animals (11, 25-27), and inhibition of
endogenous GHRH decreases both non-REM sleep and GH secretion (29, 30).
In humans, no effects of GHRH on sleep quality were found when the
peptide was injected during daytime or before sleep onset (13, 21) or
when it was given as an infusion (19, 23). In contrast, studies with
intravenous GHRH injections given during sleep have been consistent in
demonstrating robust stimulatory effects on SW sleep (18, 23, 35). A
detailed study performed in normal young men indicated that the effects of the peptide on sleep quality depend on the timing of administration. Single intravenous bolus injections of GHRH at a dosage eliciting GH
responses of a magnitude similar to those of spontaneous sleep-onset GH
pulses induced a modest increase in REM sleep without a change in SW
sleep when injected early during sleep, i.e., at a time when SW sleep
is predominant over REM sleep. In contrast, injection of a similar
dosage of GHRH in the latter part of the night, i.e., at a time when
REM sleep is predominant, was followed by an almost 10-fold increase in
SW sleep, without change in REM sleep (18). In rats, there is evidence
that the SW sleep-enhancing effects of GHRH are exerted centrally (27),
whereas the REM sleep-enhancing effects would appear to be mediated by
GH (26, 27). There are no comparable data in humans.
Recent studies have indicated that the release of GH is also under the
control of an as-yet-unidentified stimulatory pathway that may be
activated by synthetic compounds such as the GH-releasing peptides
(GHRPs) and their functional agonists (6, 16). These compounds are
thought to act as functional somatostatin antagonists (33) and also
stimulate prolactin and cortisol secretion (3). Whether this second
axis for GH stimulation is also involved in sleep regulation is not
known. Indeed, the finding of the only study to examine the effects of
injections of GHRP-6 around bedtime was an enhancement of the amount of
stage II sleep without any other significant effect on either SW sleep
or REM sleep (12). These data do not exclude the possibility that, as
was previously shown for GHRH, GHRP may have a stimulatory effect on SW
sleep when given during the latter part of the night at a time when SW
sleep is not naturally abundant. The present study was therefore designed to investigate the effects on sleep quality of a late-night intravenous bolus injection of GHRP-2 (a more potent GH secretagogue than GHRP-6) at a dosage resulting in elevations of GH within the
physiological range.
Subjects.
Seven healthy men, 24-30 yr old, were selected after a careful
physical, psychiatric, and biological evaluation. All subjects were of
normal weight (body mass index 23-25
kg/m2). Night and/or
shift workers, subjects having crossed time zones or having taken any
drug during the previous 6 wk, smokers, and subjects with sleep
complaints or with a personal or family history of psychiatric,
neurological, metabolic, or endocrine disorder were excluded. The
protocol was approved by the Institutional Review Board, and written
informed consent was given by all subjects after they had received a
complete explanation of the aims and means of the study. All
experiments were performed in the Sleep Laboratory of the Department of
Psychiatry, Erasme Hospital, Université Libre de Bruxelles,
Brussels, Belgium.
Protocol.
One week before the beginning of the investigation, the subjects spent
two consecutive nights in the sleep unit to become habituated to
laboratory conditions and experimental procedures. During the first
night, electrodes for polygraphic sleep recording were attached around
2245, but no recordings were performed. Sleep was polygraphically
recorded during the second night. This prestudy polygraphic recording
served to exclude subjects with abnormal sleep patterns. Thereafter,
the subjects had to comply with a standardized schedule of meal times
(breakfast: 0800-0900; lunch: 1200-1300; dinner:
1900-2000) and bedtimes (from 2230-2300 until 0700-0900).
ABSTRACT
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
INTRODUCTION
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
-hydroxybutyrate also
increases GH secretion in close temporal and quantitative relationship
(14, 40). A recent study using a GH-releasing hormone (GHRH) antagonist has indicated that sleep-related GH secretion appears to be primarily mediated by GHRH release (31).
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
Hormonal assays. All samples from the same individual were analyzed in the same assay. Plasma GH and prolactin levels were measured by commercially available immunoradiometric assays (Medgenix, Fleurus, Belgium). The GH assay had a lower limit of sensitivity of 0.10 µg/l, an intra-assay variation coefficient of 4%, and an extra-assay variation coefficient of 11%. The prolactin assay had a lower limit of sensitivity of 0.25 µg/l, an intra-assay variation coefficient of 7%, and an extra-assay variation coefficient of 13%.
Sleep recording and analysis. Polygraphic sleep recordings were scored at 20-s intervals in wake, I, II, III, IV and REM stages by use of standardized criteria (32). Sleep onset and morning awakening were defined as, respectively, the times of the first and last 20-s intervals scored II, III, IV, or REM. The sleep period was defined as the time interval between sleep onset and final morning awakening. Sleep efficiency was calculated as the total sleep period minus the time spent awake, expressed as percentage of the total recording time. SW sleep was defined as the total duration of stages III and IV.
To analyze possible somnogenic effects of GHRP, the total amounts of each sleep stage recorded during the 1st, 2nd, and 3rd h after GHRP were calculated and compared with the amounts recorded during corresponding hours in the placebo study. Similar calculations were performed to consider successive 90-min time intervals over this 3-h period.Statistical methods. Significant pulses of GH secretion were identified using a modification of the computer algorithm ULTRA (37, 38). The threshold for significance of a pulse was set at two times the intra-assay coefficient of variation in the relevant range of concentration. For each significant pulse, the amount of GH secreted was estimated by deconvolution based on a one-compartment model for GH clearance and variable individual half-lives, as previously described (39).
Statistical tests. All data are expressed as means ± SE except when otherwise stated. Paired comparisons were performed using the nonparametric Wilcoxon test. All statistical calculations were performed using the Statview SE+ software for Macintosh computers (Abacus Concepts, Berkeley, CA).
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RESULTS |
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Mean GH and prolactin profiles in GHRP and saline experiments are shown in Fig. 1. Spontaneous sleep-onset GH pulses were observed in all individual profiles. Their amplitude was similar in presaline and pre-GHRP experiments. The amount of GH secreted in the sleep-onset pulse ranged between 59 and 1,344 µg, averaging 483 µg. No significant GH response was observed after saline administration, whereas all GHRP injections were immediately followed by GH pulses. The magnitude of these pulses varied widely across individuals. In one subject (subject 3), the amount of GH secreted (2,080 µg) exceeded markedly the upper limit of spontaneous sleep-onset pulses. In the other six subjects, the GH secretion in response to GHRP injection ranged between 210 and 1,206 µg, averaging 818 µg, i.e., within the range of the spontaneous sleep-onset pulses.
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The classical 24-h profile of plasma prolactin levels was observed in all experiments. In addition, a transient significant elevation was observed within the 1st h after GHRP injection (P < 0.01 vs. saline).
Sleep parameters are shown in Table 1 and in Fig. 2. Sleep period time, sleep efficiency, and total durations of wake, I, II, III, IV, SW, and REM stages were similar during nights with GHRP administration and nights with saline injection. Except for a nonsignificant tendency (P < 0.08) to increased amounts of wake stage during the 1st h after the injection, no effects of GHRP administration on sleep were detected by the hourly analysis and by the 90-min analysis of sleep stages performed during the first 3 h postinjection. Similar results were obtained if subject 3, who exhibited a GH response to GHRP well beyond the upper limit of spontaneous sleep-onset pulses, was excluded from the analysis.
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DISCUSSION |
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Transient stimulations of GH and prolactin secretion observed in the present study after single intravenous injections of GHRP-2 are consistent with the results of previous studies (3). In all subjects but one, the magnitude of the GHRP-induced GH secretory pulse was within the range of spontaneous sleep-onset GH pulses.
Our data indicate that single injections of GHRP-2 in the latter part of a normal night, i.e., at a time when sleep is shallow and fragmented, had no effect on sleep in young healthy men. In particular, there was no enhancement of SW sleep and no decrease in the duration of awakenings. This is in contrast to the effects elicited in similar conditions by GHRH injections (18). In both studies, the GH secretagogue was given as a single intravenous bolus injection after 60 s of the third REM period at a dosage resulting in elevations of GH secretion within or around the upper limit of the physiological range. Because GHRH and GHRP bind to different receptors in the central nervous system and stimulate GH release by different mechanisms (2), the present results support the view that SW sleep-promoting effects of physiological doses of GHRH are not mediated by increased GH secretion but result from a direct action on brain centers, consistent with the concept that stimulation of GH release and of SW sleep by GHRH represents two independent processes, involving GHRH neurons in two different hypothalamic areas (4, 20, 28) and possibly different GHRH receptor systems.
GHRPs are GH secretagogues that act as somatostatin antagonists via specific receptors localized both in the pituitary and in the arcuate ventromedial and infundibular hypothalamus (6, 16, 33). Inconsistent data have been reported concerning the action of somatostatin on sleep. In the rodent, REM sleep was inhibited by immunoneutralization of endogenous somatostatin (9) and enhanced by intracerebroventricular administration of exogenous somatostatin (8), and non-REM sleep was inhibited by subcutaneous injections of a long-acting somatostatin analog (1). In the human, repeated intravenous injections of somatostatin did not influence sleep quality in normal young subjects (35), but REM sleep was decreased by somatostatin in the elderly (34).
GHRP-6 and GHRP-2 appear to stimulate GH secretion through different receptors in sheep but not in rats (5, 41). No comparable data are available in humans. There are no published studies of the effects of GHRP-2 on sleep. As far as GHRP-6 is concerned, a modest enhancement of stage II, without any increase in SW sleep, has been reported (12) in a study involving injections of 50 µg of GHRP-6 administered hourly from 2200 to 0100, i.e., from 1 h before until 2 h after bedtime, resulting in an important and sustained elevation of GH concentrations. The absence of stimulation of SW sleep could, however, have represented a ceiling effect, because during the early part of the night, SW stages are already abundant. The present results, obtained with GHRP-2, are consistent with the previous findings reported with GHRP-6 in failing to demonstrate a stimulation of SW sleep. They do not exclude, however, the possibility that these two related peptides involve different mechanisms of action. Additional studies on larger subject populations with both GHRP-2 and GHRP-6 are needed to further clarify the respective effects of these compounds on sleep regulation. The evidence available at the present time indicates that, in contrast to GHRH, single injections of GHRP-2 at a dosage resulting in similar GH elevations have no stimulatory effects on SW sleep, even when given at a time when SW sleep is not predominant.
Recently, we have shown that 7-day oral treatment with MK-677, a functional agonist of GHRP acting via the GHRP receptor, is associated with an increase in stage IV in normal young men (7). This intriguing finding is difficult to interpret in the context of the present study, because plasma GH levels were not elevated at the time of the sleep study (although acutely MK-677 is a powerful GH secretagogue), but plasma insulin-like growth factor I levels were markedly increased. Multiple complex mechanisms could be involved in the effects of MK-677 on sleep, with dubious relevance to the effects of direct, acute stimulation of the GHRP axis as examined in the present study.
In conclusion, the present study supports the concept that the well-documented relationship between somatotropic activity and human SW sleep regulation is primarily dependent on GHRH.
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ACKNOWLEDGEMENTS |
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We are indebted to Dr. C. Y. Bowers for providing the GHRP-2 used in the present investigation. We thank M. Zanen and D. Wasnaire for excellent technical help and B. Jacques for outstanding informatics collaboration.
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FOOTNOTES |
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This work was supported by grants from the Belgian Fonds de la Recherche Scientifique Médicale, the Université Libre de Bruxelles, and the National Institute on Aging (PO1 AG-11412).
Address for reprint requests: G. Copinschi, Laboratory of Experimental Medicine, CPI 618, School of Medicine, Université Libre de Bruxelles, route de Lennik 808, B-1070 Brussels, Belgium.
Received 27 August 1997; accepted in final form 28 January 1998.
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REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Beranek, L., F. Obál, Jr., B. Bodosi, P. Taishi, F. Lacsi,
and J. Krueger. Inhibition of non-REM sleep in response to a
long-acting somatostatin analog, sandostatin, in the rat.
J. Sleep Res. 5, Suppl. 1: 14, 1996.
2.
Bowers, C. Y.
On a peptidomimetic growth hormone-releasing peptide.
J. Clin. Endocrinol. Metab.
79:
940-942,
1994[Medline].
3.
Bowers, C. Y.,
G. A. Reynolds,
D. Durham,
C. M. Barrera,
S. S. Pezzoli,
and
M. O. Thorner.
Growth hormone (GH)-releasing peptide stimulates GH release in normal men and acts synergistically with GH-releasing hormone.
J. Clin. Endocrinol. Metab.
70:
975-982,
1990[Abstract].
4.
Bredow, S.,
P. Taishi,
F. Obál, Jr.,
N. Guha-Thakurta,
and
J. M. Krueger.
Hypothalamic growth hormone-releasing hormone mRNA varies across the day in rats.
Neuroreport
7:
2501-2505,
1996[Medline].
5.
Cheng, J.,
T. Wu,
B. Butler,
and
K. Cheng.
Growth hormone releasing peptides: a comparison of the growth hormone releasing activities of GHRP-2 and GHRP-6 in rat primary pituitary cells.
Life Sci.
60:
1385-1392,
1997[Medline].
6.
Conn, P. M.,
and
C. Y. Bowers.
A new receptor for growth hormone-release peptide.
Science
273:
923,
1996[Medline].
7.
Copinschi, G.,
R. Leproult,
A. Van Onderbergen,
A. Caufriez,
K. Y. Cole,
L. M. Schilling,
C. M. Mendel,
I. De Lepeleire,
J. A. Bolognese,
and
E. Van Cauter.
Prolonged treatment with MK-677, a novel growth hormone secretagogue, improves sleep quality in man.
Neuroendocrinology
66:
278-286,
1997[Medline].
8.
Danguir, J.
Intracerebroventricular infusions of somatostatin selectively increase paradoxical sleep in rats.
Brain Res.
367:
26-30,
1986[Medline].
9.
Danguir, J.,
and
S. de Saint-Hilaire-Kafi.
Somatostatin antiserum blocks carbachol-induced increase of paradoxical sleep in rat.
Brain Res. Bull.
20:
9-12,
1988[Medline].
10.
Désir, D.,
E. Van Cauter,
V. Fang,
E. Martino,
C. Jadot,
J.-P. Spire,
P. Noel,
S. Refetoff,
G. Copinschi,
and
J. Golstein.
Effects of "jet lag" on hormonal patterns. I. Procedures, variations in total plasma proteins, and disruption of adrenocorticotropin-cortisol periodicity.
J. Clin. Endocrinol. Metab.
52:
628-641,
1981[Medline].
11.
Ehlers, C. L.,
T. K. Reed,
and
S. J. Henriksen.
Effects of corticotropin-releasing factor and growth hormone-releasing factor on sleep and activity in rats.
Neuroendocrinology
42:
467-474,
1986[Medline].
12.
Frieboes, R.-F.,
H. Murck,
P. Maier,
T. Schier,
F. Holsboer,
and
A. Steiger.
Growth hormone-releasing peptide-6 stimulates sleep, growth hormone, ACTH and cortisol release in normal man.
Neuroendocrinology
61:
584-589,
1995[Medline].
13.
Garry, P.,
B. Roussel,
R. Cohen,
S. Biot-Laporte,
A. Elm Charfi,
M. Jouvet,
and
G. Sassolas.
Diurnal administration of human growth hormone-releasing factor does not modify sleep and sleep-related growth hormone secretion in normal young men.
Acta Endocrinol. (Copenh.)
110:
158-163,
1985[Medline].
14.
Gronfier, C.,
R. Luthringer,
M. Follenius,
N. Schaltenbrand,
J. P. Macher,
A. Muzet,
and
G. Brandenberger.
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
19:
817-824,
1996[Medline].
15.
Holl, R. W.,
M. L. Hartmann,
J. D. Veldhuis,
W. M. Taylor,
and
M. O. Thorner.
Thirty-second sampling of plasma growth hormone in man: correlation with sleep stages.
J. Clin. Endocrinol. Metab.
72:
854-861,
1991[Abstract].
16.
Howard, A. D.,
S. D. Feighner,
D. F. Cully,
J. P. Arena,
P. A. Liberator,
C. I. Rosenblum,
M. Hamelin,
D. L. Hrenuk,
O. C. Palyha,
J. Anderson,
P. S. Paress,
C. Diaz,
M. Chou,
K. K. Liu,
K. K. McKee,
S. S. Pong,
L. Chaung,
A. Elbrecht,
M. Dashkevicz,
R. Heavens,
M. Rigby,
D. Sirinathsinghji,
D. C. Dean,
D. G. Mellilo,
A. A. Patchett,
R. Nargund,
P. R. Griffin,
J. A. DeMartino,
S. K. Gupta,
J. M. Schaeffer,
R. G. Smith,
and
L. H. T. Van der Ploeg.
A receptor in pituitary and hypothalamus that functions in growth hormone release.
Science
273:
974-977,
1996[Abstract].
17.
Kaler, L. W.,
P. Gliessman,
J. Craven,
J. Hill,
and
V. Critchlow.
Loss of enhanced nocturnal growth hormone secretion in aging rhesus males.
Endocrinology
119:
1281-1284,
1986[Abstract].
18.
Kerkhofs, M.,
E. Van Cauter,
A. Van Onderbergen,
A. Caufriez,
M. O. Thorner,
and
G. Copinschi.
Sleep-promoting effects of growth hormone-releasing hormone in normal men.
Am. J. Physiol.
264 (Endocrinol. Metab. 27):
E594-E598,
1993
19.
Kern, W.,
R. Halder,
S. Al-Reda,
E. Späth-Schwalbe,
H. L. Fehm,
and
J. Born.
Systemic growth hormone does not affect human sleep.
J. Clin. Endocrinol. Metab.
76:
1428-1432,
1993[Abstract].
20.
Krueger, J.,
and
F. Obál, Jr.
Growth hormone-releasing hormone and interleukin-1 in sleep regulation.
FASEB J.
7:
645-652,
1993
21.
Kupfer, D. J.,
D. B. Jarrett,
and
C. L. Ehlers.
The effect of GRF on the EEG sleep of normal males.
Sleep
14:
87-88,
1991[Medline].
22.
Laurentie, M. P.,
B. Barenton,
J. Charrier,
R. Garcia-Villar,
P. G. Marnet,
M. Blanchard,
and
P. L. Toutain.
Instantaneous secretion rate of growth hormone in lambs: relationships with sleep, food intake, and posture.
Endocrinology
125:
642-651,
1989[Abstract].
23.
Marshall, L.,
M. Mölle,
G. Böschen,
A. Steiger,
H. Fehm,
and
J. Born.
Greater efficacy of episodic than continuous growth hormone-releasing hormone (GHRH) administration in promoting slow-wave sleep (SWS).
J. Clin. Endocrinol. Metab.
81:
1009-1013,
1996[Abstract].
24.
Mitsugi, N.,
and
F. Kimura.
Simultaneous determinations of corticosterone and growth hormone in the male rat: relation to sleep-wakefulness cycle.
Neuroendocrinology
41:
125-130,
1985[Medline].
25.
Nistico, G.,
G. B. De Sarro,
G. Bagetta,
and
E. E. Müller.
Behavioral and electrocortical spectrum power effects of growth hormone releasing factor in rats.
Neuropharmacology
26:
75-78,
1987[Medline].
26.
Obál, F., Jr.,
P. Alföldi,
A. B. Cady,
L. Johannsen,
G. Sary,
and
J. M. Krueger.
Growth hormone-releasing factor enhances sleep in rats and rabbits.
Am. J. Physiol.
255 (Regulatory Integrative Comp. Physiol. 24):
R310-R316,
1988
27.
Obál, F., Jr.,
R. Floyd,
L. Kapás,
B. Bodosi,
and
J. M. Krueger.
Effects of systemic GHRH on sleep in intact and hypophysectomized rats.
Am. J. Physiol.
270 (Endocrinol. Metab. 33):
E230-E237,
1996
28.
Obál, F., Jr.,
L. Payne,
L. Kapás,
M. Opp,
P. Alföldi,
and
J. M. Krueger.
Growth hormone releasing hormone (GHRH) in sleep regulation (Abstract).
Sleep Res.
20A:
192,
1991.
29.
Obál, F., Jr.,
L. Payne,
L. Kapás,
M. Opp,
and
J. M. Krueger.
Inhibition of growth hormone-releasing factor suppresses both sleep and growth hormone secretion in the rat.
Brain Res.
557:
149-153,
1991[Medline].
30.
Obál, F., Jr.,
L. Payne,
M. Opp,
P. Alföldi,
L. Kapás,
and
J. M. Krueger.
Growth hormone-releasing hormone antibodies suppress sleep and prevent enhancement of sleep after sleep deprivation.
Am. J. Physiol.
263 (Regulatory Integrative Comp. Physiol. 32):
R1078-R1085,
1992
31.
Ocampo-Lim, B.,
W. Guo,
R. DeMott Friberg,
A. L. Barkan,
and
C. A. Jaffe.
Nocturnal growth hormone (GH) secretion is eliminated by infusion of GH-releasing hormone antagonist.
J. Clin. Endocrinol. Metab.
81:
4396-4399,
1996[Abstract].
32.
Rechtschaffen, A.,
and
A. Kales.
A Manual of Standardized Terminology, Techniques and Scoring System for Sleep Stages of Human Subjects. Washington, DC: Government Printing Office, 1968.
33.
Smith, R. G.,
S. S. Pong,
G. Hickey,
T. Jacks,
K. Cheng,
R. Leonard,
C. J. Cohen,
J. P. Arena,
C. H. Chang,
J. Drisko,
M. Wyvratt,
M. Fisher,
R. Nargund,
and
A. Patchett.
Modulation of pulsatile GH release through a novel receptor in the hypothalamus and pituitary gland.
In: Recent Progress in Hormone Research. Bethesda, MD: The Endocrine Society, 1996, p. 261-286.
34.
Steiger, A.,
R. Frieboes,
M. Colla-Müller,
J. Guldner,
H. Murck,
T. Schier,
and
F. Holsboer.
Opposite effects of growth hormone-releasing hormone and somatostatin on the sleep EEG in elderly controls (Abstract).
Pharmacopsychiatry
28:
218,
1995.
35.
Steiger, A.,
J. Guldner,
U. Hemmeter,
B. Rothe,
K. Wiedemann,
and
F. Holsboer.
Effects of growth hormone-releasing hormone and somatostatin on sleep EEG and nocturnal hormone secretion in male controls.
Neuroendocrinology
56:
566-573,
1992[Medline].
36.
Takahashi, Y.,
D. M. Kipnis,
and
W. H. Daughaday.
Growth hormone secretion during sleep.
J. Clin. Invest.
47:
2079-2090,
1968[Medline].
37.
Van Cauter, E.
Quantitative methods for the analysis of circadian and episodic hormone fluctuations.
In: Human Pituitary Hormones: Circadian and Episodic Variations, edited by E. Van Cauter,
and G. Copinschi. The Hague: Martinus Nyhoff, 1981, p. 1-25.
38.
Van Cauter, E.
Estimating false-positive and false-negative errors in analyses of hormonal pulsatility.
Am. J. Physiol.
254 (Endocrinol. Metab. 17):
E786-E794,
1988
39.
Van Cauter, E.,
M. Kerkhofs,
A. Caufriez,
A. Van Onderbergen,
M. O. Thorner,
and
G. Copinschi.
A quantitative estimation of GH secretion in normal man: reproducibility and relation to sleep and time of day.
J. Clin. Endocrinol. Metab.
74:
1441-1450,
1992[Abstract].
40.
Van Cauter, E.,
L. Plat,
M. Scharf,
R. Leproult,
S. Cespedes,
M. L'Hermite-Balériaux,
and
G. Copinschi.
Simultaneous stimulation of slow-wave sleep and growth hormone secretion by gamma-hydroxybutyrate in normal young men.
J. Clin. Invest.
100:
745-753,
1997
41.
Wu, D.,
C. Chen,
J. Zhang,
C. Bowers,
and
I. Clarke.
The effects of GH-releasing peptide-6 (GHRP-6) and GHRP-2 on intracellular adenosine 3',5'-monophosphate (cAMP) levels and GH secretion in ovine and rat somatotrophs.
J. Endocrinol.
148:
197-205,
1996[Abstract].