Blockade of endogenous growth hormone-releasing hormone
receptors dissociates nocturnal growth hormone secretion and
Stacy K Jessup1, Beth A Malow2, Kathleen V Symons3and Ariel L Barkan1,3
1Department of Internal Medicine, Division of Endocrinology and Metabolism, University of Michigan Medical Center,2Department of Neurology,
University of Michigan Medical Center, Ann Arbor, Michigan, USA and3Department of Veterans Affairs Medical Center, Ann Arbor,
Michigan 48105, USA
(Correspondence should be addressed to A Barkan; Email: email@example.com)
Objectives: A temporal association between non-rapid eye movement (NREM) sleep stages 3 and 4 and
nocturnal augmentation of GH release was found long ago, yet the precise mechanism for this associ-
ation has not been identified. It has been shown, however that pulsatile GHRH administration
increases both slow-wave sleep (SWS) and GH. Based on these data, a role for GHRH as an inducer
of SWS was proposed. To test this hypothesis, we have performed the corollary experiment whereby
the action of endogenous GHRH has been antagonized.
Design: Healthy men (20–33 years old) had an infusion of GHRH antagonist ((N-Ac-Tyr1, D-Arg2)
GHRH-29 (NH2)) or saline for a 12-h period, between 2100 and 0900h. An i.v. bolus of GHRH
was given at 0700h and GH samples were drawn from 0700 to 0900h to document the efficacy
of GH suppression by the GHRH antagonist.
Methods: A limited montage sleep study was recorded from 2300 to 0700h during each admission.
Plasma GH concentrations were analyzed by the use of a sensitive chemiluminometric assay.
Results: Effectiveness of the GHRH antagonist was validated in all subjects by demonstrating
93^1.8% (P ¼ 0.012) suppression of GH response to a GHRH bolus. Polysomnography demonstrated
that the percentage of SWS was not different when saline and GHRH antagonist nights were com-
pared (P ¼ 0.607); other quantifiable sleep parameters were also unchanged.
Conclusions: We conclude that endogenous GHRH is indispensable for the nocturnal augmentation of
GH secretion, but that it is unlikely to participate in the genesis of SWS.
European Journal of Endocrinology 151 561–566
Sleep architecture is organized into rapid eye movement
(REM) sleep and four stages of non-REM (NREM) sleep
based on polysomnography. Based on the temporal
association between the nocturnal rise of growth hor-
mone (GH) and NREM stages 3 and 4 slow-wave
sleep (SWS), a search for a common denominator was
initiated. In a study that measured GH every 30s
during sleep, it was found that maximal GH release
occurs after a 4.5-min time delay from the onset of
SWS (1). In men, 70% of GH pulses occur together
with SWS (2). Administration of gamma-hydroxybuty-
rate to humans augmented both SWS and nocturnal
GH release (3). The interrelationships between the
somatotropic axis and sleep architecture remain to be
elucidated. The associations between SWS and GH
release may be correlative, or even causative. One possi-
bility is that the mechanisms leading to the events of
SWS promote GH release. This is supported by the
time course of the two phenomena, whereby SWS actu-
ally precedes the GH release (1). A reverse possibility,
whereby the hormonal components of the nocturnal
GH peak participate (or even cause) in the genesis of
SWS is also theoretically possible. Based on the latter
possibility, a search into potential roles of different hor-
monal components of the nocturnal GH surge as the
inducers of SWS has been launched. When exogenous
GH was given to humans, SWS was unaffected or actu-
ally decreased (4, 5). Somatostatin also did not affect
sleep architecture when given to young healthy men
(6). A synthetic ghrelin agonist, GHRP-2 given as dis-
crete boluses did not affect SWS (7). Another ghrelin
agonist, GHRP-6, actually prolonged stage 2 of sleep
(8), but SWS was not affected.
The nocturnal GH pulse is thought to be secondary
release, and it has been shown that GHRH antagonist
European Journal of Endocrinology (2004) 151 561–566 ISSN 0804-4643
q 2004 Society of the European Journal of EndocrinologyOnline version via http://www.eje.org
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Received 21 April 2004
Accepted 19 August 2004
S K Jessup and others
EUROPEAN JOURNAL OF ENDOCRINOLOGY (2004) 151