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Transcript
PHYSIOLOGICAL REVIEWS
Vol. 79, No. 2, April 1999
Printed in U.S.A.
Neuroendocrine Control of Growth Hormone Secretion
EUGENIO E. MÜLLER, VITTORIO LOCATELLI, AND DANIELA COCCHI
Department of Pharmacology, Chemotherapy, and Toxicology, University of Milan, Milan; and
Department of Biomedical and Biotechnology Sciences, University of Brescia, Brescia, Italy
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I. Introduction
II. Growth Hormone Secretion Pattern
A. Sex
B. Age-related growth hormone secretion
C. Sleep
III. Hypophysiotropic Hormones
A. Growth hormone-releasing hormone
B. Somatostatin
IV. Growth Hormone-Releasing Peptides
A. Structure-activity relationships
B. Nonpeptidyl growth hormone secretagogues
C. Site(s) and mechanism of action
D. Human studies
E. Effects on other pituitary hormones
F. Conclusions
V. Brain Messengers in the Control of Growth Hormone Secretion
A. General background
B. Characteristic features
C. Main locations of neurotransmitter and neuropeptide pathways
D. Neurotransmitters
E. Growth hormone-releasing and -inhibiting neuropeptides
VI. Pheripheral Hormonal and Metabolic Signals or Conditions Modulating Growth Hormone Secretion
A. Hormones
B. Metabolic signals
C. Physiopathology of nutritional excess or deficiency
VII. Growth Hormone Autofeedback Mechanism
A. Growth hormone
B. Insulin-like growth factor I
VIII. Concluding Remarks
Müller, Eugenio E., Vittorio Locatelli, and Daniela Cocchi. Neuroendocrine Control of Growth Hormone
Secretion. Physiol. Rev. 79: 511– 607, 1999.—The secretion of growth hormone (GH) is regulated through a complex
neuroendocrine control system, especially by the functional interplay of two hypothalamic hypophysiotropic
hormones, GH-releasing hormone (GHRH) and somatostatin (SS), exerting stimulatory and inhibitory influences,
respectively, on the somatotrope. The two hypothalamic neurohormones are subject to modulation by a host of
neurotransmitters, especially the noradrenergic and cholinergic ones and other hypothalamic neuropeptides, and are
the final mediators of metabolic, endocrine, neural, and immune influences for the secretion of GH. Since the
identification of the GHRH peptide, recombinant DNA procedures have been used to characterize the corresponding
cDNA and to clone GHRH receptor isoforms in rodent and human pituitaries. Parallel to research into the effects of
SS and its analogs on endocrine and exocrine secretions, investigations into their mechanism of action have led to
the discovery of five separate SS receptor genes encoding a family of G protein-coupled SS receptors, which are
widely expressed in the pituitary, brain, and the periphery, and to the synthesis of analogs with subtype specificity.
Better understanding of the function of GHRH, SS, and their receptors and, hence, of neural regulation of GH
secretion in health and disease has been achieved with the discovery of a new class of fairly specific, orally active,
small peptides and their congeners, the GH-releasing peptides, acting on specific, ubiquitous seven-transmembrane
domain receptors, whose natural ligands are not yet known.
0031-9333/99 $15.00 Copyright © 1999 the American Physiological Society
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MÜLLER, LOCATELLI, AND COCCHI
I. INTRODUCTION
II. GROWTH HORMONE SECRETION PATTERN
The secretion of GH is pulsatile in all species studied
so far, with its pattern not dissimilar in humans and male
rodents. In the former, an ultrasensitive immunoradiometric assay (IRMA) (limit of detection, 20 ng/l) given to
healthy men and women showed an ultradian rhythm
with an interpulse frequency of ;2 h (1101), which compared favorably with an interpulse frequency of ;3 h in
the male rat (1014) and plasma GH detectable at all time
points. In these subjects, GH levels ranged over three
orders of magnitude in both sexes.
Women of reproductive age had significantly higher
overall GH levels, a higher pulse amplitude, and a higher
baseline, but the pulse frequency was the same as in men
(mean secretion rates: 327 mg/24 h for men and 392 mg/24
h for women; Ref. 1101). These figures are ;50% lower
than previously assumed (see Ref. 1030). A new ultrasensitive GH chemiluminescence (CL) assay (limit of detec-
tion, 5 ng/l) detects serum GH concentrations in all samples collected at 10-min intervals for 24 h.
The Cluster method to estimate GH pulsatility and
deconvolution analysis, which simultaneously resolves
the endogenous hormone secretory rate and clearance
kinetics (1063), showed that pulsatile GH secretion continued in all subjects in the awake and fed state, despite
undetectable serum GH in daytime samples analyzed by a
conventional IRMA, run for comparison. Interestingly, the
CL assay also revealed for the first time a low rate of basal
(constitutive) GH secretion mixed with pulsatile and nyctohemeral variations (508).
Further studies were then done in healthy lean and
obese subjects aimed at ascertaining how age, steroid sex
hormones, and obesity, singly or jointly, influence the
basal and pulsatile modes of GH release. Basal and pulsatile GH release were found to be regulated differently
by adiposity and steroid hormones. Thus basal GH secretion rates were negatively correlated with the circulating
estrogen (E2) concentration and with an interactive effect
of age and body fat, whereas the GH secretory burst mass
was strongly positively related to serum testosterone concentrations.
Concerning the biological consequences of GH secretion, basal and pulsatile GH release may influence serum
insulin-like growth factor I (IGF-I), its main binding protein (BP), i.e., IGFBP-3, and IGFBP-1 in distinct ways
(1064). In a study in healthy men, IGFBP-3 correlated
negatively to basal GH secretion, whereas IGFBP-1 concentrations were positively correlated with this measure.
Measurements of serum IGF-I concentrations indicated
that pulsatile GH release was strongly positively correlated with the mean serum IGF-I level. Conversely, there
was no association between basal GH release rates and
serum IGF-I levels (1064). This observation is consistent
with the theory that a pulsatile GH signal is important in
acting on one or more major target tissues (e.g., the liver)
to stimulate IGF-I production in the healthy human. These
findings have major implications for the evaluation of GH
control and secretion in different experimental and clinical conditions.
Present knowledge thus indicates that the secretory
pattern of GH depends on the interaction between GHRH
and SS at the somatotroph level, although we cannot
overlook the existence of anatomic connections and functional peptide interactions within the hypothalamus (see
sect. IIIA3) and the contribution of a still elusive endogenous GHRP system (see sect. IV).
The basis of the pulsatile release of GH, however,
remains unknown. A host of nutritional, body composition, metabolic, and age-related sex steroid mechanisms,
adrenal glucocorticoids, thyroid hormones, and renal and
hepatic functions all govern pulsatile release in adults
(see sect. II, A–C), but spontaneous elevations in GH secretion are more likely to result from the ability of hypotha-
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The secretion of somatotrophin, or growth hormone
(GH), like other anterior pituitary (AP) hormones, is regulated through a complex neuroendocrine control system
that comprises two main hypothalamic regulators, GHreleasing hormone (GHRH) and somatostatin (SRIH or
SS), exerting stimulatory and inhibitory influences, respectively, on the somatotrope cell. Both GHRH and SS,
which are subject to modulation by other hypothalamic
peptides and by complex networks of neurotransmitter
neurons, are the final mediators of metabolic, endocrine,
neural, and immune influences for GH secretion in the
pituitary.
In the last decade, the rather static scenario of GH
control has been shaken by a host of advances, some
resulting from molecular biology techniques. Of particular
interest is cloning of the GHRH receptor isoforms in the
rat, mouse, and human pituitary; discovery of distinct
genes encoding a family of structurally related G proteincoupled SS receptors in brain and the pituitary and synthesis of new SS analogs with subtype specificity; identification of a novel class of fairly specific, orally active,
hexa-hepta peptides, the GH-releasing peptides (GHRP)
and their congeners, whose GH-releasing activity is
greater than GHRH; better insight into the neurotransmitter control of GH; and the involvement of somatotropic
dysfunction in a host of diseases and in the catabolic
processes related to aging.
This review updates and focuses on aspects of the
neural control of GH secretion, especially in the light of
these advances. For comprehensive surveys of GH secretory control, the reader is referred to Frohman et al. (377),
Müller (749), and Cronin and Thorner (274).
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NEUROENDOCRINE CONTROL OF GROWTH HORMONE SECRETION
GHRH pulse, ;30% were completely dissociated (378).
This variability was also seen in SS measurements, in the
sheep, where pulses were not necessarily asynchronous
with those of GHRH and did not correlate with GH
troughs, nor SS troughs with GH pulses. In addition,
active immunization of rams against SS did not change
basal and pulsatile GH secretion, whereas in the antiGHRH group, plasma GH levels were very low, and the
amplitude of GH pulses was strikingly reduced (652). The
redundant GHRH and SS pulsatility in the portal blood
may reflect neuropeptide actions beyond pure GH release,
e.g., trophic effects on the target somatotrophs (895).
It must be recalled, in addition, that the simple rat
GHRH-SS model ignores all other alleged hypophysiotrophic factors, including the endogenous GHRP system (see
sect. IV), additional modulators such as pituitary GHRH
and SS receptors, feedback effects of GH and IGF-I, and
other target gland hormones.
In humans, the neuroendocrine control of pulsatile
GH secretion is also poorly understood. Because portal
blood cannot be sampled directly in humans, most of our
understanding of the regulation of GH secretion comes
from either indirect human studies or extrapolation of
animal data. In healthy young men, a single dose of a
competitive GHRH antagonist blocked 75% of nocturnal
GH pulsatility (521), supporting the hypothesis that pulsatile GH secretion in humans is driven by GHRH. The
persistence of pulsatile GH secretion in normal and GHdeficient subjects during continuous GHRH infusion (473,
1056) and the ability of exogenous GHRH to release GH in
the face of grossly elevated GHRH levels in the ectopic
GHRH syndrome (74) are also in keeping with this suggestion.
Periodic falls in SS secretion might account for the
persistence of pulsatile GH secretion in the above conditions, a proposal in line with GH secretory profiles determined by deconvolution analysis (460). Plasma GH secretory patterns were measured in normal adult men at
baseline and during submaximal intravenous boluses of
GHRH every 2 h for 6 days (522). No evidence was found
of either acute or chronic desensitization; GH responses
were seen at every GHRH bolus, and circadian patterns of
GH secretion were similar at baseline and during the
GHRH schedule, with maxima occurring during the early
nightime hours. This pattern was consistent with a model
for the ultradian secretion of GH in which circadian SS
secretion (reduction at night?) is superimposed on more
rapid GHRH pulses.
A. Sex
Sex-related differences in GH control by GHRH and
SS have been found particularly in the rat. They include
different 1) responsiveness to exogenously administered
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lamic neuroendocrine cells themselves to promote and sustain phasic bursts of action potentials (34). Basal GH release
may also be subject to neurophysiological regulation; slow
removal of a pool of GH in plasma from trapping with a
GH-binding protein seems less likely (508).
Hypothalamic GHRH and SS functions both appear
essential for pulsatile secretion. In male rats, anti-GHRH
serum inhibited spontaneous GH pulses (1090), reduced
growth rate (207), and suppressed stimulated GH secretion (207, 548). Initial studies in male rats utilizing an
anti-SS serum bolus injection showed that pulsatile GH
secretion was preserved despite an increase in basal GH
levels (350). However, when a highly potent anti-SS serum
was infused for 6 h, it did inhibit pulsatile GH secretion
(375). The most likely explanation for the different effects
of anti-SS serum bolus injection versus continuous infusion is that the latter but not the former penetrates the
region of the arcuate nucleus (ARC), where the inhibitory
effects of SS on GHRH secretion occur (see sect. IIIA3).
Supporting this view, electrolytic lesions in the medial preoptic area (MPOA) or anterolateral hypothalamic
deafferentiation in male rats, two techniques which eliminate SS immunostaining in the median eminence (ME),
resulted in elevated plasma GH levels and no pulsatile GH
secretion. Under these experimental conditions, basal
and K1-stimulated GHRH release from the hypothalamic
ME-ARC complex in vitro was significantly increased,
although the hypothalamic GHRH content was decreased,
suggesting an increased turnover of the peptide (548).
Overall, these results suggest that SS in the hypothalamus plays a tonic inhibitory role in the regulation of
GHRH release and that GH hypersecretion in lesioned rats
is due to a combination of secretion changes of both SS
and GHRH. They are in line with the general model proposed by Tannenbaum and Ling (1013), in which GHRH
release during troughs in a sinusoidal pattern of SS release induces the episodic release of GH, and the rise in
SS suppresses baseline release. Direct measurement of
GHRH and SS in the rat portal blood would validate this
view by showing that each GH secretion episode started
by pulsatile release of GHRH, which is preceded by or
concurrent with a moderate reduction of the SS tone
(853). These portal blood measurements in the rat, however, would require confirmation, since other studies have
not been able to maintain GH pulsatility under the conditions reported by Plotsky and Vale (853) (see Ref. 895 for
references). Moreover, this model would explain patterns
of secretion in the male rat. Female rats show much more
continuous irregular GH secretion and much more regular
responses to GHRH (248, see also sect. IIA).
The proposed model of SS-GHRH interactions cannot
be extrapolated to all the animal species so far investigated. In the sheep, portal GHRH and SS levels suggest
regulation is more complex, although the majority of GH
pulses coincided with or occurred immediately after a
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MÜLLER, LOCATELLI, AND COCCHI
rat the pulsatile pattern of GH is optimal for growth,
irrespective of whether this pattern is achieved by a stimulator or inhibitor of endogenous GH secretion. The pulsatile delivery of SS would be vital in the generation of GH
pulsatility not only for its opposing action to GHRH but
also because it enables GHRH to be effective, because
unopposed exposure to the releasing hormone leads to
downregulation of GH responses.
Sex differences in the pattern of GH secretion are not
so clear-cut in humans, but there are noticeable quantitative differences, with serum GH concentrations being definitely higher in women than in men (221, 474, 1101). In a
small group of healthy middle-aged men and premenopausal women, highly sensitive immunofluorometric assays (sensitivity 0.011 mg/l) and blood sampling at 10-min
intervals showed the 24-h GH secretion was three times
higher in the women, the GH secretory episodes were
larger and more prolonged, more GH was secreted per
burst, and maximal plasma GH concentrations were
higher than in men. The frequency of pulses, timing during
the day/night estimates of baseline GH secretion, and the
endogenous clearance rates for GH were the same in both
sexes (1059) (Fig. 1).
A sex-related difference was also found in the serial
regularity of GH release in a tissue series (848). Application of novel regularity statistics (approximate entropy)
showed that the serial regularity of GH release was lower
in female humans and rats (847).
Although E2 is an obvious candidate for the mechanism that increases the mass of GH secreted per burst in
women, it is not yet known at what level(s) in the GH axis
it may act. Another question is whether the much higher
daily GH output in women has biological significance for
GH action, and what action this might have in middle age.
In GH-deficient men and women, small but frequent intravenous boluses and continuous intravenous infusion of
GH were equally effective in increasing circulating IGF-I
(532), which implies that women do not secrete more GH
than men simply to maintain the same IGF-I levels.
B. Age-Related Growth Hormone Secretion
The 24-h pattern of spontaneous GH release changes
with age in experimental animals and humans. Plasma GH
in the fetus is elevated compared with postnatal levels in
a number of species, including humans and sheep (431).
The rat, an altricial species, which is an animal model for
the midgestational hypothalamic differentiation in humans, has a rise in plasma GH immediately before birth
and a decline to near adult levels by ;18 –20 days postnatally (1078). This is coupled with striking changes in
pituitary susceptibility to GHRH, which at doses of 1–50
ng/100 g given subcutaneously in 10-day-old pups induces
clear-cut plasma GH rises. However, in 25-day-old pups,
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GHRH (248, 1085), 2) endogenous content of hypothalamic immunoreactive (IR) GHRH and SS (386), 3) hypothalamic mRNA levels of SS (238, 1044) and GHRH (40,
653), 4) pituitary GHRH receptor expression (799), and 5)
GH autofeedback mechanism(s) (169, see also sects.
IIIA8B and VII). Particularly noteworthy was the higher SS
mRNA content in the periventricular nucleus (PeVN) of
male rats than in proestrus females and the finding that in
castrated males administration of testosterone prevented
the significant reduction in SS mRNA after surgery (238).
It can be inferred from these results that were the
amount of SS available for release from the ME, sex
differences in GH secretory patterns (see also below) and
perhaps also sex differences in growth rates might be
partially attributable to a difference in the ability of PeVN
SS neurons to produce the neuropeptide.
In male and female rats, passive immunization with
specific antisera to both peptides was used to assess the
physiological roles of GHRH and SS in the dimorphic
secretion (802). An acute dose of an anti-SS serum to
males raised the GH nadir, as expected, but did not alter
other parameters of GH secretion, whereas in females it
markedly increased plasma GH levels at all time points of
the 6-h sampling period and there was, in addition, a
significant increase in GH peak amplitude, GH nadir, and
overall mean 6-h plasma GH levels. Anti-GHRH serum had
no effect on the GH nadir in males but markedly raised
the GH nadir in females.
These findings led to the conclusion that the secretory pattern of SS undoubtedly plays an important role in
this sexual dimorphism, the female pattern of SS secretion possibly being continuous rather than cyclical, its
level intermediate between the peak and troughs of SS
release suggested for males. The episodic GHRH bursting,
which does not appear to follow a specific rhythm, as in
the male, superimposed on the fairly continous SS release, would cause the erratic GH secretory profile,
present in the peripheral plasma of female rats.
This pattern of low-amplitude GH release is reminiscent of that after continuous GH infusion and may be
more effective in inducing specific biological changes,
such as GH-binding protein in plasma and hepatic cytochrome P-450-containing enzymes (955). For the role of
sex steroids in imprinting the sexually differentiated GH
secretory pattern, see also section IIIA8B.
The pattern of GH secretion in rodents seems to be of
considerable importance for optimal growth. In female
rats, GHRH pulses delivered every 3 h changed the pattern of pituitary GH release toward that of the male and
stimulated body growth, whereas continuous infusions of
GHRH were much less effective (248). Interestingly, a
similar pulsatile GH secretory pattern was achieved with
the intermittent infusion of SS, which also stimulated
body weight gain and increased pituitary GH stores (250).
This strongly supports the proposal (246, 249) that in the
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NEUROENDOCRINE CONTROL OF GROWTH HORMONE SECRETION
515
the dose of 500 ng/100 g given subcutaneoulsy has this
effect but not lower doses (205) (see also sect. IIIA9).
Moreover, in rat pups but not in young adult rats, an in
vivo and ex vivo 5-day GHRH treatment stimulated pituitary GH biosynthesis (205, 272). Consonant with these
results, in monolayer cultures of rat pituitary cells, the
stimulatory effects of GHRH and dibutyryl cAMP on GH
secretion were inversely related to age (281).
Although differential developmental regulation of pituitary GHRH receptor gene expression is very likely
involved in these events (572), maturational changes in
the somatotroph responsiveness to SS may contribute to
the pattern of circulating GH levels characteristic of early
development. In fact, pituitaries from newborn rats are
relatively resistant to the GH-suppressive effect of SS, and
sensitivity increases with age (281, 889), although in rats
brain SS mRNA is detectable by day 7 of embryonic life
(1130a) and IR-SS has been detected in the fetal rat as
early as 18.5 days of gestation (1130a).
In the human fetus, plasma GH peaks at mid-gestation, then GH levels fall in the third trimester and into the
neonatal period (540). Excessive GHRH or deficient SS
release from and function in the fetal hypothalamus, excessive somatotroph responsiveness to GHRH, deficient
negative feedback control by IGF-I, or stimulation of GH
secretion by paracrine factors may account for GH hypersecretion at mid-gestation.
Functional hypersomatotropism is still present in
small for gestational age (SGA) newborn twins as revealed by higher baseline GH levels and stronger GH
responses to GHRH than in appropriate gestational age
(AGA) twins (302, 633). Interestingly, in these studies
mean serum IGF-I was higher in SGA than in the AGA
newborns, which would rule out any underlying effect of
a defective IGF-I feedback mechanism or functional GH
resistance (see also sect. VI). Growth hormone-releasing
hormone appears in the rat and human hypothalamus by
18 –20 days and 18 –22 wk of gestation, respectively (292,
514, 748), and at late gestation and mid-gestation, respectively, rat and human fetal pituitary cells respond in vitro
to GHRH or SS by increasing or reducing GH secretion
(559, 748). Miller et al. (725) studied changes occurring
after birth in pulsatile GH release of male and female term
infants. There were significant differences between infants studied at ;28 h and later at ;80 h postnatally.
Spontaneous pulsatile release was present in all infants;
within the first 1–2 days of life, GH release was enhanced
through the amplitude and frequency of pulses, then as
the infant matured, there was a decrease in GH frequency,
amplitude, and nadir. The decrease in GH levels in older
infants very likely resulted from decreased pituitary secretion, secondary to enhanced IGF-I hypothalamo-pituitary feedback or, as shown in the postnatal rat, to
changes in the pituitary sensitivity to SS or GHRH.
Considering that rats are born at the equivalent of 100
gestational days in the human (559), the ontogeny of
neuroendocrine control and GH secretion in the human is
chronologically consistent with that in the rat.
In initial studies of the 24-h pattern of spontaneous
GH secretion, a small sample of prepubertal children
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FIG. 1. Profiles of 24-h serum growth
hormone (GH) in human female (top panels)
and male (bottom panels) subjects. Left panels indicate measured serum GH concentrations over time and curve fitted by deconvolution analysis. Right panels depict GH
secretory rate calculated from this analysis.
[From van den Bergh et al. (1059); Copyright
The Endocrine Society.]
516
MÜLLER, LOCATELLI, AND COCCHI
involved in the control of GH secretion in humans is not
so clear. To explain these discrepant findings, it would
seem, however, that testosterone itself has little or no
effect and that it is the estradiol derived from aromatization of testosterone that increases GH secretion (1065).
This is suggested by the potent action of physiological
amounts of E2 in stimulating pulsatile GH secretion and
the fact that nonsteroidal anti-E2 inhibits it (see Ref. 557
for review).
However, apart from conversion to E2, a role for
androgens cannot be dismissed. In prepubertal boys with
constitutional delayed growth, both testosterone and the
nonaromatizable androgen oxandrolone raised the daily
GH secretory rate by specifically increasing the total mass
of GH released per pulse, with no effect on GH burst
frequency or the half-life of endogenous GH (1045). Supporting these findings, an increase in GH in response to
GHRH was suggested in one study of boys with constitutional growth delay treated with oxandrolone for 2 mo
(633), and increased plasma IGF-I concentrations have
also been reported (980). In boys with isolated hypogonadotropic hypogonadism, progressively higher testosterone doses, which affected plasma E2 levels, increased the
GH secretory burst number and amplitude and GH response to combined GHRH and arginine (427).
The effect of endogenous estradiol concentrations on
total and pulsatile GH release in humans also emerges
from a study that evaluated the separate and combined
effects of age and sex in young adults and aged women
and men (474). The integrated GH concentration was
significantly higher in women than men and in the young
than the old. A major finding was that estradiol but not
testosterone concentrations correlated with indices of
total and pulsatile GH release, i.e., integrated GH concentration (IGHC), pulse amplitude, number of large pulses,
and fraction of GH secreted per pulse (FGHP) so that on
removing the variability due to free estradiol, neither sex
nor age influenced IGHC or mean pulse amplitude. The
finding, however, that aging still affected the residual
variability, i.e., large pulses and FGHP, indicated that
other factors in addition to E2 contribute.
That aging lowers GH secretion in mammals is almost a tenet of neuroendocrinology (754). In male and
female rats, the amplitude of the GH pulses is significantly
smaller, and in male rats, this results in lower mean
secretion of GH to about one-third that in young rats. In
both female and male old rats, the frequency of GH pulses
does not change with age (970). In humans, the mean
concentration of GH over 24 h is similar after the fourth
decade of life to that in prepubertal children and is about
one-quarter of that in pubertal youngsters (1120). In addition, approximate entropy analysis in healthy aging men
revealed a progressive increase in the entropy of 24-h GH
profiles, which signifies less orderliness or regularity of
GH release with age (1064).
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lacked waking GH peaks and secreted GH only during
sleep (356). This observation, however, contrasted with
many subsequent reports of GH peaks during waking
hours as well as during sleep (726, 978). Deconvolution
analysis depicted the pattern of GH secretory events subserving the changes in serum GH concentrations in normal boys at various stages of puberty and young adulthood (660). Late pubertal boys secreted more GH per 24 h
than boys in any other pubertal group and triple that of
prepubertal boys (1,800 vs. 600 mg/24 h). After normalization of GH secretion for body surface area, late pubertal
boys still had higher GH release than any other pubertal
group. The primary neuroendocrine alteration responsible for the enhanced GH secretion was an increased mass
of GH released per secretory burst, with no change in GH
burst frequency, burst duration, or serum GH half-life.
In girls, GH responses to GHRH did not change
throughout pubertal development, and the responses in
boys at midpuberty were somewhat lower than either
prepubertal or adult men (395). It cannot be excluded,
however, that periodic release of SS might have obscured
the genuine GH response to GHRH at puberty.
In young adults, total GH secretion was almost onehalf that in late pubertal boys (900 mg/24 h), but the 24-h
burst frequency was the same. This figure compares favorably with reports based on other techniques (574, 694).
However, absolute GH secretion rates estimated by deconvolution analysis are dependent on the specific assay
system, and the values reported here tend to overestimate
GH secretion compared with the more recent and sensitive assays. Studies in which a large number of prepubertal and pubertal girls and boys were evaluated for GH
secretion using the Pulsar program (713) found no correlation between GH secretion and age in the prepubertal
children, supporting the proposal that gonadal hormones
are not important for the regulation of growth and GH
secretion during childhood, whereas at puberty there was
a marked increase in GH secretion rates in both sexes
(23). However, the change was sex specific, since the
increase in GH secretion rate was an early event (stages
2– 4) in puberty for girls but a late event (stages 3– 4) in
puberty for boys, parallel to the height velocity curves of
girls and boys in puberty (1019). Shortly after cessation of
linear growth in boys, the overall peripheral GH pulse
pattern returned toward prepubertal levels so that the
concentration profiles in young men were remarkably
similar to those in prepubertal boys despite the rising
testosterone concentrations (661).
The gonadal hormones, particularly circulating androgens, appear to play a central role in the GH pulse
amplitude changes (619, 661). However, androgens alone
do not seem to account entirely for the pubertal increase
in GH pulse amplitude in humans, in view of the pattern in
young men (see above), and although ample data in rats
support it (see Ref. 970), the evidence that testosterone is
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NEUROENDOCRINE CONTROL OF GROWTH HORMONE SECRETION
C. Sleep
It has long been recognized that GH release increases
during the night (498, 1003) and nocturnal blood sampling
for GH has been proposed as a diagnostic alternative to
pharmacological testing of GH secretory capacity (470,
560). Early studies indicated a consistent relationship
between slow-wave sleep (SWS) and GH secretion during
early sleep and later during the night (503). Subsequent
studies, with 30-s sampling of plasma GH during sleep,
showed mean GH concentrations and secretory rates
were significantly higher during stage 3 and 4 sleep than
during stages 1 and 2 and rapid-eye-movement (REM)
sleep. Growth hormone secretory rates and peripheral GH
concentrations were maximally correlated with sleep
stage in a fashion suggesting that GH release is maximal
within minutes of the onset of stage 3 or 4 sleep (486). The
temporal correlation between pituitary GH secretion and
SWS is consistent with a model in which altered cortical
activity is transmitted through GHRH and SS centers to
the hypothalamus, and further stimulation by these centers is conveyed to the pituitary.
These findings supported the concept that the daily
GH secretory output is dependent on the quality and
occurrence of sleep and were consistent with results of
sleep reentry and SWS deprivation studies (923). However, a series of reports, e.g., pronounced nocturnal GH
surges divorced from the presence of SWS (526), selective
SW stage deprivation failing to suppress or delay the
sleep-onset GH pulse (126), temporal disconnection between the effect of GHRH on SWS and on GH release
(984), challenged this concept and suggested that GH and
SWS are not causally related but are two independent
outputs of a common hypothalamic GHRH mechanism.
However, studies in human African trypanosomiasis
(sleeping sickness) have shown that the association between GH secretion and SWS persisted despite disrupted
circadian rhythms (871), further suggesting that sleep and
stimulation of GH secretion are outputs of a common
mechanism.
A careful study in healthy young men examined how
normal and delayed sleep and time of day affected pulsatile GH secretion, analyzed by the deconvolution method
and blood sampling at 15-min intervals (1054). During
normal waking hours, the GH secretory rate was similar
in the evening and morning, double during wakefulness at
times of habitual sleep, and tripled during sleep even
when it was delayed until 0400 h. Interestingly, the
amount of GH secreted in response to sleep onset was
closely correlated with the levels during wakefulness,
with the hourly GH output in these young men being two
to three times greater when asleep than when awake.
Although these results demonstrated that SWS facilitates GH secretion, they did not show that SWS is obligatory for nocturnal GH secretion to occur. Approximately
one-third of the nocturnal GH pulses occurred in the
absence of SWS, and approximately one-third of the SWS
periods were not associated with increased GH secretion.
Thus circadian timing, regardless of sleep, influences somatotrophic activity, although under normal conditions
sleep occurs at the time of maximal propensity for GH
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These findings complement earlier reports of substantial changes in GH secretion in the aging human (169).
Despite evidence of a preserved pituitary GH pool (see
sect. VB3) and the strong belief that, as in old rodents, the
primary disturbance is hypothalamic, a low GH response
has been clearly shown to many secretagogues, including
GHRH (406, 478). In agreement with the GH hyposecretion, decreased plasma IGF-I levels have also been found
(see sect. IVD1). However, investigations on this topic are
not unanimous in reporting a decline in GH release with
age, and it has been suggested that a significant decline
occurs only in women (see above and Ref. 474). In a study
in 142 healthy elderly people of both sexes, aged 60 –90 yr,
basal GH levels showed a very weak positive correlation
with age, whereas IGF-I showed a highly significant negative correlation; basal GH and IGF-I did not correlate
with each other (518).
It is likely that other counfounding variables, such as
institutionalization, body mass, nutritional status, and sex
steroid hormone concentrations, exert either independent
or combined effects on total and pulsatile GH release. To
control some of the confounding variables, a group of
normal adult males was studied using deconvolution analysis to clarify the specific features of GH secretion and
clearance related to age and adiposity, alone or jointly
(509). Age was a major negative statistical determinant of
GH burst frequency and endogenous GH half-life; body
mass index (BMI), an indicator of relative adiposity, correlated negatively with GH half-life and GH secretory
burst amplitude. Age and BMI both correlated negatively
with the daily GH secretion rate and together accounted
for .60% of the variability in 24-h GH production and
clearance rates. On average, it was estimated that for a
normal BMI, each decade of increasing age reduced the
GH production rate by 14% and the GH half-life by 6%.
Each unit increase in BMI, at a given age, reduced the
daily GH secretion rate by 6%.
Thus a logical corollary is that age, sex, pubertal
status, BMI or other indices of adiposity, quality and
quantity of sleep, medication use, and physical exercise
are but a few of the confounding factors that must be
considered in the design and interpretation of clinical
studies.
For patterns of GH secretion in different pathophysiological contexts such as fasting, exercise, type I diabetes mellitus, obesity, see the corresponding sections.
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III. HYPOPHYSIOTROPIC HORMONES
A. Growth Hormone-Releasing Hormone
1. General background
The regulation of GH secretion has been the focus of
research since Reichlin’s pioneering observation in 1960
(879) in the rat that surgical destruction of the ventromedial hypothalamus slows growth velocity. Parallel to the
identification and sequencing of most of the other hypothalamic regulatory hormones at the end of the 1960s and
during the 1970s was the discovery of the GH release
inhibiting hormone SS, the principal modulator of GH
secretion (141).
Although the possibility had been advanced that
changes in SS secretion might account for all the hypothalamic influences on GH secretion, a hypothalamic
stimulating hormone was needed. Growth hormone-releasing factor or GHRH was only identified and sequenced
;10 years after SS.
The identification of GHRH represented an exception
to the rule, since this neuropeptide is unique among regulatory hormones in that it was first isolated (1121) and
sequenced (447, 892) from human and not animal tissue,
and, secondly, not from the hypothalamus but from pancreatic islet tumors, in which the ectopic secretion was
associated with hypersecretion of GH and acromegaly
(376).
The discovery of GHRH has been reviewed extensively (see Refs. 274, 749) and is only briefly alluded to
here. Growth hormone-releasing hormone was isolated in
1982 from two patients in whom pancreatic tumors had
caused acromegaly. From one of these tumors a 40-amino
acid peptide designated human pancreatic growth hormone-releasing factor hpGRF-(1O40) was isolated (892),1
and three GHRH peptides, GHRH-(1O44)-NH2, GHRH(1O40)-OH, and GHRH-(1O37)-OH, were sequenced
from the other tumor (450). Structure-activity relationships showed that the NH2-terminal 29 residues of GHRH(1O40)-OH have biological activity and indicated that
although the NH2-terminal portion of the molecule is involved in binding to the receptor, the COOH-terminal
portion is critical in regulating the potency of GHRH.
Two of the three GHRH forms found in tumors were
subsequently identified in human hypothalamus [GHRH(1O44)-NH2 and GHRH-(1O40)-OH] and differed only by
the absence in the latter of the four COOH-terminal amino
acid residues (613, 617). Identification of the GHRH sequence in pigs, goats, sheep, and cattle has shown the
existence of the 44-amino acid form amidated at the
COOH terminal (617). Rat hypothalamic GHRH (rGHRH)
contains 43 amino acids with a free acidic group. In
addition, rGHRH is structurally different from the other
GHRH peptides [14 amino acid substitutions or deletions
compared with GHRH-(1O44)] (see Refs. 756, 979).
Growth hormone-releasing hormone belongs to an
expanding family of brain-gut peptides that includes glucagon, glucagon-like peptide I (GLP-I), vasoactive intestinal polypeptide (VIP), secretin, gastric inhibitory peptide
(GIP), a peptide with histidine as NH2 terminus and isoleucine as COOH terminus (PHI), and pituitary adenylate
cyclase-activating peptide (PACAP) (160).
2. Synaptic communication in the hypothalamus
The availability of GHRH-(1O40)-OH and GHRH(1O44)-NH2 means the topography of GHRH neurons
could be established in humans and a number of animal
species (see Ref. 756 for review). There are slight species
differences in GHRH distribution. Growth hormone-releasing hormone IR is present mostly in the basal hypothalamus and is appropriate anatomically for release into
the pituitary portal vasculature. In early studies, GHRH
antisera stained neuronal cell bodies in the ARC (infundibular nucleus) of squirrel monkeys and humans with
1
The conclusion that the material of hypothalamic origin was
identical to the previously identified tumor-derived GRF avoided the
need to keep the nomenclature human pancreatic GRF or the abbreviation ‘‘hpGRF’’; the abbreviation GHRH will be used in the text and to
refer to any of the active sequences. The term somatocrinin was proposed to replace GHRH, but has not been widely accepted.
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secretion, with circadian and sleep effects being superimposed.
In a sequel to these studies, GHRH or saline was
administered intravenously to young healthy men at various times of day and stages of sleep. When injected
during the waking hours, GHRH elicited a response
whose magnitude was directly related to the amount of
spontaneous GH secretion, negatively correlated with circulating levels of IGF-I and was not influenced by time of
day. The response was greater when GHRH was given
during SWS, whereas when GHRH was given during REM,
it was similar to that observed during waking. This suggests that the two sleep stages may be associated with
reduced and enhanced SS secretion, respectively. Awakenings during sleep consistently inhibited the secretory
response to GHRH, which reappeared with resumption of
sleep (1053).
Because the intersubject variability in GH responses
was very wide but the response was quite reproducible
for each subject, it would seem that there is no diurnal
variation in the sensitivity to exogenous GHRH and that
the GH response to GHRH is dependent on the sleep or
waking condition, circulating levels of IGF-I and, possibly,
genetic and life-style factors.
For the electrophysiological effects of GHRH and
GHRP, see sections IIIA10 and IVC.
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NEUROENDOCRINE CONTROL OF GROWTH HORMONE SECRETION
pituitary somatotropes and GH storage and release in
plasma (see sect. IIB).
Colocalization studies in the rat using radioimmunologic, immunohistochemical, and in situ hybridization
techniques indicated that a subset of GHRH neurons in
the ventrolateral part of the ARC contains a large number
of molecules including tyrosine hydroxylase (TH), the key
enzyme of catecholamine (CA) biosynthesis, GABA, choline acetyltransferase (ChAT), the ACh synthesizing enzyme, neurotensin (NT), and galanin (GAL) (see Refs. 697,
756 for review) (Fig. 2). From a functional viewpoint,
particularly important colocalizations are with NT, ChAT,
and GAL, in view of the clear involvement of these compounds in GH release (see sect. VB). Other studies have
shown colocalization of GHRH with neuropeptide Y
(NPY), in neurons which do not project to the external
layer of the ME but constitute a tubero-extra-infundibular
system, not involved in direct control of the AP, but
presumably having a neuromodulatory function (see Ref.
243 and sect. VB6).
Direct proof that cells in the ventrolateral ARC are
likely to be the main source of GHRH-containing projections to the ME has been provided using a combination of
retrograde tract-tracing and immunocytochemistry in normal and GH-deficient dwarf mice (902). Inferential evidence had been provided with the use of monosodium
glutamate (MSG), a neurotoxic substance which destroys
about 80 –90% of the cell bodies in the ARC (794), without
significantly injuring other hypothalamic regions or axons
of passage. Injection of MSG into rats resulted in the
virtually complete disappearance of GHRH-stained fibers
in the ME (115), stunted skeletal growth, and severe
obesity. Interestingly, these changes were combined with
marked decreases in ME-stained fibers containing GAL,
the GABA synthesizing enzyme, glutamic acid decarboxylase (GAD), dynorphin, and enkephalins, but not those
containing SS and NPY, meaning these peptides do not
project to the ME (NPY) or to the ME from another source
(SS) (696, see also sect. IIIB1).
All in all, the localization of GHRH-IR neurons mainly in
the ARC and in the capsule surrounding the VMN is consistent with the results of stimulation and ablation studies that
implicate the medial basal hypothalamus (MBH) in the stimulatory control of GH secretion (see Ref. 749).
3. Growth hormone-releasing hormone-somatostatin
interactions
The neuronal systems regulating GHRH and SS release receive a variety of neural inputs, many of which are
described fully in the next few sections. Here it already
seems appropriate to look at the anatomic and functional
interactions occurring between GHRH and SS neurons,
which are so important for understanding many aspects
of GH control.
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fibers projecting to the ME and ending in close contact
with the portal vessels (114). Studies in macaques and
squirrel monkeys revealed GHRH-IR neurons also in the
ventromedial nucleus (VMN) (114), where GH release
may be increased by electrical stimulation (664). These
neurons were also seen in the rat hypothalamus (708 and
see below).
In the rat, GHRH-positive perikarya were located in
the following regions: ARC from the rostral portion as far
caudally as the pituitary stalk, medial perifornical region
of the lateral hypothalamus, lateral basal hypothalamus,
paraventricular nucleus (PVN) and dorsomedial nucleus
(DMN), and the medial and lateral borders of the VMN
(708). Immunocytochemical studies in humans showed a
similar distribution of GHRH-positive perikarya, mainly
within, above, and lateral to the infundibular nucleus. In
addition, some GHRH staining cells were found in the
perifornical region and in the periventricular zone (114,
115).
Careful charting of the distribution of GHRH-IR in the
brain of adults rats was consistent with at least two
distinct GHRH-containing systems, one responsible for
delivery of the peptide to portal vessels in the ME and one
whose relationship to hypophysiotropic function was less
direct (see sect. IIIA10).
Growth hormone-releasing hormone neurons innervating the external layer of the ME were centered in the
ARC on each side of the brain, whereas the other GHRHstained cells, very likely contributing to the extrahypophysiotropic GHRH-stained projections, were in the
caudal aspect of the VMN. From here, GHRH fibers could
be traced projecting to the periventricular region of the
hypothalamus including the preoptic and anterior part,
where SS-containing neurons are clustered (see below
and sect. IIIB1). Other important terminal fields were
found in discrete parts of the DMN, PVN, suprachiasmatic
nucleus (SCN), and premammillary nuclei and the MPOA
and lateral hypothalamic area. Beyond the hypothalamus,
sparse projections were traced to the lateral septal nuclei,
the bed nucleus of the stria terminalis, and the medial
nucleus of the amygdala (926). Growth hormone-releasing
hormone projections in the amygdala, a part of the visceral brain involved in emotion and responses to stress,
may account for GH responses elicited by electrical stimulation of this area in rats (663) or humans (639) and
suggest the amygdala in humans may be part of the pathways responsible for stress-induced GH release.
Immunohistochemical (292, 514) and RIA (525) measurements indicated that GHRH is first detectable at embryonic days 18 –20 in the rat, reaching adult levels at
postnatal day 30 (525), and in situ hybridization has
detected GHRH mRNA 1 day earlier (896). In the human
fetus, ontogenetic studies detected GHRH neurons between 18 and 29 wk of gestation (115, 143). These figures
are on the whole consistent with the appearance of fetal
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MÜLLER, LOCATELLI, AND COCCHI
Volume 79
The organization of hypothalamic SS-containing neurons is essentially similar in all mammalian species studied so far, including humans (see sect. IIIB1). Most hypothalamic areas contain an extensive network of SScontaining fibers, and there are IR-SS perikarya in the
anterior periventricular area and the parvocellular portion of the PVN and in the SCN, ARC, and VMN. Combined
retrograde tracing and immunohistochemistry showed
that up to 78% of periventricular neurons project to the
external layer of the ME, and other hypothalamic neurons
do not innervate this neurohemal organ (555). The SS
axons and perikarya in the ARC and VMN, two areas from
which GHRH neurons originate, indicate the existence of
anatomic and functional peptide interactions. Immunocytochemical double-labeling studies located SS-producing
neurons in the dorsomedial part of the rat ARC and found
SS-IR axons in the lateral part of the nucleus, an area
containing GHRH-synthesizing cells (622). Several somatostatinergic axon varicosities were clustered around single GHRH synthesizing cells, suggesting synaptic associations. In the external layer of the ME, axonal terminals
immunolabeled for GHRH and SS had the same pattern of
distribution and close proximity.
More morphological proof of SS-GHRH interactions
in the ARC was provided by autoradiography studies
showing a selective association of 125I-labeled SS binding
sites with a subpopulation of cells, concentrated rostrocaudally in the lateral portion of the ARC; their distribution was remarkably similar to that of GHRH-IR neurons
(338). That at least some SS receptors may be directly
linked to GHRH-containing cells was demonstrated in
colocalization autoradiography and immunohistochemistry studies in which ;30% of the IR-GHRH cells labeled
with 125I-SS in sections adjacent to GHRH cells in extraARC regions did not show SS binding (690). Interestingly,
most of the GHRH-SS colabeled cells were detected in the
ventrolateral region of the ARC, where there is a dense
fiber network of SS-nerve terminals (see above).
An ultradian pattern has also been reported in SS
binding to ARC neurons in relation to the peaks and
troughs of the GH rhythm (1010), although the changes
were in the direction opposite those expected. Further
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FIG. 2. Schematic drawing illustrating distribution of neuroactive compounds in different parts of arcuate nucleus
as well afferents to median eminence (ME). Anatomic abbreviations: DM, dorsomedial; MO, medulla oblongata; MPOA,
medial preoptic area; Pe, periventricular nucleus; pVN, parvocellular paraventricular nucleus; VM, ventromedial; VL,
ventrolateral; 3V, third ventricle. Abbreviations for neurotransmitters and peptides: CCK, cholecystokinin; ChAT, choline
acetyltransferase; CRF, corticotropin-releasing factor; DA, dopamine; DYN, dynorphin; E, epinephrine; ENK, enkephalin;
GAL, galanin; GRF, growth hormone-releasing factor; LHRH, luteinizing hormone-releasing hormone; NPK, neuropeptide
K; NPY, neuropeptide Y; NT, neurotensin; NE, norepinephrine; POMC, proopiomelanocortin; SOM, somatostatin; SP,
substance P; TRH, thyrotropin-releasing hormone; VP, vasopressin; TH, tyrosine hydroxylase. [From Meister et al. (697),
with permission from Elsevier Science.]
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NEUROENDOCRINE CONTROL OF GROWTH HORMONE SECRETION
521
direct evidence of cellular colocalization of SS receptors
and GHRH-producing cells within the ARC was provided
by in situ hybridization studies showing that in the ventrolateral portion of the ARC GHRH mRNA labeled neurons had the same distribution as 125I-SS labeled cells (97)
(Fig. 3). For the SS receptor subtypes involved, see section IIIB2.
Two other cell types could be identified in these
studies: GHRH perikarya, around the perimeter of the
VMN not associated with pericellular SS binding sites, and
very likely containing substance P and enkephalin-8 bind-
ing sites (282), and 125I-SS labeled cells not associated
with GHRH perikarya, in the periventricular zone along
the dorsal part of the third ventricle, probably associated
with b-endorphin- (558) or TH-producing (484) cells.
With regard to GHRH inputs to SS-IR neurons, only a
few of these neurons were closely approached by GHRHIR fibers, indicating that SS neurons are only scantly
innervated by GHRH cells (1098) and suggesting the relative independence of SS from GHRH.
The data reported provide strong morphological support for a direct hypothalamic control of GHRH neurons
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FIG. 3. Schematic drawings of rat arcuate
nucleus (ARC) comparing distribution of
prepro-growth hormone-releasing hormone
(GHRH) mRNA-containing neurons (left) and
125
I-SRIH-labeled cells (right) on adjacent 5-mmthick cryostat coronal sections of rat mediobasal hypothalamus at 3 anatomic levels (interaural line: 6.70, 6.20, and 5.70 mm according to
Paxinos and Watson, 1986). ARC was separated
in three parts [lateral (L), ventrobasal (VB), and
periventricular (PV)]. e, GHRH-producing cells
coidentified as 125I-SRIH labeled; V, 125I-SRIHlabeled cells; ●, 125I-SRIH-labeled cells coidentified as GHRH-synthesizing cells. Each symbol
represents 3 labeled cells. [From Bertherat et al.
(97).].
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MÜLLER, LOCATELLI, AND COCCHI
4. Distribution outside the CNS
Like other neuropeptides originally described as primarily of hypothalamic origin, GHRH has also been found
in peripheral tissue, although its physiological role as an
extrahypothalamic hormone, in addition to stimulating
GH secretion, is far from clear. Activity of GHRH outside
the brain was initially only found in neoplastic tissues
producing GHRH (see sect. IIIA1). However, the hormone
was then seen in the upper intestine, particularly in the
jejunum, with smaller amounts in the duodenum. None
was found in the ileum or colon. The peptide was confined to the epithelial mucosa, suggesting a possible endocrine role. In addition to the gastrointestinal tract,
mRNA for GHRH was found in leukocytes, where GHRH
inhibits human natural killer cell activity (819) and also
affects human leukocyte migration (1126), in the testis
(94), ovary (65), and placenta (657). In the rat testis, the
estimated size of GHRH-like immunoreactivity (GHRH-LI)
was 3.7 times that of synthetic GHRH (831), and it was
found in the interstitial tissue (740) and in mature germ
cells (831), its function being to amplify the action of GH
on Leydig cells (steroidogenesis) and of follicle-stimulating hormone on Sertoli cells (cAMP formation) (240). In
view of the existence of a blood-testis barrier and the
abundance of GHRH in rat testis, it presumably acts as an
autocrine or paracrine factor.
In the rat placenta, GHRH mRNA is distinct from that
described from the hypothalamus, and placental GHRH is
synthesized in the cytotrophoblast (657). Cells expressing
GHRH are located differently in the mouse placenta (992).
The GHRH peptide and mRNA have also been identified in
the human placenta (95). Placental GHRH may have a role
in regulating fetal pituitary somatotrophs (445) and placental growth factors in an autocrine and/or paracrine
fashion (476). Initial studies in the somatotrophs found
IR-GHRH in secretory granules and the nuclei (738), and
others found it internalized in another intracellular compartment (705).
5. Gene structure and expression
Pancreatic tumors from which the GHRH peptide
was purified provided the mRNA source for the construction of libraries from which cDNA encoding the human
GHRH precursor could be isolated (444, 685). A rat GHRH
cDNA was isolated directly from a hypothalamic library
(681). Using cDNA to screen human genomic libraries
resulted in the elucidation of the human GHRH gene
(682), and the rat and mouse GHRH genes have also been
identified in the genome (991).
Like most small peptides, GHRH is generated by the
proteolytic processing of a larger precursor protein. This
is a single copy in the human genome, and it has been
mapped to the p12 band of chromosome 20 in the human
(682) and chromosome 2 in the mouse (433). The gene
includes five exons spanning ;10 kb of DNA, with clear
segregation of the functional domains of the GHRH precursor into the five exons of the genes (for further details,
see Refs. 377, 683).
The GHRH precursor proteins identified in the human, the mouse, and the rat range in length from 103 to
108 amino acids; their sequences are fairly homologous,
with the amino acids being closest in the NH2-terminal
portion of the mature GHRH peptide, the region crucial
for GHRH binding and biological activity (160). The rat
and mouse proteins differ completely from the human
GHRH precursor near the COOH terminus. In the rat,
although most of the 104 amino acids of the GHRH precursor protein are similar to the human precursor, the last
13 residues in the COOH-terminal domains are all different (678).
The cDNA probes for GHRH made it possible to
examine gene expression in the mammalian hypothalamus. In situ hybridization analysis of GHRH mRNA in the
rat brain showed without doubt that GHRH-expressing
neurosecretory cells, as revealed by immunocytochemistry (see sect. IIIA2), are an actual site of GHRH synthesis
(89, 678, 1125). In agreement with RIA and immunohistochemical findings, most of the GHRH-expressing cells
were on the ventral surface of the hypothalamus within
the ARC, with additional cells extending into the DMN. No
substantial expression was observed in brain regions outside the hypothalamus.
It is now clear that the hormonal and metabolic
status of the animals dictates appropriate changes of
GHRH mRNA expression in ARC neurons. The GHRH
mRNA levels are higher in male than female rats, and
testosterone is reported to increase the expression of
GHRH mRNA in males and to prevent the decline due to
castration. This latter effect is shared by dihydrotestosterone, suggesting direct activation of the androgen re-
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by SS and for the concept that the two hypophysiotropic
peptides interact within the central nervous system (CNS)
to modulate GH secretion (see also sect. II). A wealth of
physiological evidence bears witness to the interaction,
including a rapid increase in plasma GH after intracerebroventricular administration of SS to anesthetized (2) or
awake rats (641), depending at least in part on hypothalamic GHRH (762); increased GHRH concentrations in
hypophysial portal blood after intracerebroventricular administration of SS antiserum (853); elevated basal GH
levels, which can be reduced by anti-GHRH serum after
lesions of the hypothalamic MPOA (548); and triggering of
GH secretion through a mechanism involving GHRH, after
acute withdrawal of endogenous (722) or exogenous SS
(210, 244, 964). For the GHRH-SS interactions in ultrashort feedback mechanisms, see section IIIB2.
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6. Secretion and metabolism
In vitro studies with the use of both long-term cultures of fetal rat hypothalamus and short-term static incubations of adult rat hypothalami with perfusion have
been used to evaluate GHRH secretion. Such systems
showed the releasing effects of K1-induced depolarization (547) and the increased release after hypophysectomy (237) and thyroidectomy (324) in response to low
glucose or intracellular glucopenia (64) and a2-adrenergic
stimulation (536). Conversely, IGF-I (959), SS (1114), and
activation of GABAergic function (63) impaired GHRH
release. Multiple second messenger pathways underlie
these effects, i.e., Ca21, phosphatidylinositol-protein kinase C, and adenylate cyclase-protein kinase A (63, 277).
In vivo picomolar to nanomolar concentrations of
GHRH have been reported in the rat and the sheep portal
venous blood. In anesthetized, hypophysectomized rats,
portal plasma levels of GHRH were ;200 pg/ml with
synchronized pulses up to 800 pg/ml (853). In freely mov-
ing, ovariectomized ewes, pulsatile GHRH secretion
reached a mean of 20 pg/ml, with peak values from 25 to
40 pg/ml and a secretion rate of 13 pg/min. About 70% of
spontaneously occurring GH peaks could be attributed to
GHRH pulses, as indicated by simultaneous measurement
of peripheral GH levels (378, see also sect. II).
Unstimulated plasma levels of GHRH were in the
range of 10 –70 pg/ml in normal adults (827, 1032), with no
apparent sex-related differences (924). Comparable values have been reported in the cerebrospinal fluid (CSF) of
children and adults of both sexes with no endocrine diseases (541). Growth hormone-releasing hormone is high
in the cord blood from term human newborns (39), as are
levels of GH (see sect. IIB). Normal children of both sexes
between ages of 8 and 18 had levels five times higher at
mid-puberty than prepuberty in girls and double in boys
(41), supporting the central role of gonadal hormones
(see also sect. IIB).
The source of GHRH-LI in human plasma is not
known, but the comparable levels in normal subjects and
patients with hypothalamic lesions (232) suggest that the
major source is not the hypothalamus (see also sect.
IIIA4). Food (972) or glucose injection (542) can raise
GHRH-LI levels, and this also occurs in patients with
hypothalamic lesions or in GH-deficient subjects. These
observations add weight to the idea that GHRH produced
in the periphery (stomach, pancreas, small intestine)
(239) may also act as a paracrine or autocrine factor. The
hypothalamic component of circulating GHRH-LI, however, is specifically stimulated by insulin-hypoglycemia
(542, 909; but see also Ref, 1022) or levodopa (231, 542,
914), but not by clonidine or arginine (1085).
Other conditions that increase circulating GHRH levels include the initial slow stage of sleep (914) and the
sauna bath in young subjects (605). For other details on
GHRH levels in GH hypo- and hypersecretory states, see
Reference 749.
Growth hormone-releasing hormone is metabolized
in human plasma by dipeptidyl peptidase type IV (DPP-IV)
and trypsinlike endopeptidases (375, 380). Degradation
comprises an initial step whereby DPP-IV removes the
NH2-terminal dipeptide (Tyr-Ala) leaving metabolites
[GHRH-(3O44)-NH2 and GHRH-(3O40)-OH] with no bioactivity. Independent cleavage by trypsinlike endopeptides at residues 11–12 also inactivates the peptide. Because the half-life of GHRH-(3O44)-NH2 in vitro is
considerably longer (55 min) than the native molecule (15
min), most of the plasma GHRH-IR is in the biologically
inactive form. Studies with bovine GHRH suggest metabolic disposal is similar to human GHRH (579).
7. Mechanism of action
Growth hormone-releasing hormone exerts its primary control of somatotrophic function by increasing GH
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ceptor as the underlying mechanism (1124) and supporting a role of androgens per se to stimulate GH secretion
(see sect. IIB). Thyroid hormone deficiency also increases
GHRH mRNA levels; also this is mediated by the decrease
in GH secretion (see below), since treatment with GH
restores normal GHRH mRNA despite persistent hypothyroidism (288, 324).
Metabolic state is also important, and in genetically
obese Zucker rats (258, 354) as well as in caloric deprivation (149), where GH secretion is decreased, GHRH
mRNA levels also drop, indicating effects divorced from
GH secretion and the primary hypothalamic origin of the
disturbance (see sect. VIC1). Streptozotocin-injected diabetic rats have diminished GH secretion, which can be
restored by an anti-SS serum (1007). However, GHRH
mRNA levels are low, and SS mRNA levels are high,
indicating a metabolic regulation independent of GH
(793) (see also sect. VI for discussion).
Hormonal feedback regulation through GH appears
to be the most important factor in GHRH mRNA expression. Growth hormone deficiency induced by target organ
removal (hypophysectomy) or selective abrogation of
GHRH function is associated with increased GHRH
mRNA levels, whereas GH treatment lowers them (237,
290, 678), although not always (202) (see sect. VII for
discussion).
Levels of hypothalamic GHRH do not always change
in parallel with GHRH mRNA (237, 386) because they also
reflect a different rate of peptide increase and impairment
of GHRH mRNA translation. Thus proper interpretation of
changes in GHRH content requires independent information on GHRH mRNA levels and/or GHRH secretion.
The expression of GHRH mRNA in the placenta and
other tissues is discussed above.
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MÜLLER, LOCATELLI, AND COCCHI
able within 5 s (487, 643); this first phase was followed by
a decline in [Ca21]i to a plateau that was always higher
than baseline and lasted 5 min (643).
In addition to GHRH, other GH secretagogues rapidly
raised intracellular Ca21 (371, 576). Incubation in low
Ca21 medium or in the presence of Ca21 channel blockers
or antagonists blocked or greatly diminished both the
GHRH-dependent increase in [Ca21]i and GH release, with
no changes in the cytosolic Ca21 levels (102, 140, 487,
644); this was taken to demonstrate that GHRH increases
[Ca21]i in somatotrophs by stimulating Ca21 influx
through L-type voltage-operated channels (VOCC). These
effects are highly dependent on external Na1 and result
from a cascade of voltage- sensitive currents (581). The
inhibitory action of SS on basal and GHRH-induced GH
release resulted from its ability to lower [Ca21]i by inhibiting Ca21 influx (643, 644). Somatostatin also inhibited
the Ca21 influx induced by other GH secretagogues, the
only exception being high K1.
These studies led to a model in which a net influx of
extracellular Ca21 through VOCC is the primary source of
the first phase of the GHRH-dependent increase in [Ca21]i
(222). Alternatively, the increase in cAMP accumulation
might increase Na1 conductance directly or through protein kinase A-dependent phosphorylation, leading to depolarization and opening of the L-type VOCC (643). A
more important role of Ca21 mobilized from intracellular
stores has also been suggested, based on a high correlation between Ca21 efflux and GH release in perfused
somatotrophs or the ability to stimulate GH secretion and
Ca21 efflux despite the absence of extracellular Ca21
(343, 789).
With regard to the interaction between the two second messenger functions, there is some evidence of a
direct relationship between cAMP and Ca21. W-7, an antagonist of the Ca21 binding protein calmodulin, inhibited
GHRH stimulation of adenylate cyclase, cAMP accumulation, and GH release, whereas the calcium ionophore
A-23187 stimulated GH secretion and cAMP production
(714, 935).
Admittedly, Ca21 effects occur together with a metabolic reaction, the hydrolysis of membrane phosphoinositides (PI), and these two processes are functionally
connected (780). It was initially reported that GHRH increased 32P incorporation into PI of rat AP cells (165);
however, this would be entirely separate from the PI
catalysis involving the production of inositol 1,4,5trisphosphate (IP3) and diacylglycerol, since GHRH did
not enhance IP3 (647). Other investigators too have found
no early effect of GHRH on PI hydrolysis (260, 370, 875).
Although GHRH does not induce PI hydrolysis, synthetic
diacylglycerols and phorbol esters, which mimic the effect of the endogenous substrate by activating protein
kinase C (184), dose-dependently stimulate GH secretion
(535, 790). These compounds bind to the cell membrane
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secretion, GH gene transcription and biosynthesis, and
somatotroph proliferation. A host of intracellular second
messenger systems including the adenylate cyclasecAMP-protein kinase A, Ca21-calmodulin, inositol phosphate-diacylglycerol-protein kinase C, and arachidonic
acid-eicosanoic pathways are activated after binding to
specific GTP-linked receptors in the plasma membranes
(see also Ref. 683).
Earlier evidence that cAMP was involved as a second
messenger in the stimulation of GH secretion rested on
the demonstration that crude ectopic GRF preparations,
cAMP analogs, and theophylline, a phosphodiesterase inhibitor, stimulated GH release (822, 938, 997). With GHRH
in pure form, it was then shown that GH release was
associated with a dose-dependent rapid stimulation of
adenylate cyclase activity and cAMP production in the
somatotrophs (102). Within 5 min of the addition of 1 nM
GHRH to cultured rat pituitary cells, intracellular cAMP
levels rose 6-fold, with a maximal response at 30 min; 10
times more GHRH was required to obtain half-maximal
stimulation of cAMP production than GH secretion, suggesting that only partial receptor occupancy is required to
elicit a maximal GH response (1066).
Growth hormone-releasing hormone-induced stimulation of cAMP production would occur in the manner
typical of receptors coupled to GTP-binding proteins
(106). The occupied GHRH receptor activates a heterotrimeric stimulatory G protein (Gs), composed of a-, b-, and
g-subunits, by catalyzing the binding of the a-subunit to
GTP. Guanosine 59-triphosphate binding leads to dissociation of the bg-subunit complex from the Gs a-subunit,
and the latter then activates the catalytic subunit of adenylate cyclase. Thus adenylate cyclase stimulation by
GHRH is dependent on GTP (769, 974), but nonhydrolyzable GTP analogs or a high concentration of GTP reduced
GHRH receptor binding (988), and stimulation of adenylate cyclase (974), consistent with existing models for
receptor-G protein interactions. Like GHRH, agents that
bypass the receptor, such as cholera toxin, which decreases the GTPase activity of Gsa (182) or forskolin,
which directly activates the catalytic subunit of adenylate
cyclase (944), potently stimulated cAMP accumulation
and GHRH release (140, 275).
In the absence of GHRH or other hypothalamic peptides, somatotropes in culture have either a stable basal
intracellular Ca21 concentration ([Ca21]i) level (487) or
asynchronous spontaneous [Ca21]i transients (487) that
result from Ca21 entry through Ca21-permeable channels
(487).
Extracellular Ca21 is required for GHRH to stimulate
cAMP accumulation in pituitary cell preparations (140),
suggesting that Ca21 is also a second messenger for
GHRH and that Ca21 acts beyond, or independently of,
cAMP. On purified preparations of normal rat somatotrophs, GHRH elicited a rapid increase in [Ca21]i detect-
Volume 79
April 1999
NEUROENDOCRINE CONTROL OF GROWTH HORMONE SECRETION
8. GHRH receptor
A) CHARACTERIZATION, CLONING, AND STRUCTURE. A better understanding of GHRH action in promoting GH secretion
and linear growth requires knowledge of the GHRH receptor (GHRH-R) structure and function. Previous studies
in intact cells or cell membrane preparations of the rat
described high-affinity low-capacity specific GHRH binding sites, using GHRH or GHRH analogs (5, 947, 1066).
Two studies reported an additional class of low-affinity
high-capacity sites (5, 6). Binding sites were also evi-
denced in bovine pituitaries (1066) and human pituitary
tumor tissue (502). Binding of GHRH resulted in the activation of adenylate cyclase, whereas guanine nucleotides inhibited hormone binding, suggesting the involvement of Gs protein (see sect. IIIA7 for details).
Initial approaches to identify GHRH-R activity based
on functional expression of the receptor in Xenopus laevis oocytes injected with pituitary mRNA were unable to
isolate an individual GHRH-R cDNA. More successful was
a strategy based on the contention that the receptor,
which utilized a G protein to transduce its signal, would
predominantly have structural features of other G proteincoupled receptors (679). This led first to the expression
cloning of the GHRH-related hormone secretin (513) and
then to the recognition that this receptor and the related
calcitonin and parathyroid hormone (PTH) receptors constituted a new subfamily of G protein-coupled receptors
(see Ref. 683).
Three groups subsequently achieved the molecular
cloning of AP receptors for GHRH in human, rat, and
mouse (393, 612, 679). The isolated cDNA encoded a
423-amino acid protein containing seven putative transmembrane domains characteristic of G protein-coupled
receptors (Fig. 4). Rat cDNA clones also had a 41-amino
acid insert at amino acid 325. However, PCR analysis of
rat pituitary mRNA only gave evidence of the shorter form
(679). The two rodent receptors were closely related (94%
identical) and were both homologous to the human receptor (82% identical). The GHRH-R colocalizes with GH
cells (612), although studies about cell-specific expression of GHRH-R are not yet complete.
As mentioned in section IIIA1, GHRH belongs to a
family of brain-gut peptides, and a similar family of receptors has now been identified that includes the VIP
receptor, the glucagon receptor, the GLP-1 receptor, the
PACAP receptor, and the GIP receptor. These peptide
receptors also show consistent homology with the GHRH
receptor (see Ref. 945).
Transient expression of rat cDNA in COS cells induced saturable, high-affinity GHRH-specific binding and
stimulated the accumulation of cAMP in response to physiological concentrations of GHRH, consistent with the
predicted coupling of the GHRH-R to a Gs protein. Binding and second messenger responses were blocked by a
specific GHRH antagonist, whereas ligands for related
receptors (see above) did not effectively compete with
GHRH for binding to its receptor (683).
Initial Northern analysis studies indicated that
GHRH-R mRNA was mainly expressed in extracts of pituitary and not in other tissues. Two transcripts of ;2.5
and 4 kb were identified in rat pituitary, 2.0 and 2.1 kb in
mouse, and 3.5 kb in ovine pituitary (393, 612, 689). Mouse
studies showed that the GHRH-R is expressed in a temporal and spatial pattern corresponding to GH gene expression (612).
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and then induce translocation of the inactive enzyme from
the cytosol to the cell membrane, resulting in a large
increase in its affinity for Ca21. Protein kinase C appears
to act synergistically with Ca21 mobilization to increase
cell product release in various systems because low levels
of Ca21 ionophore can potentiate the protein kinase activation (535). This synergism may operate through several mechanisms, and no firm conclusion has been
reached (535).
Whatever the underlying mechanism is, it is noteworthy that increased Ca21 mobilization in the pituitary enhances the sensitivity of the somatotroph to protein kinase C activators (535). It would seem, however, that this
mechanism is only marginal to the secretagogue action of
GHRH and may better account for the action of GHRP and
their analogs (see sect. IVC2), and protein kinase apparently increases GH release by mechanism(s) different
from those used by GHRH (790).
The fact that GHRH does not enhance IP3 production
and may thus be unable to mobilize intracellular Ca21
from the IP3-sensitive Ca21 pool implies only a minimal
effect on fractional Ca21 efflux. However, GHRH may
affect Ca21 efflux through the formation of arachidonic
acid, derived from the direct activation of phospholipase
A and hydrolytic cleavage of the fatty acid from membrane phospholipids or, alternatively, by hydrolysis of
diacylglycerol by diacylglyceride. Arachidonate and its
metabolites are known to mobilize Ca21 (567, 765).
Growth hormone-releasing hormone and Ca21 efflux are
discussed above.
Supporting a GHRH-arachinodate interaction, arachidonic acid elicits a dose-dependent increase in GH secretion and GHRH stimulates arachidonic acid release in
cultured rat pituitary cells (166, 534).
Prostaglandin (PG) E1, PGE2, and prostacyclin
(PGI2) enhance GH secretion in the rat in vitro (716, 800)
and in vivo (551, 800) as well as the production of cAMP
(716, 938), probably by stimulation of adenylate cyclase
through a Gs protein-coupled PG receptor (966). Growth
hormone-releasing hormone stimulates PGE2 release
from incubated rat pituitaries, and indomethacin and aspirin, two cycloxygenase inhibitors, reduce GHRH-induced GH and PGE2 release (347).
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Volume 79
The identification of the pituitary-specific transcription factor, Pit-1, which is involved in developmental generation of somatotrophs (lactotrophs and thyrotrophs)
and in the appropriate regulation of the GH gene (120,
507) and very likely also in direct regulation of the GHRHR mRNA, has contributed to our understanding of GHRHR biology. Growth hormone-releasing hormone plays a
major stimulatory role in regulation of the Pit-1 mRNA
concentration, although Pit-1 is preserved in the pituitaries of anencephalic fetuses (845), an effect mimicked by
other GH secretagogues such as PACAP-38 but not by
GHRP-6 (973). The regulation is apparently reciprocal,
since GHRH-R is not expressed in the pituitary of dw/dw
mice, which are impaired in functional Pit-1 gene expression (614). Thus GHRH-R would be dependent on Pit-1,
and a deficiency of Pit-1 would result in a lack of GHRH-R
gene expression and thus of somatotroph development.
B) FUNCTION. Information about GHRH-R regulation
and function or dysfunction offers new insights into the
control of GH secretion during development, maturity,
and aging and helps explain GH deficiency states of animals or humans leading to dwarfism and metabolic dysfunction.
Pituitaries of fetal and neonatal mammals are highly
responsive to the stimulatory effects of GHRH, compared
with mature mammals (see sect. IIB). Differences in pituitary responsiveness to GHRH may therefore contribute
to the elevated plasma GH titers characteristic of the
perinatal period and the subsequent decline in circulating
GH occurring late in life. Studies of the ontogenic development of rat GHRH-R gene expression have in fact found
the highest concentration on day 19.5 of gestation (ED
19.5), with a decline during the perinatal period to reach
a nadir at 12 days of age. The GHRH-R mRNA levels
increased at 30 days of age, corresponding to the onset of
sexual maturation, and then declined later in life (572).
Although the timing of the decline in GHRH-R mRNA,
at 12 days, did not precisely coincide with recorded
changes in GH responsiveness to GHRH in vitro and in
vivo (see sect. IIB), there was a dissociation with the
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FIG. 4. Schematic structure of GHRH
receptor. Amino acid sequence shown in
a 1-letter code is that of rat GHRH receptor. Seven membrane-spanning domains
are illustrated as cylinders crossing lipid
bilayer. Solid circles represent amino
acids that are conserved in related receptors for hormones secretin, glucagon,
glucagon-like peptide I, gastric inhibitory
peptide, vasoactive intestinal polypeptide, and pituitary adenylate cyclase-activating peptide. Open arrow indicates
approximate site of signal sequence
cleavage. Branched structures represent
2 consensus sites for N-linked glycosylation. Solid arrow indicates site of an insertion generated by alternative RNA
processing in a variant form of GHRH
receptor. [From Mayo et al. (683); Copyright The Endocrine Society.]
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NEUROENDOCRINE CONTROL OF GROWTH HORMONE SECRETION
developmental pattern of GH mRNA (see Ref. 572 for
discussion), and the maturational changes in GHRH-R
mRNA abundance were, on the whole, consistent with a
similar role in the regulation of somatotroph function
during early development. The presence of abundant
GHRH-R mRNA as early as ED 19.5 supports the idea that
GHRH-R plays a role in mediating GHRH stimulation of
somatotroph function by late fetal life and, ultimately,
that GH secretion is also involved during this period (146,
1094). These data were consistent with reports that mice
also express GHRH-R mRNA by late gestation (157, 612).
The findings of Korytko et al. (572) have been confirmed
by Horikawa et al. (489), who have extended their studies
to the developmental changes of SS receptors (see sect.
IIIB2).
Horikawa et al. (489) showed that in neonatal rats
passively immunized with a GHRH antiserum (see Ref.
207), there was a .50% decrease in GHRH-R mRNA; GH
treatment significantly reduced the pituitary GHRH-R expression in control rats but not in GHRH antiserumtreated rats (Fig. 5). The marked reduction of GHRH-R
mRNA in GHRH-deprived neonatal rats was taken to indicate failure of the developmental induction of pituitary
GHRH-R expression by GHRH itself. In control rats, GH
acted through an initial decrease of hypothalamic GHRH
synthesis induced by short-loop feedback (see sect. VIIA).
A major reduction of pituitary GHRH-R mRNA is also
observed in transgenic dwarf mice expressing a TH-human GH fusion gene in the hypothalamus (996).
Regulation of GH secretion by GHRH-R would also
be important in the sexually dimorphic expression of GH
secretion (see sect. IIA) and would thus be of physiolog-
ical significance. Normal female rats, in fact, had strikingly lower levels of pituitary GHRH-R mRNA than male
rats; in addition, female rat hypothalami had a lower
GHRH content and were less able to release GHRH than
male rats (799). Although the sex difference in GH secretion of rats cannot be extrapolated as such to humans,
these animal findings reinforce the view that hypothalamic GHRH secretion is mandatory to permit expression
of its own pituitary receptor and show, in particular, that
E2 inhibits hypothalamic GHRH secretion and pituitary
GHRH-R gene expression simultaneously.
Supporting these findings, castration raised the low
GHRH-R mRNA levels of female rats two- to threefold, an
effect counteracted by short-term E2 implants. Estrogen
also markedly suppressed GHRH-R mRNA in castrated
male rats, although orchidectomy lowered GHRH-R
mRNA only slightly, the opposite effect to ovariectomy. In
both male and female rats, castration enhanced GHRH
secretion in response to high K1 concentrations ;1.5fold, and this effect too was reversed by E2 treatment
(798).
Various other steroid hormones also modulate
GHRH-R mRNA expression. In primary cultures of rat AP
cells, 100 nM dexamethasone for 12 h increased gene
expression by fivefold; adrenalectomy and hormone replacement studies ex vivo showed corticosterone also
stimulated GHRH-R mRNA expression in the intact rat
pituitary gland (727). These findings, broadening previous
observations in vivo with dexamethasone (584), provide a
molecular mechanism to explain how glucocorticoids restore GHRH binding capacity in dispersed AP cells from
adrenalectomized rats (947) and why dexamethasone induces an acute GH secretory response when administered
to healthy humans (177) (see also sect. VIA1).
The proposition that hypothalamic GHRH is mandatory for the expression of GHRH-R in the pituitary has
now been strongly corroborated by more straightforward
experiments. Treatment of AP cell cultures with 100 nM
GHRH for 12 h increased GHRH-R mRNA levels 6-fold,
and there was a 10-fold rise in GHRH-R mRNA after cell
exposure to 100 mM dibutyryl cAMP for 12 h (727). For
thyroid hormone action at GHRH-R, see section VIA2.
The importance of pituitary GHRH-R for somatotroph function is illustrated by the fact that loss of
function mutations in GHRH-R in mouse and human leads
to severe GH deficiency syndromes. The little mouse is an
animal model for isolated GH deficiency type 1B (333), in
which the discovery of a mutation in GHRH-R (433) suggested similar mutations in GH deficiency syndromes in
the human population (see below).
Functionally, pituitary glands of the little mouse are
deficient in but not devoid of GH and are unresponsive to
GHRH in vivo and in vitro (247). Somatic growth is increased by systemically administered GH.
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FIG. 5. Changes in GH-releasing factor receptor (GRFR)-to-glyceraldeyde 3-phosphate dehydrogenase (GAPDH) ratio by treatment with
GH-releasing factor antibody (GRF-ab) and/or GH. GRFR/GAPDH were
expressed as percent (mean 6 SD of 4 independent experiments) of
group I. Treatments to each group were as follows: group I, normal
rabbit serum (control group); group II, GRF-ab; group III, normal rabbit
serum and GH; group IV, GRF-ab and GH. * P , 0.01, analyzed by
ANOVA. [From Horikawa et al. (489); Copyright The Endocrine Society.]
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MÜLLER, LOCATELLI, AND COCCHI
Volume 79
In humans, some familial cases of isolated GH deficiency have been attributed to mutations in the GH gene
itself, but GH deficiency is not always linked to this locus
(799). The GHRH-R mutations account for other instances
of GH deficiency in which the GH gene is normal. A
nonsense mutation in the human GHRH-R gene has been
reported that resulted in profound GH deficiency in two
members of a consanguineous family, (1076). The Glu-72
stop mutation identified was close to the position of the
little mutation (Asp-60-Gly), both occurring in the highly
conserved region of the extracellular domain. Conformational polymorphism analysis applied to the coding region
of the GHRH-R gene in 30 families with individuals suffering from GHD revealed a polymorphism changing
codon 57 from GCG (alanine) to ACG (threonine) in the
extracellular position of the receptor in ;20% of the
patients (836). However, the presence of this polymorphism did not seem to cause the GH deficiency in these
patients; its frequency may be helpful to identify those
patients in whom mutations in the GHRH-R gene are
likely to be a cause of their GH deficiency.
A novel form of familial isolated GH deficiency linked
to the locus for the GHRH-R has been described in a lower
valley of Pakistan. A total of 18 dwarfs were discovered in
a kindred with a high degree of consanguineity. Of several
candidate genes probed by linkage analysis, only the
GHRH-R locus on chromosome 7p14 was highly linked to
the dwarfed phenotype. Amplification and sequencing of
the GHRH-R gene in affected subjects brought to light an
amber nonsense mutation (GAG 3 TAG; Glu 5 3 Stop) in
exon 3, implying that this form too is a human homolog of
the little mouse (78).
9. Conclusions
Molecular characterization of GHRH and GHRH-R is
instrumental to a better understanding of the hypothalamic regulation of pituitary somatroph function (Fig. 6)
(see Ref. 683 for details). In brief, the model of GHRH
action proposes the interaction of the peptide with a
seven-transmembrane domain Gs-coupled receptor on the
somatotroph, leading to GH release from secretory granules, presumably mediated by a G protein interaction with
ion channels and by stimulation of intracellular cAMP
accumulation. In turn, elevated cAMP titers would lead to
the phosphorylation and activation of cAMP response
element binding protein (CREB), a transcription factor,
by protein kinase A (434, 956).
One target gene for CREB action is the pituitarydependent transcription factor Pit-1 that is involved in the
developmental generation of somatotrophs and in regulation of the genes for GH, prolactin and possibly for the
b-chain of thyroid stimulating hormone. It provides the
pathway whereby GHRH leads to increased GH synthesis
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FIG. 6. Model for GHRH signaling in pituitary somatotroph cells. Numbered symbols indicate progressive steps, as also indicated in
text (1). GHRH interaction with its receptor
leads to GH secretion (2) through receptor-induced interaction of a G protein with ion channels (3). Stimulation of adenylate cyclase by Gs
protein leads to intracellular cAMP accumulation and activation of catalytic subunit of protein kinase A (4). Protein kinase A phophorylates cAMP response element binding protein
(CREB) at serine-133, leading to CREB activation and enhanced transcription of the gene encoding pituitary-specific transcription factor
(Pit-1) (5). Pit-1 activates transcription of GH
gene, leading to increased growth hormone
mRNA and protein and replenishing cellular
stores of growth hormone (6). Pit-1 also stimulates transcription of GHRH receptor gene, leading to increased numbers of GHRH receptors on
responding somatotroph cell (7). Upstream
components of cAMP-signaling pathway appear
to have direct effects on GHRH receptor gene
expression. [Modified from Mayo et al. (683).]
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NEUROENDOCRINE CONTROL OF GROWTH HORMONE SECRETION
10. In vivo animal studies
Detailed description of the GH-releasing activity of
GHRH and its effects outside the GH axis, derived from
animal studies, is beyond the scope of this review, so
these topics are discussed here only briefly. For the clinical implications, the reader is referred to the excellent
review by Cronin and Thorner (274).
Growth hormone-releasing hormone is active in vivo,
stimulating GH secretion in anesthetized rats; conscious
rats or dogs; rats bearing stereotaxic lesions of the VMN,
ablation of the MBH, or selective destruction of the ARC;
and in every vertebrate tested so far (see Ref. 1086).
Growth hormone-releasing hormone is needed for
endogenous pulsatile GH secretion and optimal statural
growth; subacute administration of an anti-GHRH serum
to neonatal rats drastically slows growth (1089), impairs
many aspects of somatotrophic function (207), and completely abolishes spontaneous GH release (1090). Once
passive immunization ceases, no catchup growth occurs,
and the immunized rats maintain a growth rate that is
parallel to, but still lags behind, that of control rats (207).
This growth pattern is virtually identical to the pattern in
children with constitutional growth delay. The GH deprivation induced by the anti-GHRH serum delays sexual
maturation in male rats (48), probably because of the low
IGF-I titers (303).
Alterations in postnatal somatotropic function are
also obtained when GH deprivation is induced in fetal rats
on ED 16 by intra-amniotic injection of GHRH antibodies
(212), a finding supporting the concept that GH exerts an
important role in perinatal growth in the rat, as it is likely
in humans (432, 1094). On the other hand, GHRH administered over several days to weeks enhances body growth
and function in experimental animals (336, 1031). These
effects are particularly evident in mice transgenic for
GHRH, where excess GHRH exposure is associated with
elevation of serum GH and stimulation of linear growth,
increased pituitary mass, and mammosomatotroph hyper-
plasia, finally resulting in adenoma formation (see Refs.
684, 982).
There is an ontogenetic pattern in basal GH responses to exogenous GHRH; in the rhesus monkey, they
decrease from postnatal days 1 to 28 (1086), whereas in
the rat, GHRH does not raise GH levels up to postnatal
days 5–10 (204), when GH pituitary responsiveness to the
GH-releasing (205) and synthesizing (272) activities of the
peptide is at its best (see also sect. IIB). For the developmental pattern of the GHRH-R and its hormonal regulation, see section IIIA8B.
In the rat, the GHRH system shows a strong sex
dependency (40), and Spiliotis et al. (978) showed that
GHRH mRNA level and GHRH secretion were higher in
male than female rats and were reduced by orchidectomy
but increased by testosterone in castrated male rats
(1125); E2 had no effect on hypothalamic GHRH mRNA
(653, 1125).
The sexually dimorphic organization of the GHRH
system may account for the sex difference in GH secretion in the rat (see sect. IIA), a major role also being
attributed to sex-related differences in GHRH-R mRNA,
although regulation by hypothalamic SS as well cannot be
ignored (see sect. IIIB).
Consistent with the inhibitory influence of E2 on
hypothalamic and pituitary GHRH-R function is the fact
that pituitary responsiveness to GHRH is lowest in rats at
proestrus (18). This pattern is somewhat different from
humans, where GHRH’s effect does not change during the
menstrual cycle (345, 396) and GH responsiveness to
GHRH and GH secretion rate is higher in premenopausal
women than young-adult men (590) (see sect. IIA for
discussion).
11. Extrapituitary central effects
Growth hormone-releasing hormone has few extrapituitary effects, as might be expected considering its
limited distribution within the body. Huge doses (5–10
mg) of GHRH into the lateral brain ventricle of freely
moving rats reportedly induced motor and behavioral
effects and raised blood glucose levels (1008). However,
dispute over the identity of the GHRH material used in
this study (618, 1018) suggests caution in interpreting
these findings.
More reliable are the findings that GHRH promotes
sleep in animals and normal controls. Ehlers et al. (332)
and Nisticò et al. (781) found a significant increase in
SWS and a decrease in time to onset of SWS in rats after
intracerebroventricular or hippocampal injections of
GHRH. Non-REM sleep and REM sleep increased in
both rats and rabbits after intrathecal injection of
GHRH (782). Sleep was reduced in rats when GHRH
action was inhibited by a specific antagonist (784) or by
GHRH antibodies (785).
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in the pituitary but, in addition, is likely to directly regulate the synthesis of GHRH-R. This, in fact, is not expressed in the pituitary of dw/dw mice that lacks functional Pit-1 (612). In line with GHRH action through a
cAMP-dependent pathway, treatment of primary cultures
of AP cells with dibutyryl cAMP strikingly raises GHRH-R
mRNA levels (727). The inhibitory peptide SS presumably
interacts through G protein-mediated suppression of this
cAMP pathway.
Disruption in several steps of the signaling pathway
leading to GH secretion may result in GH deficiency. An
inactivating mutation in the GHRH-R has been found in
the little mouse, a model of isolated GH deficiency, and
similar alterations in receptor function play a role in some
human growth disorders.
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MÜLLER, LOCATELLI, AND COCCHI
(see sect. VIC2) may also reflect altered sensitivity or
activity of central GHRH, the compound was administered systemically to a group of AN patients at meal time,
and caloric intake and macronutrient selection were determined (1049). Growth hormone-releasing hormone
stimulated food intake (especially carbohydrates and
fats) in AN patients but reduced it in anorectic/bulimic
patients or normal controls, with a mechanism apparently
not depending on the subjects nutritional status or the
ability of the peptide to release GH. The authors’ conclusions that low levels of GHRH may contribute to the
restricted eating pattern of AN patients were not consistent with experimental, although inferential, evidence
pointing to an enhanced function of GHRH neurons in AN
(751, 929).
For other potential extrapituitary effects of GHRH,
see section IIIA4.
B. Somatostatin
With the demonstration of stimulatory CNS influences over GH secretion, evidence accumulated of an
inhibitory CNS control, based especially on observations
in subprimate and primate species (749). In humans, elevated plasma GH levels were reported in the diencephalic
syndrome of infancy, a CNS disturbance usually caused
by a tumor of the optic chiasm and anterior hypothalamus
(66, 360). More proof of a hypothalamic inhibitory influence for GH secretion was given by Krulich et al. (578),
who showed that in vitro certain fractions separated from
ovine hypothalamic extracts had consistent inhibitory effects on the release of bioassayable and then RIA GH (see
Ref. 3 for review). These authors were the first to suggest
that GH secretion was regulated by a dual system, one
stimulatory and the other inhibitory. The inhibitory factor
was named GH-inhibiting factor (GHIF).
The isolation, identification, and synthesis several
years later of a tetradecapeptide, GH release-inhibiting
hormone or somatotrophin release-inhibiting hormone
(SRIH or SS) should be credited to Guillemin and coworkers (141), who used a highly sensitive in vitro pituitary assay.
Somatostatin was first identified as a hypothalamic
peptide involved in the physiological inhibitory control of
GH and thyroid-stimulating hormone (TSH) secretion. It
soon became clear, however, that SS was ubiquitous (see
below) and inhibited the secretion of most hormones,
under physiological and pathological circumstances, and
could also inhibit exocrine secretions. Because targets of
SS action were often the same tissues where the peptide
was localized, the concept developed that, in addition to
its endocrine effects, its actions were regionally limited as
a neuroendocrine factor or in adjacent tissues, as an
autocrine or paracrine regulator (880).
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Four systemic boluses of GHRH between 22.00 and
1.00 h caused a significant increase in SWS in male controls which was evident throughout the entire sleep period (984). Entry of the peptide through the circumventricular organs and/or other CNS-permeable sites is the
most likely explanation for these findings (543).
An important question is whether peripheral effects
of GHRH, particularly the GH rise, are responsible for the
increase in SWS. Apart from the observation that the SWS
increase lasts considerably longer than the GHRH-induced GH rise (984), it is noteworthy that exogenous GH
suppresses SWS (701).
The potential of GHRH and potent long-acting analogs (161) for improving the quantity and quality of sleep,
particularly in obese patients and the elderly, where the
endogenous GHRH drive is reduced (754), has not escaped attention (see also sect. IV).
Intracerebroventricular injection of picomolar doses
of GHRH exerts another important effect, centrally mediated and independent of its GH-promoting properties, i.e.,
stimulation of food intake in rats and sheep. At higher
doses, intravenous GHRH also stimulates food intake
(893, 1007). Intracranial mapping studies have indicated
that the SCN/MPOA region of the hypothalamus is a
highly sensitive site for GHRH-induced feeding (1048) and
that this effect depends on PVN for expression. The fact
that the feeding effects of GHRH are exerted at sites
remote from the hypophysial portal system is consistent
with electrophysiological (1043) and anatomic (926) evidence focusing on the neurotransmitter-like properties of
the peptide.
The GHRH signal would contribute to both the circadian pattern of feeding behavior and macronutrient
intake. Microinjection of GHRH increased food intake
during the light phase (behaviorally inactive) of the male
rat’s cycle and either had no effect or reduced food intake
during the dark (behaviorally active) period (349), when
rats eat up to 80% of their daily food requirement.
In support of the view that GHRH is one signal
contributing to the circadian pattern of food intake,
injection of a specific GHRH antiserum into the SNC/
MPOA, at four different periods during the light-dark
cycle, suppressed feeding only at dark onset. This
strongly suggested that GHRH action in the SCN/MPOA
contributes to the feeding burst seen at dark onset
(1047). The protein-selective nature of GHRH-induced
feeding indicated a macronutrient-selective effect during the light-dark period. In rats habituated to two diets
(carbohydrate-fat and protein-fat), microinjection of a
GHRH antiserum into the SCN/MPOA blocked the increase in protein intake normally seen at dark onset but
had no effect on carbohydrate intake (312).
Few data are available on the effects of GHRH on
food intake in humans. Because the higher GH responsiveness to GHRH of subjects with anorexia nervosa (AN)
Volume 79
April 1999
NEUROENDOCRINE CONTROL OF GROWTH HORMONE SECRETION
1. Anatomic distribution
Somatostatin-producing cells are present throughout
the central and peripheral nervous systems, the gut, the
endocrine pancreas and, in small number, in the thyroid,
adrenals, submandibular glands, kidneys, prostate, and
placenta (813, 880). Within the hypothalamus, the majority of SS-positive nerve perikarya lie in the PeVN (360),
but these are also seen in the ARC and VMN (see sect.
IIIA3). They are located close to the third ventricle, in a
few layers parallel to the periventricular wall, within an
area extending from the preoptic nucleus (PON) to the
rostral margin of the VMN (357). Axons from these cells
run caudally through the hypothalamus to form a discrete
pathway toward the midline that enters the ME, where the
nerve endings extend in a compact band throughout the
zona externa.
Not all fibers from the PeVN take this route; a small
proportion of them travels through the neural stalk to the
neurohypophysis where they presumably play a role in
the regulation of the secretion of neurohypophysial hormones, arginine vasopressin (AVP) and oxytocin. Other
fibers project outside the hypothalamus to areas such as
the limbic system; others interconnect, possibly through
interneurons, with several hypothalamic nuclei, including
the ARC where GHRH is synthesized, the PON, and the
VMN, which are involved in regulating reproductive functions, and the SCN, which has a circadian pacemaker
activity (see also sect. IIIA2).
Somatostatin neurons in the anterior PeVN area interact with multiple populations of neurons such as galanin, NPY, GABA, 5-HT, endogenous opioid peptides
(EOP), and others and receive a host of neurochemically
defined terminals (96, 118). In addition to the anatomic
interactions with GHRH, there is also a connection between SS and corticotropin-releasing hormone (CRH) (reviewed in Ref. 96).
Further details on the distribution of SS neurons and
fiber systems are given in section IIIA3.
2. Gene structure and expression
The SS gene in the rat and humans has a simple
configuration, the coding region consisting of two exons
separated by an intron (see Ref. 814 for review). The
59-upstream region contains three regulatory elements,
two promoters, and a cAMP-response element (enhancer). This latter was first identified in the SS gene and is
present in a large number of genes regulated by cAMP
(736). Most agents influencing SS secretion also alter SS
gene expression. Activation of the AC-cAMP pathway
plays an important role in the stimulation of SS secretion
and mediates the effect of several agents physiologically
regulating SS gene transcription (glucagon, GHRH).
Growth hormone secretion is also autoregulated
through the stimulation of SS mRNA (see sect. VIIA).
Gonadal hormones play a significant effect contributing
to the sex-related differences in SS neuronal activity (see
sect. IIB3A).
3. Secretion from the hypothalamus
Somatostatin release from different in vitro preparations is enhanced by K1-induced membrane depolarization, mediated by Ca21 influx (818), cAMP, dopamine
(DA), glycocytopenia, IGF-I, GH, and GHRH (for these
aspects, see sects. IIIA3 and VII, A and B1). Somatostatin-14 is the main form of SS-IR released on K1 depolarization from slices of the rat hypothalamus, implying that
this is the form responsible for hypothalamic neurotransmission (841).
Contradictory results have been reported on how
different neurotransmitters affect SS release, a vital question for understanding their mechanism(s) of action (see
sect. V). Factors related to the different experimental
models used to study SS release in vitro (e.g., hypothalamic slices or explants, embryonic cell cultures, synaptosomes) may hinder evaluation of the neurotransmitter’s
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Many aspects of SS function have already been dealt
with in earlier sections, so in this section we confine
ourselves mainly to its neuroendocrine effects in relation
to the hypothalamic-pituitary unit.
Somatostatin-14 (SS-14), the native form, belongs to
a family of SS-like peptides including NH2-terminal-extended SS (SS-28) (864), a fragment corresponding to the
first 12 amino acids of SS-28 [SS-28-(1O12)], and still
larger forms that vary in molecular size and in different
species from 11.5 to 15.7 kDa.
In vertebrates, SS-14 and SS-28 have evolved from
separate encoding genes in fish to a single gene encoding
a common precursor that is differentially processed to
generate tissue-specific amounts of the two peptides
(816).
The SS-like peptides are multifunctional and are synthesized and located in most brain regions as well as in
peripheral organs, especially the gastrointestinal tract of
both vertebrate and invertebrate species (reviewed in
Refs. 814, 1081). Somatostatin-14 is the predominant form
and usually has the same sequence in different species.
Both SS-14 and SS-28 have partially overlapping but distinct bioactions and act through different receptors (see
below). In neural tissues, SS-14 predominates (ratio 4:1 in
the hypothalamus). There is virtually no SS-28 in the
stomach and the duodenum, but lower down the gut SS-28
is the most important molecular form (306).
Both SS-14 and SS-28 have similar potency and bind
all cloned receptors with high affinity (see sect. IIIB4). The
biological significance of the two forms in relation to
neuroendocrine function, however, remains to be determined.
531
532
MÜLLER, LOCATELLI, AND COCCHI
(797) have provided in vitro proof of a direct action of
gonadal steroids on SS-producing neurons. The former
authors showed that SS release from hypothalamic
fragments in culture was increased if donor male rats
had been castrated, this effect being partially reversed
by testosterone treatment. The second group showed
that exposure of cultured fetal brain cells to testosterone had an inhibitory effect on SS release and production, as indicated by the decrease in its intracellular
concentration and content in the medium. The reason(s) for the discrepancy between these results and
reports that androgens stimulate SS mRNA is not
known but might reflect the independent effects of
gonadal steroids on gene transcription and/or on the
processing, storage, or release of SS, as has been demonstrated for other neuropeptides (73).
Different from the androgens, estradiol inhibited SS
release from fetal brain cultures (352), a finding consistent with previous reports that ovariectomy increased the
amount of IR-SS in the ME and that this effect was reversed by estradiol (439). Reduction of SS release would
be related to the raised baseline GH levels observed in
female rodents (524, see also sect. IIA).
4. Receptors
Parallel to studies of the effect of SS and its analogs
on endocrine and exocrine secretion were investigations
into their mechanisms of action. Plasma membrane receptor binding of SS, and especially of analogs resistant to
degradation, was demonstrated on all target tissues (151).
Receptor binding was demonstrated in vitro to plasma
membrane preparations and to tissue sections (586) and
in vivo by radionuclide scanning (577).
Shortly after the discovery of SS-28 as a second endogenous ligand, the existence of two populations of SS
receptors (sstr) was proposed, based on the different
receptor binding potencies and actions of SS-14 and SS-28
in brain, pituitary, and islet cells (817, 979). The heterogeneity of sstr became increasingly apparent when crosslinked studies revealed a wide array of proteins of different molecular weights that bound the labeled peptide.
Cloning of the sstr family disclosed the overall complexity
of the system.
Cloning of five separate sstr genes confirmed the
existence of molecular subtypes and indicated a greater
heterogeneity in this receptor family than previously suspected (see Ref. 815 for review). Four of the human genes
are intronless, the exception being sstr2, which gives rise
to the spliced variants sstr2a and sstr2b that differ only in
the length of the cytoplasmic COOH tail. There are thus
six putative sstr subtypes highly conserved in size and
structure, displaying the putative seven-transmembrane
domain typology typical of G protein-coupled receptors;
sstr1 and sstr4 show the highest degree of sequence iden-
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action in vivo. Comparison in vivo is already difficult
because of the complex neuronal circuitry of hypothalamic-extrahypothalamic connections and accessibility of
specific sites.
Acetylcholine has been reported to inhibit (888) or to
have no effect (650) on SS-LI release from hypothalamic
fragments and to enhance SS-LI release from dispersed
cell cultures (834) and portal blood (228), whereas enhancement of the cholinergic tone in humans appears to
suppress SS release (see sect. VA3 and Ref. 749 for discussion). Dopamine in micromolar concentrations can
release SS-LI from incubated hypothalamic tissue (772)
and synaptosomal preparations (1077) and raise the SS-LI
concentration in the pituitary portal blood (228). However, DA did not have this effect when the whole MBH
was exposed to physiological concentrations of the transmitter (339), a finding more in line with in vivo results
(see sect. VA1D). Norepinephrine (NE) stimulated or had
no effect on SS-IR release from the ME (650, 771),
whereas in vivo an inhibitory role on SS function is suggested (see sect. VA1A). Finally, GABA inhibited SS-LI
release from hypothalamic cells in cultures, an action
blocked by the GABA receptor antagonist bicuculline
(385), and in line with evidence obtained in vivo (see sect.
VA5B1). Somatostatin release in vivo is stimulated by a
number of neuropeptides, including thyrotrophin-releasing hormone (TRH) (544), CRH (188, 730), and GHRH
(42). Each of these peptides administered centrally inhibits GH secretion, and these effects can be completely
counteracted by pretreatment with SS antibodies.
In contrast to CA and ACh, intraventricular injection
of 5-hydroxytryptamine (5-HT) did not affect SS-LI release into the portal blood (228), whereas centrally injected bombesin (1) or NT (3) was effective and EOP
either inhibit (326) or have no effect (957) on SS-LI release.
A) SEX-RELATED DIFFERENCES. As already mentioned in
section IIA, SS neurons play an important role in sexrelated differences in GH secretion. A significant sexrelated difference is observed in the gene expression of
hypothalamic SS (40, 238, 1044) and hypothalamic content of SS in rats (383, 440), mainly depending on gonadal
steroids, particularly by androgens.
In castrated rats, testosterone or dihydrotestosterone
raises SS mRNA levels (40, 238, 463, 1131), and male rats
have significantly more androgen receptors than females
in the PeVN (903). The sexual dimorphism of SS gene
expression is evident as early as 10 days of age and
persists throughout development, whereas GHRH gene
expression is sexually dimorphic only in the late neonate
and adult (40). It appears, therefore, that in male rats
androgens influence SS neurons through organizational
and activational roles while the sex steroids can only
activate the GHRH system.
Fernandez-Vasquez et al. (352) and Ono and Miki
Volume 79
April 1999
TABLE
533
NEUROENDOCRINE CONTROL OF GROWTH HORMONE SECRETION
1. Pattern of expression of somatostatin receptor subtypes in central nervous system
sstr2
sstr3
sstr4
sstr5
11
11
,1
.1111
11
1
11
11
1111
,1
1
1
1
1
11
11
1
11
,1
1
1
11
1111
,1
1
1
1
1
1
11
11
111
11
1
1
11
11
.1111
1
1
,1
1
,1
11
1
1
,1
,1
,1
11
11
ND
,1
1
1
,1
.1111
11
11
11
11
11
ND
11
11
ND
ND
.1111
ND
ND
Relative pattern of somatostatin receptor (sstr) expression was determined as follows: autoradiographic densities were quantitated using a
laser densitometer in 2-dimensional scan mode to obtain a densitometric value for entire autoradiographic band. Density of each band is expressed
relative to density for hippocampus, which was set to equal 11. ND signifies that sstr subtype was not detected. Thus comparisons should be made
within a given subtype between regions rather than between subtypes. [From Bruno et al. (151); copyright The Endocrine Society.]
tity. The individual subtypes show a remarkable degree of
structural conservation across species.
All sstr subtypes bind SS-14 and SS-28 with high
affinity; sstr1 and sstr4 have weak selectivity for SS-14,
whereas sstr5 appears to be SS-28 selective (816). The
octapeptide analogs octreotide, lanreotide, and vapreotide, now used clinically, bind to only three types of
sstr, with high affinity for types 2 and 5 and moderate
affinity for type 3 (152). Therefore, the receptor family can
be divided into two subclasses: 1) sstr2, sstr3, and sstr5
that recognize these analogs and constitute one subgroup,
and 2) sstr1 and sstr4 that react poorly with these compounds and make up another subgroup.
Ligand activation of endogenous sstr is associated
with a reduction in intracellular cAMP and [Ca21]i concentrations and stimulation of protein tyrosine phosphatase due to receptor activation of five major membrane
signaling pathways each involving a pertussis toxin-sensitive GTP-binding protein and comprising 1) receptor
coupling to adenylyl cyclase, 2) receptor coupling to K1
channels, 3) receptor coupling to Ca21 channels, 4) receptor coupling to exocytotic vesicles, and 5) receptor
coupling to protein phosphatase (see Refs. 337, 816 for
reviews).
The sstr are coupled to several populations of K1
channels whose activation causes hyperpolarization of
the membrane leading to cessation of spontaneous action
potential activity and a secondary reduction in [Ca21]i
(962). Somatostatin also acts directly on high-voltagedependent Ca21 channels to block Ca21 currents (501). A
further mechanism would be inhibition of Ca21 currents
through induction of cGMP, activation of cGMP protein
kinase, and phosphorylation-dependent inhibition of Ca21
channels (712).
A) TISSUE EXPRESSION OF RECEPTOR SUBTYPES. Expression
of mRNA for sstr confirmed their wide tissue distribution
with a particular pattern for each receptor type, which
does not rule out overlap, because few tissues or cells
have the mRNA for only one receptor type (151). Adult rat
pituitary features all five sstr mRNA, and the adult human
pituitary expresses the four subtypes 1, 2, 3, and 5 (286,
815). All five genes are expressed by the major pituitary
cell subsets with high levels of sstr4 and sstr5 in rat
somatotrophs and of sstr2 mRNA in rat thyrotrophs (786).
The finding that sstr5 mRNA is more abundant than sst2
mRNA in the pituitary is consistent with fact that SS-28 is
more potent than SS-14 for inhibiting GH and TSH secretion.
All five sstr mRNA are variably expressed in the brain
(151) (Table 1); sstr1 and sstr2 were found in the highest
concentrations in cortex, amygdala, hypothalamus, and
hippocampus, whereas the highest level of sstr3 was in
the cerebellum, a unique finding given the relatively low
receptor density in this area (151). Expression of sstr4
was observed throughout the CNS, but this isoform was
not found in the cerebellum. Sstr5 showed a unique pattern, occurring mainly in the hypothalamus and POA,
which suggests it has a highly specialized role in the CNS
(151).
Future attempts to correlate the regional distribution
of sstr subtypes in the CNS with the functional properties
of SS will call for the development of ligands that bind
selectively and with high affinity to each subtype. Nevertheless, the high levels of sstr1, sstr2, sstr3, and sstr4 in
such brain regions as cortex, hippocampus, hypothalamus, and amygdala suggest they are involved in processing integrative functions.
Of particular interest for our topic is the distribution
of sstr and mRNA expression in the hypothalamus, where
it provides evidence of multiple receptor subtypes. Conventional film autoradiography suggests sstr are not very
abundant in hypothalamic regions, although desaturation
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Hypothalamus
Hippocampus
Striatum
Amygdala
Olfactory tubule
Midbrain
Thalamus
Olfactory bulb
Cortex
Cerebellum
Medial pons
Preoptic area
Nucleus accumbens
Spinal cord
sstr1
534
MÜLLER, LOCATELLI, AND COCCHI
strated in rat anterior pituitary and islet cells (31, 737).
Agonist-dependent desensitization responses have been
reported after SS pretreatment for 2 h or less. Longer
agonist exposure, 24 – 42 h, upregulated sstr in GH4C1
cells and RIN 5f cells (866, 993). In CHO-K1 cells expressing all the five human sstr subtypes, sstr2, sstr3, sstr4, and
sstr5 induced rapid agonist-dependent internalization of
the ligand over 60 min; sstr1 caused virtually no internalization. Prolonged agonist treatment led to differential
upregulation of some of the sstr: after 22 h, the agonist
upregulated sstr1 by 110%, sstr2 and sstr4 by 22–26%,
whereas sstr3 and sstr5 showed no change (493).
C) REGULATION OF GENE EXPRESSION. Expression of sstr
subtypes is regulated by hormones. Glucocorticoids upregulate sstr1 and sstr2 mRNA after short-term exposure,
whereas prolonged treatment inhibits transcription of
both genes (1109). Estrogens upregulate mRNA expression of sstr2 and sstr3 in rat prolactinoma cells (1102) and
in breast cancer cells (1110). Metabolic derangements
such as starvation or diabetes lower sstr3 mRNA levels in
the pituitary and sstr5 mRNA levels in the hypothalamus
(150), but the significance of this is still obscure.
Four sstr promoters have been characterized and
contain consensus sequences for a variety of transcription factors. Rat sstr1 gene shows AP2 and Pit-1 binding
sites (464); human sstr2 and sstr4 contain several AP1 and
AP2 sites that may confer cAMP responsiveness (438).
5. Pituitary and extrapituitary effects
The physiological role of SS in pituitary responsiveness to hypothalamically driven stimulatory influences,
especially those of GHRH, and thus contributing to the
pulsatile secretion of GH, has already been extensively
discussed. Here, brief consideration is given to some in
vivo inhibitory effects of SS on the pituitary, especially in
conditions of stimulated GH release. These inhibitory effects have been shown in a number of species in addition
to rodents, e.g., dogs, monkeys, and humans. In humans,
SS prevented levodopa, exercise, hypoglycemia, and
sleep-evoked GH secretion and also lowered GH levels in
diabetic and acromegalic subjects (749).
Somatostatin may not merely inhibit GH secretion,
but under appropriate conditions may also trigger GH
release, through an intrahypothalamic site of action.
Within the PeVN, SS in fact seems to operate an ultrashort
feedback loop to inhibit its own secretion. The recent
demonstration that the distribution of neurons expressing
sstr1 mRNA in the hypothalamus overlaps the distribution
of SS has led to the proposal that sstr1 may be the autoreceptors (816).
Furthermore, SS can directly act on AP thyrotrophs
to inhibit TSH secretion or it may act on the hypothalamus to inhibit TRH secretion (880). Thyroid hormones
can stimulate SS release, although this effect appears to
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techniques considerably increase the amount of binding
(608). Of the five cloned sstr subtypes, four are synthesized in the hypothalamus, the expression of sstr5 being
particularly abundant (151). In situ hybridization showed
sstr mRNA-containing cells in all hypothalamic areas,
whereas sstr mRNA cells were restricted mainly to the
ARC, an area rich in both sstr1 and sstr2 mRNA (151).
The presence of sstr close to a subpopulation of ARC
neurons, some corresponding to GHRH neurons, has been
already discussed (see sect. IIIA3). They allow cross talk
in the GH regulatory pathway between the PeVN and the
ARC. Sstr1, sstr2, and sstr3 mRNA have been located in the
ARC and may therefore be implicated in the modulation
of GHRH secretion by SS (81, 948).
In addition, sstr1 mRNA in the ARC appears to be
regulated by GH, which further implicates this receptor
gene in the feedback regulation of GH secretion by the
ARC (448, see also sect. VIIA). In the reverse direction, the
ARC sends projections that may contain galanin and proopiomelanocortin (POMC)-derived peptides to the PeVN
(see sect. IIIB1). These feedback mechanisms involving SS
neurons play an important role in driving the pulsatile
secretion of GH.
Analysis of secreting and nonsecreting human pituitary tumors (monoclonal in origin) and rodent pituitary
tumor cells provided evidence of several sstr genes and
probably receptor proteins expressed in the same tumor
cell. Both sensitive to octapeptide analogs, sstr2 and sstr5
are expressed most frequently, whereas the expression of
sstr3 and sstr4 is much less common (815). The common
presence of sstr2 and sstr5 in pituitary tumors helps explain their responsiveness to octreotide, for which these
receptor subtypes have high affinity.
Somatostatin receptors are expressed not only in a
variety of pancreatic and intestinal tumors (glucagonomas, insulinomas, pheocromocytomas), but also in most
solid tumors; sstr1, sstr2, sstr3, and sstr4 have been shown
on endocrine tumors, but sstr5 mRNA has not been reported (815).
It would seem, therefore, that sstr and subtype-specific analogs offer new opportunities for locating a variety
of neoplasms and their metastases, inhibiting their secretory products, and providing access to the interior of the
cells themselves, since SS analogs can be internalized. An
antiproliferative effect has also been suggested for these
analogs (481).
B) DESENSITIZATION. Patients undergoing long-term therapy with SS analogs develop tolerance to side effects such
as inhibition of insulin and TSH secretion. However, the
inhibitory effect on secretory tumors persists often for
many years. This suggests that sstr in normal tissues are
regulated differently from their antiproliferative effects
on tumors (481).
Desensitization in normal cells is mainly due to agonist-dependent internalization of the receptors, as demon-
Volume 79
April 1999
NEUROENDOCRINE CONTROL OF GROWTH HORMONE SECRETION
IV. GROWTH HORMONE-RELEASING PEPTIDES
Many years before native GHRH was isolated and
sequenced, a new series of peptides with strong GHreleasing properties had been identified (732). The size
and scope of this new class, known jointly as GHRP or GH
secretagogues (GHS) and comprising nonpeptide pharmacological analogs, have grown enormously.2
The first GHRP were discovered in 1977 by Bowers et
2
text.
The acronyms GHRP and GHS are used interchangeably in the
al. (133). They were derivatives of the pentapeptide Metenkephalin but had no, or very little, opioid activity. The
pentapeptide Tyr-D-Trp-Gly-Phe-Met-NH2 had relatively
weak potency as a GH secretagogue and was active only
in vitro; however, it served as a model to design new
molecules with much greater activity (Fig. 7).
As described by Momany et al. (733), the design
approach consisted of using “structural concepts” derived
from conformational energy calculations in conjunction
with peptide synthesis and biological activity data.
Unique, and the key to the success of this approach, was
the insertion of structural data derived from conformational energy calculations into the design cycle, before
synthesis of the peptide, as well as after obtaining experimental data. A number of structurally related GH-releasing peptides were designed, with greater GH-releasing
activity. Growth hormone-releasing peptide-6 (Fig. 7) was
considered particularly suited because of its potent GHreleasing activity in vitro and in vivo.
The GH-releasing activity of GHRP-6 was demonstrated in a range of species, i.e., monkeys, sheep, pigs,
chicks, steer, and rats (134, 276, 322, 575, 655), as well as
in humans (135, 504). Growth hormone-releasing peptide-6 was orally active in rats, dogs, monkeys, and humans (132, 1079), and interestingly, it was 5.3–30 times
more effective in monkeys than in rats or dogs. In humans, 1 mg/kg GHRP-6 administered as a bolus injection
released more GH than GHRH-44 given at the same dosage and by the same route (131, 135). In healthy humans,
comparable amounts of GH were released after intravenous 1 mg/kg GHRP-6 or 300 mg/kg oral GHRP-6 (132). In
healthy volunteers, clear-cut GH release also occurred
after intranasal administration of 30 mg/kg GHRP-6; when
15 mg/kg GHRP-6 was administered intranasally every 8 h
for 3 days, serum GH and IGF-I levels increased significantly (466). In these studies, the stimulation of GH release appeared to be specific and divorced from concurrent adverse effects, with the exception of occasionally
mild sweating.
Growth hormone-releasing peptides are the most
effective GHS in experimental animals; their action is
greater than that of GHRH, with which it is synergistic,
and is well preserved in aged rats when GHRP are
administered combined with GHRH (1080). In the same
model, chronic treatment with a GHRP-6 analog,
hexarelin (296), maintained its GH-releasing effect for
up to 2 mo, did not change circulating IGF-I levels, and,
interestingly, reduced the hypothalamic somatostatin
mRNA content to the levels of young controls (189). In
senescent dogs, a 16-wk huge daily dose of hexarelin
initially primed and then blunted the GH response to
acute hexarelin, although this was easily restored after
treatment withdrawal. Despite this effect, hexarelin
raised the indices of spontaneous GH pulsatility, reduced bone resorption, and improved some biochemi-
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be indirectly mediated through a direct action to increase
GH gene transcription (see sect. VIA2). Somatostatin in
the AP can also inhibit prolactin secretion from normal
and adenomatous glands in humans and GH4C1 tumor
cells and ACTH secretion from human and mouse AtT-20
ACTH-producing tumors (817) (for interactions between
the SS system and HPA axis, see sect. VIA1). Pituitary sstr
involved in the effects of SS or its analogs have already
been discussed.
Somatostatin has no effect on basal levels of GH
synthesis, gene transcription, mRNA, or somatotroph proliferation in rat or bovine pituitary cell cultures (73, 104,
381, 960, 1020) or on the elevation of rat GH mRNA
induced by exogenous cAMP (963). It also does not influence GHRH-stimulated rat GH transcription, although it
reduced intracellular cAMP levels (381). However, it attenuated the GHRH-induced increase in somatotroph proliferation (104) and the expression of c-fos in the rat (103).
Limited data are available on how SS maintains normal GH synthesis and body growth in vivo. Despite AP
concentrations of SS two to three times higher than any
other body tissue, transgenic mice expressing a metallothionein-SS fusion gene grew at a normal rate (638) (for
details, see Ref. 377).
The extensive localization of SS in the CNS indicates
its neurotransmitter and/or neuromodulatory role. In recent years attention has focused especially on its function
in certain CNS areas such as the cortex or the hippocampus, with clinical implications for cognitive functions and
Alzheimer’s disease, and in the striatum, with implications
for movement control in Parkinson’s disease (936).
Somatostatin also plays an important physiological
role in the pancreas and gut (814, 941). It regulates the
endocrine and exocrine functions of the stomach, intestine, and pancreas and the motor functions of the first
two, partly by local or paracrine mechanisms and partly
through the circulation as a true endocrine factor. Thus
not only does SS exert its regulatory actions within organs
that have SS-containing D cells, but it also ensures a more
integrated control over the nutrient flux by acting on
remote target organs containing no D cells (941).
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MÜLLER, LOCATELLI, AND COCCHI
Volume 79
cal and morphological muscular indices, although it did
not change plasma IGF-I levels (210).
A. Structure-Activity Relationships
These peptides all need a very specific configuration
of selected aromatic rings to specifically stimulate GH
release. The native pentapeptide served as the starting
model for the development of more potent GHRP. The
prototype was GHRP-6, from which many different analogs, ranging from 7- to 3-amino acid residues (GHRP-1,
GHRP-2, hexarelin, and so on) have been synthesized and
shown to be active also in humans. Newer peptides with
smaller molecular size and less complexity have now
been synthesized in the hope of understanding the minimal tridimensional structure required (295, 1115).
Homologous desensitization occurs very rapidly in
vitro after exposure to GHRP, whereas the cells remain
sensitive to GHRH (335). Although peptidyl GHRP were
initially introduced as specific GHS, small rises in serum
cortisol and prolactin were seen in humans after intravenous infusion, bolus injection, or intranasal administration of these compounds (135). Stimulation of GH and
prolactin secretion from primary pituitary cell cultures
has also been reported (692). The real impact of these
observations in situations of long-term peptide and nonpeptide GHS therapy is not known.
Despite their potential for affecting the secretion of
more than one AP hormone (see also sect. IVE), nowadays
GHRP are the most effective GHS known and could be
profitably used in humans with GH hyposecretory disturbances to promote a pattern of GH secretion that mimics
the physiological situation better than exogenous GH.
B. Nonpeptidyl Growth Hormone Secretagogues
The strategy of stimulating pituitary GH secretion by
activating the endogenous machinery is an attractive idea
that has been pursued with the synthesis of nonpeptidyl
mimics of GHRP-6; this research has led to the discovery
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FIG. 7. Milestones of GH-releasing peptide development. [Modified from Deghenghi (295).]
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NEUROENDOCRINE CONTROL OF GROWTH HORMONE SECRETION
C. Site(s) and Mechanism of Action
Growth hormone-releasing peptide may act on the
pituitary (407, 628), although experimental evidence indicates that they are also active in the hypothalamus (314,
335, 966, 1037). Specific binding sites for GHRP have been
detected in the pituitary and hypothalamus in rats and
pigs (261, 856, 953, 1062) and in rats also in several
extrahypothalamic structures, including the substantia
nigra, CA2 and CA3 subfields, dentate gyrus of the hippocampus, and medial amygdaloid nucleus. The membrane binding sites are specific, reversible, saturable, as
well as time, temperature, pH, and concentration dependent.
Studies on pituitary and hypothalamic membranes
suggest these may be multiple binding sites with different
affinities for peptidyl and nonpeptidyl GHRP. In the rat
pituitary and hypothalamic membranes, MK-677 would
bind preferentially to a high-affinity site (dissociation constant in the picomolar range), whereas medium-affinity
(nanomolar range) and low-affinity (millimolar range)
sites for the GHRP would primarily bind GHRP-6 (261,
856, 953). Hong et al. (488) have now directly demonstrated the existence of receptor subtypes for the GHRP
using a photoactivable derivative of hexarelin. This subtype is apparently distinct from the recently cloned GHRP
receptor.
Compounds such as bombesin, neuromedin C, and
substance P (SP) did not influence these binding sites,
whereas GHRH-(1O29)-NH2 and SP were potent inhibitors of pituitary and hypothalamic GHRP-6 binding (261,
953, 1062). Competition by SP antagonists was consistent
with the reported ability of the antagonists to decrease
the release of GH by GHRP-6 in vitro and in vivo in a
dose-dependent manner (107, 226). Because SP antagonists selectively blocked the GH release elicited by GHRP
but not by GHRH and SP was ineffective in vivo and in
vitro, these compounds presumably interact with GHRP
receptors. More surprising was the inhibitory effect of the
GHRH analog, since GHRP receptors are different from
GHRH receptors, as suggested by the lower GH-releasing
activity of GHRP in vitro, the additive effect of the two
stimuli, and the fact that GHRP-6 and GHRH antagonists
do not competitively antagonize each other’s responses,
with the only exception being GHRP-2, whose action is
inhibited by GHRH antagonists (1107).
The finding of specific binding sites for peptidylGHRP in humans has confirmed the highest specific binding in the hypothalamus and pituitary but also has shown
their presence in the choroid plexus and the cerebral
cortex (746). Specific binding sites in extrahypothalamic
areas (see also above), coupled with the accessibility to
the brain of different GHRP, even when administered
peripherally (314, 315, 963), suggests these compounds
may affect brain function. Accordingly, peripherally administered GHRP modified the sleep pattern in humans
(267, 268, 372) and stimulated food intake in the rat (642)
and humans (220).
Identification of the sites(s) of action of GHRP is of
major importance; their much greater effectiveness in
vivo than in vitro suggested a major hypothalamic site
(136, 468, 624, 1037), although this view has to be tempered by the observation that after hypothalamo-pituitary
disconnection, GHRP released GH in rats (164, 654) or
sheep (364). In pigs, GHRP are effective in intact animals
and those with a hypophysial transection (468), although
in the latter GH release was reduced and depended on the
interval from surgery.
In contrast to most of these findings, GHRP were
unable to stimulate GH release in children and adults with
pituitary stalk transection, despite their responsiveness to
GHRH (465, 631, 861). Overall, these results suggest that
the hypothalamus is the primary site of action of GHRP at
least in humans and pigs.
In our studies in rats with complete surgical ablation
of the medial basal hypothalamus, the GH release elicited
by hexarelin was reduced 1 wk after surgery, whereas the
response to GHRH was maintained. Thirty days postsurgery, the GH response to an acute challenge with hexarelin or GHRH was similar to that with hexarelin 7 days
postsurgery (1037). It would seem, therefore, that the
decreased pituitary GH content resulting from the chronic
GHRH deprivation was not responsible for blunting the
GH response to GHRP.
1. Hypothalamic mechanisms
Briefly reviewed here are the possible mechanisms
underlying the GH-releasing activity of GHRP.
A) GHRH. In sheep, direct measurement of hypophysiotropic neurohormones released into the portal blood
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of a series of new compounds, the benzolactam secretagogues, reviewed in Reference 965 (Fig. 7).
Structural modifications of the original molecule led
first to the isolation of L-692,429, which was well tolerated
in animals and humans, and then to the synthesis of new
compounds culminating in the selection for clinical use of
L-163,191 and its mesylate salt MK-677, which offers superior oral potency and duration of action (811). These
new molecules are very effective in eliciting GH release,
although in vivo they also stimulate the release of ACTH
and prolactin. MK-677 also raises fasting blood glucose
and insulin concentrations in humans (220, 400, 467).
Although the oral bioactivity of this compound is greater
than the peptidyl secretagogues, the clinical use of these
molecules is currently hampered by our inadequate understanding of the pharmacodynamic profile required for
optimal efficacy.
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MÜLLER, LOCATELLI, AND COCCHI
trations remained higher than baseline, suggesting that
the GHRP-6 had reduced SS inhibitory influences on the
pituitary. Consistent with these findings, in rats, intracerebroventricular octreotide completely blocked the GH
release induced by GHRP-6 administered centrally 20 min
later. Because intracerebroventricular octreotide did not
affect the GH release stimulated by intravenous GHRH,
SS was presumably acting as a functional antagonist of
GHRP-6 at a central site. This was confirmed by Dickson
and Luckman (315), who found the GHRP-6- and MK0677-induced c-fos protein expression was attenuated in
the ARC after intravenous or intraventricular octreotide.
Data in humans also point to GHRP antagonism of SS
effects. The GH-releasing effect of hexarelin was partly
refractory not only to inhibition by compounds stimulating hypothalamic SS release but even to a dose of SS fully
effective in suppressing the GH response to GHRH (51, 53,
645). Moreover, administration of GH abolished the GH
response to GHRH, but only blunted the GH response to
hexarelin (50, 674). In view of the GH autofeedback on
hypothalamic release of SS (see sect. VIIA), this indicates
that hexarelin had counteracted the GH-induced somatostatinergic hyperactivity. Results with oral MK-677 also
suggest that nonpeptide GHS may functionally antagonize
SS action (220).
C) THE UNKNOWN FACTOR (U FACTOR). Although many
reports have clearly shown that GHRH may be necessary
for GHRP to exert their full effect, none has clearly indicated a mechanism(s) that would account satisfactorily
for the synergistic effect of GHRH and GHRP. Bowers et
al. (136) postulated that GHRP stimulated an unknown
endogenous hypothalamic factor (named U factor) which,
in combination with GHRH, would stimulate GH release
in rats with hypothalamic ablation (1037). However, the
stimulatory effects of GHRP in rats with selective GHRH
deficiency (624) also suggest a mechanism mediated by an
endogenous hypothalamic non-GHRH factor, whose existence and nature are still elusive.
2. Pituitary mechanisms
A) EFFECTS ON GH RELEASE. Sufficient experimental evidence exists that GHRH and GHRP act on the pituitary
through different mechanisms, and very likely through
different receptors. Somatotroph cells that are maximally
stimulated with GHRP can release more GH in response
to GHRH, and vice versa (223, 436). Moreover, homologous but not heterologous desensitization is seen after
continuous pituitary exposure to GHRP or GHRH (113,
219, 245, 1106).
It was thought initially that GHRP-6 acted on the
GHRH receptor, since it did not elicit GH release in the
lit/lit mouse, an animal model with a point mutation in
the GHRH receptor (433) (see sect. IIIA8B). However,
investigations using cultures of human somatotrophino-
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showed that one GHRP, hexarelin, raised GHRH concentrations without altering SS concentrations (446). Supporting the involvement of GHRH was the finding that
GHRP partially lost their ability to stimulate GH release in
adult rats passively immunized against GHRH (88, 245,
266). Systemic or intraventricular doses of GHRP-6 or the
nonpeptidyl analogs caused c-fos accumulation and electrical excitation of putative GHRH neurons in the ARC
(313), and c-fos mRNA was also induced in GHRH and
NPY ARC neurons after systemically administered KP-102
or GHRP-6 (315, 537, 963). More direct proof for GHRPGHRH interactions was provided by autoradiographic in
situ hybridization studies. They showed that in the rat
MBH there was extensive overlap between GHRP-R and
GHRH hybridizing cells in both the ARC and VMN nuclei
(1011a).
However, other findings suggest GHRH is not necessarily involved. In dogs and humans, GHRP further increased the GH release induced by a maximal effective
dose of GHRH (135, 823), and reportedly, the GH response to GHRP alone is considerably greater than to
GHRH (129 –131, 135). We showed in neonatal rats that
removal of GHRH and SS by passive immunization did not
affect the GH-releasing activity of GHRP-6 or hexarelin
(624), and there is also clear-cut, although attenuated, GH
release by administration of the same GHRP in 10-day-old
pups passively immunized against GHRH since birth (624,
628). Supporting the existence of independent mechanisms of action for GHRP and GHRH, at least under some
circumstances, is also the observation that a series of
peptidyl and nonpeptidyl GHRP at low doses did not
affect GHRH release from freshly removed rat hypothalami and, at millimolar concentrations, even inhibited
GHRH release, suggesting an ultrashort-loop feedback
with GHRH (569).
Growth hormone-releasing hormone activation thus
appears to be an intermediate, but not obligatory, step of
GHRP action; an intact hypophysial stalk is mandatory for
maximal GH response, and finally, the pituitary component of the action of these compounds is not of major
importance.
B) SS. Somatostatin involvement in GHRP action is
less controversial than that of GHRH. Somatostatin did
not seem to be directly involved in the GHRP action in
adult rats passively immunized against SS (266), and similar conclusions were reached in the infant rat (94). Other
experiments indicate that GHRP may even stimulate SS
secretion from hypothalamic fragments (452). However,
SS may play an indirect role by functioning as a GHRP
antagonist in the pituitary (245).
In conscious rats, continuous subthreshold GHRP-6
infusion together with repeated injections of GHRH induced GH responses that were uniform and greater in
magnitude than those of rats given GHRH alone. Interestingly, between repeated GHRH boli, serum GH concen-
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NEUROENDOCRINE CONTROL OF GROWTH HORMONE SECRETION
mas showed a GH responsiveness to GHRP-6 in all adenomas, whereas only one-half of them responded to
GHRH (883). As an alternative, despite the mutually exclusive pituitary binding sites for GHRH and GHRP, the
postreceptor activity triggered by GHRH would be instrumental to GHRP action (335).
In contrast to the marked synergy in vivo, only additive or mild synergistic effects were evident when GHRP
and GHRH were coincubated in vitro (21, 62, 113, 134).
It is widely recognized that GH release induced by
GHRH is paralleled by an increase in cAMP titers in the
pituitary, followed by the opening of VOCC (see sect.
21
IIIA7). The ensuing rapid increase in [Ca ]i promotes GH
release. In contrast, GHRP-6 had no such effect on cAMP
(223, 1107), but there was a synergistic increase of cAMP
levels when GHRP-6 and GHRH were administered together (223).
Although a precise definition of the molecular mechanism(s) of action of GHRP is still lacking, these compounds elicit an increase in [Ca21]i from an extracellular
source, since it was blocked by the chelation of extracellular calcium or incubation with calcium channel blockers (21, 919). It has also been shown that GHRP-1 and
GHRP-6 depolarize rat pituitary cell membranes, leading
to opening of VOCC (857), and it has been proposed that
GHRP-6 and L-692,429 may act, at least in part, through
activation of the protein kinase C pathway (224, 225).
Pong et al. (856) have described a specific binding site for
GHRP in porcine and rat pituitary membranes distinct
from that for GHRH and with the properties of a new G
protein-coupled receptor. Van der Ploeg and co-workers
(491) reported the cloning of a receptor for GHRP-6 and
nonpeptidyl GHS.
All in all, there is abundant experimental evidence
that the GHRP operate through common cellular mechanisms, involving the activation of a receptor(s) different
from that of GHRH and of intracellular mechanisms different from the cAMP pathways. It would seem, however,
from some studies that the second messengers activated
by GHRP in somatotrophs may vary depending on the
species considered (184a). Although the GHRP receptor
or, most likely, one of its subtypes, has been cloned in
humans, rats, and swine (491, 695), we still have nonconfirmation of the existence, and the nature, of the purported endogenous GHRP ligand. Figure 8 depicts schematically the hypothetical mechanisms underlying the
GH-releasing properties of GHRP.
B) EFFECTS ON GH SYNTHESIS. The GH synthesis in the
pituitary is under the positive control of GHRH (see sect.
IIIA7), an effect which involves cAMP activation but appears to be independent from changes in [Ca21]i (73). It
was therefore of interest to investigate whether GHRP
plays a role in the control of GH biosynthesis. There are
only very few reports about GHRP effects on GH mRNA
levels. In our own studies, a five-day treatment with
FIG. 9. Effects of 3–10 days of treatment with hexarelin (HEXA) on
GH mRNA levels in infant rats. Pups were treated as described in legend
to Fig. 1. Because acute challenge with hexarelin had no effect on GH
mRNA levels, in each experimental group data obtained from rats challenged with hexarelin and saline were pooled. Data are expressed as
means 6 SE of 6 determinations. NRS, normal rabbit serum; GHRH-Ab,
GH-releasing hormone antibody. * P , 0.05 vs. indicated group. [From
Torsello et al. (1038).]
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FIG. 8. Mechanisms underlying GH releasing effects of GH-releasing
peptide. Solid line refers to a probable mechanism; dotted line refers to
an hypothetical (?) mechanism. Functional, reciprocal interaction between GHRH and somatostatin neurons are also indicated (see text for
details).
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MÜLLER, LOCATELLI, AND COCCHI
D. Human Studies
Different peptidyl and nonpeptidyl GHRP are very
effective to stimulate GH secretion in humans (135). Prolonged infusions of GHRP-6 enhanced pulsatile GH secretion and raised plasma IGF-I concentrations (466, 492,
521; see also below). A challenge with GHRP-6 at the end
of the infusion elicited an attenuated GH response, not
due to depletion of GH stores, since a challenge with
GHRH stimulated GH release (492, 521). Maximally effective doses of GHRP were more effective than maximally
effective doses of GHRH (135, 137, 403), and nonpeptidyl
GHRP were clearly less potent than peptidyl GHRP (309,
335, 400, 692).
In line with the results of preclinical studies, experimental evidence in humans indicates that GHRP potentiate the GHRH-induced GH release (51, 135, 137, 422,
823) and, as maintained before, induce homologous but
not heterologous desensitization (287, 409, 492, 521,
1035), confirming that also in humans GHRP and GHRH
act on different receptors and activate different postre-
ceptor pathways. Growth hormone responses indicating
the development of a state of receptor downregulation
were only observed in humans when GHRP were delivered by continuous infusion; repeated, i.e., three times
daily, oral or intranasal doses of peptidyl GHRP for up to
15 days (405, 409), once daily oral dosing with nonpeptidyl GHRP for 4 wk (220), or intranasal peptidyl GHRP for
up to 2 yr (843) induced no signs of receptor downregulation.
However, a 16-wk treatment with subcutaneous
hexarelin, twice daily, in elderly subjects resulted in a
partial and reversible attenuation of the GH response
(871a).
The GH response to GHRP appears to have less
intrasubject variability than the GH response to GHRH
(409, 492, 686, 1055), probably in relation to its lower
sensitivity to SS action (see above). Similarly, glucocorticoids, glucose, and exogenous GH, all stimuli allegedly
triggering release of endogenous SS (see sects. VI, A1 and
B1, and VIIA), poorly inhibited the GH-releasing activity of
GHRP, and the same occurred for pirenzepine, a muscarinic M1 receptor antagonist, or salbutamol, a b2-adrenoceptor agonist, and atropine, a nonselective muscarinic
antagonist, which have in common the same mechanism
(50, 167, 401, 645, 674, 823). The modulatory action of SS
was not seen for stimuli allegedly inhibiting SS release
such as arginine, atenolol, a selective b1-antagonist, and
pyridostigmine, an inhibitor of acetylcholinesterase
(AChE) (see sect. VB), which did not affect hexarelin’s
action (407). These findings may explain why GHRP are
more effective GH releasers than GHRH in vivo.
g-Aminobutyric acidergic mechanisms appear to be
involved in the GHRP stimulatory action, since pretreatment with the benzodiazepine alprazolam blunted hexarelin-induced GH release (54).
Another point brought to light by the human studies
is the importance of viable hypothalamic connections for
full expression of GHRP activity on GH secretion. Thus, in
patients with pituitary stalk lesions, the GH-releasing activity of GHRP was severely blunted, also when these
compounds were coadministered with GHRH (631, 855,
861, 976a).
The activity of the GHRP is independent of sex but
clearly dependent on age (410). In contrast to GHRH,
which is maximally effective as a GH releaser at birth, and
then progressively loses effect with age (52, 403, 408),
GHRP are less effective at birth than at puberty or in the
young adult period, their GH-releasing activity starting to
decline only with aging, although they remain more effective than GHRH (27, 52, 87, 403, 405, 408, 718). Gonadal
steroids very likely play a role in the increased GH response to GHRP at puberty but are unable to act at later
periods; in menopausal women, a 3-mo treatment with
transdermal estradiol failed to restore the GH response to
GHRP (53). However, with aging, a host of disturbing
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hexarelin (150 mg/kg sc, twice daily) did not modify GH
mRNA levels in the pituitary of normal adult male rats
(1037). The same was true for a similar treatment schedule in rats with surgical ablation of the MBH or in intact
rats with two ectopic pituitaries transplanted under the
kidney capsule, two experimental models of reduced GH
mRNA levels.
A further approach was to study the effect of GHRP
in infant rats, in which both GHRP-6 and hexarelin are
very effective stimulators of GH secretion (296, 624,
1037). In these pups 8 –10 days of treatment with GHRP-6
or hexarelin consistently primed the pituitary to the GH
response elicited by the acute GHRP challenge, but no
effect was detected on pituitary GH mRNA levels. However, in the same pups treated since birth with an antiGHRH serum, whose pituitary GH mRNA levels were
significantly lower than controls, 5 days of treatment with
GHRP-6 or hexarelin restored GH mRNA levels to control
values (624, 1038) (Fig. 9). The same effects were seen in
young adult male rats given an anti-GHRH serum for 15
days and receiving a 10-day treatment with hexarelin
(1038).
Overall, these findings indicate that GHRP can raise
GH mRNA levels independently of endogenous GHRH;
this effect does not seem to be present in normal rats,
although it may be masked by the overwhelming action of
GHRH. The failure of GHRP to restore GH mRNA levels in
the pituitary of rats with surgical disconnection of the
hypothalamo-pituitary unit and in the ectopic pituitaries
emphasizes the concept that GHRP act mostly on the
hypothalamus and that the hypothalamo-pituitary unit
must be anatomically and functionally intact.
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NEUROENDOCRINE CONTROL OF GROWTH HORMONE SECRETION
factors may impair the GH response to most direct- or
indirect-acting stimuli to GH release.
1. Aging
2. GH-secreting tumors
Growth hormone-secreting adenomas do not have an
altered GH response to GHRP in vivo (29, 241, 451, 860),
and the marked GH release from somatotrophinoma cells
induced in vitro by GHRP-6 or GHRP-2 (15) may well
contribute to the GH response in vivo. In addition, tumors
refractory to GHRH in vitro may respond to GHRP-6 by
releasing GH (883).
Messenger RNA for the GHRP receptor has been
found present in all human pituitary somatotrophinomas so far (14, 299) and in the GH3 tumor pituitary cell
line of the rat (14). The receptor was also transcribed in
some prolactin-secreting adenomas and, more impressively, in all of 18 ACTH-secreting pituitary adenomas
studied (299).
3. Obesity
The GH response to GHRP in obesity is clear, although it is attenuated compared with lean controls (269 –
271, 561). The combination of GHRP and GHRH, however,
markedly stimulated GH secretion in obese patients (131,
269 –271, 630). Interestingly, addition to the peptide regimen of acipimox, a lipolytic inhibitor, further enhanced
the GH response (269), stressing the role of circulating
nonesterified fatty acids (NEFA) in the pathogenesis of
the GH hyposecretion of obesity (see sect. VIB3). In contrast, somatotroph responsiveness to coadministered
hexarelin and GHRH was refractory to the inhibitory effect of glucose (443). This might reflect a selective refractoriness of hypothalamic SS to glucose in obese patients,
since exogenous SS, like pirenzepine, abolished the GH
response to either GHRH or arginine.
4. Catabolic states
Prolonged critical illness is characterized by protein
catabolism and preservation of fat deposits, blunted GH
secretion, elevated serum cortisol levels, and reduced
IGF-I concentrations. In these conditions, prolonged infusion of GHRP-2, alone or combined with GHRH, strikingly
increased pulsatile GH secretion and induced a robust
rise in circulating IGF-I levels within 24 h, without affecting serum cortisol (1058). These findings open new perspectives for GHRP as potential antagonists of the catabolic state in critical care medicine.
5. GH deficiency states
A) CHILDREN. Although their exact mechanism of action
has yet to be defined, the striking effectiveness of GHRP
as GH releasers in humans prompted investigations on
their use as diagnostic tools as well as therapeutic agents
in children with GH deficiency. A number of studies have
confirmed that GHRP are effective GHS in children with
short stature and/or GH deficiency (416, 568, 594) but not
in patients with anatomic disconnection of the hypothalamo-pituitary links or with perinatal stalk transection
(630, 855, 861). The potential for these compounds as a
rapid, safe, and economical test to identify hypopituitarism due to pituitary stalk transection is evident.
An open trial in children with GH deficiency showed
that intranasal administration of hexarelin for up to 6 mo
accelerated growth (594). Similarly, in children with GH
insufficiency, GHRP-2, given subcutaneously at increasing
doses every 2 mo (from 0.3 to 3 mgzkg21zday21) for 6 mo,
raised IGF-I levels and growth velocity (709). In children
with short stature, intranasal GHRP-2, twice daily for 3
mo then three times a day for up to 18 –24 mo, induced a
modest but significant rise in growth velocity (843). However, plasma IGF-I or IGF-BP3 concentrations, or acute
GH responses to intravenous or intranasal GHRP-2 were
not changed and only the GHBP significantly increased.
Despite some positive results, long-term and doubleblind, placebo-controlled trials are mandatory before any
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That acute administration of GHRP consistently stimulates GH secretion in healthy elderly subjects (27, 52,
403, 408, 718) holds promise for restoring their reduced
GH secretion rate, which probably contributes for the
increased central obesity, reduced muscle mass and bone
mineral content, and loss of psychological well-being
(904).
The response to GHRP persisted after repeated oral
or intranasal doses of GHRP-6 or hexarelin (405), and
after oral administration, there was a tendency toward
higher IGF-I concentrations (408). In a randomized, double-blind, placebo-controlled trial in healthy elderly subjects, once daily oral MK-677 enhanced pulsatile GH release, significantly increased serum GH and IGF-I
concentrations and, at a dose of 25 mg/day, restored
serum IGF-I concentrations to levels normally seen in
young adults. Desensitization to the action of MK-677 was
not apparent after 4 wk of daily treatment (220).
It still remains to be established, however, whether
prolonged treatment with GHS has favorable effects on
body composition, functional capacity, and serum lipids,
since impairment of glucose tolerance was observed particularly in subjects with risk factors. This might limit the
therapeutic usefulness of nonpeptidyl GHS. A comparison
of the GHRP is therefore mandatory to assess their safety
because these side effects have not been reported with
peptidyl GHS. Thus it seems inappropriate as yet to extrapolate the results with a single GHRP to all the other
members of the family, even if they purportedly share a
common mechanism of action.
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MÜLLER, LOCATELLI, AND COCCHI
gated in healthy adult males whether hexarelin’s effects
on cortisol and prolactin secretion could be minimized
without compromising its GH-releasing potential. They
found that by using a combination of GHRH and a low
GHRP dose the GH release was greater than with hexarelin alone, its effect on prolactin was minimal, and there
was no effect on cortisol.
F. Conclusions
The discovery of GHRP has opened a new window on
GH regulation. Their mechanism of action is still debated;
we do not know the nature and structure of the endogenous ligand(s) (628) for GHRP receptors, although inferential evidence for an authentic hypophysiotropic function has been provided (604a), and are waiting for
conclusive data on their clinical usefulness. It is undisputed, however, that these new molecules have renewed
interest in neuroendocrinology. Moreover, so far we seem
to have looked only at the tip of the GHRP iceberg.
Detection of GHRP receptors in many tissues in addition
to the pituitary and the hypothalamus suggests still unforeseen roles for the putative endogenous ligand(s) at
both CNS and peripheral sites (628).
V. BRAIN MESSENGERS IN THE CONTROL
OF GROWTH HORMONE SECRETION
E. Effects on Other Pituitary Hormones
A. General Background
Although predominant, the activity of GHRP is not
fully specific for GH release. Reportedly, peptidyl GHRP
in vitro elicit a small but unequivocal release of prolactin
(692) and in vivo of prolactin, ACTH, and cortisol in
humans, dogs, pigs, and rats (628). In vivo, the main site
of action for stimulation of ACTH and cortisol is neither
the pituitary (225, 335) nor the adrenals because these
endocrine effects were abolished by stalk transection in
the pig (468) or hypophysectomy in the dog (937), thus
indicating a hypothalamic mechanism. Interestingly,
hexarelin was shown to release AVP from freshly prepared rat hypothalamic tissues (569).
Some GHRP maintained their prolactin-releasing effect on mammosomatotroph adenomas both in vitro (13)
and in vivo (241). This was not the case for hexarelin,
which does not stimulate prolactin release in patients
with idiopathic hyperprolactinemia, thus implying a partial resistance to GHRP in this condition (241). The precise mechanism(s) underlying these effects is still unknown.
The lack of specificity of GHRP is of concern if these
agents are to be used in clinical trials. To address this
issue, Massoud et al. (675) constructed dose-response
relationships for GH, cortisol, and prolactin and investi-
Discussion of how brain neurotransmitters and neuropeptides influence the neuroendocrine control of GH
secretion requires at least a brief mention of the main
neurobiological characteristics of these compounds and
where their pathways run. Progress has been made possible by the development of histochemical methods with
high sensitivity and sufficient specificity to permit detailed mapping of neurotransmitter and neuropeptide
pathways, introduction of steady-state and non-steadystate methods to measure turnover, very sensitive enzymatic isotopic techniques for detecting messenger molecules in microdissected hypothalamic nuclei or nuclear
subdivisions, and electrophysiological recording from single cells or ionic channels. The development of molecular
biological techniques has enabled us to clone the receptors for virtually every natural ligand considered neurotransmitter and major members of peptide families, and
the introduction of the coding sequences into test cells
means we can assess the relative effects of ligands and of
second messenger production in these cells (for review,
see Ref. 117).
The widely held distinction between classic neurotransmitter communication and peptidergic communica-
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firm conclusions can be drawn on the therapeutic utility
of GHRP in GH deficiency states.
B) ADULTS. Many studies have shown that prolonged
parenteral, intranasal, or oral administration of GHRP
enhances spontaneous pulsatile GH secretion in normal
elderly people (405, 492), or in adults with GH deficiency
(599). Growth hormone deficiency of adults has received
little attention in the past and only recently, since the
demonstration of altered body composition, increased
prevalence of cardiovascular morbidity, and decreased
life expectancy (278, 533), has been investigated more.
The problem of GH deficiency is widespread because
many patients develop life-long hormone deficiency due
to lesions induced in the hypothalamo-pituitary unit by
tumors or radiation. Growth hormone therapy has proven
very effective in these patients (278); GHRP might offer
an even better therapeutic approach for restoring a normal condition.
Growth hormone-releasing peptides would also be
important for the diagnosis of GH deficiency in adults,
which is more difficult than in children, because of the
confounding effects of many factors such as obesity, sex,
and age. A combined test of GHRP and GHRH, which
obviates many of the factors that normally inhibit GH
secretion (137, 270, 631), might be a safe and powerful
tool for the diagnosis of GH deficiency, allowing the rationale as therapeutic use of GHRP.
Volume 79
NEUROENDOCRINE CONTROL OF GROWTH HORMONE SECRETION
April 1999
10. Synthesis pathways of principal neurotransmitters. See text for definitions.
tion has been sorted out, and despite recognized differences (see below), the two systems can no longer be
considered entirely separate entities. The same compound may act differently as a transmitter (via strictly
local short-lived synaptic responses), as a neuromodulator (modulating the subsynaptic actions of a neurotransmitter-coupled event), and as a neurohormone (acting at
a distance from the site of release with no synaptic contact with the synthesizing neurons), depending on the
engagement of specific receptors (117).
Another reason why the demarcation between these
messenger molecules has become blurred is the recognition of their existence in the same neuron in different CNS
areas, as well as in the MBH. The functional role of the
costored neurotransmitters and neuropeptides remains to
be fully elucidated, although demonstration of costorage
within nerve terminals at the ME suggests corelease at
this site. These events are of particular interest for the
control of GH secretion. Because GHRH neurons of the
ARC also contain enzymes for neurotransmitter biosynthesis, neurotransmitters and neuropeptides (see sect.
IIIA2) and GHRH-induced GH release may be influenced
by some of these.
B. Characteristic Features
A detailed description of the mechanisms of biosynthesis, release, and metabolic disposal of principal neuro-
transmitters and neuropeptides and of the CNS-acting
compounds that interfere with the different metabolic
steps or with pre/postsynaptic receptors is beyond the
scope of this review, and the readers are referred to
Müller and Nisticò (756) and Bloom (117). Here only key
neurobiological features are given and a brief mention of
the regional distribution of the main neuronal systems in
the CNS.
Neurotransmitters are small molecules synthesized
in a short series of steps from precursor amino acids in
the diet. They are found in the brain in concentrations of
nanograms to micrograms per gram and show high affinity for specific receptor sites.
The first substance to be recognized as a neurotransmitter was ACh, and 5–10% of brain synapses are thought
to be cholinergic. Amino acids (GABA, glycine, glutamate,
aspartate) form the main group of central neurotransmitters (an estimated 25– 40% of synapses). The monoamines
(CA, tryptamines, histamine) account for only 1–2% of
brain synapses, but the monoamine pathways are widely
distributed throughout the brain (see sect. VC). The main
steps in neurotransmitter formation are depicted in Figure 10.
Many drugs are capable of inhibiting the functional
activity of neurotransmitter neurons. Biosynthesis inhibitors act on the different enzymatic steps, and there are
depletors of the granular pool and neurotoxic agents that
destroy neurotransmitter neurons. Neurotransmitter pre-
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FIG.
543
544
MÜLLER, LOCATELLI, AND COCCHI
C. Main Locations of Neurotransmitter and
Neuropeptide Pathways
Monoamine transmitters, that is, CA, DA, NE, epinephrine (E), indoleamines (5-HT), and histamine, have
perikarya that form ascending ventral and dorsal pathways to innervate limbic and hypothalamic structures
including the internal (NE, 5-HT) and external (DA) layers
of the ME.
In the pons and medulla, 10,000 NE-secreting
perykarya give rise to large ascending tracts. The ascending NE pathway comprises 1) a dorsal bundle that originates in the locus coeruleus and innervates the cortex, the
hippocampus, and the cerebellum and 2) a ventral bundle
that originates in the pons and medulla and gives rise to
pathways innervating the lower brain stem, the hypothalamus, and limbic system. Norepinephrine has high affinity
for both a- and b-receptors, whereas E has higher affinity
for b- than for a-receptors. These receptors are now
divided into a1A, a1B, a1c, a2A, a2B, and a2c subclasses as
well as b1, b2, and b3, that have different locations, functions, and second messenger systems (117) and affect
somatotrophic function differently.
Among the five different systems of long and medium
DA neurons, a pathway of particular relevance for neuroendocrine control is the tuberoinfundibular DA (TIDA)
pathway that innervates the ME, the area where neurotransmitters and neuropeptides are released into the hypophysial portal circulation to be conveyed to the AP.
Dopaminergic receptors can be subdivided into D1,
D2, D3, D4, and D5 sites; there are now specific agonists
and antagonists for D1, D2, and D4 receptors. No major
differences have been described in how these subclasses
of receptors affect GH secretion.
The 5-HT system arises from cell bodies in the mesencephalic and pontine raphe and sends axons especially
to the hypothalamus, ME, POA, limbic system, septal
area, striatum and cerebral cortex. On the basis of the
action of 5-HT receptor agonists and antagonists, four
subgroups of 5-HT receptors have been characterized:
5-HT1-like, 5-HT2, 5-HT3 and 5-HT4. To date, 5-HT1A–F,
5-HT2A–C, 5-HT3, and 5-HT4 –7 subtypes have been described.
Antibodies specific for the ACh-synthesizing enzyme
CAT, coupled with the use of AChE histochemistry, ligand
binding, or in situ hybridization studies, have made it
possible to outline cholinergic neurons and trace their
pathways. The enzymatic activities are present in most
hypothalamic nuclei, including the ARC and the ME. Because only small changes have been detected in CAT
concentrations in the MBH after mechanical separation of
this area, and no change at all was found in the ME, an
intrahypothalamic cholinergic pathway, similar to the
TIDA pathway, has been envisaged. This may be important in some effects of the cholinergic drugs on somatotropic function (see below), also considering the similar
distribution of somatostatinergic and cholinergic neurons
in the lateral region of the external layer of the ME (954).
There are two classes of ACh receptors, the muscarinic and the nicotinic. Five subtypes of muscarinic cholinergic receptors (M1 to M5) have been detected by molecular cloning; all five are found in the CNS.
The regional localization of histamine in the brain
and in individual nuclei of the hypothalamus has been
studied in rodents and primates. In the monkey and human hypothalamus, the highest concentrations are found
in the mammillary bodies, SON, VMN and ventrolateral
nucleus, and ME. After deafferentation of the MBH in rats,
levels of histamine do not decrease significantly in the
ARC, VMN, DMN, and ME, suggesting that histamine is
present in the posterior two-thirds of the hypothalamus in
cells intrinsic to this area. Three subtypes of histamine
receptors have been described, H1, H2, and H3. Unlike the
monoamine and amino acid transmitters, there does not
appear to be any active histamine reuptake. In addition,
no direct evidence has been obtained for release of histamine from neurons either in vivo or in vitro.
Specific antibodies raised against GAD have made it
possible to precisely locate GABAergic neurons in the
hypothalamus. A dense network of GAD-positive nerve
fibers is seen in different hypothalamic nuclei of the rodent and cat brain. In the ME, a dense immunofluorescent
plexus is found in the external layer, extending across the
entire mediolateral axis from the rostral part to the pituitary gland. The hypothesis of an intrinsic, hypothalamic
TI-GABAergic pathway projecting from the ARC to the
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cursors or inhibitors of metabolic degradation or uptake
potentiate neurotransmitter mechanisms (117).
The pathways by which neuropeptides are synthesized closely resemble those in peripheral hormone-producing tissues (117). The peptide is synthesized in the
rough endoplasmic reticulum where mRNA for the
propeptide can be translated into an amino acid sequence.
The peptide may be released intermittently rather than
tonically, the amounts stored in terminals may be large
relative to the amounts released, and the peptide may
activate receptors at much lower concentrations than the
classic transmitters. In general, concentrations of picograms to nanograms per gram are present in the brain.
These general features apply to either classical hypophysiotropic neuropeptides, GHRH and SS, or the cohort of neuropeptides whose neurohormonal role and
hypophysiotropic function are still not clear (see sect.
VB). It has proven difficult to synthesize agonists or antagonists that interact with specific receptors for peptides. However, the recent development of nonpeptidyl
agonists or antagonists (see also sect. IV) offers promise
of success.
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NEUROENDOCRINE CONTROL OF GROWTH HORMONE SECRETION
D. Neurotransmitters
1. Catecholamines
A) A2-ADRENOCEPTORS. Although formulated more than 25
years ago and based on a the pituitary “depletion”
method, subsequently shown to be fraught with inconsistencies, the concept that NE is a synaptic transmitter that
releases GRF (758) is essentially valid today. Proper evaluation of neurotransmitter function became possible with
RIA methods for the measurement of GH in rat plasma,
the awareness of the labile and episodic function of GH
secretion in the rat, and hence the adoption of chronically
cannulated rats for blood sampling (666).
Since then, evidence has accumulated that central adrenergic pathways acting through a2-adrenoceptors stimulate GH secretion in humans and rats (756). Instrumental to
this conclusion were experiments in rats with an intra-atrial
cannula, in which blockade of CA synthesis by a-methyl-ptyrosine, depletion of hypothalamic CA stores by reserpine,
and injection of 6-hydroxydopamine, a CA neurotoxin,
markedly suppressed the episodic GH secretion; these effects were counteracted by the a2-adrenoceptor clonidine,
but not the DA agonist apomorphine (759). More selective
inhibition of NE and E synthesis by blockers of DA-b-hydroxylase, the enzyme that converts DA to NE and E (see
Fig. 10), also inhibited spontaneous GH bursts, this effect
again being counteracted by clonidine (549, 578, 771). Epinephrine was presumably the main endogenous CA active
on a2-adrenoceptors, since selective blockade of E synthesis
by phenylethanolamine N-methyltransferase (PNMT) inhibitors reduced GH secretion in freely moving rats, and the
effect was reversed by clonidine (1028). There was concomitantly a reduction of E levels in the hypothalamus with no
changes in DA and NE stores. A peripheral E synthesis
blocker had no effect on GH secretion, indicating that inhibition of brain rather than adrenomedullary E was responsible (1028).
The importance of a-adrenergic mechanisms in GH
secretion was substantiated by the finding that clonidine
given acutely to 10-day-old rats induced a clear-cut rise in
plasma GH, although the effect was not dose related;
short-term administration of clonidine to 5-day-old rats
also raised plasma GH levels and pituitary GH content
(204). A sound interpretation of these findings was that in
infant rats clonidine, in addition to stimulating GH release, had elicited GH synthesis, as confirmed by measurement of pituitary [3H]leucine incorporation into GH
of infant rats treated ex vivo with the drug (272). Because
similar results were obtained in infant rats with GHRH
(272), it appeared likely that clonidine acted at least partially, through the release of endogenous GHRH.
Clonidine did not affect GH release in rats with hypothalamic destruction or from cultured AP cells (552).
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ME is supported by deafferentation experiments of the
MBH. g-Aminobutyric acid receptors are divided into two
main types: 1) GABAA, which is bicuculline sensitive and
has multiple subtypes, interacts directly with and is the
site of action of many neuroactive drugs (benzodiazepines, barbiturates), anesthetic steroids, volatile anesthetics, and alcohol; and 2) GABAB, which is bicuculline
insensitive and is present in both the CNS and the periphery, although mainly at the presynapses, at least peripherally. Specific agonists and antagonists of GABAA and
GABAB receptors are now available.
Glutamate and aspartate are found in very high
concentrations in different brain areas such as discrete
hypothalamic nuclei (ARC, VMN, PeVN), with nerve
terminals projecting to the ME. The widespread distribution of these two dicarboxylic amino acids in the
CNS and their role in the intermediary metabolism
tended to exclude any action as transmitters, but it is
now acknowledged that both amino acids exert extremely powerful excitatory effects on neurons in virtually every region of the CNS. Many receptor subtypes
have been characterized pharmacologically. They fall
into two main groups: the ionotropic and metabotropic
receptors. Ionotropic receptors can be subdivided into
N-methyl-D-aspartate (NMDA), kainate, and DL-a-amino3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA);
metabotropic receptors are activated most potently by
quisqualate.
Neurotransmitter-hypophysiotropic peptides, e.g.
GHRH and SS, interact in many ways. These include
direct action of neurotransmitters transported into hypophysial vessels (DA, E and GABA), the still elusive neurotransmitter-neurotransmitter, peptide-peptide and neurotransmitter-peptide interactions due to colocalization in
and corelease from the same neuron of two or more
molecules (Fig. 2) (457, 484, 699). Consequently, drugs
that act as agonists or antagonists at neurotransmitter
receptors or alter different aspects of neurotransmitter
function can be useful for studying the physiology and
pathophysiology of GH secretion and as diagnostic and
therapeutic tools.
Detailed mapping of the principal brain neuropeptides is beyond the scope of this review, and the reader is
referred to References 457 and 484. Briefly, however,
several hypothalamic peptides such as oxytocin, AVP,
POMC, gonadotropin-releasing hormone (GnRH), and
also GHRH all tend to be synthesized by single large
clusters of neurons that give off multibranched axons to
several distant targets. Others, such as systems that contain cholecystokinins, enkephalins, and also SS, have
many forms, with patterns varying from moderately long
connections to short axons, local-circuit neurons that are
widely disseminated throughout the brain.
545
546
MÜLLER, LOCATELLI, AND COCCHI
rhythm (HSR) (308), and that in previous in vivo studies
clonidine had disrupted the spontaneous surges of GH
release in male rats (see sect. II).
In normal adult volunteers, clonidine administered 60
or 120 min, but not 180 min, before a GHRH bolus increased the GH response to GHRH; the close relationship
between pre-GHRH plasma GH and GHRH-induced GH
peaks, not present with clonidine alone, was also lost
after pretreatment with this drug. Clonidine-induced disruption of the intrinsic HSR suggested that a2-adrenergic
pathways exert an inhibitory effect on SS release (307).
Similarly, in conscious rats, clonidine at all doses tested
failed to stimulate GH release when administered at the
time of a spontaneous peak, i.e., when the intrinsic SS
tone would be minimal. In contrast, clonidine injected at
a trough time, functionally the opposite condition, raised
plasma GH. In addition, clonidine administered during a
GH trough period before GHRH challenge potentiated the
GH response to GHRH (591).
Acute and short-term clonidine studies in dogs gave
similar findings. In old conscious beagles given GHRH and
clonidine together, twice and once daily for 10 days,
treatment significantly raised the frequency of spontaneous bursts of GH secretion, the mean GH peak amplitude,
and the total peak area evaluated in 6-h blood samples
taken at 10-min intervals (207). These effects, paradoxically, were not as marked when clonidine and GHRH
were given twice rather than only once daily. This was
presumably because the a2- adrenergic agonist downregulates its own receptors in the ARC at a higher dose (208).
The most parsimonious interpretation of these findings
is that a dual mechanism of action is exploited by a2-agonism in enhancing GH secretion, e.g., stimulation of hypothalamic GHRH and inhibition of SS neuronal function. Light
microscopic and electron microscopic evidence supports
this. Immunocytochemical double-labeling and dopamine
b-hydroxylase (DBH) and PNMT immunolabeling for tracing
the CA system (620) revealed a similar pattern of distribution with juxtaposition of catecholaminergic fibers and
GHRH neurons in the ARC. Electron microscopic examination showed axodendritic and axosomatic synaptic specialization between these systems (620).
However, in addition to these morphological findings
suggesting that the CA system stimulates GH release
through GHRH, other neuroanatomic evidence indicates
that SS structures in the anterior PeVN nucleus of the rat
hypothalamus are innervated by PNMT-immunoreactive
axons (621). These can be usefully viewed in connection
with the existence of SS synapses on GHRH neurons (see
sect. II, A3 and B). With the assumption that they originate
from hypophysiotropic SS neurons, it would seem that
afferent neuronal systems to SS cells influence GH production either by regulating SS secretion into the portal
circulation (235) or by transmitting their influence to the
GHRH neurons through SS axons (622). This complex
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In keeping with this conclusion, studies in the rat had
shown that clonidine-induced GH release was abolished
by passive immunization with anti-GHRH serum (206,
721), whereas it was not affected by anti-SS antibodies
(331). The drug was reported to stimulate GRF release in
vitro from perfused rat hypothalamus (536). It was subsequently shown that a single dose of clonidine to adult
male rats significantly lowered GHRH content, leaving
GHRH mRNA levels unaltered and raising plasma GH
while hypothalamic SS mRNA and pituitary GH mRNA
levels remained unchanged. In contrast, in rats treated
with clonidine for 1 and 3 days, hypothalamic GHRH
content fell, and there was a significant reduction in
GHRH mRNA levels. In these rats, pituitary GH content
and mRNA levels increased significantly, whereas hypothalamic SS content and mRNA remained unaltered. In
6-day clonidine-treated rats, hypothalamic GHRH content
and mRNA was still significantly reduced, plasma GH
levels were increased, although less than in 1- and 3-day
clonidine-treated rats, and pituitary GH content and
mRNA had returned to control values (294).
It would seem that in these experimental conditions,
clonidine-induced a2-adrenoceptor stimulation led directly, or through inhibition of hypothalamic SS release
(see below), to increased GHRH release from the hypothalamus and enhanced GH biosynthesis and secretion
and that as a result of greater exposure to clonidine,
circulating GH (and IGF-I) fed back to hypothalamic
GHRH neurons, thus finally reversing pituitary somatotropic hyperfunction.
Apparently, SS neurons were refractory to circulating
GH or IGF-I under these experimental conditions. In similar studies, Gil-Ad et al. (418) detected a decrease in the
hypothalamic content of SS only after acute clonidine,
and not after a 7-day treatment.
Additional, although inferential, evidence in favor of
a GHRH-mediated effect is the fact that either compound
induces sedation and sleepiness and stimulates food intake (see Ref. 479 and sect. IIIA10) and that specific
a2-adrenergic nerve terminals have been detected in the
arcuate nucleus (620).
None of the above observations, however, excludes the
possibility that clonidine may also act through inhibition of
SS pathways. In fact, in rats, clonidine failed to induce GH
release when directly instilled into the VMN, an area of
GHRH neurons (see sect. IIIA2), but was effective when
injected into the SS-rich MPOA (515). Later studies in humans showed that pretreatment with GHRH abolished the
GH response to subsequent administration of the peptide
but did not alter the GH response to clonidine (1052).
Investigations in humans and animals were then
started, to clarify the precise mechanism of action of
clonidine, the possibility being considered that GH responsiveness to GHRH may be closely dependent on the
functional status of the hypothalamic somatotroph
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NEUROENDOCRINE CONTROL OF GROWTH HORMONE SECRETION
children in this study had higher pretreatment growth
velocity (832). Negative results were also reported by
Allen et al. (26). In a later controlled study, clonidine did
accelerate the growth of short children with normal GH
secretion, although, at the dose used, it was not as effective as GH (1073).
We do not know whether the effect of clonidine
observed in some of these studies will result in better final
height. Certainly, the negative results of one of the controlled studies (832) discouraged further investigations on
a topic that, for its scientific interest and potential clinical
benefits, warrants closer attention (35).
It is noteworthy that continuous intravenous
clonidine to patients with alcohol abuse, for prevention of
alcohol withdrawal syndrome, significantly improved
their nitrogen balance and counteracted the decline of
plasma IGF-I and IGF-BP-3 seen in untreated patients
after resection of an esophageal cancer (715).
B) a1-ADRENOCEPTORS. The availability of clonidine and
its ability to stimulate GH secretion in many animal species allowed the characterization of the NE receptor subtypes mediating its neuroendocrine effect. In dogs, pretreatment with the a1-adrenoceptor antagonist prazosin
left the clonidine-induced GH rise unaltered, whereas
blockade of a2-adrenoceptors by yohimbine completely
prevented it (215). However, prazosin partially suppressed the GH secretory response to clonidine in rats,
which may indicate a mixed a1/a2-mechanism in the GHstimulating effect of the drug (578). However, in both rats
and dogs, a1-adrenoceptors might also mediate inhibitory
influences to GH release, indicating a dual NE mechanism
of control (214, 578). Overall, the results supported the
idea that a1-adrenoceptors in the CNS inhibited both tonic
and stimulated GH secretion in rats and dogs. Apparently,
the underlying mechanism involved the activation of SS
release. Thus the ability of methoxamine, an a1-adrenoceptor agonist, to suppress GH levels in infant rats was
completely abolished in animals pretreated with a SS
antiserum. However, the clear-cut GH rise induced by
prazosin was not further increased by pretreatment with
the antiserum (206).
a1-Noradrenergic inhibition would be mediated
through receptor sites in the PVN, and electrolytic lesions
of these in the rat double the amplitude of the GH curve
and the area under the curve, while blocking the GH
inhibitory effect of locally instilled methoxamine (744).
This is closely comparable to the obtained pattern under
similar conditions by bilateral destruction of the locus
coeruleus (119). Because both the PVN and the somatostatinergic hypothalamic PeVN are innervated by locus
coeruleus NA1 afferents (28), a pathway stimulatory of SS
function, presumably through PVN-CRH neurons, has
been envisaged.
Contrasting the clear-cut inhibitory effects of a1-adrenoceptor stimulation in dogs and rats are reports in
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mechanism may be used to synchronize these hypothalamic pathways to achieve precise coordination between
stimulatory and inhibitory systems (853).
The GH-releasing effect of clonidine, as expected,
was antagonized in humans and rodents by the selective
a2-adrenergic antagonists yohimbine (158) and fluparoxan (529). However, in rats metergoline, a 5-HT1/5-HT2
antagonist, and mesulergine, ritanserin, and mianserin,
5-HT1c/5-HT2 selective antagonists, all reduced clonidineinduced increases in GH levels, without affecting the
decrease in locomotor activity. These findings suggest
that clonidine stimulates the release of GH by activating
a2-adrenergic heteroreceptors on 5-HT nerve terminals
which, in turn, enhance 5-HT activity by stimulating
postsynaptic 5-HT receptors. In the same study, clonidine
failed to increase GH levels in the fawn-hooded rat, a
model of altered serotoninergic function (60).
1) Diagnostic applications. The fact that clonidine
stimulates GH secretion in a variety of species, including
humans (749), has led to a2-adrenergic stimulation being
used as a diagnostic test in children of short stature (419,
589). A single oral dose of clonidine stimulated GH release in healthy children and adolescents but not in hypopituitary children. Clonidine proved to be a more effective stimulant of GH secretion than either insulin
hypoglycemia or arginine infusion; there were, however,
false-negative responses to clonidine even in healthy subjects and wide variability in the GH release in endocrinologically short children (76). Today, the clonidine test is
still widely used in pediatric endocrinology, but it has
been largely supplanted by more recently diagnostic tests
(see sect. VA3). For a more thorough discussion of this
topic, see Reference 755.
2) Therapeutic implications. The suggestion that a
dysfunction of neurons regulating the release of GHRH
from GHRH-secreting structures may occur in some children with idiopathic GH deficiency (231, 541) prompted
efforts to stimulate the purportedly depressed neurotransmitter function, initially with a DA precursor or agonist drugs, and then with clonidine.
Promising results with dopaminergic therapy (497,
498), and the possibility that some effects, e.g. those of
levodopa, might be due at least in part to its conversion to
NE in the hypothalamus (1108), suggested the use of
clonidine in children with growth retardation. Oral
clonidine for 3 mo to 1 yr stimulated linear growth in the
majority of children, the most responsive being those in
general with low pretreatment growth velocity and
marked bone age delay. There was, however, a tendency
for growth velocity to slow with time, i.e., after the first 6
mo or 1 yr, a pattern which might be due to a2-adrenoceptor desensitization (185, 388, 739, 851). However, in a
subsequent placebo-controlled study, clonidine had no
effect on the growth of short children with normal GH
responses to provocative stimuli. Unlike other studies, the
547
548
MÜLLER, LOCATELLI, AND COCCHI
b-Adrenergic agonism and its clinical implications
especially concern salbutamol, a b2-adrenergic agonist
extensively used as a bronchodilator in the treatment of
asthma. Inhibition of GH release after GHRH treatment
and during overnight GH testing was described in type I
diabetic patients after short-term oral administration of
this drug (668). Evaluation of the short- and long-term
effects of oral salbutamol in asthmatic short children
showed that 24 h of drug treatment led to a decrease in
the overnight IC-GH concentrations and peak GH levels
after GHRH; however, after 3 mo of therapy, GH levels
were no different from baseline and rose normally after
GHRH (588). It would seem, therefore, that oral salbutamol produces no chronic deleterious changes in GH secretion and, hence, height velocity in children, although
larger long-term studies are needed to confirm this.
Whereas in vivo activation of CNS b-adrenoceptors
inhibits GH secretion in vitro, activation of these receptors stimulates GH secretion from rat pituitary cells (830).
This mechanism is presumably not evident in vivo because it is a minor effect compared with the stimulant
action of b-adrenoceptors on SS secretion, which causes
overall inhibition of GH secretion.
D) DOPAMINE. Dopaminergic pathways are involved in
the control of GH secretion, although their role appears to
be largely ancillary. In rats, dogs, and monkeys, systemic
administration of the DA precursor levodopa or directacting DA agonists stimulated GH release (see Ref. 756 for
details). However, an a-adrenergic component is also involved, as shown by the fact that a-adrenoceptor antagonists partially or completely antagonize the stimulatory
effect of DA in monkeys (985) and humans (159). Moreover, an inhibitory component seems inherent to DA’s
ability to affect GH secretion. Thus there is evidence that
monkeys have DA receptors inhibitory to GH release in
the blood-brain barrier (BBB) (985, 1036).
In healthy humans, although direct DA agonists such
as apomorphine and the ergot derivates bromocriptine,
lisuride, cabergoline, or indirect DA agonists such as amphetamine, nomifensine, or methylphenidate cause acute
GH release and increase GH release in response to GHRH
(1057), they blunt the GH response to insulin-induced
hypoglycemia, levodopa, and arginine, administered by
infusion (69, 1105). Bromocriptine (69) stimulates GH
release in children with low baseline GH, but it has a
rebound effect (inhibition, followed by rebound stimulation) or a clear-cut inhibitory effect in children with elevated baseline GH (79). These findings are best explained
by the ability of DA to release both GHRH and SS from the
rat hypothalamus (562) and by the different sensitivity of
SS and GHRH neurons to dopaminergic stimulation in
relation to the endogenous DA tone. This puzzling feature
is further complicated by the fact that DA and its agonists
inhibit GH release from rat (273) and human (656) pituitaries in vitro and inhibit GH release in conditions of
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humans of either a small increase in GH secretion during
intravenous infusions of a1-adrenergic agonists (506) or
no effect on GH secretion, with a small, not significant,
decrease after methoxamine (24). Although CA are clearly
involved in the GH response to hypoglycemia, prazosin
did not affect this response in humans (1024), suggesting
that both stimuli share the same mechanism, i.e., inhibition of hypothalamic SS function. Although there is no
information on how a1-antagonists affect the GH responses to more physiological stimuli, it would appear
that endogenous CA acting on a1-adrenoceptors are unlikely to play a role in the secretion of human GH; this
inhibitory action of CA is better accomplished through
b-adrenoceptors.
C) b-ADRENOCEPTORS. The inhibitory role of b-receptor
activation on GH release has been known for many years.
The nonspecific b-antagonist propranolol has no effect on
GH secretion under basal conditions in Caucasians (110),
whereas it does enhance the GH response to indirectacting CA agonists, such as amphetamines and desipramine (582, 877). This effect is achieved through propranolol-induced suppression of inhibitory influences mediated
by b-adrenoceptors, on which the synaptically released
CA act. The same mechanism would explain why intravenous infusion of E had no effect on GH secretion in
humans, whereas E combined with propranolol stimulated GH secretion (673). It would seem that E infusion
activates both a2- and b-adrenoceptors, with propranolol
unmasking the opposite actions of these two receptors
which, very likely located in the ME, are accessible to
infused CA (917).
It has since been shown that the b2-adrenergic agonist salbutamol inhibits the GH response to GHRH in
humans (412). This is best explained by the possibility of
b2-agonism through stimulation of the secretion of SS;
inhibition of b-receptors would inhibit SS release.
This view fits well with the marked enhancing effect
of propranolol on the GHRH-induced GH rise in children
(234) and of the selective b1-receptor antagonist atenolol
in adult humans (677) and short children (658). Moreover,
acute administration of atenolol to GH-deficient children
receiving long-term GHRH increased integrated GH secretion (659). These findings led to investigation of whether
chronic treatment with atenolol might augment the therapeutic potential of GHRH. In a double-blind placebo
controlled study, atenolol and GHRH coadministered to a
group of GH-deficient children increased growth velocity
during the first year, to a greater extent than treatment
with GHRH alone. However, during the second year of
therapy, there was no significant difference in growth
velocity between the two groups, and the mean 24-h
concentration, that had been higher in the atenolol group
during the first year, was lower in this group during the
second year (183).
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NEUROENDOCRINE CONTROL OF GROWTH HORMONE SECRETION
2. Serotonin
Serotoninergic pathways in the brain contribute stimulatory influences for GH release in rodents (45). The
situation is less clear in humans, where different drugs
that either inhibit the functional activity of serotoninergic
neurons or potentiate neurotransmitter mechanisms did
not induce the expected changes (108, 233, 702; see also
Ref. 756 for review).
Data implicating 5-HT in raising the concentrations
of circulating GH in the rat come from studies in which
inhibition of tryptophan (Trp) hydroxylase by p-chlorophenylalanine significantly inhibited GH pulsatile secretion in unanesthetized male rats (665), or blockade of
5-HT receptors with nonspecific 5-HT antagonists was
associated with suppressed GH levels (see Ref. 756). Conversely, the 5-HT precursor L-Trp, administered systemically, increased brain Trp and 5-HT levels and induced
sustained release of GH (45, 1070); the same was true for
intracerebroventricular injections of 5-HT or the direct
5-HT agonist quipazine (1070). The immediate 5-HT precursor 5-hydroxytryptophan (5-HTP) given systemically
to unanesthetized rats also potently stimulated GH secretion, an effect prevented by the nonspecific 5-HT inhibitor
cyproheptadine (967). However, after administration of
5-HTP, 5-HT may not be formed exclusively in 5-HT neurons but also in CA-containing neurons, leading ultimately
to CA release (see Ref. 756).
In keeping with this in infant rats, the brisk rise in
plasma GH induced by 5-HTP was not counteracted by
two 5-HT receptor antagonists but by blockade of dopaminergic or a-adrenergic receptors or central sympathectomy induced by 6-OHDA (255). A further note of caution
on the early 5-HT studies regards the low specificity of the
5-HT receptor antagonists often used, i.e., methysergide
and cyproheptadine. The latter also has antihistaminic,
anticholinergic, antidopaminergic, and protein synthesis
blocking properties, and the former shows paradoxical
stimulating activity on 5-HT receptors (756).
The lack of reasonably discriminating agonists and
selective antagonists for most 5-HT receptor subtypes
certainly accounts for some of the early controversial
findings (749). Now that specific receptor ligands are
available, studies have been designed to elucidate the
involvement of specific 5-HT receptor subtypes. In freely
moving conscious male rats, activation of 5-HT1A receptors by systemic administration of the specific agonist
hydroxy-2-(di-n-propylaminotetralin) or ipsapirone, or the
less specific 5-HT1B and 5-HT1c agonist 1-(m-trifluoromethyl-phenyl)piperazine failed to affect plasma GH levels at any dose tested (311).
The roles of different 5-HT receptors have been
somewhat clarified by studies on the mechanisms underlying a2-adrenoceptor-induced GH stimulation. Among
various 5-HT receptor antagonists, only metergoline, a
non-selective 5-HT1/2 antagonist, and mesulergine, a
5-HT1c/5-HT2 selective antagonist, almost completely suppressed clonidine-induced increases in GH levels,
whereas two other 5-HT1c/5-HT2 antagonists, ritanserin
and mianserin, only partially attenuated clonidine’s effect.
In these studies, a 5-HT3 receptor antagonist, MDL 7222,
spiperone, a 5-HT1A/5-HT2 antagonist, and propranolol, a
b-adrenergic/5-HT1d antagonist, were completely unable
to antagonize clonidine (60). Overall, the pharmacological
profile of these compounds and their rank order of potency suggest that 5-HT1c rather than 5-HT2 receptors
are involved in the a2-adrenoceptor stimulation-induced
GH increase in the rat. However, studies of short-term
maternal separation in preweanling rats, a model for
the syndrome of maternal deprivation in humans, which
encompasses growth retardation, weight reduction, and
social withdrawal (32), once termed psychosocial dwarfism (863), have led to the conclusion that 5-HT2A and
5-HT2c receptors were certainly involved in GH hyposecretion (553).
Whatever the real contribution of the different 5-HT
receptor subtypes, the close functional relations between
adrenergic and serotoninergic pathways involved in GH release, and the idea that brain 5-HT changes are implicated in
the etiology of affective illness and the mode of action of
antidepressants and antimanic drugs (700), might explain
why several clinical studies found blunted GH responsiveness to clonidine in depressed patients compared with controls (756). The ability of moclobemide, an antidepressant
drug and selective reversible inhibitor of type A monoamine
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pathological hypersecretion, a topic which is beyond the
scope of this review and for which the reader should refer
to Reference 1034.
In the rat, the dopaminergic hypothalamo-pituitary
axis appears to be involved in the differentiation, proliferation, and survival of pituitary cells during development. A DA transporter (DAT), which terminates DA action by amine reuptake into nerve terminals, is
presumably expressed on hypothalamic dopaminergic
neurons (698), but its relevance in calibrating DA overflow to the anterior pituitary remains unclear.
In a mouse strain with deletion of the DAT gene, it was
confirmed that DA reuptake through the transporter plays a
vital physiological role regulating hypophysiotropic dopaminergic function. These mice have an altered spatial distribution, and a dramatic reduction in the numbers of somatotroph (and lactotroph) cells, are unable to lactate and show
dwarfism. The effects of DAT deletion on pituitary function
result from elevated DA levels that strikingly reduce hypothalamic GHRH function and downregulate the lactotrope
D2 DA receptors. Dopamine-induced suppression of GHRH
function then downregulates the Pit-1/GHF, a transcription
factor that commits the pluripotent pituitary stem cell to
generate specific cell types (128).
549
550
MÜLLER, LOCATELLI, AND COCCHI
sumatriptan did not alter baseline GH levels, but still
enhanced the effect of GHRH (743). A cautious interpretation of these findings is that sumatriptan was active in
normal and obese subjects through inhibition of the somatostatinergic tone, with the only reservation in this
reasoning resting on the enhanced GH response to arginine which allegedly operates through the same mechanism. A CNS mechanism of action for sumatriptan is
suggested by its lack of effect on GH secretion in acromegaly (279).
In a group of nondepressed male alcoholics with 1 or
2 yr of abstinence from alcohol, sumatriptan failed to
increase GH secretion (1069), implying a persistent, selective loss of 5-HT1D receptor function (see also sect.
VB5B2).
Other studies of 5-HT involvement in GH regulation
in humans have used 5-HT2 receptor antagonists. In
healthy subjects, ketanserin did not modify the GH response to insulin hypoglycemia (865), whereas its companion drug ritanserin did (1027), very likely due to its
higher affinity for the 5-HT2 receptor and better penetration of the BBB.
These findings further complicate the already contradictory data in the literature. Quipazine, a nonselective
5-HT receptor antagonist, given orally, did not alter
plasma GH in normal subjects or patients with neurological disorders (809). The elusive nature of serotoninergic
modulation of GH secretion also emerges from studies
with fenfluramine, a potent 5-HT releaser and inhibitor of
5-HT reuptake. In healthy subjects, the drug inhibited the
GH release induced by the combination of L-dopa and
propranolol but not when arginine was used as a GH
stimulant. The drug alone slightly lowered baseline GH
levels (180), although it did not do so in another study
(610). Regardless of the interpretation of these findings,
overall they do not support a serotoninergic stimulatory
component in human GH secretion.
Fenfluramine has also been used to probe the function of central 5-HT neurotransmission in obese subjects,
in whom defective function has been postulated (604). In
a group of moderately obese subjects, GHRH induced a
low GH response, which further decreased after 9 wk of
treatment with fenfluramine (325). These data were taken
to indicate that a serotoninergic defect was not involved
in the low basal GH concentration or the blunted response to GHRH in obese subjects. Results were similar
in experiments in which the GH release induced by GHRH
was assessed in obese subjects after 7 days of treatment
with fluoxetine, a 5-HT reuptake inhibitor (844).
3. ACh
The initial observation that in normal subjects atropine blockade of muscarinic cholinergic receptors had no
effect on GH release elicited by insulin hypoglycemia
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oxidase (MAO-A), to markedly increase 5-HT function and
stimulate GH secretion in depressed subjects should be
evaluated in this context (766).
In Hollstein steers, systemically administered quipazine, a
nonspecific 5-HT1B,2A,2C,3 agonist and, possibly, a 5-HT1B antagonist, increased GH secretion, whereas cyproheptadine lowered it. These drugs had this effect regardless of whether cattle
ate ad libitum or were food deprived, but they did not influence
SS concentrations in plasma after feeding, suggesting that 5-HT
receptor-stimulated GH secretion is mediated within the CNS
and is involved in stimulation of pulsatile GH secretion (394). In
the monkey, however, 5-HT microinjected into the VMN did not
raise plasma GH (1036), although a significant response was
reported after systemic infusion of 5-HTP (216).
In dogs, 5-HT seems to have an inhibitory role in the
canine GH (cGH) response to insulin hypoglycemia (626,
761). Other studies in dogs aimed to establish whether a
primary 5-HT effect on cGH secretion could be distinguished from stress-related cGH stimulation. They were
prompted by the observation that while low doses of
5-HTP produced brisk cGH responses, with no signs of
distress or changes in plasma corticosteroids, high 5-HTP
doses, although able to release cGH, were associated with
behavioral and endocrine signs of stress (320). Pentobarbital sodium anesthesia abolished the rise in cGH and
corticosteroids induced by insulin-hypoglycemia, but not
an earlier increment in plasma cGH, unaccompanied by
stimulation of corticosteroid release, induced by systemically administered 5-HTP (321).
Although these elegant studies imply that the 5-HT
mechanism of GH stimulation in the dog differs from the
stress-related mechanisms of cGH release, they are biased
by the use of 5-HTP as a specific activator of 5-HT neurotransmission, as pointed out previously. In anesthetized
dogs, the effect of 5-HTP was abolished by the adrenoceptor antagonist phenoxybenzamine (1130), and the
same was true for healthy volunteers (768).
Further evidence that in some animal species activation of central 5-HT neurotransmission inhibits GH release comes from experiments in sheep where tianeptine,
a 5-HT uptake enhancer, increased GHRH release into the
hypophysial portal vessels and raised GH secretion (186).
In humans, using a variety of 5-HT receptor agonists
and antagonists, it has been seen that 5-HT pathways
stimulate, inhibit, or do not alter GH secretion (see Ref.
756 for references). Sumatriptan, a recent selective
5-HT1D receptor agonist with no activity on 5-HT2, 5-HT3,
and 5-HT4 receptors, and other neurotransmitter receptors, has permitted closer assessment of 5-HT’s effects on
basal and stimulated GH secretion. In normal prepubertal
children, sumatriptan raised basal GH levels and the GH
responses to GHRH; however, sumatriptan pretreatment
did not modify the GH response to clonidine or pyridostigmine, an inhibitor of AChE, but increased the GH response to arginine. In a group of obese children,
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NEUROENDOCRINE CONTROL OF GROWTH HORMONE SECRETION
lated GH release in normal adults or children (835, 1025).
Pirenzepine and atropine also completely blocked the GH
response to GHRH, whereas conversely, blockade of
AChE by pyridostigmine potentiated the GH response to
GHRH (672) and normalized the blunted somatotroph
responsiveness to repetitive GHRH boluses (671). Finally,
paradoxical GH responses to TRH, which occur in some
patients with insulin-dependent diabetes, endogenous depression, or liver cirrhosis, could be suppressed by pirenzepine (759).
Overall, the fact that M1 cholinergic receptors inhibited the GH response to most of the hypothalamic and
pituitary GH-releasing stimuli was consistent with the
idea that the restraint arose “downstream” of the chain of
events leading to GH release. Enhanced release of hypothalamic SS and the ensuing inhibition of somatotroph
function might explain these findings.
In vitro studies addressing the mechanism(s)
whereby ACh neurotransmission affects GH secretion
provided support for this concept. Low concentrations of
ACh inhibited the release of SS-LI from rat hypothalami in
culture, an effect shared by neostigmine and blocked by
atropine, but not by hexamethonium, a nicotinic antagonist (888). These observations were in contrast to findings
that a series of muscarinic cholinergic agonists raised
secretion of SS-LI from fetal rat hypothalami in culture, an
effect antagonized by atropine (834), and that intracerebroventricularly injected ACh in rats released SS-LI into
hypophysial blood (228). These latter findings, however,
must be interpreted with caution, since anesthesia is mandatory in these in vivo experiments and some anesthetics
already induce SS release.
Proof that abolition of GHRH-induced GH release by
cholinergic antagonists implies activation of SS release
was provided by in vivo experiments in conscious male
rats. Like in humans, pirenzepine or pilocarpine, respectively, reduced or potentiated the increase in plasma GH
induced by GHRH. These modulatory effects were not
seen in two experimental models of depletion of hypothalamic SS (629). These data indicated that in rats cholinergic modulation on GH release is through SS, in keeping
with the high density of muscarinic binding sites in the
ME (911) and their location in the lateral region of the
external layer (954), to which most of the SS nerve terminals also project (see sect. IIIB). Cholinergic neurons
would also be instrumental to the autofeedback regulation of GH secretion, through modulation of the SS tone,
in rats (1039) or humans (907) (see also sect. VIIA). Cholinergic receptor agonists and antagonists added to pituitary cells in vitro did not alter the GHRH-induced GH
release (629).
Although the relationship between SS function and
the hypothalamic cholinergic system is now generally
established, some observations still challenge it. For instance, the hypoglycemia-induced increase in GH appears
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(111) for many years hindered further studies on the
actual role of ACh in the neural control of GH secretion.
Thus only in 1978 did Bruni and Meites (147) show that in
conscious male rats intracerebroventricularly injected
ACh bromide raised plasma GH and that the same effect
was achieved by systemic injection of pilocarpine or eserine, a muscarinic agonist and an AChE inhibitor, respectively. The increase in GH release induced by pilocarpine
was antagonized by atropine, which per se did not alter
serum GH concentrations. Parallel studies in chronically
cannulated, unrestrained rats showed that systemically
administered atropine inhibited episodic GH release
(665).
In dogs, ACh neurotransmission appeared to have a
stimulatory role in GH release, through muscarinic receptors inside the BBB (173). The importance of cholinergic
mediation in the GH-releasing mechanism(s) was emphasized by the observation that in dogs (174) and humans
(825) atropine was the most effective antagonist of the
GH release induced by EOP (see sect. VB8).
Further evidence that cholinergic transmission is involved in GH accumulated from human studies. Mendelson et al. (703) reported a striking suppression of the
sleep-associated increase in GH secretion and a more
subtle blunting of the GH response to insulin-induced
hypoglycemia after administration of methscopolamine, a
muscarinic antagonist unable to cross the BBB. The same
group found that in humans infusion of piperidine, a
cholinergic nicotinic agonist, left resting GH levels unaltered but slightly enhanced sleep-related and insulin-induced GH secretion; they were led to conclude that both
nicotinic and muscarinic mechanisms were involved in
these aspects of stimulated GH release (704).
The observation that methscopolamine, which does
not cross the BBB, blunted the stimulated GH release in
humans indicated a “peripheral” site of action for cholinergic stimulation of GH release. This was borne out by the
reported ability of edrophonium and pyridostigmine, two
irreversible AChE inhibitors and quaternary ammonium
compounds, to release GH in normal subjects (609, 672).
Cholinergic muscarinic receptors have been described in
the anterior pituitary (747, 931) and the ME (954), and
ACh is a direct GH secretagogue on bovine (1120) and rat
pituitary (170).
The increasing awareness of the role played by ACh
neurotransmission in the mechanism(s) subserving GH
release led to fresh investigations of how cholinergic
function interacted with the metabolically and neurotransmitter-driven GH release. In normal men, pirenzepine, a selective antagonist of M1 receptors that barely
crosses the BBB, blocked the GH rise induced by DA and
a2-adrenoceptor stimulation (301), and atropine suppressed that after arginine, clonidine, and physical exercise (178). In line with the methscopolamine findings,
atropine or scopolamine completely abolished SWS-re-
551
552
MÜLLER, LOCATELLI, AND COCCHI
GHRH test (405) are currently the most reliable for assessing GH secretory status in children, because they
probe the maximal secretory potential of the pituitary. A
normal GH response to the combined pyridostigmine or
arginine-GHRH test does not exclude the existence of a
GH hyposecretory state due to hypothalamic dysfunction,
calling for 24-h monitoring of GH secretion.
The clear GH-releasing effect of cholinergic muscarinic agonists led to their use in the treatment of short
stature. Briefly, in a group of short children, with hormonal features peculiar to hypothalamic dysfunction,
long-term oral pyridostigmine (60 mg 3 times a day for 6
mo) did not significantly alter height velocity, mean GH
concentration, and plasma IGF-I levels, except in one
child (755). Results were similarly negative with a combination of cholinergic agonists and GHRH in the treatment of short stature (908).
Muscarinic cholinergic agonists could also be used to
investigate the hypothalamic SS (and GHRH?) system in
different physiological or pathological conditions. In rats
aged between 10 days and 29 mo, administration of GHRH
alone led to an age-related decline in the responsiveness
of GH, starting from 8 mo of age. Pretreatment with
pilocarpine potentiated the GH response to GHRH during
the entire life span, with the only exception being 10-dayold rats in which the drug had no effect. Interestingly, at
this age, the hypothalamic SS tone is very low (see sect.
IIB). Pilocarpine rejuvenated the GH response to GHRH in
the older rats (18 and 29 mo old) to the concentrations of
that found in 15-mo-old rats (807). Similarly, in a group of
normal elderly humans, pyridostigmine potentiated GH
response to GHRH, although it was still significantly
lower than in younger people (413).
These findings support the idea that in aged mammals the reduced response of GH to GHRH is only partly
due to an intrinsic defect of the somatotrophs and that
hypothalamic and/or extrahypothalamic inhibitory influences under cholinergic control are also involved. It is
common knowledge that central cholinergic function can
be impaired in the elderly brain (828), and cholinergic
agonists per se induce a blunted GH response in aged
animals (208) and humans (872).
At variance with the partial restoration of the GH
response to GHRH by pyridostigmine is the complete
restoration by pretreatment with arginine so that the increase in GH induced by arginine-GHRH cotreatment was
similar in young and old subjects, and arginine had
greater potentiating effect in elderly than in young subjects (414). These findings, while reinforcing the idea that
the pool of releasable GH is essentially preserved in the
human pituitary even during aging (see also sect. IIB),
illustrate the irreversible, age-related alteration of the
cholinergic function coupled with a reversible SS hyperfunction.
Attempts at using cholinergic blockade in GH hyper-
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to be almost totally (702) or partially (344) refractory to
cholinergic blockade, but not to the action of SS. This and
a series of other observations in animal (37) and human
models of caloric restriction (see below) suggest an extra
SS component in the modulatory action of cholinergic
drugs on GH release. Thus, in subjects with AN, pyridostigmine failed to potentiate the release of GH induced
by GHRH, whereas arginine, another GH secretagogue
allegedly acting by inhibiting release (22), fully enhanced
the GHRH-induced release of GH in these patients (409).
In sheep, a single dose of neostigmine stimulated GHRH
release into hypophysial portal vessels without changing
SS concentrations (651), and interestingly, in the rat ARC
ACh coexists in GHRH- but not in SS-containing neurons
(699).
In sum, it cannot be ruled out that GHRH is involved
in the modulatory action of cholinergic drugs on GH
release as also inferred by the fact that a competitive
GHRH antagonist suppressed the increase in GH induced
by an AChE inhibitor (520), or by the type of GH pulse
profiles evoked by a short pyridostigmine treatment in
humans (373). The dual mechanism of cholinergic agonists explains why they do not completely reverse the
defective GH release associated with obesity (415, 634)
more convincingly than a mechanism relying exclusively
on inhibition of hypothalamic SS. Instead, in obesity, the
GH hyposecretion is completely reversed by the combination of GHRH and GHRP-6, which provides an appropriate pituitary-directed GHRH and anti-SS stimulation
(270; see Ref. 752 for further discussion).
A) CLINICAL IMPLICATIONS. The availability of a class of
compounds purportedly suppressing hypothalamic SS influences, i.e., muscarinic cholinergic agonists, prompted
studies to see whether they could enhance the diagnostic
power of GHRH. When used alone, GHRH does not discriminate between normal and GH-deficient subjects;
wide inter- and intraindividual variability is frequent even
in normal subjects, and there may be no GH response to
the maximally effective dose (686, 1055). The effects of
pyridostigmine on basal and GHRH-induced GH secretion
were investigated in children with familial short stature,
constitutional growth delay, and GH deficiency, and the
results were compared with those following insulin-induced hypoglycemia or GHRH alone (416) or, in another
study, with those of normal children undergoing a series
of provocative tests (405). In normal children, the pyridostigmine-GHRH tests, unlike other GH secretagogues,
gave no false-negative responses; the minimal normal GH
response was ;20 ng/ml. The test therefore detected a
pathological response in a much wider interval than the
other tests; in patients with organic GH deficiency, peak
GH responses were lower than 6 ng/ml, whereas in patients with idiopathic GH deficiency or constitutional
growth delay, peak GH responses were 7–19 ng/ml. Thus
the pyridostigmine-GHRH test and also the arginine-
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NEUROENDOCRINE CONTROL OF GROWTH HORMONE SECRETION
4. Histamine
The role of histamine on GH release in the rat is still
debated, but most of the evidence points to inhibition by
H1 receptors. In conscious rats, intracerebroventricular
administration of histamine or a series of H1-receptor
agonists reduced GH release induced by morphine;
mepyramine, a H1-receptor antagonist, had no effect by
itself but prevented the inhibitory action of 2-methylhistamine, a H1-receptor agonist. The H2-receptor agonists
and antagonists also inhibited morphine-induced GH release but apparently with a nonspecific mechanism (776).
Similarly, nanomolar intracerebroventricular doses of histamine or amodiaquine, an inhibitor of histamine catabolism, caused a dose-related suppression of pulsatile GH
secretion (775).
At odds with these findings, in E2- and progesteroneprimed anesthetized male rats, a H1-receptor antagonist
blocked the rise in GH induced by morphine, neurotensin,
and SP, with a mechanism that could not be related
simply to the hypotensive properties of these substances
(891).
The inhibitory effect of histamine neurotransmission
on GH release has since been illustrated in neonatal and
adult rats. In the former, blockade of histamine synthesis
with a-fluoromethylhistidine (a-FMH) significantly raised
plasma GH and potentiated the GH response to an enkephalin analog; GH and SS mRNA were significantly
higher in a-FMH-treated pups, whereas GHRH mRNA levels were unaltered. In young adult male rats, acute administration of a-FMH did not change baseline GH levels but
potentiated the enkephalin-induced stimulation of GH secretion. Repeated intracerebroventricular doses of
a-FMH did not alter the hormone levels, significantly
reduced hypothalamic GHRH mRNA, and left SS and
GHmRNA unchanged (439). Overall, these findings sug-
gest an inhibitory histamine tone on GH secretion in
neonatal and adult young rats, the failure of a-FMH to
increase GH secretion in the latter being probably due to
upregulation of histamine receptors after brain histamine
depletion (862).
Data in freely moving dogs point instead to a facilitatory role on GH secretion. Of the three H1-receptor
antagonists used, only clemastine, which reportedly has
no antiserotoninergic, antiadrenergic, and anticholinergic
action, blunted hypoglycemia-induced GH release (626),
whereas diphenhydramine, clemastine, and the H2-receptor antagonist cimetidine, respectively, suppressed or
blunted the cGH release induced by an opioid peptide
(174) or by cholinergic stimulation (100).
Histamine also appears to be involved in stimulated
GH release. In normal humans, two H1-receptor antagonists significantly reduced the GH response to arginine
infusion, but neither drug affected the secretion after
insulin hypoglycemia (859). In healthy volunteers, diphenhydramine, which also has anticholinergic activity, completely suppressed the GH response to an opioid peptide,
FK 33– 824 (825). The H2-receptor antagonists have given
different results depending on the dose, length of treatment, and route of administration. Thus cimetidine at oral
therapeutic doses for 1 mo or more to patients with peptic
ulcers (990) or normal subjects (1051) did not alter baseline or stimulated GH release but reduced mean nocturnal
GH secretion (1051). The drug also reduced GH response
to insulin hypoglycemia when repeatedly administered
(858) and blunted the GH response to levodopa when
given as an intravenous bolus injection (1122). Higher
peak plasma concentrations of cimetidine after a single
intravenous bolus than after chronic oral administration
explain these results.
5. Amino acids
A) EXCITATORY AMINO ACIDS. A glutamatergic control of
GH secretion was first suggested a long time ago when it
was shown that MSG given neonatally, at doses damaging
the ARC neurons, impaired the rhythmic GH secretion in
postweaning rats (774). This compound acted similarly in
adult male rats at doses causing no neurotoxic lesions.
However, two agonists of glutamate receptors, N-methylD,L-aspartic acid (NMA) or kainic acid, increased GH secretion in adult male rats, implying that NMDA and nonNMDA receptor subtypes were involved in GH-secreting
mechanism(s) (670, 850). In the same experiments, ibotenic acid or quinolinic acid did not alter AP hormone
secretion (670).
The GH-releasing properties of systemically administered NMA were confirmed in prepubertal male rhesus
monkeys. Injection of the amino acid analog elicited a
prompt increase in GH secretion to three times the preinjection values. N-methyl-D,L-aspartic acid maintained its
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secretory states have not been successful. Insulin-dependent diabetics (IDDM) may present exaggerated nocturnal GH swings, and GH release is primarily responsible
for the dawn phenomenon, i.e., decreased sensitivity of
hepatic glucose production to insulin (754). Suppressing
of GH secretion in IDDM may improve metabolic control
and prevent the development of diabetic late complications.
After a few promising results with short- or mediumterm pirenzepine (57, 670), in further studies, atropine
and propantheline, another muscarinic cholinergic antagonist, had no effect on indices of somatotrophic function
in IDDM patients with active proliferative retinopathy
(500). These results, which recall the inability of pirenzepine to suppress 24-h GH secretion in tall children (469),
put doubt on the effectiveness of long-term treatment
muscarinic antagonists, probably because of the early
development of tolerance (916).
553
554
MÜLLER, LOCATELLI, AND COCCHI
the amino acid is not manufactured in the pituitary gland
and that EAA receptors are stimulated by hypothalamicderived glutamate transported to the target sites by the
portal vessels.
The stimulatory effect on GH secretion of hypothalamic injection of EAA strongly suggested a major CNS
site of action. It was also shown that NMDA did not
release GH in ARC-lesioned adult rats (8), indicating that
its effect was mediated by substances released from this
area. That pretreatment with a GHRH antiserum reduced
the GH-releasing effect of NMDA in neonatal rats (8) was
in keeping with the idea that a GHRH deficiency was
involved. Similar results were obtained in prepubertal
gilts in which aspartate was a more potent GH secretagogue than glutamate, but neither compound had any
effect in the GHRH antiserum-pretreated animals (71).
More proof of this mechanism was provided in male rats
at weaning by evaluating the effect of 10 days of treatment
with MK-801 on the hypothalamic content and gene expression of GHRH and SS. The drug impaired the growth
rate and reduced GH secretion with significant lowering
of the hypothalamic GHRH content and GHRH mRNA.
Hypothalamic SS content and mRNA were unaltered
(260).
This finding is seemingly in contrast to a report that
the NMDA receptor antagonist counteracted NMDA-stimulated SS release from cultured diencephalic neurons
(1022), but this might be due to differences in neuronal
organization in fetal (1022), prepubertal (260) hypothalami. In our hands too, however, quinolinic acid, an NMDA
receptor agonist, strikingly increased SS release from incubated hypothalamic fragments, this effect being completely reversed by coincubation with MK-801 (260). It
cannot be ruled out, therefore, that MK-801 may induce
changes in selective groups of hypothalamic SS-producing neurons, whose involvement might perhaps be evidenced by a more refined approach, e.g., in situ hybridization.
Although there are reports that NMDA receptor activation is required for the expression of c-fos in GnRH
neurons of female rats (602), no specific studies have
been done on c-fos induction in neurons containing GHregulatory neurohormones, although intraventricular injection of NMDA induced c-fos expression around the
PeVN and in the ARC, where GHRH and SS-containing
cell bodies are located (see sect. IIIA2). An increase in
c-fos-IR after NMDA was evident in noradrenergic cells of
the locus coeruleus (914), and this would be relevant for
the stimulatory effect of EAA on GH secretion, in view of
the major role played by NE neurons in this context.
That excitatory amino action action depends on sex
steroids was shown in adult male rats orchidectomized 1
wk before. Systemic administration of kainic acid elicited
a larger rise in plasma GH than in sham-operated controls;
the GH-releasing properties of kainic acid completely dis-
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ability to release GH when given systemically to castrated
male sheep which, unlike rodents, do not respond to the
amino acid in terms of LH release (342). A dose-related
increase of plasma GH levels after NMA was also reported
in ovariectomized ewes (341) and in intact ewes (323).
Unlike the gonadotropin system (242), NMDA seems
to stimulate GH release to much the same extent in neonatal and adult rats, as shown by its ability to increase
plasma GH in 2-day-old rats (8). Consistent with a stimulatory role of excitatory amino acid (EAA) on GH secretion in either infant or adult rats was the observation that
blockade of NMDA receptors by the noncompetitive antagonist MK-801 in immature female rats caused longlasting reduction of growth rate, GH pituitary content,
basal and GHRH-stimulated GH release, and plasma IGF-I
levels. This effect was coupled with delayed puberty and
reduced gonadotropin secretion, which mimics a condition frequent in humans (1068).
Stimulation of GH release by NMDA posed the question of the site(s) and mechanism(s) of action of EAA.
Neural loci at which systemically administered NMDA
may affect GH release comprise areas of the brain lacking
a distinct BBB, especially the circumventricular organs,
and including the ARC (868). When NMDA was tested on
pituitary fragments from neonatal or young adult rats in
static incubation, it showed no GH-releasing effect (8,
260), and stimulation of GH release was scant after incubation of pig pituitary cells with high concentrations of
glutamate or aspartate (71). Results were different, however, on isolated perfused somatotrophs, where low concentrations of NMDA induced sustained GH release that
was abolished by the concomitant addition of competitive
and noncompetitive NMDA receptor antagonists (615).
The possibility that isolation of the somatotrophs from
the other pituitary cells was responsible for the enhanced
responsiveness to NMDA in the perfusion system was
unlikely; NMDA caused dose-related GH stimulation in a
mixed population of cultured pituitary cells, as assessed
by the reverse hemolytic plaque assay (777). The same
GH-releasing effect was shared by L-glutamate or kainic
acid and was completely counteracted by selective NMDA
and non-NMDA receptor antagonists (777). The rat somatotrophs thus appeared to have both NMDA and nonNMDA ionotropic receptors.
In line with these findings, non-NMDA type of receptors were demonstrated in the anterior lobe of the rat
pituitary by immunohistochemistry (563). Other studies
have also detected the metabotropic type of EAA receptor
(1117). The demonstration of the NMDA R1 receptor subunit, in the AP and its colocalization in many cell types,
including the somatotrophs, indicate the importance of a
direct effect in the pituitary (101).
Deafferentation of the MBH reportedly leads to a
drop of glutamic acid concentrations in the MBH itself,
and in both lobes of the pituitary (869). This implies that
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NEUROENDOCRINE CONTROL OF GROWTH HORMONE SECRETION
activity with 3-mercaptopropionic acid or with bicuculline raised plasma GH concentrations (359). In freely
moving rats, systemic administration of muscimol, a direct agonist of GABAA receptors, or GAG inhibited the GH
secretory episode, whereas bicuculline methiodide, a
compound which barely crosses the BBB, induced powerful but short-lived stimulation of GH release when injected at the nadir of basal hormone levels (358).
A likely explanation of these and other findings (see
Ref. 748 for more details) is that GABA may play a dual
role in the control of GH secretion in the rat depending on
the animals physiological state. g-Aminobutyric acid
would inhibit either the SS- or the GHRH-secreting neurons, or both, also in view of its alleged inability and that
of muscimol to act directly on cultured AP cells (358) (but
see below). That GABAergic neurotransmission inhibited
SS neurons was borne out by the fact that muscimol and
bicuculline injected into the POA, an area where SScontaining perikarya are located, stimulated and inhibited,
respectively, GH secretion (1097). The GABA-SS interaction
was confirmed by the fact that GABA inhibited SS release
into the rat hypophysial portal vessels (998) and from hypothalamic cells in culture (387) and the discovery of GABA-IR
synapses on SS-IR perikarya in the PeV hypothalamus
(1097). Benzodiazepines, which reportedly act through
GABA-mediated mechanisms, also inhibited SS release from
rat diencephalic cells in vitro (989).
These and other findings led to the proposition that
GABA and its analogs only affect the PeV brain areas,
including the SS elements, when injected centrally, without impinging on more distant brain structures in which
the GHRH-secreting neurons are located (see sect. IIIA2).
These areas, which have no effective BBB, can be reached
by drugs such as systemically injected GABA and its
analogs or antagonists, which normally do not cross the
BBB. Therefore, GABA-mimetic lower GH by inhibiting
GHRH-secreting structures (see Ref. 748 for further details).
g-Aminobutyric acid acts directly on the rat pituitary
during the neonatal period, when sensitivity to hypophysiotropic factors is at its highest. Systemically injected
GABA in newborn rats significantly increased plasma GH
levels (9). This effect was very likely due to the fact that
GABA and muscimol, in micromolar concentrations, elicit
GH release from the entire pituitary of 2-day-old rats, an
effect subsiding after the ninth postnatal day. In this
system, bicuculline methiodide and picrotoxin, a known
chloride ionophore antagonist, counteracted the effect of
GABA, although at concentrations exceeding that of the
agonist by 10-fold; diazepam stimulated, but baclofen, a
stimulant of GABAB receptors, had no effect on GH secretion (9).
In further studies, a superfusion system was used to
assess the GABA effect and to provide evidence of its
mediation by specific GABA receptors. Muscimol was
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appeared in male rats estrogenized at birth, a model of
permanent decrease of plasma testosterone (850).
The results so far strongly suggest that EAA are
positive modulators of GH secretion, mainly acting
through at GH neuroregulatory hormones. It would appear that this effect is mediated by ionotropic NMDA and
non-NMDA (AMPA/kainate) receptors, with metabotropic
glutamate receptors not being involved. A direct action of
EAA on somatotrophs is unlikely, in view of the controversial data on in vitro GH secretion, and the biochemical
evidence of the presence of metabotropic but not ionotropic glutamate receptors in the pituitary. Hypothalamic
GHRH neurons would be the privileged target of EAA
action, with somatostatinergic neurons playing only an
ancillary role.
From a physiological point of view, EAA seem to be
involved in the central mechanisms triggering the endocrine events related to puberty, including the enhanced
GH secretion that accelerates body growth (see also sect.
IIIB and Ref. 139 for review). It is tempting to suggest,
therefore, that the frequent association of delayed puberty and short stature (729) may share a common etiopathogenetic denominator, namely, reduced glutamatergic function at either the GnRH- or GHRH-producing
neurons in the ARC. Were this the case, NMDA receptor
antagonists would be useful for the treatment of precocious puberty, although the inhibitory effect of noncompetitive NMDA receptor antagonists on GH secretion
would constitute an adverse event. Unlike MK-801, CGP39551, a competitive antagonist of NMDA receptors, delayed puberty in female rats but had no effect on the rate
of body growth (253). Compounds of this type would be a
better choice for the treatment of precocious puberty
than noncompetitive NMDA receptor antagonists, although further studies are needed to substantiate this in
humans, who appear to be less sensitive than animals to
the (acute) stimulatory effects of EAA on GH secretion. In
eight Caucasian males, a MSG dose 25 times the normal
daily intake had no effect on the secretion of GH and
other pituitary hormones (353).
B) INHIBITORY AMINO ACIDS. The actual role of GABA on
GH secretion has been a source of considerable controversy, and both stimulatory and inhibitory influences have
been reported. Briefly, intracerebroventricular injection
of GABA or systemic administration of amino-oxyacetic
acid, an inhibitor of GABA-T, or g-hydroxybutyrate
(GHB), a physiological metabolite of GABA, induced a
prompt dose-related increase in serum GH in conscious
and anesthetized male rats and in ovariectomized, steroidreplaced female rats (1071). Opposing the stimulatory
effect of centrally administered GABA and its analogs was
the GH-lowering effect of of two GABA-T inhibitors, ethanolamine-O-sulfate and g-acetylenic GABA (GAG), administered systemically, in conscious or pentobarbital sodium-anesthetized rats. Conversely, reducing GABAergic
555
556
MÜLLER, LOCATELLI, AND COCCHI
tion and blunted the GH response to levodopa (580).
Stimulation of GABAergic neurotransmission also inhibits
GH release during physical exercise (981), an effect which
would be counteracted by activation of the opioidergic
function (262), which might involve stimulation of GHRH
release or, alternatively, inhibition of SS secretion (see
sect. VB).
To explain some of the seemingly paradoxical findings reported, we can propose that inhibition of the GH
release stimulated by GABA and its ability to raise baseline GH share the same basic mechanism, i.e., an action
through dopaminergic neurons. Continuous stimulation
of CNS-DA receptors by GABA mimetics through DA
release (see above) would ultimately lead to a state of
partial refractoriness to DA-mediated events (insulin hypoglycemia and levodopa).
The involvement of the GABAergic system in the
GH-secreting processes would include pathological states
such as IDDM. Reportedly, this disease is characterized
by GH hypersecretion and an exaggerated GH response to
GHRH very likely due to a spontaneous decrease in hypothalamic SS tone (754, see sect. VI). Insulin-dependent
diabetes mellitus is well recognized as an autoimmune
disease (334), and the decreased SS tone may reflect
damage by an autoimmune process either directly to SS
neurons or indirectly to the brain neurotransmitters controlling SS release. GAD, the key enzyme of GABA biosynthesis, has been identified as a major autoantigen of
IDDM, being a target of both humoral and cell-mediated
autoimmunity (127).
In a study investigating the possible influence of GAD
autoimmunity on GH secretion, most of the patients with
elevated serum GAD antibody levels had significantly
higher serum GH after administration of GHRH than controls or diabetics with low GAD levels; pretreatment with
pyridostigmine, which allegedly reduces SS tone, significantly enhanced the GH response to GHRH in patients
with low GAD and in controls, but not in patients with
high GAD levels (423). It would seem, therefore, that
autoimmunity plays a major role in the exaggerated GH
response to GHRH in IDDM, through a reduction of a
GABAergic tone that stimulates SS production in the hypothalamus.
g-Hydroxybutyric acid is a breakdown product of
GABA that reportedly reduces ethanol consumption and
suppresses the ethanol withdrawal syndrome (346, 384).
In human volunteers, GHB stimulates the secretion of GH
(999), and this finding has been confirmed (398). A GABAmediated mechanism for GHB was suggested by the fact
that flumazenil, an antagonist of benzodiazepine receptors, counteracts the GH response to an oral dose of the
compound (398) and was consistent with the idea that
GBH acts on a subpopulation of the GABA complex in
close relation with benzodiazepine receptors (952). The
finding that bicuculline antagonized the stimulatory effect
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;10 times as potent as GABA in eliciting a prompt increase in GH secretion, and the effect of GABA was
antagonized by picrotoxin and bicuculline, implying the
involvement of a GABAA receptor. Continuous exposure
of neonatal pituitaries to GABA resulted in a state of
refractoriness to the action of muscimol, indicating receptor desensitization (10). Overall, these data suggested that
GABA might be one of the factors involved in maintaining
the high circulating GH levels of the early postnatal period. The mechanism by which GABA stimulates GH secretion from preloaded neonatal rat pituitaries is beyond
the scope of this review, and the reader is referred to Acs
and co-workers (11, 12) and Horvath et al. (490).
The use of a superfusion system demonstrated that
both GABA and muscimol induced a large, transient stimulation of GH secreted from adult AP, which were sensitive to inhibition by bicuculline. Baclofen did not stimulate GH secretion, whereas the effect of muscimol was
potentiated by benzodiazepines and barbiturates (33).
That GABA or GABA agonists act directly on the
pituitary is supported by the presence of low- and highaffinity GABA and muscimol receptors in the rat (36) and
human (437) pituitary, although their function appears
mainly to involve an inhibitory control on prolactin secretion.
A series of studies has shown that in healthy, psychiatric, or neurological subjects, gram amounts of GABA or
a few milligrams of muscimol induced clear-cut GH increments in plasma with a peak after 60 –90 min (1004; see
Ref. 96 for further details). Similarly, g-aminohydroxybutyric acid, a GABA derivative, did not raise plasma GH
when injected subcutaneously into normal volunteers but
did when given intrathecally to cerebrovascular disease
patients (998). Growth hormone release was also stimulated by intravenous diazepam or oral doses of other
benzodiazepines (see Ref. 533).
To the list of GABAergic compounds that stimulate
GH release in humans one must also add baclofen (573),
which has been used as a neuroendocrine probe of the
GABA system in psychiatric studies (735, 787). There is,
however, wide individual variability in the GH response to
baclofen, with ;30% of false-negative responses in normal subjects (285).
The GH-releasing effect of GABA in humans may
occur through activation of dopaminergic pathways, i.e.,
GABA would activate DA release at a site inside the BBB
(194). Because peripherally administered GABA does not
easily enter the brain, this CNS site must be incompletely
covered with a BBB, e.g., the GHRH-secreting neurons
(see above).
In sharp contrast to the above findings and consistent
with an inhibitory component of GABA action are observations related to stimulated GH release. Premedication
for a few days with either GABA (194) or baclofen (193)
inhibited hypoglycemia- and arginine-induced GH secre-
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NEUROENDOCRINE CONTROL OF GROWTH HORMONE SECRETION
2. Neurotransmitters and growth hormone
secretion
TABLE
Animals
Humans
E
a1
a2
b1
b2
NE
DA
5-HT
5-HT1
5-HT2
ACh
H
H1
H2
GABA
Glutamate
1
2
1
(1)a
(2)
1
1
12b
1c
1d
1e
1
2
?
12
1f
1g,h
12?
1
2
2
1
12c
12?
1i
1d
1e
–
1
1
1
3
3, No effect; 1, stimulation; 2, inhibition; –, action not ascertained; ?, action still questionable. Effect of activation of receptor subtypes is indicated with parentheses. E, epinephrine; NE, norepinephrine;
5-HT, 5-hydroxytryptamine; H, histamine. a In vitro; b inhibition in dog;
c
5-HT1C subtype; d slight effect; e muscarinic receptors; f N-methyl-Daspartate (NMDA) and non-NMDA receptors; g in combination with
propranolol; h inhibitory in acromegaly and in vitro anterior pituitary;
i
5-HT1D subtype.
of GHB on GH secretion (1071) was consistent with a
GABAA-receptor mediated mechanism. Some data, however, contradict the GABAergic action, such as its inability to modify the chloride function coupled with the
GABAA receptor (951); action through a postsynaptic receptor has not been proven (968).
Contrasting findings have been reported on how GHB
influences monoaminergic pathways (382). The interaction of GHB with the serotoninergic system (976) appears
interesting, considering the alleged functional deficiency
of the latter in ethanol-prone subjects (598), who are
detoxified by GHB (see above). Inferential support for
this mechanism is provided by observations that the 5-HT
receptor antagonist metergoline in male healthy volunteers blunted the GH response to GHB (397), and there
was a persistent loss of 5-HT1D receptor and GHB-mediated neurotransmission in long-term abstinent alcoholics,
as shown by their inability to make a GH secretory response to sumatriptan or GHB (1069).
Table 2 lists the stimulatory or inhibitory influences
on GH secretion of brain neurotransmitters studied so far,
as derived from experimental evidence reviewed in section VA.
E. Growth Hormone-Releasing and -Inhibiting
Neuropeptides
In addition to the specific hypothalamic regulatory
hormones for GH secretion, GHRH and SS, whose physi-
ological role is now established, and the still elusive ligand for the GHRP receptor, a host of CNS neuropeptides,
some of them originally identified in the gut or peripheral
nervous system, have marked stimulatory or inhibitory
effects on GH secretion. The list of traditional neuropeptides has recently been enriched by the inclusion of immunomodulators, especially cytokines, and a neurotransmitter gas nitric oxide (NO).
Some of these compounds are found in specific nuclei of the hypothalamus, where they often coexist with
hypophysiotropic neuropeptides or classical neurotransmitters, and at times they are detected in the hypophysial
portal blood; this and the recognition of specific binding
sites in the target pituitary gland suggest a neurohormonal
role and a hypophysiotropic function. However, these
peptides can alter endocrine function not only as hormones but also as neurotransmitters or neuromodulators,
not excluding a role as autocrine or paracrine factors in
the pituitary acting on GH secretion or somatotroph proliferation.
Because the physiological role of these peptides has
yet to be unequivocally established and their effects on
GH secretion are often unmasked by pathological situations, it seems appropriate to examine these compounds
separately from the classical hypophysiotropic neurohormones.
1. Thyrotrophin-releasing hormone and gonadotropin
hormone-releasing hormone
Thyrotrophin-releasing hormone, the first hypophysiotrophic peptide to be isolated and synthesized chemically, was so named because its primary functon is to
stimulate TSH secretion from the pituitary gland (773).
Apart from its ability to stimulate prolactin release, TRH
releases GH in animals and humans, although only in
pathological conditions (see Refs. 257, 462 for reviews).
The TRH-induced GH response which, since we are unable to provide a meaningful explanation, has been
termed “paradoxical,” appears to be mediated by various
mechanisms, some of which are mentioned below.
One postulated mechanism encompasses expression
of anomalous TRH receptors on somatotroph cells, probably in the pituitaries of acromegalic patients where the
presence of TRH-binding sites has been related to a positive individual GH response to TRH in vivo (600). Consistent with this view, TRH also stimulates GH release
from rat somatotroph lines such as GH3 (124) and GH4C1
cells (20).
There is almost general agreement on the clinical
significance of the TRH-induced GH release in acromegaly. It is frequently seen with prolactin-containing somatotrophinomas. Accordingly, TRH responders generally
had higher baseline levels of prolactin than TRH nonresponders (1082). A likely interpretation was that adeno-
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Subjects
557
558
MÜLLER, LOCATELLI, AND COCCHI
itory effect was present in a number of animal species (for
review, see Refs. 462, 749).
The most likely mediator of the inhibitory effect of
TRH on GH secretion is the somatostatinergic system.
Immunohistochemical studies indicate that more than
95% of SS-IR perikarya in the preoptic-anterior hypothalamic area and in the PVN appear to be contacted by one
or more TRH-IR terminals (1100). Furthermore, TRH
causes SS release from the hypothalamus (544, see also
sect. IIIB3), enhances plasma concentrations of SS (565),
and upregulates pituitary sstr (940).
Thyrotrophin-releasing hormone might also affect
neurotransmitter systems upstream of the SS neurons,
although it is not known how the cholinergic system
would be excluded, since enhancement of its function by
pyridostigmine in the dog did not modify the inhibitory
effect of TRH on GHRH-induced GH release (38).
In a group of cirrhotic patients, who reportedly include a high proportion of TRH responders, infusion of
DA before the TRH stimulus increased baseline GH levels
(decrease of SS tone?), and GH rise after TRH peaked
sooner (760).
In addition to TRH, other hypophysiotropic hormones also stimulate GH secretion in acromegalic subjects or patients with CNS disturbances. Like TRH, GnRH
(912) induces GH release from the pituitaries of rats
anatomically and/or functionally disconnected from the
CNS (804), and in human disorders in which TRH is also
an effective GH releaser (749).
2. CRH, AVP, and oxytocin
Among the several systems of CRH neurons, the
PVN-ME pathway is responsible for most of the hypophysiotropic actions of the peptide. A second series of CRHLI stained neurons in the basal telencephalon, hypothalamus, and brain stem are interconnected by fibers of the
medial forebrain bundle and the PeV system (756). These
neurons are thought to play an important role in autonomic and neuroendocrine responses to stress, inducing,
when activated, all the homeostatic changes that follow
the stressful event (see Ref. 756).
Corticotropin-releasing hormone reduces basal or
stimulated GH release in the rat (545, 796), an effect very
likely mediated by SS release since it was abolished by
pretreatment with an anti-SS serum (545). In addition, in
vivo, CRH raised portal concentrations and secretion
rates of SS (730) and extracellular release of SS from
hypothalamic neurons (188). These findings, which are
substantiated by the demonstration of direct synaptic
connections between CRH and SS neurons (471), point to
CRH as the mediator of the stress-induced suppression of
GH secretion in rodents.
In the rat, CRH is also needed for the regulation of
spontaneous GH release because continuous intraventric-
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matous cells containing mixed GH/prolactin cells or/and
mammosomatotroph cells possess many of the properties
of normal lactotrophs including receptors for both TRH
and DA. In contrast, acromegalic patients with pure somatotrophinomas are usually unresponsive to both the
TRH and the GH-lowering effect of dopaminergic agonists
(see Ref. 1082 for review).
The anomalous GH response to TRH might, alternatively, also result from an impairment of the inhibitory
hypothalamic control of GH secretion (257, 749), as implied by the fact that TRH induces GH release from ectopically transplanted rat pituitary glands, pituitaries incubated in vitro, pituitaries from rats with lesions of the
ME or passively immunized against SS (see Refs. 257, 462
for reviews). Thyrotrophin-releasing hormone is a strong
stimulus to GH secretion in fetal, neonatal, and prepubertal animals in which the hypothalamic control of GH
secretion is presumably functionally immature (see Refs.
257, 462 for review), and the paradoxical response may
also occur in the elderly, whose hypothalamic control of
pituitary function is diminished (75, 236).
The observation that passive SS immunization triggered the paradoxical GH response to TRH in intact rats
(805) and that in acromegaly, or other pathophysiological
conditions (rats with transplanted pituitaries), it was
blocked by infusion of SS links the anomalous GH response to SS dysfunction (462).
A further possibility is that the GH response to TRH
may be a consequence of GHRH-induced expression of
TRH receptors on the somatotroph, in agreement with the
facilitated GH release after TRH in acromegalic patients
(921) or from rat or sheep pituitaries after exposure to
GHRH (125, 597).
Thyrotrophin-releasing hormone receptors on the somatotrophs would also be unmasked when thyroid hormones are lacking or low, as in hypothyroid rats (233,
995) and humans (265).
As already mentioned, TRH-induced GH secretion is
generally absent in normal subjects, although a subpopulation of normal people may respond to TRH. Careful
studies with appropriate controls to exclude the confounding effect of GH peaks derived from spontaneous
pulsatile release showed that in healthy young men the
incidence of GH responsiveness to TRH was lower than
10%. Interestingly, in tests repeated at night, when reportedly the somatostatinergic tone is decreased (1054), 90%
of the nonresponders during the day became GH responders to TRH (172). The way the paradoxical GH response
to TRH is related to rest and inactivity might account for
its being found in hospital patients and psychiatric cases
who have altered biorhythms.
In addition to its stimulatory action, probably in the
pituitary, TRH inhibits GH secretion, acting at the hypothalamus. In healthy subjects, TRH reduced or blocked
the GH response to a variety of GH releasers. This inhib-
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NEUROENDOCRINE CONTROL OF GROWTH HORMONE SECRETION
3. Neurotensin
Growth hormone-releasing hormone is found in at
least 40% of the NT-positive neurosecretory cells in the
ventrolateral area of the ARC (779; see sect. IIIA); in the
external layer of the ME, fibers containing both NT-LI and
GHRH are close to hypophysial portal vessels (699)
(Fig. 2).
Despite unequivocal neuroanatomic evidence, the effect of NT on GH release varies, depending on either the
route of administration or the experimental model used.
Centrally administered NT lowered plasma GH levels in
anesthetized male rats (649), a finding consistent with its
ability to increase SS concentrations in hypophysial portal blood (3) or SS release from hypothalamic slices incubated in vitro (957). In contrast, in unanesthetized
ovariectomized rats, centrally injected NT increased GH
secretion (910).
To further illustrate the complexity of NT’s role in
GH regulation, after intracerebroventricular injection, an
anti-NT serum and NT exerted reciprocal effects on
plasma GH levels in ovariectomized female rats but, unexpectedly, similar inhibitory effects in male rats. As in
humans (112), in ovariectomized female rats plasma GH
levels were unaltered by systemically administered NT
but increased after systemic administration of an anti-NT
serum.
The most likely explanation lies in the possibility that
SS may have opposite effects on GHRH function, acting at
different hypothalamic sites. This might account for the
seemingly paradoxical effects of NT and anti-NT serum on
GH secretion if its effects are mediated by SS neurons.
Although it has not been demonstrated, one may infer that
NT participates in the reciprocal regulation between
GHRH and SS-producing neurons (see sect. IIIA3). In this
connection, some hypothalamic regions containing SS
neurosecretory cells, e.g., the PeVN, also contain NT receptors. An extensive review on the neuroendocrine effects of NT has been published (910).
4. VIP and PHI
Both VIP and PHI are products of the same precursor
and belong to the glucagon-secretin family of peptides,
structurally related to GHRH (86). They are synthesized in
the rodent pituitary where they may act as autocrine or
paracrine factors (44). The pituitary cell that synthesizes
them is not the somatotroph, as shown by the significantly
lower levels of VIP mRNA and peptide in the AP gland of
GHRH transgenic mice despite somatotroph hyperplasia
(499). Several VIP-containing neurons project to the hypothalamus, including the ME, and VIP has been detected
in high concentrations in portal blood (913).
In the rat, intracerebroventricular injections of VIP
induced a prompt and sustained rise in plasma GH levels
(see Ref. 749), whereas in rats (see Ref. 749) and in ewes
(925), systemic injections had no such effect. These findings suggest a hypothalamic site of action for VIP, but in
vitro findings clearly demonstrate that the peptide can
release GH, also acting on the pituitary. In cultured bovine
adenohypophysial cells, VIP, but not PHI, increased basal
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ular infusion of a CRH antagonist markedly increased GH
peak amplitude without affecting either trough levels or
the number of GH peaks (745). The same treatment significantly lowered GHRH mRNA levels in the ARC, without affecting SS mRNA in the PeVN and ARC. It would
seem, therefore, that CRH, through regulation of ARCGHRH neurons, also modulates endogenous GH secretion. Because connections between CRH and GHRH neurons have yet to be demonstrated, the inhibition of GHRH
mRNA levels by CRH might result indirectly from enhanced inhibition of GHRH neurons by SS (see sect.
IIIA3).
Controversial results have been reported on the effect of systemic CRH on GH release in humans. Barbarino
et al. (72) found CRH dose-dependently inhibited the
GHRH-induced GH release in healthy adult men and
women; this effect was not confirmed in another study,
which reported a tendency toward higher GH levels after
a similar cotreatment (901). Corticotropin-releasing hormone dose-dependently inhibited GHRH-induced GH release in children (417). It must be recalled, however, that
there is a major biological difference between rodents and
humans, with stress being inhibitory on GH release in
rodents and stimulatory in humans.
Neurons containing AVP and oxytocin not only
project from the SON and PVN to the neurohypophysis
but also send their axons to other CNS areas, such as the
ME. High concentrations of AVP and oxytocin are thus
found in the hypophysial portal blood (1129), suggesting
that these peptides may also regulate anterior pituitary
hormone secretion. This is borne out by the direct inhibitory effect of oxytocin on both basal and GHRH-stimulated GH secretion in dispersed rat AP cells (494). This
inhibition would be tonic, since intracerebroventricular
infusions of anti-oxytocin, but not anti-AVP serum, raised
plasma GH in ovariectomized rats (368).
Oxytocin, therefore, by interfering with the action of
GHRH at the AP might be one of the factors involved in
the generation of pulsatile GH secretion, a function which
could be important when oxytocin secretion is enhanced,
e.g., in pregnancy.
Rats with hereditary AVP deficiency (Brattleboro
strain) have normal GH levels and a normal GH response
to hypothalamic electrical stimulation (mentioned in Ref.
664), thus excluding a role of AVP on GH secretion. The
converse, however, is not true, since a group of GHRP
increased AVP release in an in vitro rat hypothalamic
incubation system (569).
559
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MÜLLER, LOCATELLI, AND COCCHI
5. PACAP
Pituitary adenylate cyclase-activating peptide is a 38amino acid peptide homologous to porcine VIP. Six of the
10 NH2-terminal residues are identical to those of GHRH
(731). The cDNA for PACAP encodes a PACAP precursor
that gives rise to PACAP-38, PACAP-27, and PACAP-related peptides. Since its isolation, its activity has been
amply described in a variety of tissues including pituitary,
brain, adrenal, testis, gut, and lung. Several reviews have
discussed its action in a variety of cell types and the
characteristics of the three PACAP receptors cloned to
date, two of which it apparently shares with VIP (43, 874).
Although PACAP-LI is found in nearly all brain regions so far examined, its concentration is highest in the
hypothalamus, particularly the magnocellular system and
then the parvocellular neuronal system. There is a dense
network of PACAP fibers in the external zone of the ME,
in close contact with the hypophysial portal capillaries, so
PACAP may act as a true hypophysiotropic factor (see
Ref. 874 for review). Although most studies have found no
staining for PACAP-IR in the AP, one did describe PACAPcontaining fibers in this tissue, mingling with the secretory cells (723).
In rats, normal somatotrophs express the PVR3 receptor, which preferentially binds the peptide helodermin
and is linked to the stimulation of cAMP production and
a subsequent rise in Ca21 concentrations. Differently
from normal rodent cells, human GH-producing tumor
cells express PVR1, more specific for PACAP than VIP
(see Ref. 874 for review).
In vivo PACAP stimulates the release of GH, although
this effect has been demonstrated in rats but not in sheep
or humans (see Ref. 874 for review). In rats, the in vivo
GH-releasing effect of PACAP is fairly marked, but
whether this derives from a direct action on the somatotrophs is uncertain, since in vitro PACAP has a weak
stimulatory effect on GH synthesis and release. In fact, its
GH-stimulatory effect on rat, frog, and bovine pituitary
cells was much lower than that evoked by GHRH, and GH
release peaked at different intervals (458, 1092). The delayed GH-releasing effect of PACAP was attributed to
indirect action on other cell types [i.e., stimulation of
interleukin (IL)-6 release from folliculostellate cells]
(458).
In addition to stimulating GH release, PACAP also
raised GH mRNA levels during short- and long-term incubation in a somatotroph-enriched population of female rat
pituitary cells (1067).
Similar to GHRH, but different from GHRP,
PACAP-38 increases both the number of somatotrophs
and the amount of GH released from each cell over a
period of 30 min in dispersed preparations from male rat
pituitaries (436). This suggests that PACAP and GHRH
regulate GH secretion through similar mechanisms, most
likely by activating the cAMP/protein kinase A system and
Ca21 influx.
Investigations into the physiological role of PACAP
on GH secretion are limited by the lack of specific antagonists. Yamaguchi et al. (1111) showed that PACAP(6O38), the NH2 terminal deleted PACAP-38 analog, inhibited the GH secretory effect of the native peptide.
Pituitary adenylate cyclase-activating peptide-(6O38)
also abolished 5-HTP-induced GH release in conscious
rats, suggesting that hypothalamic PACAP is involved not
only in the physiological control of GH secretion but also
in the GH release following serotoninergic stimulation
(see also sect. VA2).
Athough PACAP does not release GH in healthy humans (648), it stimulates GH release from in vitro cultured
somatotrophinomas. This action, which is coupled to
cAMP production, can only be observed in adenomas
without gsp mutations, the somatic mutation within the
gene that produces a constitutively active Gs protein (13).
In summary, it is interesting that PACAP acts as a GH
releaser, sharing the same intracellular signaling pathway
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and GHRH-stimulated GH release (969). Previous data
obtained in superfused rat pituitary cell reaggregates pretreated with dexamethasone had shown that VIP, like
PHI, strongly stimulated GH release starting from a concentration as low as 0.1 nM. In this experiment, GH secretion in cells not pretreated with dexamethasone was
unchanged, suggesting that VIP interacted with GHRH
receptors, which were upregulated by the steroid (304)
(see sect. IIIA).
In contrast to the stimulatory effect in animals, in
normal humans VIP blunted the GH peak occurring at
night without modifying the time of occurrence of the
physiological GH surge (764).
Vasoactive intestinal polypeptide stimulated GH release in subjects believed to have somatotrophinomas; in
the few patients where VIP had no effect on basal GH
release, it antagonized the inhibitory effect of DA agonists
(230). However, screening a large group of acromegalics,
Watanobe et al. (1082) observed that the positive GH
response to TRH was combined with a high sensitivity to
the inhibitory effect of DA agonists, whereas GH responsiveness to VIP and, possibly, to GnRH, existed with no or
low sensitivity to dopaminergic agents. It would seem,
therefore, that the first group of tumors had the functional
characteristics of PRL-containing somatotroph adenomas, and the latter of pure somatotrophinomas.
Subsequently, Watanobe et al. (1083) found the paradoxical GH response to VIP in hyperprolactinemic patients with or without a prolactinoma. Because the GH
response to VIP is not causally related to the presence of
a pituitary tumor, it may be surmised that hyperprolactinemia itself played a role in inducing VIP receptors
on normal or previously normal somatotrophs.
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NEUROENDOCRINE CONTROL OF GROWTH HORMONE SECRETION
as GHRH. However, the fact that it is much less potent
than GHRH in activating GH secretion and the apparent
restriction of this action to the rat makes uncertain how
important it is in the physiological regulation of GH secretion and its therapeutic use.
6. NPY
7. Galanin
Galanin is a 29-amino acid neuropeptide that does
not belong to any known peptide family and has a number
of pharmacological properties in whole animals and isolated tissues (84). It is widely distributed in the CNS,
highly concentrated in the hypothalamus, and partly colocalized with GHRH neurons in the ARC and nerve ter-
minals in the ME (see sect. IIIA2) (Fig. 2). It is also present
in the AP (see Refs. 96, 280 for reviews).
In rodents and humans, galanin increased GH secretion (77, 801) and appeared to play a role in the generation
of pulsatile GH release, since in rats injection of a specific
antiserum led to a dramatic alteration of the pulsatile
secretory pattern (96). In healthy humans, in addition to
eliciting GH secretion when given alone, galanin enhanced the GH response to GHRH (425).
In contrast, galanin lowered basal GH secretion in
most acromegalic patients, an effect also observed in
pituitary adenomas in vitro (429). The GH-inhibitory effect of galanin, which can be added to the list of paradoxical GH responses in acromegaly, reflects the presence of
adenomatous somatotrophs, since acromegalic patients
cured after surgery had a normal GH stimulatory response
to the peptide. In rodent AP incubated in vitro, galanin
had an elusive, apparently age-dependent effect (1040),
with a GH-releasing effect only during the perinatal period. In adult life, galanin inhibited GHRH-stimulated GH
release.
In perfused pituitaries from young male calves, galanin behaved as an effective stimulant of GH secretion
(70), and its action was enhanced by concomitant perfusion of the pituitary with the hypothalamus, suggesting
that the peptide exerts its optimal action when the integrity of the GHRH-pituitary axis is maintained. This study
suggests that, at least in calves, galanin-mediated GH
release occurred independently of hypothalamic SS, since
the GH response to exogenous GHRH was not modulated
by galanin.
Galanin together with GHRH in the same ARC neurons (707; see sect. IIIA2) may be the anatomic substrate
for the functional interaction between the two peptides.
Evidence for stimulation of GHRH release by galanin was
provided in vitro using incubated hypothalamic slices
(562, 707).
Consistent with a GHRH-mediated mechanism, in infant rats pretreatment with a GHRH antiserum abolished
the potent GH-releasing effect of galanin (203). However,
it would seem that galanin does not act directly on GHRHsecreting structures but requires the intervention of CA
neurons. In neonatal rats, selective inhibition of E synthesis abolished the GH-releasing effect of galanin, implying
that E provides the link between galanin-secreting and
hypophysiotropic neurons for GH control (203).
Human studies suggest galanin’s action depends on
SS. Like cholinomimetic drugs, which restrain the function of SS-producing neurons (see sect. IIIB3), pretreatment with galanin enhanced GHRH-induced GH release,
an effect counteracted by salbutamol, a b2-adrenergic
agonist (51), and restored the blunted GH response to
GHRH during GH treatment in children with constitutional growth delay (920). Conscious adult rats had a
sluggish response to galanin after pretreatment with
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Neuropepitde Y, a member of the pancreatic polypeptide family of peptides, shares significant sequence homology with pancreatic polypeptide and peptide YY.
Neuropeptide Y is the most abundant peptide in the CNS
(26). Within the hypothalamus, NPY is synthesized in
neurons of the ARC, which mainly project to the PVN
(305) (Fig. 2).
In addition to being involved in the control of food
intake and energy and substrate metabolism, NPY affects
the release of various hormones, including GH (1095). In
the rat, intraventricular injection of NPY inhibited GH
secretion (691), and a NPY antiserum led to elevated
plasma GH levels (886) and partially restored GH secretory pulses in food-deprived rats (791). The latter effect is
consistent with the increased levels of NPY in the PVN
after food deprivation in rats (603), which might contribute to the reduction of GH secretion commonly seen in
fasting rodents (1017). A similar alteration has been reported in obese rats (918) that have a striking reduction of
the somatotrophic axis (see sect. VIC1).
Chronic infusion of NPY in the lateral ventricle of the
brain, a treatment ultimately reproducing all the metabolic features of obesity, inhibited GH and IGF-I secretion
in intact female (191) and male (842) rats, strongly suggesting a causal link between excessive NPY and reduced
GH function in obesity.
The inhibitory action of NPY on GH secretion is
mediated by stimulation of SS release (886), as supported
by the demonstration of synaptic connections between
NPY-containing axons and periventricular SS neurons in
the anterior hypothalamus (472; see also sect. VIIA). A
direct inhibitory effect of NPY on GH release, through the
pituitary, was unlikely, since the peptide stimulated GH
secretion from rat perfused pituitary cells (691) or goldfish AP (826). Neuropeptide Y inhibited basal and GHRHstimulated GH secretion in human pituitary tumors (16).
For the involvement of NPY neurons in the autofeedback regulation of GH secretion, see section VIIA.
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MÜLLER, LOCATELLI, AND COCCHI
neostigmine, cysteamine, or a SS antiserum, all aimed at
lowering the endogenous somatostatinergic tone (1021).
In rat pups, pretreatment with the same antiserum significantly reduced the GH increase elicited by galanin (203).
It is apparent from both animal and human studies that
galanin plays a significant role in the regulation of GH
secretion.
8. EOP
selective blockers of m-, d-, and k-sites inhibited GH secretion after intracerebroventricular injection of b-endorphin.
In humans, the stimulatory effect of opioids on GH
secretion seems to be mediated by m-receptors (442). In
contrast, in normal volunteers, deltorphin, the most potent and selective d-opioid receptor agonist known,
blunted the GH response to several GHS, including galanin and arginine, whereas it did not affect the GH response to GHRH (297). These findings suggest that, in
contrast to rats, in humans d-opioid receptors inhibit GH
release, through modulation of hypothalamic release of
SS. According to some authors (566), in rodents GH secretion is inhibited by activation of k-receptors, although
as already discussed, k-receptors also had a stimulatory
effect in adult (523) and immature rats (329).
With regard to the potential modulatory action of
classic brain neurotransmitters, in the dog and in humans,
muscarinic cholinergic, histaminergic, and a2-adrenergic
receptor antagonists suppressed or blunted the GH rise
induced by FK 33– 824 (see Ref. 208 for review). The only
discordant finding was that yohimbine did not inhibit the
FK 33– 824-induced GH rise in humans (441) and was
effective in the dog (213).
Despite the wealth of information, the physiological
role of EOP in the regulation of GH secretion is still
unclear. An acute dose of a b-endorphin antiserum to
freely moving rats (1016) or of naloxone to human volunteers (724) did not alter plasma GH levels. In contrast,
chronic treatment with the long-lasting EOP receptor antagonist naltrexone did not modify basal GH secretion but
significantly reduced the GH peak after GHRH (1052).
These results suggest that chronic blockade of central
EOP receptors enhances the function of SS neurons.
9. Cytokines
In recent years, evidence has accumulated of common peptide signals, receptors, and functions in cells of
the immune and neuroendocrine systems, and this has
provided the logical basis for a regulatory loop between
the two (98). Receptors for IL-1a and and the corresponding mRNA have been identified in rat and mouse pituitary,
mainly in the AP. Receptors or binding sites for IL-6 and
IL-2 have also been found in the pituitary, while many
types of receptors for several cytokines have been described in the CNS (see Ref. 98 for review).
Stimulation of the HPA axis by IL-1 was the first and
most extensively studied example of how cytokines influence endocrine function. Concerning GH, in conscious
rats low intracerebroventricular doses of IL-1 (820, 885)
or tumor necrosis factor-a (887) increased GH secretion,
as did IL-2 therapy in cancer patients (58).
In another study, intracerebroventricular or ARC injection of IL-1 lowered GH levels in rats (640), suggesting an
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Studies in rats on the neuroendocrine effects of EOP
showed that these compounds, as well as opiates such as
morphine, stimulated GH secretion when administered
either systemically or ivt (148, 259). In humans, however,
some conflicting data have been reported. Thus, although
FK 33– 824, an allegedly potent and selective ligand of
brain m-receptors proved to be a strong GH releaser,
morphine and b-endorphin did not have any such effect
(see Ref. 208 for review). Despite these inconsistencies,
the effects of these compounds on GH release are specific, being completely abolished by pretreatment with the
potent but nonselective EOP receptor antagonist naloxone.
In the rat, pretreatment with a SS antiserum did not
influence the EOP-induced GH rise (328), whereas passive
immunization with a GHRH antiserum completely
blocked the GH rise induced by b-endorphin, morphine
(1088), or FK 33– 824 (721). These data indicated that
opioids stimulate pituitary GH secretion through hypothalamic GHRH release and not through inhibition of SS
release, although a small but distinct inhibition of SS
release from rat hypothalamic fragments in vitro has been
reported (326). In humans, it has been reported, though
only inferentially, that FK 33– 824 can also act by inhibiting SS release (302).
These findings disproved the direct effect of EOP on
the pituitary (539, 890). The theory was supported by the
observation that EOP antagonists, which are unable to
cross the BBB (i.e., naloxone methyl bromide), did not
affect the GH release induced by morphine (803).
Subsequently, Fodor et al. (367) suggested that opioid neurons might be implicated in the interactions between SS- and GHRH-containing neurons in the ARC. In
fact, SS receptors are present on cells containing GHRH
mRNA and POMC mRNA, and SS perikarya in the PeVN
are innervated by POMC-derived peptide-containing neurons (see sect. IVB2A).
Previous studies suggested that the EOP acted
mainly on the d-type opioid receptors, since in rats pretreatment with d-receptor antagonists abolished the GH
rise induced by morphine or b-endorphin, while naloxone
or b-funaltrexamine, a selective m-receptor antagonist,
did not (566). It has since been demonstrated that multiple opioid receptor subtypes are activated in the regulation of GH secretion by b-endorphin (523). In this study,
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NEUROENDOCRINE CONTROL OF GROWTH HORMONE SECRETION
10. NO
Nitric oxide has now been shown to be a very important intracellular and intercellular messenger in most organs of the body, involved in the control of a wide range
of physiological events. This free radical is rapidly degraded to nitrate and nitrite and is produced by NO synthase (NOS) from arginine (687, 734). Of the three known
forms of NOS, the constitutive neural isoenzyme is widely
distributed within the cells of the hypothalamus, especially in the PVN and SON, which send axons to the
neurohypophysis and the ME (142). This has raised the
intriguing possibility that NO may act as a neuroendocrine
regulator in the hypothalamus and pituitary.
Studies with NOS inhibitors such as NG-monomethylL-arginine (L-NMMA) and NO donors such as sodium
nitroprusside (SNP) or S-nitrosoacetylpenicillamine
(SNAP) have demonstrated that NO influences the release
of GHRH (884) and SS (17). The mechanism by which NO
stimulates the release of neurosecretory hormones is
through diffusion into the neurons and activation of guanylate cyclase and cyclooxygenase to synthesize cGMP and
PG, respectively (689).
Microinjected into the third ventricle of conscious,
freely moving rats, L-NMMA dramatically reduced GH pulsatility, primarily by cutting the height of the GH pulses
(884). Nitric oxide release should also be involved in the
mechanisms through which GHRH neurons modulate the
output of SS into the portal blood (17).
In the pituitary, NO secreted from folliculostellate
cells and gonadotrophs (195) modulates GHRH-induced
GH release. In freshly dissociated male rat pituitary cells,
Kato (550) showed that SNP blocked the GH-releasing
effect of GHRH, without affecting the GH release evoked
by K1 excess.
Recently, a careful series of studies has reevaluated
the involvement of NO in the control of GH secretion.
Endogenous NO deprivation induced by pretreatment
with the NOS inhibitor Nv-nitro-L-arginine methyl ester
(L-NAME) significantly attenuated GHRH, GHRP-6, and
NMDA-induced GH secretion in prepubertal male and
female rats. In vitro, neither SNP, L-NAME, nor cGMP
modified baseline GH secretion by dispersed AP cells, but
L-NAME completely blocked GHRH-induced GH release
(1026). These findings suggest that endogenous NO plays
a permissive role in the control of stimulated GH secretion and is an important factor in GH secretion in prepubertal rats.
Similar data have been obtained in the dog, in which
systemically administered L-NAME completely blocked
and the lipophilic NO donor erythrityl tetranitrate potentiated the GH-releasing effect of hexarelin (A. Rigamonti,
unpublished results). Studies with NOS inhibitors in humans are hindered by the toxicity of these substances on
the cardiovascular system. Low doses of L-NAME blocked
hypoglycemia-induced ACTH release but did not change
either the basal or stimulated GH release (1072). Interestingly, L-arginine is a potent GH secretagogue in humans
(711); however, its effect does not appear to be linked to
NO production, since other NO donors such as molsidomine in humans (570) and erythrityl tetranitrate in dogs
(Rigamonti, unpublished results) did not modify basal GH
secretion and the GH-releasing effect of arginine was not
affected by pretreatment with L-NAME.
The effects on the hypothalamus and pituitary of the
peptides evaluated so far are summarized in Table 3.
VI. PERIPHERAL HORMONAL AND METABOLIC
SIGNALS OR CONDITIONS MODULATING
GROWTH HORMONE SECRETION
A. Hormones
1. Glucocorticoids
Glucocorticoids play a crucial role in somatotroph
differentiation, which only occurs when the steroids
reach a critical concentration (1029). Incubation of GH3
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underlying inhibition of hypothalamic GHRH and/or stimulation of SS release. Wada et al. (1075) demonstrated a
significant inhibition of spontaneous GH secretion after intravenous infusion or intraventricular injection of IL-1a and
in conscious rats. No effect was observed after IL-2 or IL-6.
Numerous in vitro studies indicated that IL-1, as well
as IL-2 and IL-6 (975), stimulate GH secretion in pituitary
cultures. More contradictory results were obtained with
TNF-a, whereas interferon-g (IFN-g) was shown to inhibit
the release of GH (see Ref. 98 for review).
The stimulatory effect of IL-1 on GH release repeatedly observed in vitro and the fact that it reduces GH
pulsatile release in vivo suggest an intermediary factor
may be responsible for the latter effect. The most likely
candidates are glucocorticoids whose circulating concentrations are elevated due to IL-1-induced activation of the
HPA axis and which reportedly inhibit spontaneous GH
secretion in the rat (see sect. VIA1).
A common finding in juvenile rats and humans is the
reduction of somatic growth during infectious states. In
juvenile rats, activation of IL-1 by endotoxin lipopolysaccharide markedly reduced GH secretion, by stimulating
CRH and SS release from the hypothalamus (821).
These findings suggest that hypothalamic IL-1 in the
rat plays a role in inhibiting GH secretion. Were the
underlying mechanism shared by humans, selective therapeutic reductions of SS tone might be helpful in the
treatment of chronic diseases of childhood. The precise
role of other cytokines in these processes remains to be
elucidated.
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MÜLLER, LOCATELLI, AND COCCHI
3. Neuropeptides and growth hormone release:
action on the CNS and/or the pituitary
TABLE
CNS
Pituitary
TRH (mg)
GnRH (mg)
CRH (mg)
AVP (mg)
Oxytocin (ng)
NT (mg)
VIP (ng)
PHI (mg)
PACAP (mg)
NPY (mg)
Galanin (mg)
EOP (mg)
IL-1a (ng)
IL-1b (ng)
NO
1a2b
1a
2?d
0
?
12?
12
0
1f
–
12g
13h
2
2
1i
1c
1
0
0
2e
?
1c
1
1f
12c
12c
0
1
1
1
0, Not tested; 1, stimulation; 2, inhibition; 3, no effect; ?, controversial findings. See text for definitions. a In a host of pathological
conditions; b inhibition of stimulated GH release; c on human somatotrophinomas; d in humans; e on basal and GHRH-stimulated release; f only
in rats in vivo and in vitro; g in acromegalic patients; h b-endorphin and
morphine ineffectiveness in humans; i apparently unrelated to arginine.
cells with cortisol led to an increase in the number of
somatotrophs and a decrease of lactotrophs, implying
that the steroid modulates the functional heterogeneity of
the GH3 cell line (124).
Glucocorticoids amplify the GHRH responsiveness of
the somatotrophs, an effect linked to enhanced binding
capacity of GHRH receptors, with no change in their
affinity (946, 1002; see also sect. IIIA8B). The steroid also
affects GHRH’s ability to modulate the main second messenger system coupled to these receptors, since exposure
to dexamethasone enhanced the GHRH-stimulated accumulation of cAMP (717).
In contrast, incubation of rat pituitary cells with
dexamethasone reduced the GH response to the inhibitory effect of SS by downregulating the number but not
the affinity of sstr (487, 939), most likely secondary to a
reduction in gene transcription (1109). This is supported
by in vivo data showing that dexamethasone for 3 or 8
days dose-dependently reduced gene expression of pituitary sstr2, one of the major SS receptor subtypes (584; see
sect. III).
It appears, therefore, that glucocorticoids may
acutely increase GH secretion by enhancing somatotroph
sensitivity to GHRH and reducing somatotroph responsiveness to SS. These mechanisms, however, are not
obligatory for the GH-releasing properties of the steroids,
which can stimulate GH synthesis and release by acting
directly on animal and human pituitary cells (see Ref.
1029 for review). The stimulation of GH mRNA by glucocorticoids in primary cultures of rat pituitaries or human GH-secreting adenomas is probably regulated at the
transcriptional level (512) and may contribute to the tran-
sient rises in plasma GH observed in humans after an
acute corticosteroid dose (318, 1029).
Acute administration of corticosteroids not only elicits a GH rise but potentiates GHRH-induced (177), but not
the pyridostigmine-induced (176), GH release in humans.
Because indirect cholinergic agonists are currently
thought to release GH mainly by inhibiting SS release (see
sect. VA3), it was assumed that glucocorticoids act
through a similar mechanism. The fact that dexamethasone did not raise plasma GH in patients with AN was
taken to indicate that the functional activity of SS neurons
was decreased in these patients (928; see also sect. VA3).
Supporting the idea of a suprapituitary component in the
stimulatory action of glucocorticoids was the inability of
dexamethasone to elicit GH secretion in children with GH
deficiency due to an idiopathic hypothalamic defect (669).
Unlike a single dose, sustained delivery of supraphysiological amounts of glucocorticoids reduces somatic growth (636) and spontaneous GH secretion and
blunts the GH response to a variety of physiological and
pharmacological stimuli in rodents (1092) or humans
(369, 554). These effects occur in addition to the wellknown steroid-induced peripheral catabolic effects and
reduction of circulating IGF-I concentrations (1029).
The inhibitory effects on GH secretion can be mainly
attributed to a glucocorticoid-mediated enhancement of
hypothalamic SS release. In rats, huge doses of dexamethasone increased hypothalamic SS mRNA (767), and exposure of fetal hypothalamic cultures to high concentrations
of corticosterone raised the SS content, whereas GHRH
content was lowered (351).
These results agreed with the findings of experiments
with b-adrenergic blockade and passive immunization
with SS antibodies in suggesting that glucocorticoid excess enhances hypothalamic SS function in humans and
rats (612, 1087).
Corticosteroids may act indirectly, i.e., through an
action on b-adrenoreceptors, which inhibit GH secretion
(see sect. VA1C). In vitro exposure to glucocorticoids
increased the density of b-receptors on smooth muscle
cells (264); were a similar effect to occur on SS neurons,
this would increase the inhibitory hypothalamic influences on GH secretion.
In humans, however, pyridostigmine does not completely counteract glucocorticoid-induced GH inhibition
(300), which therefore cannot result exclusively from increased hypothalamic SS function. One possibility is that
it is due to permanent alterations of pituitary SS and
GHRH receptors. However, contrasting this would be the
finding that GHRH receptor mRNA levels in the rat AP
increase, not decrease, after short-term dexamethasone
treatment (584, see also sect. IIIA8B).
Although glucocorticoids reportedly enhance the
number and function of GHRH receptors in the rat AP,
they seem to affect hypothalamic GHRH neurons nega-
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Peptide (Dosage)
Volume 79
April 1999
NEUROENDOCRINE CONTROL OF GROWTH HORMONE SECRETION
2. Gonadal steroids
The modulatory action of E2 and androgens on GH
secretion in animals and humans, and the underlying
mechanisms, have already been discussed in other sections of the review (sects. IIA and IIIA8B), to which the
reader is referred.
3. Thyroid hormones
The effects of thyroid hormones on GH secretion and
their mechanisms of action are very similar in humans
and laboratory animals (see Ref. 429 for review). Physiological concentrations of circulating thyroid hormones
are necessary to maintain normal GH secretion, owing to
direct stimulation of the AP. Growth hormone mRNA
levels and rate of transcription increase after 3,39,5-triiodothyronine (T3) exposure, by direct action on the genome level (see Ref. 429). Conversely, in infant (288, 290)
and adult (662) rats, pituitary GH content drops steeply
with experimentally induced hypothyroidism.
Early studies on how perturbations of the pituitarythyroid axis affected central GH regulatory mechanisms
reported that in hypothyroid rats hypothalamic SS content and release were diminished and that replacement
therapy with T3 restored both to normal (92). Subsequent
studies, however, found hypothalamic SS content and
release within normal limits in rats 10 days to 5 wk after
thyroidectomy (see Ref. 429 for review). Long-term induction of hypothyrodism in the rat markedly lowered hypothalamic GHRH, which was restored to normal by thyroxine replacement therapy (546).
In our own studies in neonatal and infant rats made
hypothyroid by giving the dams propylthiouracil, we
found no functional alterations in the GHRH hypothalamic machinery with respect to euthyroid rats, despite
the lower pituitary and plasma GH concentrations (290).
These findings indicate that in neonatal rats, deprivation
of thyroid hormones primarily depresses pituitary somatotroph function and that possible changes in GHRH function are only a later event probably linked to GH deprivation and the ensuing annulment of GH autofeedback
mechanism(s) (see sect. VIIA). Consistent with this view,
in adult rats induction of hypothyroidism enhanced both
basal and K1-stimulated GHRH secretion from incubated
hypothalamic fragments 5 wk later (719), as a sort of
compensatory mechanism to reverse the hyposomatotrophinism of this condition.
Thyroid hormones also regulate GH secretion by
modulating somatotroph responsiveness to GHRH. Anterior pituitary cells from hypothyroid animals have a decreased response to GHRH in vitro (662). This reduced
GH responsiveness probably results from the diminished
pool of GHRH receptors after abrogation of thyroid function (571) (see also sect. IIIA8B).
In humans, as in other species, hypothyroidism severely impairs postnatal growth, reduces spontaneous
nocturnal GH secretion, and is correlated with impaired
circulating IGF-I levels (227), the GH response to a variety
of pharmacological stimuli being blunted (see Ref. 429).
Rodent findings suggest the decreased pituitary GH pool
due to impaired GH synthesis might also account for the
low GH secretion of hypothyroid humans.
The reciprocal hormone condition, i.e., hyperthyrodism in rats, is coupled to a reduced function of hypothalamic GHRH (531) and SS neurons, as suggested by the
suppression of K1-stimulated SS release from in vitro
incubated hypothalami (833).
As in hypothyroidism, hyperthyroid patients also
have reduced GH secretion, which is restored to normal
by antithyroid drugs (355, 922). Production of IGF-I increases in the hypothalamus after T3 administration (105),
an effect which may contribute to the diminished GH
secretion because of activation of SS function. There is
inferential evidence of an enhanced SS activity in hyperthyroid states (see Ref. 429 for review), suggesting this
may be the mechanism underlying the hyposomatotrophic function.
B. Metabolic Signals
1. Glucose
Glucose is an important regulator of GH secretion,
although GH responses to hypo- or hyperglycemia differ
among animal species. Hypoglycemia stimulates GH secretion in humans, and insulin-induced hypoglycemia is
used clinically as a test to provoke GH secretion in GHdeficient children and adults (144), although it is poorly
reproducible and gives some false-negative responses
(477, see also sect. VA3). In contrast, in rats, insulininduced hypoglycemia or intracellular glucopenia inhibits
pulsatile GH secretion (1014). This inhibitory effect oper-
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tively, especially at high doses and with sustained treatments (585). The GHRH content in and release from fetal
rat hypothalamic cells both decreased after incubation
with high doses of corticosterone (351), and the same was
true for the hypothalami of rats treated ex vivo with a
huge dose of dexamethasone (770).
In conclusion, glucocorticoids have a dual effect on
the somatotrophic axis, one short-lived and stimulatory
and the other inhibitory, after prolonged administration of
pharmacological doses. This probably results from an
action on either the pituitary, through regulation of GH
transcription, GHRH and SS receptors, or the hypothalamus, where they can affect the function of the two hypophysiotropic hormones differently. A further mechanism may be the reduction of circulating IGF-I
concentrations and the ensuing inhibition of autofeedback mechanism(s) (see sect. VIIB1).
565
566
MÜLLER, LOCATELLI, AND COCCHI
Secretion of GH is reportedly enhanced in IDDM
patients. They have higher peak frequency and interpeak
GH concentrations, despite elevated blood glucose, an
exaggerated GH response to physiological and pharmacological stimuli, and paradoxical GH secretion after TRH
(754). Indirect evidence suggests that enhanced GH secretion and responses to GHRH are likely to be related to
a decreased SS tone, perhaps subsequent to damage of SS
neurons by autoimmune processes (see sect. VA5B1 for
discussion).
In IDDM, high circulating GH levels would therefore
be unable to feed back normally on SS-producing neurons
(see sect. VIIA). In fact, GH pretreatment does not inhibit
the GH response to GHRH (420) and pyridostigmine,
which reduces SS activity (see sect. VA3), is unable to
enhance the GH response to GHRH after GH pretreatment, as it does in normal controls (424). If hypothalamic
SS function is really defective in IDDM patients, the brisk
rise of plasma GH levels elicited by clonidine must be
attributable to stimulation of GHRH neurons (see sect.
VA1A).
Different from IDDM, non-insulin-dependent diabetic
(NIDDM) patients, have impaired responsiveness to
GHRH, not only when they are obese (see below) but also
in lean subjects (421).
2. Amino acids
Amino acids are a potent stimulus for GH secretion,
either as selected nutrients or when included in a proteinrich meal (99, 283, 516). Parenteral administration of an
amino acid solution raises GH secretion by acting on
pulsatility and pulse amplitude, an effect presumably mediated by increased GHRH secretion (791). Arginine is the
most striking stimulant, although lysine, ornithine, tyrosine, glycine, and tryptophan are all effective GH releasers (564). An oral mixture of arginine and lysine evokes a
sevenfold increase of plasma GH levels (516), and a similar effect is observed after arginine aspartate (99, 163).
Arginine-induced GH secretion in humans is blocked
by antagonists of a-adrenergic and cholinergic neurotransmission (153, 178), a carbohydrate-rich diet (710),
hyperglycemia (711) and NEFA, anti-E2 (878). Estrogens
enhance arginine-induced GH secretion in men or women
(711).
The effect of arginine on GH secretion appears to be
exerted through suppression of hypothalamic SS release,
as suggested by neuropharmacological studies (22, 413,
414). Alternatively, the effect of arginine on GH and other
pituitary hormones (56, 366) may depend on its conversion to NO, a gaseous neurotransmitter (734). Arginine is
in fact a more effective GH releaser than muscarinic
cholinergic agonists (414) which inhibit SS release (629;
but see sect. VB10 for discussion).
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ates through stimulation of SS release, as shown by studies of incubated rat hypothalami (90) and the fact that
hypothalamic SS mRNA levels are increased after ex vivo
administration of insulin (763). Even severe hypoglycemia
does not alter pulsatile GH secretion in mice (1003), in
line with the reported resistance of mouse hypothalamic
SS release or mRNA levels to intracellular glucopenia
induced in vitro (924) or ex vivo (1003).
The same species differences can be observed in
hyperglycemic states (see Ref. 930 for review). In humans, acute administration of glucose inhibits GH secretion, although there is a rebound release 3– 4 h later. In
the chronic hyperglycemia of IDDM (type 1), GH secretion is often increased, particularly in poorly managed
patients, although basal GH levels can be normalized with
proper metabolic control (see Refs. 759, 985 for review).
Because GH is diabetogenic, the increased secretion of
the hormone can induce adverse effects (971) (see also
sect. VA3).
In rats, acute hyperglycemia scarcely affects GH release, whereas diabetic rats have impaired GH secretion
(see Refs. 428, 985 for review). The involvement of either
the hypothalamus or the pituitary appears to be important. In streptozotocin-induced diabetic rats, SS antiserum restored GH secretion (1007), implying that enhanced SS release was responsible for the reduction.
Hypothalamic SS (793) and SS mRNA concentrations
(808) were instead unaltered. However, in the face of low
circulating GH and IGF-I levels, this “normal” hypothalamic SS function might in fact have been inappropriately
elevated. Supporting this was the lower number of SS
receptors in pituitary membranes from diabetic rats than
in controls (793), very likely resulting from downregulation. Hypothalamic SS release into the portal blood or
from hypothalamic fragments is increased in streptozotocin-diabetic rats, but not until GH secretion had been
suppressed for several days (527).
Hypothalamic GHRH mRNA levels were low in diabetic rats compared with normal controls (793), despite
the unaltered content of the peptide, suggesting that
GHRH neuronal function was diminished. The fact that
diabetic rats are unresponsive to clonidine (625), which
releases GH partly through a GHRH-mediated mechanism
(see sect. VA1A), confirms this. Also relevant is the finding
that somatotrophs from diabetic rats have a blunted GH
response to GHRH, although this difference disappeared
when the data were normalized to account for differences
in basal GH release (793).
For the pituitary GH content of diabetic rats, reduced
(770) or preserved (625, 1007) pituitary stores have been
reported. Unlike in vitro, in vivo GH responsiveness to
GHRH was significantly enhanced in streptozotocin-diabetic rats (627). In all these studies, lack of agreement
may rest on differences in the strain of rats or length and
severity of the disease.
Volume 79
April 1999
NEUROENDOCRINE CONTROL OF GROWTH HORMONE SECRETION
3. NEFA
4. Leptin
Leptin, the product of the ob gene, is a recently
discovered hormone secreted by adipocytes (1128) that
regulates food intake and energy expenditure (162). Because GH secretion is markedly influenced by body
weight, and, in particular, adiposity (see also below),
leptin may act as a metabolic signal functionally connecting the adipose tissue with the GH/IGF-I axis. Obese mice
lacking the ob gene (1128) or obese rodents with point
mutated receptors for leptin show reduced function of the
somatotrophic axis.
Circulating leptin concentrations, which are positively correlated with abdominal and total body fat (361),
are inversely related with serum GH concentrations
(1041, 1042). In subjects with GH deficiency, low-dose GH
replacement lowered plasma leptin, with no changes in
BMI (365). The effect of GH on leptin secretion was
probably indirect, since addition of GH to cultured mature
white adipocytes did not affect leptin secretion (453).
Leptin, however, does modify GH secretion, which
decreases after administration of a leptin antiserum in
freely moving rats; intraventricular-injected leptin reverses the inhibitory effect of fasting on GH secretion
(172).
The effect of leptin on GH secretion is presumably
mediated by the long form of the ob receptor, which is
primarily located in the hypothalamus (ARC, lateral, VM,
DM nuclei) (706, 943). Preliminary results from our laboratory suggest that in the rat leptin increases GHRH function, concomitantly reducing SS activity (254).
The inhibitory effects of the ob protein on NPY gene
expression and secretion (942, 987) suggested that inhibition of NPY function was a major mechanism of action,
and this was shown to be valid by the action on feeding
behavior (see Ref. 162). Schwartz and co-workers (942,
943) showed that intracerebroventricular injection of leptin into lean rats decreased NPY gene expression in the
ARC, while increasing CRH gene expression in the PVN.
Recalling the effects of the two peptides on GH secretion
(see sect. V, E2 and E6), it appears highly likely that
inhibition of NPY function accounts for leptin GH-stimulatory action.
Erickson et al. (340), by breeding the mutant NPY
allele onto the ob/ob background, generated mice deficient in both leptin and NPY. In the absence of NPY, ob/ob
mice were less obese because they ate less and expended
more energy; they were also less severely affected by
diabetes, sterility, and somatotrophic defects. In adult
fasted rats, intraventricular leptin prevented the disappearance of GH pulsatile secretion by reducing the fasting-induced enhancement of hypothalamic NPY gene expression (1074).
The GH stimulation by leptin is hard to reconcile with
the presence of high circulating levels of the protein and
impaired somatotrophic axis of obese subjects (see below). One possible mechanism involves the development
of hypothalamic leptin receptor desensitization, as demonstrated in obese rodents.
C. Physiopathology of Nutritional Excess
or Deficiency
Discussion of the many GH deficiency and hypersecretory states is beyond the scope of this review, and the
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Nonesterified fatty acids are important among the
peripheral factors controlling GH secretion. Pharmacological reduction of circulating NEFA levels raises GH
(510), but conversely, NEFA elevation induced by the
combination of exogenous Intralipid plus heparin markedly reduces spontaneous GH secretion in different animal species (109, 342) and abolishes GH responses to
various stimuli (175, 181, 342).
How NEFA act is not clear. In rats, NEFA’s inhibitory
effect is directed at the pituitary (30, 175), but a hypothalamic site of action has also been suggested, since their in
vivo inhibitory effect on GHRH-stimulated GH release
was abolished by passive immunization with SS antiserum (505). Similar conclusions were drawn from human
studies (824).
At variance with these findings, experiments using
monolayer cultures of fetal hypothalamic neurons
showed that exposure to NEFA increased GHRH secretion and inhibited SS output, lowering SS mRNA content
(949). The differences in vivo and in vitro may result from
disruption of the normal organization in cultured dispersed neurons or the use of fetal tissue.
A pituitary site of action for NEFA was suggested
again by Alvarez et al. (30), who showed that their inhibitory effect on GHRH-stimulated GH release was also
present in normal rats pretreated with a SS antiserum, or
with hypothalamic ablation, and in hypophysectomized
rats with two AP transplanted under the kidney capsule.
The inhibitory effect of NEFA on GH secretion at the
pituitary is rapid (within minutes), dose and time dependent, and closely related to the chemical structure of the
NEFA tested (175). Although this point has not been
completely clarified, the most likely mechanism is a reduction of [Ca21]i. Cis-unsaturated NEFA, such as oleic
acid, at physiological concentrations, suppressed the
TRH-induced increase in Ca21 in primary cultures of pituitary cells and in GH3 and GH4C1 cells. In the same cells,
NEFA abolished the TRH-induced Ca21 efflux, through
plasma membrane Ca21 pumps, suggesting they perturbed the function of integral membrane proteins (829).
In summary, the inhibitory influence of NEFA on GH
secretion appears to be mainly exerted in the pituitary.
567
568
MÜLLER, LOCATELLI, AND COCCHI
reader is referred to Müller and co-workers (755, 759). We
confine ourselves here to aspects of GH control in two
pathological conditions of humans, obesity and food deprivation, where some of the hormonal and metabolic
factors alluded to previously are profoundly involved.
1. Obesity
obese rats (258), whereas gastric and pancreatic SS-IR are
elevated (1060). In contrast to these findings, Berelowitz
et al. (91) reported increased SS release from hypothalami
in vitro of genetically obese rats.
Unlike their male counterparts, genetically obese female rats had a normal pituitary response to GHRH both
in terms of GH and adenylate cyclase activation (258),
with preservation of hypothalamic GHRH function. The
mechanism underlying the sexual dimorphism of GH secretion in genetically obese rats is not known, but a
similar difference is also seen in rats with diet-induced
obesity, whose spontaneous and stimulated GH secretion
is much reduced (188, 189, 882). Rats made obese by
feeding a hypercaloric diet, although their in vivo responsiveness to GHRH was strikingly reduced, had no differences from controls in pituitary GH content and gene
expression and hypothalamic concentrations of GHRH
and SS mRNA (188, 189).
These findings underline the peripheral nature of
hyposomatotropic function in diet-induced obese rats, as
opposed to the “central” impairment of GH regulation of
the Zucker obese rats, which have a primary alteration of
GHRH function. Among the different endocrine and metabolic indices, low plasma testosterone in males (188)
and high NEFA in females (189) play a primary role in the
impairment of GH secretion. Either a defect of androgens
(849, 1088) or an excess of NEFA (see sect. VIB3) reportedly inhibits GHRH-stimulated GH secretion.
B) HUMAN STUDIES. As expected, obese people have
impaired 24-h GH secretion and blunted GH responses to
provocative stimuli, both reversed by massive weight loss
(873). Different from rodents, an alteration in the tonic
secretion and/or phasic withdrawal of SS may underlie
this GH dysfunction. Reduced GH response to a variety of
stimuli is a characteristic feature of obesity, although the
pituitary can still make at least a partial secretory response to a direct secretagogue (284, 1096). The GH response to GHRH is reportedly reduced in obese children
and adults but was significantly enhanced by pretreatment with pyridostigmine, so the mean baseline GH and
the GH responses to pyridostigmine and GHRH overlapped those of lean subjects after GHRH alone. However,
in lean subjects, combined administration of pyridostigmine and GHRH evoked a greater rise in plasma GH than
in the obese people (415, 634). These findings indicate a
role for SS, and hence SS disinhibition, in dictating the
extent of GH responsiveness to GHRH in obese subjects,
but they also imply some chronic background suppression of somatotroph function unrelated to SS.
Normal people, like obese individuals, may show
increased GH responsiveness to acute nutrient deprivation, as indicated by the fact that a short fasting enhances
GH responses to GHRH (556). Because in fasting conditions the reported increase of spontaneous GH secretory
burst frequency has been inferentially linked to functional
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A) ANIMAL STUDIES. Obese subjects have diminished GH
secretion in response to a variety of GH secretagogues
(317, 755). Because GH is a lipolytic hormone (601), impaired secretion may help perpetuate obesity.
The mechanisms underlying the defective GH secretion have yet to be fully elucidated, although the reversibility of the defect after successful weight reduction (256,
1005) strengthens the view that the impaired GH secretion
is a metabolic consequence of obesity rather than a primary disturbance.
Information from our own and other studies (19, 253,
1012) in animal models of genetic obesity point to a
striking impairment of the somatotrophic axis. Obese
male rats of the Zucker strain have reduced pulsatile
secretion of GH (1012) and pituitary responsiveness to
GHRH, both in terms of GH release and of activation of
adenylate cyclase (253). Moreover, in these obese rats,
pituitary GH gene expression and content are significantly
reduced (19) and so are hypothalamic GHRH mRNA and
GHRH content, whereas hypothalamic SS content is low
but not mRNA (19, 253).
Thus the hyposomatotropism of genetically obese
male rats is associated with a primary reduction in the
function of hypothalamic GHRH-producing neurons,
which may well be the event responsible for the attenuation of GH gene expression and the diminution of circulating plasma GH.
The picture in these rats overlaps that of aged rodents, which also have reduced GH secretion (1110) and
a lower in vitro and in vivo responsiveness to GHRH both
in terms of GH and activation of adenylate cyclase (810).
As for obese and aged rats, and quite likely, humans too
(296a), the main cause of the defective GH secretion
would be a defective function of GHRH neurons (293),
leading to unresponsiveness of GHRH receptors to the
endogenous ligand. In aged (6) but not in obese rats (7),
this is coupled with a reduction in the number of pituitary
GHRH receptors. The reduced genomic expression of
GHRH in the hypothalamus of genetically obese male and
aged rats may share a common pathophysiologic mechanism, i.e., impaired NE function (1118).
Decreased GH secretion in obese rats is unlikely to
be due to an increase in SS function or increased somatotroph sensitivity to SS, because passive immunization
against SS failed to increase the GH response to GHRH
(1012). Moreover, hypothalamic SS content and gene expression and SS function in the pituitary are preserved in
Volume 79
April 1999
NEUROENDOCRINE CONTROL OF GROWTH HORMONE SECRETION
activation of the GHRH system (1033), the effect of fasting in increasing GH secretion in obesity suggests that in
humans, like in rodents, this pathological condition is at
least partially related to a GHRH neuronal defect.
2. Food deprivation
1046) and responds to protein and energy intakes (517)
and to the quality of protein in the diet (252).
In humans, unlike rodents, GH levels are significantly
raised by fasting (475), even before the decline in serum
IGF-I starting within 48 h of beginning the fast (251). Two
days of fasting in healthy men induced a fivefold increase
in the GH production rate, by an account of an increase in
the number and amplitude of GH secretory bursts. An
increase in the frequency of GHRH release with prolonged
periods of reduced SS secretion was surmised from the
increased frequency of constituent individual secretory
bursts with prolonged intervolley nadirs. Serum IGF-I
levels were still unchanged after 56 h of fasting (461) in
the presence of increased levels of IGFBP-1 (1123). This
may reduce the bioavailable portion of IGF-I, thus limiting
IGF-I negative feedback on GH secretion before total
serum levels of IGF-I change (see also sect. VIIB1).
These findings may have some relevance when assessing the GH hypersecretion seen in patients with AN, a
disease marked by self-imposed starvation in exaggerated
attemps to maintain a thin body, and by a phobia for
weight gain and fat (389). Resting GH levels are reportedly elevated in some patients with AN (145 587) but
return to normal with recovery. This fall is unrelated to
body weight but is closely tied to the patient’s caloric
intake (390). It appears, therefore, that the elevated GH in
AN is at least partly secondary to starvation and plays an
important adaptive role.
However, an analysis by Cluster algorithm of pulsatile GH secretion at night in a group of AN patients
disclosed a GH secretory profile somewhat different from
that of sustained fasting and reminiscent of that in poorly
controlled IDDMD (see sect. VIB1). The enhanced nocturnal GH secretion was largely due to an increase in the
nonpulsatile component, although the pulsatile component was also significantly enhanced because of the larger
number of secretory episodes. The lack of correlation
between parameters of GH release and BMI indicated a
more complex hypothalamic dysregulation of GH release
than simple disinhibition of the IGF-I autofeedback mechanism subsequent to malnutrition (929).
In AN, despite exaggerated GH response to GHRH
(138, 676, 898), not confirmed in other studies (175, 713),
there is little or no GH response to insulin-induced hypoglycemia and dopaminergic stimulation which, in all, suggests hypothalamic dysfunction.
Somatostatin function may be reduced in the hypothalamus of AN patients, in view of the failure of glucose,
a stimulus which would inhibit GH secretion through
release of SS (867, see also sect. VIB1), to counter the
GHRH-induced GH rise (900), and the lack of the GHreleasing effect of short-term glucocorticoid treatment
which, in fact, is attributed to inhibition of SS secretion
(see sect. VIA1) (928). In line with this view, pirenzepine,
a drug thought to act by stimulating SS function, was only
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In rats, prolonged (24 –72 h) food deprivation inhibits
episodic GH secretion (1017) without altering the ultradian rhythm (791, 792). An intravenous dose of anti-SS
serum restored large GH pulses in food-deprived rats,
suggesting SS is involved (1012). However, hypothalamic
SS mRNA levels were unaltered in 72-h food-deprived
rats, whereas GHRH mRNA levels were markedly reduced
(149), indicating that decreased GHRH secretion plays an
important role in the inhibition of episodic GH secretion
in food-deprived rats.
Feeding after prolonged food deprivation caused a
rapid and dramatic increase in GH pulse frequency and
amplitude, and the characteristic ultradian rhythm was
restored (791, 792). This was related to caloric intake
rather than specific macronutrients, although ingestion of
an amino acid solution, but not of glucose and lipids, to
fasted rats rapidly raises the pulse frequency and amplitude of GH secretion (795). In rats with sustained food
deprivation, calorie intake restored GH pulse frequency
and amplitude even in the absence of endogenous SS (SS
antiserum or anterolateral deafferentation of the hypothalamus), suggesting this effect was mediated by activation of GHRH-producing neurons (994).
Dietary protein intake is an important factor in GH
secretion, particularly in the early postnatal period, as
illustrated by studies (456) showing that in rat pups 3 wk
of protein restriction stunted growth and caused a permanent reduction of pulsatile GH secretion in the postweaning period.
In humans, the importance of protein intake for normal GH secretion is evident from the profound disturbance in GH homeostasis of diseases involving protein
malnutrition. Fasting GH levels were high in children with
kwashiorkor (underweight, edema, hypoalbuminemia,
and dermatosis) or marasmus (,60% expected weight for
age, no edema), and these levels were not normally reduced by induced hyperglycemia, did not correlate with
fasting blood glucose, or dropped when an adequate carbohydrate but protein-free diet was given (846), indicating
a state of GH resistance. Fasting GH and glucose-induced
suppressibility returned to normal with oral protein. Levels of GH in patients before and after amino acid or
albumin infusions correlated inversely with some plasma
branched chain amino acids (leucine, isoleucine, and valine) (846).
Limited growth in this malnourished children, despite elevated GH, depends on the defective secretion of
IGF-I, which is closely related to nutritional status (840,
569
570
MÜLLER, LOCATELLI, AND COCCHI
VII. GROWTH HORMONE AUTOFEEDBACK
MECHANISM
Evidence has accumulated over many years that
there are long, short, and ultrashort loops in the feedback
regulation of GH secretion (see Ref. 750). Because GH
lacks a distinct target endocrine gland, it was suggested
that it feeds back on the hypothalamus to regulate its own
secretion. The feedback regulation of GH presumably
involves either activation of SS or inhibition of GHRH
function, or both, not forgetting the apparent action on
the pituitary through blood-borne IGF-I. In addition to GH
itself, brain neurotransmitters, neuropeptides, and many
factors directly or indirectly related to GH secretion, such
as NEFA, glucose, glucocorticoids and thyroid and gonadal hormones, have important roles in somatotroph
function (see sect. VI).
A. Growth Hormone
Early data (reviewed in Ref. 749) showed that rats
with ectopic somatotrophic tumors had reduced pituitary
4. Factors or conditions that stimulate or inhibit
GH secretion in primates
TABLE
Factors
Increase
Neurogenic
Sleep stages 3 and 4
Stress
Physical
Psychological
Monoaminergic
stimuli
Epinephrine, a2adrenergic
stimulation
DA agonists
b-Adrenergic
antagonists
5-HT agonists
Muscarinic
cholinergic agonists
GABA agonists
g-Hydroxybutyrate
Hypoglycemia
Fasting
Decreased NEFA
levels
Amino acids
IDDM
Liver cirrhosis
Anorexia nervosa
Renal failure
GHRH
GHRP
Decreased IGF-I
levels
Estrogens
Androgens
Glucocorticoids†
Glucagon
Metabolic
Hormonal*
Inhibition
REM sleep
a1-Adrenergic stimulation
DA agonists‡
b-Adrenergic agonists
5-HT antagonists
Muscarinic cholinergic
antagonists
Hyperglycemia
Increased NEFA levels
Obesity
Somatostatin
Increased IGF-I levels
Hypo-hyperthyroidism
Glucocorticoids
* For the sake of clarity, growth hormone-releasing and inhibitory
neuropeptides (see sect. VIB) have been omitted. † Under acute treatment. ‡ In acromegaly. See text for definitions.
levels of GH and their pituitary synthesize GH at a reduced rate in vitro (691). In rodents, the infusion of GH
blocked the GH release induced by insulin hypoglycemia,
determined using as an end point the “tibia test” bioassay
(757); in humans, treatment with GH prevented insulin
hypoglycemia-induced elevations of GH (4). These studies
implied that elevated levels of circulating GH have an
autofeedback action at the level of the hypothalamus or
pituitary.
With the advent of specific RIA, it was possible to
show that short-term hypophysectomy was associated
with a decrease in the hypothalamic content of SS and
that SS levels could be restored to normal after GH administration (480, 812). Similarly, hypothalamic SS content could be reduced by selective passive immunization
against GH (93). However, true assessment of the dynamics underlying these changes only became possible with
molecular cloning techniques.
The knowledge that alterations of hypothalamic SS
titers were due to changes in SS synthesis and release
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partially effective in blocking the GHRH-induced GH secretion in AN patients, whereas it completely suppressed
it after recovery, as it did in controls (899, 1001). Similarly, in dogs in a chronic state of caloric restriction, a
standard dose of pirenzepine failed to prevent the GHRHinduced GH rise, and double the dose was needed (37).
Conversely, pyridostigmine, a GH secretagogue allegedly
acting through inhibition of SS release (see sect. VA3), had
no effect on the GHRH-induced GH rise in either AN
patients (409) or in calorically restricted dogs (37), while
clearly enhancing it in controls.
However, in AN patients, arginine, another GH secretagogue allegedly acting through inhibition of SS release
(see sect. VIB2), strikingly enhanced the GHRH-induced
GH rise, like in controls, and blunted the GH response to
the second of two consecutive boluses of GHRH (409),
indicating that a SS-mediated autofeedback mechanism
was preserved.
In all, animal and human experiments showing that
cholinergic drugs do not affect the GHRH-induced GH rise
do not provide evidence that SS function is defective in
states of caloric deprivation, but rather indicate the existence of (primary?) hypothalamic cholinergic hyperfunction. In rats under caloric restriction with reduced titers
of circulating IGF-I, IGF-I receptors in the ME are upregulated (121). This may be a homeostatic mechanism to
suppress GH secretion by maintaining SS secretion during
food shortages or other metabolic conditions involving
low plasma IGF-I levels (see sect. VIIB1). Table 4 sections
out series of factors or conditions that affect GH secretion.
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NEUROENDOCRINE CONTROL OF GROWTH HORMONE SECRETION
Although extensive studies have been done in animal
models to elucidate the various components of this regulatory system, studies in humans have been limited because of the inaccessibility of the hypothalamus and pituitary and their vascular connections. However, in
healthy subjects given an acute dose of GH, total suppression of the subsequent GH response to GHRH (906),
before any rise of circulating IGF-I (907), was evident.
Moreover, similar to what is observed with SS antiserum
in the rat (592, 1039) or with muscarinic cholinergic agonists inhibiting hypothalamic SS release (1039; and see
sect. VB3), in humans too this class of compounds (671,
907) completely restored the GH response to GHRH, inhibited by a previous GHRH bolus (410, 672), suggesting
SS is involved in the short-loop negative autofeedback.
However, these experiments, which imply the intervention of the GH-SS axis, cannot exclude a mechanism
mediated by blood-borne or locally produced IGF-I (see
also below).
However, the GH-mediated inhibitory feedback has
more experimental than clinical relevance, as shown in
GH-deficient patients who, despite chronic treatment with
GHRH, have persistently elevated GH and IGF-I plasma
levels (1035), or patients with ectopic GHRH secretion
who develop acromegaly (376).
In addition to SS, GHRH is also implicated in GH
feedback mechanisms. In rats, intracerebroventricular infusion of GH reduced the amplitude of spontaneous GH
secretory bursts, an effect that was counteracted not by
SS antiserum but by the combination of supramaximal
systemic doses of GHRH and SS antibodies (592). A more
direct approach had relied on direct measurement of
GHRH-IR in the hypothalamus of hypophysectomized
rats. Hypothalamic GHRH-IR concentrations were reduced in these rats and were partially restored after GH
treatment (386). However, in this instance, simple evaluation of GHRH content was misleading and contrasted the
reported ability of GH to lower hypothalamic GHRH content in intact rats (386) or rats with a GH-secreting tumor
(799). In a sequel to these studies, it was shown that
GHRH mRNA was significantly increased in the hypothalamus of hypophysectomized rats and was partially reduced by GH (237, 290).
The negative-feedback action of GH on GHRH mRNA
was also demonstrated in infant rats, in which a dose of
GH reduced pituitary GH content and abolished the GH
rise in response to acute GHRH; this was restored to
normal when GH treatment was combined with GHRH
(207).
These findings might be relevant to the GH therapy of
nonclassical GH-deficient short children, whose GHRHsecreting neurons are functionally preserved (399, 1055).
However, a recent study in children with severe short
stature and impaired GH responses to suprapituitary stimuli but normal responsiveness to GHRH negates this
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derived from experiments in which SS mRNA was measured in individual cells of the rat PeVN. Hypophysectomy
lowered the level of the messenger, per cell, an effect
completely reversed by administration of GH. In the same
experiments, intact GH-treated rats had higher levels of
the messenger than vehicle-treated rats (897). That this
effect was actually due to GH was also implied by in vitro
experiments, adding GH to MBH preparations (93). Moreover, in vivo intraventricular injections of GH raised SS
levels in rat portal blood after a latency of 20 – 40 min,
suggesting action more on SS synthesis than release
(235). Supporting these findings, three different dwarf
mutant models of mice lacking GH, i.e., Ames dwarf df/df
mice (496), Snell dwarf (dw/dw) mice (788), and transgenic dwarf mice with genetic ablation of GH-expressing
cells had a selected depletion of SS mRNA in the PeVN
(85).
The developmental role of GH on hypophysiotropic
SS neurons has been studied in Ames dwarf df/df mice.
Total SS mRNA levels were deficient in their PeVN shortly
after the developmental onset of SS transcription. The
absence of GH autofeedback was very likely responsible
for SS mRNA deficiency in 7-day-old dwarf Ames mice
compared with phenotypically normal DF/? controls, suggesting that GH receptors may be present on the PeVN
neurons at or before 7 days of age in DF/? mice (496).
Because the amount of SS mRNA per expressing cell in
the PeVN of Ames dwarf mice was not reduced, the
decrease in total SS mRNA of the whole expressing cells,
also present in adults, was the result of an early failure to
achieve a normal population of SS-expressing neurons
(496). No studies on the developmental appearance of
GHRH receptor mRNA have been reported so far in Ames
dwarf mice, a topic worth further investigation to clarify
the developmental role of GH on SS neurons.
Transgenic mice expressing heterologous and ectopic GH have been used as models for studying the
feedback effects of elevated nonregulated GH on hypophysiotropic neurons and peripheral functions. It
would seem that feedback effects extend beyond dynamic
regulation to influence hypophysiotropic neuron differentiation and/or survival, when the deficiency (see above),
or excess of GH is genetic and lifelong, such as in spontaneous mutant or transgenic models (837). Somatostatin
expression was markedly increased in mice bearing either
bovine or human transgenes. Human, but not bovine, GH
reportedly has lactogenic properties in mice and appears
to stimulate prolactin-inhibiting TIDA neurons. The results in the murine transgene models suggested that although even extremely high levels of circulating GH of
bovine origin did not stimulate TIDA neurons, lifelong
high levels of human GH had a stimulatory and graded
effect on the developmental differentiation of TH and DA
production, supporting the concept of prolactin as a trophic factor for TIDA neurons.
571
572
MÜLLER, LOCATELLI, AND COCCHI
tors have been found in the choroid plexus, hippocampus,
hypothalamus, and pituitary gland (583, 1084). Receptors
in the choroid plexus are involved in transporting the
hormone across the BBB (583). Growth hormone is reportedly present in low concentrations in the CSF in
humans (616), but direct evidence that it can cross the
BBB has been recently provided in GH-deficient adults
where CSF GH levels rose significantly after 1 or 21 mo of
GH treatment (154, 528). This was accompanied by parallel increases in IGF-I, IGFBP-3, and b-endorphin concentrations and by decreases in homovanillic acid, VIP,
and free thyroxine concentrations. These changes in CSF
composition might explain the gain in psychological wellbeing usually reported in GH-deficient patients after they
start GH treatment.
The mRNA for GH receptors was widely expressed in
the PeVN, PVN, and ARC of the hypothalamus (155). In
the PeVN and PVN, the majority of SS neurons coexpressed GH receptor mRNA, suggesting that GH acts
directly on SS at these sites. Intriguing was the observation that GH receptor mRNA was also expressed in the
ARC, although the vast majority of GHRH and SS cells of
the ARC did not appear to express it, implying that GH
effects in ARC were transduced by other neurons (155).
However, single- and double-label in situ hybridization
showed that GH induced c-fos expression in the ARC of
intact rats (156) and in the ARC and PeVN of hypophysectomized rats (728), indicating that immediate early
gene expression plays a role in the feedback actions of
GH into the brain. However, although c-fos-expressing
neurons in the medial ARC were abundant, few if any
were GHRH or SS neurons.
The pattern of distribution of c-fos expression in the
ARC was strikingly similar to that of GH-receptor mRNA,
suggesting that receptor binding and the induction of c-fos
gene expression in this nucleus occurred within the same
population of unidentified cells.
The precise identity of these cells remained elusive
until Kamegai et al. (538) demonstrated that GH induces
the expression of c-fos mRNA in NPY neurons of the ARC.
Although this suggested that most NPY neurons were
responsive to GH, it remained to be established whether
GH acts directly on NPY neurons or whether there was
some other population of cells receiving the GH signal.
Studies of coexpression of GH receptor mRNA and NPY
mRNA in the ARC indicated that the majority of NPY
neurons in the ARC coexpressed GH receptor mRNA
(217). Granted that NPY neurons may serve as a receiving
network for the GH signal, it remains to be seen how, or
even if, the signal is relayed to GHRH or SS neurons in the
ARC (see also sect. VB6).
Another neuropeptide, galanin, which is coexpressed
in GHRH neurons (699, 778; see sect. IIIA2), seems to be
involved in the feedback control of GH. Galanin mRNA is
reduced in GHRH neurons of Lewis dwarf rats and in
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mechanism. During GH therapy, the GH response to a
GHRH bolus was only slightly reduced, and a second
bolus of GHRH elicited a GH response similar to that in
the pretreatment test (927). This indicates a significant
resilience of GHRH neurons to the feedback mechanisms
triggered by elevated circulating GH concentrations.
Feedback regulation of GHRH function by GH has
been studied in animal models of spontaneous GH deficiency (933). In Ames dwarf mice not only was total
GHRH mRNA expression enhanced, but the number of
GHRH-IR neurons was increased (838). Conversely, transgenic mice bearing a TH-human GH transgene had targeted expression of GH in the PeVN, ARC, and adrenal
medulla and were growth retarded (68). They also had
low pituitary GH and GH mRNA and low hepatic IGF-I
mRNA and serum IGF-I levels. In these rats, feedback
effects occurred in the PeVN and ARC, leading to increases of SS and its messenger and decreases in GHRH
and its messenger (996).
Lowering GHRH function during fetal life in these
mice affected the density of pituitary GHRH receptors and
impaired somatotroph development (996). Thus this type
of transgenic mouse serves as a model of idiopathic GH
deficiency in humans and a means for studying factors
affecting somatotroph proliferation (374).
Flavell et al. (362) reported that in transgenic rats
targeting the expression of human GH (hGH) to GHRH
neurons can induce dominant dwarfism. A line of these
rats bearing a single copy of a GHRH-hGH transgene had
low levels of production of hypothalamic GHRH and
mRNA, in contrast to the increased GHRH expression
accompanying GH deficiency in other models of dwarfism. These rats also had a sexually dimorphic pattern of
GH secretion and a lower GH response to GHRH or
GHRP-6 challenge than their nontransgenic littermates;
nevertheless, despite the pituitary GH deficiency and
dwarfism, repeated dosing of GHRH or GHRP-6 did stimulate their growth. To our knowledge, these rats are the
first genetic animal model of GH deficiency in which
dwarfism could be corrected by exogenous GH secretagogues (1093).
In contrast to the feedback data in young rats, the
feedback effects of GH are disrupted in senescent rats,
which are spontaneously deficient in GH. In 20-mo-old
male rats, 4 days of treatment with GH increased plasma
IGF-I levels but did not significantly change hypothalamic
GHRH and SS mRNA levels (291). However, old rats
apparently losing their ability to sense the feedback action of GH in the hypothalamus responded normally to
GH with increases in SS and IGF-I gene expression in the
cerebral hemispheres (637). This may explain the improvement of some psychological symptoms after GH
treatment in GH-deficient patients (see also below).
The direct feedback action of GH on the brain involves GH binding to its own receptor. Specific GH recep-
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NEUROENDOCRINE CONTROL OF GROWTH HORMONE SECRETION
B. Insulin-Like Growth Factor I
Insulin-like growth factor I participates in the growth
and function of almost every organ in the body (283) and
is synthesized primarily in the liver, although it is produced everywhere in the body. Insulin-like growth factor
I shows structural similarities with IGF-II and insulin,
with which it has in common 60% of amino acids. However, unlike insulin, which circulates in picomolar concentrations and has a short half-life, IGF-I and -II circulate
in nanomolar concentrations and have a much longer
half-life because they are largely bound to a variety of BP,
six of which have been characterized (530). These BP, like
IGF-I and IGF-II, are synthesized by most tissues, where
they act in an autocrine or paracrine manner to regulate
different functions (530). Both IGF-I and IGF-II are essential for fetal development (67), and nanomolar concentrations persist in the circulation into adult life.
The main role of IGF-I after birth is to regulate
growth, whereas that of IGF-II is still unknown (606). The
circulating BP modulate the activity of these growth factors by limiting their access to specific tissues and receptors. Binding protein 3 binds .95% of circulating IGF-I
and -II. This complex binds an acid-labile protein subunit,
forming a ternary complex that has a serum half-life of
many hours. Once released from this complex, the IGF
can enter target tissues with the aid of other BP. Growth
hormone raises the serum concentrations of BP-3 and the
acid-soluble subunit (530). Some IGF-I BP have a greater
affinity for IGF than receptors. This can prevent activation of intracellular signaling pathways (606).
The local production of IGF-I is under different control in different tissues. For example, GH, parathyroid
hormone, and sex steroids regulate the production of
IGF-I in bone, whereas sex steroids are the main regulators of locally produced IGF-I in the reproductive system.
The functions of circulating IGF-I are becoming clearer,
but the actions of locally produced IGF have yet to be
defined. Age, sex, nutritional status, and GH affect serum
IGF-I concentrations. Plasma levels of IGF-I are low at
birth, rise substantially during childhood and puberty, and
begin to decline in the third decade (59, 607), after the
changes in GH secretion.
Complete disruption of the IGF-I gene in a 15-yr-old
boy who presented with severe intrauterine growth failure, deafness, and mild mental retardation indicates that
the absence of IGF-I is compatible with life. However, it
suggests that IGF-I plays a major role in human fetal
growth and CNS development (1104) (see also below). In
addition, low IGF-I levels may result from GH deficiency
or from mutations in the gene encoding the GH receptor,
such as in Laron dwarfism (593).
The nutritional status also markedly affects plasma
IGF-I concentrations. Starvation causes complete resistance to GH, and restriction of protein or calories causes
a lesser degree of resistance with a consequent reduction
of hepatic IGF-I production (517). Low IGF-I levels with
GH resistance are also seen in other catabolic states, such
as severe trauma and sepsis. In IDDM, hepatic resistance
to GH, with elevated serum GH and low IGF-I levels in
plasma, result probably from an inadequate insufficient
action of insulin on the liver (450). During puberty, these
changes may limit somatic growth. The high levels of GH
may worsen the hyperglycemia by opposing the peripheral actions of insulin in poorly controlled IDDM or
NIDDM. Treatment with IGF-I improves glycemic control
in IDDM and reduces insulin resistance by lowering serum GH and glucagon (61, 327), and in NIDDM it prevents
hyperinsulinemia (742, 1127).
Over recent years, there has been increasing interest
in the roles of IGF-I within the CNS. In addition to its
activity on proliferation and differentiation during embryonic and postnatal development (67, 623, 876), IGF-I also
promotes survival and stimulates neurite outgrowth from
central and peripheral neurons in culture. Insulin-like
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hypophysectomized rats and is restored by exogenous GH
(218). A subset of SS neurons in the PeVN also expresses
the galanin receptor mRNA, whereas few GHRH neurons,
if any, appeared to do so (218). Galanin, like its cotransmitter GHRH, is the target for GH action, and galanin may
play a role in the feedback control of GH secretion,
through a direct effect on SS neurons. These, in turn,
would inhibit GHRH ARC neurons, although the underlying mechanism remains to be elucidated.
High levels of expression of the mRNA for two prototypic receptors of the SS family, sstr1 and sstr2, have
been found (81), and 2 wk after hypophysectomy, sstr1
and sstr2 mRNA labeling density was reduced in the ARC.
Seven days of treatment with hGH raised the labeling
density of sstr1 mRNA selectively in the ARC of hypophysectomized rats (448). Thus the expression of sst1 and
sst2 receptor subtypes must be under the regulatory influence of pituitary hormones, and GH may participate in
its own secretion by modulating hypothalamic SS and,
secondarily, by up- or downregulating sst1 receptor
mRNA on GHRH-containing neurons. However, in view of
the long-term exposure to GH reported in this study, it is
still questionable whether this regulatory feedback mechanism would operate under physiological conditions and
participate in the genesis of episodic GH secretion or is
only manifested under pharmacological conditions.
Growth hormone, in addition to its direct short-loop
effects on the hypothalamic neurons, directly affects lipolysis and impairs glucose metabolism and indirectly
affects growth by stimulating the production of IGF-I.
Therefore, IGF-I, NEFA, and glucose might all have roles
in the long-loop feedback regulation of GH secretion (see
sect. VI, B1 and B3).
573
574
MÜLLER, LOCATELLI, AND COCCHI
1. Feedback actions of IGF-I
It has long been known that a long-loop feedback
regulation of GH secretion is operated by IGF-I. Berelowitz et al. (90) were the first to demonstrate that a purified
IGF-I preparation inhibited GH release from pituitary cells
in culture and stimulated dose-related release of SS from
hypothalamic explants. The IGF long-loop feedback was
further strengthened by the finding (1011) that intraventricular injection of a preparation containing both IGF-I
and -II markedly suppressed spontaneous GH secretion in
the rat. Insulin-like growth factor I receptors have been
found in normal rat pituitary cells and in human GHsecreting adenomas (196). Insulin-like growth factor I has
a potent and persistent inhibitory action on cultured human pituitary adenoma cells, resulting in the reduction of
GH release, under basal and stimulated conditions (197);
it dose-dependently lowers the levels of GH mRNA (1115).
It also has inhibitory action, not only on GH gene expression but also on the pituitary specific transcriptional factor GHF-I/Pit-I (973).
Although in vitro data clearly demonstrated the inhibitory role of IGF-I in the pituitary, in vivo experiments
in rats and humans yielded contrasting results. As mentioned above, experiments in rats indicated that IGF participate in GH regulation through a hypothalamic action.
However, those experiments suffered the limitation of
having used a partially purified IGF preparation (1011), a
point that was reexamined with the advent of recombinant IGF preparations. Separate intraventricular injection
of IGF-I and -II, even at high concentrations, did not
modify the pulsatile pattern of GH secretion in the rat.
Only combined IGF-I and -II significantly inhibited GH
secretion (454, 455). The mechanism of this interaction is
still not clear.
How IGF-I affects SS and GHRH mRNA levels was
studied in GHRH-deprived rats. No effect was seen after
systemic administration of IGF-I, whereas intraventricular IGF-I lowered GHRH mRNA and raised SS mRNA
levels (924). The difference between rats and humans was
not explained. In the rat, GH secretion was inhibited only
after intraventricular injection, whereas in humans, it was
also inhibited after peripheral administration (196). It was
initially shown that an intravenous bolus injection of IGFI immediately inhibited GH secretion, in normal and
Laron dwarf patients, also reducing blood glucose (596).
In normal subjects, a low-dose euglycemic infusion of
IGF-I rapidly suppressed the GH secretion enhanced by
fasting (459) or by GHRH or hexarelin (M. Rolla, unpublished results), indicating an action most likely through
IGF-I receptors and independent of its insulin-like metabolic actions.
The observation that in ewes intraventricular infusions of IGF-I and IGF-II, alone or in combination, had no
affect on GH secretion whereas intrapituitary infusion
inhibited it (363) strongly suggests the pituitary is the
main site of IGF feedback on GH. In the rat, continuous
infusion of IGF-I for 3 days significantly raised SS mRNA
levels in the hypothalamus of control and starved rats. In
the same model, repeated doses of rhGH stimulated SS
mRNA levels in control but not starved rats, indicating
that IGF-I generation was necessary in the GH autofeedback mechanisms operated through SS neurons (416).
The physiological relevance of the feedback effect of
IGF-I on the CNS depends on its access in vivo to those
areas that participate in SS and GHRH secretion. Specific
binding sites for IGF-I have been found in the pituitary, in
the external palisade zone of the ME, where SS nerve
terminals project (122), and in other brain areas (435);
IGF-I is also present in the CSF (80).
By all these mechanisms IGF-I inhibits the posttranslational processing of GH and reduces GH exocytosis,
antagonizing the effect of GHRH and blunting the GHreleasing actions of forskolin, cAMP, and TPA (741, 1112).
The relevant IGFBP role in the effect of the peptide is now
understood to be important. It is thus possible that spe-
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growth factor I increases oligodendrocyte-induced myelin
synthesis and survival (1116). Targeted disruption of the
IGF-I gene results in reduced brain size, hypomyelination,
and neuronal loss (82).
Insulin-like growth factor I mRNA is transiently expressed in CNS areas related to long projection neurons
(123, 387). The transient expression of IGF-I by projection
neurons during axon growth and synaptogenesis suggests
it has an important role in these processes (123). This
contention is borne out by the permanent expression of
IGF-I and its receptors in the olfactory bulb, where neuroand synaptogenesis persist during adult life (123). Insulinlike growth factor I therefore has a pleiotropic role in the
CNS essential for proliferation, differentiation, and survival in the developing brain, and in several neuropathological conditions (319), gene expression reaching its
highest levels in the early phase of neuronal growth,
myelination, or nerve regeneration.
Concerning the factors and mechanisms involved in
the regulation of CNS IGF-I gene expression, Wood et al.
(1104) reported that in adult hypophysectomized rats GH
given centrally or systemically could restore normal IGF-I
mRNA levels. Ye et al. (1116) found that GH played a role
in the regulation of brain IGF-I gene expression during
development too. Growth hormone, which regulates IGF-I
gene expression, may be produced in the brain (482) or
from the pituitary, since GH levels in brain are reduced
after hypophysectomy (483), and systemically administered GH increases brain IGF-I mRNA (1104).
In addition, IGF-I might reach the brain from the
periphery, since IGF-I transport across the BBB into specific thalamic and hypothalamic nuclei has been reported
(881).
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NEUROENDOCRINE CONTROL OF GROWTH HORMONE SECRETION
cies differences of IGF-I’s effects on GH secretion after
different routes of administration are related to different
expression of IGFBP in the CNS (196).
All in all, IGF-I can play an important role in the
feedback control of GH by acting acutely on SS secretion
which, in turn, inhibits pituitary GH secretion and in the
long run by acting directly on the pituitary.
VIII. CONCLUDING REMARKS
We acknowledge the help of Dr. Antonello Rigamonti in the
preparation of the figures and tables and of Maria Lupo for
diligent secretarial assistance.
Experiments carried out by the authors were supported by
contributions and Special Research Project “Aging” of the Center for National Research, Rome, Italy.
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The neural control of GH secretion in mammals is
thought to be exerted primarily through the subtle interplay of GHRH, the physiological stimulator of GH synthesis and release and of somatotroph proliferation, and SS,
which through its inhibitory influences is the principal
modulator of GH release and regulator of GH pulsatility.
The identification, characterization, and cloning of animal
and human GHRH receptors should extend our understanding of GH regulation under different physiological
and pathological conditions, leading us to use GHRH
better for the therapy of pituitary dwarfism, GH deficiency
of adults, and other GH deficiency states.
A variety of recently cloned sstr subtypes mediate the
various effects of SS and will help us correlate their
regional distribution within the CNS with the peptides’
functional properties. Development of subtype-selective
SS agonists and antagonists may result in new therapies
for the treatment of CNS and peripheral tumors and neurological disorders in which the SS system is reportedly
altered. A new family of extremely effective GH releasers,
the peptidyl and nonpeptidyl GH-releasing peptides,
whose mechanism of action and endogenous receptor
ligands have yet to be identified, nevertheless offer therapeutic potential in a variety of hyposomatotrophic
states, when given alone or in combination with GHRH.
They are also posing questions about some traditional
beliefs of GH regulation, adding new complexity to the
understanding of how the classic brain neurotransmitters,
GHRH and SS, but also an increasing cohort of GH-releasing and inhibiting neuropeptides, transduce peripheral
metabolic, endocrine, and immune influences into a neuroendocrine response.
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