Neuroendocrine Control of Growth Hormone Secretion
Neuroendocrine Control of Growth Hormone Secretion
Neuroendocrine Control of Growth Hormone Secretion
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PHYSIOLOGICAL REVIEWS<br />
Vol. 79, No. 2, April 1999<br />
Printed in U.S.A.<br />
<strong>Neuroendocrine</strong> <strong>Control</strong> <strong>of</strong> <strong>Growth</strong> <strong>Hormone</strong> <strong>Secretion</strong><br />
EUGENIO E. MÜLLER, VITTORIO LOCATELLI, AND DANIELA COCCHI<br />
Department <strong>of</strong> Pharmacology, Chemotherapy, and Toxicology, University <strong>of</strong> Milan, Milan; and<br />
Department <strong>of</strong> Biomedical and Biotechnology Sciences, University <strong>of</strong> Brescia, Brescia, Italy<br />
I. Introduction 512<br />
II. <strong>Growth</strong> <strong>Hormone</strong> <strong>Secretion</strong> Pattern 512<br />
A. Sex 513<br />
B. Age-related growth hormone secretion 514<br />
C. Sleep 517<br />
III. Hypophysiotropic <strong>Hormone</strong>s 518<br />
A. <strong>Growth</strong> hormone-releasing hormone 518<br />
B. Somatostatin 530<br />
IV. <strong>Growth</strong> <strong>Hormone</strong>-Releasing Peptides 535<br />
A. Structure-activity relationships 536<br />
B. Nonpeptidyl growth hormone secretagogues 536<br />
C. Site(s) and mechanism <strong>of</strong> action 537<br />
D. Human studies 540<br />
E. Effects on other pituitary hormones 542<br />
F. Conclusions 542<br />
V. Brain Messengers in the <strong>Control</strong> <strong>of</strong> <strong>Growth</strong> <strong>Hormone</strong> <strong>Secretion</strong> 542<br />
A. General background 542<br />
B. Characteristic features 543<br />
C. Main locations <strong>of</strong> neurotransmitter and neuropeptide pathways 544<br />
D. Neurotransmitters 545<br />
E. <strong>Growth</strong> hormone-releasing and -inhibiting neuropeptides 557<br />
VI. Pheripheral Hormonal and Metabolic Signals or Conditions Modulating <strong>Growth</strong> <strong>Hormone</strong> <strong>Secretion</strong> 563<br />
A. <strong>Hormone</strong>s 563<br />
B. Metabolic signals 565<br />
C. Physiopathology <strong>of</strong> nutritional excess or deficiency 567<br />
VII. <strong>Growth</strong> <strong>Hormone</strong> Aut<strong>of</strong>eedback Mechanism 570<br />
A. <strong>Growth</strong> hormone 570<br />
B. Insulin-like growth factor I 573<br />
VIII. Concluding Remarks 575<br />
Müller, Eugenio E., Vittorio Locatelli, and Daniela Cocchi. <strong>Neuroendocrine</strong> <strong>Control</strong> <strong>of</strong> <strong>Growth</strong> <strong>Hormone</strong><br />
<strong>Secretion</strong>. Physiol. Rev. 79: 511–607, 1999.—The secretion <strong>of</strong> growth hormone (GH) is regulated through a complex<br />
neuroendocrine control system, especially by the functional interplay <strong>of</strong> two hypothalamic hypophysiotropic<br />
hormones, GH-releasing hormone (GHRH) and somatostatin (SS), exerting stimulatory and inhibitory influences,<br />
respectively, on the somatotrope. The two hypothalamic neurohormones are subject to modulation by a host <strong>of</strong><br />
neurotransmitters, especially the noradrenergic and cholinergic ones and other hypothalamic neuropeptides, and are<br />
the final mediators <strong>of</strong> metabolic, endocrine, neural, and immune influences for the secretion <strong>of</strong> GH. Since the<br />
identification <strong>of</strong> the GHRH peptide, recombinant DNA procedures have been used to characterize the corresponding<br />
cDNA and to clone GHRH receptor is<strong>of</strong>orms in rodent and human pituitaries. Parallel to research into the effects <strong>of</strong><br />
SS and its analogs on endocrine and exocrine secretions, investigations into their mechanism <strong>of</strong> action have led to<br />
the discovery <strong>of</strong> five separate SS receptor genes encoding a family <strong>of</strong> G protein-coupled SS receptors, which are<br />
widely expressed in the pituitary, brain, and the periphery, and to the synthesis <strong>of</strong> analogs with subtype specificity.<br />
Better understanding <strong>of</strong> the function <strong>of</strong> GHRH, SS, and their receptors and, hence, <strong>of</strong> neural regulation <strong>of</strong> GH<br />
secretion in health and disease has been achieved with the discovery <strong>of</strong> a new class <strong>of</strong> fairly specific, orally active,<br />
small peptides and their congeners, the GH-releasing peptides, acting on specific, ubiquitous seven-transmembrane<br />
domain receptors, whose natural ligands are not yet known.<br />
0031-9333/99 $15.00 Copyright © 1999 the American Physiological Society 511
512 MÜLLER, LOCATELLI, AND COCCHI Volume 79<br />
I. INTRODUCTION<br />
The secretion <strong>of</strong> somatotrophin, or growth hormone<br />
(GH), like other anterior pituitary (AP) hormones, is regulated<br />
through a complex neuroendocrine control system<br />
that comprises two main hypothalamic regulators, GHreleasing<br />
hormone (GHRH) and somatostatin (SRIH or<br />
SS), exerting stimulatory and inhibitory influences, respectively,<br />
on the somatotrope cell. Both GHRH and SS,<br />
which are subject to modulation by other hypothalamic<br />
peptides and by complex networks <strong>of</strong> neurotransmitter<br />
neurons, are the final mediators <strong>of</strong> metabolic, endocrine,<br />
neural, and immune influences for GH secretion in the<br />
pituitary.<br />
In the last decade, the rather static scenario <strong>of</strong> GH<br />
control has been shaken by a host <strong>of</strong> advances, some<br />
resulting from molecular biology techniques. Of particular<br />
interest is cloning <strong>of</strong> the GHRH receptor is<strong>of</strong>orms in the<br />
rat, mouse, and human pituitary; discovery <strong>of</strong> distinct<br />
genes encoding a family <strong>of</strong> structurally related G proteincoupled<br />
SS receptors in brain and the pituitary and synthesis<br />
<strong>of</strong> new SS analogs with subtype specificity; identification<br />
<strong>of</strong> a novel class <strong>of</strong> fairly specific, orally active,<br />
hexa-hepta peptides, the GH-releasing peptides (GHRP)<br />
and their congeners, whose GH-releasing activity is<br />
greater than GHRH; better insight into the neurotransmitter<br />
control <strong>of</strong> GH; and the involvement <strong>of</strong> somatotropic<br />
dysfunction in a host <strong>of</strong> diseases and in the catabolic<br />
processes related to aging.<br />
This review updates and focuses on aspects <strong>of</strong> the<br />
neural control <strong>of</strong> GH secretion, especially in the light <strong>of</strong><br />
these advances. For comprehensive surveys <strong>of</strong> GH secretory<br />
control, the reader is referred to Frohman et al. (377),<br />
Müller (749), and Cronin and Thorner (274).<br />
II. GROWTH HORMONE SECRETION PATTERN<br />
The secretion <strong>of</strong> GH is pulsatile in all species studied<br />
so far, with its pattern not dissimilar in humans and male<br />
rodents. In the former, an ultrasensitive immunoradiometric<br />
assay (IRMA) (limit <strong>of</strong> detection, 20 ng/l) given to<br />
healthy men and women showed an ultradian rhythm<br />
with an interpulse frequency <strong>of</strong> 2 h (1101), which compared<br />
favorably with an interpulse frequency <strong>of</strong> 3 hin<br />
the male rat (1014) and plasma GH detectable at all time<br />
points. In these subjects, GH levels ranged over three<br />
orders <strong>of</strong> magnitude in both sexes.<br />
Women <strong>of</strong> reproductive age had significantly higher<br />
overall GH levels, a higher pulse amplitude, and a higher<br />
baseline, but the pulse frequency was the same as in men<br />
(mean secretion rates: 327 g/24 h for men and 392 g/24<br />
h for women; Ref. 1101). These figures are 50% lower<br />
than previously assumed (see Ref. 1030). A new ultrasensitive<br />
GH chemiluminescence (CL) assay (limit <strong>of</strong> detec-<br />
tion, 5 ng/l) detects serum GH concentrations in all samples<br />
collected at 10-min intervals for 24 h.<br />
The Cluster method to estimate GH pulsatility and<br />
deconvolution analysis, which simultaneously resolves<br />
the endogenous hormone secretory rate and clearance<br />
kinetics (1063), showed that pulsatile GH secretion continued<br />
in all subjects in the awake and fed state, despite<br />
undetectable serum GH in daytime samples analyzed by a<br />
conventional IRMA, run for comparison. Interestingly, the<br />
CL assay also revealed for the first time a low rate <strong>of</strong> basal<br />
(constitutive) GH secretion mixed with pulsatile and nyctohemeral<br />
variations (508).<br />
Further studies were then done in healthy lean and<br />
obese subjects aimed at ascertaining how age, steroid sex<br />
hormones, and obesity, singly or jointly, influence the<br />
basal and pulsatile modes <strong>of</strong> GH release. Basal and pulsatile<br />
GH release were found to be regulated differently<br />
by adiposity and steroid hormones. Thus basal GH secretion<br />
rates were negatively correlated with the circulating<br />
estrogen (E 2) concentration and with an interactive effect<br />
<strong>of</strong> age and body fat, whereas the GH secretory burst mass<br />
was strongly positively related to serum testosterone concentrations.<br />
Concerning the biological consequences <strong>of</strong> GH secretion,<br />
basal and pulsatile GH release may influence serum<br />
insulin-like growth factor I (IGF-I), its main binding protein<br />
(BP), i.e., IGFBP-3, and IGFBP-1 in distinct ways<br />
(1064). In a study in healthy men, IGFBP-3 correlated<br />
negatively to basal GH secretion, whereas IGFBP-1 concentrations<br />
were positively correlated with this measure.<br />
Measurements <strong>of</strong> serum IGF-I concentrations indicated<br />
that pulsatile GH release was strongly positively correlated<br />
with the mean serum IGF-I level. Conversely, there<br />
was no association between basal GH release rates and<br />
serum IGF-I levels (1064). This observation is consistent<br />
with the theory that a pulsatile GH signal is important in<br />
acting on one or more major target tissues (e.g., the liver)<br />
to stimulate IGF-I production in the healthy human. These<br />
findings have major implications for the evaluation <strong>of</strong> GH<br />
control and secretion in different experimental and clinical<br />
conditions.<br />
Present knowledge thus indicates that the secretory<br />
pattern <strong>of</strong> GH depends on the interaction between GHRH<br />
and SS at the somatotroph level, although we cannot<br />
overlook the existence <strong>of</strong> anatomic connections and functional<br />
peptide interactions within the hypothalamus (see<br />
sect. IIIA3) and the contribution <strong>of</strong> a still elusive endogenous<br />
GHRP system (see sect. IV).<br />
The basis <strong>of</strong> the pulsatile release <strong>of</strong> GH, however,<br />
remains unknown. A host <strong>of</strong> nutritional, body composition,<br />
metabolic, and age-related sex steroid mechanisms,<br />
adrenal glucocorticoids, thyroid hormones, and renal and<br />
hepatic functions all govern pulsatile release in adults<br />
(see sect. II, A–C), but spontaneous elevations in GH secretion<br />
are more likely to result from the ability <strong>of</strong> hypotha-
April 1999 NEUROENDOCRINE CONTROL OF GROWTH HORMONE SECRETION 513<br />
lamic neuroendocrine cells themselves to promote and sustain<br />
phasic bursts <strong>of</strong> action potentials (34). Basal GH release<br />
may also be subject to neurophysiological regulation; slow<br />
removal <strong>of</strong> a pool <strong>of</strong> GH in plasma from trapping with a<br />
GH-binding protein seems less likely (508).<br />
Hypothalamic GHRH and SS functions both appear<br />
essential for pulsatile secretion. In male rats, anti-GHRH<br />
serum inhibited spontaneous GH pulses (1090), reduced<br />
growth rate (207), and suppressed stimulated GH secretion<br />
(207, 548). Initial studies in male rats utilizing an<br />
anti-SS serum bolus injection showed that pulsatile GH<br />
secretion was preserved despite an increase in basal GH<br />
levels (350). However, when a highly potent anti-SS serum<br />
was infused for 6 h, it did inhibit pulsatile GH secretion<br />
(375). The most likely explanation for the different effects<br />
<strong>of</strong> anti-SS serum bolus injection versus continuous infusion<br />
is that the latter but not the former penetrates the<br />
region <strong>of</strong> the arcuate nucleus (ARC), where the inhibitory<br />
effects <strong>of</strong> SS on GHRH secretion occur (see sect. IIIA3).<br />
Supporting this view, electrolytic lesions in the medial<br />
preoptic area (MPOA) or anterolateral hypothalamic<br />
deafferentiation in male rats, two techniques which eliminate<br />
SS immunostaining in the median eminence (ME),<br />
resulted in elevated plasma GH levels and no pulsatile GH<br />
secretion. Under these experimental conditions, basal<br />
and K -stimulated GHRH release from the hypothalamic<br />
ME-ARC complex in vitro was significantly increased,<br />
although the hypothalamic GHRH content was decreased,<br />
suggesting an increased turnover <strong>of</strong> the peptide (548).<br />
Overall, these results suggest that SS in the hypothalamus<br />
plays a tonic inhibitory role in the regulation <strong>of</strong><br />
GHRH release and that GH hypersecretion in lesioned rats<br />
is due to a combination <strong>of</strong> secretion changes <strong>of</strong> both SS<br />
and GHRH. They are in line with the general model proposed<br />
by Tannenbaum and Ling (1013), in which GHRH<br />
release during troughs in a sinusoidal pattern <strong>of</strong> SS release<br />
induces the episodic release <strong>of</strong> GH, and the rise in<br />
SS suppresses baseline release. Direct measurement <strong>of</strong><br />
GHRH and SS in the rat portal blood would validate this<br />
view by showing that each GH secretion episode started<br />
by pulsatile release <strong>of</strong> GHRH, which is preceded by or<br />
concurrent with a moderate reduction <strong>of</strong> the SS tone<br />
(853). These portal blood measurements in the rat, however,<br />
would require confirmation, since other studies have<br />
not been able to maintain GH pulsatility under the conditions<br />
reported by Plotsky and Vale (853) (see Ref. 895 for<br />
references). Moreover, this model would explain patterns<br />
<strong>of</strong> secretion in the male rat. Female rats show much more<br />
continuous irregular GH secretion and much more regular<br />
responses to GHRH (248, see also sect. IIA).<br />
The proposed model <strong>of</strong> SS-GHRH interactions cannot<br />
be extrapolated to all the animal species so far investigated.<br />
In the sheep, portal GHRH and SS levels suggest<br />
regulation is more complex, although the majority <strong>of</strong> GH<br />
pulses coincided with or occurred immediately after a<br />
GHRH pulse, 30% were completely dissociated (378).<br />
This variability was also seen in SS measurements, in the<br />
sheep, where pulses were not necessarily asynchronous<br />
with those <strong>of</strong> GHRH and did not correlate with GH<br />
troughs, nor SS troughs with GH pulses. In addition,<br />
active immunization <strong>of</strong> rams against SS did not change<br />
basal and pulsatile GH secretion, whereas in the anti-<br />
GHRH group, plasma GH levels were very low, and the<br />
amplitude <strong>of</strong> GH pulses was strikingly reduced (652). The<br />
redundant GHRH and SS pulsatility in the portal blood<br />
may reflect neuropeptide actions beyond pure GH release,<br />
e.g., trophic effects on the target somatotrophs (895).<br />
It must be recalled, in addition, that the simple rat<br />
GHRH-SS model ignores all other alleged hypophysiotrophic<br />
factors, including the endogenous GHRP system (see<br />
sect. IV), additional modulators such as pituitary GHRH<br />
and SS receptors, feedback effects <strong>of</strong> GH and IGF-I, and<br />
other target gland hormones.<br />
In humans, the neuroendocrine control <strong>of</strong> pulsatile<br />
GH secretion is also poorly understood. Because portal<br />
blood cannot be sampled directly in humans, most <strong>of</strong> our<br />
understanding <strong>of</strong> the regulation <strong>of</strong> GH secretion comes<br />
from either indirect human studies or extrapolation <strong>of</strong><br />
animal data. In healthy young men, a single dose <strong>of</strong> a<br />
competitive GHRH antagonist blocked 75% <strong>of</strong> nocturnal<br />
GH pulsatility (521), supporting the hypothesis that pulsatile<br />
GH secretion in humans is driven by GHRH. The<br />
persistence <strong>of</strong> pulsatile GH secretion in normal and GHdeficient<br />
subjects during continuous GHRH infusion (473,<br />
1056) and the ability <strong>of</strong> exogenous GHRH to release GH in<br />
the face <strong>of</strong> grossly elevated GHRH levels in the ectopic<br />
GHRH syndrome (74) are also in keeping with this suggestion.<br />
Periodic falls in SS secretion might account for the<br />
persistence <strong>of</strong> pulsatile GH secretion in the above conditions,<br />
a proposal in line with GH secretory pr<strong>of</strong>iles determined<br />
by deconvolution analysis (460). Plasma GH secretory<br />
patterns were measured in normal adult men at<br />
baseline and during submaximal intravenous boluses <strong>of</strong><br />
GHRH every 2 h for 6 days (522). No evidence was found<br />
<strong>of</strong> either acute or chronic desensitization; GH responses<br />
were seen at every GHRH bolus, and circadian patterns <strong>of</strong><br />
GH secretion were similar at baseline and during the<br />
GHRH schedule, with maxima occurring during the early<br />
nightime hours. This pattern was consistent with a model<br />
for the ultradian secretion <strong>of</strong> GH in which circadian SS<br />
secretion (reduction at night?) is superimposed on more<br />
rapid GHRH pulses.<br />
A. Sex<br />
Sex-related differences in GH control by GHRH and<br />
SS have been found particularly in the rat. They include<br />
different 1) responsiveness to exogenously administered
514 MÜLLER, LOCATELLI, AND COCCHI Volume 79<br />
GHRH (248, 1085), 2) endogenous content <strong>of</strong> hypothalamic<br />
immunoreactive (IR) GHRH and SS (386), 3) hypothalamic<br />
mRNA levels <strong>of</strong> SS (238, 1044) and GHRH (40,<br />
653), 4) pituitary GHRH receptor expression (799), and 5)<br />
GH aut<strong>of</strong>eedback mechanism(s) (169, see also sects.<br />
IIIA8B and VII). Particularly noteworthy was the higher SS<br />
mRNA content in the periventricular nucleus (PeVN) <strong>of</strong><br />
male rats than in proestrus females and the finding that in<br />
castrated males administration <strong>of</strong> testosterone prevented<br />
the significant reduction in SS mRNA after surgery (238).<br />
It can be inferred from these results that were the<br />
amount <strong>of</strong> SS available for release from the ME, sex<br />
differences in GH secretory patterns (see also below) and<br />
perhaps also sex differences in growth rates might be<br />
partially attributable to a difference in the ability <strong>of</strong> PeVN<br />
SS neurons to produce the neuropeptide.<br />
In male and female rats, passive immunization with<br />
specific antisera to both peptides was used to assess the<br />
physiological roles <strong>of</strong> GHRH and SS in the dimorphic<br />
secretion (802). An acute dose <strong>of</strong> an anti-SS serum to<br />
males raised the GH nadir, as expected, but did not alter<br />
other parameters <strong>of</strong> GH secretion, whereas in females it<br />
markedly increased plasma GH levels at all time points <strong>of</strong><br />
the 6-h sampling period and there was, in addition, a<br />
significant increase in GH peak amplitude, GH nadir, and<br />
overall mean 6-h plasma GH levels. Anti-GHRH serum had<br />
no effect on the GH nadir in males but markedly raised<br />
the GH nadir in females.<br />
These findings led to the conclusion that the secretory<br />
pattern <strong>of</strong> SS undoubtedly plays an important role in<br />
this sexual dimorphism, the female pattern <strong>of</strong> SS secretion<br />
possibly being continuous rather than cyclical, its<br />
level intermediate between the peak and troughs <strong>of</strong> SS<br />
release suggested for males. The episodic GHRH bursting,<br />
which does not appear to follow a specific rhythm, as in<br />
the male, superimposed on the fairly continous SS release,<br />
would cause the erratic GH secretory pr<strong>of</strong>ile,<br />
present in the peripheral plasma <strong>of</strong> female rats.<br />
This pattern <strong>of</strong> low-amplitude GH release is reminiscent<br />
<strong>of</strong> that after continuous GH infusion and may be<br />
more effective in inducing specific biological changes,<br />
such as GH-binding protein in plasma and hepatic cytochrome<br />
P-450-containing enzymes (955). For the role <strong>of</strong><br />
sex steroids in imprinting the sexually differentiated GH<br />
secretory pattern, see also section IIIA8B.<br />
The pattern <strong>of</strong> GH secretion in rodents seems to be <strong>of</strong><br />
considerable importance for optimal growth. In female<br />
rats, GHRH pulses delivered every 3 h changed the pattern<br />
<strong>of</strong> pituitary GH release toward that <strong>of</strong> the male and<br />
stimulated body growth, whereas continuous infusions <strong>of</strong><br />
GHRH were much less effective (248). Interestingly, a<br />
similar pulsatile GH secretory pattern was achieved with<br />
the intermittent infusion <strong>of</strong> SS, which also stimulated<br />
body weight gain and increased pituitary GH stores (250).<br />
This strongly supports the proposal (246, 249) that in the<br />
rat the pulsatile pattern <strong>of</strong> GH is optimal for growth,<br />
irrespective <strong>of</strong> whether this pattern is achieved by a stimulator<br />
or inhibitor <strong>of</strong> endogenous GH secretion. The pulsatile<br />
delivery <strong>of</strong> SS would be vital in the generation <strong>of</strong> GH<br />
pulsatility not only for its opposing action to GHRH but<br />
also because it enables GHRH to be effective, because<br />
unopposed exposure to the releasing hormone leads to<br />
downregulation <strong>of</strong> GH responses.<br />
Sex differences in the pattern <strong>of</strong> GH secretion are not<br />
so clear-cut in humans, but there are noticeable quantitative<br />
differences, with serum GH concentrations being definitely<br />
higher in women than in men (221, 474, 1101). In a<br />
small group <strong>of</strong> healthy middle-aged men and premenopausal<br />
women, highly sensitive immun<strong>of</strong>luorometric assays<br />
(sensitivity 0.011 g/l) and blood sampling at 10-min<br />
intervals showed the 24-h GH secretion was three times<br />
higher in the women, the GH secretory episodes were<br />
larger and more prolonged, more GH was secreted per<br />
burst, and maximal plasma GH concentrations were<br />
higher than in men. The frequency <strong>of</strong> pulses, timing during<br />
the day/night estimates <strong>of</strong> baseline GH secretion, and the<br />
endogenous clearance rates for GH were the same in both<br />
sexes (1059) (Fig. 1).<br />
A sex-related difference was also found in the serial<br />
regularity <strong>of</strong> GH release in a tissue series (848). Application<br />
<strong>of</strong> novel regularity statistics (approximate entropy)<br />
showed that the serial regularity <strong>of</strong> GH release was lower<br />
in female humans and rats (847).<br />
Although E 2 is an obvious candidate for the mechanism<br />
that increases the mass <strong>of</strong> GH secreted per burst in<br />
women, it is not yet known at what level(s) in the GH axis<br />
it may act. Another question is whether the much higher<br />
daily GH output in women has biological significance for<br />
GH action, and what action this might have in middle age.<br />
In GH-deficient men and women, small but frequent intravenous<br />
boluses and continuous intravenous infusion <strong>of</strong><br />
GH were equally effective in increasing circulating IGF-I<br />
(532), which implies that women do not secrete more GH<br />
than men simply to maintain the same IGF-I levels.<br />
B. Age-Related <strong>Growth</strong> <strong>Hormone</strong> <strong>Secretion</strong><br />
The 24-h pattern <strong>of</strong> spontaneous GH release changes<br />
with age in experimental animals and humans. Plasma GH<br />
in the fetus is elevated compared with postnatal levels in<br />
a number <strong>of</strong> species, including humans and sheep (431).<br />
The rat, an altricial species, which is an animal model for<br />
the midgestational hypothalamic differentiation in humans,<br />
has a rise in plasma GH immediately before birth<br />
and a decline to near adult levels by 18–20 days postnatally<br />
(1078). This is coupled with striking changes in<br />
pituitary susceptibility to GHRH, which at doses <strong>of</strong> 1–50<br />
ng/100 g given subcutaneously in 10-day-old pups induces<br />
clear-cut plasma GH rises. However, in 25-day-old pups,
April 1999 NEUROENDOCRINE CONTROL OF GROWTH HORMONE SECRETION 515<br />
the dose <strong>of</strong> 500 ng/100 g given subcutaneoulsy has this<br />
effect but not lower doses (205) (see also sect. IIIA9).<br />
Moreover, in rat pups but not in young adult rats, an in<br />
vivo and ex vivo 5-day GHRH treatment stimulated pituitary<br />
GH biosynthesis (205, 272). Consonant with these<br />
results, in monolayer cultures <strong>of</strong> rat pituitary cells, the<br />
stimulatory effects <strong>of</strong> GHRH and dibutyryl cAMP on GH<br />
secretion were inversely related to age (281).<br />
Although differential developmental regulation <strong>of</strong> pituitary<br />
GHRH receptor gene expression is very likely<br />
involved in these events (572), maturational changes in<br />
the somatotroph responsiveness to SS may contribute to<br />
the pattern <strong>of</strong> circulating GH levels characteristic <strong>of</strong> early<br />
development. In fact, pituitaries from newborn rats are<br />
relatively resistant to the GH-suppressive effect <strong>of</strong> SS, and<br />
sensitivity increases with age (281, 889), although in rats<br />
brain SS mRNA is detectable by day 7 <strong>of</strong> embryonic life<br />
(1130a) and IR-SS has been detected in the fetal rat as<br />
early as 18.5 days <strong>of</strong> gestation (1130a).<br />
In the human fetus, plasma GH peaks at mid-gestation,<br />
then GH levels fall in the third trimester and into the<br />
neonatal period (540). Excessive GHRH or deficient SS<br />
release from and function in the fetal hypothalamus, excessive<br />
somatotroph responsiveness to GHRH, deficient<br />
negative feedback control by IGF-I, or stimulation <strong>of</strong> GH<br />
secretion by paracrine factors may account for GH hypersecretion<br />
at mid-gestation.<br />
Functional hypersomatotropism is still present in<br />
small for gestational age (SGA) newborn twins as revealed<br />
by higher baseline GH levels and stronger GH<br />
FIG. 1. Pr<strong>of</strong>iles <strong>of</strong> 24-h serum growth<br />
hormone (GH) in human female (top panels)<br />
and male (bottom panels) subjects. Left panels<br />
indicate measured serum GH concentrations<br />
over time and curve fitted by deconvolution<br />
analysis. Right panels depict GH<br />
secretory rate calculated from this analysis.<br />
[From van den Bergh et al. (1059); Copyright<br />
The Endocrine Society.]<br />
responses to GHRH than in appropriate gestational age<br />
(AGA) twins (302, 633). Interestingly, in these studies<br />
mean serum IGF-I was higher in SGA than in the AGA<br />
newborns, which would rule out any underlying effect <strong>of</strong><br />
a defective IGF-I feedback mechanism or functional GH<br />
resistance (see also sect. VI). <strong>Growth</strong> hormone-releasing<br />
hormone appears in the rat and human hypothalamus by<br />
18–20 days and 18–22 wk <strong>of</strong> gestation, respectively (292,<br />
514, 748), and at late gestation and mid-gestation, respectively,<br />
rat and human fetal pituitary cells respond in vitro<br />
to GHRH or SS by increasing or reducing GH secretion<br />
(559, 748). Miller et al. (725) studied changes occurring<br />
after birth in pulsatile GH release <strong>of</strong> male and female term<br />
infants. There were significant differences between infants<br />
studied at 28 h and later at 80 h postnatally.<br />
Spontaneous pulsatile release was present in all infants;<br />
within the first 1–2 days <strong>of</strong> life, GH release was enhanced<br />
through the amplitude and frequency <strong>of</strong> pulses, then as<br />
the infant matured, there was a decrease in GH frequency,<br />
amplitude, and nadir. The decrease in GH levels in older<br />
infants very likely resulted from decreased pituitary secretion,<br />
secondary to enhanced IGF-I hypothalamo-pituitary<br />
feedback or, as shown in the postnatal rat, to<br />
changes in the pituitary sensitivity to SS or GHRH.<br />
Considering that rats are born at the equivalent <strong>of</strong> 100<br />
gestational days in the human (559), the ontogeny <strong>of</strong><br />
neuroendocrine control and GH secretion in the human is<br />
chronologically consistent with that in the rat.<br />
In initial studies <strong>of</strong> the 24-h pattern <strong>of</strong> spontaneous<br />
GH secretion, a small sample <strong>of</strong> prepubertal children
516 MÜLLER, LOCATELLI, AND COCCHI Volume 79<br />
lacked waking GH peaks and secreted GH only during<br />
sleep (356). This observation, however, contrasted with<br />
many subsequent reports <strong>of</strong> GH peaks during waking<br />
hours as well as during sleep (726, 978). Deconvolution<br />
analysis depicted the pattern <strong>of</strong> GH secretory events subserving<br />
the changes in serum GH concentrations in normal<br />
boys at various stages <strong>of</strong> puberty and young adulthood<br />
(660). Late pubertal boys secreted more GH per 24 h<br />
than boys in any other pubertal group and triple that <strong>of</strong><br />
prepubertal boys (1,800 vs. 600 g/24 h). After normalization<br />
<strong>of</strong> GH secretion for body surface area, late pubertal<br />
boys still had higher GH release than any other pubertal<br />
group. The primary neuroendocrine alteration responsible<br />
for the enhanced GH secretion was an increased mass<br />
<strong>of</strong> GH released per secretory burst, with no change in GH<br />
burst frequency, burst duration, or serum GH half-life.<br />
In girls, GH responses to GHRH did not change<br />
throughout pubertal development, and the responses in<br />
boys at midpuberty were somewhat lower than either<br />
prepubertal or adult men (395). It cannot be excluded,<br />
however, that periodic release <strong>of</strong> SS might have obscured<br />
the genuine GH response to GHRH at puberty.<br />
In young adults, total GH secretion was almost onehalf<br />
that in late pubertal boys (900 g/24 h), but the 24-h<br />
burst frequency was the same. This figure compares favorably<br />
with reports based on other techniques (574, 694).<br />
However, absolute GH secretion rates estimated by deconvolution<br />
analysis are dependent on the specific assay<br />
system, and the values reported here tend to overestimate<br />
GH secretion compared with the more recent and sensitive<br />
assays. Studies in which a large number <strong>of</strong> prepubertal<br />
and pubertal girls and boys were evaluated for GH<br />
secretion using the Pulsar program (713) found no correlation<br />
between GH secretion and age in the prepubertal<br />
children, supporting the proposal that gonadal hormones<br />
are not important for the regulation <strong>of</strong> growth and GH<br />
secretion during childhood, whereas at puberty there was<br />
a marked increase in GH secretion rates in both sexes<br />
(23). However, the change was sex specific, since the<br />
increase in GH secretion rate was an early event (stages<br />
2–4) in puberty for girls but a late event (stages 3–4) in<br />
puberty for boys, parallel to the height velocity curves <strong>of</strong><br />
girls and boys in puberty (1019). Shortly after cessation <strong>of</strong><br />
linear growth in boys, the overall peripheral GH pulse<br />
pattern returned toward prepubertal levels so that the<br />
concentration pr<strong>of</strong>iles in young men were remarkably<br />
similar to those in prepubertal boys despite the rising<br />
testosterone concentrations (661).<br />
The gonadal hormones, particularly circulating androgens,<br />
appear to play a central role in the GH pulse<br />
amplitude changes (619, 661). However, androgens alone<br />
do not seem to account entirely for the pubertal increase<br />
in GH pulse amplitude in humans, in view <strong>of</strong> the pattern in<br />
young men (see above), and although ample data in rats<br />
support it (see Ref. 970), the evidence that testosterone is<br />
involved in the control <strong>of</strong> GH secretion in humans is not<br />
so clear. To explain these discrepant findings, it would<br />
seem, however, that testosterone itself has little or no<br />
effect and that it is the estradiol derived from aromatization<br />
<strong>of</strong> testosterone that increases GH secretion (1065).<br />
This is suggested by the potent action <strong>of</strong> physiological<br />
amounts <strong>of</strong> E 2 in stimulating pulsatile GH secretion and<br />
the fact that nonsteroidal anti-E 2 inhibits it (see Ref. 557<br />
for review).<br />
However, apart from conversion to E 2, a role for<br />
androgens cannot be dismissed. In prepubertal boys with<br />
constitutional delayed growth, both testosterone and the<br />
nonaromatizable androgen oxandrolone raised the daily<br />
GH secretory rate by specifically increasing the total mass<br />
<strong>of</strong> GH released per pulse, with no effect on GH burst<br />
frequency or the half-life <strong>of</strong> endogenous GH (1045). Supporting<br />
these findings, an increase in GH in response to<br />
GHRH was suggested in one study <strong>of</strong> boys with constitutional<br />
growth delay treated with oxandrolone for 2 mo<br />
(633), and increased plasma IGF-I concentrations have<br />
also been reported (980). In boys with isolated hypogonadotropic<br />
hypogonadism, progressively higher testosterone<br />
doses, which affected plasma E 2 levels, increased the<br />
GH secretory burst number and amplitude and GH response<br />
to combined GHRH and arginine (427).<br />
The effect <strong>of</strong> endogenous estradiol concentrations on<br />
total and pulsatile GH release in humans also emerges<br />
from a study that evaluated the separate and combined<br />
effects <strong>of</strong> age and sex in young adults and aged women<br />
and men (474). The integrated GH concentration was<br />
significantly higher in women than men and in the young<br />
than the old. A major finding was that estradiol but not<br />
testosterone concentrations correlated with indices <strong>of</strong><br />
total and pulsatile GH release, i.e., integrated GH concentration<br />
(IGHC), pulse amplitude, number <strong>of</strong> large pulses,<br />
and fraction <strong>of</strong> GH secreted per pulse (FGHP) so that on<br />
removing the variability due to free estradiol, neither sex<br />
nor age influenced IGHC or mean pulse amplitude. The<br />
finding, however, that aging still affected the residual<br />
variability, i.e., large pulses and FGHP, indicated that<br />
other factors in addition to E 2 contribute.<br />
That aging lowers GH secretion in mammals is almost<br />
a tenet <strong>of</strong> neuroendocrinology (754). In male and<br />
female rats, the amplitude <strong>of</strong> the GH pulses is significantly<br />
smaller, and in male rats, this results in lower mean<br />
secretion <strong>of</strong> GH to about one-third that in young rats. In<br />
both female and male old rats, the frequency <strong>of</strong> GH pulses<br />
does not change with age (970). In humans, the mean<br />
concentration <strong>of</strong> GH over 24 h is similar after the fourth<br />
decade <strong>of</strong> life to that in prepubertal children and is about<br />
one-quarter <strong>of</strong> that in pubertal youngsters (1120). In addition,<br />
approximate entropy analysis in healthy aging men<br />
revealed a progressive increase in the entropy <strong>of</strong> 24-h GH<br />
pr<strong>of</strong>iles, which signifies less orderliness or regularity <strong>of</strong><br />
GH release with age (1064).
April 1999 NEUROENDOCRINE CONTROL OF GROWTH HORMONE SECRETION 517<br />
These findings complement earlier reports <strong>of</strong> substantial<br />
changes in GH secretion in the aging human (169).<br />
Despite evidence <strong>of</strong> a preserved pituitary GH pool (see<br />
sect. VB3) and the strong belief that, as in old rodents, the<br />
primary disturbance is hypothalamic, a low GH response<br />
has been clearly shown to many secretagogues, including<br />
GHRH (406, 478). In agreement with the GH hyposecretion,<br />
decreased plasma IGF-I levels have also been found<br />
(see sect. IVD1). However, investigations on this topic are<br />
not unanimous in reporting a decline in GH release with<br />
age, and it has been suggested that a significant decline<br />
occurs only in women (see above and Ref. 474). In a study<br />
in 142 healthy elderly people <strong>of</strong> both sexes, aged 60–90 yr,<br />
basal GH levels showed a very weak positive correlation<br />
with age, whereas IGF-I showed a highly significant negative<br />
correlation; basal GH and IGF-I did not correlate<br />
with each other (518).<br />
It is likely that other counfounding variables, such as<br />
institutionalization, body mass, nutritional status, and sex<br />
steroid hormone concentrations, exert either independent<br />
or combined effects on total and pulsatile GH release. To<br />
control some <strong>of</strong> the confounding variables, a group <strong>of</strong><br />
normal adult males was studied using deconvolution analysis<br />
to clarify the specific features <strong>of</strong> GH secretion and<br />
clearance related to age and adiposity, alone or jointly<br />
(509). Age was a major negative statistical determinant <strong>of</strong><br />
GH burst frequency and endogenous GH half-life; body<br />
mass index (BMI), an indicator <strong>of</strong> relative adiposity, correlated<br />
negatively with GH half-life and GH secretory<br />
burst amplitude. Age and BMI both correlated negatively<br />
with the daily GH secretion rate and together accounted<br />
for 60% <strong>of</strong> the variability in 24-h GH production and<br />
clearance rates. On average, it was estimated that for a<br />
normal BMI, each decade <strong>of</strong> increasing age reduced the<br />
GH production rate by 14% and the GH half-life by 6%.<br />
Each unit increase in BMI, at a given age, reduced the<br />
daily GH secretion rate by 6%.<br />
Thus a logical corollary is that age, sex, pubertal<br />
status, BMI or other indices <strong>of</strong> adiposity, quality and<br />
quantity <strong>of</strong> sleep, medication use, and physical exercise<br />
are but a few <strong>of</strong> the confounding factors that must be<br />
considered in the design and interpretation <strong>of</strong> clinical<br />
studies.<br />
For patterns <strong>of</strong> GH secretion in different pathophysiological<br />
contexts such as fasting, exercise, type I diabetes<br />
mellitus, obesity, see the corresponding sections.<br />
C. Sleep<br />
It has long been recognized that GH release increases<br />
during the night (498, 1003) and nocturnal blood sampling<br />
for GH has been proposed as a diagnostic alternative to<br />
pharmacological testing <strong>of</strong> GH secretory capacity (470,<br />
560). Early studies indicated a consistent relationship<br />
between slow-wave sleep (SWS) and GH secretion during<br />
early sleep and later during the night (503). Subsequent<br />
studies, with 30-s sampling <strong>of</strong> plasma GH during sleep,<br />
showed mean GH concentrations and secretory rates<br />
were significantly higher during stage 3 and 4 sleep than<br />
during stages 1 and 2 and rapid-eye-movement (REM)<br />
sleep. <strong>Growth</strong> hormone secretory rates and peripheral GH<br />
concentrations were maximally correlated with sleep<br />
stage in a fashion suggesting that GH release is maximal<br />
within minutes <strong>of</strong> the onset <strong>of</strong> stage 3 or 4 sleep (486). The<br />
temporal correlation between pituitary GH secretion and<br />
SWS is consistent with a model in which altered cortical<br />
activity is transmitted through GHRH and SS centers to<br />
the hypothalamus, and further stimulation by these centers<br />
is conveyed to the pituitary.<br />
These findings supported the concept that the daily<br />
GH secretory output is dependent on the quality and<br />
occurrence <strong>of</strong> sleep and were consistent with results <strong>of</strong><br />
sleep reentry and SWS deprivation studies (923). However,<br />
a series <strong>of</strong> reports, e.g., pronounced nocturnal GH<br />
surges divorced from the presence <strong>of</strong> SWS (526), selective<br />
SW stage deprivation failing to suppress or delay the<br />
sleep-onset GH pulse (126), temporal disconnection between<br />
the effect <strong>of</strong> GHRH on SWS and on GH release<br />
(984), challenged this concept and suggested that GH and<br />
SWS are not causally related but are two independent<br />
outputs <strong>of</strong> a common hypothalamic GHRH mechanism.<br />
However, studies in human African trypanosomiasis<br />
(sleeping sickness) have shown that the association between<br />
GH secretion and SWS persisted despite disrupted<br />
circadian rhythms (871), further suggesting that sleep and<br />
stimulation <strong>of</strong> GH secretion are outputs <strong>of</strong> a common<br />
mechanism.<br />
A careful study in healthy young men examined how<br />
normal and delayed sleep and time <strong>of</strong> day affected pulsatile<br />
GH secretion, analyzed by the deconvolution method<br />
and blood sampling at 15-min intervals (1054). During<br />
normal waking hours, the GH secretory rate was similar<br />
in the evening and morning, double during wakefulness at<br />
times <strong>of</strong> habitual sleep, and tripled during sleep even<br />
when it was delayed until 0400 h. Interestingly, the<br />
amount <strong>of</strong> GH secreted in response to sleep onset was<br />
closely correlated with the levels during wakefulness,<br />
with the hourly GH output in these young men being two<br />
to three times greater when asleep than when awake.<br />
Although these results demonstrated that SWS facilitates<br />
GH secretion, they did not show that SWS is obligatory<br />
for nocturnal GH secretion to occur. Approximately<br />
one-third <strong>of</strong> the nocturnal GH pulses occurred in the<br />
absence <strong>of</strong> SWS, and approximately one-third <strong>of</strong> the SWS<br />
periods were not associated with increased GH secretion.<br />
Thus circadian timing, regardless <strong>of</strong> sleep, influences somatotrophic<br />
activity, although under normal conditions<br />
sleep occurs at the time <strong>of</strong> maximal propensity for GH
518 MÜLLER, LOCATELLI, AND COCCHI Volume 79<br />
secretion, with circadian and sleep effects being superimposed.<br />
In a sequel to these studies, GHRH or saline was<br />
administered intravenously to young healthy men at various<br />
times <strong>of</strong> day and stages <strong>of</strong> sleep. When injected<br />
during the waking hours, GHRH elicited a response<br />
whose magnitude was directly related to the amount <strong>of</strong><br />
spontaneous GH secretion, negatively correlated with circulating<br />
levels <strong>of</strong> IGF-I and was not influenced by time <strong>of</strong><br />
day. The response was greater when GHRH was given<br />
during SWS, whereas when GHRH was given during REM,<br />
it was similar to that observed during waking. This suggests<br />
that the two sleep stages may be associated with<br />
reduced and enhanced SS secretion, respectively. Awakenings<br />
during sleep consistently inhibited the secretory<br />
response to GHRH, which reappeared with resumption <strong>of</strong><br />
sleep (1053).<br />
Because the intersubject variability in GH responses<br />
was very wide but the response was quite reproducible<br />
for each subject, it would seem that there is no diurnal<br />
variation in the sensitivity to exogenous GHRH and that<br />
the GH response to GHRH is dependent on the sleep or<br />
waking condition, circulating levels <strong>of</strong> IGF-I and, possibly,<br />
genetic and life-style factors.<br />
For the electrophysiological effects <strong>of</strong> GHRH and<br />
GHRP, see sections IIIA10 and IVC.<br />
III. HYPOPHYSIOTROPIC HORMONES<br />
A. <strong>Growth</strong> <strong>Hormone</strong>-Releasing <strong>Hormone</strong><br />
1. General background<br />
The regulation <strong>of</strong> GH secretion has been the focus <strong>of</strong><br />
research since Reichlin’s pioneering observation in 1960<br />
(879) in the rat that surgical destruction <strong>of</strong> the ventromedial<br />
hypothalamus slows growth velocity. Parallel to the<br />
identification and sequencing <strong>of</strong> most <strong>of</strong> the other hypothalamic<br />
regulatory hormones at the end <strong>of</strong> the 1960s and<br />
during the 1970s was the discovery <strong>of</strong> the GH release<br />
inhibiting hormone SS, the principal modulator <strong>of</strong> GH<br />
secretion (141).<br />
Although the possibility had been advanced that<br />
changes in SS secretion might account for all the hypothalamic<br />
influences on GH secretion, a hypothalamic<br />
stimulating hormone was needed. <strong>Growth</strong> hormone-releasing<br />
factor or GHRH was only identified and sequenced<br />
10 years after SS.<br />
The identification <strong>of</strong> GHRH represented an exception<br />
to the rule, since this neuropeptide is unique among regulatory<br />
hormones in that it was first isolated (1121) and<br />
sequenced (447, 892) from human and not animal tissue,<br />
and, secondly, not from the hypothalamus but from pancreatic<br />
islet tumors, in which the ectopic secretion was<br />
associated with hypersecretion <strong>of</strong> GH and acromegaly<br />
(376).<br />
The discovery <strong>of</strong> GHRH has been reviewed extensively<br />
(see Refs. 274, 749) and is only briefly alluded to<br />
here. <strong>Growth</strong> hormone-releasing hormone was isolated in<br />
1982 from two patients in whom pancreatic tumors had<br />
caused acromegaly. From one <strong>of</strong> these tumors a 40-amino<br />
acid peptide designated human pancreatic growth hormone-releasing<br />
factor hpGRF-(1O40) was isolated (892), 1<br />
and three GHRH peptides, GHRH-(1O44)-NH 2, GHRH-<br />
(1O40)-OH, and GHRH-(1O37)-OH, were sequenced<br />
from the other tumor (450). Structure-activity relationships<br />
showed that the NH 2-terminal 29 residues <strong>of</strong> GHRH-<br />
(1O40)-OH have biological activity and indicated that<br />
although the NH 2-terminal portion <strong>of</strong> the molecule is involved<br />
in binding to the receptor, the COOH-terminal<br />
portion is critical in regulating the potency <strong>of</strong> GHRH.<br />
Two <strong>of</strong> the three GHRH forms found in tumors were<br />
subsequently identified in human hypothalamus [GHRH-<br />
(1O44)-NH 2 and GHRH-(1O40)-OH] and differed only by<br />
the absence in the latter <strong>of</strong> the four COOH-terminal amino<br />
acid residues (613, 617). Identification <strong>of</strong> the GHRH sequence<br />
in pigs, goats, sheep, and cattle has shown the<br />
existence <strong>of</strong> the 44-amino acid form amidated at the<br />
COOH terminal (617). Rat hypothalamic GHRH (rGHRH)<br />
contains 43 amino acids with a free acidic group. In<br />
addition, rGHRH is structurally different from the other<br />
GHRH peptides [14 amino acid substitutions or deletions<br />
compared with GHRH-(1O44)] (see Refs. 756, 979).<br />
<strong>Growth</strong> hormone-releasing hormone belongs to an<br />
expanding family <strong>of</strong> brain-gut peptides that includes glucagon,<br />
glucagon-like peptide I (GLP-I), vasoactive intestinal<br />
polypeptide (VIP), secretin, gastric inhibitory peptide<br />
(GIP), a peptide with histidine as NH 2 terminus and isoleucine<br />
as COOH terminus (PHI), and pituitary adenylate<br />
cyclase-activating peptide (PACAP) (160).<br />
2. Synaptic communication in the hypothalamus<br />
The availability <strong>of</strong> GHRH-(1O40)-OH and GHRH-<br />
(1O44)-NH2 means the topography <strong>of</strong> GHRH neurons<br />
could be established in humans and a number <strong>of</strong> animal<br />
species (see Ref. 756 for review). There are slight species<br />
differences in GHRH distribution. <strong>Growth</strong> hormone-releasing<br />
hormone IR is present mostly in the basal hypothalamus<br />
and is appropriate anatomically for release into<br />
the pituitary portal vasculature. In early studies, GHRH<br />
antisera stained neuronal cell bodies in the ARC (infundibular<br />
nucleus) <strong>of</strong> squirrel monkeys and humans with<br />
1 The conclusion that the material <strong>of</strong> hypothalamic origin was<br />
identical to the previously identified tumor-derived GRF avoided the<br />
need to keep the nomenclature human pancreatic GRF or the abbreviation<br />
‘‘hpGRF’’; the abbreviation GHRH will be used in the text and to<br />
refer to any <strong>of</strong> the active sequences. The term somatocrinin was proposed<br />
to replace GHRH, but has not been widely accepted.
April 1999 NEUROENDOCRINE CONTROL OF GROWTH HORMONE SECRETION 519<br />
fibers projecting to the ME and ending in close contact<br />
with the portal vessels (114). Studies in macaques and<br />
squirrel monkeys revealed GHRH-IR neurons also in the<br />
ventromedial nucleus (VMN) (114), where GH release<br />
may be increased by electrical stimulation (664). These<br />
neurons were also seen in the rat hypothalamus (708 and<br />
see below).<br />
In the rat, GHRH-positive perikarya were located in<br />
the following regions: ARC from the rostral portion as far<br />
caudally as the pituitary stalk, medial perifornical region<br />
<strong>of</strong> the lateral hypothalamus, lateral basal hypothalamus,<br />
paraventricular nucleus (PVN) and dorsomedial nucleus<br />
(DMN), and the medial and lateral borders <strong>of</strong> the VMN<br />
(708). Immunocytochemical studies in humans showed a<br />
similar distribution <strong>of</strong> GHRH-positive perikarya, mainly<br />
within, above, and lateral to the infundibular nucleus. In<br />
addition, some GHRH staining cells were found in the<br />
perifornical region and in the periventricular zone (114,<br />
115).<br />
Careful charting <strong>of</strong> the distribution <strong>of</strong> GHRH-IR in the<br />
brain <strong>of</strong> adults rats was consistent with at least two<br />
distinct GHRH-containing systems, one responsible for<br />
delivery <strong>of</strong> the peptide to portal vessels in the ME and one<br />
whose relationship to hypophysiotropic function was less<br />
direct (see sect. IIIA10).<br />
<strong>Growth</strong> hormone-releasing hormone neurons innervating<br />
the external layer <strong>of</strong> the ME were centered in the<br />
ARC on each side <strong>of</strong> the brain, whereas the other GHRHstained<br />
cells, very likely contributing to the extrahypophysiotropic<br />
GHRH-stained projections, were in the<br />
caudal aspect <strong>of</strong> the VMN. From here, GHRH fibers could<br />
be traced projecting to the periventricular region <strong>of</strong> the<br />
hypothalamus including the preoptic and anterior part,<br />
where SS-containing neurons are clustered (see below<br />
and sect. IIIB1). Other important terminal fields were<br />
found in discrete parts <strong>of</strong> the DMN, PVN, suprachiasmatic<br />
nucleus (SCN), and premammillary nuclei and the MPOA<br />
and lateral hypothalamic area. Beyond the hypothalamus,<br />
sparse projections were traced to the lateral septal nuclei,<br />
the bed nucleus <strong>of</strong> the stria terminalis, and the medial<br />
nucleus <strong>of</strong> the amygdala (926). <strong>Growth</strong> hormone-releasing<br />
hormone projections in the amygdala, a part <strong>of</strong> the visceral<br />
brain involved in emotion and responses to stress,<br />
may account for GH responses elicited by electrical stimulation<br />
<strong>of</strong> this area in rats (663) or humans (639) and<br />
suggest the amygdala in humans may be part <strong>of</strong> the pathways<br />
responsible for stress-induced GH release.<br />
Immunohistochemical (292, 514) and RIA (525) measurements<br />
indicated that GHRH is first detectable at embryonic<br />
days 18–20 in the rat, reaching adult levels at<br />
postnatal day 30 (525), and in situ hybridization has<br />
detected GHRH mRNA 1 day earlier (896). In the human<br />
fetus, ontogenetic studies detected GHRH neurons between<br />
18 and 29 wk <strong>of</strong> gestation (115, 143). These figures<br />
are on the whole consistent with the appearance <strong>of</strong> fetal<br />
pituitary somatotropes and GH storage and release in<br />
plasma (see sect. IIB).<br />
Colocalization studies in the rat using radioimmunologic,<br />
immunohistochemical, and in situ hybridization<br />
techniques indicated that a subset <strong>of</strong> GHRH neurons in<br />
the ventrolateral part <strong>of</strong> the ARC contains a large number<br />
<strong>of</strong> molecules including tyrosine hydroxylase (TH), the key<br />
enzyme <strong>of</strong> catecholamine (CA) biosynthesis, GABA, choline<br />
acetyltransferase (ChAT), the ACh synthesizing enzyme,<br />
neurotensin (NT), and galanin (GAL) (see Refs. 697,<br />
756 for review) (Fig. 2). From a functional viewpoint,<br />
particularly important colocalizations are with NT, ChAT,<br />
and GAL, in view <strong>of</strong> the clear involvement <strong>of</strong> these compounds<br />
in GH release (see sect. VB). Other studies have<br />
shown colocalization <strong>of</strong> GHRH with neuropeptide Y<br />
(NPY), in neurons which do not project to the external<br />
layer <strong>of</strong> the ME but constitute a tubero-extra-infundibular<br />
system, not involved in direct control <strong>of</strong> the AP, but<br />
presumably having a neuromodulatory function (see Ref.<br />
243 and sect. VB6).<br />
Direct pro<strong>of</strong> that cells in the ventrolateral ARC are<br />
likely to be the main source <strong>of</strong> GHRH-containing projections<br />
to the ME has been provided using a combination <strong>of</strong><br />
retrograde tract-tracing and immunocytochemistry in normal<br />
and GH-deficient dwarf mice (902). Inferential evidence<br />
had been provided with the use <strong>of</strong> monosodium<br />
glutamate (MSG), a neurotoxic substance which destroys<br />
about 80–90% <strong>of</strong> the cell bodies in the ARC (794), without<br />
significantly injuring other hypothalamic regions or axons<br />
<strong>of</strong> passage. Injection <strong>of</strong> MSG into rats resulted in the<br />
virtually complete disappearance <strong>of</strong> GHRH-stained fibers<br />
in the ME (115), stunted skeletal growth, and severe<br />
obesity. Interestingly, these changes were combined with<br />
marked decreases in ME-stained fibers containing GAL,<br />
the GABA synthesizing enzyme, glutamic acid decarboxylase<br />
(GAD), dynorphin, and enkephalins, but not those<br />
containing SS and NPY, meaning these peptides do not<br />
project to the ME (NPY) or to the ME from another source<br />
(SS) (696, see also sect. IIIB1).<br />
All in all, the localization <strong>of</strong> GHRH-IR neurons mainly in<br />
the ARC and in the capsule surrounding the VMN is consistent<br />
with the results <strong>of</strong> stimulation and ablation studies that<br />
implicate the medial basal hypothalamus (MBH) in the stimulatory<br />
control <strong>of</strong> GH secretion (see Ref. 749).<br />
3. <strong>Growth</strong> hormone-releasing hormone-somatostatin<br />
interactions<br />
The neuronal systems regulating GHRH and SS release<br />
receive a variety <strong>of</strong> neural inputs, many <strong>of</strong> which are<br />
described fully in the next few sections. Here it already<br />
seems appropriate to look at the anatomic and functional<br />
interactions occurring between GHRH and SS neurons,<br />
which are so important for understanding many aspects<br />
<strong>of</strong> GH control.
520 MÜLLER, LOCATELLI, AND COCCHI Volume 79<br />
FIG. 2. Schematic drawing illustrating distribution <strong>of</strong> neuroactive compounds in different parts <strong>of</strong> arcuate nucleus<br />
as well afferents to median eminence (ME). Anatomic abbreviations: DM, dorsomedial; MO, medulla oblongata; MPOA,<br />
medial preoptic area; Pe, periventricular nucleus; pVN, parvocellular paraventricular nucleus; VM, ventromedial; VL,<br />
ventrolateral; 3V, third ventricle. Abbreviations for neurotransmitters and peptides: CCK, cholecystokinin; ChAT, choline<br />
acetyltransferase; CRF, corticotropin-releasing factor; DA, dopamine; DYN, dynorphin; E, epinephrine; ENK, enkephalin;<br />
GAL, galanin; GRF, growth hormone-releasing factor; LHRH, luteinizing hormone-releasing hormone; NPK, neuropeptide<br />
K; NPY, neuropeptide Y; NT, neurotensin; NE, norepinephrine; POMC, proopiomelanocortin; SOM, somatostatin; SP,<br />
substance P; TRH, thyrotropin-releasing hormone; VP, vasopressin; TH, tyrosine hydroxylase. [From Meister et al. (697),<br />
with permission from Elsevier Science.]<br />
The organization <strong>of</strong> hypothalamic SS-containing neurons<br />
is essentially similar in all mammalian species studied<br />
so far, including humans (see sect. IIIB1). Most hypothalamic<br />
areas contain an extensive network <strong>of</strong> SScontaining<br />
fibers, and there are IR-SS perikarya in the<br />
anterior periventricular area and the parvocellular portion<br />
<strong>of</strong> the PVN and in the SCN, ARC, and VMN. Combined<br />
retrograde tracing and immunohistochemistry showed<br />
that up to 78% <strong>of</strong> periventricular neurons project to the<br />
external layer <strong>of</strong> the ME, and other hypothalamic neurons<br />
do not innervate this neurohemal organ (555). The SS<br />
axons and perikarya in the ARC and VMN, two areas from<br />
which GHRH neurons originate, indicate the existence <strong>of</strong><br />
anatomic and functional peptide interactions. Immunocytochemical<br />
double-labeling studies located SS-producing<br />
neurons in the dorsomedial part <strong>of</strong> the rat ARC and found<br />
SS-IR axons in the lateral part <strong>of</strong> the nucleus, an area<br />
containing GHRH-synthesizing cells (622). Several somatostatinergic<br />
axon varicosities were clustered around single<br />
GHRH synthesizing cells, suggesting synaptic associations.<br />
In the external layer <strong>of</strong> the ME, axonal terminals<br />
immunolabeled for GHRH and SS had the same pattern <strong>of</strong><br />
distribution and close proximity.<br />
More morphological pro<strong>of</strong> <strong>of</strong> SS-GHRH interactions<br />
in the ARC was provided by autoradiography studies<br />
showing a selective association <strong>of</strong> 125 I-labeled SS binding<br />
sites with a subpopulation <strong>of</strong> cells, concentrated rostrocaudally<br />
in the lateral portion <strong>of</strong> the ARC; their distribution<br />
was remarkably similar to that <strong>of</strong> GHRH-IR neurons<br />
(338). That at least some SS receptors may be directly<br />
linked to GHRH-containing cells was demonstrated in<br />
colocalization autoradiography and immunohistochemistry<br />
studies in which 30% <strong>of</strong> the IR-GHRH cells labeled<br />
with 125 I-SS in sections adjacent to GHRH cells in extra-<br />
ARC regions did not show SS binding (690). Interestingly,<br />
most <strong>of</strong> the GHRH-SS colabeled cells were detected in the<br />
ventrolateral region <strong>of</strong> the ARC, where there is a dense<br />
fiber network <strong>of</strong> SS-nerve terminals (see above).<br />
An ultradian pattern has also been reported in SS<br />
binding to ARC neurons in relation to the peaks and<br />
troughs <strong>of</strong> the GH rhythm (1010), although the changes<br />
were in the direction opposite those expected. Further
April 1999 NEUROENDOCRINE CONTROL OF GROWTH HORMONE SECRETION 521<br />
direct evidence <strong>of</strong> cellular colocalization <strong>of</strong> SS receptors<br />
and GHRH-producing cells within the ARC was provided<br />
by in situ hybridization studies showing that in the ventrolateral<br />
portion <strong>of</strong> the ARC GHRH mRNA labeled neurons<br />
had the same distribution as 125 I-SS labeled cells (97)<br />
(Fig. 3). For the SS receptor subtypes involved, see section<br />
IIIB2.<br />
Two other cell types could be identified in these<br />
studies: GHRH perikarya, around the perimeter <strong>of</strong> the<br />
VMN not associated with pericellular SS binding sites, and<br />
very likely containing substance P and enkephalin-8 bind-<br />
FIG. 3. Schematic drawings <strong>of</strong> rat arcuate<br />
nucleus (ARC) comparing distribution <strong>of</strong><br />
prepro-growth hormone-releasing hormone<br />
(GHRH) mRNA-containing neurons (left) and<br />
125 I-SRIH-labeled cells (right) on adjacent 5-mthick<br />
cryostat coronal sections <strong>of</strong> rat mediobasal<br />
hypothalamus at 3 anatomic levels (interaural<br />
line: 6.70, 6.20, and 5.70 mm according to<br />
Paxinos and Watson, 1986). ARC was separated<br />
in three parts [lateral (L), ventrobasal (VB), and<br />
periventricular (PV)]. e, GHRH-producing cells<br />
coidentified as 125 I-SRIH labeled; , 125 I-SRIHlabeled<br />
cells; ●, 125 I-SRIH-labeled cells coidentified<br />
as GHRH-synthesizing cells. Each symbol<br />
represents 3 labeled cells. [From Bertherat et al.<br />
(97).].<br />
ing sites (282), and 125 I-SS labeled cells not associated<br />
with GHRH perikarya, in the periventricular zone along<br />
the dorsal part <strong>of</strong> the third ventricle, probably associated<br />
with -endorphin- (558) or TH-producing (484) cells.<br />
With regard to GHRH inputs to SS-IR neurons, only a<br />
few <strong>of</strong> these neurons were closely approached by GHRH-<br />
IR fibers, indicating that SS neurons are only scantly<br />
innervated by GHRH cells (1098) and suggesting the relative<br />
independence <strong>of</strong> SS from GHRH.<br />
The data reported provide strong morphological support<br />
for a direct hypothalamic control <strong>of</strong> GHRH neurons
522 MÜLLER, LOCATELLI, AND COCCHI Volume 79<br />
by SS and for the concept that the two hypophysiotropic<br />
peptides interact within the central nervous system (CNS)<br />
to modulate GH secretion (see also sect. II). A wealth <strong>of</strong><br />
physiological evidence bears witness to the interaction,<br />
including a rapid increase in plasma GH after intracerebroventricular<br />
administration <strong>of</strong> SS to anesthetized (2) or<br />
awake rats (641), depending at least in part on hypothalamic<br />
GHRH (762); increased GHRH concentrations in<br />
hypophysial portal blood after intracerebroventricular administration<br />
<strong>of</strong> SS antiserum (853); elevated basal GH<br />
levels, which can be reduced by anti-GHRH serum after<br />
lesions <strong>of</strong> the hypothalamic MPOA (548); and triggering <strong>of</strong><br />
GH secretion through a mechanism involving GHRH, after<br />
acute withdrawal <strong>of</strong> endogenous (722) or exogenous SS<br />
(210, 244, 964). For the GHRH-SS interactions in ultrashort<br />
feedback mechanisms, see section IIIB2.<br />
4. Distribution outside the CNS<br />
Like other neuropeptides originally described as primarily<br />
<strong>of</strong> hypothalamic origin, GHRH has also been found<br />
in peripheral tissue, although its physiological role as an<br />
extrahypothalamic hormone, in addition to stimulating<br />
GH secretion, is far from clear. Activity <strong>of</strong> GHRH outside<br />
the brain was initially only found in neoplastic tissues<br />
producing GHRH (see sect. IIIA1). However, the hormone<br />
was then seen in the upper intestine, particularly in the<br />
jejunum, with smaller amounts in the duodenum. None<br />
was found in the ileum or colon. The peptide was confined<br />
to the epithelial mucosa, suggesting a possible endocrine<br />
role. In addition to the gastrointestinal tract,<br />
mRNA for GHRH was found in leukocytes, where GHRH<br />
inhibits human natural killer cell activity (819) and also<br />
affects human leukocyte migration (1126), in the testis<br />
(94), ovary (65), and placenta (657). In the rat testis, the<br />
estimated size <strong>of</strong> GHRH-like immunoreactivity (GHRH-LI)<br />
was 3.7 times that <strong>of</strong> synthetic GHRH (831), and it was<br />
found in the interstitial tissue (740) and in mature germ<br />
cells (831), its function being to amplify the action <strong>of</strong> GH<br />
on Leydig cells (steroidogenesis) and <strong>of</strong> follicle-stimulating<br />
hormone on Sertoli cells (cAMP formation) (240). In<br />
view <strong>of</strong> the existence <strong>of</strong> a blood-testis barrier and the<br />
abundance <strong>of</strong> GHRH in rat testis, it presumably acts as an<br />
autocrine or paracrine factor.<br />
In the rat placenta, GHRH mRNA is distinct from that<br />
described from the hypothalamus, and placental GHRH is<br />
synthesized in the cytotrophoblast (657). Cells expressing<br />
GHRH are located differently in the mouse placenta (992).<br />
The GHRH peptide and mRNA have also been identified in<br />
the human placenta (95). Placental GHRH may have a role<br />
in regulating fetal pituitary somatotrophs (445) and placental<br />
growth factors in an autocrine and/or paracrine<br />
fashion (476). Initial studies in the somatotrophs found<br />
IR-GHRH in secretory granules and the nuclei (738), and<br />
others found it internalized in another intracellular compartment<br />
(705).<br />
5. Gene structure and expression<br />
Pancreatic tumors from which the GHRH peptide<br />
was purified provided the mRNA source for the construction<br />
<strong>of</strong> libraries from which cDNA encoding the human<br />
GHRH precursor could be isolated (444, 685). A rat GHRH<br />
cDNA was isolated directly from a hypothalamic library<br />
(681). Using cDNA to screen human genomic libraries<br />
resulted in the elucidation <strong>of</strong> the human GHRH gene<br />
(682), and the rat and mouse GHRH genes have also been<br />
identified in the genome (991).<br />
Like most small peptides, GHRH is generated by the<br />
proteolytic processing <strong>of</strong> a larger precursor protein. This<br />
is a single copy in the human genome, and it has been<br />
mapped to the p12 band <strong>of</strong> chromosome 20 in the human<br />
(682) and chromosome 2 in the mouse (433). The gene<br />
includes five exons spanning 10 kb <strong>of</strong> DNA, with clear<br />
segregation <strong>of</strong> the functional domains <strong>of</strong> the GHRH precursor<br />
into the five exons <strong>of</strong> the genes (for further details,<br />
see Refs. 377, 683).<br />
The GHRH precursor proteins identified in the human,<br />
the mouse, and the rat range in length from 103 to<br />
108 amino acids; their sequences are fairly homologous,<br />
with the amino acids being closest in the NH 2-terminal<br />
portion <strong>of</strong> the mature GHRH peptide, the region crucial<br />
for GHRH binding and biological activity (160). The rat<br />
and mouse proteins differ completely from the human<br />
GHRH precursor near the COOH terminus. In the rat,<br />
although most <strong>of</strong> the 104 amino acids <strong>of</strong> the GHRH precursor<br />
protein are similar to the human precursor, the last<br />
13 residues in the COOH-terminal domains are all different<br />
(678).<br />
The cDNA probes for GHRH made it possible to<br />
examine gene expression in the mammalian hypothalamus.<br />
In situ hybridization analysis <strong>of</strong> GHRH mRNA in the<br />
rat brain showed without doubt that GHRH-expressing<br />
neurosecretory cells, as revealed by immunocytochemistry<br />
(see sect. IIIA2), are an actual site <strong>of</strong> GHRH synthesis<br />
(89, 678, 1125). In agreement with RIA and immunohistochemical<br />
findings, most <strong>of</strong> the GHRH-expressing cells<br />
were on the ventral surface <strong>of</strong> the hypothalamus within<br />
the ARC, with additional cells extending into the DMN. No<br />
substantial expression was observed in brain regions outside<br />
the hypothalamus.<br />
It is now clear that the hormonal and metabolic<br />
status <strong>of</strong> the animals dictates appropriate changes <strong>of</strong><br />
GHRH mRNA expression in ARC neurons. The GHRH<br />
mRNA levels are higher in male than female rats, and<br />
testosterone is reported to increase the expression <strong>of</strong><br />
GHRH mRNA in males and to prevent the decline due to<br />
castration. This latter effect is shared by dihydrotestosterone,<br />
suggesting direct activation <strong>of</strong> the androgen re-
April 1999 NEUROENDOCRINE CONTROL OF GROWTH HORMONE SECRETION 523<br />
ceptor as the underlying mechanism (1124) and supporting<br />
a role <strong>of</strong> androgens per se to stimulate GH secretion<br />
(see sect. IIB). Thyroid hormone deficiency also increases<br />
GHRH mRNA levels; also this is mediated by the decrease<br />
in GH secretion (see below), since treatment with GH<br />
restores normal GHRH mRNA despite persistent hypothyroidism<br />
(288, 324).<br />
Metabolic state is also important, and in genetically<br />
obese Zucker rats (258, 354) as well as in caloric deprivation<br />
(149), where GH secretion is decreased, GHRH<br />
mRNA levels also drop, indicating effects divorced from<br />
GH secretion and the primary hypothalamic origin <strong>of</strong> the<br />
disturbance (see sect. VIC1). Streptozotocin-injected diabetic<br />
rats have diminished GH secretion, which can be<br />
restored by an anti-SS serum (1007). However, GHRH<br />
mRNA levels are low, and SS mRNA levels are high,<br />
indicating a metabolic regulation independent <strong>of</strong> GH<br />
(793) (see also sect. VI for discussion).<br />
Hormonal feedback regulation through GH appears<br />
to be the most important factor in GHRH mRNA expression.<br />
<strong>Growth</strong> hormone deficiency induced by target organ<br />
removal (hypophysectomy) or selective abrogation <strong>of</strong><br />
GHRH function is associated with increased GHRH<br />
mRNA levels, whereas GH treatment lowers them (237,<br />
290, 678), although not always (202) (see sect. VII for<br />
discussion).<br />
Levels <strong>of</strong> hypothalamic GHRH do not always change<br />
in parallel with GHRH mRNA (237, 386) because they also<br />
reflect a different rate <strong>of</strong> peptide increase and impairment<br />
<strong>of</strong> GHRH mRNA translation. Thus proper interpretation <strong>of</strong><br />
changes in GHRH content requires independent information<br />
on GHRH mRNA levels and/or GHRH secretion.<br />
The expression <strong>of</strong> GHRH mRNA in the placenta and<br />
other tissues is discussed above.<br />
6. <strong>Secretion</strong> and metabolism<br />
In vitro studies with the use <strong>of</strong> both long-term cultures<br />
<strong>of</strong> fetal rat hypothalamus and short-term static incubations<br />
<strong>of</strong> adult rat hypothalami with perfusion have<br />
been used to evaluate GHRH secretion. Such systems<br />
showed the releasing effects <strong>of</strong> K -induced depolarization<br />
(547) and the increased release after hypophysectomy<br />
(237) and thyroidectomy (324) in response to low<br />
glucose or intracellular glucopenia (64) and 2-adrenergic<br />
stimulation (536). Conversely, IGF-I (959), SS (1114), and<br />
activation <strong>of</strong> GABAergic function (63) impaired GHRH<br />
release. Multiple second messenger pathways underlie<br />
these effects, i.e., Ca 2 , phosphatidylinositol-protein kinase<br />
C, and adenylate cyclase-protein kinase A (63, 277).<br />
In vivo picomolar to nanomolar concentrations <strong>of</strong><br />
GHRH have been reported in the rat and the sheep portal<br />
venous blood. In anesthetized, hypophysectomized rats,<br />
portal plasma levels <strong>of</strong> GHRH were 200 pg/ml with<br />
synchronized pulses up to 800 pg/ml (853). In freely mov-<br />
ing, ovariectomized ewes, pulsatile GHRH secretion<br />
reached a mean <strong>of</strong> 20 pg/ml, with peak values from 25 to<br />
40 pg/ml and a secretion rate <strong>of</strong> 13 pg/min. About 70% <strong>of</strong><br />
spontaneously occurring GH peaks could be attributed to<br />
GHRH pulses, as indicated by simultaneous measurement<br />
<strong>of</strong> peripheral GH levels (378, see also sect. II).<br />
Unstimulated plasma levels <strong>of</strong> GHRH were in the<br />
range <strong>of</strong> 10–70 pg/ml in normal adults (827, 1032), with no<br />
apparent sex-related differences (924). Comparable values<br />
have been reported in the cerebrospinal fluid (CSF) <strong>of</strong><br />
children and adults <strong>of</strong> both sexes with no endocrine diseases<br />
(541). <strong>Growth</strong> hormone-releasing hormone is high<br />
in the cord blood from term human newborns (39), as are<br />
levels <strong>of</strong> GH (see sect. IIB). Normal children <strong>of</strong> both sexes<br />
between ages <strong>of</strong> 8 and 18 had levels five times higher at<br />
mid-puberty than prepuberty in girls and double in boys<br />
(41), supporting the central role <strong>of</strong> gonadal hormones<br />
(see also sect. IIB).<br />
The source <strong>of</strong> GHRH-LI in human plasma is not<br />
known, but the comparable levels in normal subjects and<br />
patients with hypothalamic lesions (232) suggest that the<br />
major source is not the hypothalamus (see also sect.<br />
IIIA4). Food (972) or glucose injection (542) can raise<br />
GHRH-LI levels, and this also occurs in patients with<br />
hypothalamic lesions or in GH-deficient subjects. These<br />
observations add weight to the idea that GHRH produced<br />
in the periphery (stomach, pancreas, small intestine)<br />
(239) may also act as a paracrine or autocrine factor. The<br />
hypothalamic component <strong>of</strong> circulating GHRH-LI, however,<br />
is specifically stimulated by insulin-hypoglycemia<br />
(542, 909; but see also Ref, 1022) or levodopa (231, 542,<br />
914), but not by clonidine or arginine (1085).<br />
Other conditions that increase circulating GHRH levels<br />
include the initial slow stage <strong>of</strong> sleep (914) and the<br />
sauna bath in young subjects (605). For other details on<br />
GHRH levels in GH hypo- and hypersecretory states, see<br />
Reference 749.<br />
<strong>Growth</strong> hormone-releasing hormone is metabolized<br />
in human plasma by dipeptidyl peptidase type IV (DPP-IV)<br />
and trypsinlike endopeptidases (375, 380). Degradation<br />
comprises an initial step whereby DPP-IV removes the<br />
NH 2-terminal dipeptide (Tyr-Ala) leaving metabolites<br />
[GHRH-(3O44)-NH 2 and GHRH-(3O40)-OH] with no bioactivity.<br />
Independent cleavage by trypsinlike endopeptides<br />
at residues 11–12 also inactivates the peptide. Because<br />
the half-life <strong>of</strong> GHRH-(3O44)-NH 2 in vitro is<br />
considerably longer (55 min) than the native molecule (15<br />
min), most <strong>of</strong> the plasma GHRH-IR is in the biologically<br />
inactive form. Studies with bovine GHRH suggest metabolic<br />
disposal is similar to human GHRH (579).<br />
7. Mechanism <strong>of</strong> action<br />
<strong>Growth</strong> hormone-releasing hormone exerts its primary<br />
control <strong>of</strong> somatotrophic function by increasing GH
524 MÜLLER, LOCATELLI, AND COCCHI Volume 79<br />
secretion, GH gene transcription and biosynthesis, and<br />
somatotroph proliferation. A host <strong>of</strong> intracellular second<br />
messenger systems including the adenylate cyclasecAMP-protein<br />
kinase A, Ca 2 -calmodulin, inositol phosphate-diacylglycerol-protein<br />
kinase C, and arachidonic<br />
acid-eicosanoic pathways are activated after binding to<br />
specific GTP-linked receptors in the plasma membranes<br />
(see also Ref. 683).<br />
Earlier evidence that cAMP was involved as a second<br />
messenger in the stimulation <strong>of</strong> GH secretion rested on<br />
the demonstration that crude ectopic GRF preparations,<br />
cAMP analogs, and theophylline, a phosphodiesterase inhibitor,<br />
stimulated GH release (822, 938, 997). With GHRH<br />
in pure form, it was then shown that GH release was<br />
associated with a dose-dependent rapid stimulation <strong>of</strong><br />
adenylate cyclase activity and cAMP production in the<br />
somatotrophs (102). Within 5 min <strong>of</strong> the addition <strong>of</strong> 1 nM<br />
GHRH to cultured rat pituitary cells, intracellular cAMP<br />
levels rose 6-fold, with a maximal response at 30 min; 10<br />
times more GHRH was required to obtain half-maximal<br />
stimulation <strong>of</strong> cAMP production than GH secretion, suggesting<br />
that only partial receptor occupancy is required to<br />
elicit a maximal GH response (1066).<br />
<strong>Growth</strong> hormone-releasing hormone-induced stimulation<br />
<strong>of</strong> cAMP production would occur in the manner<br />
typical <strong>of</strong> receptors coupled to GTP-binding proteins<br />
(106). The occupied GHRH receptor activates a heterotrimeric<br />
stimulatory G protein (G s), composed <strong>of</strong> -, -, and<br />
-subunits, by catalyzing the binding <strong>of</strong> the -subunit to<br />
GTP. Guanosine 5-triphosphate binding leads to dissociation<br />
<strong>of</strong> the -subunit complex from the G s -subunit,<br />
and the latter then activates the catalytic subunit <strong>of</strong> adenylate<br />
cyclase. Thus adenylate cyclase stimulation by<br />
GHRH is dependent on GTP (769, 974), but nonhydrolyzable<br />
GTP analogs or a high concentration <strong>of</strong> GTP reduced<br />
GHRH receptor binding (988), and stimulation <strong>of</strong> adenylate<br />
cyclase (974), consistent with existing models for<br />
receptor-G protein interactions. Like GHRH, agents that<br />
bypass the receptor, such as cholera toxin, which decreases<br />
the GTPase activity <strong>of</strong> G s (182) or forskolin,<br />
which directly activates the catalytic subunit <strong>of</strong> adenylate<br />
cyclase (944), potently stimulated cAMP accumulation<br />
and GHRH release (140, 275).<br />
In the absence <strong>of</strong> GHRH or other hypothalamic peptides,<br />
somatotropes in culture have either a stable basal<br />
intracellular Ca 2 concentration ([Ca 2 ] i) level (487) or<br />
asynchronous spontaneous [Ca 2 ] i transients (487) that<br />
result from Ca 2 entry through Ca 2 -permeable channels<br />
(487).<br />
Extracellular Ca 2 is required for GHRH to stimulate<br />
cAMP accumulation in pituitary cell preparations (140),<br />
suggesting that Ca 2 is also a second messenger for<br />
GHRH and that Ca 2 acts beyond, or independently <strong>of</strong>,<br />
cAMP. On purified preparations <strong>of</strong> normal rat somatotrophs,<br />
GHRH elicited a rapid increase in [Ca 2 ] i detect-<br />
able within 5 s (487, 643); this first phase was followed by<br />
a decline in [Ca 2 ] i to a plateau that was always higher<br />
than baseline and lasted 5 min (643).<br />
In addition to GHRH, other GH secretagogues rapidly<br />
raised intracellular Ca 2 (371, 576). Incubation in low<br />
Ca 2 medium or in the presence <strong>of</strong> Ca 2 channel blockers<br />
or antagonists blocked or greatly diminished both the<br />
GHRH-dependent increase in [Ca 2 ] i and GH release, with<br />
no changes in the cytosolic Ca 2 levels (102, 140, 487,<br />
644); this was taken to demonstrate that GHRH increases<br />
[Ca 2 ] i in somatotrophs by stimulating Ca 2 influx<br />
through L-type voltage-operated channels (VOCC). These<br />
effects are highly dependent on external Na and result<br />
from a cascade <strong>of</strong> voltage- sensitive currents (581). The<br />
inhibitory action <strong>of</strong> SS on basal and GHRH-induced GH<br />
release resulted from its ability to lower [Ca 2 ] i by inhibiting<br />
Ca 2 influx (643, 644). Somatostatin also inhibited<br />
the Ca 2 influx induced by other GH secretagogues, the<br />
only exception being high K .<br />
These studies led to a model in which a net influx <strong>of</strong><br />
extracellular Ca 2 through VOCC is the primary source <strong>of</strong><br />
the first phase <strong>of</strong> the GHRH-dependent increase in [Ca 2 ] i<br />
(222). Alternatively, the increase in cAMP accumulation<br />
might increase Na conductance directly or through protein<br />
kinase A-dependent phosphorylation, leading to depolarization<br />
and opening <strong>of</strong> the L-type VOCC (643). A<br />
more important role <strong>of</strong> Ca 2 mobilized from intracellular<br />
stores has also been suggested, based on a high correlation<br />
between Ca 2 efflux and GH release in perfused<br />
somatotrophs or the ability to stimulate GH secretion and<br />
Ca 2 efflux despite the absence <strong>of</strong> extracellular Ca 2<br />
(343, 789).<br />
With regard to the interaction between the two second<br />
messenger functions, there is some evidence <strong>of</strong> a<br />
direct relationship between cAMP and Ca 2 . W-7, an antagonist<br />
<strong>of</strong> the Ca 2 binding protein calmodulin, inhibited<br />
GHRH stimulation <strong>of</strong> adenylate cyclase, cAMP accumulation,<br />
and GH release, whereas the calcium ionophore<br />
A-23187 stimulated GH secretion and cAMP production<br />
(714, 935).<br />
Admittedly, Ca 2 effects occur together with a metabolic<br />
reaction, the hydrolysis <strong>of</strong> membrane phosphoinositides<br />
(PI), and these two processes are functionally<br />
connected (780). It was initially reported that GHRH increased<br />
32 P incorporation into PI <strong>of</strong> rat AP cells (165);<br />
however, this would be entirely separate from the PI<br />
catalysis involving the production <strong>of</strong> inositol 1,4,5trisphosphate<br />
(IP 3) and diacylglycerol, since GHRH did<br />
not enhance IP 3 (647). Other investigators too have found<br />
no early effect <strong>of</strong> GHRH on PI hydrolysis (260, 370, 875).<br />
Although GHRH does not induce PI hydrolysis, synthetic<br />
diacylglycerols and phorbol esters, which mimic the effect<br />
<strong>of</strong> the endogenous substrate by activating protein<br />
kinase C (184), dose-dependently stimulate GH secretion<br />
(535, 790). These compounds bind to the cell membrane
April 1999 NEUROENDOCRINE CONTROL OF GROWTH HORMONE SECRETION 525<br />
and then induce translocation <strong>of</strong> the inactive enzyme from<br />
the cytosol to the cell membrane, resulting in a large<br />
increase in its affinity for Ca 2 . Protein kinase C appears<br />
to act synergistically with Ca 2 mobilization to increase<br />
cell product release in various systems because low levels<br />
<strong>of</strong> Ca 2 ionophore can potentiate the protein kinase activation<br />
(535). This synergism may operate through several<br />
mechanisms, and no firm conclusion has been<br />
reached (535).<br />
Whatever the underlying mechanism is, it is noteworthy<br />
that increased Ca 2 mobilization in the pituitary enhances<br />
the sensitivity <strong>of</strong> the somatotroph to protein kinase<br />
C activators (535). It would seem, however, that this<br />
mechanism is only marginal to the secretagogue action <strong>of</strong><br />
GHRH and may better account for the action <strong>of</strong> GHRP and<br />
their analogs (see sect. IVC2), and protein kinase apparently<br />
increases GH release by mechanism(s) different<br />
from those used by GHRH (790).<br />
The fact that GHRH does not enhance IP 3 production<br />
and may thus be unable to mobilize intracellular Ca 2<br />
from the IP 3-sensitive Ca 2 pool implies only a minimal<br />
effect on fractional Ca 2 efflux. However, GHRH may<br />
affect Ca 2 efflux through the formation <strong>of</strong> arachidonic<br />
acid, derived from the direct activation <strong>of</strong> phospholipase<br />
A and hydrolytic cleavage <strong>of</strong> the fatty acid from membrane<br />
phospholipids or, alternatively, by hydrolysis <strong>of</strong><br />
diacylglycerol by diacylglyceride. Arachidonate and its<br />
metabolites are known to mobilize Ca 2 (567, 765).<br />
<strong>Growth</strong> hormone-releasing hormone and Ca 2 efflux are<br />
discussed above.<br />
Supporting a GHRH-arachinodate interaction, arachidonic<br />
acid elicits a dose-dependent increase in GH secretion<br />
and GHRH stimulates arachidonic acid release in<br />
cultured rat pituitary cells (166, 534).<br />
Prostaglandin (PG) E 1, PGE 2, and prostacyclin<br />
(PGI 2) enhance GH secretion in the rat in vitro (716, 800)<br />
and in vivo (551, 800) as well as the production <strong>of</strong> cAMP<br />
(716, 938), probably by stimulation <strong>of</strong> adenylate cyclase<br />
through a G s protein-coupled PG receptor (966). <strong>Growth</strong><br />
hormone-releasing hormone stimulates PGE 2 release<br />
from incubated rat pituitaries, and indomethacin and aspirin,<br />
two cycloxygenase inhibitors, reduce GHRH-induced<br />
GH and PGE 2 release (347).<br />
8. GHRH receptor<br />
A) CHARACTERIZATION, CLONING, AND STRUCTURE. A better understanding<br />
<strong>of</strong> GHRH action in promoting GH secretion<br />
and linear growth requires knowledge <strong>of</strong> the GHRH receptor<br />
(GHRH-R) structure and function. Previous studies<br />
in intact cells or cell membrane preparations <strong>of</strong> the rat<br />
described high-affinity low-capacity specific GHRH binding<br />
sites, using GHRH or GHRH analogs (5, 947, 1066).<br />
Two studies reported an additional class <strong>of</strong> low-affinity<br />
high-capacity sites (5, 6). Binding sites were also evi-<br />
denced in bovine pituitaries (1066) and human pituitary<br />
tumor tissue (502). Binding <strong>of</strong> GHRH resulted in the activation<br />
<strong>of</strong> adenylate cyclase, whereas guanine nucleotides<br />
inhibited hormone binding, suggesting the involvement<br />
<strong>of</strong> G s protein (see sect. IIIA7 for details).<br />
Initial approaches to identify GHRH-R activity based<br />
on functional expression <strong>of</strong> the receptor in Xenopus laevis<br />
oocytes injected with pituitary mRNA were unable to<br />
isolate an individual GHRH-R cDNA. More successful was<br />
a strategy based on the contention that the receptor,<br />
which utilized a G protein to transduce its signal, would<br />
predominantly have structural features <strong>of</strong> other G proteincoupled<br />
receptors (679). This led first to the expression<br />
cloning <strong>of</strong> the GHRH-related hormone secretin (513) and<br />
then to the recognition that this receptor and the related<br />
calcitonin and parathyroid hormone (PTH) receptors constituted<br />
a new subfamily <strong>of</strong> G protein-coupled receptors<br />
(see Ref. 683).<br />
Three groups subsequently achieved the molecular<br />
cloning <strong>of</strong> AP receptors for GHRH in human, rat, and<br />
mouse (393, 612, 679). The isolated cDNA encoded a<br />
423-amino acid protein containing seven putative transmembrane<br />
domains characteristic <strong>of</strong> G protein-coupled<br />
receptors (Fig. 4). Rat cDNA clones also had a 41-amino<br />
acid insert at amino acid 325. However, PCR analysis <strong>of</strong><br />
rat pituitary mRNA only gave evidence <strong>of</strong> the shorter form<br />
(679). The two rodent receptors were closely related (94%<br />
identical) and were both homologous to the human receptor<br />
(82% identical). The GHRH-R colocalizes with GH<br />
cells (612), although studies about cell-specific expression<br />
<strong>of</strong> GHRH-R are not yet complete.<br />
As mentioned in section IIIA1, GHRH belongs to a<br />
family <strong>of</strong> brain-gut peptides, and a similar family <strong>of</strong> receptors<br />
has now been identified that includes the VIP<br />
receptor, the glucagon receptor, the GLP-1 receptor, the<br />
PACAP receptor, and the GIP receptor. These peptide<br />
receptors also show consistent homology with the GHRH<br />
receptor (see Ref. 945).<br />
Transient expression <strong>of</strong> rat cDNA in COS cells induced<br />
saturable, high-affinity GHRH-specific binding and<br />
stimulated the accumulation <strong>of</strong> cAMP in response to physiological<br />
concentrations <strong>of</strong> GHRH, consistent with the<br />
predicted coupling <strong>of</strong> the GHRH-R to a G s protein. Binding<br />
and second messenger responses were blocked by a<br />
specific GHRH antagonist, whereas ligands for related<br />
receptors (see above) did not effectively compete with<br />
GHRH for binding to its receptor (683).<br />
Initial Northern analysis studies indicated that<br />
GHRH-R mRNA was mainly expressed in extracts <strong>of</strong> pituitary<br />
and not in other tissues. Two transcripts <strong>of</strong> 2.5<br />
and 4 kb were identified in rat pituitary, 2.0 and 2.1 kb in<br />
mouse, and 3.5 kb in ovine pituitary (393, 612, 689). Mouse<br />
studies showed that the GHRH-R is expressed in a temporal<br />
and spatial pattern corresponding to GH gene expression<br />
(612).
526 MÜLLER, LOCATELLI, AND COCCHI Volume 79<br />
The identification <strong>of</strong> the pituitary-specific transcription<br />
factor, Pit-1, which is involved in developmental generation<br />
<strong>of</strong> somatotrophs (lactotrophs and thyrotrophs)<br />
and in the appropriate regulation <strong>of</strong> the GH gene (120,<br />
507) and very likely also in direct regulation <strong>of</strong> the GHRH-<br />
R mRNA, has contributed to our understanding <strong>of</strong> GHRH-<br />
R biology. <strong>Growth</strong> hormone-releasing hormone plays a<br />
major stimulatory role in regulation <strong>of</strong> the Pit-1 mRNA<br />
concentration, although Pit-1 is preserved in the pituitaries<br />
<strong>of</strong> anencephalic fetuses (845), an effect mimicked by<br />
other GH secretagogues such as PACAP-38 but not by<br />
GHRP-6 (973). The regulation is apparently reciprocal,<br />
since GHRH-R is not expressed in the pituitary <strong>of</strong> dw/dw<br />
mice, which are impaired in functional Pit-1 gene expression<br />
(614). Thus GHRH-R would be dependent on Pit-1,<br />
and a deficiency <strong>of</strong> Pit-1 would result in a lack <strong>of</strong> GHRH-R<br />
gene expression and thus <strong>of</strong> somatotroph development.<br />
B) FUNCTION. Information about GHRH-R regulation<br />
and function or dysfunction <strong>of</strong>fers new insights into the<br />
control <strong>of</strong> GH secretion during development, maturity,<br />
FIG. 4. Schematic structure <strong>of</strong> GHRH<br />
receptor. Amino acid sequence shown in<br />
a 1-letter code is that <strong>of</strong> rat GHRH receptor.<br />
Seven membrane-spanning domains<br />
are illustrated as cylinders crossing lipid<br />
bilayer. Solid circles represent amino<br />
acids that are conserved in related receptors<br />
for hormones secretin, glucagon,<br />
glucagon-like peptide I, gastric inhibitory<br />
peptide, vasoactive intestinal polypeptide,<br />
and pituitary adenylate cyclase-activating<br />
peptide. Open arrow indicates<br />
approximate site <strong>of</strong> signal sequence<br />
cleavage. Branched structures represent<br />
2 consensus sites for N-linked glycosylation.<br />
Solid arrow indicates site <strong>of</strong> an insertion<br />
generated by alternative RNA<br />
processing in a variant form <strong>of</strong> GHRH<br />
receptor. [From Mayo et al. (683); Copyright<br />
The Endocrine Society.]<br />
and aging and helps explain GH deficiency states <strong>of</strong> animals<br />
or humans leading to dwarfism and metabolic dysfunction.<br />
Pituitaries <strong>of</strong> fetal and neonatal mammals are highly<br />
responsive to the stimulatory effects <strong>of</strong> GHRH, compared<br />
with mature mammals (see sect. IIB). Differences in pituitary<br />
responsiveness to GHRH may therefore contribute<br />
to the elevated plasma GH titers characteristic <strong>of</strong> the<br />
perinatal period and the subsequent decline in circulating<br />
GH occurring late in life. Studies <strong>of</strong> the ontogenic development<br />
<strong>of</strong> rat GHRH-R gene expression have in fact found<br />
the highest concentration on day 19.5 <strong>of</strong> gestation (ED<br />
19.5), with a decline during the perinatal period to reach<br />
a nadir at 12 days <strong>of</strong> age. The GHRH-R mRNA levels<br />
increased at 30 days <strong>of</strong> age, corresponding to the onset <strong>of</strong><br />
sexual maturation, and then declined later in life (572).<br />
Although the timing <strong>of</strong> the decline in GHRH-R mRNA,<br />
at 12 days, did not precisely coincide with recorded<br />
changes in GH responsiveness to GHRH in vitro and in<br />
vivo (see sect. IIB), there was a dissociation with the
April 1999 NEUROENDOCRINE CONTROL OF GROWTH HORMONE SECRETION 527<br />
FIG. 5. Changes in GH-releasing factor receptor (GRFR)-to-glyceraldeyde<br />
3-phosphate dehydrogenase (GAPDH) ratio by treatment with<br />
GH-releasing factor antibody (GRF-ab) and/or GH. GRFR/GAPDH were<br />
expressed as percent (mean SD <strong>of</strong> 4 independent experiments) <strong>of</strong><br />
group I. Treatments to each group were as follows: group I, normal<br />
rabbit serum (control group); group II, GRF-ab; group III, normal rabbit<br />
serum and GH; group IV, GRF-ab and GH. * P 0.01, analyzed by<br />
ANOVA. [From Horikawa et al. (489); Copyright The Endocrine Society.]<br />
developmental pattern <strong>of</strong> GH mRNA (see Ref. 572 for<br />
discussion), and the maturational changes in GHRH-R<br />
mRNA abundance were, on the whole, consistent with a<br />
similar role in the regulation <strong>of</strong> somatotroph function<br />
during early development. The presence <strong>of</strong> abundant<br />
GHRH-R mRNA as early as ED 19.5 supports the idea that<br />
GHRH-R plays a role in mediating GHRH stimulation <strong>of</strong><br />
somatotroph function by late fetal life and, ultimately,<br />
that GH secretion is also involved during this period (146,<br />
1094). These data were consistent with reports that mice<br />
also express GHRH-R mRNA by late gestation (157, 612).<br />
The findings <strong>of</strong> Korytko et al. (572) have been confirmed<br />
by Horikawa et al. (489), who have extended their studies<br />
to the developmental changes <strong>of</strong> SS receptors (see sect.<br />
IIIB2).<br />
Horikawa et al. (489) showed that in neonatal rats<br />
passively immunized with a GHRH antiserum (see Ref.<br />
207), there was a 50% decrease in GHRH-R mRNA; GH<br />
treatment significantly reduced the pituitary GHRH-R expression<br />
in control rats but not in GHRH antiserumtreated<br />
rats (Fig. 5). The marked reduction <strong>of</strong> GHRH-R<br />
mRNA in GHRH-deprived neonatal rats was taken to indicate<br />
failure <strong>of</strong> the developmental induction <strong>of</strong> pituitary<br />
GHRH-R expression by GHRH itself. In control rats, GH<br />
acted through an initial decrease <strong>of</strong> hypothalamic GHRH<br />
synthesis induced by short-loop feedback (see sect. VIIA).<br />
A major reduction <strong>of</strong> pituitary GHRH-R mRNA is also<br />
observed in transgenic dwarf mice expressing a TH-human<br />
GH fusion gene in the hypothalamus (996).<br />
Regulation <strong>of</strong> GH secretion by GHRH-R would also<br />
be important in the sexually dimorphic expression <strong>of</strong> GH<br />
secretion (see sect. IIA) and would thus be <strong>of</strong> physiolog-<br />
ical significance. Normal female rats, in fact, had strikingly<br />
lower levels <strong>of</strong> pituitary GHRH-R mRNA than male<br />
rats; in addition, female rat hypothalami had a lower<br />
GHRH content and were less able to release GHRH than<br />
male rats (799). Although the sex difference in GH secretion<br />
<strong>of</strong> rats cannot be extrapolated as such to humans,<br />
these animal findings reinforce the view that hypothalamic<br />
GHRH secretion is mandatory to permit expression<br />
<strong>of</strong> its own pituitary receptor and show, in particular, that<br />
E 2 inhibits hypothalamic GHRH secretion and pituitary<br />
GHRH-R gene expression simultaneously.<br />
Supporting these findings, castration raised the low<br />
GHRH-R mRNA levels <strong>of</strong> female rats two- to threefold, an<br />
effect counteracted by short-term E 2 implants. Estrogen<br />
also markedly suppressed GHRH-R mRNA in castrated<br />
male rats, although orchidectomy lowered GHRH-R<br />
mRNA only slightly, the opposite effect to ovariectomy. In<br />
both male and female rats, castration enhanced GHRH<br />
secretion in response to high K concentrations 1.5fold,<br />
and this effect too was reversed by E 2 treatment<br />
(798).<br />
Various other steroid hormones also modulate<br />
GHRH-R mRNA expression. In primary cultures <strong>of</strong> rat AP<br />
cells, 100 nM dexamethasone for 12 h increased gene<br />
expression by fivefold; adrenalectomy and hormone replacement<br />
studies ex vivo showed corticosterone also<br />
stimulated GHRH-R mRNA expression in the intact rat<br />
pituitary gland (727). These findings, broadening previous<br />
observations in vivo with dexamethasone (584), provide a<br />
molecular mechanism to explain how glucocorticoids restore<br />
GHRH binding capacity in dispersed AP cells from<br />
adrenalectomized rats (947) and why dexamethasone induces<br />
an acute GH secretory response when administered<br />
to healthy humans (177) (see also sect. VIA1).<br />
The proposition that hypothalamic GHRH is mandatory<br />
for the expression <strong>of</strong> GHRH-R in the pituitary has<br />
now been strongly corroborated by more straightforward<br />
experiments. Treatment <strong>of</strong> AP cell cultures with 100 nM<br />
GHRH for 12 h increased GHRH-R mRNA levels 6-fold,<br />
and there was a 10-fold rise in GHRH-R mRNA after cell<br />
exposure to 100 mM dibutyryl cAMP for 12 h (727). For<br />
thyroid hormone action at GHRH-R, see section VIA2.<br />
The importance <strong>of</strong> pituitary GHRH-R for somatotroph<br />
function is illustrated by the fact that loss <strong>of</strong><br />
function mutations in GHRH-R in mouse and human leads<br />
to severe GH deficiency syndromes. The little mouse is an<br />
animal model for isolated GH deficiency type 1B (333), in<br />
which the discovery <strong>of</strong> a mutation in GHRH-R (433) suggested<br />
similar mutations in GH deficiency syndromes in<br />
the human population (see below).<br />
Functionally, pituitary glands <strong>of</strong> the little mouse are<br />
deficient in but not devoid <strong>of</strong> GH and are unresponsive to<br />
GHRH in vivo and in vitro (247). Somatic growth is increased<br />
by systemically administered GH.
528 MÜLLER, LOCATELLI, AND COCCHI Volume 79<br />
In humans, some familial cases <strong>of</strong> isolated GH deficiency<br />
have been attributed to mutations in the GH gene<br />
itself, but GH deficiency is not always linked to this locus<br />
(799). The GHRH-R mutations account for other instances<br />
<strong>of</strong> GH deficiency in which the GH gene is normal. A<br />
nonsense mutation in the human GHRH-R gene has been<br />
reported that resulted in pr<strong>of</strong>ound GH deficiency in two<br />
members <strong>of</strong> a consanguineous family, (1076). The Glu-72<br />
stop mutation identified was close to the position <strong>of</strong> the<br />
little mutation (Asp-60-Gly), both occurring in the highly<br />
conserved region <strong>of</strong> the extracellular domain. Conformational<br />
polymorphism analysis applied to the coding region<br />
<strong>of</strong> the GHRH-R gene in 30 families with individuals suffering<br />
from GHD revealed a polymorphism changing<br />
codon 57 from GCG (alanine) to ACG (threonine) in the<br />
extracellular position <strong>of</strong> the receptor in 20% <strong>of</strong> the<br />
patients (836). However, the presence <strong>of</strong> this polymorphism<br />
did not seem to cause the GH deficiency in these<br />
patients; its frequency may be helpful to identify those<br />
patients in whom mutations in the GHRH-R gene are<br />
likely to be a cause <strong>of</strong> their GH deficiency.<br />
A novel form <strong>of</strong> familial isolated GH deficiency linked<br />
to the locus for the GHRH-R has been described in a lower<br />
valley <strong>of</strong> Pakistan. A total <strong>of</strong> 18 dwarfs were discovered in<br />
a kindred with a high degree <strong>of</strong> consanguineity. Of several<br />
candidate genes probed by linkage analysis, only the<br />
GHRH-R locus on chromosome 7p14 was highly linked to<br />
the dwarfed phenotype. Amplification and sequencing <strong>of</strong><br />
the GHRH-R gene in affected subjects brought to light an<br />
amber nonsense mutation (GAG 3 TAG; Glu 5 3 Stop) in<br />
exon 3, implying that this form too is a human homolog <strong>of</strong><br />
the little mouse (78).<br />
9. Conclusions<br />
FIG. 6. Model for GHRH signaling in pituitary<br />
somatotroph cells. Numbered symbols indicate<br />
progressive steps, as also indicated in<br />
text (1). GHRH interaction with its receptor<br />
leads to GH secretion (2) through receptor-induced<br />
interaction <strong>of</strong> a G protein with ion channels<br />
(3). Stimulation <strong>of</strong> adenylate cyclase by G s<br />
protein leads to intracellular cAMP accumulation<br />
and activation <strong>of</strong> catalytic subunit <strong>of</strong> protein<br />
kinase A (4). Protein kinase A phophorylates<br />
cAMP response element binding protein<br />
(CREB) at serine-133, leading to CREB activation<br />
and enhanced transcription <strong>of</strong> the gene encoding<br />
pituitary-specific transcription factor<br />
(Pit-1) (5). Pit-1 activates transcription <strong>of</strong> GH<br />
gene, leading to increased growth hormone<br />
mRNA and protein and replenishing cellular<br />
stores <strong>of</strong> growth hormone (6). Pit-1 also stimulates<br />
transcription <strong>of</strong> GHRH receptor gene, leading<br />
to increased numbers <strong>of</strong> GHRH receptors on<br />
responding somatotroph cell (7). Upstream<br />
components <strong>of</strong> cAMP-signaling pathway appear<br />
to have direct effects on GHRH receptor gene<br />
expression. [Modified from Mayo et al. (683).]<br />
Molecular characterization <strong>of</strong> GHRH and GHRH-R is<br />
instrumental to a better understanding <strong>of</strong> the hypothalamic<br />
regulation <strong>of</strong> pituitary somatroph function (Fig. 6)<br />
(see Ref. 683 for details). In brief, the model <strong>of</strong> GHRH<br />
action proposes the interaction <strong>of</strong> the peptide with a<br />
seven-transmembrane domain G s-coupled receptor on the<br />
somatotroph, leading to GH release from secretory granules,<br />
presumably mediated by a G protein interaction with<br />
ion channels and by stimulation <strong>of</strong> intracellular cAMP<br />
accumulation. In turn, elevated cAMP titers would lead to<br />
the phosphorylation and activation <strong>of</strong> cAMP response<br />
element binding protein (CREB), a transcription factor,<br />
by protein kinase A (434, 956).<br />
One target gene for CREB action is the pituitarydependent<br />
transcription factor Pit-1 that is involved in the<br />
developmental generation <strong>of</strong> somatotrophs and in regulation<br />
<strong>of</strong> the genes for GH, prolactin and possibly for the<br />
-chain <strong>of</strong> thyroid stimulating hormone. It provides the<br />
pathway whereby GHRH leads to increased GH synthesis
April 1999 NEUROENDOCRINE CONTROL OF GROWTH HORMONE SECRETION 529<br />
in the pituitary but, in addition, is likely to directly regulate<br />
the synthesis <strong>of</strong> GHRH-R. This, in fact, is not expressed<br />
in the pituitary <strong>of</strong> dw/dw mice that lacks functional<br />
Pit-1 (612). In line with GHRH action through a<br />
cAMP-dependent pathway, treatment <strong>of</strong> primary cultures<br />
<strong>of</strong> AP cells with dibutyryl cAMP strikingly raises GHRH-R<br />
mRNA levels (727). The inhibitory peptide SS presumably<br />
interacts through G protein-mediated suppression <strong>of</strong> this<br />
cAMP pathway.<br />
Disruption in several steps <strong>of</strong> the signaling pathway<br />
leading to GH secretion may result in GH deficiency. An<br />
inactivating mutation in the GHRH-R has been found in<br />
the little mouse, a model <strong>of</strong> isolated GH deficiency, and<br />
similar alterations in receptor function play a role in some<br />
human growth disorders.<br />
10. In vivo animal studies<br />
Detailed description <strong>of</strong> the GH-releasing activity <strong>of</strong><br />
GHRH and its effects outside the GH axis, derived from<br />
animal studies, is beyond the scope <strong>of</strong> this review, so<br />
these topics are discussed here only briefly. For the clinical<br />
implications, the reader is referred to the excellent<br />
review by Cronin and Thorner (274).<br />
<strong>Growth</strong> hormone-releasing hormone is active in vivo,<br />
stimulating GH secretion in anesthetized rats; conscious<br />
rats or dogs; rats bearing stereotaxic lesions <strong>of</strong> the VMN,<br />
ablation <strong>of</strong> the MBH, or selective destruction <strong>of</strong> the ARC;<br />
and in every vertebrate tested so far (see Ref. 1086).<br />
<strong>Growth</strong> hormone-releasing hormone is needed for<br />
endogenous pulsatile GH secretion and optimal statural<br />
growth; subacute administration <strong>of</strong> an anti-GHRH serum<br />
to neonatal rats drastically slows growth (1089), impairs<br />
many aspects <strong>of</strong> somatotrophic function (207), and completely<br />
abolishes spontaneous GH release (1090). Once<br />
passive immunization ceases, no catchup growth occurs,<br />
and the immunized rats maintain a growth rate that is<br />
parallel to, but still lags behind, that <strong>of</strong> control rats (207).<br />
This growth pattern is virtually identical to the pattern in<br />
children with constitutional growth delay. The GH deprivation<br />
induced by the anti-GHRH serum delays sexual<br />
maturation in male rats (48), probably because <strong>of</strong> the low<br />
IGF-I titers (303).<br />
Alterations in postnatal somatotropic function are<br />
also obtained when GH deprivation is induced in fetal rats<br />
on ED 16 by intra-amniotic injection <strong>of</strong> GHRH antibodies<br />
(212), a finding supporting the concept that GH exerts an<br />
important role in perinatal growth in the rat, as it is likely<br />
in humans (432, 1094). On the other hand, GHRH administered<br />
over several days to weeks enhances body growth<br />
and function in experimental animals (336, 1031). These<br />
effects are particularly evident in mice transgenic for<br />
GHRH, where excess GHRH exposure is associated with<br />
elevation <strong>of</strong> serum GH and stimulation <strong>of</strong> linear growth,<br />
increased pituitary mass, and mammosomatotroph hyper-<br />
plasia, finally resulting in adenoma formation (see Refs.<br />
684, 982).<br />
There is an ontogenetic pattern in basal GH responses<br />
to exogenous GHRH; in the rhesus monkey, they<br />
decrease from postnatal days 1 to 28 (1086), whereas in<br />
the rat, GHRH does not raise GH levels up to postnatal<br />
days 5–10 (204), when GH pituitary responsiveness to the<br />
GH-releasing (205) and synthesizing (272) activities <strong>of</strong> the<br />
peptide is at its best (see also sect. IIB). For the developmental<br />
pattern <strong>of</strong> the GHRH-R and its hormonal regulation,<br />
see section IIIA8B.<br />
In the rat, the GHRH system shows a strong sex<br />
dependency (40), and Spiliotis et al. (978) showed that<br />
GHRH mRNA level and GHRH secretion were higher in<br />
male than female rats and were reduced by orchidectomy<br />
but increased by testosterone in castrated male rats<br />
(1125); E 2 had no effect on hypothalamic GHRH mRNA<br />
(653, 1125).<br />
The sexually dimorphic organization <strong>of</strong> the GHRH<br />
system may account for the sex difference in GH secretion<br />
in the rat (see sect. IIA), a major role also being<br />
attributed to sex-related differences in GHRH-R mRNA,<br />
although regulation by hypothalamic SS as well cannot be<br />
ignored (see sect. IIIB).<br />
Consistent with the inhibitory influence <strong>of</strong> E 2 on<br />
hypothalamic and pituitary GHRH-R function is the fact<br />
that pituitary responsiveness to GHRH is lowest in rats at<br />
proestrus (18). This pattern is somewhat different from<br />
humans, where GHRH’s effect does not change during the<br />
menstrual cycle (345, 396) and GH responsiveness to<br />
GHRH and GH secretion rate is higher in premenopausal<br />
women than young-adult men (590) (see sect. IIA for<br />
discussion).<br />
11. Extrapituitary central effects<br />
<strong>Growth</strong> hormone-releasing hormone has few extrapituitary<br />
effects, as might be expected considering its<br />
limited distribution within the body. Huge doses (5–10<br />
g) <strong>of</strong> GHRH into the lateral brain ventricle <strong>of</strong> freely<br />
moving rats reportedly induced motor and behavioral<br />
effects and raised blood glucose levels (1008). However,<br />
dispute over the identity <strong>of</strong> the GHRH material used in<br />
this study (618, 1018) suggests caution in interpreting<br />
these findings.<br />
More reliable are the findings that GHRH promotes<br />
sleep in animals and normal controls. Ehlers et al. (332)<br />
and Nisticò et al. (781) found a significant increase in<br />
SWS and a decrease in time to onset <strong>of</strong> SWS in rats after<br />
intracerebroventricular or hippocampal injections <strong>of</strong><br />
GHRH. Non-REM sleep and REM sleep increased in<br />
both rats and rabbits after intrathecal injection <strong>of</strong><br />
GHRH (782). Sleep was reduced in rats when GHRH<br />
action was inhibited by a specific antagonist (784) or by<br />
GHRH antibodies (785).
530 MÜLLER, LOCATELLI, AND COCCHI Volume 79<br />
Four systemic boluses <strong>of</strong> GHRH between 22.00 and<br />
1.00 h caused a significant increase in SWS in male controls<br />
which was evident throughout the entire sleep period<br />
(984). Entry <strong>of</strong> the peptide through the circumventricular<br />
organs and/or other CNS-permeable sites is the<br />
most likely explanation for these findings (543).<br />
An important question is whether peripheral effects<br />
<strong>of</strong> GHRH, particularly the GH rise, are responsible for the<br />
increase in SWS. Apart from the observation that the SWS<br />
increase lasts considerably longer than the GHRH-induced<br />
GH rise (984), it is noteworthy that exogenous GH<br />
suppresses SWS (701).<br />
The potential <strong>of</strong> GHRH and potent long-acting analogs<br />
(161) for improving the quantity and quality <strong>of</strong> sleep,<br />
particularly in obese patients and the elderly, where the<br />
endogenous GHRH drive is reduced (754), has not escaped<br />
attention (see also sect. IV).<br />
Intracerebroventricular injection <strong>of</strong> picomolar doses<br />
<strong>of</strong> GHRH exerts another important effect, centrally mediated<br />
and independent <strong>of</strong> its GH-promoting properties, i.e.,<br />
stimulation <strong>of</strong> food intake in rats and sheep. At higher<br />
doses, intravenous GHRH also stimulates food intake<br />
(893, 1007). Intracranial mapping studies have indicated<br />
that the SCN/MPOA region <strong>of</strong> the hypothalamus is a<br />
highly sensitive site for GHRH-induced feeding (1048) and<br />
that this effect depends on PVN for expression. The fact<br />
that the feeding effects <strong>of</strong> GHRH are exerted at sites<br />
remote from the hypophysial portal system is consistent<br />
with electrophysiological (1043) and anatomic (926) evidence<br />
focusing on the neurotransmitter-like properties <strong>of</strong><br />
the peptide.<br />
The GHRH signal would contribute to both the circadian<br />
pattern <strong>of</strong> feeding behavior and macronutrient<br />
intake. Microinjection <strong>of</strong> GHRH increased food intake<br />
during the light phase (behaviorally inactive) <strong>of</strong> the male<br />
rat’s cycle and either had no effect or reduced food intake<br />
during the dark (behaviorally active) period (349), when<br />
rats eat up to 80% <strong>of</strong> their daily food requirement.<br />
In support <strong>of</strong> the view that GHRH is one signal<br />
contributing to the circadian pattern <strong>of</strong> food intake,<br />
injection <strong>of</strong> a specific GHRH antiserum into the SNC/<br />
MPOA, at four different periods during the light-dark<br />
cycle, suppressed feeding only at dark onset. This<br />
strongly suggested that GHRH action in the SCN/MPOA<br />
contributes to the feeding burst seen at dark onset<br />
(1047). The protein-selective nature <strong>of</strong> GHRH-induced<br />
feeding indicated a macronutrient-selective effect during<br />
the light-dark period. In rats habituated to two diets<br />
(carbohydrate-fat and protein-fat), microinjection <strong>of</strong> a<br />
GHRH antiserum into the SCN/MPOA blocked the increase<br />
in protein intake normally seen at dark onset but<br />
had no effect on carbohydrate intake (312).<br />
Few data are available on the effects <strong>of</strong> GHRH on<br />
food intake in humans. Because the higher GH responsiveness<br />
to GHRH <strong>of</strong> subjects with anorexia nervosa (AN)<br />
(see sect. VIC2) may also reflect altered sensitivity or<br />
activity <strong>of</strong> central GHRH, the compound was administered<br />
systemically to a group <strong>of</strong> AN patients at meal time,<br />
and caloric intake and macronutrient selection were determined<br />
(1049). <strong>Growth</strong> hormone-releasing hormone<br />
stimulated food intake (especially carbohydrates and<br />
fats) in AN patients but reduced it in anorectic/bulimic<br />
patients or normal controls, with a mechanism apparently<br />
not depending on the subjects nutritional status or the<br />
ability <strong>of</strong> the peptide to release GH. The authors’ conclusions<br />
that low levels <strong>of</strong> GHRH may contribute to the<br />
restricted eating pattern <strong>of</strong> AN patients were not consistent<br />
with experimental, although inferential, evidence<br />
pointing to an enhanced function <strong>of</strong> GHRH neurons in AN<br />
(751, 929).<br />
For other potential extrapituitary effects <strong>of</strong> GHRH,<br />
see section IIIA4.<br />
B. Somatostatin<br />
With the demonstration <strong>of</strong> stimulatory CNS influences<br />
over GH secretion, evidence accumulated <strong>of</strong> an<br />
inhibitory CNS control, based especially on observations<br />
in subprimate and primate species (749). In humans, elevated<br />
plasma GH levels were reported in the diencephalic<br />
syndrome <strong>of</strong> infancy, a CNS disturbance usually caused<br />
by a tumor <strong>of</strong> the optic chiasm and anterior hypothalamus<br />
(66, 360). More pro<strong>of</strong> <strong>of</strong> a hypothalamic inhibitory influence<br />
for GH secretion was given by Krulich et al. (578),<br />
who showed that in vitro certain fractions separated from<br />
ovine hypothalamic extracts had consistent inhibitory effects<br />
on the release <strong>of</strong> bioassayable and then RIA GH (see<br />
Ref. 3 for review). These authors were the first to suggest<br />
that GH secretion was regulated by a dual system, one<br />
stimulatory and the other inhibitory. The inhibitory factor<br />
was named GH-inhibiting factor (GHIF).<br />
The isolation, identification, and synthesis several<br />
years later <strong>of</strong> a tetradecapeptide, GH release-inhibiting<br />
hormone or somatotrophin release-inhibiting hormone<br />
(SRIH or SS) should be credited to Guillemin and coworkers<br />
(141), who used a highly sensitive in vitro pituitary<br />
assay.<br />
Somatostatin was first identified as a hypothalamic<br />
peptide involved in the physiological inhibitory control <strong>of</strong><br />
GH and thyroid-stimulating hormone (TSH) secretion. It<br />
soon became clear, however, that SS was ubiquitous (see<br />
below) and inhibited the secretion <strong>of</strong> most hormones,<br />
under physiological and pathological circumstances, and<br />
could also inhibit exocrine secretions. Because targets <strong>of</strong><br />
SS action were <strong>of</strong>ten the same tissues where the peptide<br />
was localized, the concept developed that, in addition to<br />
its endocrine effects, its actions were regionally limited as<br />
a neuroendocrine factor or in adjacent tissues, as an<br />
autocrine or paracrine regulator (880).
April 1999 NEUROENDOCRINE CONTROL OF GROWTH HORMONE SECRETION 531<br />
Many aspects <strong>of</strong> SS function have already been dealt<br />
with in earlier sections, so in this section we confine<br />
ourselves mainly to its neuroendocrine effects in relation<br />
to the hypothalamic-pituitary unit.<br />
Somatostatin-14 (SS-14), the native form, belongs to<br />
a family <strong>of</strong> SS-like peptides including NH 2-terminal-extended<br />
SS (SS-28) (864), a fragment corresponding to the<br />
first 12 amino acids <strong>of</strong> SS-28 [SS-28-(1O12)], and still<br />
larger forms that vary in molecular size and in different<br />
species from 11.5 to 15.7 kDa.<br />
In vertebrates, SS-14 and SS-28 have evolved from<br />
separate encoding genes in fish to a single gene encoding<br />
a common precursor that is differentially processed to<br />
generate tissue-specific amounts <strong>of</strong> the two peptides<br />
(816).<br />
The SS-like peptides are multifunctional and are synthesized<br />
and located in most brain regions as well as in<br />
peripheral organs, especially the gastrointestinal tract <strong>of</strong><br />
both vertebrate and invertebrate species (reviewed in<br />
Refs. 814, 1081). Somatostatin-14 is the predominant form<br />
and usually has the same sequence in different species.<br />
Both SS-14 and SS-28 have partially overlapping but distinct<br />
bioactions and act through different receptors (see<br />
below). In neural tissues, SS-14 predominates (ratio 4:1 in<br />
the hypothalamus). There is virtually no SS-28 in the<br />
stomach and the duodenum, but lower down the gut SS-28<br />
is the most important molecular form (306).<br />
Both SS-14 and SS-28 have similar potency and bind<br />
all cloned receptors with high affinity (see sect. IIIB4). The<br />
biological significance <strong>of</strong> the two forms in relation to<br />
neuroendocrine function, however, remains to be determined.<br />
1. Anatomic distribution<br />
Somatostatin-producing cells are present throughout<br />
the central and peripheral nervous systems, the gut, the<br />
endocrine pancreas and, in small number, in the thyroid,<br />
adrenals, submandibular glands, kidneys, prostate, and<br />
placenta (813, 880). Within the hypothalamus, the majority<br />
<strong>of</strong> SS-positive nerve perikarya lie in the PeVN (360),<br />
but these are also seen in the ARC and VMN (see sect.<br />
IIIA3). They are located close to the third ventricle, in a<br />
few layers parallel to the periventricular wall, within an<br />
area extending from the preoptic nucleus (PON) to the<br />
rostral margin <strong>of</strong> the VMN (357). Axons from these cells<br />
run caudally through the hypothalamus to form a discrete<br />
pathway toward the midline that enters the ME, where the<br />
nerve endings extend in a compact band throughout the<br />
zona externa.<br />
Not all fibers from the PeVN take this route; a small<br />
proportion <strong>of</strong> them travels through the neural stalk to the<br />
neurohypophysis where they presumably play a role in<br />
the regulation <strong>of</strong> the secretion <strong>of</strong> neurohypophysial hormones,<br />
arginine vasopressin (AVP) and oxytocin. Other<br />
fibers project outside the hypothalamus to areas such as<br />
the limbic system; others interconnect, possibly through<br />
interneurons, with several hypothalamic nuclei, including<br />
the ARC where GHRH is synthesized, the PON, and the<br />
VMN, which are involved in regulating reproductive functions,<br />
and the SCN, which has a circadian pacemaker<br />
activity (see also sect. IIIA2).<br />
Somatostatin neurons in the anterior PeVN area interact<br />
with multiple populations <strong>of</strong> neurons such as galanin,<br />
NPY, GABA, 5-HT, endogenous opioid peptides<br />
(EOP), and others and receive a host <strong>of</strong> neurochemically<br />
defined terminals (96, 118). In addition to the anatomic<br />
interactions with GHRH, there is also a connection between<br />
SS and corticotropin-releasing hormone (CRH) (reviewed<br />
in Ref. 96).<br />
Further details on the distribution <strong>of</strong> SS neurons and<br />
fiber systems are given in section IIIA3.<br />
2. Gene structure and expression<br />
The SS gene in the rat and humans has a simple<br />
configuration, the coding region consisting <strong>of</strong> two exons<br />
separated by an intron (see Ref. 814 for review). The<br />
5-upstream region contains three regulatory elements,<br />
two promoters, and a cAMP-response element (enhancer).<br />
This latter was first identified in the SS gene and is<br />
present in a large number <strong>of</strong> genes regulated by cAMP<br />
(736). Most agents influencing SS secretion also alter SS<br />
gene expression. Activation <strong>of</strong> the AC-cAMP pathway<br />
plays an important role in the stimulation <strong>of</strong> SS secretion<br />
and mediates the effect <strong>of</strong> several agents physiologically<br />
regulating SS gene transcription (glucagon, GHRH).<br />
<strong>Growth</strong> hormone secretion is also autoregulated<br />
through the stimulation <strong>of</strong> SS mRNA (see sect. VIIA).<br />
Gonadal hormones play a significant effect contributing<br />
to the sex-related differences in SS neuronal activity (see<br />
sect. IIB3A).<br />
3. <strong>Secretion</strong> from the hypothalamus<br />
Somatostatin release from different in vitro preparations<br />
is enhanced by K -induced membrane depolarization,<br />
mediated by Ca 2 influx (818), cAMP, dopamine<br />
(DA), glycocytopenia, IGF-I, GH, and GHRH (for these<br />
aspects, see sects. IIIA3 and VII, A and B1). Somatostatin-14<br />
is the main form <strong>of</strong> SS-IR released on K depolarization<br />
from slices <strong>of</strong> the rat hypothalamus, implying that<br />
this is the form responsible for hypothalamic neurotransmission<br />
(841).<br />
Contradictory results have been reported on how<br />
different neurotransmitters affect SS release, a vital question<br />
for understanding their mechanism(s) <strong>of</strong> action (see<br />
sect. V). Factors related to the different experimental<br />
models used to study SS release in vitro (e.g., hypothalamic<br />
slices or explants, embryonic cell cultures, synaptosomes)<br />
may hinder evaluation <strong>of</strong> the neurotransmitter’s
532 MÜLLER, LOCATELLI, AND COCCHI Volume 79<br />
action in vivo. Comparison in vivo is already difficult<br />
because <strong>of</strong> the complex neuronal circuitry <strong>of</strong> hypothalamic-extrahypothalamic<br />
connections and accessibility <strong>of</strong><br />
specific sites.<br />
Acetylcholine has been reported to inhibit (888) or to<br />
have no effect (650) on SS-LI release from hypothalamic<br />
fragments and to enhance SS-LI release from dispersed<br />
cell cultures (834) and portal blood (228), whereas enhancement<br />
<strong>of</strong> the cholinergic tone in humans appears to<br />
suppress SS release (see sect. VA3 and Ref. 749 for discussion).<br />
Dopamine in micromolar concentrations can<br />
release SS-LI from incubated hypothalamic tissue (772)<br />
and synaptosomal preparations (1077) and raise the SS-LI<br />
concentration in the pituitary portal blood (228). However,<br />
DA did not have this effect when the whole MBH<br />
was exposed to physiological concentrations <strong>of</strong> the transmitter<br />
(339), a finding more in line with in vivo results<br />
(see sect. VA1D). Norepinephrine (NE) stimulated or had<br />
no effect on SS-IR release from the ME (650, 771),<br />
whereas in vivo an inhibitory role on SS function is suggested<br />
(see sect. VA1A). Finally, GABA inhibited SS-LI<br />
release from hypothalamic cells in cultures, an action<br />
blocked by the GABA receptor antagonist bicuculline<br />
(385), and in line with evidence obtained in vivo (see sect.<br />
VA5B1). Somatostatin release in vivo is stimulated by a<br />
number <strong>of</strong> neuropeptides, including thyrotrophin-releasing<br />
hormone (TRH) (544), CRH (188, 730), and GHRH<br />
(42). Each <strong>of</strong> these peptides administered centrally inhibits<br />
GH secretion, and these effects can be completely<br />
counteracted by pretreatment with SS antibodies.<br />
In contrast to CA and ACh, intraventricular injection<br />
<strong>of</strong> 5-hydroxytryptamine (5-HT) did not affect SS-LI release<br />
into the portal blood (228), whereas centrally injected<br />
bombesin (1) or NT (3) was effective and EOP<br />
either inhibit (326) or have no effect (957) on SS-LI release.<br />
A) SEX-RELATED DIFFERENCES. As already mentioned in<br />
section IIA, SS neurons play an important role in sexrelated<br />
differences in GH secretion. A significant sexrelated<br />
difference is observed in the gene expression <strong>of</strong><br />
hypothalamic SS (40, 238, 1044) and hypothalamic content<br />
<strong>of</strong> SS in rats (383, 440), mainly depending on gonadal<br />
steroids, particularly by androgens.<br />
In castrated rats, testosterone or dihydrotestosterone<br />
raises SS mRNA levels (40, 238, 463, 1131), and male rats<br />
have significantly more androgen receptors than females<br />
in the PeVN (903). The sexual dimorphism <strong>of</strong> SS gene<br />
expression is evident as early as 10 days <strong>of</strong> age and<br />
persists throughout development, whereas GHRH gene<br />
expression is sexually dimorphic only in the late neonate<br />
and adult (40). It appears, therefore, that in male rats<br />
androgens influence SS neurons through organizational<br />
and activational roles while the sex steroids can only<br />
activate the GHRH system.<br />
Fernandez-Vasquez et al. (352) and Ono and Miki<br />
(797) have provided in vitro pro<strong>of</strong> <strong>of</strong> a direct action <strong>of</strong><br />
gonadal steroids on SS-producing neurons. The former<br />
authors showed that SS release from hypothalamic<br />
fragments in culture was increased if donor male rats<br />
had been castrated, this effect being partially reversed<br />
by testosterone treatment. The second group showed<br />
that exposure <strong>of</strong> cultured fetal brain cells to testosterone<br />
had an inhibitory effect on SS release and production,<br />
as indicated by the decrease in its intracellular<br />
concentration and content in the medium. The reason(s)<br />
for the discrepancy between these results and<br />
reports that androgens stimulate SS mRNA is not<br />
known but might reflect the independent effects <strong>of</strong><br />
gonadal steroids on gene transcription and/or on the<br />
processing, storage, or release <strong>of</strong> SS, as has been demonstrated<br />
for other neuropeptides (73).<br />
Different from the androgens, estradiol inhibited SS<br />
release from fetal brain cultures (352), a finding consistent<br />
with previous reports that ovariectomy increased the<br />
amount <strong>of</strong> IR-SS in the ME and that this effect was reversed<br />
by estradiol (439). Reduction <strong>of</strong> SS release would<br />
be related to the raised baseline GH levels observed in<br />
female rodents (524, see also sect. IIA).<br />
4. Receptors<br />
Parallel to studies <strong>of</strong> the effect <strong>of</strong> SS and its analogs<br />
on endocrine and exocrine secretion were investigations<br />
into their mechanisms <strong>of</strong> action. Plasma membrane receptor<br />
binding <strong>of</strong> SS, and especially <strong>of</strong> analogs resistant to<br />
degradation, was demonstrated on all target tissues (151).<br />
Receptor binding was demonstrated in vitro to plasma<br />
membrane preparations and to tissue sections (586) and<br />
in vivo by radionuclide scanning (577).<br />
Shortly after the discovery <strong>of</strong> SS-28 as a second endogenous<br />
ligand, the existence <strong>of</strong> two populations <strong>of</strong> SS<br />
receptors (sstr) was proposed, based on the different<br />
receptor binding potencies and actions <strong>of</strong> SS-14 and SS-28<br />
in brain, pituitary, and islet cells (817, 979). The heterogeneity<br />
<strong>of</strong> sstr became increasingly apparent when crosslinked<br />
studies revealed a wide array <strong>of</strong> proteins <strong>of</strong> different<br />
molecular weights that bound the labeled peptide.<br />
Cloning <strong>of</strong> the sstr family disclosed the overall complexity<br />
<strong>of</strong> the system.<br />
Cloning <strong>of</strong> five separate sstr genes confirmed the<br />
existence <strong>of</strong> molecular subtypes and indicated a greater<br />
heterogeneity in this receptor family than previously suspected<br />
(see Ref. 815 for review). Four <strong>of</strong> the human genes<br />
are intronless, the exception being sstr 2, which gives rise<br />
to the spliced variants sstr 2a and sstr 2b that differ only in<br />
the length <strong>of</strong> the cytoplasmic COOH tail. There are thus<br />
six putative sstr subtypes highly conserved in size and<br />
structure, displaying the putative seven-transmembrane<br />
domain typology typical <strong>of</strong> G protein-coupled receptors;<br />
sstr 1 and sstr 4 show the highest degree <strong>of</strong> sequence iden-
April 1999 NEUROENDOCRINE CONTROL OF GROWTH HORMONE SECRETION 533<br />
TABLE 1. Pattern <strong>of</strong> expression <strong>of</strong> somatostatin receptor subtypes in central nervous system<br />
tity. The individual subtypes show a remarkable degree <strong>of</strong><br />
structural conservation across species.<br />
All sstr subtypes bind SS-14 and SS-28 with high<br />
affinity; sstr 1 and sstr 4 have weak selectivity for SS-14,<br />
whereas sstr 5 appears to be SS-28 selective (816). The<br />
octapeptide analogs octreotide, lanreotide, and vapreotide,<br />
now used clinically, bind to only three types <strong>of</strong><br />
sstr, with high affinity for types 2 and 5 and moderate<br />
affinity for type 3 (152). Therefore, the receptor family can<br />
be divided into two subclasses: 1) sstr 2, sstr 3, and sstr 5<br />
that recognize these analogs and constitute one subgroup,<br />
and 2) sstr 1 and sstr 4 that react poorly with these compounds<br />
and make up another subgroup.<br />
Ligand activation <strong>of</strong> endogenous sstr is associated<br />
with a reduction in intracellular cAMP and [Ca 2 ] i concentrations<br />
and stimulation <strong>of</strong> protein tyrosine phosphatase<br />
due to receptor activation <strong>of</strong> five major membrane<br />
signaling pathways each involving a pertussis toxin-sensitive<br />
GTP-binding protein and comprising 1) receptor<br />
coupling to adenylyl cyclase, 2) receptor coupling to K <br />
channels, 3) receptor coupling to Ca 2 channels, 4) receptor<br />
coupling to exocytotic vesicles, and 5) receptor<br />
coupling to protein phosphatase (see Refs. 337, 816 for<br />
reviews).<br />
The sstr are coupled to several populations <strong>of</strong> K <br />
channels whose activation causes hyperpolarization <strong>of</strong><br />
the membrane leading to cessation <strong>of</strong> spontaneous action<br />
potential activity and a secondary reduction in [Ca 2 ] i<br />
(962). Somatostatin also acts directly on high-voltagedependent<br />
Ca 2 channels to block Ca 2 currents (501). A<br />
further mechanism would be inhibition <strong>of</strong> Ca 2 currents<br />
through induction <strong>of</strong> cGMP, activation <strong>of</strong> cGMP protein<br />
kinase, and phosphorylation-dependent inhibition <strong>of</strong> Ca 2<br />
channels (712).<br />
A) TISSUE EXPRESSION OF RECEPTOR SUBTYPES. Expression<br />
<strong>of</strong> mRNA for sstr confirmed their wide tissue distribution<br />
sstr 1 sstr 2 sstr 3 sstr 4 sstr 5<br />
Hypothalamus <br />
Hippocampus <br />
Striatum <br />
Amygdala <br />
Olfactory tubule <br />
Midbrain <br />
Thalamus ND<br />
Olfactory bulb <br />
Cortex <br />
Cerebellum ND ND<br />
Medial pons ND<br />
Preoptic area <br />
Nucleus accumbens ND<br />
Spinal cord ND<br />
Relative pattern <strong>of</strong> somatostatin receptor (sstr) expression was determined as follows: autoradiographic densities were quantitated using a<br />
laser densitometer in 2-dimensional scan mode to obtain a densitometric value for entire autoradiographic band. Density <strong>of</strong> each band is expressed<br />
relative to density for hippocampus, which was set to equal . ND signifies that sstr subtype was not detected. Thus comparisons should be made<br />
within a given subtype between regions rather than between subtypes. [From Bruno et al. (151); copyright The Endocrine Society.]<br />
with a particular pattern for each receptor type, which<br />
does not rule out overlap, because few tissues or cells<br />
have the mRNA for only one receptor type (151). Adult rat<br />
pituitary features all five sstr mRNA, and the adult human<br />
pituitary expresses the four subtypes 1, 2, 3, and 5 (286,<br />
815). All five genes are expressed by the major pituitary<br />
cell subsets with high levels <strong>of</strong> sstr 4 and sstr 5 in rat<br />
somatotrophs and <strong>of</strong> sstr 2 mRNA in rat thyrotrophs (786).<br />
The finding that sstr 5 mRNA is more abundant than sst 2<br />
mRNA in the pituitary is consistent with fact that SS-28 is<br />
more potent than SS-14 for inhibiting GH and TSH secretion.<br />
All five sstr mRNA are variably expressed in the brain<br />
(151) (Table 1); sstr 1 and sstr 2 were found in the highest<br />
concentrations in cortex, amygdala, hypothalamus, and<br />
hippocampus, whereas the highest level <strong>of</strong> sstr 3 was in<br />
the cerebellum, a unique finding given the relatively low<br />
receptor density in this area (151). Expression <strong>of</strong> sstr 4<br />
was observed throughout the CNS, but this is<strong>of</strong>orm was<br />
not found in the cerebellum. Sstr 5 showed a unique pattern,<br />
occurring mainly in the hypothalamus and POA,<br />
which suggests it has a highly specialized role in the CNS<br />
(151).<br />
Future attempts to correlate the regional distribution<br />
<strong>of</strong> sstr subtypes in the CNS with the functional properties<br />
<strong>of</strong> SS will call for the development <strong>of</strong> ligands that bind<br />
selectively and with high affinity to each subtype. Nevertheless,<br />
the high levels <strong>of</strong> sstr 1, sstr 2, sstr 3, and sstr 4 in<br />
such brain regions as cortex, hippocampus, hypothalamus,<br />
and amygdala suggest they are involved in processing<br />
integrative functions.<br />
Of particular interest for our topic is the distribution<br />
<strong>of</strong> sstr and mRNA expression in the hypothalamus, where<br />
it provides evidence <strong>of</strong> multiple receptor subtypes. Conventional<br />
film autoradiography suggests sstr are not very<br />
abundant in hypothalamic regions, although desaturation
534 MÜLLER, LOCATELLI, AND COCCHI Volume 79<br />
techniques considerably increase the amount <strong>of</strong> binding<br />
(608). Of the five cloned sstr subtypes, four are synthesized<br />
in the hypothalamus, the expression <strong>of</strong> sstr 5 being<br />
particularly abundant (151). In situ hybridization showed<br />
sstr mRNA-containing cells in all hypothalamic areas,<br />
whereas sstr mRNA cells were restricted mainly to the<br />
ARC, an area rich in both sstr 1 and sstr 2 mRNA (151).<br />
The presence <strong>of</strong> sstr close to a subpopulation <strong>of</strong> ARC<br />
neurons, some corresponding to GHRH neurons, has been<br />
already discussed (see sect. IIIA3). They allow cross talk<br />
in the GH regulatory pathway between the PeVN and the<br />
ARC. Sstr 1, sstr 2, and sstr 3 mRNA have been located in the<br />
ARC and may therefore be implicated in the modulation<br />
<strong>of</strong> GHRH secretion by SS (81, 948).<br />
In addition, sstr 1 mRNA in the ARC appears to be<br />
regulated by GH, which further implicates this receptor<br />
gene in the feedback regulation <strong>of</strong> GH secretion by the<br />
ARC (448, see also sect. VIIA). In the reverse direction, the<br />
ARC sends projections that may contain galanin and proopiomelanocortin<br />
(POMC)-derived peptides to the PeVN<br />
(see sect. IIIB1). These feedback mechanisms involving SS<br />
neurons play an important role in driving the pulsatile<br />
secretion <strong>of</strong> GH.<br />
Analysis <strong>of</strong> secreting and nonsecreting human pituitary<br />
tumors (monoclonal in origin) and rodent pituitary<br />
tumor cells provided evidence <strong>of</strong> several sstr genes and<br />
probably receptor proteins expressed in the same tumor<br />
cell. Both sensitive to octapeptide analogs, sstr 2 and sstr 5<br />
are expressed most frequently, whereas the expression <strong>of</strong><br />
sstr 3 and sstr 4 is much less common (815). The common<br />
presence <strong>of</strong> sstr 2 and sstr 5 in pituitary tumors helps explain<br />
their responsiveness to octreotide, for which these<br />
receptor subtypes have high affinity.<br />
Somatostatin receptors are expressed not only in a<br />
variety <strong>of</strong> pancreatic and intestinal tumors (glucagonomas,<br />
insulinomas, pheocromocytomas), but also in most<br />
solid tumors; sstr 1, sstr 2, sstr 3, and sstr 4 have been shown<br />
on endocrine tumors, but sstr 5 mRNA has not been reported<br />
(815).<br />
It would seem, therefore, that sstr and subtype-specific<br />
analogs <strong>of</strong>fer new opportunities for locating a variety<br />
<strong>of</strong> neoplasms and their metastases, inhibiting their secretory<br />
products, and providing access to the interior <strong>of</strong> the<br />
cells themselves, since SS analogs can be internalized. An<br />
antiproliferative effect has also been suggested for these<br />
analogs (481).<br />
B) DESENSITIZATION. Patients undergoing long-term therapy<br />
with SS analogs develop tolerance to side effects such<br />
as inhibition <strong>of</strong> insulin and TSH secretion. However, the<br />
inhibitory effect on secretory tumors persists <strong>of</strong>ten for<br />
many years. This suggests that sstr in normal tissues are<br />
regulated differently from their antiproliferative effects<br />
on tumors (481).<br />
Desensitization in normal cells is mainly due to agonist-dependent<br />
internalization <strong>of</strong> the receptors, as demon-<br />
strated in rat anterior pituitary and islet cells (31, 737).<br />
Agonist-dependent desensitization responses have been<br />
reported after SS pretreatment for 2horless. Longer<br />
agonist exposure, 24–42 h, upregulated sstr in GH 4C 1<br />
cells and RIN 5f cells (866, 993). In CHO-K 1 cells expressing<br />
all the five human sstr subtypes, sstr 2, sstr 3, sstr 4, and<br />
sstr 5 induced rapid agonist-dependent internalization <strong>of</strong><br />
the ligand over 60 min; sstr 1 caused virtually no internalization.<br />
Prolonged agonist treatment led to differential<br />
upregulation <strong>of</strong> some <strong>of</strong> the sstr: after 22 h, the agonist<br />
upregulated sstr 1 by 110%, sstr 2 and sstr 4 by 22–26%,<br />
whereas sstr 3 and sstr 5 showed no change (493).<br />
C) REGULATION OF GENE EXPRESSION. Expression <strong>of</strong> sstr<br />
subtypes is regulated by hormones. Glucocorticoids upregulate<br />
sstr 1 and sstr 2 mRNA after short-term exposure,<br />
whereas prolonged treatment inhibits transcription <strong>of</strong><br />
both genes (1109). Estrogens upregulate mRNA expression<br />
<strong>of</strong> sstr 2 and sstr 3 in rat prolactinoma cells (1102) and<br />
in breast cancer cells (1110). Metabolic derangements<br />
such as starvation or diabetes lower sstr 3 mRNA levels in<br />
the pituitary and sstr 5 mRNA levels in the hypothalamus<br />
(150), but the significance <strong>of</strong> this is still obscure.<br />
Four sstr promoters have been characterized and<br />
contain consensus sequences for a variety <strong>of</strong> transcription<br />
factors. Rat sstr 1 gene shows AP2 and Pit-1 binding<br />
sites (464); human sstr 2 and sstr 4 contain several AP1 and<br />
AP2 sites that may confer cAMP responsiveness (438).<br />
5. Pituitary and extrapituitary effects<br />
The physiological role <strong>of</strong> SS in pituitary responsiveness<br />
to hypothalamically driven stimulatory influences,<br />
especially those <strong>of</strong> GHRH, and thus contributing to the<br />
pulsatile secretion <strong>of</strong> GH, has already been extensively<br />
discussed. Here, brief consideration is given to some in<br />
vivo inhibitory effects <strong>of</strong> SS on the pituitary, especially in<br />
conditions <strong>of</strong> stimulated GH release. These inhibitory effects<br />
have been shown in a number <strong>of</strong> species in addition<br />
to rodents, e.g., dogs, monkeys, and humans. In humans,<br />
SS prevented levodopa, exercise, hypoglycemia, and<br />
sleep-evoked GH secretion and also lowered GH levels in<br />
diabetic and acromegalic subjects (749).<br />
Somatostatin may not merely inhibit GH secretion,<br />
but under appropriate conditions may also trigger GH<br />
release, through an intrahypothalamic site <strong>of</strong> action.<br />
Within the PeVN, SS in fact seems to operate an ultrashort<br />
feedback loop to inhibit its own secretion. The recent<br />
demonstration that the distribution <strong>of</strong> neurons expressing<br />
sstr 1 mRNA in the hypothalamus overlaps the distribution<br />
<strong>of</strong> SS has led to the proposal that sstr 1 may be the autoreceptors<br />
(816).<br />
Furthermore, SS can directly act on AP thyrotrophs<br />
to inhibit TSH secretion or it may act on the hypothalamus<br />
to inhibit TRH secretion (880). Thyroid hormones<br />
can stimulate SS release, although this effect appears to
April 1999 NEUROENDOCRINE CONTROL OF GROWTH HORMONE SECRETION 535<br />
be indirectly mediated through a direct action to increase<br />
GH gene transcription (see sect. VIA2). Somatostatin in<br />
the AP can also inhibit prolactin secretion from normal<br />
and adenomatous glands in humans and GH 4C 1 tumor<br />
cells and ACTH secretion from human and mouse AtT-20<br />
ACTH-producing tumors (817) (for interactions between<br />
the SS system and HPA axis, see sect. VIA1). Pituitary sstr<br />
involved in the effects <strong>of</strong> SS or its analogs have already<br />
been discussed.<br />
Somatostatin has no effect on basal levels <strong>of</strong> GH<br />
synthesis, gene transcription, mRNA, or somatotroph proliferation<br />
in rat or bovine pituitary cell cultures (73, 104,<br />
381, 960, 1020) or on the elevation <strong>of</strong> rat GH mRNA<br />
induced by exogenous cAMP (963). It also does not influence<br />
GHRH-stimulated rat GH transcription, although it<br />
reduced intracellular cAMP levels (381). However, it attenuated<br />
the GHRH-induced increase in somatotroph proliferation<br />
(104) and the expression <strong>of</strong> c-fos in the rat (103).<br />
Limited data are available on how SS maintains normal<br />
GH synthesis and body growth in vivo. Despite AP<br />
concentrations <strong>of</strong> SS two to three times higher than any<br />
other body tissue, transgenic mice expressing a metallothionein-SS<br />
fusion gene grew at a normal rate (638) (for<br />
details, see Ref. 377).<br />
The extensive localization <strong>of</strong> SS in the CNS indicates<br />
its neurotransmitter and/or neuromodulatory role. In recent<br />
years attention has focused especially on its function<br />
in certain CNS areas such as the cortex or the hippocampus,<br />
with clinical implications for cognitive functions and<br />
Alzheimer’s disease, and in the striatum, with implications<br />
for movement control in Parkinson’s disease (936).<br />
Somatostatin also plays an important physiological<br />
role in the pancreas and gut (814, 941). It regulates the<br />
endocrine and exocrine functions <strong>of</strong> the stomach, intestine,<br />
and pancreas and the motor functions <strong>of</strong> the first<br />
two, partly by local or paracrine mechanisms and partly<br />
through the circulation as a true endocrine factor. Thus<br />
not only does SS exert its regulatory actions within organs<br />
that have SS-containing D cells, but it also ensures a more<br />
integrated control over the nutrient flux by acting on<br />
remote target organs containing no D cells (941).<br />
IV. GROWTH HORMONE-RELEASING PEPTIDES<br />
Many years before native GHRH was isolated and<br />
sequenced, a new series <strong>of</strong> peptides with strong GHreleasing<br />
properties had been identified (732). The size<br />
and scope <strong>of</strong> this new class, known jointly as GHRP or GH<br />
secretagogues (GHS) and comprising nonpeptide pharmacological<br />
analogs, have grown enormously. 2<br />
The first GHRP were discovered in 1977 by Bowers et<br />
2<br />
The acronyms GHRP and GHS are used interchangeably in the<br />
text.<br />
al. (133). They were derivatives <strong>of</strong> the pentapeptide Metenkephalin<br />
but had no, or very little, opioid activity. The<br />
pentapeptide Tyr-D-Trp-Gly-Phe-Met-NH 2 had relatively<br />
weak potency as a GH secretagogue and was active only<br />
in vitro; however, it served as a model to design new<br />
molecules with much greater activity (Fig. 7).<br />
As described by Momany et al. (733), the design<br />
approach consisted <strong>of</strong> using “structural concepts” derived<br />
from conformational energy calculations in conjunction<br />
with peptide synthesis and biological activity data.<br />
Unique, and the key to the success <strong>of</strong> this approach, was<br />
the insertion <strong>of</strong> structural data derived from conformational<br />
energy calculations into the design cycle, before<br />
synthesis <strong>of</strong> the peptide, as well as after obtaining experimental<br />
data. A number <strong>of</strong> structurally related GH-releasing<br />
peptides were designed, with greater GH-releasing<br />
activity. <strong>Growth</strong> hormone-releasing peptide-6 (Fig. 7) was<br />
considered particularly suited because <strong>of</strong> its potent GHreleasing<br />
activity in vitro and in vivo.<br />
The GH-releasing activity <strong>of</strong> GHRP-6 was demonstrated<br />
in a range <strong>of</strong> species, i.e., monkeys, sheep, pigs,<br />
chicks, steer, and rats (134, 276, 322, 575, 655), as well as<br />
in humans (135, 504). <strong>Growth</strong> hormone-releasing peptide-6<br />
was orally active in rats, dogs, monkeys, and humans<br />
(132, 1079), and interestingly, it was 5.3–30 times<br />
more effective in monkeys than in rats or dogs. In humans,<br />
1 g/kg GHRP-6 administered as a bolus injection<br />
released more GH than GHRH-44 given at the same dosage<br />
and by the same route (131, 135). In healthy humans,<br />
comparable amounts <strong>of</strong> GH were released after intravenous<br />
1 g/kg GHRP-6 or 300 g/kg oral GHRP-6 (132). In<br />
healthy volunteers, clear-cut GH release also occurred<br />
after intranasal administration <strong>of</strong> 30 g/kg GHRP-6; when<br />
15 g/kg GHRP-6 was administered intranasally every 8 h<br />
for 3 days, serum GH and IGF-I levels increased significantly<br />
(466). In these studies, the stimulation <strong>of</strong> GH release<br />
appeared to be specific and divorced from concurrent<br />
adverse effects, with the exception <strong>of</strong> occasionally<br />
mild sweating.<br />
<strong>Growth</strong> hormone-releasing peptides are the most<br />
effective GHS in experimental animals; their action is<br />
greater than that <strong>of</strong> GHRH, with which it is synergistic,<br />
and is well preserved in aged rats when GHRP are<br />
administered combined with GHRH (1080). In the same<br />
model, chronic treatment with a GHRP-6 analog,<br />
hexarelin (296), maintained its GH-releasing effect for<br />
up to 2 mo, did not change circulating IGF-I levels, and,<br />
interestingly, reduced the hypothalamic somatostatin<br />
mRNA content to the levels <strong>of</strong> young controls (189). In<br />
senescent dogs, a 16-wk huge daily dose <strong>of</strong> hexarelin<br />
initially primed and then blunted the GH response to<br />
acute hexarelin, although this was easily restored after<br />
treatment withdrawal. Despite this effect, hexarelin<br />
raised the indices <strong>of</strong> spontaneous GH pulsatility, reduced<br />
bone resorption, and improved some biochemi-
536 MÜLLER, LOCATELLI, AND COCCHI Volume 79<br />
cal and morphological muscular indices, although it did<br />
not change plasma IGF-I levels (210).<br />
A. Structure-Activity Relationships<br />
These peptides all need a very specific configuration<br />
<strong>of</strong> selected aromatic rings to specifically stimulate GH<br />
release. The native pentapeptide served as the starting<br />
model for the development <strong>of</strong> more potent GHRP. The<br />
prototype was GHRP-6, from which many different analogs,<br />
ranging from 7- to 3-amino acid residues (GHRP-1,<br />
GHRP-2, hexarelin, and so on) have been synthesized and<br />
shown to be active also in humans. Newer peptides with<br />
smaller molecular size and less complexity have now<br />
been synthesized in the hope <strong>of</strong> understanding the minimal<br />
tridimensional structure required (295, 1115).<br />
Homologous desensitization occurs very rapidly in<br />
vitro after exposure to GHRP, whereas the cells remain<br />
sensitive to GHRH (335). Although peptidyl GHRP were<br />
initially introduced as specific GHS, small rises in serum<br />
FIG. 7. Milestones <strong>of</strong> GH-releasing peptide development.<br />
[Modified from Deghenghi (295).]<br />
cortisol and prolactin were seen in humans after intravenous<br />
infusion, bolus injection, or intranasal administration<br />
<strong>of</strong> these compounds (135). Stimulation <strong>of</strong> GH and<br />
prolactin secretion from primary pituitary cell cultures<br />
has also been reported (692). The real impact <strong>of</strong> these<br />
observations in situations <strong>of</strong> long-term peptide and nonpeptide<br />
GHS therapy is not known.<br />
Despite their potential for affecting the secretion <strong>of</strong><br />
more than one AP hormone (see also sect. IVE), nowadays<br />
GHRP are the most effective GHS known and could be<br />
pr<strong>of</strong>itably used in humans with GH hyposecretory disturbances<br />
to promote a pattern <strong>of</strong> GH secretion that mimics<br />
the physiological situation better than exogenous GH.<br />
B. Nonpeptidyl <strong>Growth</strong> <strong>Hormone</strong> Secretagogues<br />
The strategy <strong>of</strong> stimulating pituitary GH secretion by<br />
activating the endogenous machinery is an attractive idea<br />
that has been pursued with the synthesis <strong>of</strong> nonpeptidyl<br />
mimics <strong>of</strong> GHRP-6; this research has led to the discovery
April 1999 NEUROENDOCRINE CONTROL OF GROWTH HORMONE SECRETION 537<br />
<strong>of</strong> a series <strong>of</strong> new compounds, the benzolactam secretagogues,<br />
reviewed in Reference 965 (Fig. 7).<br />
Structural modifications <strong>of</strong> the original molecule led<br />
first to the isolation <strong>of</strong> L-692,429, which was well tolerated<br />
in animals and humans, and then to the synthesis <strong>of</strong> new<br />
compounds culminating in the selection for clinical use <strong>of</strong><br />
L-163,191 and its mesylate salt MK-677, which <strong>of</strong>fers superior<br />
oral potency and duration <strong>of</strong> action (811). These<br />
new molecules are very effective in eliciting GH release,<br />
although in vivo they also stimulate the release <strong>of</strong> ACTH<br />
and prolactin. MK-677 also raises fasting blood glucose<br />
and insulin concentrations in humans (220, 400, 467).<br />
Although the oral bioactivity <strong>of</strong> this compound is greater<br />
than the peptidyl secretagogues, the clinical use <strong>of</strong> these<br />
molecules is currently hampered by our inadequate understanding<br />
<strong>of</strong> the pharmacodynamic pr<strong>of</strong>ile required for<br />
optimal efficacy.<br />
C. Site(s) and Mechanism <strong>of</strong> Action<br />
<strong>Growth</strong> hormone-releasing peptide may act on the<br />
pituitary (407, 628), although experimental evidence indicates<br />
that they are also active in the hypothalamus (314,<br />
335, 966, 1037). Specific binding sites for GHRP have been<br />
detected in the pituitary and hypothalamus in rats and<br />
pigs (261, 856, 953, 1062) and in rats also in several<br />
extrahypothalamic structures, including the substantia<br />
nigra, CA 2 and CA 3 subfields, dentate gyrus <strong>of</strong> the hippocampus,<br />
and medial amygdaloid nucleus. The membrane<br />
binding sites are specific, reversible, saturable, as<br />
well as time, temperature, pH, and concentration dependent.<br />
Studies on pituitary and hypothalamic membranes<br />
suggest these may be multiple binding sites with different<br />
affinities for peptidyl and nonpeptidyl GHRP. In the rat<br />
pituitary and hypothalamic membranes, MK-677 would<br />
bind preferentially to a high-affinity site (dissociation constant<br />
in the picomolar range), whereas medium-affinity<br />
(nanomolar range) and low-affinity (millimolar range)<br />
sites for the GHRP would primarily bind GHRP-6 (261,<br />
856, 953). Hong et al. (488) have now directly demonstrated<br />
the existence <strong>of</strong> receptor subtypes for the GHRP<br />
using a photoactivable derivative <strong>of</strong> hexarelin. This subtype<br />
is apparently distinct from the recently cloned GHRP<br />
receptor.<br />
Compounds such as bombesin, neuromedin C, and<br />
substance P (SP) did not influence these binding sites,<br />
whereas GHRH-(1O29)-NH 2 and SP were potent inhibitors<br />
<strong>of</strong> pituitary and hypothalamic GHRP-6 binding (261,<br />
953, 1062). Competition by SP antagonists was consistent<br />
with the reported ability <strong>of</strong> the antagonists to decrease<br />
the release <strong>of</strong> GH by GHRP-6 in vitro and in vivo in a<br />
dose-dependent manner (107, 226). Because SP antagonists<br />
selectively blocked the GH release elicited by GHRP<br />
but not by GHRH and SP was ineffective in vivo and in<br />
vitro, these compounds presumably interact with GHRP<br />
receptors. More surprising was the inhibitory effect <strong>of</strong> the<br />
GHRH analog, since GHRP receptors are different from<br />
GHRH receptors, as suggested by the lower GH-releasing<br />
activity <strong>of</strong> GHRP in vitro, the additive effect <strong>of</strong> the two<br />
stimuli, and the fact that GHRP-6 and GHRH antagonists<br />
do not competitively antagonize each other’s responses,<br />
with the only exception being GHRP-2, whose action is<br />
inhibited by GHRH antagonists (1107).<br />
The finding <strong>of</strong> specific binding sites for peptidyl-<br />
GHRP in humans has confirmed the highest specific binding<br />
in the hypothalamus and pituitary but also has shown<br />
their presence in the choroid plexus and the cerebral<br />
cortex (746). Specific binding sites in extrahypothalamic<br />
areas (see also above), coupled with the accessibility to<br />
the brain <strong>of</strong> different GHRP, even when administered<br />
peripherally (314, 315, 963), suggests these compounds<br />
may affect brain function. Accordingly, peripherally administered<br />
GHRP modified the sleep pattern in humans<br />
(267, 268, 372) and stimulated food intake in the rat (642)<br />
and humans (220).<br />
Identification <strong>of</strong> the sites(s) <strong>of</strong> action <strong>of</strong> GHRP is <strong>of</strong><br />
major importance; their much greater effectiveness in<br />
vivo than in vitro suggested a major hypothalamic site<br />
(136, 468, 624, 1037), although this view has to be tempered<br />
by the observation that after hypothalamo-pituitary<br />
disconnection, GHRP released GH in rats (164, 654) or<br />
sheep (364). In pigs, GHRP are effective in intact animals<br />
and those with a hypophysial transection (468), although<br />
in the latter GH release was reduced and depended on the<br />
interval from surgery.<br />
In contrast to most <strong>of</strong> these findings, GHRP were<br />
unable to stimulate GH release in children and adults with<br />
pituitary stalk transection, despite their responsiveness to<br />
GHRH (465, 631, 861). Overall, these results suggest that<br />
the hypothalamus is the primary site <strong>of</strong> action <strong>of</strong> GHRP at<br />
least in humans and pigs.<br />
In our studies in rats with complete surgical ablation<br />
<strong>of</strong> the medial basal hypothalamus, the GH release elicited<br />
by hexarelin was reduced 1 wk after surgery, whereas the<br />
response to GHRH was maintained. Thirty days postsurgery,<br />
the GH response to an acute challenge with hexarelin<br />
or GHRH was similar to that with hexarelin 7 days<br />
postsurgery (1037). It would seem, therefore, that the<br />
decreased pituitary GH content resulting from the chronic<br />
GHRH deprivation was not responsible for blunting the<br />
GH response to GHRP.<br />
1. Hypothalamic mechanisms<br />
Briefly reviewed here are the possible mechanisms<br />
underlying the GH-releasing activity <strong>of</strong> GHRP.<br />
A) GHRH. In sheep, direct measurement <strong>of</strong> hypophysiotropic<br />
neurohormones released into the portal blood
538 MÜLLER, LOCATELLI, AND COCCHI Volume 79<br />
showed that one GHRP, hexarelin, raised GHRH concentrations<br />
without altering SS concentrations (446). Supporting<br />
the involvement <strong>of</strong> GHRH was the finding that<br />
GHRP partially lost their ability to stimulate GH release in<br />
adult rats passively immunized against GHRH (88, 245,<br />
266). Systemic or intraventricular doses <strong>of</strong> GHRP-6 or the<br />
nonpeptidyl analogs caused c-fos accumulation and electrical<br />
excitation <strong>of</strong> putative GHRH neurons in the ARC<br />
(313), and c-fos mRNA was also induced in GHRH and<br />
NPY ARC neurons after systemically administered KP-102<br />
or GHRP-6 (315, 537, 963). More direct pro<strong>of</strong> for GHRP-<br />
GHRH interactions was provided by autoradiographic in<br />
situ hybridization studies. They showed that in the rat<br />
MBH there was extensive overlap between GHRP-R and<br />
GHRH hybridizing cells in both the ARC and VMN nuclei<br />
(1011a).<br />
However, other findings suggest GHRH is not necessarily<br />
involved. In dogs and humans, GHRP further increased<br />
the GH release induced by a maximal effective<br />
dose <strong>of</strong> GHRH (135, 823), and reportedly, the GH response<br />
to GHRP alone is considerably greater than to<br />
GHRH (129–131, 135). We showed in neonatal rats that<br />
removal <strong>of</strong> GHRH and SS by passive immunization did not<br />
affect the GH-releasing activity <strong>of</strong> GHRP-6 or hexarelin<br />
(624), and there is also clear-cut, although attenuated, GH<br />
release by administration <strong>of</strong> the same GHRP in 10-day-old<br />
pups passively immunized against GHRH since birth (624,<br />
628). Supporting the existence <strong>of</strong> independent mechanisms<br />
<strong>of</strong> action for GHRP and GHRH, at least under some<br />
circumstances, is also the observation that a series <strong>of</strong><br />
peptidyl and nonpeptidyl GHRP at low doses did not<br />
affect GHRH release from freshly removed rat hypothalami<br />
and, at millimolar concentrations, even inhibited<br />
GHRH release, suggesting an ultrashort-loop feedback<br />
with GHRH (569).<br />
<strong>Growth</strong> hormone-releasing hormone activation thus<br />
appears to be an intermediate, but not obligatory, step <strong>of</strong><br />
GHRP action; an intact hypophysial stalk is mandatory for<br />
maximal GH response, and finally, the pituitary component<br />
<strong>of</strong> the action <strong>of</strong> these compounds is not <strong>of</strong> major<br />
importance.<br />
B) SS. Somatostatin involvement in GHRP action is<br />
less controversial than that <strong>of</strong> GHRH. Somatostatin did<br />
not seem to be directly involved in the GHRP action in<br />
adult rats passively immunized against SS (266), and similar<br />
conclusions were reached in the infant rat (94). Other<br />
experiments indicate that GHRP may even stimulate SS<br />
secretion from hypothalamic fragments (452). However,<br />
SS may play an indirect role by functioning as a GHRP<br />
antagonist in the pituitary (245).<br />
In conscious rats, continuous subthreshold GHRP-6<br />
infusion together with repeated injections <strong>of</strong> GHRH induced<br />
GH responses that were uniform and greater in<br />
magnitude than those <strong>of</strong> rats given GHRH alone. Interestingly,<br />
between repeated GHRH boli, serum GH concen-<br />
trations remained higher than baseline, suggesting that<br />
the GHRP-6 had reduced SS inhibitory influences on the<br />
pituitary. Consistent with these findings, in rats, intracerebroventricular<br />
octreotide completely blocked the GH<br />
release induced by GHRP-6 administered centrally 20 min<br />
later. Because intracerebroventricular octreotide did not<br />
affect the GH release stimulated by intravenous GHRH,<br />
SS was presumably acting as a functional antagonist <strong>of</strong><br />
GHRP-6 at a central site. This was confirmed by Dickson<br />
and Luckman (315), who found the GHRP-6- and MK-<br />
0677-induced c-fos protein expression was attenuated in<br />
the ARC after intravenous or intraventricular octreotide.<br />
Data in humans also point to GHRP antagonism <strong>of</strong> SS<br />
effects. The GH-releasing effect <strong>of</strong> hexarelin was partly<br />
refractory not only to inhibition by compounds stimulating<br />
hypothalamic SS release but even to a dose <strong>of</strong> SS fully<br />
effective in suppressing the GH response to GHRH (51, 53,<br />
645). Moreover, administration <strong>of</strong> GH abolished the GH<br />
response to GHRH, but only blunted the GH response to<br />
hexarelin (50, 674). In view <strong>of</strong> the GH aut<strong>of</strong>eedback on<br />
hypothalamic release <strong>of</strong> SS (see sect. VIIA), this indicates<br />
that hexarelin had counteracted the GH-induced somatostatinergic<br />
hyperactivity. Results with oral MK-677 also<br />
suggest that nonpeptide GHS may functionally antagonize<br />
SS action (220).<br />
C) THE UNKNOWN FACTOR (U FACTOR). Although many<br />
reports have clearly shown that GHRH may be necessary<br />
for GHRP to exert their full effect, none has clearly indicated<br />
a mechanism(s) that would account satisfactorily<br />
for the synergistic effect <strong>of</strong> GHRH and GHRP. Bowers et<br />
al. (136) postulated that GHRP stimulated an unknown<br />
endogenous hypothalamic factor (named U factor) which,<br />
in combination with GHRH, would stimulate GH release<br />
in rats with hypothalamic ablation (1037). However, the<br />
stimulatory effects <strong>of</strong> GHRP in rats with selective GHRH<br />
deficiency (624) also suggest a mechanism mediated by an<br />
endogenous hypothalamic non-GHRH factor, whose existence<br />
and nature are still elusive.<br />
2. Pituitary mechanisms<br />
A) EFFECTS ON GH RELEASE. Sufficient experimental evidence<br />
exists that GHRH and GHRP act on the pituitary<br />
through different mechanisms, and very likely through<br />
different receptors. Somatotroph cells that are maximally<br />
stimulated with GHRP can release more GH in response<br />
to GHRH, and vice versa (223, 436). Moreover, homologous<br />
but not heterologous desensitization is seen after<br />
continuous pituitary exposure to GHRP or GHRH (113,<br />
219, 245, 1106).<br />
It was thought initially that GHRP-6 acted on the<br />
GHRH receptor, since it did not elicit GH release in the<br />
lit/lit mouse, an animal model with a point mutation in<br />
the GHRH receptor (433) (see sect. IIIA8B). However,<br />
investigations using cultures <strong>of</strong> human somatotrophino-
April 1999 NEUROENDOCRINE CONTROL OF GROWTH HORMONE SECRETION 539<br />
FIG. 8. Mechanisms underlying GH releasing effects <strong>of</strong> GH-releasing<br />
peptide. Solid line refers to a probable mechanism; dotted line refers to<br />
an hypothetical (?) mechanism. Functional, reciprocal interaction between<br />
GHRH and somatostatin neurons are also indicated (see text for<br />
details).<br />
mas showed a GH responsiveness to GHRP-6 in all adenomas,<br />
whereas only one-half <strong>of</strong> them responded to<br />
GHRH (883). As an alternative, despite the mutually exclusive<br />
pituitary binding sites for GHRH and GHRP, the<br />
postreceptor activity triggered by GHRH would be instrumental<br />
to GHRP action (335).<br />
In contrast to the marked synergy in vivo, only additive<br />
or mild synergistic effects were evident when GHRP<br />
and GHRH were coincubated in vitro (21, 62, 113, 134).<br />
It is widely recognized that GH release induced by<br />
GHRH is paralleled by an increase in cAMP titers in the<br />
pituitary, followed by the opening <strong>of</strong> VOCC (see sect.<br />
IIIA7). The ensuing rapid increase in [Ca 2 ] i promotes GH<br />
release. In contrast, GHRP-6 had no such effect on cAMP<br />
(223, 1107), but there was a synergistic increase <strong>of</strong> cAMP<br />
levels when GHRP-6 and GHRH were administered together<br />
(223).<br />
Although a precise definition <strong>of</strong> the molecular mechanism(s)<br />
<strong>of</strong> action <strong>of</strong> GHRP is still lacking, these compounds<br />
elicit an increase in [Ca 2 ] i from an extracellular<br />
source, since it was blocked by the chelation <strong>of</strong> extracellular<br />
calcium or incubation with calcium channel blockers<br />
(21, 919). It has also been shown that GHRP-1 and<br />
GHRP-6 depolarize rat pituitary cell membranes, leading<br />
to opening <strong>of</strong> VOCC (857), and it has been proposed that<br />
GHRP-6 and L-692,429 may act, at least in part, through<br />
activation <strong>of</strong> the protein kinase C pathway (224, 225).<br />
Pong et al. (856) have described a specific binding site for<br />
GHRP in porcine and rat pituitary membranes distinct<br />
from that for GHRH and with the properties <strong>of</strong> a new G<br />
protein-coupled receptor. Van der Ploeg and co-workers<br />
(491) reported the cloning <strong>of</strong> a receptor for GHRP-6 and<br />
nonpeptidyl GHS.<br />
All in all, there is abundant experimental evidence<br />
that the GHRP operate through common cellular mechanisms,<br />
involving the activation <strong>of</strong> a receptor(s) different<br />
from that <strong>of</strong> GHRH and <strong>of</strong> intracellular mechanisms different<br />
from the cAMP pathways. It would seem, however,<br />
from some studies that the second messengers activated<br />
by GHRP in somatotrophs may vary depending on the<br />
species considered (184a). Although the GHRP receptor<br />
or, most likely, one <strong>of</strong> its subtypes, has been cloned in<br />
humans, rats, and swine (491, 695), we still have nonconfirmation<br />
<strong>of</strong> the existence, and the nature, <strong>of</strong> the purported<br />
endogenous GHRP ligand. Figure 8 depicts schematically<br />
the hypothetical mechanisms underlying the<br />
GH-releasing properties <strong>of</strong> GHRP.<br />
B) EFFECTS ON GH SYNTHESIS. The GH synthesis in the<br />
pituitary is under the positive control <strong>of</strong> GHRH (see sect.<br />
IIIA7), an effect which involves cAMP activation but appears<br />
to be independent from changes in [Ca 2 ] i (73). It<br />
was therefore <strong>of</strong> interest to investigate whether GHRP<br />
plays a role in the control <strong>of</strong> GH biosynthesis. There are<br />
only very few reports about GHRP effects on GH mRNA<br />
levels. In our own studies, a five-day treatment with<br />
FIG. 9. Effects <strong>of</strong> 3–10 days <strong>of</strong> treatment with hexarelin (HEXA) on<br />
GH mRNA levels in infant rats. Pups were treated as described in legend<br />
to Fig. 1. Because acute challenge with hexarelin had no effect on GH<br />
mRNA levels, in each experimental group data obtained from rats challenged<br />
with hexarelin and saline were pooled. Data are expressed as<br />
means SE <strong>of</strong> 6 determinations. NRS, normal rabbit serum; GHRH-Ab,<br />
GH-releasing hormone antibody. * P 0.05 vs. indicated group. [From<br />
Torsello et al. (1038).]
540 MÜLLER, LOCATELLI, AND COCCHI Volume 79<br />
hexarelin (150 g/kg sc, twice daily) did not modify GH<br />
mRNA levels in the pituitary <strong>of</strong> normal adult male rats<br />
(1037). The same was true for a similar treatment schedule<br />
in rats with surgical ablation <strong>of</strong> the MBH or in intact<br />
rats with two ectopic pituitaries transplanted under the<br />
kidney capsule, two experimental models <strong>of</strong> reduced GH<br />
mRNA levels.<br />
A further approach was to study the effect <strong>of</strong> GHRP<br />
in infant rats, in which both GHRP-6 and hexarelin are<br />
very effective stimulators <strong>of</strong> GH secretion (296, 624,<br />
1037). In these pups 8–10 days <strong>of</strong> treatment with GHRP-6<br />
or hexarelin consistently primed the pituitary to the GH<br />
response elicited by the acute GHRP challenge, but no<br />
effect was detected on pituitary GH mRNA levels. However,<br />
in the same pups treated since birth with an anti-<br />
GHRH serum, whose pituitary GH mRNA levels were<br />
significantly lower than controls, 5 days <strong>of</strong> treatment with<br />
GHRP-6 or hexarelin restored GH mRNA levels to control<br />
values (624, 1038) (Fig. 9). The same effects were seen in<br />
young adult male rats given an anti-GHRH serum for 15<br />
days and receiving a 10-day treatment with hexarelin<br />
(1038).<br />
Overall, these findings indicate that GHRP can raise<br />
GH mRNA levels independently <strong>of</strong> endogenous GHRH;<br />
this effect does not seem to be present in normal rats,<br />
although it may be masked by the overwhelming action <strong>of</strong><br />
GHRH. The failure <strong>of</strong> GHRP to restore GH mRNA levels in<br />
the pituitary <strong>of</strong> rats with surgical disconnection <strong>of</strong> the<br />
hypothalamo-pituitary unit and in the ectopic pituitaries<br />
emphasizes the concept that GHRP act mostly on the<br />
hypothalamus and that the hypothalamo-pituitary unit<br />
must be anatomically and functionally intact.<br />
D. Human Studies<br />
Different peptidyl and nonpeptidyl GHRP are very<br />
effective to stimulate GH secretion in humans (135). Prolonged<br />
infusions <strong>of</strong> GHRP-6 enhanced pulsatile GH secretion<br />
and raised plasma IGF-I concentrations (466, 492,<br />
521; see also below). A challenge with GHRP-6 at the end<br />
<strong>of</strong> the infusion elicited an attenuated GH response, not<br />
due to depletion <strong>of</strong> GH stores, since a challenge with<br />
GHRH stimulated GH release (492, 521). Maximally effective<br />
doses <strong>of</strong> GHRP were more effective than maximally<br />
effective doses <strong>of</strong> GHRH (135, 137, 403), and nonpeptidyl<br />
GHRP were clearly less potent than peptidyl GHRP (309,<br />
335, 400, 692).<br />
In line with the results <strong>of</strong> preclinical studies, experimental<br />
evidence in humans indicates that GHRP potentiate<br />
the GHRH-induced GH release (51, 135, 137, 422,<br />
823) and, as maintained before, induce homologous but<br />
not heterologous desensitization (287, 409, 492, 521,<br />
1035), confirming that also in humans GHRP and GHRH<br />
act on different receptors and activate different postre-<br />
ceptor pathways. <strong>Growth</strong> hormone responses indicating<br />
the development <strong>of</strong> a state <strong>of</strong> receptor downregulation<br />
were only observed in humans when GHRP were delivered<br />
by continuous infusion; repeated, i.e., three times<br />
daily, oral or intranasal doses <strong>of</strong> peptidyl GHRP for up to<br />
15 days (405, 409), once daily oral dosing with nonpeptidyl<br />
GHRP for 4 wk (220), or intranasal peptidyl GHRP for<br />
up to 2 yr (843) induced no signs <strong>of</strong> receptor downregulation.<br />
However, a 16-wk treatment with subcutaneous<br />
hexarelin, twice daily, in elderly subjects resulted in a<br />
partial and reversible attenuation <strong>of</strong> the GH response<br />
(871a).<br />
The GH response to GHRP appears to have less<br />
intrasubject variability than the GH response to GHRH<br />
(409, 492, 686, 1055), probably in relation to its lower<br />
sensitivity to SS action (see above). Similarly, glucocorticoids,<br />
glucose, and exogenous GH, all stimuli allegedly<br />
triggering release <strong>of</strong> endogenous SS (see sects. VI, A1 and<br />
B1, and VIIA), poorly inhibited the GH-releasing activity <strong>of</strong><br />
GHRP, and the same occurred for pirenzepine, a muscarinic<br />
M 1 receptor antagonist, or salbutamol, a 2-adrenoceptor<br />
agonist, and atropine, a nonselective muscarinic<br />
antagonist, which have in common the same mechanism<br />
(50, 167, 401, 645, 674, 823). The modulatory action <strong>of</strong> SS<br />
was not seen for stimuli allegedly inhibiting SS release<br />
such as arginine, atenolol, a selective 1-antagonist, and<br />
pyridostigmine, an inhibitor <strong>of</strong> acetylcholinesterase<br />
(AChE) (see sect. VB), which did not affect hexarelin’s<br />
action (407). These findings may explain why GHRP are<br />
more effective GH releasers than GHRH in vivo.<br />
-Aminobutyric acidergic mechanisms appear to be<br />
involved in the GHRP stimulatory action, since pretreatment<br />
with the benzodiazepine alprazolam blunted hexarelin-induced<br />
GH release (54).<br />
Another point brought to light by the human studies<br />
is the importance <strong>of</strong> viable hypothalamic connections for<br />
full expression <strong>of</strong> GHRP activity on GH secretion. Thus, in<br />
patients with pituitary stalk lesions, the GH-releasing activity<br />
<strong>of</strong> GHRP was severely blunted, also when these<br />
compounds were coadministered with GHRH (631, 855,<br />
861, 976a).<br />
The activity <strong>of</strong> the GHRP is independent <strong>of</strong> sex but<br />
clearly dependent on age (410). In contrast to GHRH,<br />
which is maximally effective as a GH releaser at birth, and<br />
then progressively loses effect with age (52, 403, 408),<br />
GHRP are less effective at birth than at puberty or in the<br />
young adult period, their GH-releasing activity starting to<br />
decline only with aging, although they remain more effective<br />
than GHRH (27, 52, 87, 403, 405, 408, 718). Gonadal<br />
steroids very likely play a role in the increased GH response<br />
to GHRP at puberty but are unable to act at later<br />
periods; in menopausal women, a 3-mo treatment with<br />
transdermal estradiol failed to restore the GH response to<br />
GHRP (53). However, with aging, a host <strong>of</strong> disturbing
April 1999 NEUROENDOCRINE CONTROL OF GROWTH HORMONE SECRETION 541<br />
factors may impair the GH response to most direct- or<br />
indirect-acting stimuli to GH release.<br />
1. Aging<br />
That acute administration <strong>of</strong> GHRP consistently stimulates<br />
GH secretion in healthy elderly subjects (27, 52,<br />
403, 408, 718) holds promise for restoring their reduced<br />
GH secretion rate, which probably contributes for the<br />
increased central obesity, reduced muscle mass and bone<br />
mineral content, and loss <strong>of</strong> psychological well-being<br />
(904).<br />
The response to GHRP persisted after repeated oral<br />
or intranasal doses <strong>of</strong> GHRP-6 or hexarelin (405), and<br />
after oral administration, there was a tendency toward<br />
higher IGF-I concentrations (408). In a randomized, double-blind,<br />
placebo-controlled trial in healthy elderly subjects,<br />
once daily oral MK-677 enhanced pulsatile GH release,<br />
significantly increased serum GH and IGF-I<br />
concentrations and, at a dose <strong>of</strong> 25 mg/day, restored<br />
serum IGF-I concentrations to levels normally seen in<br />
young adults. Desensitization to the action <strong>of</strong> MK-677 was<br />
not apparent after 4 wk <strong>of</strong> daily treatment (220).<br />
It still remains to be established, however, whether<br />
prolonged treatment with GHS has favorable effects on<br />
body composition, functional capacity, and serum lipids,<br />
since impairment <strong>of</strong> glucose tolerance was observed particularly<br />
in subjects with risk factors. This might limit the<br />
therapeutic usefulness <strong>of</strong> nonpeptidyl GHS. A comparison<br />
<strong>of</strong> the GHRP is therefore mandatory to assess their safety<br />
because these side effects have not been reported with<br />
peptidyl GHS. Thus it seems inappropriate as yet to extrapolate<br />
the results with a single GHRP to all the other<br />
members <strong>of</strong> the family, even if they purportedly share a<br />
common mechanism <strong>of</strong> action.<br />
2. GH-secreting tumors<br />
<strong>Growth</strong> hormone-secreting adenomas do not have an<br />
altered GH response to GHRP in vivo (29, 241, 451, 860),<br />
and the marked GH release from somatotrophinoma cells<br />
induced in vitro by GHRP-6 or GHRP-2 (15) may well<br />
contribute to the GH response in vivo. In addition, tumors<br />
refractory to GHRH in vitro may respond to GHRP-6 by<br />
releasing GH (883).<br />
Messenger RNA for the GHRP receptor has been<br />
found present in all human pituitary somatotrophinomas<br />
so far (14, 299) and in the GH3 tumor pituitary cell<br />
line <strong>of</strong> the rat (14). The receptor was also transcribed in<br />
some prolactin-secreting adenomas and, more impressively,<br />
in all <strong>of</strong> 18 ACTH-secreting pituitary adenomas<br />
studied (299).<br />
3. Obesity<br />
The GH response to GHRP in obesity is clear, although<br />
it is attenuated compared with lean controls (269–<br />
271, 561). The combination <strong>of</strong> GHRP and GHRH, however,<br />
markedly stimulated GH secretion in obese patients (131,<br />
269–271, 630). Interestingly, addition to the peptide regimen<br />
<strong>of</strong> acipimox, a lipolytic inhibitor, further enhanced<br />
the GH response (269), stressing the role <strong>of</strong> circulating<br />
nonesterified fatty acids (NEFA) in the pathogenesis <strong>of</strong><br />
the GH hyposecretion <strong>of</strong> obesity (see sect. VIB3). In contrast,<br />
somatotroph responsiveness to coadministered<br />
hexarelin and GHRH was refractory to the inhibitory effect<br />
<strong>of</strong> glucose (443). This might reflect a selective refractoriness<br />
<strong>of</strong> hypothalamic SS to glucose in obese patients,<br />
since exogenous SS, like pirenzepine, abolished the GH<br />
response to either GHRH or arginine.<br />
4. Catabolic states<br />
Prolonged critical illness is characterized by protein<br />
catabolism and preservation <strong>of</strong> fat deposits, blunted GH<br />
secretion, elevated serum cortisol levels, and reduced<br />
IGF-I concentrations. In these conditions, prolonged infusion<br />
<strong>of</strong> GHRP-2, alone or combined with GHRH, strikingly<br />
increased pulsatile GH secretion and induced a robust<br />
rise in circulating IGF-I levels within 24 h, without affecting<br />
serum cortisol (1058). These findings open new perspectives<br />
for GHRP as potential antagonists <strong>of</strong> the catabolic<br />
state in critical care medicine.<br />
5. GH deficiency states<br />
A) CHILDREN. Although their exact mechanism <strong>of</strong> action<br />
has yet to be defined, the striking effectiveness <strong>of</strong> GHRP<br />
as GH releasers in humans prompted investigations on<br />
their use as diagnostic tools as well as therapeutic agents<br />
in children with GH deficiency. A number <strong>of</strong> studies have<br />
confirmed that GHRP are effective GHS in children with<br />
short stature and/or GH deficiency (416, 568, 594) but not<br />
in patients with anatomic disconnection <strong>of</strong> the hypothalamo-pituitary<br />
links or with perinatal stalk transection<br />
(630, 855, 861). The potential for these compounds as a<br />
rapid, safe, and economical test to identify hypopituitarism<br />
due to pituitary stalk transection is evident.<br />
An open trial in children with GH deficiency showed<br />
that intranasal administration <strong>of</strong> hexarelin for up to 6 mo<br />
accelerated growth (594). Similarly, in children with GH<br />
insufficiency, GHRP-2, given subcutaneously at increasing<br />
doses every 2 mo (from 0.3 to 3 mgkg 1 day 1 ) for 6 mo,<br />
raised IGF-I levels and growth velocity (709). In children<br />
with short stature, intranasal GHRP-2, twice daily for 3<br />
mo then three times a day for up to 18–24 mo, induced a<br />
modest but significant rise in growth velocity (843). However,<br />
plasma IGF-I or IGF-BP3 concentrations, or acute<br />
GH responses to intravenous or intranasal GHRP-2 were<br />
not changed and only the GHBP significantly increased.<br />
Despite some positive results, long-term and doubleblind,<br />
placebo-controlled trials are mandatory before any
542 MÜLLER, LOCATELLI, AND COCCHI Volume 79<br />
firm conclusions can be drawn on the therapeutic utility<br />
<strong>of</strong> GHRP in GH deficiency states.<br />
B) ADULTS. Many studies have shown that prolonged<br />
parenteral, intranasal, or oral administration <strong>of</strong> GHRP<br />
enhances spontaneous pulsatile GH secretion in normal<br />
elderly people (405, 492), or in adults with GH deficiency<br />
(599). <strong>Growth</strong> hormone deficiency <strong>of</strong> adults has received<br />
little attention in the past and only recently, since the<br />
demonstration <strong>of</strong> altered body composition, increased<br />
prevalence <strong>of</strong> cardiovascular morbidity, and decreased<br />
life expectancy (278, 533), has been investigated more.<br />
The problem <strong>of</strong> GH deficiency is widespread because<br />
many patients develop life-long hormone deficiency due<br />
to lesions induced in the hypothalamo-pituitary unit by<br />
tumors or radiation. <strong>Growth</strong> hormone therapy has proven<br />
very effective in these patients (278); GHRP might <strong>of</strong>fer<br />
an even better therapeutic approach for restoring a normal<br />
condition.<br />
<strong>Growth</strong> hormone-releasing peptides would also be<br />
important for the diagnosis <strong>of</strong> GH deficiency in adults,<br />
which is more difficult than in children, because <strong>of</strong> the<br />
confounding effects <strong>of</strong> many factors such as obesity, sex,<br />
and age. A combined test <strong>of</strong> GHRP and GHRH, which<br />
obviates many <strong>of</strong> the factors that normally inhibit GH<br />
secretion (137, 270, 631), might be a safe and powerful<br />
tool for the diagnosis <strong>of</strong> GH deficiency, allowing the rationale<br />
as therapeutic use <strong>of</strong> GHRP.<br />
E. Effects on Other Pituitary <strong>Hormone</strong>s<br />
Although predominant, the activity <strong>of</strong> GHRP is not<br />
fully specific for GH release. Reportedly, peptidyl GHRP<br />
in vitro elicit a small but unequivocal release <strong>of</strong> prolactin<br />
(692) and in vivo <strong>of</strong> prolactin, ACTH, and cortisol in<br />
humans, dogs, pigs, and rats (628). In vivo, the main site<br />
<strong>of</strong> action for stimulation <strong>of</strong> ACTH and cortisol is neither<br />
the pituitary (225, 335) nor the adrenals because these<br />
endocrine effects were abolished by stalk transection in<br />
the pig (468) or hypophysectomy in the dog (937), thus<br />
indicating a hypothalamic mechanism. Interestingly,<br />
hexarelin was shown to release AVP from freshly prepared<br />
rat hypothalamic tissues (569).<br />
Some GHRP maintained their prolactin-releasing effect<br />
on mammosomatotroph adenomas both in vitro (13)<br />
and in vivo (241). This was not the case for hexarelin,<br />
which does not stimulate prolactin release in patients<br />
with idiopathic hyperprolactinemia, thus implying a partial<br />
resistance to GHRP in this condition (241). The precise<br />
mechanism(s) underlying these effects is still unknown.<br />
The lack <strong>of</strong> specificity <strong>of</strong> GHRP is <strong>of</strong> concern if these<br />
agents are to be used in clinical trials. To address this<br />
issue, Massoud et al. (675) constructed dose-response<br />
relationships for GH, cortisol, and prolactin and investi-<br />
gated in healthy adult males whether hexarelin’s effects<br />
on cortisol and prolactin secretion could be minimized<br />
without compromising its GH-releasing potential. They<br />
found that by using a combination <strong>of</strong> GHRH and a low<br />
GHRP dose the GH release was greater than with hexarelin<br />
alone, its effect on prolactin was minimal, and there<br />
was no effect on cortisol.<br />
F. Conclusions<br />
The discovery <strong>of</strong> GHRP has opened a new window on<br />
GH regulation. Their mechanism <strong>of</strong> action is still debated;<br />
we do not know the nature and structure <strong>of</strong> the endogenous<br />
ligand(s) (628) for GHRP receptors, although inferential<br />
evidence for an authentic hypophysiotropic function<br />
has been provided (604a), and are waiting for<br />
conclusive data on their clinical usefulness. It is undisputed,<br />
however, that these new molecules have renewed<br />
interest in neuroendocrinology. Moreover, so far we seem<br />
to have looked only at the tip <strong>of</strong> the GHRP iceberg.<br />
Detection <strong>of</strong> GHRP receptors in many tissues in addition<br />
to the pituitary and the hypothalamus suggests still unforeseen<br />
roles for the putative endogenous ligand(s) at<br />
both CNS and peripheral sites (628).<br />
V. BRAIN MESSENGERS IN THE CONTROL<br />
OF GROWTH HORMONE SECRETION<br />
A. General Background<br />
Discussion <strong>of</strong> how brain neurotransmitters and neuropeptides<br />
influence the neuroendocrine control <strong>of</strong> GH<br />
secretion requires at least a brief mention <strong>of</strong> the main<br />
neurobiological characteristics <strong>of</strong> these compounds and<br />
where their pathways run. Progress has been made possible<br />
by the development <strong>of</strong> histochemical methods with<br />
high sensitivity and sufficient specificity to permit detailed<br />
mapping <strong>of</strong> neurotransmitter and neuropeptide<br />
pathways, introduction <strong>of</strong> steady-state and non-steadystate<br />
methods to measure turnover, very sensitive enzymatic<br />
isotopic techniques for detecting messenger molecules<br />
in microdissected hypothalamic nuclei or nuclear<br />
subdivisions, and electrophysiological recording from single<br />
cells or ionic channels. The development <strong>of</strong> molecular<br />
biological techniques has enabled us to clone the receptors<br />
for virtually every natural ligand considered neurotransmitter<br />
and major members <strong>of</strong> peptide families, and<br />
the introduction <strong>of</strong> the coding sequences into test cells<br />
means we can assess the relative effects <strong>of</strong> ligands and <strong>of</strong><br />
second messenger production in these cells (for review,<br />
see Ref. 117).<br />
The widely held distinction between classic neurotransmitter<br />
communication and peptidergic communica-
April 1999 NEUROENDOCRINE CONTROL OF GROWTH HORMONE SECRETION 543<br />
tion has been sorted out, and despite recognized differences<br />
(see below), the two systems can no longer be<br />
considered entirely separate entities. The same compound<br />
may act differently as a transmitter (via strictly<br />
local short-lived synaptic responses), as a neuromodulator<br />
(modulating the subsynaptic actions <strong>of</strong> a neurotransmitter-coupled<br />
event), and as a neurohormone (acting at<br />
a distance from the site <strong>of</strong> release with no synaptic contact<br />
with the synthesizing neurons), depending on the<br />
engagement <strong>of</strong> specific receptors (117).<br />
Another reason why the demarcation between these<br />
messenger molecules has become blurred is the recognition<br />
<strong>of</strong> their existence in the same neuron in different CNS<br />
areas, as well as in the MBH. The functional role <strong>of</strong> the<br />
costored neurotransmitters and neuropeptides remains to<br />
be fully elucidated, although demonstration <strong>of</strong> costorage<br />
within nerve terminals at the ME suggests corelease at<br />
this site. These events are <strong>of</strong> particular interest for the<br />
control <strong>of</strong> GH secretion. Because GHRH neurons <strong>of</strong> the<br />
ARC also contain enzymes for neurotransmitter biosynthesis,<br />
neurotransmitters and neuropeptides (see sect.<br />
IIIA2) and GHRH-induced GH release may be influenced<br />
by some <strong>of</strong> these.<br />
B. Characteristic Features<br />
FIG. 10. Synthesis pathways <strong>of</strong> principal neurotransmitters. See text for definitions.<br />
A detailed description <strong>of</strong> the mechanisms <strong>of</strong> biosynthesis,<br />
release, and metabolic disposal <strong>of</strong> principal neuro-<br />
transmitters and neuropeptides and <strong>of</strong> the CNS-acting<br />
compounds that interfere with the different metabolic<br />
steps or with pre/postsynaptic receptors is beyond the<br />
scope <strong>of</strong> this review, and the readers are referred to<br />
Müller and Nisticò (756) and Bloom (117). Here only key<br />
neurobiological features are given and a brief mention <strong>of</strong><br />
the regional distribution <strong>of</strong> the main neuronal systems in<br />
the CNS.<br />
Neurotransmitters are small molecules synthesized<br />
in a short series <strong>of</strong> steps from precursor amino acids in<br />
the diet. They are found in the brain in concentrations <strong>of</strong><br />
nanograms to micrograms per gram and show high affinity<br />
for specific receptor sites.<br />
The first substance to be recognized as a neurotransmitter<br />
was ACh, and 5–10% <strong>of</strong> brain synapses are thought<br />
to be cholinergic. Amino acids (GABA, glycine, glutamate,<br />
aspartate) form the main group <strong>of</strong> central neurotransmitters<br />
(an estimated 25–40% <strong>of</strong> synapses). The monoamines<br />
(CA, tryptamines, histamine) account for only 1–2% <strong>of</strong><br />
brain synapses, but the monoamine pathways are widely<br />
distributed throughout the brain (see sect. VC). The main<br />
steps in neurotransmitter formation are depicted in Figure<br />
10.<br />
Many drugs are capable <strong>of</strong> inhibiting the functional<br />
activity <strong>of</strong> neurotransmitter neurons. Biosynthesis inhibitors<br />
act on the different enzymatic steps, and there are<br />
depletors <strong>of</strong> the granular pool and neurotoxic agents that<br />
destroy neurotransmitter neurons. Neurotransmitter pre-
544 MÜLLER, LOCATELLI, AND COCCHI Volume 79<br />
cursors or inhibitors <strong>of</strong> metabolic degradation or uptake<br />
potentiate neurotransmitter mechanisms (117).<br />
The pathways by which neuropeptides are synthesized<br />
closely resemble those in peripheral hormone-producing<br />
tissues (117). The peptide is synthesized in the<br />
rough endoplasmic reticulum where mRNA for the<br />
propeptide can be translated into an amino acid sequence.<br />
The peptide may be released intermittently rather than<br />
tonically, the amounts stored in terminals may be large<br />
relative to the amounts released, and the peptide may<br />
activate receptors at much lower concentrations than the<br />
classic transmitters. In general, concentrations <strong>of</strong> picograms<br />
to nanograms per gram are present in the brain.<br />
These general features apply to either classical hypophysiotropic<br />
neuropeptides, GHRH and SS, or the cohort<br />
<strong>of</strong> neuropeptides whose neurohormonal role and<br />
hypophysiotropic function are still not clear (see sect.<br />
VB). It has proven difficult to synthesize agonists or antagonists<br />
that interact with specific receptors for peptides.<br />
However, the recent development <strong>of</strong> nonpeptidyl<br />
agonists or antagonists (see also sect. IV) <strong>of</strong>fers promise<br />
<strong>of</strong> success.<br />
C. Main Locations <strong>of</strong> Neurotransmitter and<br />
Neuropeptide Pathways<br />
Monoamine transmitters, that is, CA, DA, NE, epinephrine<br />
(E), indoleamines (5-HT), and histamine, have<br />
perikarya that form ascending ventral and dorsal pathways<br />
to innervate limbic and hypothalamic structures<br />
including the internal (NE, 5-HT) and external (DA) layers<br />
<strong>of</strong> the ME.<br />
In the pons and medulla, 10,000 NE-secreting<br />
perykarya give rise to large ascending tracts. The ascending<br />
NE pathway comprises 1) a dorsal bundle that originates<br />
in the locus coeruleus and innervates the cortex, the<br />
hippocampus, and the cerebellum and 2) a ventral bundle<br />
that originates in the pons and medulla and gives rise to<br />
pathways innervating the lower brain stem, the hypothalamus,<br />
and limbic system. Norepinephrine has high affinity<br />
for both - and -receptors, whereas E has higher affinity<br />
for - than for -receptors. These receptors are now<br />
divided into 1A, 1B, 1c, 2A, 2B, and 2c subclasses as<br />
well as 1, 2, and 3, that have different locations, functions,<br />
and second messenger systems (117) and affect<br />
somatotrophic function differently.<br />
Among the five different systems <strong>of</strong> long and medium<br />
DA neurons, a pathway <strong>of</strong> particular relevance for neuroendocrine<br />
control is the tuberoinfundibular DA (TIDA)<br />
pathway that innervates the ME, the area where neurotransmitters<br />
and neuropeptides are released into the hypophysial<br />
portal circulation to be conveyed to the AP.<br />
Dopaminergic receptors can be subdivided into D 1,<br />
D 2,D 3,D 4, and D 5 sites; there are now specific agonists<br />
and antagonists for D 1,D 2, and D 4 receptors. No major<br />
differences have been described in how these subclasses<br />
<strong>of</strong> receptors affect GH secretion.<br />
The 5-HT system arises from cell bodies in the mesencephalic<br />
and pontine raphe and sends axons especially<br />
to the hypothalamus, ME, POA, limbic system, septal<br />
area, striatum and cerebral cortex. On the basis <strong>of</strong> the<br />
action <strong>of</strong> 5-HT receptor agonists and antagonists, four<br />
subgroups <strong>of</strong> 5-HT receptors have been characterized:<br />
5-HT 1-like, 5-HT 2, 5-HT 3 and 5-HT 4. To date, 5-HT 1A–F,<br />
5-HT 2A–C, 5-HT 3, and 5-HT 4–7 subtypes have been described.<br />
Antibodies specific for the ACh-synthesizing enzyme<br />
CAT, coupled with the use <strong>of</strong> AChE histochemistry, ligand<br />
binding, or in situ hybridization studies, have made it<br />
possible to outline cholinergic neurons and trace their<br />
pathways. The enzymatic activities are present in most<br />
hypothalamic nuclei, including the ARC and the ME. Because<br />
only small changes have been detected in CAT<br />
concentrations in the MBH after mechanical separation <strong>of</strong><br />
this area, and no change at all was found in the ME, an<br />
intrahypothalamic cholinergic pathway, similar to the<br />
TIDA pathway, has been envisaged. This may be important<br />
in some effects <strong>of</strong> the cholinergic drugs on somatotropic<br />
function (see below), also considering the similar<br />
distribution <strong>of</strong> somatostatinergic and cholinergic neurons<br />
in the lateral region <strong>of</strong> the external layer <strong>of</strong> the ME (954).<br />
There are two classes <strong>of</strong> ACh receptors, the muscarinic<br />
and the nicotinic. Five subtypes <strong>of</strong> muscarinic cholinergic<br />
receptors (M 1 to M 5) have been detected by molecular<br />
cloning; all five are found in the CNS.<br />
The regional localization <strong>of</strong> histamine in the brain<br />
and in individual nuclei <strong>of</strong> the hypothalamus has been<br />
studied in rodents and primates. In the monkey and human<br />
hypothalamus, the highest concentrations are found<br />
in the mammillary bodies, SON, VMN and ventrolateral<br />
nucleus, and ME. After deafferentation <strong>of</strong> the MBH in rats,<br />
levels <strong>of</strong> histamine do not decrease significantly in the<br />
ARC, VMN, DMN, and ME, suggesting that histamine is<br />
present in the posterior two-thirds <strong>of</strong> the hypothalamus in<br />
cells intrinsic to this area. Three subtypes <strong>of</strong> histamine<br />
receptors have been described, H 1,H 2, and H 3. Unlike the<br />
monoamine and amino acid transmitters, there does not<br />
appear to be any active histamine reuptake. In addition,<br />
no direct evidence has been obtained for release <strong>of</strong> histamine<br />
from neurons either in vivo or in vitro.<br />
Specific antibodies raised against GAD have made it<br />
possible to precisely locate GABAergic neurons in the<br />
hypothalamus. A dense network <strong>of</strong> GAD-positive nerve<br />
fibers is seen in different hypothalamic nuclei <strong>of</strong> the rodent<br />
and cat brain. In the ME, a dense immun<strong>of</strong>luorescent<br />
plexus is found in the external layer, extending across the<br />
entire mediolateral axis from the rostral part to the pituitary<br />
gland. The hypothesis <strong>of</strong> an intrinsic, hypothalamic<br />
TI-GABAergic pathway projecting from the ARC to the
April 1999 NEUROENDOCRINE CONTROL OF GROWTH HORMONE SECRETION 545<br />
ME is supported by deafferentation experiments <strong>of</strong> the<br />
MBH. -Aminobutyric acid receptors are divided into two<br />
main types: 1) GABA A, which is bicuculline sensitive and<br />
has multiple subtypes, interacts directly with and is the<br />
site <strong>of</strong> action <strong>of</strong> many neuroactive drugs (benzodiazepines,<br />
barbiturates), anesthetic steroids, volatile anesthetics,<br />
and alcohol; and 2) GABA B, which is bicuculline<br />
insensitive and is present in both the CNS and the periphery,<br />
although mainly at the presynapses, at least peripherally.<br />
Specific agonists and antagonists <strong>of</strong> GABA A and<br />
GABA B receptors are now available.<br />
Glutamate and aspartate are found in very high<br />
concentrations in different brain areas such as discrete<br />
hypothalamic nuclei (ARC, VMN, PeVN), with nerve<br />
terminals projecting to the ME. The widespread distribution<br />
<strong>of</strong> these two dicarboxylic amino acids in the<br />
CNS and their role in the intermediary metabolism<br />
tended to exclude any action as transmitters, but it is<br />
now acknowledged that both amino acids exert extremely<br />
powerful excitatory effects on neurons in virtually<br />
every region <strong>of</strong> the CNS. Many receptor subtypes<br />
have been characterized pharmacologically. They fall<br />
into two main groups: the ionotropic and metabotropic<br />
receptors. Ionotropic receptors can be subdivided into<br />
N-methyl-D-aspartate (NMDA), kainate, and DL--amino-<br />
3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA);<br />
metabotropic receptors are activated most potently by<br />
quisqualate.<br />
Neurotransmitter-hypophysiotropic peptides, e.g.<br />
GHRH and SS, interact in many ways. These include<br />
direct action <strong>of</strong> neurotransmitters transported into hypophysial<br />
vessels (DA, E and GABA), the still elusive neurotransmitter-neurotransmitter,<br />
peptide-peptide and neurotransmitter-peptide<br />
interactions due to colocalization in<br />
and corelease from the same neuron <strong>of</strong> two or more<br />
molecules (Fig. 2) (457, 484, 699). Consequently, drugs<br />
that act as agonists or antagonists at neurotransmitter<br />
receptors or alter different aspects <strong>of</strong> neurotransmitter<br />
function can be useful for studying the physiology and<br />
pathophysiology <strong>of</strong> GH secretion and as diagnostic and<br />
therapeutic tools.<br />
Detailed mapping <strong>of</strong> the principal brain neuropeptides<br />
is beyond the scope <strong>of</strong> this review, and the reader is<br />
referred to References 457 and 484. Briefly, however,<br />
several hypothalamic peptides such as oxytocin, AVP,<br />
POMC, gonadotropin-releasing hormone (GnRH), and<br />
also GHRH all tend to be synthesized by single large<br />
clusters <strong>of</strong> neurons that give <strong>of</strong>f multibranched axons to<br />
several distant targets. Others, such as systems that contain<br />
cholecystokinins, enkephalins, and also SS, have<br />
many forms, with patterns varying from moderately long<br />
connections to short axons, local-circuit neurons that are<br />
widely disseminated throughout the brain.<br />
D. Neurotransmitters<br />
1. Catecholamines<br />
A) 2-ADRENOCEPTORS. Although formulated more than 25<br />
years ago and based on a the pituitary “depletion”<br />
method, subsequently shown to be fraught with inconsistencies,<br />
the concept that NE is a synaptic transmitter that<br />
releases GRF (758) is essentially valid today. Proper evaluation<br />
<strong>of</strong> neurotransmitter function became possible with<br />
RIA methods for the measurement <strong>of</strong> GH in rat plasma,<br />
the awareness <strong>of</strong> the labile and episodic function <strong>of</strong> GH<br />
secretion in the rat, and hence the adoption <strong>of</strong> chronically<br />
cannulated rats for blood sampling (666).<br />
Since then, evidence has accumulated that central adrenergic<br />
pathways acting through 2-adrenoceptors stimulate<br />
GH secretion in humans and rats (756). Instrumental to<br />
this conclusion were experiments in rats with an intra-atrial<br />
cannula, in which blockade <strong>of</strong> CA synthesis by -methyl-ptyrosine,<br />
depletion <strong>of</strong> hypothalamic CA stores by reserpine,<br />
and injection <strong>of</strong> 6-hydroxydopamine, a CA neurotoxin,<br />
markedly suppressed the episodic GH secretion; these effects<br />
were counteracted by the 2-adrenoceptor clonidine,<br />
but not the DA agonist apomorphine (759). More selective<br />
inhibition <strong>of</strong> NE and E synthesis by blockers <strong>of</strong> DA--hydroxylase,<br />
the enzyme that converts DA to NE and E (see<br />
Fig. 10), also inhibited spontaneous GH bursts, this effect<br />
again being counteracted by clonidine (549, 578, 771). Epinephrine<br />
was presumably the main endogenous CA active<br />
on 2-adrenoceptors, since selective blockade <strong>of</strong> E synthesis<br />
by phenylethanolamine N-methyltransferase (PNMT) inhibitors<br />
reduced GH secretion in freely moving rats, and the<br />
effect was reversed by clonidine (1028). There was concomitantly<br />
a reduction <strong>of</strong> E levels in the hypothalamus with no<br />
changes in DA and NE stores. A peripheral E synthesis<br />
blocker had no effect on GH secretion, indicating that inhibition<br />
<strong>of</strong> brain rather than adrenomedullary E was responsible<br />
(1028).<br />
The importance <strong>of</strong> -adrenergic mechanisms in GH<br />
secretion was substantiated by the finding that clonidine<br />
given acutely to 10-day-old rats induced a clear-cut rise in<br />
plasma GH, although the effect was not dose related;<br />
short-term administration <strong>of</strong> clonidine to 5-day-old rats<br />
also raised plasma GH levels and pituitary GH content<br />
(204). A sound interpretation <strong>of</strong> these findings was that in<br />
infant rats clonidine, in addition to stimulating GH release,<br />
had elicited GH synthesis, as confirmed by measurement<br />
<strong>of</strong> pituitary [ 3 H]leucine incorporation into GH<br />
<strong>of</strong> infant rats treated ex vivo with the drug (272). Because<br />
similar results were obtained in infant rats with GHRH<br />
(272), it appeared likely that clonidine acted at least partially,<br />
through the release <strong>of</strong> endogenous GHRH.<br />
Clonidine did not affect GH release in rats with hypothalamic<br />
destruction or from cultured AP cells (552).
546 MÜLLER, LOCATELLI, AND COCCHI Volume 79<br />
In keeping with this conclusion, studies in the rat had<br />
shown that clonidine-induced GH release was abolished<br />
by passive immunization with anti-GHRH serum (206,<br />
721), whereas it was not affected by anti-SS antibodies<br />
(331). The drug was reported to stimulate GRF release in<br />
vitro from perfused rat hypothalamus (536). It was subsequently<br />
shown that a single dose <strong>of</strong> clonidine to adult<br />
male rats significantly lowered GHRH content, leaving<br />
GHRH mRNA levels unaltered and raising plasma GH<br />
while hypothalamic SS mRNA and pituitary GH mRNA<br />
levels remained unchanged. In contrast, in rats treated<br />
with clonidine for 1 and 3 days, hypothalamic GHRH<br />
content fell, and there was a significant reduction in<br />
GHRH mRNA levels. In these rats, pituitary GH content<br />
and mRNA levels increased significantly, whereas hypothalamic<br />
SS content and mRNA remained unaltered. In<br />
6-day clonidine-treated rats, hypothalamic GHRH content<br />
and mRNA was still significantly reduced, plasma GH<br />
levels were increased, although less than in 1- and 3-day<br />
clonidine-treated rats, and pituitary GH content and<br />
mRNA had returned to control values (294).<br />
It would seem that in these experimental conditions,<br />
clonidine-induced 2-adrenoceptor stimulation led directly,<br />
or through inhibition <strong>of</strong> hypothalamic SS release<br />
(see below), to increased GHRH release from the hypothalamus<br />
and enhanced GH biosynthesis and secretion<br />
and that as a result <strong>of</strong> greater exposure to clonidine,<br />
circulating GH (and IGF-I) fed back to hypothalamic<br />
GHRH neurons, thus finally reversing pituitary somatotropic<br />
hyperfunction.<br />
Apparently, SS neurons were refractory to circulating<br />
GH or IGF-I under these experimental conditions. In similar<br />
studies, Gil-Ad et al. (418) detected a decrease in the<br />
hypothalamic content <strong>of</strong> SS only after acute clonidine,<br />
and not after a 7-day treatment.<br />
Additional, although inferential, evidence in favor <strong>of</strong><br />
a GHRH-mediated effect is the fact that either compound<br />
induces sedation and sleepiness and stimulates food intake<br />
(see Ref. 479 and sect. IIIA10) and that specific<br />
2-adrenergic nerve terminals have been detected in the<br />
arcuate nucleus (620).<br />
None <strong>of</strong> the above observations, however, excludes the<br />
possibility that clonidine may also act through inhibition <strong>of</strong><br />
SS pathways. In fact, in rats, clonidine failed to induce GH<br />
release when directly instilled into the VMN, an area <strong>of</strong><br />
GHRH neurons (see sect. IIIA2), but was effective when<br />
injected into the SS-rich MPOA (515). Later studies in humans<br />
showed that pretreatment with GHRH abolished the<br />
GH response to subsequent administration <strong>of</strong> the peptide<br />
but did not alter the GH response to clonidine (1052).<br />
Investigations in humans and animals were then<br />
started, to clarify the precise mechanism <strong>of</strong> action <strong>of</strong><br />
clonidine, the possibility being considered that GH responsiveness<br />
to GHRH may be closely dependent on the<br />
functional status <strong>of</strong> the hypothalamic somatotroph<br />
rhythm (HSR) (308), and that in previous in vivo studies<br />
clonidine had disrupted the spontaneous surges <strong>of</strong> GH<br />
release in male rats (see sect. II).<br />
In normal adult volunteers, clonidine administered 60<br />
or 120 min, but not 180 min, before a GHRH bolus increased<br />
the GH response to GHRH; the close relationship<br />
between pre-GHRH plasma GH and GHRH-induced GH<br />
peaks, not present with clonidine alone, was also lost<br />
after pretreatment with this drug. Clonidine-induced disruption<br />
<strong>of</strong> the intrinsic HSR suggested that 2-adrenergic<br />
pathways exert an inhibitory effect on SS release (307).<br />
Similarly, in conscious rats, clonidine at all doses tested<br />
failed to stimulate GH release when administered at the<br />
time <strong>of</strong> a spontaneous peak, i.e., when the intrinsic SS<br />
tone would be minimal. In contrast, clonidine injected at<br />
a trough time, functionally the opposite condition, raised<br />
plasma GH. In addition, clonidine administered during a<br />
GH trough period before GHRH challenge potentiated the<br />
GH response to GHRH (591).<br />
Acute and short-term clonidine studies in dogs gave<br />
similar findings. In old conscious beagles given GHRH and<br />
clonidine together, twice and once daily for 10 days,<br />
treatment significantly raised the frequency <strong>of</strong> spontaneous<br />
bursts <strong>of</strong> GH secretion, the mean GH peak amplitude,<br />
and the total peak area evaluated in 6-h blood samples<br />
taken at 10-min intervals (207). These effects, paradoxically,<br />
were not as marked when clonidine and GHRH<br />
were given twice rather than only once daily. This was<br />
presumably because the 2- adrenergic agonist downregulates<br />
its own receptors in the ARC at a higher dose (208).<br />
The most parsimonious interpretation <strong>of</strong> these findings<br />
is that a dual mechanism <strong>of</strong> action is exploited by 2-agonism<br />
in enhancing GH secretion, e.g., stimulation <strong>of</strong> hypothalamic<br />
GHRH and inhibition <strong>of</strong> SS neuronal function. Light<br />
microscopic and electron microscopic evidence supports<br />
this. Immunocytochemical double-labeling and dopamine<br />
-hydroxylase (DBH) and PNMT immunolabeling for tracing<br />
the CA system (620) revealed a similar pattern <strong>of</strong> distribution<br />
with juxtaposition <strong>of</strong> catecholaminergic fibers and<br />
GHRH neurons in the ARC. Electron microscopic examination<br />
showed axodendritic and axosomatic synaptic specialization<br />
between these systems (620).<br />
However, in addition to these morphological findings<br />
suggesting that the CA system stimulates GH release<br />
through GHRH, other neuroanatomic evidence indicates<br />
that SS structures in the anterior PeVN nucleus <strong>of</strong> the rat<br />
hypothalamus are innervated by PNMT-immunoreactive<br />
axons (621). These can be usefully viewed in connection<br />
with the existence <strong>of</strong> SS synapses on GHRH neurons (see<br />
sect. II, A3 and B). With the assumption that they originate<br />
from hypophysiotropic SS neurons, it would seem that<br />
afferent neuronal systems to SS cells influence GH production<br />
either by regulating SS secretion into the portal<br />
circulation (235) or by transmitting their influence to the<br />
GHRH neurons through SS axons (622). This complex
April 1999 NEUROENDOCRINE CONTROL OF GROWTH HORMONE SECRETION 547<br />
mechanism may be used to synchronize these hypothalamic<br />
pathways to achieve precise coordination between<br />
stimulatory and inhibitory systems (853).<br />
The GH-releasing effect <strong>of</strong> clonidine, as expected,<br />
was antagonized in humans and rodents by the selective<br />
2-adrenergic antagonists yohimbine (158) and fluparoxan<br />
(529). However, in rats metergoline, a 5-HT 1/5-HT 2<br />
antagonist, and mesulergine, ritanserin, and mianserin,<br />
5-HT 1c/5-HT 2 selective antagonists, all reduced clonidineinduced<br />
increases in GH levels, without affecting the<br />
decrease in locomotor activity. These findings suggest<br />
that clonidine stimulates the release <strong>of</strong> GH by activating<br />
2-adrenergic heteroreceptors on 5-HT nerve terminals<br />
which, in turn, enhance 5-HT activity by stimulating<br />
postsynaptic 5-HT receptors. In the same study, clonidine<br />
failed to increase GH levels in the fawn-hooded rat, a<br />
model <strong>of</strong> altered serotoninergic function (60).<br />
1) Diagnostic applications. The fact that clonidine<br />
stimulates GH secretion in a variety <strong>of</strong> species, including<br />
humans (749), has led to 2-adrenergic stimulation being<br />
used as a diagnostic test in children <strong>of</strong> short stature (419,<br />
589). A single oral dose <strong>of</strong> clonidine stimulated GH release<br />
in healthy children and adolescents but not in hypopituitary<br />
children. Clonidine proved to be a more effective<br />
stimulant <strong>of</strong> GH secretion than either insulin<br />
hypoglycemia or arginine infusion; there were, however,<br />
false-negative responses to clonidine even in healthy subjects<br />
and wide variability in the GH release in endocrinologically<br />
short children (76). Today, the clonidine test is<br />
still widely used in pediatric endocrinology, but it has<br />
been largely supplanted by more recently diagnostic tests<br />
(see sect. VA3). For a more thorough discussion <strong>of</strong> this<br />
topic, see Reference 755.<br />
2) Therapeutic implications. The suggestion that a<br />
dysfunction <strong>of</strong> neurons regulating the release <strong>of</strong> GHRH<br />
from GHRH-secreting structures may occur in some children<br />
with idiopathic GH deficiency (231, 541) prompted<br />
efforts to stimulate the purportedly depressed neurotransmitter<br />
function, initially with a DA precursor or agonist<br />
drugs, and then with clonidine.<br />
Promising results with dopaminergic therapy (497,<br />
498), and the possibility that some effects, e.g. those <strong>of</strong><br />
levodopa, might be due at least in part to its conversion to<br />
NE in the hypothalamus (1108), suggested the use <strong>of</strong><br />
clonidine in children with growth retardation. Oral<br />
clonidine for 3 mo to 1 yr stimulated linear growth in the<br />
majority <strong>of</strong> children, the most responsive being those in<br />
general with low pretreatment growth velocity and<br />
marked bone age delay. There was, however, a tendency<br />
for growth velocity to slow with time, i.e., after the first 6<br />
mo or 1 yr, a pattern which might be due to 2-adrenoceptor<br />
desensitization (185, 388, 739, 851). However, in a<br />
subsequent placebo-controlled study, clonidine had no<br />
effect on the growth <strong>of</strong> short children with normal GH<br />
responses to provocative stimuli. Unlike other studies, the<br />
children in this study had higher pretreatment growth<br />
velocity (832). Negative results were also reported by<br />
Allen et al. (26). In a later controlled study, clonidine did<br />
accelerate the growth <strong>of</strong> short children with normal GH<br />
secretion, although, at the dose used, it was not as effective<br />
as GH (1073).<br />
We do not know whether the effect <strong>of</strong> clonidine<br />
observed in some <strong>of</strong> these studies will result in better final<br />
height. Certainly, the negative results <strong>of</strong> one <strong>of</strong> the controlled<br />
studies (832) discouraged further investigations on<br />
a topic that, for its scientific interest and potential clinical<br />
benefits, warrants closer attention (35).<br />
It is noteworthy that continuous intravenous<br />
clonidine to patients with alcohol abuse, for prevention <strong>of</strong><br />
alcohol withdrawal syndrome, significantly improved<br />
their nitrogen balance and counteracted the decline <strong>of</strong><br />
plasma IGF-I and IGF-BP-3 seen in untreated patients<br />
after resection <strong>of</strong> an esophageal cancer (715).<br />
B) 1-ADRENOCEPTORS. The availability <strong>of</strong> clonidine and<br />
its ability to stimulate GH secretion in many animal species<br />
allowed the characterization <strong>of</strong> the NE receptor subtypes<br />
mediating its neuroendocrine effect. In dogs, pretreatment<br />
with the 1-adrenoceptor antagonist prazosin<br />
left the clonidine-induced GH rise unaltered, whereas<br />
blockade <strong>of</strong> 2-adrenoceptors by yohimbine completely<br />
prevented it (215). However, prazosin partially suppressed<br />
the GH secretory response to clonidine in rats,<br />
which may indicate a mixed 1/ 2-mechanism in the GHstimulating<br />
effect <strong>of</strong> the drug (578). However, in both rats<br />
and dogs, 1-adrenoceptors might also mediate inhibitory<br />
influences to GH release, indicating a dual NE mechanism<br />
<strong>of</strong> control (214, 578). Overall, the results supported the<br />
idea that 1-adrenoceptors in the CNS inhibited both tonic<br />
and stimulated GH secretion in rats and dogs. Apparently,<br />
the underlying mechanism involved the activation <strong>of</strong> SS<br />
release. Thus the ability <strong>of</strong> methoxamine, an 1-adrenoceptor<br />
agonist, to suppress GH levels in infant rats was<br />
completely abolished in animals pretreated with a SS<br />
antiserum. However, the clear-cut GH rise induced by<br />
prazosin was not further increased by pretreatment with<br />
the antiserum (206).<br />
1-Noradrenergic inhibition would be mediated<br />
through receptor sites in the PVN, and electrolytic lesions<br />
<strong>of</strong> these in the rat double the amplitude <strong>of</strong> the GH curve<br />
and the area under the curve, while blocking the GH<br />
inhibitory effect <strong>of</strong> locally instilled methoxamine (744).<br />
This is closely comparable to the obtained pattern under<br />
similar conditions by bilateral destruction <strong>of</strong> the locus<br />
coeruleus (119). Because both the PVN and the somatostatinergic<br />
hypothalamic PeVN are innervated by locus<br />
coeruleus NA 1 afferents (28), a pathway stimulatory <strong>of</strong> SS<br />
function, presumably through PVN-CRH neurons, has<br />
been envisaged.<br />
Contrasting the clear-cut inhibitory effects <strong>of</strong> 1-adrenoceptor<br />
stimulation in dogs and rats are reports in
548 MÜLLER, LOCATELLI, AND COCCHI Volume 79<br />
humans <strong>of</strong> either a small increase in GH secretion during<br />
intravenous infusions <strong>of</strong> 1-adrenergic agonists (506) or<br />
no effect on GH secretion, with a small, not significant,<br />
decrease after methoxamine (24). Although CA are clearly<br />
involved in the GH response to hypoglycemia, prazosin<br />
did not affect this response in humans (1024), suggesting<br />
that both stimuli share the same mechanism, i.e., inhibition<br />
<strong>of</strong> hypothalamic SS function. Although there is no<br />
information on how 1-antagonists affect the GH responses<br />
to more physiological stimuli, it would appear<br />
that endogenous CA acting on 1-adrenoceptors are unlikely<br />
to play a role in the secretion <strong>of</strong> human GH; this<br />
inhibitory action <strong>of</strong> CA is better accomplished through<br />
-adrenoceptors.<br />
C) -ADRENOCEPTORS. The inhibitory role <strong>of</strong> -receptor<br />
activation on GH release has been known for many years.<br />
The nonspecific -antagonist propranolol has no effect on<br />
GH secretion under basal conditions in Caucasians (110),<br />
whereas it does enhance the GH response to indirectacting<br />
CA agonists, such as amphetamines and desipramine<br />
(582, 877). This effect is achieved through propranolol-induced<br />
suppression <strong>of</strong> inhibitory influences mediated<br />
by -adrenoceptors, on which the synaptically released<br />
CA act. The same mechanism would explain why intravenous<br />
infusion <strong>of</strong> E had no effect on GH secretion in<br />
humans, whereas E combined with propranolol stimulated<br />
GH secretion (673). It would seem that E infusion<br />
activates both 2- and -adrenoceptors, with propranolol<br />
unmasking the opposite actions <strong>of</strong> these two receptors<br />
which, very likely located in the ME, are accessible to<br />
infused CA (917).<br />
It has since been shown that the 2-adrenergic agonist<br />
salbutamol inhibits the GH response to GHRH in<br />
humans (412). This is best explained by the possibility <strong>of</strong><br />
2-agonism through stimulation <strong>of</strong> the secretion <strong>of</strong> SS;<br />
inhibition <strong>of</strong> -receptors would inhibit SS release.<br />
This view fits well with the marked enhancing effect<br />
<strong>of</strong> propranolol on the GHRH-induced GH rise in children<br />
(234) and <strong>of</strong> the selective 1-receptor antagonist atenolol<br />
in adult humans (677) and short children (658). Moreover,<br />
acute administration <strong>of</strong> atenolol to GH-deficient children<br />
receiving long-term GHRH increased integrated GH secretion<br />
(659). These findings led to investigation <strong>of</strong> whether<br />
chronic treatment with atenolol might augment the therapeutic<br />
potential <strong>of</strong> GHRH. In a double-blind placebo<br />
controlled study, atenolol and GHRH coadministered to a<br />
group <strong>of</strong> GH-deficient children increased growth velocity<br />
during the first year, to a greater extent than treatment<br />
with GHRH alone. However, during the second year <strong>of</strong><br />
therapy, there was no significant difference in growth<br />
velocity between the two groups, and the mean 24-h<br />
concentration, that had been higher in the atenolol group<br />
during the first year, was lower in this group during the<br />
second year (183).<br />
-Adrenergic agonism and its clinical implications<br />
especially concern salbutamol, a 2-adrenergic agonist<br />
extensively used as a bronchodilator in the treatment <strong>of</strong><br />
asthma. Inhibition <strong>of</strong> GH release after GHRH treatment<br />
and during overnight GH testing was described in type I<br />
diabetic patients after short-term oral administration <strong>of</strong><br />
this drug (668). Evaluation <strong>of</strong> the short- and long-term<br />
effects <strong>of</strong> oral salbutamol in asthmatic short children<br />
showed that 24 h <strong>of</strong> drug treatment led to a decrease in<br />
the overnight IC-GH concentrations and peak GH levels<br />
after GHRH; however, after 3 mo <strong>of</strong> therapy, GH levels<br />
were no different from baseline and rose normally after<br />
GHRH (588). It would seem, therefore, that oral salbutamol<br />
produces no chronic deleterious changes in GH secretion<br />
and, hence, height velocity in children, although<br />
larger long-term studies are needed to confirm this.<br />
Whereas in vivo activation <strong>of</strong> CNS -adrenoceptors<br />
inhibits GH secretion in vitro, activation <strong>of</strong> these receptors<br />
stimulates GH secretion from rat pituitary cells (830).<br />
This mechanism is presumably not evident in vivo because<br />
it is a minor effect compared with the stimulant<br />
action <strong>of</strong> -adrenoceptors on SS secretion, which causes<br />
overall inhibition <strong>of</strong> GH secretion.<br />
D) DOPAMINE. Dopaminergic pathways are involved in<br />
the control <strong>of</strong> GH secretion, although their role appears to<br />
be largely ancillary. In rats, dogs, and monkeys, systemic<br />
administration <strong>of</strong> the DA precursor levodopa or directacting<br />
DA agonists stimulated GH release (see Ref. 756 for<br />
details). However, an -adrenergic component is also involved,<br />
as shown by the fact that -adrenoceptor antagonists<br />
partially or completely antagonize the stimulatory<br />
effect <strong>of</strong> DA in monkeys (985) and humans (159). Moreover,<br />
an inhibitory component seems inherent to DA’s<br />
ability to affect GH secretion. Thus there is evidence that<br />
monkeys have DA receptors inhibitory to GH release in<br />
the blood-brain barrier (BBB) (985, 1036).<br />
In healthy humans, although direct DA agonists such<br />
as apomorphine and the ergot derivates bromocriptine,<br />
lisuride, cabergoline, or indirect DA agonists such as amphetamine,<br />
nomifensine, or methylphenidate cause acute<br />
GH release and increase GH release in response to GHRH<br />
(1057), they blunt the GH response to insulin-induced<br />
hypoglycemia, levodopa, and arginine, administered by<br />
infusion (69, 1105). Bromocriptine (69) stimulates GH<br />
release in children with low baseline GH, but it has a<br />
rebound effect (inhibition, followed by rebound stimulation)<br />
or a clear-cut inhibitory effect in children with elevated<br />
baseline GH (79). These findings are best explained<br />
by the ability <strong>of</strong> DA to release both GHRH and SS from the<br />
rat hypothalamus (562) and by the different sensitivity <strong>of</strong><br />
SS and GHRH neurons to dopaminergic stimulation in<br />
relation to the endogenous DA tone. This puzzling feature<br />
is further complicated by the fact that DA and its agonists<br />
inhibit GH release from rat (273) and human (656) pituitaries<br />
in vitro and inhibit GH release in conditions <strong>of</strong>
April 1999 NEUROENDOCRINE CONTROL OF GROWTH HORMONE SECRETION 549<br />
pathological hypersecretion, a topic which is beyond the<br />
scope <strong>of</strong> this review and for which the reader should refer<br />
to Reference 1034.<br />
In the rat, the dopaminergic hypothalamo-pituitary<br />
axis appears to be involved in the differentiation, proliferation,<br />
and survival <strong>of</strong> pituitary cells during development.<br />
A DA transporter (DAT), which terminates DA action<br />
by amine reuptake into nerve terminals, is<br />
presumably expressed on hypothalamic dopaminergic<br />
neurons (698), but its relevance in calibrating DA overflow<br />
to the anterior pituitary remains unclear.<br />
In a mouse strain with deletion <strong>of</strong> the DAT gene, it was<br />
confirmed that DA reuptake through the transporter plays a<br />
vital physiological role regulating hypophysiotropic dopaminergic<br />
function. These mice have an altered spatial distribution,<br />
and a dramatic reduction in the numbers <strong>of</strong> somatotroph<br />
(and lactotroph) cells, are unable to lactate and show<br />
dwarfism. The effects <strong>of</strong> DAT deletion on pituitary function<br />
result from elevated DA levels that strikingly reduce hypothalamic<br />
GHRH function and downregulate the lactotrope<br />
D 2 DA receptors. Dopamine-induced suppression <strong>of</strong> GHRH<br />
function then downregulates the Pit-1/GHF, a transcription<br />
factor that commits the pluripotent pituitary stem cell to<br />
generate specific cell types (128).<br />
2. Serotonin<br />
Serotoninergic pathways in the brain contribute stimulatory<br />
influences for GH release in rodents (45). The<br />
situation is less clear in humans, where different drugs<br />
that either inhibit the functional activity <strong>of</strong> serotoninergic<br />
neurons or potentiate neurotransmitter mechanisms did<br />
not induce the expected changes (108, 233, 702; see also<br />
Ref. 756 for review).<br />
Data implicating 5-HT in raising the concentrations<br />
<strong>of</strong> circulating GH in the rat come from studies in which<br />
inhibition <strong>of</strong> tryptophan (Trp) hydroxylase by p-chlorophenylalanine<br />
significantly inhibited GH pulsatile secretion<br />
in unanesthetized male rats (665), or blockade <strong>of</strong><br />
5-HT receptors with nonspecific 5-HT antagonists was<br />
associated with suppressed GH levels (see Ref. 756). Conversely,<br />
the 5-HT precursor L-Trp, administered systemically,<br />
increased brain Trp and 5-HT levels and induced<br />
sustained release <strong>of</strong> GH (45, 1070); the same was true for<br />
intracerebroventricular injections <strong>of</strong> 5-HT or the direct<br />
5-HT agonist quipazine (1070). The immediate 5-HT precursor<br />
5-hydroxytryptophan (5-HTP) given systemically<br />
to unanesthetized rats also potently stimulated GH secretion,<br />
an effect prevented by the nonspecific 5-HT inhibitor<br />
cyproheptadine (967). However, after administration <strong>of</strong><br />
5-HTP, 5-HT may not be formed exclusively in 5-HT neurons<br />
but also in CA-containing neurons, leading ultimately<br />
to CA release (see Ref. 756).<br />
In keeping with this in infant rats, the brisk rise in<br />
plasma GH induced by 5-HTP was not counteracted by<br />
two 5-HT receptor antagonists but by blockade <strong>of</strong> dopaminergic<br />
or -adrenergic receptors or central sympathectomy<br />
induced by 6-OHDA (255). A further note <strong>of</strong> caution<br />
on the early 5-HT studies regards the low specificity <strong>of</strong> the<br />
5-HT receptor antagonists <strong>of</strong>ten used, i.e., methysergide<br />
and cyproheptadine. The latter also has antihistaminic,<br />
anticholinergic, antidopaminergic, and protein synthesis<br />
blocking properties, and the former shows paradoxical<br />
stimulating activity on 5-HT receptors (756).<br />
The lack <strong>of</strong> reasonably discriminating agonists and<br />
selective antagonists for most 5-HT receptor subtypes<br />
certainly accounts for some <strong>of</strong> the early controversial<br />
findings (749). Now that specific receptor ligands are<br />
available, studies have been designed to elucidate the<br />
involvement <strong>of</strong> specific 5-HT receptor subtypes. In freely<br />
moving conscious male rats, activation <strong>of</strong> 5-HT 1A receptors<br />
by systemic administration <strong>of</strong> the specific agonist<br />
hydroxy-2-(di-n-propylaminotetralin) or ipsapirone, or the<br />
less specific 5-HT 1B and 5-HT1 c agonist 1-(m-trifluoromethyl-phenyl)piperazine<br />
failed to affect plasma GH levels<br />
at any dose tested (311).<br />
The roles <strong>of</strong> different 5-HT receptors have been<br />
somewhat clarified by studies on the mechanisms underlying<br />
2-adrenoceptor-induced GH stimulation. Among<br />
various 5-HT receptor antagonists, only metergoline, a<br />
non-selective 5-HT 1/2 antagonist, and mesulergine, a<br />
5-HT 1c/5-HT 2 selective antagonist, almost completely suppressed<br />
clonidine-induced increases in GH levels,<br />
whereas two other 5-HT 1c/5-HT 2 antagonists, ritanserin<br />
and mianserin, only partially attenuated clonidine’s effect.<br />
In these studies, a 5-HT 3 receptor antagonist, MDL 7222,<br />
spiperone, a 5-HT 1A/5-HT 2 antagonist, and propranolol, a<br />
-adrenergic/5-HT 1d antagonist, were completely unable<br />
to antagonize clonidine (60). Overall, the pharmacological<br />
pr<strong>of</strong>ile <strong>of</strong> these compounds and their rank order <strong>of</strong> potency<br />
suggest that 5-HT 1c rather than 5-HT 2 receptors<br />
are involved in the 2-adrenoceptor stimulation-induced<br />
GH increase in the rat. However, studies <strong>of</strong> short-term<br />
maternal separation in preweanling rats, a model for<br />
the syndrome <strong>of</strong> maternal deprivation in humans, which<br />
encompasses growth retardation, weight reduction, and<br />
social withdrawal (32), once termed psychosocial dwarfism<br />
(863), have led to the conclusion that 5-HT 2A and<br />
5-HT 2c receptors were certainly involved in GH hyposecretion<br />
(553).<br />
Whatever the real contribution <strong>of</strong> the different 5-HT<br />
receptor subtypes, the close functional relations between<br />
adrenergic and serotoninergic pathways involved in GH release,<br />
and the idea that brain 5-HT changes are implicated in<br />
the etiology <strong>of</strong> affective illness and the mode <strong>of</strong> action <strong>of</strong><br />
antidepressants and antimanic drugs (700), might explain<br />
why several clinical studies found blunted GH responsiveness<br />
to clonidine in depressed patients compared with controls<br />
(756). The ability <strong>of</strong> moclobemide, an antidepressant<br />
drug and selective reversible inhibitor <strong>of</strong> type A monoamine
550 MÜLLER, LOCATELLI, AND COCCHI Volume 79<br />
oxidase (MAO-A), to markedly increase 5-HT function and<br />
stimulate GH secretion in depressed subjects should be<br />
evaluated in this context (766).<br />
In Hollstein steers, systemically administered quipazine, a<br />
nonspecific 5-HT 1B,2A,2C,3 agonist and, possibly, a 5-HT 1B antagonist,<br />
increased GH secretion, whereas cyproheptadine lowered<br />
it. These drugs had this effect regardless <strong>of</strong> whether cattle<br />
ate ad libitum or were food deprived, but they did not influence<br />
SS concentrations in plasma after feeding, suggesting that 5-HT<br />
receptor-stimulated GH secretion is mediated within the CNS<br />
and is involved in stimulation <strong>of</strong> pulsatile GH secretion (394). In<br />
the monkey, however, 5-HT microinjected into the VMN did not<br />
raise plasma GH (1036), although a significant response was<br />
reported after systemic infusion <strong>of</strong> 5-HTP (216).<br />
In dogs, 5-HT seems to have an inhibitory role in the<br />
canine GH (cGH) response to insulin hypoglycemia (626,<br />
761). Other studies in dogs aimed to establish whether a<br />
primary 5-HT effect on cGH secretion could be distinguished<br />
from stress-related cGH stimulation. They were<br />
prompted by the observation that while low doses <strong>of</strong><br />
5-HTP produced brisk cGH responses, with no signs <strong>of</strong><br />
distress or changes in plasma corticosteroids, high 5-HTP<br />
doses, although able to release cGH, were associated with<br />
behavioral and endocrine signs <strong>of</strong> stress (320). Pentobarbital<br />
sodium anesthesia abolished the rise in cGH and<br />
corticosteroids induced by insulin-hypoglycemia, but not<br />
an earlier increment in plasma cGH, unaccompanied by<br />
stimulation <strong>of</strong> corticosteroid release, induced by systemically<br />
administered 5-HTP (321).<br />
Although these elegant studies imply that the 5-HT<br />
mechanism <strong>of</strong> GH stimulation in the dog differs from the<br />
stress-related mechanisms <strong>of</strong> cGH release, they are biased<br />
by the use <strong>of</strong> 5-HTP as a specific activator <strong>of</strong> 5-HT neurotransmission,<br />
as pointed out previously. In anesthetized<br />
dogs, the effect <strong>of</strong> 5-HTP was abolished by the adrenoceptor<br />
antagonist phenoxybenzamine (1130), and the<br />
same was true for healthy volunteers (768).<br />
Further evidence that in some animal species activation<br />
<strong>of</strong> central 5-HT neurotransmission inhibits GH release<br />
comes from experiments in sheep where tianeptine,<br />
a 5-HT uptake enhancer, increased GHRH release into the<br />
hypophysial portal vessels and raised GH secretion (186).<br />
In humans, using a variety <strong>of</strong> 5-HT receptor agonists<br />
and antagonists, it has been seen that 5-HT pathways<br />
stimulate, inhibit, or do not alter GH secretion (see Ref.<br />
756 for references). Sumatriptan, a recent selective<br />
5-HT 1D receptor agonist with no activity on 5-HT 2, 5-HT 3,<br />
and 5-HT 4 receptors, and other neurotransmitter receptors,<br />
has permitted closer assessment <strong>of</strong> 5-HT’s effects on<br />
basal and stimulated GH secretion. In normal prepubertal<br />
children, sumatriptan raised basal GH levels and the GH<br />
responses to GHRH; however, sumatriptan pretreatment<br />
did not modify the GH response to clonidine or pyridostigmine,<br />
an inhibitor <strong>of</strong> AChE, but increased the GH response<br />
to arginine. In a group <strong>of</strong> obese children,<br />
sumatriptan did not alter baseline GH levels, but still<br />
enhanced the effect <strong>of</strong> GHRH (743). A cautious interpretation<br />
<strong>of</strong> these findings is that sumatriptan was active in<br />
normal and obese subjects through inhibition <strong>of</strong> the somatostatinergic<br />
tone, with the only reservation in this<br />
reasoning resting on the enhanced GH response to arginine<br />
which allegedly operates through the same mechanism.<br />
A CNS mechanism <strong>of</strong> action for sumatriptan is<br />
suggested by its lack <strong>of</strong> effect on GH secretion in acromegaly<br />
(279).<br />
In a group <strong>of</strong> nondepressed male alcoholics with 1 or<br />
2 yr <strong>of</strong> abstinence from alcohol, sumatriptan failed to<br />
increase GH secretion (1069), implying a persistent, selective<br />
loss <strong>of</strong> 5-HT 1D receptor function (see also sect.<br />
VB5B2).<br />
Other studies <strong>of</strong> 5-HT involvement in GH regulation<br />
in humans have used 5-HT 2 receptor antagonists. In<br />
healthy subjects, ketanserin did not modify the GH response<br />
to insulin hypoglycemia (865), whereas its companion<br />
drug ritanserin did (1027), very likely due to its<br />
higher affinity for the 5-HT 2 receptor and better penetration<br />
<strong>of</strong> the BBB.<br />
These findings further complicate the already contradictory<br />
data in the literature. Quipazine, a nonselective<br />
5-HT receptor antagonist, given orally, did not alter<br />
plasma GH in normal subjects or patients with neurological<br />
disorders (809). The elusive nature <strong>of</strong> serotoninergic<br />
modulation <strong>of</strong> GH secretion also emerges from studies<br />
with fenfluramine, a potent 5-HT releaser and inhibitor <strong>of</strong><br />
5-HT reuptake. In healthy subjects, the drug inhibited the<br />
GH release induced by the combination <strong>of</strong> L-dopa and<br />
propranolol but not when arginine was used as a GH<br />
stimulant. The drug alone slightly lowered baseline GH<br />
levels (180), although it did not do so in another study<br />
(610). Regardless <strong>of</strong> the interpretation <strong>of</strong> these findings,<br />
overall they do not support a serotoninergic stimulatory<br />
component in human GH secretion.<br />
Fenfluramine has also been used to probe the function<br />
<strong>of</strong> central 5-HT neurotransmission in obese subjects,<br />
in whom defective function has been postulated (604). In<br />
a group <strong>of</strong> moderately obese subjects, GHRH induced a<br />
low GH response, which further decreased after 9 wk <strong>of</strong><br />
treatment with fenfluramine (325). These data were taken<br />
to indicate that a serotoninergic defect was not involved<br />
in the low basal GH concentration or the blunted response<br />
to GHRH in obese subjects. Results were similar<br />
in experiments in which the GH release induced by GHRH<br />
was assessed in obese subjects after 7 days <strong>of</strong> treatment<br />
with fluoxetine, a 5-HT reuptake inhibitor (844).<br />
3. ACh<br />
The initial observation that in normal subjects atropine<br />
blockade <strong>of</strong> muscarinic cholinergic receptors had no<br />
effect on GH release elicited by insulin hypoglycemia
April 1999 NEUROENDOCRINE CONTROL OF GROWTH HORMONE SECRETION 551<br />
(111) for many years hindered further studies on the<br />
actual role <strong>of</strong> ACh in the neural control <strong>of</strong> GH secretion.<br />
Thus only in 1978 did Bruni and Meites (147) show that in<br />
conscious male rats intracerebroventricularly injected<br />
ACh bromide raised plasma GH and that the same effect<br />
was achieved by systemic injection <strong>of</strong> pilocarpine or eserine,<br />
a muscarinic agonist and an AChE inhibitor, respectively.<br />
The increase in GH release induced by pilocarpine<br />
was antagonized by atropine, which per se did not alter<br />
serum GH concentrations. Parallel studies in chronically<br />
cannulated, unrestrained rats showed that systemically<br />
administered atropine inhibited episodic GH release<br />
(665).<br />
In dogs, ACh neurotransmission appeared to have a<br />
stimulatory role in GH release, through muscarinic receptors<br />
inside the BBB (173). The importance <strong>of</strong> cholinergic<br />
mediation in the GH-releasing mechanism(s) was emphasized<br />
by the observation that in dogs (174) and humans<br />
(825) atropine was the most effective antagonist <strong>of</strong> the<br />
GH release induced by EOP (see sect. VB8).<br />
Further evidence that cholinergic transmission is involved<br />
in GH accumulated from human studies. Mendelson<br />
et al. (703) reported a striking suppression <strong>of</strong> the<br />
sleep-associated increase in GH secretion and a more<br />
subtle blunting <strong>of</strong> the GH response to insulin-induced<br />
hypoglycemia after administration <strong>of</strong> methscopolamine, a<br />
muscarinic antagonist unable to cross the BBB. The same<br />
group found that in humans infusion <strong>of</strong> piperidine, a<br />
cholinergic nicotinic agonist, left resting GH levels unaltered<br />
but slightly enhanced sleep-related and insulin-induced<br />
GH secretion; they were led to conclude that both<br />
nicotinic and muscarinic mechanisms were involved in<br />
these aspects <strong>of</strong> stimulated GH release (704).<br />
The observation that methscopolamine, which does<br />
not cross the BBB, blunted the stimulated GH release in<br />
humans indicated a “peripheral” site <strong>of</strong> action for cholinergic<br />
stimulation <strong>of</strong> GH release. This was borne out by the<br />
reported ability <strong>of</strong> edrophonium and pyridostigmine, two<br />
irreversible AChE inhibitors and quaternary ammonium<br />
compounds, to release GH in normal subjects (609, 672).<br />
Cholinergic muscarinic receptors have been described in<br />
the anterior pituitary (747, 931) and the ME (954), and<br />
ACh is a direct GH secretagogue on bovine (1120) and rat<br />
pituitary (170).<br />
The increasing awareness <strong>of</strong> the role played by ACh<br />
neurotransmission in the mechanism(s) subserving GH<br />
release led to fresh investigations <strong>of</strong> how cholinergic<br />
function interacted with the metabolically and neurotransmitter-driven<br />
GH release. In normal men, pirenzepine,<br />
a selective antagonist <strong>of</strong> M 1 receptors that barely<br />
crosses the BBB, blocked the GH rise induced by DA and<br />
2-adrenoceptor stimulation (301), and atropine suppressed<br />
that after arginine, clonidine, and physical exercise<br />
(178). In line with the methscopolamine findings,<br />
atropine or scopolamine completely abolished SWS-re-<br />
lated GH release in normal adults or children (835, 1025).<br />
Pirenzepine and atropine also completely blocked the GH<br />
response to GHRH, whereas conversely, blockade <strong>of</strong><br />
AChE by pyridostigmine potentiated the GH response to<br />
GHRH (672) and normalized the blunted somatotroph<br />
responsiveness to repetitive GHRH boluses (671). Finally,<br />
paradoxical GH responses to TRH, which occur in some<br />
patients with insulin-dependent diabetes, endogenous depression,<br />
or liver cirrhosis, could be suppressed by pirenzepine<br />
(759).<br />
Overall, the fact that M 1 cholinergic receptors inhibited<br />
the GH response to most <strong>of</strong> the hypothalamic and<br />
pituitary GH-releasing stimuli was consistent with the<br />
idea that the restraint arose “downstream” <strong>of</strong> the chain <strong>of</strong><br />
events leading to GH release. Enhanced release <strong>of</strong> hypothalamic<br />
SS and the ensuing inhibition <strong>of</strong> somatotroph<br />
function might explain these findings.<br />
In vitro studies addressing the mechanism(s)<br />
whereby ACh neurotransmission affects GH secretion<br />
provided support for this concept. Low concentrations <strong>of</strong><br />
ACh inhibited the release <strong>of</strong> SS-LI from rat hypothalami in<br />
culture, an effect shared by neostigmine and blocked by<br />
atropine, but not by hexamethonium, a nicotinic antagonist<br />
(888). These observations were in contrast to findings<br />
that a series <strong>of</strong> muscarinic cholinergic agonists raised<br />
secretion <strong>of</strong> SS-LI from fetal rat hypothalami in culture, an<br />
effect antagonized by atropine (834), and that intracerebroventricularly<br />
injected ACh in rats released SS-LI into<br />
hypophysial blood (228). These latter findings, however,<br />
must be interpreted with caution, since anesthesia is mandatory<br />
in these in vivo experiments and some anesthetics<br />
already induce SS release.<br />
Pro<strong>of</strong> that abolition <strong>of</strong> GHRH-induced GH release by<br />
cholinergic antagonists implies activation <strong>of</strong> SS release<br />
was provided by in vivo experiments in conscious male<br />
rats. Like in humans, pirenzepine or pilocarpine, respectively,<br />
reduced or potentiated the increase in plasma GH<br />
induced by GHRH. These modulatory effects were not<br />
seen in two experimental models <strong>of</strong> depletion <strong>of</strong> hypothalamic<br />
SS (629). These data indicated that in rats cholinergic<br />
modulation on GH release is through SS, in keeping<br />
with the high density <strong>of</strong> muscarinic binding sites in the<br />
ME (911) and their location in the lateral region <strong>of</strong> the<br />
external layer (954), to which most <strong>of</strong> the SS nerve terminals<br />
also project (see sect. IIIB). Cholinergic neurons<br />
would also be instrumental to the aut<strong>of</strong>eedback regulation<br />
<strong>of</strong> GH secretion, through modulation <strong>of</strong> the SS tone,<br />
in rats (1039) or humans (907) (see also sect. VIIA). Cholinergic<br />
receptor agonists and antagonists added to pituitary<br />
cells in vitro did not alter the GHRH-induced GH<br />
release (629).<br />
Although the relationship between SS function and<br />
the hypothalamic cholinergic system is now generally<br />
established, some observations still challenge it. For instance,<br />
the hypoglycemia-induced increase in GH appears
552 MÜLLER, LOCATELLI, AND COCCHI Volume 79<br />
to be almost totally (702) or partially (344) refractory to<br />
cholinergic blockade, but not to the action <strong>of</strong> SS. This and<br />
a series <strong>of</strong> other observations in animal (37) and human<br />
models <strong>of</strong> caloric restriction (see below) suggest an extra<br />
SS component in the modulatory action <strong>of</strong> cholinergic<br />
drugs on GH release. Thus, in subjects with AN, pyridostigmine<br />
failed to potentiate the release <strong>of</strong> GH induced<br />
by GHRH, whereas arginine, another GH secretagogue<br />
allegedly acting by inhibiting release (22), fully enhanced<br />
the GHRH-induced release <strong>of</strong> GH in these patients (409).<br />
In sheep, a single dose <strong>of</strong> neostigmine stimulated GHRH<br />
release into hypophysial portal vessels without changing<br />
SS concentrations (651), and interestingly, in the rat ARC<br />
ACh coexists in GHRH- but not in SS-containing neurons<br />
(699).<br />
In sum, it cannot be ruled out that GHRH is involved<br />
in the modulatory action <strong>of</strong> cholinergic drugs on GH<br />
release as also inferred by the fact that a competitive<br />
GHRH antagonist suppressed the increase in GH induced<br />
by an AChE inhibitor (520), or by the type <strong>of</strong> GH pulse<br />
pr<strong>of</strong>iles evoked by a short pyridostigmine treatment in<br />
humans (373). The dual mechanism <strong>of</strong> cholinergic agonists<br />
explains why they do not completely reverse the<br />
defective GH release associated with obesity (415, 634)<br />
more convincingly than a mechanism relying exclusively<br />
on inhibition <strong>of</strong> hypothalamic SS. Instead, in obesity, the<br />
GH hyposecretion is completely reversed by the combination<br />
<strong>of</strong> GHRH and GHRP-6, which provides an appropriate<br />
pituitary-directed GHRH and anti-SS stimulation<br />
(270; see Ref. 752 for further discussion).<br />
A) CLINICAL IMPLICATIONS. The availability <strong>of</strong> a class <strong>of</strong><br />
compounds purportedly suppressing hypothalamic SS influences,<br />
i.e., muscarinic cholinergic agonists, prompted<br />
studies to see whether they could enhance the diagnostic<br />
power <strong>of</strong> GHRH. When used alone, GHRH does not discriminate<br />
between normal and GH-deficient subjects;<br />
wide inter- and intraindividual variability is frequent even<br />
in normal subjects, and there may be no GH response to<br />
the maximally effective dose (686, 1055). The effects <strong>of</strong><br />
pyridostigmine on basal and GHRH-induced GH secretion<br />
were investigated in children with familial short stature,<br />
constitutional growth delay, and GH deficiency, and the<br />
results were compared with those following insulin-induced<br />
hypoglycemia or GHRH alone (416) or, in another<br />
study, with those <strong>of</strong> normal children undergoing a series<br />
<strong>of</strong> provocative tests (405). In normal children, the pyridostigmine-GHRH<br />
tests, unlike other GH secretagogues,<br />
gave no false-negative responses; the minimal normal GH<br />
response was 20 ng/ml. The test therefore detected a<br />
pathological response in a much wider interval than the<br />
other tests; in patients with organic GH deficiency, peak<br />
GH responses were lower than 6 ng/ml, whereas in patients<br />
with idiopathic GH deficiency or constitutional<br />
growth delay, peak GH responses were 7–19 ng/ml. Thus<br />
the pyridostigmine-GHRH test and also the arginine-<br />
GHRH test (405) are currently the most reliable for assessing<br />
GH secretory status in children, because they<br />
probe the maximal secretory potential <strong>of</strong> the pituitary. A<br />
normal GH response to the combined pyridostigmine or<br />
arginine-GHRH test does not exclude the existence <strong>of</strong> a<br />
GH hyposecretory state due to hypothalamic dysfunction,<br />
calling for 24-h monitoring <strong>of</strong> GH secretion.<br />
The clear GH-releasing effect <strong>of</strong> cholinergic muscarinic<br />
agonists led to their use in the treatment <strong>of</strong> short<br />
stature. Briefly, in a group <strong>of</strong> short children, with hormonal<br />
features peculiar to hypothalamic dysfunction,<br />
long-term oral pyridostigmine (60 mg 3 times a day for 6<br />
mo) did not significantly alter height velocity, mean GH<br />
concentration, and plasma IGF-I levels, except in one<br />
child (755). Results were similarly negative with a combination<br />
<strong>of</strong> cholinergic agonists and GHRH in the treatment<br />
<strong>of</strong> short stature (908).<br />
Muscarinic cholinergic agonists could also be used to<br />
investigate the hypothalamic SS (and GHRH?) system in<br />
different physiological or pathological conditions. In rats<br />
aged between 10 days and 29 mo, administration <strong>of</strong> GHRH<br />
alone led to an age-related decline in the responsiveness<br />
<strong>of</strong> GH, starting from 8 mo <strong>of</strong> age. Pretreatment with<br />
pilocarpine potentiated the GH response to GHRH during<br />
the entire life span, with the only exception being 10-dayold<br />
rats in which the drug had no effect. Interestingly, at<br />
this age, the hypothalamic SS tone is very low (see sect.<br />
IIB). Pilocarpine rejuvenated the GH response to GHRH in<br />
the older rats (18 and 29 mo old) to the concentrations <strong>of</strong><br />
that found in 15-mo-old rats (807). Similarly, in a group <strong>of</strong><br />
normal elderly humans, pyridostigmine potentiated GH<br />
response to GHRH, although it was still significantly<br />
lower than in younger people (413).<br />
These findings support the idea that in aged mammals<br />
the reduced response <strong>of</strong> GH to GHRH is only partly<br />
due to an intrinsic defect <strong>of</strong> the somatotrophs and that<br />
hypothalamic and/or extrahypothalamic inhibitory influences<br />
under cholinergic control are also involved. It is<br />
common knowledge that central cholinergic function can<br />
be impaired in the elderly brain (828), and cholinergic<br />
agonists per se induce a blunted GH response in aged<br />
animals (208) and humans (872).<br />
At variance with the partial restoration <strong>of</strong> the GH<br />
response to GHRH by pyridostigmine is the complete<br />
restoration by pretreatment with arginine so that the increase<br />
in GH induced by arginine-GHRH cotreatment was<br />
similar in young and old subjects, and arginine had<br />
greater potentiating effect in elderly than in young subjects<br />
(414). These findings, while reinforcing the idea that<br />
the pool <strong>of</strong> releasable GH is essentially preserved in the<br />
human pituitary even during aging (see also sect. IIB),<br />
illustrate the irreversible, age-related alteration <strong>of</strong> the<br />
cholinergic function coupled with a reversible SS hyperfunction.<br />
Attempts at using cholinergic blockade in GH hyper-
April 1999 NEUROENDOCRINE CONTROL OF GROWTH HORMONE SECRETION 553<br />
secretory states have not been successful. Insulin-dependent<br />
diabetics (IDDM) may present exaggerated nocturnal<br />
GH swings, and GH release is primarily responsible<br />
for the dawn phenomenon, i.e., decreased sensitivity <strong>of</strong><br />
hepatic glucose production to insulin (754). Suppressing<br />
<strong>of</strong> GH secretion in IDDM may improve metabolic control<br />
and prevent the development <strong>of</strong> diabetic late complications.<br />
After a few promising results with short- or mediumterm<br />
pirenzepine (57, 670), in further studies, atropine<br />
and propantheline, another muscarinic cholinergic antagonist,<br />
had no effect on indices <strong>of</strong> somatotrophic function<br />
in IDDM patients with active proliferative retinopathy<br />
(500). These results, which recall the inability <strong>of</strong> pirenzepine<br />
to suppress 24-h GH secretion in tall children (469),<br />
put doubt on the effectiveness <strong>of</strong> long-term treatment<br />
muscarinic antagonists, probably because <strong>of</strong> the early<br />
development <strong>of</strong> tolerance (916).<br />
4. Histamine<br />
The role <strong>of</strong> histamine on GH release in the rat is still<br />
debated, but most <strong>of</strong> the evidence points to inhibition by<br />
H 1 receptors. In conscious rats, intracerebroventricular<br />
administration <strong>of</strong> histamine or a series <strong>of</strong> H 1-receptor<br />
agonists reduced GH release induced by morphine;<br />
mepyramine, a H 1-receptor antagonist, had no effect by<br />
itself but prevented the inhibitory action <strong>of</strong> 2-methylhistamine,<br />
a H 1-receptor agonist. The H 2-receptor agonists<br />
and antagonists also inhibited morphine-induced GH release<br />
but apparently with a nonspecific mechanism (776).<br />
Similarly, nanomolar intracerebroventricular doses <strong>of</strong> histamine<br />
or amodiaquine, an inhibitor <strong>of</strong> histamine catabolism,<br />
caused a dose-related suppression <strong>of</strong> pulsatile GH<br />
secretion (775).<br />
At odds with these findings, in E 2- and progesteroneprimed<br />
anesthetized male rats, a H 1-receptor antagonist<br />
blocked the rise in GH induced by morphine, neurotensin,<br />
and SP, with a mechanism that could not be related<br />
simply to the hypotensive properties <strong>of</strong> these substances<br />
(891).<br />
The inhibitory effect <strong>of</strong> histamine neurotransmission<br />
on GH release has since been illustrated in neonatal and<br />
adult rats. In the former, blockade <strong>of</strong> histamine synthesis<br />
with -fluoromethylhistidine (-FMH) significantly raised<br />
plasma GH and potentiated the GH response to an enkephalin<br />
analog; GH and SS mRNA were significantly<br />
higher in -FMH-treated pups, whereas GHRH mRNA levels<br />
were unaltered. In young adult male rats, acute administration<br />
<strong>of</strong> -FMH did not change baseline GH levels but<br />
potentiated the enkephalin-induced stimulation <strong>of</strong> GH secretion.<br />
Repeated intracerebroventricular doses <strong>of</strong><br />
-FMH did not alter the hormone levels, significantly<br />
reduced hypothalamic GHRH mRNA, and left SS and<br />
GHmRNA unchanged (439). Overall, these findings sug-<br />
gest an inhibitory histamine tone on GH secretion in<br />
neonatal and adult young rats, the failure <strong>of</strong> -FMH to<br />
increase GH secretion in the latter being probably due to<br />
upregulation <strong>of</strong> histamine receptors after brain histamine<br />
depletion (862).<br />
Data in freely moving dogs point instead to a facilitatory<br />
role on GH secretion. Of the three H 1-receptor<br />
antagonists used, only clemastine, which reportedly has<br />
no antiserotoninergic, antiadrenergic, and anticholinergic<br />
action, blunted hypoglycemia-induced GH release (626),<br />
whereas diphenhydramine, clemastine, and the H 2-receptor<br />
antagonist cimetidine, respectively, suppressed or<br />
blunted the cGH release induced by an opioid peptide<br />
(174) or by cholinergic stimulation (100).<br />
Histamine also appears to be involved in stimulated<br />
GH release. In normal humans, two H 1-receptor antagonists<br />
significantly reduced the GH response to arginine<br />
infusion, but neither drug affected the secretion after<br />
insulin hypoglycemia (859). In healthy volunteers, diphenhydramine,<br />
which also has anticholinergic activity, completely<br />
suppressed the GH response to an opioid peptide,<br />
FK 33–824 (825). The H 2-receptor antagonists have given<br />
different results depending on the dose, length <strong>of</strong> treatment,<br />
and route <strong>of</strong> administration. Thus cimetidine at oral<br />
therapeutic doses for 1 mo or more to patients with peptic<br />
ulcers (990) or normal subjects (1051) did not alter baseline<br />
or stimulated GH release but reduced mean nocturnal<br />
GH secretion (1051). The drug also reduced GH response<br />
to insulin hypoglycemia when repeatedly administered<br />
(858) and blunted the GH response to levodopa when<br />
given as an intravenous bolus injection (1122). Higher<br />
peak plasma concentrations <strong>of</strong> cimetidine after a single<br />
intravenous bolus than after chronic oral administration<br />
explain these results.<br />
5. Amino acids<br />
A) EXCITATORY AMINO ACIDS. A glutamatergic control <strong>of</strong><br />
GH secretion was first suggested a long time ago when it<br />
was shown that MSG given neonatally, at doses damaging<br />
the ARC neurons, impaired the rhythmic GH secretion in<br />
postweaning rats (774). This compound acted similarly in<br />
adult male rats at doses causing no neurotoxic lesions.<br />
However, two agonists <strong>of</strong> glutamate receptors, N-methyl-<br />
D,L-aspartic acid (NMA) or kainic acid, increased GH secretion<br />
in adult male rats, implying that NMDA and non-<br />
NMDA receptor subtypes were involved in GH-secreting<br />
mechanism(s) (670, 850). In the same experiments, ibotenic<br />
acid or quinolinic acid did not alter AP hormone<br />
secretion (670).<br />
The GH-releasing properties <strong>of</strong> systemically administered<br />
NMA were confirmed in prepubertal male rhesus<br />
monkeys. Injection <strong>of</strong> the amino acid analog elicited a<br />
prompt increase in GH secretion to three times the preinjection<br />
values. N-methyl-D,L-aspartic acid maintained its
554 MÜLLER, LOCATELLI, AND COCCHI Volume 79<br />
ability to release GH when given systemically to castrated<br />
male sheep which, unlike rodents, do not respond to the<br />
amino acid in terms <strong>of</strong> LH release (342). A dose-related<br />
increase <strong>of</strong> plasma GH levels after NMA was also reported<br />
in ovariectomized ewes (341) and in intact ewes (323).<br />
Unlike the gonadotropin system (242), NMDA seems<br />
to stimulate GH release to much the same extent in neonatal<br />
and adult rats, as shown by its ability to increase<br />
plasma GH in 2-day-old rats (8). Consistent with a stimulatory<br />
role <strong>of</strong> excitatory amino acid (EAA) on GH secretion<br />
in either infant or adult rats was the observation that<br />
blockade <strong>of</strong> NMDA receptors by the noncompetitive antagonist<br />
MK-801 in immature female rats caused longlasting<br />
reduction <strong>of</strong> growth rate, GH pituitary content,<br />
basal and GHRH-stimulated GH release, and plasma IGF-I<br />
levels. This effect was coupled with delayed puberty and<br />
reduced gonadotropin secretion, which mimics a condition<br />
frequent in humans (1068).<br />
Stimulation <strong>of</strong> GH release by NMDA posed the question<br />
<strong>of</strong> the site(s) and mechanism(s) <strong>of</strong> action <strong>of</strong> EAA.<br />
Neural loci at which systemically administered NMDA<br />
may affect GH release comprise areas <strong>of</strong> the brain lacking<br />
a distinct BBB, especially the circumventricular organs,<br />
and including the ARC (868). When NMDA was tested on<br />
pituitary fragments from neonatal or young adult rats in<br />
static incubation, it showed no GH-releasing effect (8,<br />
260), and stimulation <strong>of</strong> GH release was scant after incubation<br />
<strong>of</strong> pig pituitary cells with high concentrations <strong>of</strong><br />
glutamate or aspartate (71). Results were different, however,<br />
on isolated perfused somatotrophs, where low concentrations<br />
<strong>of</strong> NMDA induced sustained GH release that<br />
was abolished by the concomitant addition <strong>of</strong> competitive<br />
and noncompetitive NMDA receptor antagonists (615).<br />
The possibility that isolation <strong>of</strong> the somatotrophs from<br />
the other pituitary cells was responsible for the enhanced<br />
responsiveness to NMDA in the perfusion system was<br />
unlikely; NMDA caused dose-related GH stimulation in a<br />
mixed population <strong>of</strong> cultured pituitary cells, as assessed<br />
by the reverse hemolytic plaque assay (777). The same<br />
GH-releasing effect was shared by L-glutamate or kainic<br />
acid and was completely counteracted by selective NMDA<br />
and non-NMDA receptor antagonists (777). The rat somatotrophs<br />
thus appeared to have both NMDA and non-<br />
NMDA ionotropic receptors.<br />
In line with these findings, non-NMDA type <strong>of</strong> receptors<br />
were demonstrated in the anterior lobe <strong>of</strong> the rat<br />
pituitary by immunohistochemistry (563). Other studies<br />
have also detected the metabotropic type <strong>of</strong> EAA receptor<br />
(1117). The demonstration <strong>of</strong> the NMDA R 1 receptor subunit,<br />
in the AP and its colocalization in many cell types,<br />
including the somatotrophs, indicate the importance <strong>of</strong> a<br />
direct effect in the pituitary (101).<br />
Deafferentation <strong>of</strong> the MBH reportedly leads to a<br />
drop <strong>of</strong> glutamic acid concentrations in the MBH itself,<br />
and in both lobes <strong>of</strong> the pituitary (869). This implies that<br />
the amino acid is not manufactured in the pituitary gland<br />
and that EAA receptors are stimulated by hypothalamicderived<br />
glutamate transported to the target sites by the<br />
portal vessels.<br />
The stimulatory effect on GH secretion <strong>of</strong> hypothalamic<br />
injection <strong>of</strong> EAA strongly suggested a major CNS<br />
site <strong>of</strong> action. It was also shown that NMDA did not<br />
release GH in ARC-lesioned adult rats (8), indicating that<br />
its effect was mediated by substances released from this<br />
area. That pretreatment with a GHRH antiserum reduced<br />
the GH-releasing effect <strong>of</strong> NMDA in neonatal rats (8) was<br />
in keeping with the idea that a GHRH deficiency was<br />
involved. Similar results were obtained in prepubertal<br />
gilts in which aspartate was a more potent GH secretagogue<br />
than glutamate, but neither compound had any<br />
effect in the GHRH antiserum-pretreated animals (71).<br />
More pro<strong>of</strong> <strong>of</strong> this mechanism was provided in male rats<br />
at weaning by evaluating the effect <strong>of</strong> 10 days <strong>of</strong> treatment<br />
with MK-801 on the hypothalamic content and gene expression<br />
<strong>of</strong> GHRH and SS. The drug impaired the growth<br />
rate and reduced GH secretion with significant lowering<br />
<strong>of</strong> the hypothalamic GHRH content and GHRH mRNA.<br />
Hypothalamic SS content and mRNA were unaltered<br />
(260).<br />
This finding is seemingly in contrast to a report that<br />
the NMDA receptor antagonist counteracted NMDA-stimulated<br />
SS release from cultured diencephalic neurons<br />
(1022), but this might be due to differences in neuronal<br />
organization in fetal (1022), prepubertal (260) hypothalami.<br />
In our hands too, however, quinolinic acid, an NMDA<br />
receptor agonist, strikingly increased SS release from incubated<br />
hypothalamic fragments, this effect being completely<br />
reversed by coincubation with MK-801 (260). It<br />
cannot be ruled out, therefore, that MK-801 may induce<br />
changes in selective groups <strong>of</strong> hypothalamic SS-producing<br />
neurons, whose involvement might perhaps be evidenced<br />
by a more refined approach, e.g., in situ hybridization.<br />
Although there are reports that NMDA receptor activation<br />
is required for the expression <strong>of</strong> c-fos in GnRH<br />
neurons <strong>of</strong> female rats (602), no specific studies have<br />
been done on c-fos induction in neurons containing GHregulatory<br />
neurohormones, although intraventricular injection<br />
<strong>of</strong> NMDA induced c-fos expression around the<br />
PeVN and in the ARC, where GHRH and SS-containing<br />
cell bodies are located (see sect. IIIA2). An increase in<br />
c-fos-IR after NMDA was evident in noradrenergic cells <strong>of</strong><br />
the locus coeruleus (914), and this would be relevant for<br />
the stimulatory effect <strong>of</strong> EAA on GH secretion, in view <strong>of</strong><br />
the major role played by NE neurons in this context.<br />
That excitatory amino action action depends on sex<br />
steroids was shown in adult male rats orchidectomized 1<br />
wk before. Systemic administration <strong>of</strong> kainic acid elicited<br />
a larger rise in plasma GH than in sham-operated controls;<br />
the GH-releasing properties <strong>of</strong> kainic acid completely dis-
April 1999 NEUROENDOCRINE CONTROL OF GROWTH HORMONE SECRETION 555<br />
appeared in male rats estrogenized at birth, a model <strong>of</strong><br />
permanent decrease <strong>of</strong> plasma testosterone (850).<br />
The results so far strongly suggest that EAA are<br />
positive modulators <strong>of</strong> GH secretion, mainly acting<br />
through at GH neuroregulatory hormones. It would appear<br />
that this effect is mediated by ionotropic NMDA and<br />
non-NMDA (AMPA/kainate) receptors, with metabotropic<br />
glutamate receptors not being involved. A direct action <strong>of</strong><br />
EAA on somatotrophs is unlikely, in view <strong>of</strong> the controversial<br />
data on in vitro GH secretion, and the biochemical<br />
evidence <strong>of</strong> the presence <strong>of</strong> metabotropic but not ionotropic<br />
glutamate receptors in the pituitary. Hypothalamic<br />
GHRH neurons would be the privileged target <strong>of</strong> EAA<br />
action, with somatostatinergic neurons playing only an<br />
ancillary role.<br />
From a physiological point <strong>of</strong> view, EAA seem to be<br />
involved in the central mechanisms triggering the endocrine<br />
events related to puberty, including the enhanced<br />
GH secretion that accelerates body growth (see also sect.<br />
IIIB and Ref. 139 for review). It is tempting to suggest,<br />
therefore, that the frequent association <strong>of</strong> delayed puberty<br />
and short stature (729) may share a common etiopathogenetic<br />
denominator, namely, reduced glutamatergic<br />
function at either the GnRH- or GHRH-producing<br />
neurons in the ARC. Were this the case, NMDA receptor<br />
antagonists would be useful for the treatment <strong>of</strong> precocious<br />
puberty, although the inhibitory effect <strong>of</strong> noncompetitive<br />
NMDA receptor antagonists on GH secretion<br />
would constitute an adverse event. Unlike MK-801, CGP-<br />
39551, a competitive antagonist <strong>of</strong> NMDA receptors, delayed<br />
puberty in female rats but had no effect on the rate<br />
<strong>of</strong> body growth (253). Compounds <strong>of</strong> this type would be a<br />
better choice for the treatment <strong>of</strong> precocious puberty<br />
than noncompetitive NMDA receptor antagonists, although<br />
further studies are needed to substantiate this in<br />
humans, who appear to be less sensitive than animals to<br />
the (acute) stimulatory effects <strong>of</strong> EAA on GH secretion. In<br />
eight Caucasian males, a MSG dose 25 times the normal<br />
daily intake had no effect on the secretion <strong>of</strong> GH and<br />
other pituitary hormones (353).<br />
B) INHIBITORY AMINO ACIDS. The actual role <strong>of</strong> GABA on<br />
GH secretion has been a source <strong>of</strong> considerable controversy,<br />
and both stimulatory and inhibitory influences have<br />
been reported. Briefly, intracerebroventricular injection<br />
<strong>of</strong> GABA or systemic administration <strong>of</strong> amino-oxyacetic<br />
acid, an inhibitor <strong>of</strong> GABA-T, or -hydroxybutyrate<br />
(GHB), a physiological metabolite <strong>of</strong> GABA, induced a<br />
prompt dose-related increase in serum GH in conscious<br />
and anesthetized male rats and in ovariectomized, steroidreplaced<br />
female rats (1071). Opposing the stimulatory<br />
effect <strong>of</strong> centrally administered GABA and its analogs was<br />
the GH-lowering effect <strong>of</strong> <strong>of</strong> two GABA-T inhibitors, ethanolamine-O-sulfate<br />
and -acetylenic GABA (GAG), administered<br />
systemically, in conscious or pentobarbital sodium-anesthetized<br />
rats. Conversely, reducing GABAergic<br />
activity with 3-mercaptopropionic acid or with bicuculline<br />
raised plasma GH concentrations (359). In freely<br />
moving rats, systemic administration <strong>of</strong> muscimol, a direct<br />
agonist <strong>of</strong> GABA A receptors, or GAG inhibited the GH<br />
secretory episode, whereas bicuculline methiodide, a<br />
compound which barely crosses the BBB, induced powerful<br />
but short-lived stimulation <strong>of</strong> GH release when injected<br />
at the nadir <strong>of</strong> basal hormone levels (358).<br />
A likely explanation <strong>of</strong> these and other findings (see<br />
Ref. 748 for more details) is that GABA may play a dual<br />
role in the control <strong>of</strong> GH secretion in the rat depending on<br />
the animals physiological state. -Aminobutyric acid<br />
would inhibit either the SS- or the GHRH-secreting neurons,<br />
or both, also in view <strong>of</strong> its alleged inability and that<br />
<strong>of</strong> muscimol to act directly on cultured AP cells (358) (but<br />
see below). That GABAergic neurotransmission inhibited<br />
SS neurons was borne out by the fact that muscimol and<br />
bicuculline injected into the POA, an area where SScontaining<br />
perikarya are located, stimulated and inhibited,<br />
respectively, GH secretion (1097). The GABA-SS interaction<br />
was confirmed by the fact that GABA inhibited SS release<br />
into the rat hypophysial portal vessels (998) and from hypothalamic<br />
cells in culture (387) and the discovery <strong>of</strong> GABA-IR<br />
synapses on SS-IR perikarya in the PeV hypothalamus<br />
(1097). Benzodiazepines, which reportedly act through<br />
GABA-mediated mechanisms, also inhibited SS release from<br />
rat diencephalic cells in vitro (989).<br />
These and other findings led to the proposition that<br />
GABA and its analogs only affect the PeV brain areas,<br />
including the SS elements, when injected centrally, without<br />
impinging on more distant brain structures in which<br />
the GHRH-secreting neurons are located (see sect. IIIA2).<br />
These areas, which have no effective BBB, can be reached<br />
by drugs such as systemically injected GABA and its<br />
analogs or antagonists, which normally do not cross the<br />
BBB. Therefore, GABA-mimetic lower GH by inhibiting<br />
GHRH-secreting structures (see Ref. 748 for further details).<br />
-Aminobutyric acid acts directly on the rat pituitary<br />
during the neonatal period, when sensitivity to hypophysiotropic<br />
factors is at its highest. Systemically injected<br />
GABA in newborn rats significantly increased plasma GH<br />
levels (9). This effect was very likely due to the fact that<br />
GABA and muscimol, in micromolar concentrations, elicit<br />
GH release from the entire pituitary <strong>of</strong> 2-day-old rats, an<br />
effect subsiding after the ninth postnatal day. In this<br />
system, bicuculline methiodide and picrotoxin, a known<br />
chloride ionophore antagonist, counteracted the effect <strong>of</strong><br />
GABA, although at concentrations exceeding that <strong>of</strong> the<br />
agonist by 10-fold; diazepam stimulated, but bacl<strong>of</strong>en, a<br />
stimulant <strong>of</strong> GABA B receptors, had no effect on GH secretion<br />
(9).<br />
In further studies, a superfusion system was used to<br />
assess the GABA effect and to provide evidence <strong>of</strong> its<br />
mediation by specific GABA receptors. Muscimol was
556 MÜLLER, LOCATELLI, AND COCCHI Volume 79<br />
10 times as potent as GABA in eliciting a prompt increase<br />
in GH secretion, and the effect <strong>of</strong> GABA was<br />
antagonized by picrotoxin and bicuculline, implying the<br />
involvement <strong>of</strong> a GABA A receptor. Continuous exposure<br />
<strong>of</strong> neonatal pituitaries to GABA resulted in a state <strong>of</strong><br />
refractoriness to the action <strong>of</strong> muscimol, indicating receptor<br />
desensitization (10). Overall, these data suggested that<br />
GABA might be one <strong>of</strong> the factors involved in maintaining<br />
the high circulating GH levels <strong>of</strong> the early postnatal period.<br />
The mechanism by which GABA stimulates GH secretion<br />
from preloaded neonatal rat pituitaries is beyond<br />
the scope <strong>of</strong> this review, and the reader is referred to Acs<br />
and co-workers (11, 12) and Horvath et al. (490).<br />
The use <strong>of</strong> a superfusion system demonstrated that<br />
both GABA and muscimol induced a large, transient stimulation<br />
<strong>of</strong> GH secreted from adult AP, which were sensitive<br />
to inhibition by bicuculline. Bacl<strong>of</strong>en did not stimulate<br />
GH secretion, whereas the effect <strong>of</strong> muscimol was<br />
potentiated by benzodiazepines and barbiturates (33).<br />
That GABA or GABA agonists act directly on the<br />
pituitary is supported by the presence <strong>of</strong> low- and highaffinity<br />
GABA and muscimol receptors in the rat (36) and<br />
human (437) pituitary, although their function appears<br />
mainly to involve an inhibitory control on prolactin secretion.<br />
A series <strong>of</strong> studies has shown that in healthy, psychiatric,<br />
or neurological subjects, gram amounts <strong>of</strong> GABA or<br />
a few milligrams <strong>of</strong> muscimol induced clear-cut GH increments<br />
in plasma with a peak after 60–90 min (1004; see<br />
Ref. 96 for further details). Similarly, -aminohydroxybutyric<br />
acid, a GABA derivative, did not raise plasma GH<br />
when injected subcutaneously into normal volunteers but<br />
did when given intrathecally to cerebrovascular disease<br />
patients (998). <strong>Growth</strong> hormone release was also stimulated<br />
by intravenous diazepam or oral doses <strong>of</strong> other<br />
benzodiazepines (see Ref. 533).<br />
To the list <strong>of</strong> GABAergic compounds that stimulate<br />
GH release in humans one must also add bacl<strong>of</strong>en (573),<br />
which has been used as a neuroendocrine probe <strong>of</strong> the<br />
GABA system in psychiatric studies (735, 787). There is,<br />
however, wide individual variability in the GH response to<br />
bacl<strong>of</strong>en, with 30% <strong>of</strong> false-negative responses in normal<br />
subjects (285).<br />
The GH-releasing effect <strong>of</strong> GABA in humans may<br />
occur through activation <strong>of</strong> dopaminergic pathways, i.e.,<br />
GABA would activate DA release at a site inside the BBB<br />
(194). Because peripherally administered GABA does not<br />
easily enter the brain, this CNS site must be incompletely<br />
covered with a BBB, e.g., the GHRH-secreting neurons<br />
(see above).<br />
In sharp contrast to the above findings and consistent<br />
with an inhibitory component <strong>of</strong> GABA action are observations<br />
related to stimulated GH release. Premedication<br />
for a few days with either GABA (194) or bacl<strong>of</strong>en (193)<br />
inhibited hypoglycemia- and arginine-induced GH secre-<br />
tion and blunted the GH response to levodopa (580).<br />
Stimulation <strong>of</strong> GABAergic neurotransmission also inhibits<br />
GH release during physical exercise (981), an effect which<br />
would be counteracted by activation <strong>of</strong> the opioidergic<br />
function (262), which might involve stimulation <strong>of</strong> GHRH<br />
release or, alternatively, inhibition <strong>of</strong> SS secretion (see<br />
sect. VB).<br />
To explain some <strong>of</strong> the seemingly paradoxical findings<br />
reported, we can propose that inhibition <strong>of</strong> the GH<br />
release stimulated by GABA and its ability to raise baseline<br />
GH share the same basic mechanism, i.e., an action<br />
through dopaminergic neurons. Continuous stimulation<br />
<strong>of</strong> CNS-DA receptors by GABA mimetics through DA<br />
release (see above) would ultimately lead to a state <strong>of</strong><br />
partial refractoriness to DA-mediated events (insulin hypoglycemia<br />
and levodopa).<br />
The involvement <strong>of</strong> the GABAergic system in the<br />
GH-secreting processes would include pathological states<br />
such as IDDM. Reportedly, this disease is characterized<br />
by GH hypersecretion and an exaggerated GH response to<br />
GHRH very likely due to a spontaneous decrease in hypothalamic<br />
SS tone (754, see sect. VI). Insulin-dependent<br />
diabetes mellitus is well recognized as an autoimmune<br />
disease (334), and the decreased SS tone may reflect<br />
damage by an autoimmune process either directly to SS<br />
neurons or indirectly to the brain neurotransmitters controlling<br />
SS release. GAD, the key enzyme <strong>of</strong> GABA biosynthesis,<br />
has been identified as a major autoantigen <strong>of</strong><br />
IDDM, being a target <strong>of</strong> both humoral and cell-mediated<br />
autoimmunity (127).<br />
In a study investigating the possible influence <strong>of</strong> GAD<br />
autoimmunity on GH secretion, most <strong>of</strong> the patients with<br />
elevated serum GAD antibody levels had significantly<br />
higher serum GH after administration <strong>of</strong> GHRH than controls<br />
or diabetics with low GAD levels; pretreatment with<br />
pyridostigmine, which allegedly reduces SS tone, significantly<br />
enhanced the GH response to GHRH in patients<br />
with low GAD and in controls, but not in patients with<br />
high GAD levels (423). It would seem, therefore, that<br />
autoimmunity plays a major role in the exaggerated GH<br />
response to GHRH in IDDM, through a reduction <strong>of</strong> a<br />
GABAergic tone that stimulates SS production in the hypothalamus.<br />
-Hydroxybutyric acid is a breakdown product <strong>of</strong><br />
GABA that reportedly reduces ethanol consumption and<br />
suppresses the ethanol withdrawal syndrome (346, 384).<br />
In human volunteers, GHB stimulates the secretion <strong>of</strong> GH<br />
(999), and this finding has been confirmed (398). A GABAmediated<br />
mechanism for GHB was suggested by the fact<br />
that flumazenil, an antagonist <strong>of</strong> benzodiazepine receptors,<br />
counteracts the GH response to an oral dose <strong>of</strong> the<br />
compound (398) and was consistent with the idea that<br />
GBH acts on a subpopulation <strong>of</strong> the GABA complex in<br />
close relation with benzodiazepine receptors (952). The<br />
finding that bicuculline antagonized the stimulatory effect
April 1999 NEUROENDOCRINE CONTROL OF GROWTH HORMONE SECRETION 557<br />
TABLE 2. Neurotransmitters and growth hormone<br />
secretion<br />
Subjects Animals Humans<br />
E 1 1 g,h<br />
1 2 12?<br />
2 1 1<br />
1<br />
(1) a<br />
2 (2) 2<br />
NE 1 1<br />
DA 1 12 c<br />
5-HT 12 b<br />
12?<br />
5-HT1 5-HT2 1 c<br />
1 d<br />
<strong>of</strong> GHB on GH secretion (1071) was consistent with a<br />
GABA A-receptor mediated mechanism. Some data, however,<br />
contradict the GABAergic action, such as its inability<br />
to modify the chloride function coupled with the<br />
GABA A receptor (951); action through a postsynaptic receptor<br />
has not been proven (968).<br />
Contrasting findings have been reported on how GHB<br />
influences monoaminergic pathways (382). The interaction<br />
<strong>of</strong> GHB with the serotoninergic system (976) appears<br />
interesting, considering the alleged functional deficiency<br />
<strong>of</strong> the latter in ethanol-prone subjects (598), who are<br />
detoxified by GHB (see above). Inferential support for<br />
this mechanism is provided by observations that the 5-HT<br />
receptor antagonist metergoline in male healthy volunteers<br />
blunted the GH response to GHB (397), and there<br />
was a persistent loss <strong>of</strong> 5-HT1 D receptor and GHB-mediated<br />
neurotransmission in long-term abstinent alcoholics,<br />
as shown by their inability to make a GH secretory response<br />
to sumatriptan or GHB (1069).<br />
Table 2 lists the stimulatory or inhibitory influences<br />
on GH secretion <strong>of</strong> brain neurotransmitters studied so far,<br />
as derived from experimental evidence reviewed in section<br />
VA.<br />
E. <strong>Growth</strong> <strong>Hormone</strong>-Releasing and -Inhibiting<br />
Neuropeptides<br />
In addition to the specific hypothalamic regulatory<br />
hormones for GH secretion, GHRH and SS, whose physi-<br />
2<br />
1 i<br />
1 d<br />
1 e<br />
ACh 1 e<br />
H 1 –<br />
H1 2 1<br />
H2 ? 1<br />
GABA 12 1<br />
Glutamate 1 f<br />
3<br />
3, No effect; 1, stimulation; 2, inhibition; –, action not ascertained;<br />
?, action still questionable. Effect <strong>of</strong> activation <strong>of</strong> receptor subtypes<br />
is indicated with parentheses. E, epinephrine; NE, norepinephrine;<br />
5-HT, 5-hydroxytryptamine; H, histamine. a In vitro; b inhibition in dog;<br />
c 5-HT1C subtype; d slight effect; e muscarinic receptors; f N-methyl-Daspartate<br />
(NMDA) and non-NMDA receptors; g in combination with<br />
propranolol; h inhibitory in acromegaly and in vitro anterior pituitary;<br />
i 5-HT1D subtype.<br />
ological role is now established, and the still elusive ligand<br />
for the GHRP receptor, a host <strong>of</strong> CNS neuropeptides,<br />
some <strong>of</strong> them originally identified in the gut or peripheral<br />
nervous system, have marked stimulatory or inhibitory<br />
effects on GH secretion. The list <strong>of</strong> traditional neuropeptides<br />
has recently been enriched by the inclusion <strong>of</strong> immunomodulators,<br />
especially cytokines, and a neurotransmitter<br />
gas nitric oxide (NO).<br />
Some <strong>of</strong> these compounds are found in specific nuclei<br />
<strong>of</strong> the hypothalamus, where they <strong>of</strong>ten coexist with<br />
hypophysiotropic neuropeptides or classical neurotransmitters,<br />
and at times they are detected in the hypophysial<br />
portal blood; this and the recognition <strong>of</strong> specific binding<br />
sites in the target pituitary gland suggest a neurohormonal<br />
role and a hypophysiotropic function. However, these<br />
peptides can alter endocrine function not only as hormones<br />
but also as neurotransmitters or neuromodulators,<br />
not excluding a role as autocrine or paracrine factors in<br />
the pituitary acting on GH secretion or somatotroph proliferation.<br />
Because the physiological role <strong>of</strong> these peptides has<br />
yet to be unequivocally established and their effects on<br />
GH secretion are <strong>of</strong>ten unmasked by pathological situations,<br />
it seems appropriate to examine these compounds<br />
separately from the classical hypophysiotropic neurohormones.<br />
1. Thyrotrophin-releasing hormone and gonadotropin<br />
hormone-releasing hormone<br />
Thyrotrophin-releasing hormone, the first hypophysiotrophic<br />
peptide to be isolated and synthesized chemically,<br />
was so named because its primary functon is to<br />
stimulate TSH secretion from the pituitary gland (773).<br />
Apart from its ability to stimulate prolactin release, TRH<br />
releases GH in animals and humans, although only in<br />
pathological conditions (see Refs. 257, 462 for reviews).<br />
The TRH-induced GH response which, since we are unable<br />
to provide a meaningful explanation, has been<br />
termed “paradoxical,” appears to be mediated by various<br />
mechanisms, some <strong>of</strong> which are mentioned below.<br />
One postulated mechanism encompasses expression<br />
<strong>of</strong> anomalous TRH receptors on somatotroph cells, probably<br />
in the pituitaries <strong>of</strong> acromegalic patients where the<br />
presence <strong>of</strong> TRH-binding sites has been related to a positive<br />
individual GH response to TRH in vivo (600). Consistent<br />
with this view, TRH also stimulates GH release<br />
from rat somatotroph lines such as GH 3 (124) and GH 4C 1<br />
cells (20).<br />
There is almost general agreement on the clinical<br />
significance <strong>of</strong> the TRH-induced GH release in acromegaly.<br />
It is frequently seen with prolactin-containing somatotrophinomas.<br />
Accordingly, TRH responders generally<br />
had higher baseline levels <strong>of</strong> prolactin than TRH nonresponders<br />
(1082). A likely interpretation was that adeno-
558 MÜLLER, LOCATELLI, AND COCCHI Volume 79<br />
matous cells containing mixed GH/prolactin cells or/and<br />
mammosomatotroph cells possess many <strong>of</strong> the properties<br />
<strong>of</strong> normal lactotrophs including receptors for both TRH<br />
and DA. In contrast, acromegalic patients with pure somatotrophinomas<br />
are usually unresponsive to both the<br />
TRH and the GH-lowering effect <strong>of</strong> dopaminergic agonists<br />
(see Ref. 1082 for review).<br />
The anomalous GH response to TRH might, alternatively,<br />
also result from an impairment <strong>of</strong> the inhibitory<br />
hypothalamic control <strong>of</strong> GH secretion (257, 749), as implied<br />
by the fact that TRH induces GH release from ectopically<br />
transplanted rat pituitary glands, pituitaries incubated<br />
in vitro, pituitaries from rats with lesions <strong>of</strong> the<br />
ME or passively immunized against SS (see Refs. 257, 462<br />
for reviews). Thyrotrophin-releasing hormone is a strong<br />
stimulus to GH secretion in fetal, neonatal, and prepubertal<br />
animals in which the hypothalamic control <strong>of</strong> GH<br />
secretion is presumably functionally immature (see Refs.<br />
257, 462 for review), and the paradoxical response may<br />
also occur in the elderly, whose hypothalamic control <strong>of</strong><br />
pituitary function is diminished (75, 236).<br />
The observation that passive SS immunization triggered<br />
the paradoxical GH response to TRH in intact rats<br />
(805) and that in acromegaly, or other pathophysiological<br />
conditions (rats with transplanted pituitaries), it was<br />
blocked by infusion <strong>of</strong> SS links the anomalous GH response<br />
to SS dysfunction (462).<br />
A further possibility is that the GH response to TRH<br />
may be a consequence <strong>of</strong> GHRH-induced expression <strong>of</strong><br />
TRH receptors on the somatotroph, in agreement with the<br />
facilitated GH release after TRH in acromegalic patients<br />
(921) or from rat or sheep pituitaries after exposure to<br />
GHRH (125, 597).<br />
Thyrotrophin-releasing hormone receptors on the somatotrophs<br />
would also be unmasked when thyroid hormones<br />
are lacking or low, as in hypothyroid rats (233,<br />
995) and humans (265).<br />
As already mentioned, TRH-induced GH secretion is<br />
generally absent in normal subjects, although a subpopulation<br />
<strong>of</strong> normal people may respond to TRH. Careful<br />
studies with appropriate controls to exclude the confounding<br />
effect <strong>of</strong> GH peaks derived from spontaneous<br />
pulsatile release showed that in healthy young men the<br />
incidence <strong>of</strong> GH responsiveness to TRH was lower than<br />
10%. Interestingly, in tests repeated at night, when reportedly<br />
the somatostatinergic tone is decreased (1054), 90%<br />
<strong>of</strong> the nonresponders during the day became GH responders<br />
to TRH (172). The way the paradoxical GH response<br />
to TRH is related to rest and inactivity might account for<br />
its being found in hospital patients and psychiatric cases<br />
who have altered biorhythms.<br />
In addition to its stimulatory action, probably in the<br />
pituitary, TRH inhibits GH secretion, acting at the hypothalamus.<br />
In healthy subjects, TRH reduced or blocked<br />
the GH response to a variety <strong>of</strong> GH releasers. This inhib-<br />
itory effect was present in a number <strong>of</strong> animal species (for<br />
review, see Refs. 462, 749).<br />
The most likely mediator <strong>of</strong> the inhibitory effect <strong>of</strong><br />
TRH on GH secretion is the somatostatinergic system.<br />
Immunohistochemical studies indicate that more than<br />
95% <strong>of</strong> SS-IR perikarya in the preoptic-anterior hypothalamic<br />
area and in the PVN appear to be contacted by one<br />
or more TRH-IR terminals (1100). Furthermore, TRH<br />
causes SS release from the hypothalamus (544, see also<br />
sect. IIIB3), enhances plasma concentrations <strong>of</strong> SS (565),<br />
and upregulates pituitary sstr (940).<br />
Thyrotrophin-releasing hormone might also affect<br />
neurotransmitter systems upstream <strong>of</strong> the SS neurons,<br />
although it is not known how the cholinergic system<br />
would be excluded, since enhancement <strong>of</strong> its function by<br />
pyridostigmine in the dog did not modify the inhibitory<br />
effect <strong>of</strong> TRH on GHRH-induced GH release (38).<br />
In a group <strong>of</strong> cirrhotic patients, who reportedly include<br />
a high proportion <strong>of</strong> TRH responders, infusion <strong>of</strong><br />
DA before the TRH stimulus increased baseline GH levels<br />
(decrease <strong>of</strong> SS tone?), and GH rise after TRH peaked<br />
sooner (760).<br />
In addition to TRH, other hypophysiotropic hormones<br />
also stimulate GH secretion in acromegalic subjects<br />
or patients with CNS disturbances. Like TRH, GnRH<br />
(912) induces GH release from the pituitaries <strong>of</strong> rats<br />
anatomically and/or functionally disconnected from the<br />
CNS (804), and in human disorders in which TRH is also<br />
an effective GH releaser (749).<br />
2. CRH, AVP, and oxytocin<br />
Among the several systems <strong>of</strong> CRH neurons, the<br />
PVN-ME pathway is responsible for most <strong>of</strong> the hypophysiotropic<br />
actions <strong>of</strong> the peptide. A second series <strong>of</strong> CRH-<br />
LI stained neurons in the basal telencephalon, hypothalamus,<br />
and brain stem are interconnected by fibers <strong>of</strong> the<br />
medial forebrain bundle and the PeV system (756). These<br />
neurons are thought to play an important role in autonomic<br />
and neuroendocrine responses to stress, inducing,<br />
when activated, all the homeostatic changes that follow<br />
the stressful event (see Ref. 756).<br />
Corticotropin-releasing hormone reduces basal or<br />
stimulated GH release in the rat (545, 796), an effect very<br />
likely mediated by SS release since it was abolished by<br />
pretreatment with an anti-SS serum (545). In addition, in<br />
vivo, CRH raised portal concentrations and secretion<br />
rates <strong>of</strong> SS (730) and extracellular release <strong>of</strong> SS from<br />
hypothalamic neurons (188). These findings, which are<br />
substantiated by the demonstration <strong>of</strong> direct synaptic<br />
connections between CRH and SS neurons (471), point to<br />
CRH as the mediator <strong>of</strong> the stress-induced suppression <strong>of</strong><br />
GH secretion in rodents.<br />
In the rat, CRH is also needed for the regulation <strong>of</strong><br />
spontaneous GH release because continuous intraventric-
April 1999 NEUROENDOCRINE CONTROL OF GROWTH HORMONE SECRETION 559<br />
ular infusion <strong>of</strong> a CRH antagonist markedly increased GH<br />
peak amplitude without affecting either trough levels or<br />
the number <strong>of</strong> GH peaks (745). The same treatment significantly<br />
lowered GHRH mRNA levels in the ARC, without<br />
affecting SS mRNA in the PeVN and ARC. It would<br />
seem, therefore, that CRH, through regulation <strong>of</strong> ARC-<br />
GHRH neurons, also modulates endogenous GH secretion.<br />
Because connections between CRH and GHRH neurons<br />
have yet to be demonstrated, the inhibition <strong>of</strong> GHRH<br />
mRNA levels by CRH might result indirectly from enhanced<br />
inhibition <strong>of</strong> GHRH neurons by SS (see sect.<br />
IIIA3).<br />
Controversial results have been reported on the effect<br />
<strong>of</strong> systemic CRH on GH release in humans. Barbarino<br />
et al. (72) found CRH dose-dependently inhibited the<br />
GHRH-induced GH release in healthy adult men and<br />
women; this effect was not confirmed in another study,<br />
which reported a tendency toward higher GH levels after<br />
a similar cotreatment (901). Corticotropin-releasing hormone<br />
dose-dependently inhibited GHRH-induced GH release<br />
in children (417). It must be recalled, however, that<br />
there is a major biological difference between rodents and<br />
humans, with stress being inhibitory on GH release in<br />
rodents and stimulatory in humans.<br />
Neurons containing AVP and oxytocin not only<br />
project from the SON and PVN to the neurohypophysis<br />
but also send their axons to other CNS areas, such as the<br />
ME. High concentrations <strong>of</strong> AVP and oxytocin are thus<br />
found in the hypophysial portal blood (1129), suggesting<br />
that these peptides may also regulate anterior pituitary<br />
hormone secretion. This is borne out by the direct inhibitory<br />
effect <strong>of</strong> oxytocin on both basal and GHRH-stimulated<br />
GH secretion in dispersed rat AP cells (494). This<br />
inhibition would be tonic, since intracerebroventricular<br />
infusions <strong>of</strong> anti-oxytocin, but not anti-AVP serum, raised<br />
plasma GH in ovariectomized rats (368).<br />
Oxytocin, therefore, by interfering with the action <strong>of</strong><br />
GHRH at the AP might be one <strong>of</strong> the factors involved in<br />
the generation <strong>of</strong> pulsatile GH secretion, a function which<br />
could be important when oxytocin secretion is enhanced,<br />
e.g., in pregnancy.<br />
Rats with hereditary AVP deficiency (Brattleboro<br />
strain) have normal GH levels and a normal GH response<br />
to hypothalamic electrical stimulation (mentioned in Ref.<br />
664), thus excluding a role <strong>of</strong> AVP on GH secretion. The<br />
converse, however, is not true, since a group <strong>of</strong> GHRP<br />
increased AVP release in an in vitro rat hypothalamic<br />
incubation system (569).<br />
3. Neurotensin<br />
<strong>Growth</strong> hormone-releasing hormone is found in at<br />
least 40% <strong>of</strong> the NT-positive neurosecretory cells in the<br />
ventrolateral area <strong>of</strong> the ARC (779; see sect. IIIA); in the<br />
external layer <strong>of</strong> the ME, fibers containing both NT-LI and<br />
GHRH are close to hypophysial portal vessels (699)<br />
(Fig. 2).<br />
Despite unequivocal neuroanatomic evidence, the effect<br />
<strong>of</strong> NT on GH release varies, depending on either the<br />
route <strong>of</strong> administration or the experimental model used.<br />
Centrally administered NT lowered plasma GH levels in<br />
anesthetized male rats (649), a finding consistent with its<br />
ability to increase SS concentrations in hypophysial portal<br />
blood (3) or SS release from hypothalamic slices incubated<br />
in vitro (957). In contrast, in unanesthetized<br />
ovariectomized rats, centrally injected NT increased GH<br />
secretion (910).<br />
To further illustrate the complexity <strong>of</strong> NT’s role in<br />
GH regulation, after intracerebroventricular injection, an<br />
anti-NT serum and NT exerted reciprocal effects on<br />
plasma GH levels in ovariectomized female rats but, unexpectedly,<br />
similar inhibitory effects in male rats. As in<br />
humans (112), in ovariectomized female rats plasma GH<br />
levels were unaltered by systemically administered NT<br />
but increased after systemic administration <strong>of</strong> an anti-NT<br />
serum.<br />
The most likely explanation lies in the possibility that<br />
SS may have opposite effects on GHRH function, acting at<br />
different hypothalamic sites. This might account for the<br />
seemingly paradoxical effects <strong>of</strong> NT and anti-NT serum on<br />
GH secretion if its effects are mediated by SS neurons.<br />
Although it has not been demonstrated, one may infer that<br />
NT participates in the reciprocal regulation between<br />
GHRH and SS-producing neurons (see sect. IIIA3). In this<br />
connection, some hypothalamic regions containing SS<br />
neurosecretory cells, e.g., the PeVN, also contain NT receptors.<br />
An extensive review on the neuroendocrine effects<br />
<strong>of</strong> NT has been published (910).<br />
4. VIP and PHI<br />
Both VIP and PHI are products <strong>of</strong> the same precursor<br />
and belong to the glucagon-secretin family <strong>of</strong> peptides,<br />
structurally related to GHRH (86). They are synthesized in<br />
the rodent pituitary where they may act as autocrine or<br />
paracrine factors (44). The pituitary cell that synthesizes<br />
them is not the somatotroph, as shown by the significantly<br />
lower levels <strong>of</strong> VIP mRNA and peptide in the AP gland <strong>of</strong><br />
GHRH transgenic mice despite somatotroph hyperplasia<br />
(499). Several VIP-containing neurons project to the hypothalamus,<br />
including the ME, and VIP has been detected<br />
in high concentrations in portal blood (913).<br />
In the rat, intracerebroventricular injections <strong>of</strong> VIP<br />
induced a prompt and sustained rise in plasma GH levels<br />
(see Ref. 749), whereas in rats (see Ref. 749) and in ewes<br />
(925), systemic injections had no such effect. These findings<br />
suggest a hypothalamic site <strong>of</strong> action for VIP, but in<br />
vitro findings clearly demonstrate that the peptide can<br />
release GH, also acting on the pituitary. In cultured bovine<br />
adenohypophysial cells, VIP, but not PHI, increased basal
560 MÜLLER, LOCATELLI, AND COCCHI Volume 79<br />
and GHRH-stimulated GH release (969). Previous data<br />
obtained in superfused rat pituitary cell reaggregates pretreated<br />
with dexamethasone had shown that VIP, like<br />
PHI, strongly stimulated GH release starting from a concentration<br />
as low as 0.1 nM. In this experiment, GH secretion<br />
in cells not pretreated with dexamethasone was<br />
unchanged, suggesting that VIP interacted with GHRH<br />
receptors, which were upregulated by the steroid (304)<br />
(see sect. IIIA).<br />
In contrast to the stimulatory effect in animals, in<br />
normal humans VIP blunted the GH peak occurring at<br />
night without modifying the time <strong>of</strong> occurrence <strong>of</strong> the<br />
physiological GH surge (764).<br />
Vasoactive intestinal polypeptide stimulated GH release<br />
in subjects believed to have somatotrophinomas; in<br />
the few patients where VIP had no effect on basal GH<br />
release, it antagonized the inhibitory effect <strong>of</strong> DA agonists<br />
(230). However, screening a large group <strong>of</strong> acromegalics,<br />
Watanobe et al. (1082) observed that the positive GH<br />
response to TRH was combined with a high sensitivity to<br />
the inhibitory effect <strong>of</strong> DA agonists, whereas GH responsiveness<br />
to VIP and, possibly, to GnRH, existed with no or<br />
low sensitivity to dopaminergic agents. It would seem,<br />
therefore, that the first group <strong>of</strong> tumors had the functional<br />
characteristics <strong>of</strong> PRL-containing somatotroph adenomas,<br />
and the latter <strong>of</strong> pure somatotrophinomas.<br />
Subsequently, Watanobe et al. (1083) found the paradoxical<br />
GH response to VIP in hyperprolactinemic patients<br />
with or without a prolactinoma. Because the GH<br />
response to VIP is not causally related to the presence <strong>of</strong><br />
a pituitary tumor, it may be surmised that hyperprolactinemia<br />
itself played a role in inducing VIP receptors<br />
on normal or previously normal somatotrophs.<br />
5. PACAP<br />
Pituitary adenylate cyclase-activating peptide is a 38amino<br />
acid peptide homologous to porcine VIP. Six <strong>of</strong> the<br />
10 NH 2-terminal residues are identical to those <strong>of</strong> GHRH<br />
(731). The cDNA for PACAP encodes a PACAP precursor<br />
that gives rise to PACAP-38, PACAP-27, and PACAP-related<br />
peptides. Since its isolation, its activity has been<br />
amply described in a variety <strong>of</strong> tissues including pituitary,<br />
brain, adrenal, testis, gut, and lung. Several reviews have<br />
discussed its action in a variety <strong>of</strong> cell types and the<br />
characteristics <strong>of</strong> the three PACAP receptors cloned to<br />
date, two <strong>of</strong> which it apparently shares with VIP (43, 874).<br />
Although PACAP-LI is found in nearly all brain regions<br />
so far examined, its concentration is highest in the<br />
hypothalamus, particularly the magnocellular system and<br />
then the parvocellular neuronal system. There is a dense<br />
network <strong>of</strong> PACAP fibers in the external zone <strong>of</strong> the ME,<br />
in close contact with the hypophysial portal capillaries, so<br />
PACAP may act as a true hypophysiotropic factor (see<br />
Ref. 874 for review). Although most studies have found no<br />
staining for PACAP-IR in the AP, one did describe PACAPcontaining<br />
fibers in this tissue, mingling with the secretory<br />
cells (723).<br />
In rats, normal somatotrophs express the PVR3 receptor,<br />
which preferentially binds the peptide helodermin<br />
and is linked to the stimulation <strong>of</strong> cAMP production and<br />
a subsequent rise in Ca 2 concentrations. Differently<br />
from normal rodent cells, human GH-producing tumor<br />
cells express PVR1, more specific for PACAP than VIP<br />
(see Ref. 874 for review).<br />
In vivo PACAP stimulates the release <strong>of</strong> GH, although<br />
this effect has been demonstrated in rats but not in sheep<br />
or humans (see Ref. 874 for review). In rats, the in vivo<br />
GH-releasing effect <strong>of</strong> PACAP is fairly marked, but<br />
whether this derives from a direct action on the somatotrophs<br />
is uncertain, since in vitro PACAP has a weak<br />
stimulatory effect on GH synthesis and release. In fact, its<br />
GH-stimulatory effect on rat, frog, and bovine pituitary<br />
cells was much lower than that evoked by GHRH, and GH<br />
release peaked at different intervals (458, 1092). The delayed<br />
GH-releasing effect <strong>of</strong> PACAP was attributed to<br />
indirect action on other cell types [i.e., stimulation <strong>of</strong><br />
interleukin (IL)-6 release from folliculostellate cells]<br />
(458).<br />
In addition to stimulating GH release, PACAP also<br />
raised GH mRNA levels during short- and long-term incubation<br />
in a somatotroph-enriched population <strong>of</strong> female rat<br />
pituitary cells (1067).<br />
Similar to GHRH, but different from GHRP,<br />
PACAP-38 increases both the number <strong>of</strong> somatotrophs<br />
and the amount <strong>of</strong> GH released from each cell over a<br />
period <strong>of</strong> 30 min in dispersed preparations from male rat<br />
pituitaries (436). This suggests that PACAP and GHRH<br />
regulate GH secretion through similar mechanisms, most<br />
likely by activating the cAMP/protein kinase A system and<br />
Ca 2 influx.<br />
Investigations into the physiological role <strong>of</strong> PACAP<br />
on GH secretion are limited by the lack <strong>of</strong> specific antagonists.<br />
Yamaguchi et al. (1111) showed that PACAP-<br />
(6O38), the NH 2 terminal deleted PACAP-38 analog, inhibited<br />
the GH secretory effect <strong>of</strong> the native peptide.<br />
Pituitary adenylate cyclase-activating peptide-(6O38)<br />
also abolished 5-HTP-induced GH release in conscious<br />
rats, suggesting that hypothalamic PACAP is involved not<br />
only in the physiological control <strong>of</strong> GH secretion but also<br />
in the GH release following serotoninergic stimulation<br />
(see also sect. VA2).<br />
Athough PACAP does not release GH in healthy humans<br />
(648), it stimulates GH release from in vitro cultured<br />
somatotrophinomas. This action, which is coupled to<br />
cAMP production, can only be observed in adenomas<br />
without gsp mutations, the somatic mutation within the<br />
gene that produces a constitutively active G s protein (13).<br />
In summary, it is interesting that PACAP acts as a GH<br />
releaser, sharing the same intracellular signaling pathway
April 1999 NEUROENDOCRINE CONTROL OF GROWTH HORMONE SECRETION 561<br />
as GHRH. However, the fact that it is much less potent<br />
than GHRH in activating GH secretion and the apparent<br />
restriction <strong>of</strong> this action to the rat makes uncertain how<br />
important it is in the physiological regulation <strong>of</strong> GH secretion<br />
and its therapeutic use.<br />
6. NPY<br />
Neuropepitde Y, a member <strong>of</strong> the pancreatic polypeptide<br />
family <strong>of</strong> peptides, shares significant sequence homology<br />
with pancreatic polypeptide and peptide YY.<br />
Neuropeptide Y is the most abundant peptide in the CNS<br />
(26). Within the hypothalamus, NPY is synthesized in<br />
neurons <strong>of</strong> the ARC, which mainly project to the PVN<br />
(305) (Fig. 2).<br />
In addition to being involved in the control <strong>of</strong> food<br />
intake and energy and substrate metabolism, NPY affects<br />
the release <strong>of</strong> various hormones, including GH (1095). In<br />
the rat, intraventricular injection <strong>of</strong> NPY inhibited GH<br />
secretion (691), and a NPY antiserum led to elevated<br />
plasma GH levels (886) and partially restored GH secretory<br />
pulses in food-deprived rats (791). The latter effect is<br />
consistent with the increased levels <strong>of</strong> NPY in the PVN<br />
after food deprivation in rats (603), which might contribute<br />
to the reduction <strong>of</strong> GH secretion commonly seen in<br />
fasting rodents (1017). A similar alteration has been reported<br />
in obese rats (918) that have a striking reduction <strong>of</strong><br />
the somatotrophic axis (see sect. VIC1).<br />
Chronic infusion <strong>of</strong> NPY in the lateral ventricle <strong>of</strong> the<br />
brain, a treatment ultimately reproducing all the metabolic<br />
features <strong>of</strong> obesity, inhibited GH and IGF-I secretion<br />
in intact female (191) and male (842) rats, strongly suggesting<br />
a causal link between excessive NPY and reduced<br />
GH function in obesity.<br />
The inhibitory action <strong>of</strong> NPY on GH secretion is<br />
mediated by stimulation <strong>of</strong> SS release (886), as supported<br />
by the demonstration <strong>of</strong> synaptic connections between<br />
NPY-containing axons and periventricular SS neurons in<br />
the anterior hypothalamus (472; see also sect. VIIA). A<br />
direct inhibitory effect <strong>of</strong> NPY on GH release, through the<br />
pituitary, was unlikely, since the peptide stimulated GH<br />
secretion from rat perfused pituitary cells (691) or goldfish<br />
AP (826). Neuropeptide Y inhibited basal and GHRHstimulated<br />
GH secretion in human pituitary tumors (16).<br />
For the involvement <strong>of</strong> NPY neurons in the aut<strong>of</strong>eedback<br />
regulation <strong>of</strong> GH secretion, see section VIIA.<br />
7. Galanin<br />
Galanin is a 29-amino acid neuropeptide that does<br />
not belong to any known peptide family and has a number<br />
<strong>of</strong> pharmacological properties in whole animals and isolated<br />
tissues (84). It is widely distributed in the CNS,<br />
highly concentrated in the hypothalamus, and partly colocalized<br />
with GHRH neurons in the ARC and nerve ter-<br />
minals in the ME (see sect. IIIA2) (Fig. 2). It is also present<br />
in the AP (see Refs. 96, 280 for reviews).<br />
In rodents and humans, galanin increased GH secretion<br />
(77, 801) and appeared to play a role in the generation<br />
<strong>of</strong> pulsatile GH release, since in rats injection <strong>of</strong> a specific<br />
antiserum led to a dramatic alteration <strong>of</strong> the pulsatile<br />
secretory pattern (96). In healthy humans, in addition to<br />
eliciting GH secretion when given alone, galanin enhanced<br />
the GH response to GHRH (425).<br />
In contrast, galanin lowered basal GH secretion in<br />
most acromegalic patients, an effect also observed in<br />
pituitary adenomas in vitro (429). The GH-inhibitory effect<br />
<strong>of</strong> galanin, which can be added to the list <strong>of</strong> paradoxical<br />
GH responses in acromegaly, reflects the presence <strong>of</strong><br />
adenomatous somatotrophs, since acromegalic patients<br />
cured after surgery had a normal GH stimulatory response<br />
to the peptide. In rodent AP incubated in vitro, galanin<br />
had an elusive, apparently age-dependent effect (1040),<br />
with a GH-releasing effect only during the perinatal period.<br />
In adult life, galanin inhibited GHRH-stimulated GH<br />
release.<br />
In perfused pituitaries from young male calves, galanin<br />
behaved as an effective stimulant <strong>of</strong> GH secretion<br />
(70), and its action was enhanced by concomitant perfusion<br />
<strong>of</strong> the pituitary with the hypothalamus, suggesting<br />
that the peptide exerts its optimal action when the integrity<br />
<strong>of</strong> the GHRH-pituitary axis is maintained. This study<br />
suggests that, at least in calves, galanin-mediated GH<br />
release occurred independently <strong>of</strong> hypothalamic SS, since<br />
the GH response to exogenous GHRH was not modulated<br />
by galanin.<br />
Galanin together with GHRH in the same ARC neurons<br />
(707; see sect. IIIA2) may be the anatomic substrate<br />
for the functional interaction between the two peptides.<br />
Evidence for stimulation <strong>of</strong> GHRH release by galanin was<br />
provided in vitro using incubated hypothalamic slices<br />
(562, 707).<br />
Consistent with a GHRH-mediated mechanism, in infant<br />
rats pretreatment with a GHRH antiserum abolished<br />
the potent GH-releasing effect <strong>of</strong> galanin (203). However,<br />
it would seem that galanin does not act directly on GHRHsecreting<br />
structures but requires the intervention <strong>of</strong> CA<br />
neurons. In neonatal rats, selective inhibition <strong>of</strong> E synthesis<br />
abolished the GH-releasing effect <strong>of</strong> galanin, implying<br />
that E provides the link between galanin-secreting and<br />
hypophysiotropic neurons for GH control (203).<br />
Human studies suggest galanin’s action depends on<br />
SS. Like cholinomimetic drugs, which restrain the function<br />
<strong>of</strong> SS-producing neurons (see sect. IIIB3), pretreatment<br />
with galanin enhanced GHRH-induced GH release,<br />
an effect counteracted by salbutamol, a 2-adrenergic<br />
agonist (51), and restored the blunted GH response to<br />
GHRH during GH treatment in children with constitutional<br />
growth delay (920). Conscious adult rats had a<br />
sluggish response to galanin after pretreatment with
562 MÜLLER, LOCATELLI, AND COCCHI Volume 79<br />
neostigmine, cysteamine, or a SS antiserum, all aimed at<br />
lowering the endogenous somatostatinergic tone (1021).<br />
In rat pups, pretreatment with the same antiserum significantly<br />
reduced the GH increase elicited by galanin (203).<br />
It is apparent from both animal and human studies that<br />
galanin plays a significant role in the regulation <strong>of</strong> GH<br />
secretion.<br />
8. EOP<br />
Studies in rats on the neuroendocrine effects <strong>of</strong> EOP<br />
showed that these compounds, as well as opiates such as<br />
morphine, stimulated GH secretion when administered<br />
either systemically or ivt (148, 259). In humans, however,<br />
some conflicting data have been reported. Thus, although<br />
FK 33–824, an allegedly potent and selective ligand <strong>of</strong><br />
brain -receptors proved to be a strong GH releaser,<br />
morphine and -endorphin did not have any such effect<br />
(see Ref. 208 for review). Despite these inconsistencies,<br />
the effects <strong>of</strong> these compounds on GH release are specific,<br />
being completely abolished by pretreatment with the<br />
potent but nonselective EOP receptor antagonist naloxone.<br />
In the rat, pretreatment with a SS antiserum did not<br />
influence the EOP-induced GH rise (328), whereas passive<br />
immunization with a GHRH antiserum completely<br />
blocked the GH rise induced by -endorphin, morphine<br />
(1088), or FK 33–824 (721). These data indicated that<br />
opioids stimulate pituitary GH secretion through hypothalamic<br />
GHRH release and not through inhibition <strong>of</strong> SS<br />
release, although a small but distinct inhibition <strong>of</strong> SS<br />
release from rat hypothalamic fragments in vitro has been<br />
reported (326). In humans, it has been reported, though<br />
only inferentially, that FK 33–824 can also act by inhibiting<br />
SS release (302).<br />
These findings disproved the direct effect <strong>of</strong> EOP on<br />
the pituitary (539, 890). The theory was supported by the<br />
observation that EOP antagonists, which are unable to<br />
cross the BBB (i.e., naloxone methyl bromide), did not<br />
affect the GH release induced by morphine (803).<br />
Subsequently, Fodor et al. (367) suggested that opioid<br />
neurons might be implicated in the interactions between<br />
SS- and GHRH-containing neurons in the ARC. In<br />
fact, SS receptors are present on cells containing GHRH<br />
mRNA and POMC mRNA, and SS perikarya in the PeVN<br />
are innervated by POMC-derived peptide-containing neurons<br />
(see sect. IVB2A).<br />
Previous studies suggested that the EOP acted<br />
mainly on the -type opioid receptors, since in rats pretreatment<br />
with -receptor antagonists abolished the GH<br />
rise induced by morphine or -endorphin, while naloxone<br />
or -funaltrexamine, a selective -receptor antagonist,<br />
did not (566). It has since been demonstrated that multiple<br />
opioid receptor subtypes are activated in the regulation<br />
<strong>of</strong> GH secretion by -endorphin (523). In this study,<br />
selective blockers <strong>of</strong> -, -, and -sites inhibited GH secretion<br />
after intracerebroventricular injection <strong>of</strong> -endorphin.<br />
In humans, the stimulatory effect <strong>of</strong> opioids on GH<br />
secretion seems to be mediated by -receptors (442). In<br />
contrast, in normal volunteers, deltorphin, the most potent<br />
and selective -opioid receptor agonist known,<br />
blunted the GH response to several GHS, including galanin<br />
and arginine, whereas it did not affect the GH response<br />
to GHRH (297). These findings suggest that, in<br />
contrast to rats, in humans -opioid receptors inhibit GH<br />
release, through modulation <strong>of</strong> hypothalamic release <strong>of</strong><br />
SS. According to some authors (566), in rodents GH secretion<br />
is inhibited by activation <strong>of</strong> -receptors, although<br />
as already discussed, -receptors also had a stimulatory<br />
effect in adult (523) and immature rats (329).<br />
With regard to the potential modulatory action <strong>of</strong><br />
classic brain neurotransmitters, in the dog and in humans,<br />
muscarinic cholinergic, histaminergic, and 2-adrenergic<br />
receptor antagonists suppressed or blunted the GH rise<br />
induced by FK 33–824 (see Ref. 208 for review). The only<br />
discordant finding was that yohimbine did not inhibit the<br />
FK 33–824-induced GH rise in humans (441) and was<br />
effective in the dog (213).<br />
Despite the wealth <strong>of</strong> information, the physiological<br />
role <strong>of</strong> EOP in the regulation <strong>of</strong> GH secretion is still<br />
unclear. An acute dose <strong>of</strong> a -endorphin antiserum to<br />
freely moving rats (1016) or <strong>of</strong> naloxone to human volunteers<br />
(724) did not alter plasma GH levels. In contrast,<br />
chronic treatment with the long-lasting EOP receptor antagonist<br />
naltrexone did not modify basal GH secretion but<br />
significantly reduced the GH peak after GHRH (1052).<br />
These results suggest that chronic blockade <strong>of</strong> central<br />
EOP receptors enhances the function <strong>of</strong> SS neurons.<br />
9. Cytokines<br />
In recent years, evidence has accumulated <strong>of</strong> common<br />
peptide signals, receptors, and functions in cells <strong>of</strong><br />
the immune and neuroendocrine systems, and this has<br />
provided the logical basis for a regulatory loop between<br />
the two (98). Receptors for IL-1 and and the corresponding<br />
mRNA have been identified in rat and mouse pituitary,<br />
mainly in the AP. Receptors or binding sites for IL-6 and<br />
IL-2 have also been found in the pituitary, while many<br />
types <strong>of</strong> receptors for several cytokines have been described<br />
in the CNS (see Ref. 98 for review).<br />
Stimulation <strong>of</strong> the HPA axis by IL-1 was the first and<br />
most extensively studied example <strong>of</strong> how cytokines influence<br />
endocrine function. Concerning GH, in conscious<br />
rats low intracerebroventricular doses <strong>of</strong> IL-1 (820, 885)<br />
or tumor necrosis factor- (887) increased GH secretion,<br />
as did IL-2 therapy in cancer patients (58).<br />
In another study, intracerebroventricular or ARC injection<br />
<strong>of</strong> IL-1 lowered GH levels in rats (640), suggesting an
April 1999 NEUROENDOCRINE CONTROL OF GROWTH HORMONE SECRETION 563<br />
underlying inhibition <strong>of</strong> hypothalamic GHRH and/or stimulation<br />
<strong>of</strong> SS release. Wada et al. (1075) demonstrated a<br />
significant inhibition <strong>of</strong> spontaneous GH secretion after intravenous<br />
infusion or intraventricular injection <strong>of</strong> IL-1 and<br />
in conscious rats. No effect was observed after IL-2 or IL-6.<br />
Numerous in vitro studies indicated that IL-1, as well<br />
as IL-2 and IL-6 (975), stimulate GH secretion in pituitary<br />
cultures. More contradictory results were obtained with<br />
TNF-, whereas interferon- (IFN-) was shown to inhibit<br />
the release <strong>of</strong> GH (see Ref. 98 for review).<br />
The stimulatory effect <strong>of</strong> IL-1 on GH release repeatedly<br />
observed in vitro and the fact that it reduces GH<br />
pulsatile release in vivo suggest an intermediary factor<br />
may be responsible for the latter effect. The most likely<br />
candidates are glucocorticoids whose circulating concentrations<br />
are elevated due to IL-1-induced activation <strong>of</strong> the<br />
HPA axis and which reportedly inhibit spontaneous GH<br />
secretion in the rat (see sect. VIA1).<br />
A common finding in juvenile rats and humans is the<br />
reduction <strong>of</strong> somatic growth during infectious states. In<br />
juvenile rats, activation <strong>of</strong> IL-1 by endotoxin lipopolysaccharide<br />
markedly reduced GH secretion, by stimulating<br />
CRH and SS release from the hypothalamus (821).<br />
These findings suggest that hypothalamic IL-1 in the<br />
rat plays a role in inhibiting GH secretion. Were the<br />
underlying mechanism shared by humans, selective therapeutic<br />
reductions <strong>of</strong> SS tone might be helpful in the<br />
treatment <strong>of</strong> chronic diseases <strong>of</strong> childhood. The precise<br />
role <strong>of</strong> other cytokines in these processes remains to be<br />
elucidated.<br />
10. NO<br />
Nitric oxide has now been shown to be a very important<br />
intracellular and intercellular messenger in most organs<br />
<strong>of</strong> the body, involved in the control <strong>of</strong> a wide range<br />
<strong>of</strong> physiological events. This free radical is rapidly degraded<br />
to nitrate and nitrite and is produced by NO synthase<br />
(NOS) from arginine (687, 734). Of the three known<br />
forms <strong>of</strong> NOS, the constitutive neural isoenzyme is widely<br />
distributed within the cells <strong>of</strong> the hypothalamus, especially<br />
in the PVN and SON, which send axons to the<br />
neurohypophysis and the ME (142). This has raised the<br />
intriguing possibility that NO may act as a neuroendocrine<br />
regulator in the hypothalamus and pituitary.<br />
Studies with NOS inhibitors such as N G -monomethyl-<br />
L-arginine (L-NMMA) and NO donors such as sodium<br />
nitroprusside (SNP) or S-nitrosoacetylpenicillamine<br />
(SNAP) have demonstrated that NO influences the release<br />
<strong>of</strong> GHRH (884) and SS (17). The mechanism by which NO<br />
stimulates the release <strong>of</strong> neurosecretory hormones is<br />
through diffusion into the neurons and activation <strong>of</strong> guanylate<br />
cyclase and cyclooxygenase to synthesize cGMP and<br />
PG, respectively (689).<br />
Microinjected into the third ventricle <strong>of</strong> conscious,<br />
freely moving rats, L-NMMA dramatically reduced GH pulsatility,<br />
primarily by cutting the height <strong>of</strong> the GH pulses<br />
(884). Nitric oxide release should also be involved in the<br />
mechanisms through which GHRH neurons modulate the<br />
output <strong>of</strong> SS into the portal blood (17).<br />
In the pituitary, NO secreted from folliculostellate<br />
cells and gonadotrophs (195) modulates GHRH-induced<br />
GH release. In freshly dissociated male rat pituitary cells,<br />
Kato (550) showed that SNP blocked the GH-releasing<br />
effect <strong>of</strong> GHRH, without affecting the GH release evoked<br />
by K excess.<br />
Recently, a careful series <strong>of</strong> studies has reevaluated<br />
the involvement <strong>of</strong> NO in the control <strong>of</strong> GH secretion.<br />
Endogenous NO deprivation induced by pretreatment<br />
with the NOS inhibitor N -nitro-L-arginine methyl ester<br />
(L-NAME) significantly attenuated GHRH, GHRP-6, and<br />
NMDA-induced GH secretion in prepubertal male and<br />
female rats. In vitro, neither SNP, L-NAME, nor cGMP<br />
modified baseline GH secretion by dispersed AP cells, but<br />
L-NAME completely blocked GHRH-induced GH release<br />
(1026). These findings suggest that endogenous NO plays<br />
a permissive role in the control <strong>of</strong> stimulated GH secretion<br />
and is an important factor in GH secretion in prepubertal<br />
rats.<br />
Similar data have been obtained in the dog, in which<br />
systemically administered L-NAME completely blocked<br />
and the lipophilic NO donor erythrityl tetranitrate potentiated<br />
the GH-releasing effect <strong>of</strong> hexarelin (A. Rigamonti,<br />
unpublished results). Studies with NOS inhibitors in humans<br />
are hindered by the toxicity <strong>of</strong> these substances on<br />
the cardiovascular system. Low doses <strong>of</strong> L-NAME blocked<br />
hypoglycemia-induced ACTH release but did not change<br />
either the basal or stimulated GH release (1072). Interestingly,<br />
L-arginine is a potent GH secretagogue in humans<br />
(711); however, its effect does not appear to be linked to<br />
NO production, since other NO donors such as molsidomine<br />
in humans (570) and erythrityl tetranitrate in dogs<br />
(Rigamonti, unpublished results) did not modify basal GH<br />
secretion and the GH-releasing effect <strong>of</strong> arginine was not<br />
affected by pretreatment with L-NAME.<br />
The effects on the hypothalamus and pituitary <strong>of</strong> the<br />
peptides evaluated so far are summarized in Table 3.<br />
VI. PERIPHERAL HORMONAL AND METABOLIC<br />
SIGNALS OR CONDITIONS MODULATING<br />
GROWTH HORMONE SECRETION<br />
A. <strong>Hormone</strong>s<br />
1. Glucocorticoids<br />
Glucocorticoids play a crucial role in somatotroph<br />
differentiation, which only occurs when the steroids<br />
reach a critical concentration (1029). Incubation <strong>of</strong> GH 3
564 MÜLLER, LOCATELLI, AND COCCHI Volume 79<br />
TABLE 3. Neuropeptides and growth hormone release:<br />
action on the CNS and/or the pituitary<br />
Peptide (Dosage) CNS Pituitary<br />
TRH (g) 1 a 2 b<br />
1 c<br />
GnRH (g) 1 a<br />
1<br />
CRH (g) 2? d<br />
0<br />
AVP (g) 0 0<br />
Oxytocin (ng) ? 2 e<br />
NT (g) 12? ?<br />
VIP (ng) 12 1 c<br />
PHI (g) 0 1<br />
PACAP (g) 1 f<br />
1 f<br />
NPY (g) – 12 c<br />
Galanin (g) 12 g<br />
12 c<br />
EOP (g) 13 h<br />
0<br />
IL-1 (ng) 2 1<br />
IL-1 (ng) 2 1<br />
NO 1 i<br />
1<br />
0, Not tested; 1, stimulation; 2, inhibition; 3, no effect; ?, controversial<br />
findings. See text for definitions. a In a host <strong>of</strong> pathological<br />
conditions; b inhibition <strong>of</strong> stimulated GH release; c on human somatotrophinomas;<br />
d in humans; e on basal and GHRH-stimulated release; f only<br />
in rats in vivo and in vitro; g in acromegalic patients; h -endorphin and<br />
morphine ineffectiveness in humans; i apparently unrelated to arginine.<br />
cells with cortisol led to an increase in the number <strong>of</strong><br />
somatotrophs and a decrease <strong>of</strong> lactotrophs, implying<br />
that the steroid modulates the functional heterogeneity <strong>of</strong><br />
the GH 3 cell line (124).<br />
Glucocorticoids amplify the GHRH responsiveness <strong>of</strong><br />
the somatotrophs, an effect linked to enhanced binding<br />
capacity <strong>of</strong> GHRH receptors, with no change in their<br />
affinity (946, 1002; see also sect. IIIA8B). The steroid also<br />
affects GHRH’s ability to modulate the main second messenger<br />
system coupled to these receptors, since exposure<br />
to dexamethasone enhanced the GHRH-stimulated accumulation<br />
<strong>of</strong> cAMP (717).<br />
In contrast, incubation <strong>of</strong> rat pituitary cells with<br />
dexamethasone reduced the GH response to the inhibitory<br />
effect <strong>of</strong> SS by downregulating the number but not<br />
the affinity <strong>of</strong> sstr (487, 939), most likely secondary to a<br />
reduction in gene transcription (1109). This is supported<br />
by in vivo data showing that dexamethasone for 3 or 8<br />
days dose-dependently reduced gene expression <strong>of</strong> pituitary<br />
sstr 2, one <strong>of</strong> the major SS receptor subtypes (584; see<br />
sect. III).<br />
It appears, therefore, that glucocorticoids may<br />
acutely increase GH secretion by enhancing somatotroph<br />
sensitivity to GHRH and reducing somatotroph responsiveness<br />
to SS. These mechanisms, however, are not<br />
obligatory for the GH-releasing properties <strong>of</strong> the steroids,<br />
which can stimulate GH synthesis and release by acting<br />
directly on animal and human pituitary cells (see Ref.<br />
1029 for review). The stimulation <strong>of</strong> GH mRNA by glucocorticoids<br />
in primary cultures <strong>of</strong> rat pituitaries or human<br />
GH-secreting adenomas is probably regulated at the<br />
transcriptional level (512) and may contribute to the tran-<br />
sient rises in plasma GH observed in humans after an<br />
acute corticosteroid dose (318, 1029).<br />
Acute administration <strong>of</strong> corticosteroids not only elicits<br />
a GH rise but potentiates GHRH-induced (177), but not<br />
the pyridostigmine-induced (176), GH release in humans.<br />
Because indirect cholinergic agonists are currently<br />
thought to release GH mainly by inhibiting SS release (see<br />
sect. VA3), it was assumed that glucocorticoids act<br />
through a similar mechanism. The fact that dexamethasone<br />
did not raise plasma GH in patients with AN was<br />
taken to indicate that the functional activity <strong>of</strong> SS neurons<br />
was decreased in these patients (928; see also sect. VA3).<br />
Supporting the idea <strong>of</strong> a suprapituitary component in the<br />
stimulatory action <strong>of</strong> glucocorticoids was the inability <strong>of</strong><br />
dexamethasone to elicit GH secretion in children with GH<br />
deficiency due to an idiopathic hypothalamic defect (669).<br />
Unlike a single dose, sustained delivery <strong>of</strong> supraphysiological<br />
amounts <strong>of</strong> glucocorticoids reduces somatic<br />
growth (636) and spontaneous GH secretion and<br />
blunts the GH response to a variety <strong>of</strong> physiological and<br />
pharmacological stimuli in rodents (1092) or humans<br />
(369, 554). These effects occur in addition to the wellknown<br />
steroid-induced peripheral catabolic effects and<br />
reduction <strong>of</strong> circulating IGF-I concentrations (1029).<br />
The inhibitory effects on GH secretion can be mainly<br />
attributed to a glucocorticoid-mediated enhancement <strong>of</strong><br />
hypothalamic SS release. In rats, huge doses <strong>of</strong> dexamethasone<br />
increased hypothalamic SS mRNA (767), and exposure<br />
<strong>of</strong> fetal hypothalamic cultures to high concentrations<br />
<strong>of</strong> corticosterone raised the SS content, whereas GHRH<br />
content was lowered (351).<br />
These results agreed with the findings <strong>of</strong> experiments<br />
with -adrenergic blockade and passive immunization<br />
with SS antibodies in suggesting that glucocorticoid excess<br />
enhances hypothalamic SS function in humans and<br />
rats (612, 1087).<br />
Corticosteroids may act indirectly, i.e., through an<br />
action on -adrenoreceptors, which inhibit GH secretion<br />
(see sect. VA1C). In vitro exposure to glucocorticoids<br />
increased the density <strong>of</strong> -receptors on smooth muscle<br />
cells (264); were a similar effect to occur on SS neurons,<br />
this would increase the inhibitory hypothalamic influences<br />
on GH secretion.<br />
In humans, however, pyridostigmine does not completely<br />
counteract glucocorticoid-induced GH inhibition<br />
(300), which therefore cannot result exclusively from increased<br />
hypothalamic SS function. One possibility is that<br />
it is due to permanent alterations <strong>of</strong> pituitary SS and<br />
GHRH receptors. However, contrasting this would be the<br />
finding that GHRH receptor mRNA levels in the rat AP<br />
increase, not decrease, after short-term dexamethasone<br />
treatment (584, see also sect. IIIA8B).<br />
Although glucocorticoids reportedly enhance the<br />
number and function <strong>of</strong> GHRH receptors in the rat AP,<br />
they seem to affect hypothalamic GHRH neurons nega-
April 1999 NEUROENDOCRINE CONTROL OF GROWTH HORMONE SECRETION 565<br />
tively, especially at high doses and with sustained treatments<br />
(585). The GHRH content in and release from fetal<br />
rat hypothalamic cells both decreased after incubation<br />
with high doses <strong>of</strong> corticosterone (351), and the same was<br />
true for the hypothalami <strong>of</strong> rats treated ex vivo with a<br />
huge dose <strong>of</strong> dexamethasone (770).<br />
In conclusion, glucocorticoids have a dual effect on<br />
the somatotrophic axis, one short-lived and stimulatory<br />
and the other inhibitory, after prolonged administration <strong>of</strong><br />
pharmacological doses. This probably results from an<br />
action on either the pituitary, through regulation <strong>of</strong> GH<br />
transcription, GHRH and SS receptors, or the hypothalamus,<br />
where they can affect the function <strong>of</strong> the two hypophysiotropic<br />
hormones differently. A further mechanism<br />
may be the reduction <strong>of</strong> circulating IGF-I<br />
concentrations and the ensuing inhibition <strong>of</strong> aut<strong>of</strong>eedback<br />
mechanism(s) (see sect. VIIB1).<br />
2. Gonadal steroids<br />
The modulatory action <strong>of</strong> E2 and androgens on GH<br />
secretion in animals and humans, and the underlying<br />
mechanisms, have already been discussed in other sections<br />
<strong>of</strong> the review (sects. IIA and IIIA8B), to which the<br />
reader is referred.<br />
3. Thyroid hormones<br />
The effects <strong>of</strong> thyroid hormones on GH secretion and<br />
their mechanisms <strong>of</strong> action are very similar in humans<br />
and laboratory animals (see Ref. 429 for review). Physiological<br />
concentrations <strong>of</strong> circulating thyroid hormones<br />
are necessary to maintain normal GH secretion, owing to<br />
direct stimulation <strong>of</strong> the AP. <strong>Growth</strong> hormone mRNA<br />
levels and rate <strong>of</strong> transcription increase after 3,3,5-triiodothyronine<br />
(T3) exposure, by direct action on the genome<br />
level (see Ref. 429). Conversely, in infant (288, 290)<br />
and adult (662) rats, pituitary GH content drops steeply<br />
with experimentally induced hypothyroidism.<br />
Early studies on how perturbations <strong>of</strong> the pituitarythyroid<br />
axis affected central GH regulatory mechanisms<br />
reported that in hypothyroid rats hypothalamic SS content<br />
and release were diminished and that replacement<br />
therapy with T3 restored both to normal (92). Subsequent<br />
studies, however, found hypothalamic SS content and<br />
release within normal limits in rats 10 days to 5 wk after<br />
thyroidectomy (see Ref. 429 for review). Long-term induction<br />
<strong>of</strong> hypothyrodism in the rat markedly lowered hypothalamic<br />
GHRH, which was restored to normal by thyroxine<br />
replacement therapy (546).<br />
In our own studies in neonatal and infant rats made<br />
hypothyroid by giving the dams propylthiouracil, we<br />
found no functional alterations in the GHRH hypothalamic<br />
machinery with respect to euthyroid rats, despite<br />
the lower pituitary and plasma GH concentrations (290).<br />
These findings indicate that in neonatal rats, deprivation<br />
<strong>of</strong> thyroid hormones primarily depresses pituitary somatotroph<br />
function and that possible changes in GHRH function<br />
are only a later event probably linked to GH deprivation<br />
and the ensuing annulment <strong>of</strong> GH aut<strong>of</strong>eedback<br />
mechanism(s) (see sect. VIIA). Consistent with this view,<br />
in adult rats induction <strong>of</strong> hypothyroidism enhanced both<br />
basal and K -stimulated GHRH secretion from incubated<br />
hypothalamic fragments 5 wk later (719), as a sort <strong>of</strong><br />
compensatory mechanism to reverse the hyposomatotrophinism<br />
<strong>of</strong> this condition.<br />
Thyroid hormones also regulate GH secretion by<br />
modulating somatotroph responsiveness to GHRH. Anterior<br />
pituitary cells from hypothyroid animals have a decreased<br />
response to GHRH in vitro (662). This reduced<br />
GH responsiveness probably results from the diminished<br />
pool <strong>of</strong> GHRH receptors after abrogation <strong>of</strong> thyroid function<br />
(571) (see also sect. IIIA8B).<br />
In humans, as in other species, hypothyroidism severely<br />
impairs postnatal growth, reduces spontaneous<br />
nocturnal GH secretion, and is correlated with impaired<br />
circulating IGF-I levels (227), the GH response to a variety<br />
<strong>of</strong> pharmacological stimuli being blunted (see Ref. 429).<br />
Rodent findings suggest the decreased pituitary GH pool<br />
due to impaired GH synthesis might also account for the<br />
low GH secretion <strong>of</strong> hypothyroid humans.<br />
The reciprocal hormone condition, i.e., hyperthyrodism<br />
in rats, is coupled to a reduced function <strong>of</strong> hypothalamic<br />
GHRH (531) and SS neurons, as suggested by the<br />
suppression <strong>of</strong> K -stimulated SS release from in vitro<br />
incubated hypothalami (833).<br />
As in hypothyroidism, hyperthyroid patients also<br />
have reduced GH secretion, which is restored to normal<br />
by antithyroid drugs (355, 922). Production <strong>of</strong> IGF-I increases<br />
in the hypothalamus after T 3 administration (105),<br />
an effect which may contribute to the diminished GH<br />
secretion because <strong>of</strong> activation <strong>of</strong> SS function. There is<br />
inferential evidence <strong>of</strong> an enhanced SS activity in hyperthyroid<br />
states (see Ref. 429 for review), suggesting this<br />
may be the mechanism underlying the hyposomatotrophic<br />
function.<br />
B. Metabolic Signals<br />
1. Glucose<br />
Glucose is an important regulator <strong>of</strong> GH secretion,<br />
although GH responses to hypo- or hyperglycemia differ<br />
among animal species. Hypoglycemia stimulates GH secretion<br />
in humans, and insulin-induced hypoglycemia is<br />
used clinically as a test to provoke GH secretion in GHdeficient<br />
children and adults (144), although it is poorly<br />
reproducible and gives some false-negative responses<br />
(477, see also sect. VA3). In contrast, in rats, insulininduced<br />
hypoglycemia or intracellular glucopenia inhibits<br />
pulsatile GH secretion (1014). This inhibitory effect oper-
566 MÜLLER, LOCATELLI, AND COCCHI Volume 79<br />
ates through stimulation <strong>of</strong> SS release, as shown by studies<br />
<strong>of</strong> incubated rat hypothalami (90) and the fact that<br />
hypothalamic SS mRNA levels are increased after ex vivo<br />
administration <strong>of</strong> insulin (763). Even severe hypoglycemia<br />
does not alter pulsatile GH secretion in mice (1003), in<br />
line with the reported resistance <strong>of</strong> mouse hypothalamic<br />
SS release or mRNA levels to intracellular glucopenia<br />
induced in vitro (924) or ex vivo (1003).<br />
The same species differences can be observed in<br />
hyperglycemic states (see Ref. 930 for review). In humans,<br />
acute administration <strong>of</strong> glucose inhibits GH secretion,<br />
although there is a rebound release 3–4 h later. In<br />
the chronic hyperglycemia <strong>of</strong> IDDM (type 1), GH secretion<br />
is <strong>of</strong>ten increased, particularly in poorly managed<br />
patients, although basal GH levels can be normalized with<br />
proper metabolic control (see Refs. 759, 985 for review).<br />
Because GH is diabetogenic, the increased secretion <strong>of</strong><br />
the hormone can induce adverse effects (971) (see also<br />
sect. VA3).<br />
In rats, acute hyperglycemia scarcely affects GH release,<br />
whereas diabetic rats have impaired GH secretion<br />
(see Refs. 428, 985 for review). The involvement <strong>of</strong> either<br />
the hypothalamus or the pituitary appears to be important.<br />
In streptozotocin-induced diabetic rats, SS antiserum<br />
restored GH secretion (1007), implying that enhanced<br />
SS release was responsible for the reduction.<br />
Hypothalamic SS (793) and SS mRNA concentrations<br />
(808) were instead unaltered. However, in the face <strong>of</strong> low<br />
circulating GH and IGF-I levels, this “normal” hypothalamic<br />
SS function might in fact have been inappropriately<br />
elevated. Supporting this was the lower number <strong>of</strong> SS<br />
receptors in pituitary membranes from diabetic rats than<br />
in controls (793), very likely resulting from downregulation.<br />
Hypothalamic SS release into the portal blood or<br />
from hypothalamic fragments is increased in streptozotocin-diabetic<br />
rats, but not until GH secretion had been<br />
suppressed for several days (527).<br />
Hypothalamic GHRH mRNA levels were low in diabetic<br />
rats compared with normal controls (793), despite<br />
the unaltered content <strong>of</strong> the peptide, suggesting that<br />
GHRH neuronal function was diminished. The fact that<br />
diabetic rats are unresponsive to clonidine (625), which<br />
releases GH partly through a GHRH-mediated mechanism<br />
(see sect. VA1A), confirms this. Also relevant is the finding<br />
that somatotrophs from diabetic rats have a blunted GH<br />
response to GHRH, although this difference disappeared<br />
when the data were normalized to account for differences<br />
in basal GH release (793).<br />
For the pituitary GH content <strong>of</strong> diabetic rats, reduced<br />
(770) or preserved (625, 1007) pituitary stores have been<br />
reported. Unlike in vitro, in vivo GH responsiveness to<br />
GHRH was significantly enhanced in streptozotocin-diabetic<br />
rats (627). In all these studies, lack <strong>of</strong> agreement<br />
may rest on differences in the strain <strong>of</strong> rats or length and<br />
severity <strong>of</strong> the disease.<br />
<strong>Secretion</strong> <strong>of</strong> GH is reportedly enhanced in IDDM<br />
patients. They have higher peak frequency and interpeak<br />
GH concentrations, despite elevated blood glucose, an<br />
exaggerated GH response to physiological and pharmacological<br />
stimuli, and paradoxical GH secretion after TRH<br />
(754). Indirect evidence suggests that enhanced GH secretion<br />
and responses to GHRH are likely to be related to<br />
a decreased SS tone, perhaps subsequent to damage <strong>of</strong> SS<br />
neurons by autoimmune processes (see sect. VA5B1 for<br />
discussion).<br />
In IDDM, high circulating GH levels would therefore<br />
be unable to feed back normally on SS-producing neurons<br />
(see sect. VIIA). In fact, GH pretreatment does not inhibit<br />
the GH response to GHRH (420) and pyridostigmine,<br />
which reduces SS activity (see sect. VA3), is unable to<br />
enhance the GH response to GHRH after GH pretreatment,<br />
as it does in normal controls (424). If hypothalamic<br />
SS function is really defective in IDDM patients, the brisk<br />
rise <strong>of</strong> plasma GH levels elicited by clonidine must be<br />
attributable to stimulation <strong>of</strong> GHRH neurons (see sect.<br />
VA1A).<br />
Different from IDDM, non-insulin-dependent diabetic<br />
(NIDDM) patients, have impaired responsiveness to<br />
GHRH, not only when they are obese (see below) but also<br />
in lean subjects (421).<br />
2. Amino acids<br />
Amino acids are a potent stimulus for GH secretion,<br />
either as selected nutrients or when included in a proteinrich<br />
meal (99, 283, 516). Parenteral administration <strong>of</strong> an<br />
amino acid solution raises GH secretion by acting on<br />
pulsatility and pulse amplitude, an effect presumably mediated<br />
by increased GHRH secretion (791). Arginine is the<br />
most striking stimulant, although lysine, ornithine, tyrosine,<br />
glycine, and tryptophan are all effective GH releasers<br />
(564). An oral mixture <strong>of</strong> arginine and lysine evokes a<br />
sevenfold increase <strong>of</strong> plasma GH levels (516), and a similar<br />
effect is observed after arginine aspartate (99, 163).<br />
Arginine-induced GH secretion in humans is blocked<br />
by antagonists <strong>of</strong> -adrenergic and cholinergic neurotransmission<br />
(153, 178), a carbohydrate-rich diet (710),<br />
hyperglycemia (711) and NEFA, anti-E 2 (878). Estrogens<br />
enhance arginine-induced GH secretion in men or women<br />
(711).<br />
The effect <strong>of</strong> arginine on GH secretion appears to be<br />
exerted through suppression <strong>of</strong> hypothalamic SS release,<br />
as suggested by neuropharmacological studies (22, 413,<br />
414). Alternatively, the effect <strong>of</strong> arginine on GH and other<br />
pituitary hormones (56, 366) may depend on its conversion<br />
to NO, a gaseous neurotransmitter (734). Arginine is<br />
in fact a more effective GH releaser than muscarinic<br />
cholinergic agonists (414) which inhibit SS release (629;<br />
but see sect. VB10 for discussion).
April 1999 NEUROENDOCRINE CONTROL OF GROWTH HORMONE SECRETION 567<br />
3. NEFA<br />
Nonesterified fatty acids are important among the<br />
peripheral factors controlling GH secretion. Pharmacological<br />
reduction <strong>of</strong> circulating NEFA levels raises GH<br />
(510), but conversely, NEFA elevation induced by the<br />
combination <strong>of</strong> exogenous Intralipid plus heparin markedly<br />
reduces spontaneous GH secretion in different animal<br />
species (109, 342) and abolishes GH responses to<br />
various stimuli (175, 181, 342).<br />
How NEFA act is not clear. In rats, NEFA’s inhibitory<br />
effect is directed at the pituitary (30, 175), but a hypothalamic<br />
site <strong>of</strong> action has also been suggested, since their in<br />
vivo inhibitory effect on GHRH-stimulated GH release<br />
was abolished by passive immunization with SS antiserum<br />
(505). Similar conclusions were drawn from human<br />
studies (824).<br />
At variance with these findings, experiments using<br />
monolayer cultures <strong>of</strong> fetal hypothalamic neurons<br />
showed that exposure to NEFA increased GHRH secretion<br />
and inhibited SS output, lowering SS mRNA content<br />
(949). The differences in vivo and in vitro may result from<br />
disruption <strong>of</strong> the normal organization in cultured dispersed<br />
neurons or the use <strong>of</strong> fetal tissue.<br />
A pituitary site <strong>of</strong> action for NEFA was suggested<br />
again by Alvarez et al. (30), who showed that their inhibitory<br />
effect on GHRH-stimulated GH release was also<br />
present in normal rats pretreated with a SS antiserum, or<br />
with hypothalamic ablation, and in hypophysectomized<br />
rats with two AP transplanted under the kidney capsule.<br />
The inhibitory effect <strong>of</strong> NEFA on GH secretion at the<br />
pituitary is rapid (within minutes), dose and time dependent,<br />
and closely related to the chemical structure <strong>of</strong> the<br />
NEFA tested (175). Although this point has not been<br />
completely clarified, the most likely mechanism is a reduction<br />
<strong>of</strong> [Ca 2 ] i. Cis-unsaturated NEFA, such as oleic<br />
acid, at physiological concentrations, suppressed the<br />
TRH-induced increase in Ca 2 in primary cultures <strong>of</strong> pituitary<br />
cells and in GH 3 and GH 4C 1 cells. In the same cells,<br />
NEFA abolished the TRH-induced Ca 2 efflux, through<br />
plasma membrane Ca 2 pumps, suggesting they perturbed<br />
the function <strong>of</strong> integral membrane proteins (829).<br />
In summary, the inhibitory influence <strong>of</strong> NEFA on GH<br />
secretion appears to be mainly exerted in the pituitary.<br />
4. Leptin<br />
Leptin, the product <strong>of</strong> the ob gene, is a recently<br />
discovered hormone secreted by adipocytes (1128) that<br />
regulates food intake and energy expenditure (162). Because<br />
GH secretion is markedly influenced by body<br />
weight, and, in particular, adiposity (see also below),<br />
leptin may act as a metabolic signal functionally connecting<br />
the adipose tissue with the GH/IGF-I axis. Obese mice<br />
lacking the ob gene (1128) or obese rodents with point<br />
mutated receptors for leptin show reduced function <strong>of</strong> the<br />
somatotrophic axis.<br />
Circulating leptin concentrations, which are positively<br />
correlated with abdominal and total body fat (361),<br />
are inversely related with serum GH concentrations<br />
(1041, 1042). In subjects with GH deficiency, low-dose GH<br />
replacement lowered plasma leptin, with no changes in<br />
BMI (365). The effect <strong>of</strong> GH on leptin secretion was<br />
probably indirect, since addition <strong>of</strong> GH to cultured mature<br />
white adipocytes did not affect leptin secretion (453).<br />
Leptin, however, does modify GH secretion, which<br />
decreases after administration <strong>of</strong> a leptin antiserum in<br />
freely moving rats; intraventricular-injected leptin reverses<br />
the inhibitory effect <strong>of</strong> fasting on GH secretion<br />
(172).<br />
The effect <strong>of</strong> leptin on GH secretion is presumably<br />
mediated by the long form <strong>of</strong> the ob receptor, which is<br />
primarily located in the hypothalamus (ARC, lateral, VM,<br />
DM nuclei) (706, 943). Preliminary results from our laboratory<br />
suggest that in the rat leptin increases GHRH function,<br />
concomitantly reducing SS activity (254).<br />
The inhibitory effects <strong>of</strong> the ob protein on NPY gene<br />
expression and secretion (942, 987) suggested that inhibition<br />
<strong>of</strong> NPY function was a major mechanism <strong>of</strong> action,<br />
and this was shown to be valid by the action on feeding<br />
behavior (see Ref. 162). Schwartz and co-workers (942,<br />
943) showed that intracerebroventricular injection <strong>of</strong> leptin<br />
into lean rats decreased NPY gene expression in the<br />
ARC, while increasing CRH gene expression in the PVN.<br />
Recalling the effects <strong>of</strong> the two peptides on GH secretion<br />
(see sect. V, E2 and E6), it appears highly likely that<br />
inhibition <strong>of</strong> NPY function accounts for leptin GH-stimulatory<br />
action.<br />
Erickson et al. (340), by breeding the mutant NPY<br />
allele onto the ob/ob background, generated mice deficient<br />
in both leptin and NPY. In the absence <strong>of</strong> NPY, ob/ob<br />
mice were less obese because they ate less and expended<br />
more energy; they were also less severely affected by<br />
diabetes, sterility, and somatotrophic defects. In adult<br />
fasted rats, intraventricular leptin prevented the disappearance<br />
<strong>of</strong> GH pulsatile secretion by reducing the fasting-induced<br />
enhancement <strong>of</strong> hypothalamic NPY gene expression<br />
(1074).<br />
The GH stimulation by leptin is hard to reconcile with<br />
the presence <strong>of</strong> high circulating levels <strong>of</strong> the protein and<br />
impaired somatotrophic axis <strong>of</strong> obese subjects (see below).<br />
One possible mechanism involves the development<br />
<strong>of</strong> hypothalamic leptin receptor desensitization, as demonstrated<br />
in obese rodents.<br />
C. Physiopathology <strong>of</strong> Nutritional Excess<br />
or Deficiency<br />
Discussion <strong>of</strong> the many GH deficiency and hypersecretory<br />
states is beyond the scope <strong>of</strong> this review, and the
568 MÜLLER, LOCATELLI, AND COCCHI Volume 79<br />
reader is referred to Müller and co-workers (755, 759). We<br />
confine ourselves here to aspects <strong>of</strong> GH control in two<br />
pathological conditions <strong>of</strong> humans, obesity and food deprivation,<br />
where some <strong>of</strong> the hormonal and metabolic<br />
factors alluded to previously are pr<strong>of</strong>oundly involved.<br />
1. Obesity<br />
A) ANIMAL STUDIES. Obese subjects have diminished GH<br />
secretion in response to a variety <strong>of</strong> GH secretagogues<br />
(317, 755). Because GH is a lipolytic hormone (601), impaired<br />
secretion may help perpetuate obesity.<br />
The mechanisms underlying the defective GH secretion<br />
have yet to be fully elucidated, although the reversibility<br />
<strong>of</strong> the defect after successful weight reduction (256,<br />
1005) strengthens the view that the impaired GH secretion<br />
is a metabolic consequence <strong>of</strong> obesity rather than a primary<br />
disturbance.<br />
Information from our own and other studies (19, 253,<br />
1012) in animal models <strong>of</strong> genetic obesity point to a<br />
striking impairment <strong>of</strong> the somatotrophic axis. Obese<br />
male rats <strong>of</strong> the Zucker strain have reduced pulsatile<br />
secretion <strong>of</strong> GH (1012) and pituitary responsiveness to<br />
GHRH, both in terms <strong>of</strong> GH release and <strong>of</strong> activation <strong>of</strong><br />
adenylate cyclase (253). Moreover, in these obese rats,<br />
pituitary GH gene expression and content are significantly<br />
reduced (19) and so are hypothalamic GHRH mRNA and<br />
GHRH content, whereas hypothalamic SS content is low<br />
but not mRNA (19, 253).<br />
Thus the hyposomatotropism <strong>of</strong> genetically obese<br />
male rats is associated with a primary reduction in the<br />
function <strong>of</strong> hypothalamic GHRH-producing neurons,<br />
which may well be the event responsible for the attenuation<br />
<strong>of</strong> GH gene expression and the diminution <strong>of</strong> circulating<br />
plasma GH.<br />
The picture in these rats overlaps that <strong>of</strong> aged rodents,<br />
which also have reduced GH secretion (1110) and<br />
a lower in vitro and in vivo responsiveness to GHRH both<br />
in terms <strong>of</strong> GH and activation <strong>of</strong> adenylate cyclase (810).<br />
As for obese and aged rats, and quite likely, humans too<br />
(296a), the main cause <strong>of</strong> the defective GH secretion<br />
would be a defective function <strong>of</strong> GHRH neurons (293),<br />
leading to unresponsiveness <strong>of</strong> GHRH receptors to the<br />
endogenous ligand. In aged (6) but not in obese rats (7),<br />
this is coupled with a reduction in the number <strong>of</strong> pituitary<br />
GHRH receptors. The reduced genomic expression <strong>of</strong><br />
GHRH in the hypothalamus <strong>of</strong> genetically obese male and<br />
aged rats may share a common pathophysiologic mechanism,<br />
i.e., impaired NE function (1118).<br />
Decreased GH secretion in obese rats is unlikely to<br />
be due to an increase in SS function or increased somatotroph<br />
sensitivity to SS, because passive immunization<br />
against SS failed to increase the GH response to GHRH<br />
(1012). Moreover, hypothalamic SS content and gene expression<br />
and SS function in the pituitary are preserved in<br />
obese rats (258), whereas gastric and pancreatic SS-IR are<br />
elevated (1060). In contrast to these findings, Berelowitz<br />
et al. (91) reported increased SS release from hypothalami<br />
in vitro <strong>of</strong> genetically obese rats.<br />
Unlike their male counterparts, genetically obese female<br />
rats had a normal pituitary response to GHRH both<br />
in terms <strong>of</strong> GH and adenylate cyclase activation (258),<br />
with preservation <strong>of</strong> hypothalamic GHRH function. The<br />
mechanism underlying the sexual dimorphism <strong>of</strong> GH secretion<br />
in genetically obese rats is not known, but a<br />
similar difference is also seen in rats with diet-induced<br />
obesity, whose spontaneous and stimulated GH secretion<br />
is much reduced (188, 189, 882). Rats made obese by<br />
feeding a hypercaloric diet, although their in vivo responsiveness<br />
to GHRH was strikingly reduced, had no differences<br />
from controls in pituitary GH content and gene<br />
expression and hypothalamic concentrations <strong>of</strong> GHRH<br />
and SS mRNA (188, 189).<br />
These findings underline the peripheral nature <strong>of</strong><br />
hyposomatotropic function in diet-induced obese rats, as<br />
opposed to the “central” impairment <strong>of</strong> GH regulation <strong>of</strong><br />
the Zucker obese rats, which have a primary alteration <strong>of</strong><br />
GHRH function. Among the different endocrine and metabolic<br />
indices, low plasma testosterone in males (188)<br />
and high NEFA in females (189) play a primary role in the<br />
impairment <strong>of</strong> GH secretion. Either a defect <strong>of</strong> androgens<br />
(849, 1088) or an excess <strong>of</strong> NEFA (see sect. VIB3) reportedly<br />
inhibits GHRH-stimulated GH secretion.<br />
B) HUMAN STUDIES. As expected, obese people have<br />
impaired 24-h GH secretion and blunted GH responses to<br />
provocative stimuli, both reversed by massive weight loss<br />
(873). Different from rodents, an alteration in the tonic<br />
secretion and/or phasic withdrawal <strong>of</strong> SS may underlie<br />
this GH dysfunction. Reduced GH response to a variety <strong>of</strong><br />
stimuli is a characteristic feature <strong>of</strong> obesity, although the<br />
pituitary can still make at least a partial secretory response<br />
to a direct secretagogue (284, 1096). The GH response<br />
to GHRH is reportedly reduced in obese children<br />
and adults but was significantly enhanced by pretreatment<br />
with pyridostigmine, so the mean baseline GH and<br />
the GH responses to pyridostigmine and GHRH overlapped<br />
those <strong>of</strong> lean subjects after GHRH alone. However,<br />
in lean subjects, combined administration <strong>of</strong> pyridostigmine<br />
and GHRH evoked a greater rise in plasma GH than<br />
in the obese people (415, 634). These findings indicate a<br />
role for SS, and hence SS disinhibition, in dictating the<br />
extent <strong>of</strong> GH responsiveness to GHRH in obese subjects,<br />
but they also imply some chronic background suppression<br />
<strong>of</strong> somatotroph function unrelated to SS.<br />
Normal people, like obese individuals, may show<br />
increased GH responsiveness to acute nutrient deprivation,<br />
as indicated by the fact that a short fasting enhances<br />
GH responses to GHRH (556). Because in fasting conditions<br />
the reported increase <strong>of</strong> spontaneous GH secretory<br />
burst frequency has been inferentially linked to functional
April 1999 NEUROENDOCRINE CONTROL OF GROWTH HORMONE SECRETION 569<br />
activation <strong>of</strong> the GHRH system (1033), the effect <strong>of</strong> fasting<br />
in increasing GH secretion in obesity suggests that in<br />
humans, like in rodents, this pathological condition is at<br />
least partially related to a GHRH neuronal defect.<br />
2. Food deprivation<br />
In rats, prolonged (24–72 h) food deprivation inhibits<br />
episodic GH secretion (1017) without altering the ultradian<br />
rhythm (791, 792). An intravenous dose <strong>of</strong> anti-SS<br />
serum restored large GH pulses in food-deprived rats,<br />
suggesting SS is involved (1012). However, hypothalamic<br />
SS mRNA levels were unaltered in 72-h food-deprived<br />
rats, whereas GHRH mRNA levels were markedly reduced<br />
(149), indicating that decreased GHRH secretion plays an<br />
important role in the inhibition <strong>of</strong> episodic GH secretion<br />
in food-deprived rats.<br />
Feeding after prolonged food deprivation caused a<br />
rapid and dramatic increase in GH pulse frequency and<br />
amplitude, and the characteristic ultradian rhythm was<br />
restored (791, 792). This was related to caloric intake<br />
rather than specific macronutrients, although ingestion <strong>of</strong><br />
an amino acid solution, but not <strong>of</strong> glucose and lipids, to<br />
fasted rats rapidly raises the pulse frequency and amplitude<br />
<strong>of</strong> GH secretion (795). In rats with sustained food<br />
deprivation, calorie intake restored GH pulse frequency<br />
and amplitude even in the absence <strong>of</strong> endogenous SS (SS<br />
antiserum or anterolateral deafferentation <strong>of</strong> the hypothalamus),<br />
suggesting this effect was mediated by activation<br />
<strong>of</strong> GHRH-producing neurons (994).<br />
Dietary protein intake is an important factor in GH<br />
secretion, particularly in the early postnatal period, as<br />
illustrated by studies (456) showing that in rat pups 3 wk<br />
<strong>of</strong> protein restriction stunted growth and caused a permanent<br />
reduction <strong>of</strong> pulsatile GH secretion in the postweaning<br />
period.<br />
In humans, the importance <strong>of</strong> protein intake for normal<br />
GH secretion is evident from the pr<strong>of</strong>ound disturbance<br />
in GH homeostasis <strong>of</strong> diseases involving protein<br />
malnutrition. Fasting GH levels were high in children with<br />
kwashiorkor (underweight, edema, hypoalbuminemia,<br />
and dermatosis) or marasmus (60% expected weight for<br />
age, no edema), and these levels were not normally reduced<br />
by induced hyperglycemia, did not correlate with<br />
fasting blood glucose, or dropped when an adequate carbohydrate<br />
but protein-free diet was given (846), indicating<br />
a state <strong>of</strong> GH resistance. Fasting GH and glucose-induced<br />
suppressibility returned to normal with oral protein. Levels<br />
<strong>of</strong> GH in patients before and after amino acid or<br />
albumin infusions correlated inversely with some plasma<br />
branched chain amino acids (leucine, isoleucine, and valine)<br />
(846).<br />
Limited growth in this malnourished children, despite<br />
elevated GH, depends on the defective secretion <strong>of</strong><br />
IGF-I, which is closely related to nutritional status (840,<br />
1046) and responds to protein and energy intakes (517)<br />
and to the quality <strong>of</strong> protein in the diet (252).<br />
In humans, unlike rodents, GH levels are significantly<br />
raised by fasting (475), even before the decline in serum<br />
IGF-I starting within 48 h <strong>of</strong> beginning the fast (251). Two<br />
days <strong>of</strong> fasting in healthy men induced a fivefold increase<br />
in the GH production rate, by an account <strong>of</strong> an increase in<br />
the number and amplitude <strong>of</strong> GH secretory bursts. An<br />
increase in the frequency <strong>of</strong> GHRH release with prolonged<br />
periods <strong>of</strong> reduced SS secretion was surmised from the<br />
increased frequency <strong>of</strong> constituent individual secretory<br />
bursts with prolonged intervolley nadirs. Serum IGF-I<br />
levels were still unchanged after 56 h <strong>of</strong> fasting (461) in<br />
the presence <strong>of</strong> increased levels <strong>of</strong> IGFBP-1 (1123). This<br />
may reduce the bioavailable portion <strong>of</strong> IGF-I, thus limiting<br />
IGF-I negative feedback on GH secretion before total<br />
serum levels <strong>of</strong> IGF-I change (see also sect. VIIB1).<br />
These findings may have some relevance when assessing<br />
the GH hypersecretion seen in patients with AN, a<br />
disease marked by self-imposed starvation in exaggerated<br />
attemps to maintain a thin body, and by a phobia for<br />
weight gain and fat (389). Resting GH levels are reportedly<br />
elevated in some patients with AN (145 587) but<br />
return to normal with recovery. This fall is unrelated to<br />
body weight but is closely tied to the patient’s caloric<br />
intake (390). It appears, therefore, that the elevated GH in<br />
AN is at least partly secondary to starvation and plays an<br />
important adaptive role.<br />
However, an analysis by Cluster algorithm <strong>of</strong> pulsatile<br />
GH secretion at night in a group <strong>of</strong> AN patients<br />
disclosed a GH secretory pr<strong>of</strong>ile somewhat different from<br />
that <strong>of</strong> sustained fasting and reminiscent <strong>of</strong> that in poorly<br />
controlled IDDMD (see sect. VIB1). The enhanced nocturnal<br />
GH secretion was largely due to an increase in the<br />
nonpulsatile component, although the pulsatile component<br />
was also significantly enhanced because <strong>of</strong> the larger<br />
number <strong>of</strong> secretory episodes. The lack <strong>of</strong> correlation<br />
between parameters <strong>of</strong> GH release and BMI indicated a<br />
more complex hypothalamic dysregulation <strong>of</strong> GH release<br />
than simple disinhibition <strong>of</strong> the IGF-I aut<strong>of</strong>eedback mechanism<br />
subsequent to malnutrition (929).<br />
In AN, despite exaggerated GH response to GHRH<br />
(138, 676, 898), not confirmed in other studies (175, 713),<br />
there is little or no GH response to insulin-induced hypoglycemia<br />
and dopaminergic stimulation which, in all, suggests<br />
hypothalamic dysfunction.<br />
Somatostatin function may be reduced in the hypothalamus<br />
<strong>of</strong> AN patients, in view <strong>of</strong> the failure <strong>of</strong> glucose,<br />
a stimulus which would inhibit GH secretion through<br />
release <strong>of</strong> SS (867, see also sect. VIB1), to counter the<br />
GHRH-induced GH rise (900), and the lack <strong>of</strong> the GHreleasing<br />
effect <strong>of</strong> short-term glucocorticoid treatment<br />
which, in fact, is attributed to inhibition <strong>of</strong> SS secretion<br />
(see sect. VIA1) (928). In line with this view, pirenzepine,<br />
a drug thought to act by stimulating SS function, was only
570 MÜLLER, LOCATELLI, AND COCCHI Volume 79<br />
partially effective in blocking the GHRH-induced GH secretion<br />
in AN patients, whereas it completely suppressed<br />
it after recovery, as it did in controls (899, 1001). Similarly,<br />
in dogs in a chronic state <strong>of</strong> caloric restriction, a<br />
standard dose <strong>of</strong> pirenzepine failed to prevent the GHRHinduced<br />
GH rise, and double the dose was needed (37).<br />
Conversely, pyridostigmine, a GH secretagogue allegedly<br />
acting through inhibition <strong>of</strong> SS release (see sect. VA3), had<br />
no effect on the GHRH-induced GH rise in either AN<br />
patients (409) or in calorically restricted dogs (37), while<br />
clearly enhancing it in controls.<br />
However, in AN patients, arginine, another GH secretagogue<br />
allegedly acting through inhibition <strong>of</strong> SS release<br />
(see sect. VIB2), strikingly enhanced the GHRH-induced<br />
GH rise, like in controls, and blunted the GH response to<br />
the second <strong>of</strong> two consecutive boluses <strong>of</strong> GHRH (409),<br />
indicating that a SS-mediated aut<strong>of</strong>eedback mechanism<br />
was preserved.<br />
In all, animal and human experiments showing that<br />
cholinergic drugs do not affect the GHRH-induced GH rise<br />
do not provide evidence that SS function is defective in<br />
states <strong>of</strong> caloric deprivation, but rather indicate the existence<br />
<strong>of</strong> (primary?) hypothalamic cholinergic hyperfunction.<br />
In rats under caloric restriction with reduced titers<br />
<strong>of</strong> circulating IGF-I, IGF-I receptors in the ME are upregulated<br />
(121). This may be a homeostatic mechanism to<br />
suppress GH secretion by maintaining SS secretion during<br />
food shortages or other metabolic conditions involving<br />
low plasma IGF-I levels (see sect. VIIB1). Table 4 sections<br />
out series <strong>of</strong> factors or conditions that affect GH secretion.<br />
VII. GROWTH HORMONE AUTOFEEDBACK<br />
MECHANISM<br />
Evidence has accumulated over many years that<br />
there are long, short, and ultrashort loops in the feedback<br />
regulation <strong>of</strong> GH secretion (see Ref. 750). Because GH<br />
lacks a distinct target endocrine gland, it was suggested<br />
that it feeds back on the hypothalamus to regulate its own<br />
secretion. The feedback regulation <strong>of</strong> GH presumably<br />
involves either activation <strong>of</strong> SS or inhibition <strong>of</strong> GHRH<br />
function, or both, not forgetting the apparent action on<br />
the pituitary through blood-borne IGF-I. In addition to GH<br />
itself, brain neurotransmitters, neuropeptides, and many<br />
factors directly or indirectly related to GH secretion, such<br />
as NEFA, glucose, glucocorticoids and thyroid and gonadal<br />
hormones, have important roles in somatotroph<br />
function (see sect. VI).<br />
A. <strong>Growth</strong> <strong>Hormone</strong><br />
Early data (reviewed in Ref. 749) showed that rats<br />
with ectopic somatotrophic tumors had reduced pituitary<br />
TABLE 4. Factors or conditions that stimulate or inhibit<br />
GH secretion in primates<br />
Factors Increase Inhibition<br />
Neurogenic Sleep stages 3 and 4<br />
Stress<br />
Physical<br />
Psychological<br />
Monoaminergic<br />
stimuli<br />
REM sleep<br />
Epinephrine, 2 adrenergic<br />
stimulation<br />
1-Adrenergic stimulation<br />
DA agonists DA agonists‡<br />
-Adrenergic<br />
antagonists<br />
-Adrenergic agonists<br />
5-HT agonists 5-HT antagonists<br />
Muscarinic<br />
Muscarinic cholinergic<br />
cholinergic agonists<br />
GABA agonists<br />
-Hydroxybutyrate<br />
antagonists<br />
Metabolic Hypoglycemia<br />
Fasting<br />
Hyperglycemia<br />
Decreased NEFA<br />
levels<br />
Amino acids<br />
Increased NEFA levels<br />
IDDM<br />
Liver cirrhosis<br />
Anorexia nervosa<br />
Renal failure<br />
Obesity<br />
Hormonal* GHRH<br />
GHRP<br />
Somatostatin<br />
Decreased IGF-I<br />
levels<br />
Increased IGF-I levels<br />
Estrogens<br />
Androgens<br />
Hypo-hyperthyroidism<br />
Glucocorticoids†<br />
Glucagon<br />
Glucocorticoids<br />
* For the sake <strong>of</strong> clarity, growth hormone-releasing and inhibitory<br />
neuropeptides (see sect. VIB) have been omitted. † Under acute treatment.<br />
‡ In acromegaly. See text for definitions.<br />
levels <strong>of</strong> GH and their pituitary synthesize GH at a reduced<br />
rate in vitro (691). In rodents, the infusion <strong>of</strong> GH<br />
blocked the GH release induced by insulin hypoglycemia,<br />
determined using as an end point the “tibia test” bioassay<br />
(757); in humans, treatment with GH prevented insulin<br />
hypoglycemia-induced elevations <strong>of</strong> GH (4). These studies<br />
implied that elevated levels <strong>of</strong> circulating GH have an<br />
aut<strong>of</strong>eedback action at the level <strong>of</strong> the hypothalamus or<br />
pituitary.<br />
With the advent <strong>of</strong> specific RIA, it was possible to<br />
show that short-term hypophysectomy was associated<br />
with a decrease in the hypothalamic content <strong>of</strong> SS and<br />
that SS levels could be restored to normal after GH administration<br />
(480, 812). Similarly, hypothalamic SS content<br />
could be reduced by selective passive immunization<br />
against GH (93). However, true assessment <strong>of</strong> the dynamics<br />
underlying these changes only became possible with<br />
molecular cloning techniques.<br />
The knowledge that alterations <strong>of</strong> hypothalamic SS<br />
titers were due to changes in SS synthesis and release
April 1999 NEUROENDOCRINE CONTROL OF GROWTH HORMONE SECRETION 571<br />
derived from experiments in which SS mRNA was measured<br />
in individual cells <strong>of</strong> the rat PeVN. Hypophysectomy<br />
lowered the level <strong>of</strong> the messenger, per cell, an effect<br />
completely reversed by administration <strong>of</strong> GH. In the same<br />
experiments, intact GH-treated rats had higher levels <strong>of</strong><br />
the messenger than vehicle-treated rats (897). That this<br />
effect was actually due to GH was also implied by in vitro<br />
experiments, adding GH to MBH preparations (93). Moreover,<br />
in vivo intraventricular injections <strong>of</strong> GH raised SS<br />
levels in rat portal blood after a latency <strong>of</strong> 20–40 min,<br />
suggesting action more on SS synthesis than release<br />
(235). Supporting these findings, three different dwarf<br />
mutant models <strong>of</strong> mice lacking GH, i.e., Ames dwarf df/df<br />
mice (496), Snell dwarf (dw/dw) mice (788), and transgenic<br />
dwarf mice with genetic ablation <strong>of</strong> GH-expressing<br />
cells had a selected depletion <strong>of</strong> SS mRNA in the PeVN<br />
(85).<br />
The developmental role <strong>of</strong> GH on hypophysiotropic<br />
SS neurons has been studied in Ames dwarf df/df mice.<br />
Total SS mRNA levels were deficient in their PeVN shortly<br />
after the developmental onset <strong>of</strong> SS transcription. The<br />
absence <strong>of</strong> GH aut<strong>of</strong>eedback was very likely responsible<br />
for SS mRNA deficiency in 7-day-old dwarf Ames mice<br />
compared with phenotypically normal DF/? controls, suggesting<br />
that GH receptors may be present on the PeVN<br />
neurons at or before 7 days <strong>of</strong> age in DF/? mice (496).<br />
Because the amount <strong>of</strong> SS mRNA per expressing cell in<br />
the PeVN <strong>of</strong> Ames dwarf mice was not reduced, the<br />
decrease in total SS mRNA <strong>of</strong> the whole expressing cells,<br />
also present in adults, was the result <strong>of</strong> an early failure to<br />
achieve a normal population <strong>of</strong> SS-expressing neurons<br />
(496). No studies on the developmental appearance <strong>of</strong><br />
GHRH receptor mRNA have been reported so far in Ames<br />
dwarf mice, a topic worth further investigation to clarify<br />
the developmental role <strong>of</strong> GH on SS neurons.<br />
Transgenic mice expressing heterologous and ectopic<br />
GH have been used as models for studying the<br />
feedback effects <strong>of</strong> elevated nonregulated GH on hypophysiotropic<br />
neurons and peripheral functions. It<br />
would seem that feedback effects extend beyond dynamic<br />
regulation to influence hypophysiotropic neuron differentiation<br />
and/or survival, when the deficiency (see above),<br />
or excess <strong>of</strong> GH is genetic and lifelong, such as in spontaneous<br />
mutant or transgenic models (837). Somatostatin<br />
expression was markedly increased in mice bearing either<br />
bovine or human transgenes. Human, but not bovine, GH<br />
reportedly has lactogenic properties in mice and appears<br />
to stimulate prolactin-inhibiting TIDA neurons. The results<br />
in the murine transgene models suggested that although<br />
even extremely high levels <strong>of</strong> circulating GH <strong>of</strong><br />
bovine origin did not stimulate TIDA neurons, lifelong<br />
high levels <strong>of</strong> human GH had a stimulatory and graded<br />
effect on the developmental differentiation <strong>of</strong> TH and DA<br />
production, supporting the concept <strong>of</strong> prolactin as a trophic<br />
factor for TIDA neurons.<br />
Although extensive studies have been done in animal<br />
models to elucidate the various components <strong>of</strong> this regulatory<br />
system, studies in humans have been limited because<br />
<strong>of</strong> the inaccessibility <strong>of</strong> the hypothalamus and pituitary<br />
and their vascular connections. However, in<br />
healthy subjects given an acute dose <strong>of</strong> GH, total suppression<br />
<strong>of</strong> the subsequent GH response to GHRH (906),<br />
before any rise <strong>of</strong> circulating IGF-I (907), was evident.<br />
Moreover, similar to what is observed with SS antiserum<br />
in the rat (592, 1039) or with muscarinic cholinergic agonists<br />
inhibiting hypothalamic SS release (1039; and see<br />
sect. VB3), in humans too this class <strong>of</strong> compounds (671,<br />
907) completely restored the GH response to GHRH, inhibited<br />
by a previous GHRH bolus (410, 672), suggesting<br />
SS is involved in the short-loop negative aut<strong>of</strong>eedback.<br />
However, these experiments, which imply the intervention<br />
<strong>of</strong> the GH-SS axis, cannot exclude a mechanism<br />
mediated by blood-borne or locally produced IGF-I (see<br />
also below).<br />
However, the GH-mediated inhibitory feedback has<br />
more experimental than clinical relevance, as shown in<br />
GH-deficient patients who, despite chronic treatment with<br />
GHRH, have persistently elevated GH and IGF-I plasma<br />
levels (1035), or patients with ectopic GHRH secretion<br />
who develop acromegaly (376).<br />
In addition to SS, GHRH is also implicated in GH<br />
feedback mechanisms. In rats, intracerebroventricular infusion<br />
<strong>of</strong> GH reduced the amplitude <strong>of</strong> spontaneous GH<br />
secretory bursts, an effect that was counteracted not by<br />
SS antiserum but by the combination <strong>of</strong> supramaximal<br />
systemic doses <strong>of</strong> GHRH and SS antibodies (592). A more<br />
direct approach had relied on direct measurement <strong>of</strong><br />
GHRH-IR in the hypothalamus <strong>of</strong> hypophysectomized<br />
rats. Hypothalamic GHRH-IR concentrations were reduced<br />
in these rats and were partially restored after GH<br />
treatment (386). However, in this instance, simple evaluation<br />
<strong>of</strong> GHRH content was misleading and contrasted the<br />
reported ability <strong>of</strong> GH to lower hypothalamic GHRH content<br />
in intact rats (386) or rats with a GH-secreting tumor<br />
(799). In a sequel to these studies, it was shown that<br />
GHRH mRNA was significantly increased in the hypothalamus<br />
<strong>of</strong> hypophysectomized rats and was partially reduced<br />
by GH (237, 290).<br />
The negative-feedback action <strong>of</strong> GH on GHRH mRNA<br />
was also demonstrated in infant rats, in which a dose <strong>of</strong><br />
GH reduced pituitary GH content and abolished the GH<br />
rise in response to acute GHRH; this was restored to<br />
normal when GH treatment was combined with GHRH<br />
(207).<br />
These findings might be relevant to the GH therapy <strong>of</strong><br />
nonclassical GH-deficient short children, whose GHRHsecreting<br />
neurons are functionally preserved (399, 1055).<br />
However, a recent study in children with severe short<br />
stature and impaired GH responses to suprapituitary stimuli<br />
but normal responsiveness to GHRH negates this
572 MÜLLER, LOCATELLI, AND COCCHI Volume 79<br />
mechanism. During GH therapy, the GH response to a<br />
GHRH bolus was only slightly reduced, and a second<br />
bolus <strong>of</strong> GHRH elicited a GH response similar to that in<br />
the pretreatment test (927). This indicates a significant<br />
resilience <strong>of</strong> GHRH neurons to the feedback mechanisms<br />
triggered by elevated circulating GH concentrations.<br />
Feedback regulation <strong>of</strong> GHRH function by GH has<br />
been studied in animal models <strong>of</strong> spontaneous GH deficiency<br />
(933). In Ames dwarf mice not only was total<br />
GHRH mRNA expression enhanced, but the number <strong>of</strong><br />
GHRH-IR neurons was increased (838). Conversely, transgenic<br />
mice bearing a TH-human GH transgene had targeted<br />
expression <strong>of</strong> GH in the PeVN, ARC, and adrenal<br />
medulla and were growth retarded (68). They also had<br />
low pituitary GH and GH mRNA and low hepatic IGF-I<br />
mRNA and serum IGF-I levels. In these rats, feedback<br />
effects occurred in the PeVN and ARC, leading to increases<br />
<strong>of</strong> SS and its messenger and decreases in GHRH<br />
and its messenger (996).<br />
Lowering GHRH function during fetal life in these<br />
mice affected the density <strong>of</strong> pituitary GHRH receptors and<br />
impaired somatotroph development (996). Thus this type<br />
<strong>of</strong> transgenic mouse serves as a model <strong>of</strong> idiopathic GH<br />
deficiency in humans and a means for studying factors<br />
affecting somatotroph proliferation (374).<br />
Flavell et al. (362) reported that in transgenic rats<br />
targeting the expression <strong>of</strong> human GH (hGH) to GHRH<br />
neurons can induce dominant dwarfism. A line <strong>of</strong> these<br />
rats bearing a single copy <strong>of</strong> a GHRH-hGH transgene had<br />
low levels <strong>of</strong> production <strong>of</strong> hypothalamic GHRH and<br />
mRNA, in contrast to the increased GHRH expression<br />
accompanying GH deficiency in other models <strong>of</strong> dwarfism.<br />
These rats also had a sexually dimorphic pattern <strong>of</strong><br />
GH secretion and a lower GH response to GHRH or<br />
GHRP-6 challenge than their nontransgenic littermates;<br />
nevertheless, despite the pituitary GH deficiency and<br />
dwarfism, repeated dosing <strong>of</strong> GHRH or GHRP-6 did stimulate<br />
their growth. To our knowledge, these rats are the<br />
first genetic animal model <strong>of</strong> GH deficiency in which<br />
dwarfism could be corrected by exogenous GH secretagogues<br />
(1093).<br />
In contrast to the feedback data in young rats, the<br />
feedback effects <strong>of</strong> GH are disrupted in senescent rats,<br />
which are spontaneously deficient in GH. In 20-mo-old<br />
male rats, 4 days <strong>of</strong> treatment with GH increased plasma<br />
IGF-I levels but did not significantly change hypothalamic<br />
GHRH and SS mRNA levels (291). However, old rats<br />
apparently losing their ability to sense the feedback action<br />
<strong>of</strong> GH in the hypothalamus responded normally to<br />
GH with increases in SS and IGF-I gene expression in the<br />
cerebral hemispheres (637). This may explain the improvement<br />
<strong>of</strong> some psychological symptoms after GH<br />
treatment in GH-deficient patients (see also below).<br />
The direct feedback action <strong>of</strong> GH on the brain involves<br />
GH binding to its own receptor. Specific GH recep-<br />
tors have been found in the choroid plexus, hippocampus,<br />
hypothalamus, and pituitary gland (583, 1084). Receptors<br />
in the choroid plexus are involved in transporting the<br />
hormone across the BBB (583). <strong>Growth</strong> hormone is reportedly<br />
present in low concentrations in the CSF in<br />
humans (616), but direct evidence that it can cross the<br />
BBB has been recently provided in GH-deficient adults<br />
where CSF GH levels rose significantly after 1 or 21 mo <strong>of</strong><br />
GH treatment (154, 528). This was accompanied by parallel<br />
increases in IGF-I, IGFBP-3, and -endorphin concentrations<br />
and by decreases in homovanillic acid, VIP,<br />
and free thyroxine concentrations. These changes in CSF<br />
composition might explain the gain in psychological wellbeing<br />
usually reported in GH-deficient patients after they<br />
start GH treatment.<br />
The mRNA for GH receptors was widely expressed in<br />
the PeVN, PVN, and ARC <strong>of</strong> the hypothalamus (155). In<br />
the PeVN and PVN, the majority <strong>of</strong> SS neurons coexpressed<br />
GH receptor mRNA, suggesting that GH acts<br />
directly on SS at these sites. Intriguing was the observation<br />
that GH receptor mRNA was also expressed in the<br />
ARC, although the vast majority <strong>of</strong> GHRH and SS cells <strong>of</strong><br />
the ARC did not appear to express it, implying that GH<br />
effects in ARC were transduced by other neurons (155).<br />
However, single- and double-label in situ hybridization<br />
showed that GH induced c-fos expression in the ARC <strong>of</strong><br />
intact rats (156) and in the ARC and PeVN <strong>of</strong> hypophysectomized<br />
rats (728), indicating that immediate early<br />
gene expression plays a role in the feedback actions <strong>of</strong><br />
GH into the brain. However, although c-fos-expressing<br />
neurons in the medial ARC were abundant, few if any<br />
were GHRH or SS neurons.<br />
The pattern <strong>of</strong> distribution <strong>of</strong> c-fos expression in the<br />
ARC was strikingly similar to that <strong>of</strong> GH-receptor mRNA,<br />
suggesting that receptor binding and the induction <strong>of</strong> c-fos<br />
gene expression in this nucleus occurred within the same<br />
population <strong>of</strong> unidentified cells.<br />
The precise identity <strong>of</strong> these cells remained elusive<br />
until Kamegai et al. (538) demonstrated that GH induces<br />
the expression <strong>of</strong> c-fos mRNA in NPY neurons <strong>of</strong> the ARC.<br />
Although this suggested that most NPY neurons were<br />
responsive to GH, it remained to be established whether<br />
GH acts directly on NPY neurons or whether there was<br />
some other population <strong>of</strong> cells receiving the GH signal.<br />
Studies <strong>of</strong> coexpression <strong>of</strong> GH receptor mRNA and NPY<br />
mRNA in the ARC indicated that the majority <strong>of</strong> NPY<br />
neurons in the ARC coexpressed GH receptor mRNA<br />
(217). Granted that NPY neurons may serve as a receiving<br />
network for the GH signal, it remains to be seen how, or<br />
even if, the signal is relayed to GHRH or SS neurons in the<br />
ARC (see also sect. VB6).<br />
Another neuropeptide, galanin, which is coexpressed<br />
in GHRH neurons (699, 778; see sect. IIIA2), seems to be<br />
involved in the feedback control <strong>of</strong> GH. Galanin mRNA is<br />
reduced in GHRH neurons <strong>of</strong> Lewis dwarf rats and in
April 1999 NEUROENDOCRINE CONTROL OF GROWTH HORMONE SECRETION 573<br />
hypophysectomized rats and is restored by exogenous GH<br />
(218). A subset <strong>of</strong> SS neurons in the PeVN also expresses<br />
the galanin receptor mRNA, whereas few GHRH neurons,<br />
if any, appeared to do so (218). Galanin, like its cotransmitter<br />
GHRH, is the target for GH action, and galanin may<br />
play a role in the feedback control <strong>of</strong> GH secretion,<br />
through a direct effect on SS neurons. These, in turn,<br />
would inhibit GHRH ARC neurons, although the underlying<br />
mechanism remains to be elucidated.<br />
High levels <strong>of</strong> expression <strong>of</strong> the mRNA for two prototypic<br />
receptors <strong>of</strong> the SS family, sstr1 and sstr2, have<br />
been found (81), and 2 wk after hypophysectomy, sstr1<br />
and sstr2 mRNA labeling density was reduced in the ARC.<br />
Seven days <strong>of</strong> treatment with hGH raised the labeling<br />
density <strong>of</strong> sstr1 mRNA selectively in the ARC <strong>of</strong> hypophysectomized<br />
rats (448). Thus the expression <strong>of</strong> sst1 and<br />
sst2 receptor subtypes must be under the regulatory influence<br />
<strong>of</strong> pituitary hormones, and GH may participate in<br />
its own secretion by modulating hypothalamic SS and,<br />
secondarily, by up- or downregulating sst1 receptor<br />
mRNA on GHRH-containing neurons. However, in view <strong>of</strong><br />
the long-term exposure to GH reported in this study, it is<br />
still questionable whether this regulatory feedback mechanism<br />
would operate under physiological conditions and<br />
participate in the genesis <strong>of</strong> episodic GH secretion or is<br />
only manifested under pharmacological conditions.<br />
<strong>Growth</strong> hormone, in addition to its direct short-loop<br />
effects on the hypothalamic neurons, directly affects lipolysis<br />
and impairs glucose metabolism and indirectly<br />
affects growth by stimulating the production <strong>of</strong> IGF-I.<br />
Therefore, IGF-I, NEFA, and glucose might all have roles<br />
in the long-loop feedback regulation <strong>of</strong> GH secretion (see<br />
sect. VI, B1 and B3).<br />
B. Insulin-Like <strong>Growth</strong> Factor I<br />
Insulin-like growth factor I participates in the growth<br />
and function <strong>of</strong> almost every organ in the body (283) and<br />
is synthesized primarily in the liver, although it is produced<br />
everywhere in the body. Insulin-like growth factor<br />
I shows structural similarities with IGF-II and insulin,<br />
with which it has in common 60% <strong>of</strong> amino acids. However,<br />
unlike insulin, which circulates in picomolar concentrations<br />
and has a short half-life, IGF-I and -II circulate<br />
in nanomolar concentrations and have a much longer<br />
half-life because they are largely bound to a variety <strong>of</strong> BP,<br />
six <strong>of</strong> which have been characterized (530). These BP, like<br />
IGF-I and IGF-II, are synthesized by most tissues, where<br />
they act in an autocrine or paracrine manner to regulate<br />
different functions (530). Both IGF-I and IGF-II are essential<br />
for fetal development (67), and nanomolar concentrations<br />
persist in the circulation into adult life.<br />
The main role <strong>of</strong> IGF-I after birth is to regulate<br />
growth, whereas that <strong>of</strong> IGF-II is still unknown (606). The<br />
circulating BP modulate the activity <strong>of</strong> these growth factors<br />
by limiting their access to specific tissues and receptors.<br />
Binding protein 3 binds 95% <strong>of</strong> circulating IGF-I<br />
and -II. This complex binds an acid-labile protein subunit,<br />
forming a ternary complex that has a serum half-life <strong>of</strong><br />
many hours. Once released from this complex, the IGF<br />
can enter target tissues with the aid <strong>of</strong> other BP. <strong>Growth</strong><br />
hormone raises the serum concentrations <strong>of</strong> BP-3 and the<br />
acid-soluble subunit (530). Some IGF-I BP have a greater<br />
affinity for IGF than receptors. This can prevent activation<br />
<strong>of</strong> intracellular signaling pathways (606).<br />
The local production <strong>of</strong> IGF-I is under different control<br />
in different tissues. For example, GH, parathyroid<br />
hormone, and sex steroids regulate the production <strong>of</strong><br />
IGF-I in bone, whereas sex steroids are the main regulators<br />
<strong>of</strong> locally produced IGF-I in the reproductive system.<br />
The functions <strong>of</strong> circulating IGF-I are becoming clearer,<br />
but the actions <strong>of</strong> locally produced IGF have yet to be<br />
defined. Age, sex, nutritional status, and GH affect serum<br />
IGF-I concentrations. Plasma levels <strong>of</strong> IGF-I are low at<br />
birth, rise substantially during childhood and puberty, and<br />
begin to decline in the third decade (59, 607), after the<br />
changes in GH secretion.<br />
Complete disruption <strong>of</strong> the IGF-I gene in a 15-yr-old<br />
boy who presented with severe intrauterine growth failure,<br />
deafness, and mild mental retardation indicates that<br />
the absence <strong>of</strong> IGF-I is compatible with life. However, it<br />
suggests that IGF-I plays a major role in human fetal<br />
growth and CNS development (1104) (see also below). In<br />
addition, low IGF-I levels may result from GH deficiency<br />
or from mutations in the gene encoding the GH receptor,<br />
such as in Laron dwarfism (593).<br />
The nutritional status also markedly affects plasma<br />
IGF-I concentrations. Starvation causes complete resistance<br />
to GH, and restriction <strong>of</strong> protein or calories causes<br />
a lesser degree <strong>of</strong> resistance with a consequent reduction<br />
<strong>of</strong> hepatic IGF-I production (517). Low IGF-I levels with<br />
GH resistance are also seen in other catabolic states, such<br />
as severe trauma and sepsis. In IDDM, hepatic resistance<br />
to GH, with elevated serum GH and low IGF-I levels in<br />
plasma, result probably from an inadequate insufficient<br />
action <strong>of</strong> insulin on the liver (450). During puberty, these<br />
changes may limit somatic growth. The high levels <strong>of</strong> GH<br />
may worsen the hyperglycemia by opposing the peripheral<br />
actions <strong>of</strong> insulin in poorly controlled IDDM or<br />
NIDDM. Treatment with IGF-I improves glycemic control<br />
in IDDM and reduces insulin resistance by lowering serum<br />
GH and glucagon (61, 327), and in NIDDM it prevents<br />
hyperinsulinemia (742, 1127).<br />
Over recent years, there has been increasing interest<br />
in the roles <strong>of</strong> IGF-I within the CNS. In addition to its<br />
activity on proliferation and differentiation during embryonic<br />
and postnatal development (67, 623, 876), IGF-I also<br />
promotes survival and stimulates neurite outgrowth from<br />
central and peripheral neurons in culture. Insulin-like
574 MÜLLER, LOCATELLI, AND COCCHI Volume 79<br />
growth factor I increases oligodendrocyte-induced myelin<br />
synthesis and survival (1116). Targeted disruption <strong>of</strong> the<br />
IGF-I gene results in reduced brain size, hypomyelination,<br />
and neuronal loss (82).<br />
Insulin-like growth factor I mRNA is transiently expressed<br />
in CNS areas related to long projection neurons<br />
(123, 387). The transient expression <strong>of</strong> IGF-I by projection<br />
neurons during axon growth and synaptogenesis suggests<br />
it has an important role in these processes (123). This<br />
contention is borne out by the permanent expression <strong>of</strong><br />
IGF-I and its receptors in the olfactory bulb, where neuroand<br />
synaptogenesis persist during adult life (123). Insulinlike<br />
growth factor I therefore has a pleiotropic role in the<br />
CNS essential for proliferation, differentiation, and survival<br />
in the developing brain, and in several neuropathological<br />
conditions (319), gene expression reaching its<br />
highest levels in the early phase <strong>of</strong> neuronal growth,<br />
myelination, or nerve regeneration.<br />
Concerning the factors and mechanisms involved in<br />
the regulation <strong>of</strong> CNS IGF-I gene expression, Wood et al.<br />
(1104) reported that in adult hypophysectomized rats GH<br />
given centrally or systemically could restore normal IGF-I<br />
mRNA levels. Ye et al. (1116) found that GH played a role<br />
in the regulation <strong>of</strong> brain IGF-I gene expression during<br />
development too. <strong>Growth</strong> hormone, which regulates IGF-I<br />
gene expression, may be produced in the brain (482) or<br />
from the pituitary, since GH levels in brain are reduced<br />
after hypophysectomy (483), and systemically administered<br />
GH increases brain IGF-I mRNA (1104).<br />
In addition, IGF-I might reach the brain from the<br />
periphery, since IGF-I transport across the BBB into specific<br />
thalamic and hypothalamic nuclei has been reported<br />
(881).<br />
1. Feedback actions <strong>of</strong> IGF-I<br />
It has long been known that a long-loop feedback<br />
regulation <strong>of</strong> GH secretion is operated by IGF-I. Berelowitz<br />
et al. (90) were the first to demonstrate that a purified<br />
IGF-I preparation inhibited GH release from pituitary cells<br />
in culture and stimulated dose-related release <strong>of</strong> SS from<br />
hypothalamic explants. The IGF long-loop feedback was<br />
further strengthened by the finding (1011) that intraventricular<br />
injection <strong>of</strong> a preparation containing both IGF-I<br />
and -II markedly suppressed spontaneous GH secretion in<br />
the rat. Insulin-like growth factor I receptors have been<br />
found in normal rat pituitary cells and in human GHsecreting<br />
adenomas (196). Insulin-like growth factor I has<br />
a potent and persistent inhibitory action on cultured human<br />
pituitary adenoma cells, resulting in the reduction <strong>of</strong><br />
GH release, under basal and stimulated conditions (197);<br />
it dose-dependently lowers the levels <strong>of</strong> GH mRNA (1115).<br />
It also has inhibitory action, not only on GH gene expression<br />
but also on the pituitary specific transcriptional factor<br />
GHF-I/Pit-I (973).<br />
Although in vitro data clearly demonstrated the inhibitory<br />
role <strong>of</strong> IGF-I in the pituitary, in vivo experiments<br />
in rats and humans yielded contrasting results. As mentioned<br />
above, experiments in rats indicated that IGF participate<br />
in GH regulation through a hypothalamic action.<br />
However, those experiments suffered the limitation <strong>of</strong><br />
having used a partially purified IGF preparation (1011), a<br />
point that was reexamined with the advent <strong>of</strong> recombinant<br />
IGF preparations. Separate intraventricular injection<br />
<strong>of</strong> IGF-I and -II, even at high concentrations, did not<br />
modify the pulsatile pattern <strong>of</strong> GH secretion in the rat.<br />
Only combined IGF-I and -II significantly inhibited GH<br />
secretion (454, 455). The mechanism <strong>of</strong> this interaction is<br />
still not clear.<br />
How IGF-I affects SS and GHRH mRNA levels was<br />
studied in GHRH-deprived rats. No effect was seen after<br />
systemic administration <strong>of</strong> IGF-I, whereas intraventricular<br />
IGF-I lowered GHRH mRNA and raised SS mRNA<br />
levels (924). The difference between rats and humans was<br />
not explained. In the rat, GH secretion was inhibited only<br />
after intraventricular injection, whereas in humans, it was<br />
also inhibited after peripheral administration (196). It was<br />
initially shown that an intravenous bolus injection <strong>of</strong> IGF-<br />
I immediately inhibited GH secretion, in normal and<br />
Laron dwarf patients, also reducing blood glucose (596).<br />
In normal subjects, a low-dose euglycemic infusion <strong>of</strong><br />
IGF-I rapidly suppressed the GH secretion enhanced by<br />
fasting (459) or by GHRH or hexarelin (M. Rolla, unpublished<br />
results), indicating an action most likely through<br />
IGF-I receptors and independent <strong>of</strong> its insulin-like metabolic<br />
actions.<br />
The observation that in ewes intraventricular infusions<br />
<strong>of</strong> IGF-I and IGF-II, alone or in combination, had no<br />
affect on GH secretion whereas intrapituitary infusion<br />
inhibited it (363) strongly suggests the pituitary is the<br />
main site <strong>of</strong> IGF feedback on GH. In the rat, continuous<br />
infusion <strong>of</strong> IGF-I for 3 days significantly raised SS mRNA<br />
levels in the hypothalamus <strong>of</strong> control and starved rats. In<br />
the same model, repeated doses <strong>of</strong> rhGH stimulated SS<br />
mRNA levels in control but not starved rats, indicating<br />
that IGF-I generation was necessary in the GH aut<strong>of</strong>eedback<br />
mechanisms operated through SS neurons (416).<br />
The physiological relevance <strong>of</strong> the feedback effect <strong>of</strong><br />
IGF-I on the CNS depends on its access in vivo to those<br />
areas that participate in SS and GHRH secretion. Specific<br />
binding sites for IGF-I have been found in the pituitary, in<br />
the external palisade zone <strong>of</strong> the ME, where SS nerve<br />
terminals project (122), and in other brain areas (435);<br />
IGF-I is also present in the CSF (80).<br />
By all these mechanisms IGF-I inhibits the posttranslational<br />
processing <strong>of</strong> GH and reduces GH exocytosis,<br />
antagonizing the effect <strong>of</strong> GHRH and blunting the GHreleasing<br />
actions <strong>of</strong> forskolin, cAMP, and TPA (741, 1112).<br />
The relevant IGFBP role in the effect <strong>of</strong> the peptide is now<br />
understood to be important. It is thus possible that spe-
April 1999 NEUROENDOCRINE CONTROL OF GROWTH HORMONE SECRETION 575<br />
cies differences <strong>of</strong> IGF-I’s effects on GH secretion after<br />
different routes <strong>of</strong> administration are related to different<br />
expression <strong>of</strong> IGFBP in the CNS (196).<br />
All in all, IGF-I can play an important role in the<br />
feedback control <strong>of</strong> GH by acting acutely on SS secretion<br />
which, in turn, inhibits pituitary GH secretion and in the<br />
long run by acting directly on the pituitary.<br />
VIII. CONCLUDING REMARKS<br />
The neural control <strong>of</strong> GH secretion in mammals is<br />
thought to be exerted primarily through the subtle interplay<br />
<strong>of</strong> GHRH, the physiological stimulator <strong>of</strong> GH synthesis<br />
and release and <strong>of</strong> somatotroph proliferation, and SS,<br />
which through its inhibitory influences is the principal<br />
modulator <strong>of</strong> GH release and regulator <strong>of</strong> GH pulsatility.<br />
The identification, characterization, and cloning <strong>of</strong> animal<br />
and human GHRH receptors should extend our understanding<br />
<strong>of</strong> GH regulation under different physiological<br />
and pathological conditions, leading us to use GHRH<br />
better for the therapy <strong>of</strong> pituitary dwarfism, GH deficiency<br />
<strong>of</strong> adults, and other GH deficiency states.<br />
A variety <strong>of</strong> recently cloned sstr subtypes mediate the<br />
various effects <strong>of</strong> SS and will help us correlate their<br />
regional distribution within the CNS with the peptides’<br />
functional properties. Development <strong>of</strong> subtype-selective<br />
SS agonists and antagonists may result in new therapies<br />
for the treatment <strong>of</strong> CNS and peripheral tumors and neurological<br />
disorders in which the SS system is reportedly<br />
altered. A new family <strong>of</strong> extremely effective GH releasers,<br />
the peptidyl and nonpeptidyl GH-releasing peptides,<br />
whose mechanism <strong>of</strong> action and endogenous receptor<br />
ligands have yet to be identified, nevertheless <strong>of</strong>fer therapeutic<br />
potential in a variety <strong>of</strong> hyposomatotrophic<br />
states, when given alone or in combination with GHRH.<br />
They are also posing questions about some traditional<br />
beliefs <strong>of</strong> GH regulation, adding new complexity to the<br />
understanding <strong>of</strong> how the classic brain neurotransmitters,<br />
GHRH and SS, but also an increasing cohort <strong>of</strong> GH-releasing<br />
and inhibiting neuropeptides, transduce peripheral<br />
metabolic, endocrine, and immune influences into a neuroendocrine<br />
response.<br />
We acknowledge the help <strong>of</strong> Dr. Antonello Rigamonti in the<br />
preparation <strong>of</strong> the figures and tables and <strong>of</strong> Maria Lupo for<br />
diligent secretarial assistance.<br />
Experiments carried out by the authors were supported by<br />
contributions and Special Research Project “Aging” <strong>of</strong> the Center<br />
for National Research, Rome, Italy.<br />
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