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Neuroendocrine Regulation of Growth Hormone Secretion

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 Neuroendocrine Regulation of Growth
Hormone Secretion
Frederik J. Steyn,1 Virginie Tolle,2 Chen Chen,3 and Jacques Epelbaum*2

ABSTRACT
This article reviews the main findings that emerged in the intervening years since the previous
volume on hormonal control of growth in the section on the endocrine system of the Handbook
of Physiology concerning the intra- and extrahypothalamic neuronal networks connecting growth
hormone releasing hormone (GHRH) and somatostatin hypophysiotropic neurons and the integra-
tion between regulators of food intake/metabolism and GH release. Among these findings, the
discovery of ghrelin still raises many unanswered questions. One important event was the appli-
cation of deconvolution analysis to the pulsatile patterns of GH secretion in different mammalian
species, including Man, according to gender, hormonal environment and ageing. Concerning
this last phenomenon, a great body of evidence now supports the role of an attenuation of the
GHRH/GH/Insulin-like growth factor-1 (IGF-1) axis in the control of mammalian aging. © 2016
American Physiological Society. Compr Physiol 6:687-735, 2016.

Introduction govern patterned GH release, and thus neuroendocrine control

The aim of the present article is not to recapitulate the
enormous amount of research that followed the discovery of,
the neurohormones that directly regulate GH secretion from
the pituitary. This has been fully covered in chapters 8 to 12
in the volume V on hormonal control of growth in Section 7,
the endocrine system, of the Handbook of Physiology:
Growth hormone-releasing hormone: discovery, regulation,
and actions (160), somatostatin (507), growth hormone
releasing peptides (55), feedback regulation of growth
hormone secretion (564), and the growth hormone secretory
pattern and statural growth (438). Rather, this article will
describe main findings that emerged in the intervening
years concerning the intra- and extrahypothalamic neuronal
networks connecting growth hormone releasing hormone
(GHRH) and somatostatin hypophysiotropic neurons and the
integration between regulators of food intake/metabolism
and GH release, among which the discovery of ghrelin still
raises many unanswered questions. One important event was
the application of deconvolution analysis to the pulsatile
patterns of GH secretion in different mammalian species,
including man, according to gender, hormonal environment,
and ageing. Application of mathematical models (including
deconvolution analysis) to define parameters of GH release
provides a proxy, unbiased by human interpretation, to define
key characteristics of GH release. While many observations
focus predominantly on the amount of GH release, patterning
of pulsatility largely defines the physiological actions of GH,
contributing in the tissue-specific divergence in GH action.
This patterning is largely controlled via the hypothalamus,
reflecting interactions between GH pulse generators. Proxy
measures of pulsatility (through deconvolution) are critically
important should we hope to define neuronal interactions that
of GH output.
Feedback Control of GH
The secretion of GH from the anterior pituitary gland is regu-
lated by complex homeostatic interactions, mediated by neu-
ral and peripheral influences. These regulators of GH release
define the amount of GH released during a single secre-
tory event, and the frequency at which these events occur.
This results in the pulsatile appearance of GH in circulation
(Fig. 1). The collective interactions between all endogenous
regulators of GH release contribute to interim (ultradian) and
enduring (circadian and infradian) fluctuations in the amount
and patterning of GH release. This pattern of GH release is
conserved across all mammalian species characterized to date,
although the amount and frequency of secretory events may
vary dramatically between species.
While the clearance of GH partially contributes to the
intermittent peaks and troughs in circulating GH, feedback
mechanisms largely modify GH release relative to phys-
iological demand. To understand the complex interplay
* Correspondence to jacques.epelbaum@inserm.fr
1 University of Queensland Centre for Clinical Research and the
School of Biomedical Sciences, University of Queensland, St. Lucia,
Brisbane, Queensland, Australia
2 Unité Mixte de Recherche en Santé 894 INSERM, Centre de
Psychiatrie et Neurosciences, Université Paris Descartes, Sorbonne
Paris Cité, Paris, France
3 School of Biomedical Sciences, University of Queensland, St. Lucia,
Brisbane, Queensland, Australia
Published online, April 2016 (comprehensivephysiology.com)
DOI: 10.1002/cphy.c150002
Copyright © American Physiological Society.

Volume 6, April 2016 687

Growth Hormone Axis Comprehensive Physiology

Ultradian

Infradian
Home Long-loop feedback
ostatic
Ultrashort loop Pressur
Short-loop feedback es

Peak
Peak

Trough
Trough

Trough

Hours Days/weeks/months Years Time

Figure 1 Contribution of feedback regulation to GH release. Ultrashort and short-loop feedback mech-
anisms contribute largely to the generation of a single GH secretory event, modulating output over hours.
This culminates in the ultradian pulsatile appearance of GH in circulation, defined by peaks and troughs
in GH release. In turn, long-loop feedback mechanisms contribute to the infradian regulation of secretion,
modulating peak GH release and patterning over extended periods of time. Given homeostatic pressures
(metabolic, reproductive, age associated), cross-talk between short and long-loop mechanisms (illustrated
as white double arrows) ensure physiological GH secretion. For this, long-loop feedback mechanisms will
modulate ultradian responses, whereas ultradian patterns may impact infradian feedback.

between factors that regulate the release of GH, one must first
define the nature of the various feedback mechanisms that
contribute to the regulation of GH release in general. These
interactions are varied and, given the complexities associated
with the release of GH, it is not feasible to provide a detailed
overview of all interactions that shape GH release. Rather, we
will provide an overview of the most commonly associated
feedback mechanisms thought to contribute to ultradian and
infradian patterns of GH release. To account for life-long
changes in GH release, we will first provide an overview of
mechanisms that shape ultradian GH secretory events before
extending the discussion to factors that shape infradian GH
release. While ultra short-loop feedback and short-loop feed-
back mechanisms generally shape ultradian, and long-loop
feedback mechanisms generally shape infradian GH secretion
profiles, true homeostatic control of GH release is defined by
the collective interactions of these mechanisms. In this way,
long-loop feedback pressure can define the nature of ultra
short- and short-loop feedback (and thus daily GH secretion
patterns), whereas ultrashort- and short-loop feedback
ultimately impact infradian GH secretion, and thus long-loop
feedback control of GH release. This is schematically
illustrated in Figure 1. (174, 546)
Somatostatin and GHRH are predominant factors that
regulate pulsatile GH release, and thus this section will
predominantly detail interactions between somatotrophs and
hypothalamic somatostatin and GHRH neurons (as examples
of ultrashort-loop and short-loop feedback). We extend obser-
vations to feedback effects from IGF-1 (as an example of
long-loop feedback); however, it must be noted that IGF-1 is
not the sole regulator of long-lasting changes in GH release.
Many factors that contribute to infradian GH secretion are
discussed throughout the remainder of this review. For a fur-
ther comprehensive overview of feedback mechanisms, please
consult prior reviews on this topic (174, 546), or Chapter 12
in the volume on hormonal control of growth in the section on
the endocrine system of the Handbook of Physiology (438).
The nature an interaction sites of feedback interactions spe-
cific to the GH axis are summarized in Figure 2. As illustrated
in this article, our understanding of GH feedback and mech-
anisms that define physiologically relevant GH output are
continuously evolving.
Ultrashort-loop feedback control of GH release
During ultra short-loop feedback, secretory products from
a cell feed back to the same cell to modify the function of
the cell itself. This is often referred to as “autoregulation”
or “autocrine regulation.” In this instance, pituitary soma-
totrophs respond to GH, whereas somatostatin and GHRH
neurons may respond to somatostatin and GHRH, respec-
tively. Ultrashort-loop feedback shapes somatotroph activity,
and somatostatin and GHRH neuronal activity, contributing
to ultradian patterns of GH release. In addition, long-acting
effects of ultrashort-loop feedback mechanisms may con-
tribute to infradian variations in GH release, or a derangement
in GH secretion patterning. For example, overexpression of
GH receptors (GH-R) in mice contributes to somatotroph

688 Volume 6, April 2016

Comprehensive Physiology
Figure 2 Feedback mechanisms. The release of GH from the ante-
rior pituitary gland is mediated through feedback mechanisms, act-
ing on three levels. Somatostatin and GH release is controlled through
ultrashort-loop feedback (orange arrows), whereby somatostatin and
GH modulates it own release. While ultrashort-loop feedback is pro-
posed for GHRH, evidence for this is not conclusive (illustrated by
broken line arrow). GH pulsatility is regulated by short-loop feedback
between somatostatin, GHRH and GH (blue arrows). GH acts within
the hypothalamus to stimulate somatostatin and possibly inhibit GHRH
release in the median eminence (ME; note, for GHRH neurons, com-
pelling evidence for GH feedback does not exist). Once released into
portal circulation, somatostatin travels to the pituitary gland where it
inhibits GH release, whereas GHRH stimulates GH release. In addition,
somatostatin inhibits GHRH activity, and it is thought that GHRH neu-
rons may stimulate somatostatin neuronal activity, and therefore somato-
statin release. The release of GH relative to physiological demand
is entrained through a number of peripheral factors. In this instance,
long-loop feedback (illustrated in green arrows) from insulin-like growth
factor-1 (IGF-1, produced in the liver in response to GH) results in
the suppression of GH release through the stimulation of somatostatin
release, and the inhibition of GH and GHRH release.
atrophy and hypoplasia (480, 481), and presumably a persis-
tent derangement in GH secretion pattern. To account for the
collective impact of short- and long-loop feedback effects
on the neuroendocrine control of GH release, one must first
define the nature of autocrine regulation within somatostatin
and GHRH neurons and somatotrophs.
Hypothalamic ultrashort-loop feedback: GHRH
and Somatostatin
GHRH. Initial observations showed a marked inhibition of
circulating GH following icv treatment with human pancre-
atic growth hormone-releasing factor (504) (To be consistent,
GHRH is used in this article as the sole acronym though
the neurohormone was initially known as growth-hormone-
releasing factor (GRF, GHRF), and later as somatoliberin
or somatocrinin]. This suppressive effect persisted regardless
of pretreatment with somatostatin antiserum, suggesting that
central administration of GRF inhibited GH secretion inde-
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Growth Hormone Axis
pendent of somatostatin. Presumably, this was in response
to exogenous GHRH-mediated suppression of GHRH neu-
ronal activity, reflecting the removal of GH stimulation. While
these observations were corroborated (311), demonstrating a
marked decrease in circulating levels of GH following cen-
tral administration of low dosages of GHRH (2 and 20 ng),
interpretation of the initial suppression of circulating GH fol-
lowing GHRH (505) may have been compromised by the pres-
ence of high levels of corticotrophin-releasing-factor (CRF)
in the “GRF” preparation (516). As discussed later on in
this article, CRF is a potent inhibitor of GH release, acting
peripherally and centrally (436). In light of this, it appears
that initial observations that documented the central actions
of GHRH on GH release may not involve autocrine feed-
back of GHRH to inhibit pituitary GH release. Indeed, injec-
tion of higher dosages of GHRH into the third ventricle
increase circulating levels of GH, suggesting that the per-
ceived potential positive autocrine effects of GHRH may in
fact have occurred as a consequence of exogenous GHRH
crossing the median eminence and directly interacting with
pituitary somatotrophs (311). Given historical difficulties to
define the autocrine actions of GHRH within the hypotha-
lamus, potential in vivo GHRH autoregulation requires fur-
ther validation. Moreover, current measures cannot account
for possible indirect somatostatin-mediated effects, and thus
alterations in GHRH function as a consequence of GHRH-
mediated somatostatin feedback (see somatostatin-mediated
short-loop feedback). Surprisingly, the development and char-
acterization of transgenic mice that express green fluorescent
protein (GFP) in GHRH neurons (23) has not yet heralded
studies that address autocrine regulation of GHRH activity.
Somatostatin. Compared to GHRH, potential autocrine
effects between somatostatin and somatostatin producing neu-
rons are better established. Somatostatin analogues modify
somatostatin release from isolated hypothalamic cell cultures,
suppressing somatostatin release (411). Up to 55% of somato-
statin expressing neurons in mouse hypothalamic neurons in
culture express sst1 receptors while sst2 receptor expression
amounts to roughly 40% (422) and the inhibitory autofeed-
back of somatostatin is likely to depend on sstr1 receptors
(287). Very low dosages of icv-administered somatostatin
stimulate GH release (577). Accordingly, somatostatin may
promote the release of GH by suppressing its own release.
While directly promoting the hypersecretion of GH, these
effects cannot account for somatostatin-induced suppression
of GHRH (see somatostatin and GHRH mediated short-loop
feedback).
Pituitary ultrashort-loop feedback: Growth Hormone
Somatotrophs express GH receptors (152), suggesting a
functional role for GH in mediating somatotroph-specific
GH release. Potential autocrine and paracrine effects of
IGF-1 within the pituitary gland confound functional studies
that define the autocrine effects of GH on somatotrophs.
Nonetheless, compelling evidence from isolated primary
689
Growth Hormone Axis
somatotrophs (175, 444) and GH secreting cell-lines (includ-
ing GH3 cells) (289, 444) demonstrate direct inhibitory
actions of GH on somatotrophs. In all assessed cases,
GH modulates basal GH release without altering GHRH
mediated GH secretion. These observations highlight a very
critical caveat when using cell lines and isolated primary
cells to model somatotroph interactions (289). Inevitably,
the accumulation of GH in culture will inhibit GH release,
thereby altering cell responses during prolonged incubation
periods or when changing incubation conditions. These
concerns are further highlighted by numerous in vivo studies
confirming that GH can regulate its own transcription,
translation and secretion (564). Given the complexities of
the GH axis, and the existence of numerous interacting
feedback mechanisms, the exact direct effect of GH feedback
on somatotroph specific GH release is hard to define. This is
further highlighted by diverging observations between in vitro
and in vivo measures. For example, GH does not modify
GHRH mediated GH release from isolated somatotrophs
(175, 444), whereas exogenous GH blunts the pituitary GH
response to GHRH (417). In vivo, the observed actions of
GH on GH release may occur in response to direct actions of
GH on somatotrophs, or more likely, through indirect actions
including IGF-1 or somatostatin mediated effects.
Recent advances in in vivo imaging methodologies con-
firmed that structural and not only pharmacological inter-
actions between somatotrophs might facilitate the autocrine
regulation of GH release. In the mouse, interactions between
somatotrophs are established at a very young age (embryonic
day 15.5), with clusters of somatotrophs forming a continuum
of cells during the growth of the pituitary gland (238). These
clusters are interconnected by strands of somatotrophs (53),
joined through highly specialized gap junctions that medi-
ate calcium-signaling events that facilitate network activity.
Indeed, it is thought that this arrangement may provide a sub-
stratum for long-term or sustained changes in somatotroph
network activity (294). While a comprehensive assessment of
in vivo GH output relative to somatotroph clustering is needed,
substantial changes in GH output in mice occur during peri-
ods of natural reorganization of the somatotroph network. For
example, the reorganization of the somatotroph network is
sustained following birth, and extensive clustering of soma-
totrophs in male mice occurs between 40 and 70 days of
age (452). This period of development is characterized by
the establishment of pulsatile GH secretory patterns remi-
nisce of adult male mice (503). Therefore, it is thought that
pubertal maturation of GH release, while mediated through
hypothalamic regulators, occurs in response to reorganization
of autocrine somatotroph interactions (293). This process is
facilitated by feedback from gonadal hormones, as illustrated
by the loss of organization following prepubertal castration
(53). For a comprehensive overview of network arrangements
within the pituitary gland, the relationships between soma-
totrophs, blood vessels and other endocrine cells, and potential
mechanisms of information exchange between somatotrophs,
please refer to (294).
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Comprehensive Physiology
Short-loop feedback control of GH release
Short-loop feedback is defined by regulation of hypotha-
lamic factors by pituitary hormones or other hypothalamic
hormones. For the GH axis this involves the feedback of
GH to mediate hypothalamic regulators or interactions
between hypothalamic regulators (paracrine regulation), in
this instance GHRH and somatostatin. Hallmark studies
by Brazeau and Vale (60) in Guillemin’s laboratory and
Tannenbaum and Ling (513) first demonstrated interactions
between somatostatin and GHRH. It was observed that GHRH
failed to induce the release of GH in rats when somatostatin
levels were thought to be elevated (this was confirmed by pre-
treatment with antisomatostatin antibodies) (513). From these
studies, it was proposed that somatostatin and GHRH are
released alternately. This was confirmed (415), and provided
the premise for many of the studies documenting short-loop
interactions between these key hypothalamic regulators
of pulsatile GH release.
Hypothalamic short-loop feedback: GHRH and
Somatostatin
GHRH and somatostatin are thought to act in concert to reg-
ulate the production and release of GH. As part of this feed-
back interaction, GHRH and somatostatin may also modulate
the synthesis and secretion of each other through bidirec-
tional hypothalamic interactions. Initial observations mapped
the distribution of hypophysiotropic somatostatin producing
neurons in the anterior periventricular nucleus (PevN) of
the hypothalamus (see also 507). Moreover, somatostatin-
producing neurons are also located within the dorsomedial
portion of the ARC, with axons projecting to the ventrolat-
eral portion of the nucleus (the location of GHRH neurons).
Dual labeling revealed the juxtaposition of these somato-
statin fibers with dendrites and cell bodies of GHRH neu-
rons (304). This was corroborated by subsequent studies
(219, 576). Morphological assessment of these interactions
revealed synaptic interactions with GHRH neurons (219,304),
suggesting that the physiological interactions that mediate the
pulsatile release of GH originate within the hypothalamus.
Of interest, combined retrograde tracing of somatostatin and
GHRH neurons revealed a very limited number of co-labeled
somatostatin fibers following Fluorogold injections into the
basal hypothalamus, whereas occasional GHRH fibers were
doubly labeled following Fluorogold injections to the pre-
optic anterior hypothalamic area (576). Indeed, subsequent
observations questioned interactions between somatostatin
and GHRH neurons, proposing the absence of major direct
connections between hypophysiotropic GHRH and somato-
statin neurons (146). While questioning interactions between
GHRH and somatostatin neurons, these observations further
suggest that GHRH may not exert the same direct level of
control on somatostatin neurons as somatostatin neurons do
on GHRH neurons. Indeed, other neuropeptides, including
neuropeptide Y and POMC derived ß-endorphin and α-MSH
Volume 6, April 2016
Comprehensive Physiology
(145) may indirectly facilitate GHRH-induced stimulation of
somatostatin.
In line with the respective inhibitory and stimulatory
roles of somatostatin and GHRH on GH release, one may
anticipate that somatostatin neurons inhibit GHRH activity
whereas GHRH may stimulate somatostatin neurons. Indeed,
removal of somatostatin increases GHRH message in the rat
(42), and treatment of perifused hypothalamic tissue with
somatostatin inhibits basal GHRH release (591). Conversely,
exposure to GHRH promotes somatostatin content and release
from cultured primary hypothalamic cells (118). In an effort
to better define interactions between somatostatin and GHRH
neurons, Katakami and colleagues showed that icv treatment
with hGHRH suppresses anticipated spontaneous GH pulses
(251). This suppressive effect of GHRH was prevented
following pretreatment with antisomatostatin antiserum,
indicating the presence of an inhibitory feedback system that
governs GHRH-mediated GH release. Subsequent observa-
tions confirmed that icv treatment with GHRH induced a
significant rise in portal plasma concentrations of somato-
statin and a rise in somatostatin production rate (351). In line
with this, isolation of somatostatin neurons from feedback
from GHRH neurons [through lesion of the arcuate nucleus
(ArcN)] resulted in an overall decrease in somatostatin tone,
and a decrease in somatostatin content within the median
eminence (454). This was further corroborated by a decrease
in somatostatin content in the median eminence following
immunoneutralization of GHRH neurons with anti-GHRH
antibodies (118). While providing convincing evidence to
demonstrate a clear relationship between somatostatin and
GHRH in mediating GH release, the true physiological
interactions between these factors need careful validation.
For example, within sheep withdrawal of somatostatin does
not necessarily precede GH pulses (75,525), and somatostatin
release may rise or remain unchanged immediately prior to
a rise in circulating levels of GH (75). Derangements in the
proposed relationship between somatostatin, GHRH and GH
may reflect the complexity of interplay between other key
regulators. Similar arguments against the existence of a sim-
plified feedback interaction between these factors are seen in
other species, including the rat (296). For the purpose of this
section, the majority of factors that modify GH release, and
neuronal populations that contribute to the central regulation
of GH release were largely ignored. This allows an opportu-
nity to describe feedback interactions between somatostatin,
GHRH and GH; factors deemed as principal regulators of
GH release. Other regulators of GH release are discussed
throughout the remainder of this article and can also be found
in chapter 11 from Handbook of Physiology Section 7, the
endocrine system, vol V Hormonal control of growth (564).
Pituitary short-loop feedback: Growth Hormone
Growth hormone receptors are distributed throughout the
hypothalamus, with mRNA expression detected within the
arcuate nucleus, PevN, supraoptic nucleus, the ventrolateral
Volume 6, April 2016
Growth Hormone Axis
region of the ventromedial nucleus and the paraventricu-
lar nucleus (38, 70, 348). Moreover, hypophysiotropic PevN
somatostatin neurons express GH receptors (68, 349). This
provides a structural premise for the potential regulation of
GHRH and somatostatin release by GH. While the mecha-
nisms that accounts for transport of GH into the brain remains
unclear, peripheral GH does cross the blood brain barrier (399)
supporting potential direct regulatory effects.
While it is thought that feedback between GH and its prin-
cipal hypothalamic regulators may largely contribute to the
autoregulation of GH release, functional measures of activa-
tion of somatostatin and GHRH neurons following GH admin-
istration suggest otherwise. Indeed, GH may only impact a
small subset of somatostatin and GHRH expressing neurons.
For example, rGH injections in the rat contributes to less than
11% of activation of GHRH neurons and only 5% activa-
tion of somatostatin neurons as measured by cFos expression
(69). As detailed later, this limited interaction may be suffi-
cient to modulate the output of GH relative to physiological
demand; however, it is important to note that other regula-
tors of GH release may facilitate hypothalamic GH feedback.
For example, the majority of arcuate neuropeptide-Y (NPY)
expressing neurons in the rat coexpress the GH receptors
(82,349), while icv administration of NPY inhibit GH release
(429), presumably through promoting somatostatin release
(349). Short-loop feedback interactions specific to hypotha-
lamic somatostatin and GHRH release that account for the
pulsatile release of GH from the anterior pituitary gland are
summarized in Figure 3.
Elevated GH concentrations are associated with a decrease
in hypothalamic GHRH mRNA expression (43, 91, 116, 117);
however, this may not contribute to altered GHRH release.
For example, an elevation in endogenous GH tone is asso-
ciated with a decrease (39, 318) or no change (245) in
hypothalamic GHRH content, while GH treatment increases
hypothalamic GHRH content (296, 343). GH deficiency is
associated with a reduction in hypothalamic GHRH content
(164, 253, 337), and this reduction in GHRH content is par-
tially reversed following GH treatment (164,253). It should be
noted, that while an increase in GHRH content and decrease in
GHRH mRNA is consistent with an inhibition of GH release,
hypothalamic GHRH content likely reflect the net difference
between GHRH synthesis and release. Therefore, observa-
tions that contrast hypothalamic GH content with peripheral
GH release, but that do not provide measures of synthesis
and release of GHRH must be cautiously interpreted. More-
over, the effects of GH on GHRH mRNA or content vary
relative to age and gender. In aged rats (20 months old),
treatment with GH does not suppress hypothalamic GHRH
mRNA expression (117), whereas the negative effects of GH
on GHRH content in female rats is greatly diminished (318).
The lack of consistent changes in altered GHRH output rela-
tive to GH suggests that feedback between GH and somato-
statin, and consequential changes in somatostatin release may
more likely underpin hypothalamic events (including GHRH
content and release) that regulate episodic GH release, and
691
Growth Hormone Axis Comprehensive Physiology

Figure 3 Interactions between somatostatin and GHRH that account for the pulsatile pattern of GH secretion. Comprehensive in vivo and in vitro
assessment of the production and release of GH has resulted in the evolution of theory of peripheral and centrally mediated mechanisms that
modulate the pulsatile release of GH. Periods of prevailing low levels of circulating GH (1) are associated with reduced somatostatin release into
pituitary portal vasculature (2). The withdrawal of somatostatin inhibition of GHRH neurons (3) and somatotrophs (3) culminates in the release
of GHRH into pituitary portal vasculature (4), and the stimulation of GH release (5). Periods of prevailing elevated levels of circulating GH (6)
are associated with the activation of somatostatin-expressing neurons (7) and inactivation of GHRH-expressing neurons (7). The resulting rise in
somatostatin activity contributes to the direct inhibition of GHRH-neuronal activity (8) and the release of somatostatin into portal vasculature (8), cul-
minating in reduced somatotroph activity (9) and the cessation of the release of GH into peripheral circulation (10). Complex interactions between
central, pituitary and peripheral factors may disrupt these hypothalamic interactions, resulting in physiologically relevant GH release. Colored
arrows indicate selective activation of mechanisms coupled with prevailing low/basal (left schematic) or elevated/peak (right schematic) levels
of peripheral circulating GH. Green arrows indicate stimulatory pathways. Orange arrows indicate inhibitory pathways. Additional abbrevia-
tions: GHR, growth hormone receptor; SRIF-R, somatostatin receptor; GHRH-R, growth hormone releasing hormone receptor; PevN, periventricular
nucleus; ArcN, arcuate nucleus; PG, pituitary gland.

may be dependent on other factors that modulate GH release
relative to age and reproductive function.
As with GHRH, reported effects of GH in modulating
hypothalamic somatostatin mRNA and protein content and
release varies considerably. This is underpinned by the
potential for other factors to modulate somatostatin activity,
a shift in the timing between GH signaling and somatostatin
transcription and release, and the heterogeneous nature of
somatostatin assessment. Nonetheless, the bulk of observa-
tions suggest that GH stimulates somatostatin release. To this
extent, a reduction in endogenous circulating GH levels result
in an increase in hypothalamic somatostatin content (39,246),
whereas exogenous GH treatment results in an increase in
hypothalamic somatostatin content (343). While a persistent
decrease in circulating GH levels contributes to a reduction
in hypothalamic somatostatin mRNA expression (43),
somatostatin mRNA expression may not accurately reflect
altered somatostatin or GH release at that time. For example,
the immediate cessation of pulsatile GH release in mice
following food withdrawal is associated with an initial rise

692 Volume 6, April 2016

Comprehensive Physiology
in somatostatin mRNA expression within the arcuate/PevN
complex, whereas somatostatin mRNA expression is greatly
diminished following an extended period of suppressed
GH release (487). This biphasic response in somatostatin
mRNA expression likely reflects the role of somatostatin in
suppressing GH release in fasting rodents (509), whereas the
subsequent reduction in somatostatin mRNA content occurs
in response to diminished feedback from GH needed to sus-
tain somatostatin activity (as discussed earlier). The in vitro
assessment of hypothalamic somatostatin release in response
to GH treatment confirms this feedback relationship, wherein
GH exposure stimulates hypothalamic somatostatin content
and release (5, 39, 117, 206, 353, 472). Indeed, it is thought
that somatostatin is the primary feedback mechanisms for the
rhythmic release of GH in rodents (558). For this notion to
be correct, one must however assume that rhythmical activity
from GHRH neurons exist independent of feedback from GH
(558), a premise not entirely confirmed as yet.
Long-loop feedback control of GH release
A large number of peripheral factors impact GH secretion,
ensuring the entrainment of GH release relative to physio-
logical demand. While contributing to the patterned release
of GH, these factors generally modify the production and
release of GH over weeks, months, and years. In this regard,
long-loop feedback within the GH axis is defined by the reg-
ulation of other hormones or molecules that are secreted from
extrahypothalamic or pituitary sites. For the purpose of this
section, we will only discuss the role of IGF-1 in regulat-
ing GH release, however numerous other factors participate
in this process. These are discussed in detail throughout the
remainder of this article. It is important to note that long-
loop regulators of GH release may not interact with all pri-
mary components of the hypothalamic/GH axis, and therefore
may solely impact somatostatin, GHRH, and/or somatotroph
activity. Regardless, the actions of IGF-1 on GH release are
inhibitory, and generally reflected by observed inhibitory
effects of IGF-1 on somatotrophs and GHRH neurons,
and stimulatory effects of IGF-1 on somatostatin neurons
(Fig. 2).
IGF-1 is expressed within the pituitary gland (137). Thus,
while more commonly considered an endocrine regulator of
GH release, IGF-1 may act in a paracrine fashion to regulate
GH release. The role of IGF-1 as a paracrine regulator of GH
release will not be discussed here. Rather, this section will
focus on established interactions between liver-derived IGF-
1 and primary components of the GH axis; somatotrophs and
somatostatin or GHRH releasing neurons.
IGF-1 treatment inhibits GH gene transcription, GH
mRNA expression and GH release from isolated somatotrophs
(357, 590). In vivo, selective deletion of IGF-1 receptor (IGF-
1R) expression on somatotrophs results in an overall rise in
circulating levels of GH (162). The nature of this change in GH
pulsatility remains undefined, as current measures are limited
Volume 6, April 2016
Growth Hormone Axis
to single one off samples (162) or extrapolation of pulsatility
by rank-plot analysis (163). Regardless, these observations
agree with initial observations demonstrating a direct rela-
tionship between the abundance of IGF-1R on somatotrophs
and GH release (587), and the attenuation of GH release in
response to IGF-1 (587).
While the actions of IGF-1 within the pituitary gland are
well defined, the role of IGF-1 in regulating both hypotha-
lamic somatostatin and GHRH action remains somewhat
unresolved. The IGF-1 receptor is abundantly expressed
throughout the hypothalamus, including the ArcN, dorsal and
ventromedial nuclei of the hypothalamus, and the median
eminence (573). It thus seems likely that IGF-1 will inter-
act on different levels to modulate GH release. Intracere-
broventricular administration of IGF-1 in rats results in a
decrease in GH pulse amplitude (1, 511), an increase in
hypothalamic somatostatin mRNA expression, and a decrease
in hypothalamic GHRH mRNA expression (453). By contrast,
peripheral injections of IGF-1 in the GH deficient dwarf rat
do not impact hypothalamic somatostatin or GHRH mRNA
expression (453). This suggests divergent and independent
actions of IGF-1 on hypothalamic and pituitary mediated
GH release. Periodic GH pulse frequency is largely depen-
dent on GHRH release (159, 237, 415), and thus the observed
reduction in GH pulse frequency following sustained IGF-1
infusion in humans is potentially due to an attenuation of
GHRH secretion. This is in line with the suppression of
GHRH synthesis and secretion in rat hypothalamic tissue fol-
lowing IGF-1 treatment (473), and in rats in vivo following
icv IGF-1 treatment (453). Given the magnitude of the sup-
pressive effects of IGF-1 infusion on pulsatile GH release
in humans, it is unlikely that this diminished release of GH
occurs solely in response to altered GHRH feedback. Indeed,
initial observations demonstrated a stimulatory role for IGF-1
(termed somatomedin-C at the time) on hypothalamic somato-
statin release, wherein purified somatomedin-C (218) pro-
moted the dose-dependent release of somatostatin from intact
rat hypothalamic tissue (40). Subsequent observations con-
firmed that continuous infusion of IGF-1 in fed and fasting
males inhibited pulsatile GH release, primarily through the
reduction of spontaneous GH pulse amplitude and pulse fre-
quency (41). Moreover, IGF-1 infusion attenuated GHRH-
induced GH release, suggesting that IGF-1 may promote
somatostatin release to inhibit GH secretion. While describing
a simple feedback mechanism whereby IGF-1 modulates GH
release, these observations highlighted the complex nature
through which IGF-1 is thought to modulate hypothalamic
and pituitary control of GH release (Fig. 2).
Central Regulation of GH Secretion
Many neurotransmitters and neuropeptides modulate the
activity of the GH/IGF-1 axis by interacting with GHRH and
somatostatin or by directly acting at the level of the soma-
totroph to modify GH release. This has been extensively
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Growth Hormone Axis
reviewed elsewhere (174, 326, 536) and only the most vali-
dated ones are described herein.
Neuromodulators
Monoamines [Dopamine (DA), Norepinephrine (NE), Sero-
tonin] are of considerable importance in the neural reg-
ulation of GH secretion. The high concentration of these
monoamines in the hypothalamus, particularly in the median
eminence, suggests that monoamines have important regula-
tory functions for the release of the hypothalamic hypophys-
iotropic hormones. Here we provide a general overview of
the role of monoamines in the regulation of GH output,
focusing selectively on catecholamines, serotonin, and acetyl-
choline (Fig. 4). For a comprehensive overview of the role
of monoamines in regulating GH output, please refer to
(133, 174, 327, 362, 536).
Catecholamines
The role of catecholamines in the regulation of GH secretion
has been extensively investigated since the observation that
GH secretion was inhibited in animals treated with an inhibitor
of tyrosine hydroxylase biosynthesis (130).
Figure 4 Hypothalamic control—neuromodulators. The control of
GH release from somatostatin and GHRH-expressing neurons is medi-
ated through interactions with hypothalamic neuromodulators. In this
instance, dopamine (DA) and adrenaline [acting through selective
activation of the α1-receptor subtype (α1-R)] stimulates somatostatin-
neuronal activity, thereby inhibiting GH release. Adrenaline [acting
through selective activation of the α2-receptor subtype (α2-R)], serotonin
(5-HT), and acetylcholine (Ach) stimulate GH release, through inhibi-
tion of somatostatin-expressing neurons. By comparison, activation of
GHRH-expressing neuronal activity by adrenaline (acting through selec-
tive activation of the α2-R) and 5-HT results in increased GH output. In
turn, acting through select activation of the β2-receptor subtype (β2-R),
adrenaline inhibits GH release by inhibiting GHRH-neuronal activity.
Stimulatory interactions are highlighted in green arrows. Inhibitory inter-
actions are highlighted in orange arrows. Additional abbreviations:
ME, median eminence.
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Comprehensive Physiology
L-DOPA (L-3,4-dihydroxyphenylalanine). In primates,
catecholamines stimulate GH secretion. Indeed, oral admin-
istration of L-DOPA, the precursor of both NE and DA,
causes release of GH in humans (56). Evidence for nora-
drenergic control is derived from experiments showing that
L-DOPA-induced GH release is blocked by phentolamine, an
α-adrenergic blocking agent (247). In addition, clonidine, a
central α-agonist, promotes GH release in men (284). GH is
also released in men by subemetic doses of apomorphine, a
centrally active dopaminergic stimulator (64). This does not
seem to be a stress response, as it is not accompanied by a rise
in plasma cortisol (64, 283). Both L-DOPA-induced (347)
and apomorphine-induced (136) GH release are attenuated
by prior glucose administration, which indicates that glucore-
ceptor stimulation can partially override catecholaminergic
stimuli for GH release.
Dopamine. The specific involvement of dopamine in the
regulation of GH secretion is not clearly demonstrated. Its
action seems to be mediated in the pituitary gland rather than
in the hypothalamus. Indeed, dopamine or a D1-R agonist
induces a transitory increase in GH release both in vitro from
pituitary cells in culture and in vivo after destruction of the
mediobasal hypothalamus (49). In contrast, dopamine would
rather exert an inhibitory effect in the hypothalamus since
it stimulates somatostatin release by hypothalamic explants
(49).
Adrenaline and noradrenaline. Both adrenaline and nora-
drenaline play a major role in the regulation of GH secretion
under the stimulatory control of α2-adrenergic receptors
and inhibitory control of α1- and β-adrenergic receptors.
α2-Adrenergic agonists, such as clonidine, stimulate GH
secretion in both humans (49) and rats (49, 130, 446) and
α2-adrenergic antagonist, yohimbine, blocks the increase
in GH induced by clonidine. In contrast, methoxamine, an
α1-adrenergic agonist, reduces the amplitude of GH secretory
peaks in the rat (47) and isoproterenol, a β-adrenergic agonist,
inhibits GHRH-induced GH secretion (279).
Evidence from intravenous administrations of pharma-
cological agents to urethane-anesthetized rats suggests that
β-receptors are important in the regulation of GH release
(255). Intravenous administration of chlorpromazine elic-
its GH release, an effect that is blocked by propranolol.
The chlorpromazine response is attenuated by hypothalamic
lesions and by posterior hypothalamic cuts, suggesting that
neural inputs to the hypothalamus are important for the medi-
ation of monoaminergic GH response in rodent species (254).
There is little evidence suggesting that monoamines reg-
ulate GH secretion directly at the pituitary level. Rather,
monoamines may function as neurotransmitters in the relay
of these responses to GHRH and somatostatin neurons. α2-
adrenergic receptor agonists may act via stimulation of GHRH
release. Indeed, clonidine stimulates GHRH release from per-
ifused rat hypothalamic explants (241) and is not able to
stimulate GH secretion in rats treated with an anti-GHRH
antibody (344). In addition, clonidine would act by inhibiting
somatostatin since it potentiates GHRH-induced GH response
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Comprehensive Physiology
in rats in conditions of elevated somatostatin tone (299, 300)
as well as in humans (127). α1/β-adrenergic receptor ago-
nists would regulate GH secretion by modulating somatostatin
release. Immunoneutralization of somatostatin in young rats
completely prevents GH secretion induced by methoxamine,
an α1-adrenergic receptor agonist. In addition, in both rats
and humans, GH response to GHRH is potentiated by pro-
pranolol, a β-adrenergic receptor antagonist (258) that can
inhibit somatostatin release in vitro (433). In contrast, a β2-
adrenergic receptor agonist, isoproterenol, suppresses GH
response to GHRH, and its GH-inhibiting effect is blocked
by an antisomatostatin antibody (279). These data demon-
strate that inhibition of GH secretion induced by α1- and
β-adrenergic receptors are partly mediated by an increase in
the somatostatin endogenous tone (433).
Serotonin
In the rat, icv administration of serotonin increases plasma GH
concentrations (556) whereas inhibitors of serotonin synthesis
or serotonin receptors antagonists reduce plasma GH concen-
trations. Serotonin has no effect in the pituitary gland (256)
but modulation of hypothalamic somatostatin and GHRH
release is suggested by the presence of serotoninergic fibers
in PevN and ArcN nuclei. Indeed, serotonin inhibits somato-
statin release in vitro from perifused rat hypothalamic explants
(432) and in vivo, the serotonin-induced GH increase is sup-
pressed by an anti-GHRH antibody (365).
Oral administration of L-Tryptophan or 5-
hydroxytryptophan (5-HTP) in men causes a mild GH
release (229). In addition, the GH response to hypoglycemia
is blocked by the serotonin antagonists methysergide and
cyproheptadine (46, 475). Administration of 5-HTP is also
effective in causing GH release in the Rhesus monkey. The
effect of serotonin is observed in all species tested, indicating
a consistent interspecies effect.
Acetylcholine
Acetylcholine plays an important role in the central control
of GH secretion in humans (73) as well as in animals (65).
Muscarinic cholinergic agonists stimulate basal GH secre-
tion and potentiate GH response to GHRH. Conversely, mus-
carinic antagonists inhibit spontaneous GH secretion and GH
response to GHRH (308, 327). A direct action on the pitu-
itary is not likely (308) while, at the hypothalamic level,
acetylcholine acts by blocking hypothalamic somatostatin
release rather than by stimulating GHRH release. Indeed,
somatostatin release from hypothalamus in culture is inhib-
ited by acetylcholine or neostigmine, a cholinergic agonist
(431). In addition, in animals depleted from somatostatin
by cysteamine or an antisomatostatin antibody, acetylcholine
has no effect (308). In contrast, immunoneutralization of
GHRH by a GHRH-specific antibody does not prevent GH
release induced by pyridostigmine, an inhibitor of acetyl-
choline esterase (566).
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Growth Hormone Axis
Neuropeptides
Neuropeptide Y
Neuropeptide-Y is a 36 amino-acid peptide (520) that belongs
to the family of pancreatic polypeptides. Hypothalamic neu-
rons expressing NPY are mostly present within the arcuate,
paraventricular, and the periventricular nuclei (113) (Fig. 5).
GH release is considerably diminished following central NPY
treatment (76, 192), with chronic administration of NPY into
the lateral ventricle contributing to a reduction in circulating
levels of GH (413) and IGF-1 (425). Central administration of
NPY also silences the pulsatile release of GH. This effect is
Figure 5 Intrahypothalamic interactions—neuropeptides. Complex
intrahypothalamic interactions control the activity of somatostatin-
expressing and GHRH-expressing neurons, thereby regulating the
pulsatile release of GH. Corticotrophin releasing hormone (CRH)-
expressing neurons within the paraventricular nucleus (PvN) stimu-
late somatostatin activity, thereby inhibiting GH release. This is mod-
ulated through activation of CRH-expressing neurons by neuropeptide-
Y (NPY)-expressing neurons within the arcuate nucleus (ArcN), acting
through the Y-1 (Y1-R) and Y-2 (Y2-R) receptor subtypes. CRH activity
is further modulated through activation of the melanocortin receptor
subtype-4 (MC4-R). NPY-expressing neurons further inhibit GH release
through activation of somatostatin-expressing neurons. Of interest, NPY-
expressing neurons may indirectly promote the release of GH through
the activation of pro-opiomelanocortin (POMC)-expressing neurons,
which inhibits somatostatin-expressing neuronal activity. This control
of GH release is further modulated through the stimulation of NPY-
expressing neurons by somatostatin (within the ArcN), and through
activation of GHRH expressing neurons by low levels of somatostatin.
Stimulatory interactions are highlighted in green arrows. Inhibitory
interactions are highlighted in orange arrows. Additional abbrevia-
tions: ME, median eminence; SST1, somatostatin receptor subtype-1,
SST2, somatostatin receptor subtype-2; SST3, somatostatin receptor
subtype-3; SST5, somatostatin receptor subtype-5; Y1-R, Neuropeptide-
Y specific receptor subtype-1; Y2-R, neuropeptide-Y specific receptor
subtype-2; GAL-R1, galanin receptor subtype-1; GAL-R2, galanin recep-
tor subtype-2; MC3R, melanocortin receptor subtype-3.
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Growth Hormone Axis
abolished by anterolateral deafferentation of the medial basal
hypothalamus, a procedure that disrupts the somatostatiner-
gic input to the MBH (349), suggesting that NPY selectively
modulates hypothalamic regulators that prime the periodic
release of GH through interactions with hypophysiotropic
PevN somatostatin neurons. Of interest, central injection of
NPY to specifically target neuronal populations within the
ArcN and PevN inhibit GH release, whereas similar injec-
tions of IGF-1 do not alter GH output (349). To this extent,
NPY activation may trump IGF-1 as a key regulator of cen-
trally mediated GH feedback. Indeed, the vast majority (95%)
of NPY neurons within the ArcN express GH receptors (244),
exceeding the observed abundance of GH receptors on arcuate
GHRH (70,82) and somatostatin expressing neurons (68). For
NPY, expression of the GH receptors is restricted to the ArcN
(84). GH is thought to only act on select hypothalamic somato-
statin and GHRH neurons. Initial reports demonstrated that
GH treatment activated 11% of GHRH neurons and 5% of
hypothalamic ArcN somatostatin neurons (69). Subsequent
observations demonstrated that GH administration induced
cFos expression in only 60% of PeVN somatostatin express-
ing neurons, whereas cFos expression did not overlap with
distribution of GHRH neurons in the arcuate nucleus (349).
By comparison, GH treatment induced cFos expression in
65% of NPY expressing neurons within the ArcN (349), sug-
gesting that the NPY system may indeed be a critical inter-
mediate in the regulation of GHRH activity in response to
prevailing changes in circulating levels of GH, and thus GH
feedback. While the expression of cFos illustrates activation
of NPY under these conditions, it should be noted that cFos
expression does not accurately reflect direct interaction with
NPY neurons, and thus current observations cannot exclude
the role of possible intermediates that couple somatostatin
or GHRH neurons with NPY neurons. Regardless, available
data suggest that this may represent a fundamental mechanism
whereby the output of GH to meet physiological demand is
coupled to changes in food intake and nutrient availability
(485).
In the rat, NPY fibers originating within the ArcN
project through the PevN where they surround somatostatin
expressing neurons (204). This is corroborated in the sheep
(528) and in the mouse (225), further validating direct
interactions between NPY and somatostatin neurons through
synaptic structures. In the mouse, overnight fasting results
in the suppression of pulsatile GH release, occurring almost
immediately following the withdrawal of food. This occurs
alongside an initial elevation in somatostatin and NPY
mRNA expression within the ArcN/PevN complex (487),
suggesting a potential functional role of NPY in mediating the
suppression of GH release following food withdrawal (486).
Indeed, germline deletion of NPY in mice does not impact
pulsatile GH release under ad libitum fed conditions, whereas
loss of NPY signaling recovers the suppression of pulsatile
GH release normally observed in fasting (225). Considering
well-established species differences wherein food restriction
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Comprehensive Physiology
tends to increase (i.e., humans and sheep) or decrease the pul-
satile release of GH (i.e., rats and mice), in spite of apparently
similar neuroanatomical wiring, the nature of the interaction
between NPY and hypothalamic regulators of GH release
to account for differential effects on GH output remains
completely unexplored.
The actions of NPY are mediated via a family of high
affinity receptors (407), including Y1R, Y2R, Y4R, Y5R, and
in mice and rabbits, the Y6R receptor (142, 199). It is gener-
ally assumed that the postsynaptic Y1R regulates food intake
(257), whereas the Y2R inhibits the synthesis and release
of NPY (62). Central administration of an Y1R agonist
suppresses circulating levels of GH in the rat (496), whereas
germline deletion of Y1R in mice (Y1R−/− mice) recovers
fasting GH release as is seen in NPY−/− mice. Moreover,
GH release in Y1R−/− mice during the ad libitum fed state
remains unchanged (225). While suggesting that the Y1R acts
as an intermediate between NPY and somatostatin expressing
neurons, verification of Y1R expression on somatostatin
neurons is yet to be confirmed. The Y1R is widely expressed
within the periventricular and paraventricular nuclei (266),
areas characterized by the abundant expression of somato-
statin mRNA (503), and thus this seems likely. The Y1R com-
monly signals via inhibitory G (Gi) protein-signaling path-
ways, and therefore is anticipated to inactivate somatostatin-
expressing neurons. This contradicts the perceived actions
of the Y1R on somatostatin mediated GH output in Y1R–/–
mice. Therefore, should the Y1R promote somatostatin
release, interactions via the Y1R may occur indirectly through
the inactivation of other neuronal intermediates, or through
interactions that counter the traditional role of the Y1R. For
the latter, Y1R mediated activation of neuronal function can
occur via non-Gi mediated processed (99).
As with the Y1R, selective antagonists for Y2R (porcine
NPY 13-36 and Porcine NPY 3-36) inhibit GH secretion
(496). Surprisingly, unlike the Y1R, germline loss of the Y2R
does not recover GH release in fasting mice, whereas fast-
ing reduces pituitary GH immunoreactivity in wild-type but
not Y2R−/− mice (301). This suggests that the Y2R partic-
ipates in GHRH mediated GH release, or GHRH mediated
GH production. Indeed, assessment of pulsatile GH release
in ad libitum fed Y2R−/− mice revealed a significant decline
in peak GH release, a derangement in pulse frequency and
irregularity, and a reduction in body length (225). Moreover,
GHRH neurons express the Y2R (301), whereas antagonism
of the Y2R increases electrical activity of GHRH neurons in
mice (393). It remains unclear whether Y2R-mediated actions
on GH release occur independent of somatostatin expressing
neurons. NPY neurons do not participate in the regulation of
GH pulsatility under fed conditions (225), and thus the Y2R
may contribute to GH release independent of NPY, acting
via other factors including PYY. Alternatively, as the Y2R
inhibits NPY release (62, 87), and deletion of Y2R increases
hypothalamic NPY mRNA expression (448), loss of Y2R sig-
naling in mice may have simply altered the role of NPY in
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Comprehensive Physiology
mediating GH feedback, thereby impairing GH release. As
with the Y1R, this system remains unexplored, and substan-
tive evidence is needed before a complete understanding of
the role of NPY, Y1R, and Y2R in the production and release
of GH can be substantiated.
Compared to Y1R and Y2R, the role of Y4, Y5, and Y6
receptors in regulating GH release is almost completely unex-
plored. The Y4R subtype (also known as PPYR1) has a greater
binding affinity for pancreatic polypeptide (199), and thus
may interact with the GH axis independent of NPY. Whilst
Y4R deficient mice (Y4R−/− mice) have a lean phenotype,
recent observations suggest that these receptors likely con-
trol gonadotropin releasing hormone (GnRH) activity (448),
establishing a premise for the regulation of other hypotha-
lamic neuronal populations. Loss of Y4R signaling in mice
contributes to suppressed pituitary GH content in fasting, sug-
gesting that the Y4R may to some extent directly control GH
release (301). By comparison, Y1 and Y5 receptor subtypes
may act in concert to regulate food intake (129), and thus the
actions of the Y5R in mediating GH release may be synergis-
tic to that of the Y1R. Vasoactive intestinal peptide express-
ing neurons in the suprachiasmatic nucleus may participate
in the regulation of GHRH activity, an effect that may be
through Y6R (594). Germline deletion of Y6R in mice results
in low levels of hypothalamic GHRH mRNA expression and
reduced circulating levels of IGF-1 (594). This suggests that
loss of Y6R expression impairs GH output, and provide com-
pelling evidence to suggest that Y6R in mice may predict
GH release relative to physiological demand. While we are
yet to establish the functional roles of NPY and Y-receptors
in all mammalian species, it is entirely likely that the NPY
systems acts as a critical intermediate between GH output and
physiological demand.
Galanin
Galanin is a 29 amino-acid peptide purified in 1983 from pig
intestine (208,521). At the level of the central nervous system,
galanin is present in majority at the level of the hypothalamus,
in the ventrolateral portion of the median preoptic area as well
as in the paraventricular nucleus, supraoptic, dorsomedial and
arcuate nuclei (305, 336, 340, 458). At the level of the ArcN,
galanin is expressed in a subpopulation of GHRH neurons
(380) (Fig. 5).
Three different receptor subtypes for galanin have been
identified: GAL-R1, GAL-R2 and GAL-R3 (67, 276). They
are 7 transmembrane-domain receptors and present homolo-
gies with GPR54 (295). Binding sites are concentrated in the
median eminence and hypothalamus (57, 333, 338). Galanin
immunoreactive fibers are detected in the median eminence
(14, 397) suggesting that galanin may exert a direct effect on
somatotrophs. A stimulatory effect has been reported in vitro
(302,455) but not in all studies (226,394). This effect could be
relayed through GAL-R2, which is expressed in the pituitary
gland (583).
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Growth Hormone Axis
The action of galanin on GH secretion is thought to occur
predominantly within in the central nervous system. Indeed,
in the rat, galanin stimulates GH secretion after iv or icv
administration but the effect is stronger after central injec-
tions (367,394). In addition, immunoneutralization of galanin
in the central nervous system or administration of a GAL-R1
antagonist decreases both GH peak amplitude and frequency
(161, 319), suggesting that the endogenous peptide partici-
pates in the regulation of GH rhythmic secretion via activation
of GAL-R1.
The effect of galanin may be partly due to an increase
in GHRH release. Indeed, in vitro, galanin is able to induce
GHRH release from hypothalamic explants or slices (4, 267).
In vivo, passive immunoneutralization with an anti-GHRH
antibody abolishes galanin-induced GH release (366, 367).
It remains to be determined whether this effect is direct or
indirect as GAL-R1 is modestly expressed on arcuate GHRH
neurons compared to its expression in PeN somatostatin neu-
rons; 35% of somatostatin neurons in the PeN contain galanin
receptors mRNA and 5% of GHRH neurons in the Arc contain
galanin receptors mRNA using double-label in situ hybridiza-
tion (83). Galanin-induced GH secretion seems to also involve
somatostatin: galanin-induced GH secretion is blocked by
administration of an antisomatostatin antibody (518). A direct
effect of the peptide on somatostatin neurons is possible since
galanin immunoreactive axonal fibers, arising from the ArcN
(146) are closely apposed to somatostatin cell body’s in the
PevN (305) that express GAL-R1 (83).
Neurotransmitters could also be involved in mediating
galanin effects on GH secretion. Anatomical interactions exist
between galanin and several hypothalamic neurotransmitters,
such as catecholamine or γ-Aminobutyric acid (GABA), and
catecholaminergic and GABA antagonists suppress galanin-
induced GH release (338).
Proopiomelanocortin-derived peptides
Proopiomelanocortin is a prohormone cleaved into sev-
eral peptides that are biologically active: melanotropins
(α-, β-, and γ-MSH), endorphins (α-, β-, and γ-endorphins),
adrenocorticotropic hormone (ACTH) and corticotrophin-
like-intermediate lobe peptide (CLIP). The last two are mainly
synthesized in corticotroph cells and melanotroph cells of the
pituitary gland, as well as in the gastrointestinal tract. In the
central nervous system, proopiomelanocortin (POMC) neu-
rons are localized in the ArcN of the hypothalamus (Fig. 5)
and in the nucleus of the solitary tract (NTS) (532). The dif-
ferent endorphin peptides bind four different opiate receptors
(μ, κ, δ, and γ), closely related to somatostatin receptors.
Opiate receptors mRNA (by in situ hybridization) or binding
sites (by radioautography) and receptor proteins (by immuno-
histochemistry) distributions vary depending on the receptor
subtype. Whereas μ and k receptors are largely distributed, the
∂ subtype is limited to a few brain areas (including the ven-
tromedial hypothalamus). In most hypothalamic nuclei and
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Growth Hormone Axis
median eminence, a high density of κ receptors is observed,
μ and k receptors being even more expressed in the medial
preoptic area (321, 322, 358).
In the rat, iv administration of POMC-derived peptides
like α-MSH (489), β-endorphin (437), and other opiate pep-
tide such as met-enkephalin (66) induces an increase in
plasma GH levels. Accordingly, female melanocortin-3 recep-
tor (MC3R) knockout (MC3R−/−) and melanocortin-4 recep-
tor (MC4R) knockout (MC4R−/−) mice exhibit a dimin-
ished responsiveness to the GH-releasing effects of ghrelin
(471). However, the role of the melanocortins in the con-
trol of ultradian GH secretion remains controversial. Block-
ade of melanocortin receptors by the nonselective antago-
nist, SHU9119, does not modify the activity of the soma-
totropic axis (424). Moreover, in Man, obesity due to MC4R
deficiency is associated with increased linear growth and
final height, fasting hyperinsulinemia, and incompletely sup-
pressed growth hormone secretion (328). Concerning opioid-
POMC-derived peptides, Naloxone, a μ receptor antagonist,
decreases circulating GH (66) or it does not alter parame-
ters of GH secretion (515, 559). Despite high concentrations
of ß-endorphin in the portal blood (306), opioid peptides do
not act directly on the somatotroph cell (437) but may rather
act through modulation of GHRH and somatostatin neurons.
GH response to an administration of opiates is consider-
ably reduced after selective destruction of GHRH neurons
in the ArcN by monosodium glutamate (13) or immunoneu-
tralization of endogenous GHRH (344, 563). Alternatively,
the increase in GH secretion after administration of μ opioid
receptors agonists in the PevN (578) is in favor of an inhibitory
effect of opiate peptides on somatostatin release. Opiate pep-
tides are indeed able to inhibit somatostatin release induced by
potassium depolarization from hypothalamic explants (128).
The existence of anatomical connections between POMC
and GHRH neurons on one side, POMC and somatostatin
neurons on the other side, suggests that POMC neurons could
regulate GH secretion by connecting ArcN GHRH neurons
and PeVN somatostatin neurons. Indeed, in the ArcN, β-
endorphin immunoreactive fibers were shown in close appo-
sition to GHRH cell bodies (112) and to somatostatin cell
bodies in the PevN (146). Reciprocally, binding sites that are
sensitive to octreotide, a somatostatin-receptor 2 preferring
agonist, are present on POMC positive neurons (145, 147),
suggesting that somatostatin neurons also modulate the activ-
ity of POMC neurons.
Corticotropin-releasing hormone
Corticotropin-releasing hormone is a 41 amino-acid peptide
(477) synthesized in various regions within the central ner-
vous system. CRH is highly expressed in the paraventricular
nucleus (498) (Fig. 5). CRH decreases basal GH secretion in
the rat after icv injection (252, 391, 436) and GHRH-induced
GH release in humans (24). This effect seems to be relayed
through an increase in somatostatin release as the inhibitory
effect of CRH on GH release is abolished by a treatment
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Comprehensive Physiology
with an antisomatostatin antibody (252, 436). Furthermore,
icv administration of CRH increases somatostatin concentra-
tions in pituitary portal blood (351). CRH could also modulate
GH secretion by inhibiting GHRH neurons: continuous treat-
ment with a CRH antagonist increases the amplitude of GH
pulses as well as GHRH expression (360).
CRH neurons in the PV nucleus are also direct targets
of ArcN NPY neurons as evidenced by anterograde tracing
(297). To this extent, CRH neurons may serve as a critical
intermediates in the regulation of GH output following
changes in food intake, and therefore alterations in NPY
activity.
Numerous anatomical data demonstrate a complex inter-
action between several neuropeptides and opioid peptides.
For example, galanin and POMC ArcN neurons are inter-
connected (220) and NPY-containing fibers project to β-
endorphin positive neurons that send synapses onto dopamin-
ergic neurons (221, 222). An additional level of complexity
is represented by the numerous colocalizations that occur in
ArcN (207). Moreover, the degree of colocalization of neu-
ropeptides in GHRH or somatostatin neurons varies accord-
ing to adiposity (232), stressing the relationship between
metabolism and GH secretion. This is reviewed in the fol-
lowing section.
Integration between Regulators of Food
Intake/Metabolism and GH Release
The production and release of GH changes considerably rela-
tive to food intake and body composition. Therefore, it is not
surprising that a number of intermediates that are traditionally
seen as regulators of food intake and metabolic balance con-
tribute to the short- and long-term regulation of GH release.
Of these, discovery and the identification of the actions of
ghrelin (a potent orexigenic factor) highlighted an additional
level of control, whereby traditional regulators of GH pulsatil-
ity (somatostatin and GHRH) are no longer seen as the only
modulators of GH pulsatility. Rather, it is now accepted that
GH output is largely modified by metabolic needs, and thus is
under feedback control of numerous intermediates that signal
hunger, satiety, or excess or under nutrition. Indeed, many of
the mechanisms that modify GH output relative to nutrient
supply are yet to be defined. To this extent, it is not yet possi-
ble to provide an exhaustive list of all factors that modify GH
output relative to nutritional or metabolic demand. Therefore,
this section will predominantly focus on ghrelin and ghrelin
derived peptides, and an only a brief summary of other regu-
lators (including insulin, free fatty acids and glucose) will be
provided.
Ghrelin
GH secretagogues and ghrelin discovery
In their search for compounds able to mimic or amplify
the endogenous secretion of GH, Bowers and collaborators
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Comprehensive Physiology Growth Hormone Axis

directed their attention to opiates known to stimulate GH

and PRL secretion. In doing so, they synthesized a derivative
from Met-enkephalin, GHRP-6 (His-D-Trp-Ala-Trp-D-Phe-
Lys-NH2), devoid of opiate activity. GHRP-6 was the first
synthetic GH secretagogue (GHS) described to have activ-
ity in vivo without binding any receptor known to stimulate
GH secretion. During the subsequent 20 years, compounds
that are smaller, more stable, and soluble have been devel-
oped and are either peptides (54, 123) or non-peptides such
as L692-429, L-692-585, or MK-0677 (88, 89, 404). A spe-
cific receptor for these synthetic compounds, the GH secreta-
gogues receptor (GHS-R), was cloned from porcine pituitary
in 1996 (223). The effects of GHS on GH release have been
described in humans as well as in different animal species
such as the sheep (183), the guinea pig (138, 139) and the rat
(93, 100, 586). The effects of GHS are not completely spe-
cific of GH secretion, as some have reported an activation of
the hypothalamic-pituitary-adrenal (HPA) axis by GHRP-6
for example (526). In humans, GHS stimulate GH, prolactin,
ACTH and cortisol (157). Discovery and characterization of
GHS and the GHS-R lead to the eventual identification of the
potent endogenous GH agonist, ghrelin.

Ghrelin: structure and function
In 1999, ghrelin was isolated as the endogenous ligand for
the GHS-R1a (273, 531) and for its ability to stimulate GH
secretion (273,274). A cDNA, identical to preproghrelin, was
cloned independently and named prepro-Motilin Related Pep-
tide (preproMTLRP) (531). Ghrelin is a 28 AA peptide that
is posttranslationally modified with an eight-carbon fatty acid
on a serine in position 3 by the enzyme Ghrelin-O-Acyl-
Transferase (GOAT) (185, 592). The acylation of ghrelin is
required to activate the GHS-R and to mediate its effects
on GH secretion and food intake. Indeed, acylated ghrelin
potently stimulates GH secretion both in vitro and in vivo in
several animal species, including rodents (530), non-human
primates (263) and humans (63, 502, 549). In humans, con-
tinuous infusion of ghrelin during a 24-h period stimulates
pulsatile (burst mass as well as frequency) and entropic (the
GH secretory pattern becomes more irregular) modes of GH
secretion (549).
Ghrelin: mechanism of action
The GHS-R is highly expressed in the pituitary gland as
well as in the hypothalamus (178, 181, 361, 593), suggest-
ing both direct and indirect mechanism of action (Fig. 6).
Using a GHSR-eGFP reporter mouse line, it was found that
77% of somatotrophs express GHS-R-eGFP in both males
and females (428). In the same mouse line, eGFP expression
is low in several midbrain regions and in several hypothala-
mic nuclei, particularly the ArcN, where robust GHSR mRNA
expression is well characterized (512,575); thereby question-
ing the model (320).
Figure 6 Ghrelin acts within the hypothalamus and the anterior pitu-
itary gland indirectly (through inhibiting somatostatin- and stimulat-
ing GHRH-neuronal activity), and directly by stimulating somatotrophs,
respectively. The actions of ghrelin are mediated through select acti-
vation of the GHS-R. Actions of ghrelin on GH release may involve
interactions with feeding circuits, specifically through neuropeptide-Y
(NPY)-expressing neurons located within the arcuate nucleus (ArcN).
Stimulatory interactions are highlighted in green arrows. Inhibitory
interactions are highlighted in orange arrows. Additional abbrevia-
tions: ME, median eminence; PevN, periventricular nucleus; PvN, par-
aventricular nucleus; POMC, pro-opiomelanocortin; GAL, galanin.
Ghrelin-induced GH release from somatotrophs is
mediated through increased intracellular Ca2+ levels via IP3
signaling pathway [reviewed in (262)]. GH response to GH
secretagogues is only partially dependent on the GHRH sig-
naling, as the response to acutely injected GHRP-2 is severely
reduced but not completely blunted in lit/lit mice bearing a
mutation in the GHRH-R (409). In addition to a direct stimu-
latory effect on the pituitary, ghrelin amplifies GH secretory
pattern by indirect hypothalamic actions. In rat hypothalamic
slices in vitro, 85% of ArcN neurons projecting to the median
eminence are excited by ghrelin and inhibited by somatostatin
(356). The expression of the GHS-R1a in 25% of ArcN
GHRH neurons suggests that the effect of ghrelin is direct
on GHRH neurons (512, 575). Consistent with these neu-
roanatomical observations, ghrelin stimulatory action on GH
is partly mediated via a modulation of the activity of GHRH
neurons, as it disappears after passive immunization with
an anti-GHRH antiserum (508), and ghrelin can stimulate
GHRH release from hypothalamic explants (582). In addi-
tion, in GHRH-eGFP mice, ghrelin increases GHRH neurons
excitability by increasing their firing rate (393). Although
initially reported as purely postsynaptic, others demonstrated

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Growth Hormone Axis
that ghrelin decreases GABA-ergic synaptic transmission
in 44% of recorded GHRH neurons, an effect blocked by
a selective GHS-R antagonist, while it did not involve glu-
tamatergic neurotransmission (141). Unlike GHRH, ghrelin
seems refractory to the inhibitory action of somatostatin.
Indeed, ghrelin stimulates GH secretion when administered
intravenously during either low (peak GH) or high (trough
GH) endogenous somatostatin tone in the rat (530). However,
icv injection of ghrelin at trough times does not significantly
increase plasma GH levels (508); even though ghrelin inhibits
somatostatin release from perifused rat hypothalamus (530).
In prepubertal sheep, ghrelin infusion for 6 hours during
3 consecutive days increases accumulation of somatostatin
stores in the PevN perikarya and in the terminals of the
median eminence, resulting in enhanced GH release (416),
suggesting that ghrelin impairs somatostatin release in this
species as well.
In addition to its primary effect as a GH secretagogue,
ghrelin exerts a powerful orexigenic effect after acute injec-
tion (533), primarily mediated through NPY/Agouti-related
protein-expressing neurons in the ArcN [GHS-R is highly
expressed in this population of neurons (373)]. These neu-
rons modulate GH secretion through their connections to
somatostatin-expressing neurons in the PevN (225) provid-
ing a potential intermediate site of action in the regulation of
ghrelin-mediated GH release.
The vagus nerve is a mediator of ghrelin-induced GH
secretion and is necessary for the full GH releasing activity
of ghrelin. Indeed, animals with a disruption of vagal con-
nections display a decreased GH response to peripheral and
central ghrelin injections (7). Interestingly, blockade of the
peripheral cannabinoid-1 receptor subtype with rimonabant
reduces ghrelin-induced GH secretion but does not modify
GHRH-induced GH secretion, whereas vagotomy suppresses
the inhibitory action of rimonabant on GH. This suggests that
the endocannabinoid system relays the effects of ghrelin on
GH secretion by the vagus nerve (6).
Pharmacology
Several GHS-R antagonists have been developed to decipher
the role of the ghrelin/GHS-R pathway in physiological condi-
tions. Repeated injections of the antagonist [d-Lys3]-GHRP6,
an analog of one of the synthetic GHS (18), does not modify
ultradian GH secretion (388) although it suppresses feeding
in mice after acute or chronic icv injections (18). Results
obtained with this compound are difficult to interpret because
it also binds melanocortin receptors (459). Another developed
molecule, JMV2810, antagonizes the effects of hexarelin (a
synthetic ghrelin agonist) on food intake but not on GH secre-
tion after acute injection (126) but JMV2810 effects per se
on spontaneous GH secretion or food intake were not inves-
tigated. Subcutaneous or central infusion of another selective
GHS-R antagonist, BIM-28163, during 48 h-administration
through an osmotic mini-pump in rats decreased the amplitude
of GH secretory peaks by 46% without significantly affecting
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Comprehensive Physiology
food intake (600). However, when administered at high doses,
BIM-28163 displayed an agonist activity in addition to its
antagonist properties as it increased food intake and weight
gain as well as cFos activity in the dorsomedial nucleus of the
hypothalamus (189, 194). These effects could be mediated
through actions on a receptor distinct from the GHS-R1a.
Taken together, these data suggest that endogenous ghrelin,
via its action on the GHS-R1a, amplifies the pulsatile pattern
of GH secretion but the mechanisms by which endogenous
ghrelin modifies food intake remain to be defined and may
involve a novel receptor.
The difficulty to interpret data from pharmacological
manipulations of the GHS-R1a is further complicated by;
(i) the fact that this receptor is associated with multiple signal
transduction pathways (72,212), (ii) the existence of a variety
of ligands or cofactors in addition to ghrelin, like adenosine,
that can interact with the GHS-R at different binding sites
(474) or that can behave as positive or negative modulators of
endogenous ghrelin signaling (406), and (iii) the existence of
constitutive activity for the GHS-R (212, 213, 215, 216, 400).
Genetics
Transgenic mice in which ghrelin-producing cells develop
into ghrelinoma with elevated plasma ghrelin levels exhibit
elevated IGF-1 levels and display increased GH response
to GHRH, although they have reduced appetite and body
weight, suggesting that chronic elevation of ghrelin activates
the GH/IGF-1 axis (236). In contrast, adult preproghrelin
knockout (ghrl−/−) mice have no major weight or growth
alterations under balanced feeding environment (494). In
young ghrl−/− mice, the amplitude of GH secretory bursts is
reduced compared to wild-type littermates whereas the secre-
tory pattern is not significantly altered (195). This suggests
that endogenous ghrelin acts as an amplifier of GH pulsatility.
In contrast, GHS-R knockout mice (Ghsr−/−) present with
mildly lower body weights and reduced IGF-1 levels (495),
supporting a role of the GHS-R in growth. Possible compen-
satory mechanisms due to the absence of ghrelin during the
developmental period to explain the lack of strong phenotype
in ghrl−/− mice have been ruled out. Indeed, despite induc-
tion of a postweaning reduction in circulating ghrelin levels
in mice expressing human diphtheria toxin receptor (DTR)
in ghrelin-secreting cells and treated with DTR, no evidence
of growth retardation was observed: body weight, nasoanal
length and IGF-1 plasma levels were unmodified. Pulsatile
GH secretion was not measured in these mice and a reduced
GH response to GHRH was only observed in 5-week-old
males but not females (15). To this extent, different genetic
mouse lines targeting the various forms of ghrelin or ghrelin
receptors have only added to the array of questions regarding
the true endogenous role of ghrelin in regulating GH pulsatil-
ity, and the actions of GH on body composition and growth.
Constitutive activity of the ghrelin receptor could pro-
vide a residual signaling in mice lacking ghrelin (412). Phys-
iological significance supporting a link between GHS-R1a
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Comprehensive Physiology
constitutive activity and the activity of the GH/IGF-1 axis
is substantiated by human genetic studies. Interestingly, in
humans, rare natural mutations of the GHS-R, transmitted
on a dominant or a recessive mode, are associated with short
stature and/or GH deficiency (400,401). Furthermore, the dis-
ease mechanism shared by the very few cases documented so
far is a complete or a partial loss of constitutive activity of
the mutant GHSR1a receptors (A204E, F279L, and R237W)
(215, 400, 560).
As stated earlier, the activity of ghrelin to stimulate GH
secretion and food intake depends on the presence of an eight-
carbon fatty acid residue attached to Ser in position 3. Mice
invalidated for the GOAT gene (Goat−/− mice), encoding the
enzyme that acylates ghrelin, are currently the most appropri-
ate model to investigate specifically the role of acylated ghre-
lin in the regulation of GH secretion and feeding, as circulating
acylated ghrelin secretion is totally absent in this model (598).
In contrast to Ghsr−/− mice, growth retardation or changes
in body composition have not been reported in Goat−/− mice
(598). A moderate reduction in weight was only observed
when mice were fed an octanoate rich diet (264). As observed
in ghrsl−/− or Ghsr−/− mice, food consumption is not altered
in Goat−/− mice. Current observations from Goat−/− mice
show derangements in peak GH output, specific to young
age, and an overall rise in GH pulse frequency and irregular-
ity (584). In this context, the acylated form of ghrelin may
contribute to peak GH output, while entraining mechanisms
of patterned GH release. It remains unclear why this derange-
ment in GH output does not contribute to clearly discernable
differences in body length.
One important function of GH is to regulate glucose
and lipid metabolism as it induces hyperglycemia and elicits
changes in fat distribution and mobilization. When submit-
ted to a 60% caloric restriction, young Goat−/− mice have
reduced GH secretion and are unable to maintain normal blood
glucose (598). Thus, acylated ghrelin, although not essential
for normal growth, may have an essential function in mice
during adulthood by elevating GH levels during severe caloric
restriction, thereby maintaining fasting blood glucose levels
and allowing survival.
Relationship between ultradian ghrelin and GH
secretion
Growth hormone and ghrelin secretory patterns were not
strictly correlated in two studies measuring total or acy-
lated ghrelin circulating levels in freely behaving rats sampled
every 20 min (529, 601). Accordingly, GH secretory pattern
(peak frequency or number) is not modified after treatment
with a GHS-R1a antagonist (600) or in ghrl−/− mice (195).
In contrast, in humans, using a higher sampling frequency
and very selective sandwich enzyme-linked immunosorbent
assays (377), a clear relationship between acyl ghrelin and
GH secretion was observed (mean of the individual peak cor-
relations 0.70 ± 0.04). This was only seen in subjects given
standardized meals and correlation dropped in fasted subjects
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Growth Hormone Axis
(0.29 ± 0.08) further suggesting a divergent role for ghrelin
in the control of GH release relative to nutrient supply. This
is corroborated in mouse studies, wherein the suppression of
GH release in the mouse during fasting does not coincide with
altered acylated ghrelin release (487), whereas the eventual
rise in circulating levels of ghrelin during a prolonged fast
does not correspond to an increase in GH output (486).
Other ghrelin-derived peptides
The preproghrelin gene encodes other functional or nonfunc-
tional molecules in addition to acylated ghrelin, including des-
acylated ghrelin and obestatin, or other C-terminal proghrelin
peptides whose physiological significance still needs to be
clarified (466). To this extent, a lack of ghrelin in preproghre-
lin deficient animals might be counterbalanced by the lack of
other proghrelin-derived molecules with postulated antago-
nistic actions.
Des-acylated ghrelin is the most abundant form in
plasma and accounts for up to 80% to 90% of total ghrelin
(274). Although nonendocrine biological activities have been
attributed to the binding of des-acylated ghrelin to an uniden-
tified receptor, recent studies suggest that it also modulates the
effects of acylated ghrelin (231). However, it does not bind to
the GHS-R and there currently is no pharmacological tool to
examine its biological role. At any rate, this ghrelin variant is
inactive on GH secretion and studies investigating its effects
on feeding have not been conclusive (17, 230). Interestingly,
transgenic mice overexpressing des-acylated ghrelin had sig-
nificantly reduced body weight, reduced food intake and body
fat mass and moderately decreased linear growth compared to
nontransgenic mice at 44 weeks of age (17). These data sug-
gest that des-acylated ghrelin modulates, through an unchar-
acterized pathway, growth and metabolism.
Obestatin, (contraction of “obese” and “statin” denot-
ing suppression) is another bioactive 23 amino-acid pep-
tide derived from the C-terminal portion of the 117 AA
preproghrelin precursor. It was originally proposed as the
endogenous ligand for GPR-39 (332, 597). Obestatin was
initially shown to decrease appetite and weight gain thus
opposing ghrelin effects but subsequent studies failed to con-
firm such effects or that obestatin was the cognate ligand
for GPR39 (86, 214, 292). Obestatin was also described as a
functional antagonist of ghrelin actions in rodents (332, 597).
Physiological effects of obestatin on GH are not consistent
from one study to another. Whereas some studies do not
observe any effect of obestatin per se after acute injections
in rats (601), other studies report that obestatin decreases
GH secretion in vivo and plasma IGF-1 levels after chronic
treatment in mice and non-human primates (312). In rodents,
obestatin antagonizes GH secretion and food intake induced
by ghrelin only when ghrelin and obestatin are administered
in equimolar quantities (196, 312, 381, 601). A direct action
of obestatin on somatotrophs has not been clearly validated.
In pituitary cell cultures from non-human primates (baboon)
and mice, obestatin inhibits GH expression and release after
701
Growth Hormone Axis
24 h of incubation and inhibits ghrelin-induced GH secretion,
suggesting a pituitary site of action. This is associated with
a reduction in the expression of pituitary GHRH-R, SST1,
and SST2 (312). However, earlier studies in rat perifused
pituitaries did not detect a direct action at the pituitary level
(597, 601). It is possible that ghrelin and obestatin interact
pharmacologically at the hypothalamic level to modulate food
intake and GH secretion. Obestatin treatment causes a reduc-
tion in hypothalamic GHRH expression (312). In addition,
obestatin antagonizes ghrelin-induced cFos activation in the
arcuate nucleus and antagonizes ghrelin-induced inhibition of
GABA synaptic transmission onto GHRH neurons (141,195).
Concerning the importance of preproghrelin derived pep-
tides in terms of phylogeny, it should be noted that genes
encoding ghrelin and GOAT are missing in the platypus
genome, whilst, as reported in other species, the GHS-R is
present and expressed in brain, pancreas, kidney, intestine,
heart, and stomach (198).
Insulin
In both humans and animals, acute and chronic GH treatment
differentially impacts carbohydrate and lipid metabolism.
Acute effects of GH are thought to be insulin-like,
resulting in a decrease in blood glucose, the stimulation of
muscle glucose uptake, and an increase in adipose-specific
glucose transport and lipogenesis (114, 354). Provocation
of GH release in humans through the administration of
insulin (insulin-induced hypoglycemia) is often used to assess
GH-axis function (153). The insulin-mediated GH response
observed in humans most likely occurs in response to the acute
fall in glucose levels (445), and thus not through direct insulin
action. This glucose-dependence is further demonstrated by
the inhibition of GH and GHRH-induced GH release follow-
ing an acute rise in blood glucose levels (commonly seen dur-
ing oral or intravenous glucose loading) (115, 166, 470). Crit-
ically, plasma GH levels in other species following insulin-
induced hypoglycemia does not reflect increased GH release,
with measures from pigs, dogs, and cats showing no or a
modest change in GH output in response to insulin induced
hypoglycemia (275,315,534). Insulin-induced hypoglycemia
in sheep promotes the release of somatostatin into portal
circulation, culminating in the eventual suppression of GH
release (159). Within the rats and rabbits, GH release is sup-
pressed (331, 501). Since the mean period of the GH rhythm
was not significantly altered by hyperglycemia—although the
amplitude of the pulses of half of the hyperglycemic rats was
markedly depressed—it was initially concluded that insulin
does not significantly affect the endogenous ultradian rhythm
of GH secretion in the rat (514). Similar reports exist in
Man, with data showing no direct correlation in immediate
peak GH release relative to circulating glucose or insulin
levels (71,420). Moreover, early reports failed to consistently
demonstrate altered postprandial GH output specific to a meal
(8,22), suggesting that GH release may not be coupled to food
intake. This premise was significantly revised following the
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Comprehensive Physiology
discovery of ghrelin (273), and the identification of neuronal
mechanisms that couple GH output with food intake.
Chronic actions of GH counter insulin function, resulting
in peripheral insulin insensitivity, and insulin hypersecretion
[reviewed in (555)]. The well-defined anti-insulin actions of
GH may underscore the progressive decline in GH release
resulting in GH deficiency that is commonly seen in obe-
sity (375, 426, 548). Indeed, the progressive decline in GH
secretion with weight gain correlates with a rise in cir-
culating levels of insulin in both humans (550) and mice
(488). This suggests that GH release is tightly controlled by
prolonged changes in energy intake, and potentially insulin
release. Indices of this inverse relationship exist across many
metabolic states. In humans, fasting (227), malnutrition result-
ing in anorexia (345), and insulin-dependent type-1 diabetes
mellitus (10, 19, 191, 197) are associated with decreased lev-
els of insulin and a rise in GH release, whereas hyperphagia
(106,107) and obesity (375,426,548) are associated with ele-
vations in circulating measures of insulin and a fall in GH
release. Given this well-established relationship, it comes as
a surprise that few observations exist to establish a functional
relationship whereby insulin may define GH release.
Anecdotal evidence from humans suggests a potential
direct link between hypoinsulinemia and GH excess. Inten-
sive insulin treatment in type-1-diabetic patients reverses GH
hypersecretion (19), whereas calorie restriction to reverse
hyperinsulinemia (259) results in the recovery of GH secre-
tion, presumably in response to a reduction in insulin levels
(119). Evidence that define the relationship between GH and
insulin secretion almost always document opposing changes
in GH insulin release, whereas attempts to disrupt this balance
to define the physiological context of inverse GH/insulin bal-
ance are scarce. Overeating in humans suppresses GH release
(106, 107). This occurs before observable changes in weight
gain, and alongside an elevation of 24-h insulin secretion. GH
treatment at this time (to reverse the suppression of endoge-
nous levels of GH) results in a further increase in mean daily
circulating levels of insulin, fasting insulin, and the insulin
response to a meal (106). In this context, the physiological
suppression of GH during sustained periods of calorie excess
would facilitate insulin action (106). This is in line with the
established role of GH as a regulator of insulin sensitivity.
Importantly, these measures also highlight the existence of a
potential feedback-mechanism whereby insulin may mediate
GH release.
Insulin inhibits GH synthesis from isolated pituitary cells
by inhibiting GH gene expression (588, 589). Insulin acts
selectively on insulin receptors within the pituitary gland
(314) to suppress GH release from isolated somatotrophs
(314,334). These effects persist regardless of the development
of systemic insulin resistance (314), suggesting that soma-
totrophs remain insulin responsive in obesity. Thus, insulin
may modulate GH release relative to weight gain, and promote
the sustained suppression of GH release in obesity, regardless
of systemic insulin resistance. Targeted in vivo deletion of
insulin receptors from somatotrophs results in an increase
Volume 6, April 2016
Comprehensive Physiology
in pituitary GH content and release (163). Based on selec-
tive inactivation of the Insr and IgfIr genes in mouse soma-
totrophs, it can be concluded that the suppressive actions of
insulin on GH release occur independent of IGF-1 (163). It
is thus likely that insulin levels predict GH release indepen-
dent of IGF-1, and that insulin may provide critical feedback
to alter GH release relative to long-term metabolic require-
ments. It should be noted that loss of somatotroph-specific
insulin receptor expression does not completely reverse the
suppression of GH release seen during dietary induced weight
gain and obesity (163), and therefore insulin may not solely
predict GH release in weight gain and obesity. Alternatively,
the actions of insulin on GH release may not be restricted to
the anterior pituitary gland. Insulin receptors are expressed
throughout the hypothalamus, including the ArcN and PevN
(148, 201, 249, 572); however, a comprehensive assessment
of the role of insulin in regulating hypothalamic control of
GH output is needed. Thus, while insulin may modulate GH
release acting through the hypothalamus, this premise remains
completely unexplored. As insulin does not predict ultra-
dian patterns of GH release (discussed earlier), the actions
of insulin within the hypothalamus to mediate GH output
may be limited to the infradian regulation of peak GH output.
Free fatty acids
An important metabolic effect of GH is to drive the release of
free fatty acid (FFA) from adipose tissues (193,205), whereas
FFAs in turn may exert feedback on GH release (the physi-
ological context of this remains to be confirmed). Studies in
humans and animals using a lipid infusion approach revealed
a direct inhibitory effect of FFA on GH secretion, presumably
through the direct suppression of GH release from soma-
totrophs and an indirect inhibition of somatotrophs at the
hypothalamic level (9, 61, 74). Interestingly, in obesity, an
increase in circulating levels of FFA coincides with a decrease
in GH secretion, and the pharmacological suppression of FFA
by the antilipolytic drug acipimox is associated with a recov-
ery of GH secretion in obese subjects (12,105,374,418). Thus,
it was proposed that impairment of GH secretion observed in
obesity may occur as a consequence of an elevation in circu-
lating levels of FFA (171). However, a recent meta-analysis
has demonstrated relatively stable circulating levels of FFA
regardless of the severity of obesity (250), and thus it remains
unknown whether obesity-associated alterations in circulat-
ing levels of FFAs contribute to altered GH output. In agree-
ment with this, a reduction of GH secretion following dietary-
induced body weight gain does occur in mice without an eleva-
tion of FFA concentrations (224). Therefore, the impairment
of GH secretion in the early stage of obesity may not occur in
response to an elevation of FFA, at least directly. Rather, given
that elevated levels of FFA are associated with insulin resis-
tance and the hypersecretion of insulin (242), decreased GH
secretion in obesity may occur as a consequence of altered
insulin feedback, rather than in response to an elevation in
circulating levels of FFAs. To this extent, the recovery of GH
Volume 6, April 2016
Growth Hormone Axis
release that is seen following acute treatment with acipimox
may also occur as a consequence of altered insulin feedback.
Acipimox reduces circulating levels of insulin in obese sub-
jects (12, 418), and thus the reduction of GH secretion as
observed in obesity may simply reflect prevailing levels of
insulin.
In humans, the augmented secretion of GH during fasting
is thought to stimulate the release of FFA (193, 205). Indeed,
reversal of the fasting induced rise in GH release in humans
impairs whole body lipolysis, as measured through a partial
reduction in glycerol Ra (the rate of appearance of glycerol, an
index of lipolysis) following antagonism of GH output during
a 24 and 48 hour fast (449). Of interest, these observations
further demonstrate that, while contributing to the rise in FFA
release, factors other than GH predominantly promote FFA
release in fasted humans. Interestingly, in fasted mice GH does
not mediate the rise in FFA release. Rather, a rapid elevation
in FFA release following food withdrawal occurs alongside
the suppression of GH secretion. In addition, the elevation
in circulating levels of FFAs in response to food deprivation
persists in GH receptor knockout mice (487). This suggests
that, unlike in humans, GH does not contribute to the early
rise of FFA in mice in response to fasting. Species difference
should therefore be considered in future studies regarding the
relationship between GH and FFA during fasting conditions.
Although there are still many unanswered questions, it is
generally believed that circulating FFA levels are negatively
correlated with GH levels in all species, mainly through mod-
ification of pituitary response to hypothalamic GHRH and/or
somatostatin signals.
Leptin
Leptin is a hormone secreted from adipocytes in proportion
to fat mass (154, 316). By inhibiting appetite and promoting
energy utilization, leptin plays an important role in main-
taining energy homeostasis (243). The effect of leptin on
regulating GH secretion is well established; however, some
debate persists regarding potential inhibitory and stimulatory
actions.
In vitro studies support a direct stimulatory role of leptin
on GH release using pig pituitary slices alone or coincubated
with the stalk median eminence (2, 450). However, a direct
inhibitory effect of leptin on ovine pituitary somatotrophs is
also well documented (439, 440), with a decrease in GHRH-
stimulated GH secretion from leptin-treated primary cultured
cells. Such inhibitory effect may depend on the nutritional
status of the animals (265). In vivo, central infusion of leptin
promotes GH secretion by acting concurrently at GHRH and
somatostatin neurons in rodents (96, 510, 561), and the fast-
ing induced fall in GH secretion in rats is fully prevented by
central leptin administration (288). In addition, somatotroph
specific deletion of leptin receptors results in a reduction in
GH immunopositive cell numbers and an overall reduction in
GH secretion (90). Thus, leptin appears to maintain GH secre-
tion in a normal range while mediating GH output relative to
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nutrient supply. The mechanisms of action through which
leptin modulates GH release in the rodent remain unknown,
and may require interactions with neuronal intermediates. For
example, leptin modifies NPY-expressing neuronal activity
[specific to food-intake (479)], whereas NPY-neurons are crit-
ically involved in the regulation of GH release. In this context,
leptin infusion in the rodent may prevent the rise in NPY activ-
ity that is normally associated with fasting, thereby preventing
NPY-mediated suppression of GH release. However, the bio-
logical significance of this interaction (considering species
differences) remains completely unexplored in humans.
Leptin may act as an adipostat, signaling nutrient status
to the hypothalamus, thereby mediating long-term changes
in hypothalamic control of hormone output. During periods
of excess, such as obesity, an increase in circulating levels
of leptin is observed alongside a decrease in GH secretion
(352, 488). This can be attributed to an impairment of lep-
tin signaling and/or the development of leptin resistance due
to severe obesity (369, 599). Conversely, administration of
leptin in leptin deficient ob/ob mice restores impaired GH
secretion (313). However, in other obesity models, prevailing
elevated endogenous leptin levels makes it irrational to add
exogenous leptin. In humans, congenital absence of leptin or
mutations of the leptin receptor result in a reduction in GH
secretion (95) and a blunted GH response to GH stimuli (396).
In this context, it is more than likely that other inhibitory fac-
tors (including insulin) may override the stimulatory effect
of leptin and ultimately contribute to the suppression in GH
secretion in obesity.
Fasting results in a decline in leptin levels out of pro-
portion to the reduction of body fat mass (51, 568). Inter-
estingly, administration of recombinant methanoyl human
leptin (r-metHuLeptin) to normal weight subjects following
72 h of fasting (to reverse the fasting associated hypolepti-
naemia) (80) or to hypothalamic amenorrhea women (with
chronic energy deficit and relative leptin deficiency) does
not alter GH secretion (81). Thus, unlike rodents whereby
administration of leptin restores suppressed GH secretion
following food deprivation (288), leptin deficiency may not
serve a direct inhibitory signal on GH secretion during long-
term fasting in humans. It is worth mentioning that fasting-
induced immediate change in GH secretion is contradictory
between rodents (decrease) and humans (increase), therefore,
species difference in the role of leptin in mediating GH secre-
tion should not be ignored. Nevertheless, it should be noted
that r-metHuLeptin replacement does increase the starvation-
induced decrease of total IGF-I (a major by-product regulated
by GH) in humans (81). Thus, the role of leptin in regulating
IGF-1 independent of GH requires further investigation.
Glucose
Generally, elevated glucose levels in plasma (hyperglycemia)
occurs alongside a reduction in basal and pulsatile GH secre-
tion, whereas reduced glucose levels (hypoglycemia) occurs
alongside an increase in GH release in humans, and in large
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animals. Species difference exists clearly between laboratory
animals (mainly rodents) and humans. In this section, we will
briefly discuss existing data on rodents and humans, focus-
ing on GH levels under hyper- or hypoglycemic conditions.
Attempts for in vivo assessment of GH output relative to cir-
culating levels of glucose are compromised by accompanying
changes in circulating levels in insulin. As previously dis-
cussed, insulin is a key regulator of GH release, and thus
must be considered alongside attempts to define the actions
of glucose on GH release.
Hypoglycemia
The regulation of GH secretion during hypoglycemia may
occur at the level of the pituitary gland, and/or hypothalamus
through interactions with GHRH and somatostatin neurons.
Since brain tissues use almost exclusively glucose to provide
energy (395), determination and regulation of glucose in cir-
culation becomes essential in keeping normal brain function.
Moreover, glucose-sensing neurons contribute to the appro-
priate physiological responses to maintain peripheral glucose
levels within a normal range. To this extent, GHRH neurons
may contribute to peripheral glucose homeostasis. Through
over expression of glucokinase (a critical enzyme that facil-
itates phosphorylation of glucose to glucose-6-phosphate)
in EGFP-tagged ribosomal protein construct mice, it was
demonstrated that hypoglycemia activates GHRH neurons
(478). It is important to note, however, that hypoglycemia
in mice causes a reduction in GH release (486,487), a process
thought to be mediated by selective activation of NPY neurons
(225) Therefore, the role of direct glucose sensing in GHRH
neurons, in combination with the effect of endogenous sys-
tems that may modulate GH release specific to hypoglycemia
are yet to be defined. Herein, neuronal integration with other
systems, including NPY expressing neurons, may override
GHRH responses. See above (page 9-10) for a more com-
prehensive overview of the role of NPY in mediating GH
output.
Hyperglycemia
In diabetic rat models, either type I or type II, depressed GH
release and blunted GH response to GHRH were reported
(48, 239, 378). Hyperglycemia inhibits GH secretion through
both direct and indirect mechanisms, by a direct action
on pituitary somatotrophs to blunt GH release in response
to GHRH stimulation (389), or by hyperglycemia-induced
hyperinsulinemia and hypersomatostatinemia (405). Hyper-
glycemia causes elevated plasma levels of somatostatin-like
immunoreactivity (405) and administration of somatostatin
antiserum to streptozotocin-induced diabetic rats resulted in
an increase in GH plasma level (506). Such results also
indicate that pituitary somatotroph responses to somato-
statin may also be involved. In isolated pituitary cells from
streptozotocin-induced diabetic rats, GHRH induced GH
secretion is significantly reduced (389). The GH content of
pituitaries and GHRH content of hypothalamus from diabetic
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Comprehensive Physiology
rats are also significantly decreased compared to control rats
(389). Growth hormone releasing hormone receptor levels
in pituitary glands have been evaluated in streptozotocin-
induced diabetic rats and the increase of the 2.5-kb GHRH-R
mRNA transcript coincided with a decrease of hypothalamic
GHRH mRNA levels (33). Overall, the depressed GH secre-
tion induced by hyperglycemia may result from a combina-
tion of decreased GH content in the pituitary gland, increased
release of somatostatin in hypothalamus. However, given the
anticipated actions of insulin, elevated insulin secretion within
these models may account for reduced pituitary-sensitivity to
GHRH stimulation, and diminished GHRH synthesis.
In human diabetes, GH secretion shows different charac-
teristics according to different stages and types of diabetes.
In type I diabetes without significant obesity, pulsatile GH
secretion is increased (19, 197). This occurs alongside an
increase in somatotroph sensitivity to GHRH (414). This dif-
fers from type I diabetic rat models, showing a remarkable
species difference. The increase in sensitivity of somatotrophs
to GHRH might be caused by a decrease in somatostatin out-
put from hypothalamus to pituitary gland (234). In type II
diabetes with obesity, GH levels are decreased significantly
compared to lean individual, but also to nonobese diabetic
patients (172, 278, 430). This suggests that the impact of obe-
sity compounds diabetic derangements in GH release. Impor-
tantly, intensive insulin treatment to reverse hyperglycemia in
type I diabetic patients is associated with a return of circulat-
ing levels of IGF-1 to that seen in nondiabetic individuals (10).
Again, this observation suggests that normalized glucose lev-
els following insulin treatment may be the overriding factor
that modulates GH-axis function relative to hyperglycemia,
and therefore insulin may serve as a critical regulator of altered
GH release in both type I and II diabetic patients, and relative
to hyperglycemia in general. This is a very different possibil-
ity from rodent studies as discussed above.
Secretion of GH Throughout Lifespan
As detailed above, the production and release of GH is tightly
controlled by physiological needs, and in particular metabolic
requirements. This is of specific importance during adult-
hood, however the biological roles of GH varies greatly with
age and reproductive status, with sexual maturation and the
awakening of the reproductive axis largely determining GH
patterning and release during childhood and in puberty. This
section will document release of GH relative to sexual matu-
ration and ageing, focusing on childhood, puberty, adulthood,
and old age. Given differential effects on steroid hormones
on GH action and release, this section will further detail sex
specific alterations in GH output, and will briefly consider the
effects of estrogens, pregnancy, and lactation on GH output
in females. Circadian patterns of GH release in Man change
considerably relative to sleep and stress, and thus the effects
of sleep and stress on GH release will be discussed. While
observations are predominantly limited to Man, other species
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Growth Hormone Axis
will be discussed when references to GH in Man are not avail-
able, or when mechanistic insights were obtained from other
species. In this regard it is important to note that while the
pulsatile appearance of GH in circulation is conserved across
all mammals characterized to date, the amount of GH release,
and patterns of GH output across species differ considerably.
This may be due to differential sampling practices (i.e., dif-
fering sample intervals, assay sensitivity, and statistical anal-
ysis) or may reflect underlying biological properties of GH
release that are specific to each species. Indeed, differences in
GH output between small and large mammals are thought to
occur as a consequence of differing metabolic needs. We will
not provide a comprehensive overview of GH output across
species, as this does not directly contribute to the general
aims of this article. A summary of GH output in Man and in
different mammalian species is provided in Tables 1 and 2,
respectively. For this, observations were limited to publica-
tions wherein measures of pulse irregularity [i.e., approximate
entropy (ApEn)] were provided.
Transition of GH release from infancy to puberty,
and into adulthood and old age
In utero and infancy
In Man, fetal GH in circulation is detected by 10 weeks of
gestation. Fetal GH originates independent from maternal or
placenta-derived GH, with data demonstrating an elevation
of GH in fetal blood when compared to maternal blood and
amniotic fluid assessed at the same time (203). This is in
agreement with prior observations that demonstrate fetal pitu-
itary GH synthesis (364), further demonstrating a rise in fetal
GH release from 7 and 20 weeks of gestation. Collectively,
these observations suggest that maternal GH does not play a
significant role in the release of fetal GH. Indeed, fetal GH
is pulsatile [as verified in fetal calves and lambs (109) (31)]
and thus likely under fetal hypothalamic control. This sug-
gest that the emergence of feedback systems in utero that
occur independent of maternal systems. To this extent, fetal
IGF-I feedback contributes to the decrease in utero GH levels
between week 20 of gestation and birth (203).
While profound GH deficiency in utero contributes to
reduced longitudinal bone growth (176), and GH-gene defects
contribute to a slight decrease in body length at birth [approx.
2 cm when compared to controls (121)], the overall actions
of fetal GH in gestation are not yet fully understood. Indeed,
attempts to define specific GH actions are somewhat com-
promised by the complexity of factors that contribute to fetal
development and growth. To this extent, GH may not criti-
cally contribute to normal fetal growth, and reports of nor-
mal fetal growth in the absence of fetal GH exist (434). Full
consideration of fetal-specific factors that contribute to fetal
growth cannot be discussed here, and the reader is advised
to consult recent expert reviews on this topic (203). Diffi-
culties to define potential effects of GH on fetal physiology
are further complicated by potential maternal GH effects on
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Table 1 Growth Hormone Pulsatility Parameters in Humans According to Gender and Age

Gender Age Burst No. of pulses

(n) (years) Total GH Secretion rate Mean GH Burst mass amplitude Basal ApEn per 24 h Sampling frequency/period Reference

Prepubertal
M (17) 10.6 n/a 130 ug/L.24 h 2.5 ug/L∗ 6 ug/L∗ n/a 8.7 ug/L.min 0.64∗ 22 (11 × 2) 10 min, 12 h starting at 1800 h (9)
M (5) 9.5 n/a n/a 3.4 ug/L n/a n/a n/a 0.90 n/a 30 min, 24 h, starting at 1000 h (2)
F(11) 9.9 n/a 148 ug/L.24 h 2.8 ug/L∗ 8 ug/L∗ n/a 8.5 ug/L.min 0.60∗ 18 (9 × 2) 10 min, 12 h starting at 1800 h (9)
F (6) 9.1 n/a n/a 3.6 ug/L n/a n/a n/a 0.70 n/a 30 min, 24 h, starting at 1000 h (2)
Adolescent
M (13) 14.9 n/a 364 ug/L.24 h 5.9 ug/L∗ 14 ug/L∗ n/a 7.2 ug/L.min 0.61∗ 22 (11 × 2) 10 min, 12 h starting at 1800 h (9)
F (17) 14.1 n/a 270 ug/L.24 h 3.7 ug/L∗ 8 ug/L∗ n/a 8.2 ug/L.min 0.74∗ 24 (12 × 2) 10 min, 12 h starting at 1800 h (9)
Adult
M (6) 27 15 ug.24 h n/a n/a 1.8 ug/L n/a 0.9 ug/24 h 0.19 8.5 10 min, 24 h starting at 0900 h (5)
M (11) 20-28 n/a 73.3 ug/L.24 h 1.4 ug/L 3.82 ug/L n/a 3.3 ug/L.24 h 0.24 19 10 min, 24 h starting at 0800 h (3)
M (8) 26 n/a n/a 1.3 ug/L 3.6 ug/L∗ n/a 0.2 ug/L∗ 0.42 n/a 10 min, 7.5 h starting at 0630 h (6)
M (41) 43 35.8 ug/L.24 h n/a 0.4 ug/L 4.6 ug/L 4.6 ug/L 3.5 ug/L 0.34 12 10 min, 24 h (starting time not specified) (8)
F(9) 28 60 ug.24 h n/a n/a 4.9 ug/L n/a 2.3 ug/24 h 0.44 13 10 min, 24 h starting at 0900 h (5)
F (6) 22 n/a n/a 3.2 ug/L 5.1 ug/L∗ n/a 0.4 ug/L∗ 0.55 n/a 10 min, 7.5 h starting at 0630 h (6)
F (59) 38 53.1 ug/L.24 h n/a 0.5 ug/L 3.8 ug/L 3.8 ug/L 6.9 ug/L 0.43 11 10 min, 24 h (starting time not specified) (8)
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Aged
M (45) 64.2 n/a n/a 0.3 ug/L n/a n/a n/a 0.60 n/a 20 min, 24 h, starting at 0600 h (1)
M (16) 70.2 n/a n/a n/a 2.9 ug/L 0.1 ug/L.min 0.8 ug/L.12 h 0.65 11.6 (5.8 × 2) 20 min, 12 h, starting at 2000 h (4)
F (38) 64.6 n/a n/a 0.5 ug/L n/a n/a n/a 0.81 n/a 20 min, 24 h, starting at 0600 h (1)
F 12) 63 n/a n/a 5.8 ug/L n/a 0.06 ug/L/h 0.57 n/a 10 min, 6 h, starting at 0800 h (7)
GHRH-R mutants
M(4) 23-30 n/a n/a 0.04 ug/L 0.05 ug/L <1% of 0.02-0.03 ug/L 1.284 15.3 10 min, 24 h starting at 0800 h (3)
normal
M (1) 24 2.7 ug.24 h n/a n/a 0.10 ug/L <4% of 0.5 ug/24 h 0.82 21 10 min, 24 h starting at 0900 h (5)
normal∗
F (1) 23 1.6 ug.24 h n/a n/a 0.06 ug/L <3% of 0.2 ug/24 h 1.17 23 10 min, 24 h starting at 0900 h (5)
normal∗

1. Charmandari E, Pincus SM, Matthews DR, Dennison E, Fall CH, and Hindmarsh PC. Joint growth hormone and cortisol spontaneous secretion is more asynchronous in older females than in
their male counterparts. J Clin Endocrinol Metab 86: 3393-3399, 2001.
2. Ilias I, Ghizzoni L, and Mastorakos G. Orderliness of cortisol, growth hormone, and leptin secretion in short-normal pre-pubertal boys and girls. Med Sci Monit 15: CR242-CR247, 2009.
3. Maheshwari HG, Pezzoli SS, Rahim A, Shalet SM, Thorner MO, and Baumann G. Pulsatile growth hormone secretion persists in genetic growth hormone-releasing hormone resistance. Am J
Physiol Endocrinol Metab 282: E943-E951, 2002.
4. Muniyappa R, Sorkin JD, Veldhuis JD, Harman SM, Munzer T, Bhasin S, and Blackman MR. Long-term testosterone supplementation augments overnight growth hormone secretion in healthy
older men. Am J Physiol Endocrinol Metab 293: E769-E775, 2007.
5. Roelfsema F, Biermasz NR, Veldman RG, Veldhuis JD, Frolich M, Stokvis-Brantsma WH, and Wit JM. GH secretion in patients with an inactivating defect of the GHRH receptor is pulsatile:
evidence for a role for non-GHRH inputs into the generation of GH pulses. J Clin Endocrinol Metab 86: 2459-2464, 2001.
6. Veldhuis JD, Farhy L, Weltman AL, Kuipers J, Weltman J, and Wideman L. Gender modulates sequential suppression and recovery of pulsatile growth hormone secretion by physiological
feedback signals in young adults. J Clin Endocrinol Metab 90: 2874-2881, 2005.
7. Veldhuis JD, Keenan DM, Bailey JN, Adeniji A, Miles JM, Paulo R, Cosma M, and Soares-Welch C. Testosterone supplementation in older men restrains insulin-like growth factor’s dose-dependent
feedback inhibition of pulsatile growth hormone secretion. J Clin Endocrinol Metab 94: 246-254, 2009.
8. Veldhuis JD, Roelfsema F, Keenan DM, and Pincus S. Gender, age, body mass index, and IGF-I individually and jointly determine distinct GH dynamics: analyses in one hundred healthy adults.
J Clin Endocrinol Metab 96: 115-121, 2011.
9. Veldhuis JD, Roemmich JN, and Rogol AD. Gender and sexual maturation-dependent contrasts in the neuroregulation of growth hormone secretion in prepubertal and late adolescent males
and females–a general clinical research center-based study. J Clin Endocrinol Metab 85: 2385-2394, 2000.

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Table 2 Growth Hormone Pulsatility Parameters in Mammalian Species According to Gender, Hormonal Status, and Age

Species gender Age Pulsatile secretion Burst No of pulses Sampling frequency/

or GNX (n) (years) Total GH rate Mean GH Burst mass amplitude Basal ApEn per 24 h period Reference

Macaques
M (4) 5-6 y n/a n/a 2.4 ng/mL 18.5 ng/mL n/a n/a 0.50 8.5 15 min, 15 h starting (4)
(5.3 × 1.6) at 0700 h
M (4) 5-6 y n/a n/a 2.4 ng/mL 7 ng/mL 1.5 ng/mL.min n/a 0.50 11.2 15 min, 15 h starting
(7.0 × 1.6) at 0700 h
Horses Gelding 1.7 y 441 ug/L.8 h 435 ug/L.8 h 2.8 ug/L 2.8 ug/L 0.86 ug/L.min 6.5 ug/L.8 h 0.60 25.8 5 min, 8 h starting at (1)
(12) (8.6 × 3) 2200 h
Goats
M (5) 1y n/a n/a n/a 155 ng/mL 38 ng/mL <0.8 ng/mL n/a 10.7-13.4 15 min, 24 h starting (5)
(4-5 × 2.7) at 1000 h
ORCHI (11) 1-2 y n/a n/a n/a 100-155 ng/mL 40-78 ng/mL <0.8 ng/mL n/a 10.7-18.7 15 min, 6 h starting
(4-5 × 2.7) at 1000 h
OVX (6) 2-4 y n/a n/a n/a n/a n/a <0.8 ng/mL 0.65 ∼10.7 15 min, 9 h starting (10)
(∼4 × 2.7) at 0600 h
Ewes
OVX (7) 2-4 y n/a n/a n/a n/a 3.0 ug/L 0.7 ng/mL 0.93 26.4 5 min, 4 h starting at (9)
(4.4 × 6) 0900 h
OVX (5) 2-3 y n/a n/a n/a n/a 38.4 ng/mL 17 ng/mL 1,02 18.4 10 min, 6 h starting (2)
(4.6 × 4) at 0830 h
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Volume 6, April 2016

F (5) 0.3 y n/a n/a n/a n/a 75 ng/mL 8 ng/mL 0.95 14.0 15 min, 6 h starting (6)
(3.5 × 4) at 1000 h
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OVX (6) 0.3 y n/a n/a n/a n/a 70 ng/mL 5 ng/mL 0.55 14.0 15 min, 6 h starting
(3.5 × 4) at 1000 h
M (8) 0.3 y n/a n/a 36 ng/mL n/a 99 ng/mL 15 ng/mL 0.79 6.1 20 min, 9 h starting (8)
(2.3 × 2.7) at 1000 h
Mice
M (7) 0.2 y 1257 ng/mL.6 h 1200 ng/mL.6 h n/a n/a 301 ng/mL.6 h 57 ng/mL.6 h 0.46 18.4 10 min, 6 h starting (7)
(4.6 × 4) at 0600 h
M (6) 0.2 y 881 ng/mL.6 h 724 ng/mL.6 h n/a n/a 301 ng/mL.6 h 87 ng/mL.6 h 0.50 18.0 10 min, 6 h starting
(4.5 × 4) at 0600 h
M (6) 0.2 y 280 ng/mL.6 h 200 ng/mL.6 h n/a n/a 40 ng/mL.6 h 80 ng/mL.6 h 0.75 22.0 10 min, 6 h starting (3)
(5.5 × 4) 1000 h
M (5) 0.7 y 280 ng/mL.6 h 200 ng/mL.6 h n/a n/a 55 ng/mL.6 h 80 ng/mL.6 h 0.50 16.0 10 min, 6 h starting
(4.0 × 4) 1000 h

1. de Graaf-Roelfsema E, Veldhuis PP, Keizer HA, van Ginneken MM, van Dam KG, Johnson ML, Barneveld A, Menheere PP, van Breda E, Wijnberg ID, and van der Kolk JH. Overtrained horses
alter their resting pulsatile growth hormone secretion. Am J Physiol Regul Integr Comp Physiol 297: R403-R411, 2009.
2. Grouselle D, Chaillou E, Caraty A, Bluet-Pajot MT, Zizzari P, Tillet Y, and Epelbaum J. Pulsatile cerebrospinal fluid and plasma ghrelin in relation to growth hormone secretion and food intake
in the sheep. J Neuroendocrinol 20: 1138-1146, 2008.
3. Hassouna R, Zizzari P, Tomasetto C, Veldhuis JD, Fiquet O, Labarthe A, Cognet J, Steyn F, Chen C, Epelbaum J, and Tolle V. An early reduction in GH peak amplitude in preproghrelin-deficient
male mice has a minor impact on linear growth. Endocrinology 155: 3561-3571, 2014.
4. Lado-Abeal J, Veldhuis JD, and Norman RL. Glucose relays information regarding nutritional status to the neural circuits that control the somatotropic, corticotropic, and gonadotropic axes in
adult male rhesus macaques. Endocrinology 143: 403-410, 2002.
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145-151, 2002.
6. Painson JC, Veldhuis JD, and Tannenbaum GS. Single exposure to testosterone in adulthood rapidly induces regularity in the growth hormone release process. Am J Physiol Endocrinol Metab
278: E933-E940, 2000.
7. Steyn FJ, Huang L, Ngo ST, Leong JW, Tan HY, Xie TY, Parlow AF, Veldhuis JD, Waters MJ, and Chen C. Development of a method for the determination of pulsatile growth hormone secretion
in mice. Endocrinology 152: 3165-3171, 2011.
8. Tolle V, Bassant M-H, Zizzari P, Poindessous-Jazat F, Tomasetto C, Epelbaum J, and Bluet-Pajot M-T. Ultradian rhythmicity of ghrelin secretion in relation with GH, feeding behavior, and
sleep-wake patterns in rats. Endocrinology 143: 1353-1361, 2002.
9. Veldhuis JD, Fletcher TP, Gatford KL, Egan AR, and Clarke IJ. Hypophyseal-portal somatostatin (SRIH) and jugular venous growth hormone secretion in the conscious unrestrained ewe.
Neuroendocrinology 75: 83-91, 2002.
10. Yonezawa T, Mogi K, Li JY, Sako R, Manabe N, Yamanouchi K, and Nishihara M. Negative correlation between neuropeptide Y profile in the cerebrospinal fluid and growth hormone pulses
in the peripheral circulation in goats. Neuroendocrinology 91: 308-317, 2010.

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fetal growth. Indeed, maternal GH modulates placental func-
tion, enhancing fetal growth by enhancing nutrient exchange
between the mother and fetus (168). Mechanisms of maternal-
enhanced fetal growth will not be discussed here, as these
effects largely diverge from the neuroendocrine regulation
of fetal GH release (see below maternal control of GH in
pregnancy).
Following birth, growth continues at the same rate as is
seen in utero until approximately 6 to 10 months of age,
after which growth slows during childhood. The appearance
of GH, and onset of pulsatile release occurs within the first
hours of birth. This is characterized by the emergence of GH
secretory bursts within the first day/night (120). The amount
of GH produced relative to the surface area of the newborn
greatly exceeds that seen in childhood or adulthood. Prema-
ture birth is associated with increased GH secretion, thought
to occur as a consequence of withdrawal of feedback by IGF-1
(174).
Childhood
Estimates of GH secretion rates during childhood (prior to
puberty) range between 100 and 600 μg/day (228, 324, 325,
441, 442, 552). Given variable observations between studies,
accurate estimates of GH release throughout childhood may
be best-inferred following longitudinal assessment. Longitu-
dinal assessment of GH output in healthy boys ranging from
9.5 years of age to close to 12 years of age revealed a fourfold
range in GH output parameters between individuals, whereas
within individual variability was minimal (325). Within this
cohort, GH pulse amplitude largely contributed to between-
individual variability in mean GH release. By comparison,
pulse frequency was mostly conserved. No change in GH
release (within individuals) was observed with advanced age,
and thus it is inferred that GH release in childhood remains
stable. This observation matches that from earlier reports, con-
firming little to no change in mean GH concentrations, mean
day-time and night-time GH concentrations, mean night-time
GH pulse amplitude and the number of GH secretory events in
boys aged under 9 years of age when compared to prepubertal
boys over 9 years of age (441). By contrast, all parameters in
prepubertal girls at 8 years of age increased when compared
to girls that were younger than 8 years of age, demonstrating
sex differences in the timing of the increase in GH release rel-
ative to pubertal maturation (441). Of interest, the differential
change in the onset of increased GH output between boys and
girls reflect altered growth rates documented between sexes,
wherein increased growth rate occurs earlier in puberty in
girls (158, 517).
Puberty
The transition of childhood into puberty occurs alongside
a number of critical physiological changes, mediated by
endocrine responses to sexual maturation of the gonads, and
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is associated with the greatest period of change in GH levels
and patterning that is observed throughout life. Emerging
feedback from sex-steroid hormones is largely responsible
for the transition of altered GH release throughout puberty,
as demonstrated following administration of estrogen or
testosterone to individuals with ovarian (330) or testicular
(173, 303, 537) dysfunction that results in impaired steroid
hormone production. In all instances, steroid hormone treat-
ments mostly improve GH output to that normally seen in
healthy individuals. Regarding GH release, pubertal matura-
tion is associated with a dramatic rise in GH output. The first
comprehensive study to document this described progressive
changes in GH output in boys and girls, reflecting an increase
in mean GH levels that occur largely in response to an increase
in GH pulse amplitude, and not GH pulse frequency (441).
Increased GH output reflected progression through pubertal
maturation, as assessed through breast development in girls
and testicular volume in boys. In girls, mean GH output
correlated negatively with BMI, whereas this was not the case
for boys. These observations were verified following the lon-
gitudinal assessment of GH output in developing boys, adding
that alterations in GH output relative to pubertal maturation
does not occur in response to altered GH clearance/half-life
(325).
The mechanism of increased GH release throughout
puberty is unique, in that the rise in GH secretion at this time
occurs alongside an elevation in circulating levels of IGF-1
(hypersomatotropism) (441). In this regard, anticipated feed-
back between GH and IGF-1 does not predict GH release.
Moreover, this is not coupled with hepatic GH resistance,
as is often seen in conditions wherein GH/IGF-1 balance is
disrupted (174). It is thought that alterations in the sensitivity
of hypothalamic-pituitary feedback mechanisms may account
for derangements in GH/IGF-1 interactions during puberty [as
discussed in (174)]; however, this remains to be confirmed.
Despite continued production of adult sex-steroid hormones,
the duration of this period of GH/IGF-1 hypersecretion is lim-
ited, and it therefore remains unclear why GH output declines
to prepubertal and below prepubertal levels with increased
age. Of interest, feedback mechanisms associated with the
accumulation of adipose tissue may contribute to the progres-
sive decline in GH release following pubertal maturation, as
was demonstrated in early-adult mice in response to high fat
feeding (224).
Adulthood
An exponential decline in mean 24-h GH concentrations is
observed in men and women, starting from 18 to 25 years
of age, with GH output halving on average every 7 years
(174). This occurs regardless of sustained adult levels of
sex hormones, and is accompanied by the gradual decline
in circulating levels of IGF-1. A number of factors may con-
tribute to this progressive decline in GH release (often referred
to as somatopause), including age, body composition (and
Volume 6, April 2016
Comprehensive Physiology
notably adiposity), and exercise capacity. These factors pri-
marily impact GH burst mass, and not GH pulse frequency
(233,548,570), suggesting that factors that impact GH release
with age act predominantly on the pituitary gland, modifying
pituitary output or responses to hypothalamic cues. Of inter-
est, gender determines the severity of the impact of age, obe-
sity and exercise on GH output (570). Compared to men,
healthy premenopausal females are protected from the impact
of age and relative adiposity on daily GH output, whereas
this effect is lost in postmenopausal females in the absence of
gonadal hormone replacement therapy (102). While the clear-
ance of GH secretion between males and females is conserved,
GH output in females is greatly amplified, and characterized
by approximately twofold greater peaks in GH release (541).
Clinical observations [as detailed previously (551)] suggest
that an elevation in endogenous estrogen in females con-
tributes to increased peak GH output through; (i) accentuating
feedback by GH following a GH secretory event (545), (ii)
by augmenting somatostatin withdrawal-induced GH release
(545), (iii) by promoting endogenous actions of GHRH (390)
and the potency of exogenous GHRH (547) on GH release,
(iv) by reducing pituitary responsiveness to somatostatin (59),
and (v) by opposing GH feedback on GHRH stimulation (11).
Given the close relationship between GH output and steroid
hormones (and in particular estrogen), it comes as no surprise
that GH release within females varies considerably relative to
reproductive status.
Divergent control of GH release in females relative
to reproductive status
As detailed earlier, a number of factors contribute to alter GH
output between females and males following sexual matura-
tion, and throughout life (Fig. 7). Importantly, sexual differ-
entiation may occur prior to birth, with the prenatal steroid
hormone environment regulating critical differences in the
number of GHRH neurons, their responses to postpubertal
steroids, adult hypothalamic synaptic organization (including
synaptic inputs and glial cell morphology), and the number
and responsiveness of somatotroph that dictate adult GH out-
put. This article will focus predominantly on the differen-
tiation of GH secretory patterns that occur during pubertal
maturation, and in adulthood. The reader is asked to refer to
excellent reviews on neonatal development for a more com-
prehensive overview of factors that predict GH release prior
to birth (92). Moreover, while differences in GH release most
likely occur as a consequence of steroid hormone feedback,
further changes in GH output are observed specific to dif-
ferent metabolic states that occur as a consequence of addi-
tional reproductive pressures that are encountered throughout
female adult life. Of these, altered GH output relative to the
menstrual cycle, and pregnancy and lactation demonstrate
additional feedback mechanisms between central and periph-
eral regulators of GH release that are not seen in males. These
Volume 6, April 2016
Growth Hormone Axis
will be briefly discussed below, focusing in particular on the
role of estrogen in the regulation of GH release.
Estrogen
Pubertal maturation and the emergence of the ovulatory cycle
is associated with an increase in serum GH levels, and the
emergence of alterations in GH output that are correlated
with changes in serum estradiol levels. Assessment of pul-
satile GH output in pubertal girls revealed a twofold to three-
fold increase in peak GH release from the onset of puberty to
menarche. This increase is correlated with rising circulating
levels of estrogen (571), suggesting that endogenous estradiol
production in females further increases GH secretion. Indeed,
initial observations suggested a twofold rise in GH secretion
in women across the menstrual cycle (151). This was con-
firmed following the assessment of pulsatile GH release in
females, wherein a twofold rise in GH release was observed
toward the late follicular stage of the menstrual cycle (140).
To this extent, use of estrogens for superovulation induces
a significant rise in GH release (579). It is now well estab-
lished that circulating patterns of GH release in males versus
females vary considerably, with increased peak GH output
in females occurring as a consequence of increased levels of
circulating levels of estradiol. To this extent, treatment of men
with diethylstilbestrol (a potent estrogen) results a shift in the
pulsatile pattern of GH release to reflect that commonly seen
in females (151).
Alterations in GH output in response to estrogens is
thought to occur as a consequence of altered negative feed-
back, wherein the actions of IGF-1 on hypothalamic com-
ponents of the GH-axis are greatly diminished (574). This is
somewhat controversial (35), with evidence suggesting a com-
plex relationship between IGF-1, estrogen, and GH output.
At low dosages, estrogens increase GH output, whereas high
dosages of estrogens may decrease levels of bioactive IGF-1.
Moreover, the route of estrogen administration significantly
alters the effect of estradiol on GH release. Assessment of
pulsatile GH output in pre- and postmenopausal women fol-
lowing oral versus transdermal estradiol treatment revealed
divergent effects on GH release. In two independent stud-
ies, oral estradiol treatment increased 24 h mean and pul-
satile GH release and decreased circulating levels of IGF-1,
whereas transdermal estrogen treatment increased circulat-
ing levels of IGF-1 in postmenopausal to that seen in pre-
menopausal women without altering the pulsatile release of
GH (36, 569). Thus, it is thought that oral administration of
estrogen increases GH release through lowering circulating
levels of IGF-1, thereby reducing negative feedback. These
observations further highlight that the reduced GH output fol-
lowing menopause is not due to a reduction in circulating
levels estrogen (569). To this extent, neither oral nor transder-
mal estrogen treatment in postmenopausal women can reverse
age-related reductions in spontaneous or GHRH-stimulated
GH and IGF-I release (36).
711
Growth Hormone Axis Comprehensive Physiology

Figure 7 Differential GH secretory patterns between males and females. Mechanisms that promote GH output in adulthood are established during
pubertal maturation. For males, this results in the establishment of adult-specific GH release by 18 to 25 years of age, and the progressive decline
in peak and total GH release with age. Differential patterns and amounts of GH release between males and females occur as a consequence of
altered feedback to the hypothalamus and anterior pituitary gland, predominantly in response to circulating levels of estrogen. Increased circulating
levels of estrogen are associated with an overall rise in peak amplitude, pulse frequency, and total GH release in females when compared to males.
A further rise in peak and total GH release in females is observed during the follicular stage of the ovarian cycle, the period characterized by a rise
in circulating levels of estrogen (peaking prior to ovulation). Feedback from placental-derived GH to the anterior pituitary gland contributes to the
suppression of maternal GH release during pregnancy. Resumption of maternal GH output following birth is critical for sustained milk production
through prevention of involution of mammary gland tissue. Acting through direct mechanisms, or indirectly through insulin-like growth factor-1
(IGF-1), GH is thought to further promote the transport of nutrients to maternal milk.

712 Volume 6, April 2016

Comprehensive Physiology Growth Hormone Axis

Pregnancy (535). Comprehensive reviews should be consulted for addi-

tional information specific to maternal fetal GH interactions,
Initial observations suggested a progressive rise in maternal
and the role of placental GH on fetal growth (177).
GH (268) and IGF-I (190) in pregnancy; however, subsequent
use of selective antibodies to distinguish maternal versus pla-
cental GH demonstrated the replacement of maternal GH by Lactation
placental GH relative to placental development. Specifically, a
The withdrawal of the placenta, and therefore placental GH,
progressive rise in circulating levels of placental-derived GH,
is associated with the resumption of maternal GH production.
starting from 20 weeks of gestation was observed (134, 150).
Observations from all mammalian species assessed to date
More recent direct measures confirmed the progressive rise
argue for a critical role for GH in regulating milk production
of placental GH starting from 8 to 10 weeks of pregnancy,
and release. Indeed, GH treatment enhances milk produc-
peaking at 35 to 36 weeks of pregnancy (309). This progres-
tion in humans (346), and GH treatment may therapeutically
sive rise in placental GH replaces maternal GH, with maternal
improve lactational insufficiency in mothers with preterm
levels gradually decreasing to near undetectable amounts in
infants (184). In dairy ruminants, GH treatment improves
circulation (134,150). In this regard, it was proposed that pla-
milk yield (32) and milk triglyceride content (310). In lactat-
cental GH or others pregnancy-related factors (placental lac-
ing rats the inhibition of GH release causes a reduction in milk
togen, IGF_1) act at the level of the anterior pituitary gland to
yield and milk fat (144). IGF-1 is positively related to milk
suppress GH release (122). However comprehensive data to
fat composition and milk yield (186), and thus it is thought
exclude potential direct inhibitory effects of placental GH on
that GH induces IGF-1 release to regulate milk composition
the human hypothalamus do not exist. Unlike maternal GH,
(143). Of interest, the reintroduction of previously removed
placental GH release is not pulsatile (134), and thus contin-
pups and the resumption of the suckling reflex induces a surge
ued feedback should completely silence maternal GH release.
in maternal plasma GH release (435). As the suckling reflex
Placental GH is secreted solely into maternal circulation, and
is accompanied by a concomitant increase in circulating GH
thus the function of placental GH is not completely clear.
and prolactin release (435, 456), common mechanisms may
Given the actions of GH in regulating energy metabolism,
modulate prolactin and GH release. Alternatively, suckling-
prolonged elevation of placental GH may induce relative
induced changes in prolactin release may facilitate increased
insulin resistance, allowing for the preferential transfer of glu-
GH output. Over the course of development, lactotrophs dis-
cose to the fetus, while shifting maternal energy homeostasis
play transient coexpression of GH secretory capability (285)
to encourage maternal dependence on lipolysis for energy
and both systems are under common control of endogenous
(177). This remains to be verified, especially as pregnancy
opiates (435). These observations suggest close integration
in the mother (although highly variable between individu-
of the mechanisms that facilitate production and release of
als) is commonly associated with weight gain due to increase
GH and prolactin. In the context of lactation, both GH and
adiposity (http://www.ncbi.nlm.nih.gov/books/NBK32815/),
prolactin are required to maximize milk yield, milk fat con-
and thus a lipolytic state normally associated with reduced
tent and the inhibition of mammary gland involution (143),
GH secretion.
and thus prolactin and GH may act synergistically to modulate
Maternal GH deficiency documented prior to pregnancy
lipolytic function of mammary tissue, as suggested previously
does not impact birth outcomes (111), suggesting that prevail-
(25, 26).
ing maternal GH levels does not impair fetal development. By
IGF-1 is a survival factor in mammary tissue morphology,
contrast, intrauterine growth retardation is associated with low
mediating mammogenesis (143) and lactogenesis (186). GH
or deficient maternal IGF-1 and placental GH levels (350).
acts directly on the mammary epithelium to induce paracrine
This suggests that maternal GH deficiency specific to preg-
IGF-1 production by the mammary stroma (143). Accord-
nancy may compromise fetal growth. Fetal production of GH
ingly, GH may modulate established effects of IGF-1 as a
occurs by 12 weeks of gestation (34), whereas placental GH
survival factor in mammary tissue. Should this occur, lacta-
does not cross the placenta (150). Therefore, it is unlikely
tion must be associated with a rise in GH release. Morpho-
that maternal GH directly contributes to fetal growth. Rather,
logical changes within pituitary gland contradict this notion,
maternal-derived GH may be critical for the exchange of fac-
as structural changes within the anterior pituitary gland favor
tors essential for optimal fetal growth (202). Given limited
the production of lactogens. Gestation and lactation in humans
correlative evidence for the role of placental and maternal
(482) and rats (187) is associated with pituitary hypertrophy
IGF-1 in fetal growth, it is thought that these maternally
and hyperplasia. In lactating rats, this is characterized by the
derived hormones likely contribute to maternal responses to
presence of numerous hypertrophied lactotrophs, a significant
pregnancy, potentially mediating maternal nutrient transfer.
increase in the percentage of lactotrophs, and a corresponding
Indeed, treatment of pregnant pigs with GH during early preg-
decrease in somatotroph number. This morphological change
nancy removes maternal constraints on fetal growth, resulting
is reversed following weaning, and therefore the cessation
in increased size of prodigy at birth (167). Recent observations
of suckling (187). In humans, lactation is known to reduce
confirmed that these positive effects occurred predominantly
GH mRNA expression and increase prolactin mRNA expres-
in response to enhanced maternal nutrient transfer to the fetus
sion (482). Moreover, as lactation proceeds, somatotroph cells

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Growth Hormone Axis
transdifferentiate into mammosomatotrophs (131) with the
ability to secrete prolactin and GH. These transdifferentiated
cells eventually develop into lactotrophs (554). Therefore, due
to the extent of observed transdifferentiation coupled with
morphological changes within the gland, one may anticipate
an overall reduction in GH output (131). This contradicts
anticipated actions of GH on IGF-1, and consequential GH
and IGF-1 mediated effects on maternal milk quality and
mammary gland morphology. At any rate, the transdifferen-
tiation of mammosomatotrophs remains an interesting obser-
vation that needs to be further validated with modern genetic
methods for tracing cell lineages. Given potential morpho-
logical changes within the pituitary gland to favor lactogen
output, should an increase in GH release be observed in lac-
tation, this shift in GH output may occur as a direct con-
sequence of altered hypothalamic control or altered soma-
totrophs responses to hypothalamic (and possibly peripheral)
feedback. Alternatively, as prolactin may increase circulating
levels of IGF-1, acting directly within the liver (368), the role
of GH as a key regulator of IGF-1 in lactation may be dimin-
ished, with prolactin directly promoting the anti-involution
and lipolytic actions of IGF-1. However, this seems unlikely,
as serum IGF-1 levels do not appear to contribute to the mam-
motrophic actions of PRL (132). Given the well-established
role of GH in sustaining optimal lactation, it is surprising
that mechanisms that define GH release in lactation remains
completely unexplored.
GH regulation and sleep
Bidirectional interactions between the activity of the GH/IGF-
1 axis and sleep regulation have been observed (210, 483,
540). In humans, GH secretion is directly linked to the sleep-
wake cycle. Indeed, GH is secreted preferentially during sleep
and maximal GH secretory burst occurs within minutes after
the onset of slow-wave sleep (SWS). When the sleep cycle
is delayed or advanced, GH secretion is either delayed or
advanced to coincide with the first episode of sleep. In rodents,
the link between GH secretion and sleep-wake cycles are more
difficult to confirm, as sleep patterns in rodents are defined by
multiple and sporadic wake/sleep phases over a 24 h period
(529).
The association between GH secretion and sleep is con-
served in subjects with sleep disorders, wherein altered
episodes of wakefulness and sleep are observed throughout
the day; the beginning of the SWS precedes the GH burst
(423). In healthy subjects, when sleep is delayed by several
hours, the nocturnal GH burst is also delayed (179, 427, 567).
In narcoleptic subjects, the nocturnal GH secretory burst is
considerably reduced or absent (44, 94, 200). Sleep depriva-
tion also impacts GH secretion, and the nocturnal GH secre-
tory burst is suppressed after 24 h of sleep deprivation. The
absence of peak nocturnal GH secretion is compensated for
by larger peaks during the day, whereas total GH secretion
per 24 h remains constant (58). In addition, an increase in GH
secretion is observed during the early sleep cycle following
714
Comprehensive Physiology
sleep deprivation (553). Although there is a strong link
between sleep-wake cycle and GH secretion, it is difficult
to define whether sleep modulates GH secretion or whether
GH influences sleep-wake cycles. SWS seems to precede the
nocturnal GH burst but some studies observed that the noc-
turnal GH burst precedes the beginning of the SWS or that
a third of SWS episodes are not associated to GH secretion
(539).
Recent reviews have described the effects of GHRH and
GH secretagogues on sleep-wake cycles (260, 519). In rats,
rabbits and humans, exogenous GHRH promotes nonrapid
eye movement (NREM) sleep and suppression of endoge-
nous GHRH (with antagonists, antibodies, somatostatin stim-
ulation or high doses of GH or IGF-1 through negative feed-
back) inhibits NREM sleep (386). Indeed, GHRH increases
the duration and/or intensity of NREM sleep, including SWS,
with a greater efficacy of episodic than continuous GHRH
administration (323). After sleep deprivation, GHRH also
enhances NREM sleep (463). The sleep-promoting effect of
GHRH is observed after ip and icv injections as well as after
direct injections in the preoptic area in male rats (385, 596)
and in healthy young men (261, 323, 410, 484). Surprisingly,
an opposite effect is reported in young women (329). In trans-
genic mice with reduced GHRH, NREM sleep is suppressed
during both the light dark periods but REM sleep is unmodi-
fied (595).
Genetic alterations that compromise GHRH transmission
are associated with reduced NREM sleep in both rodents
and in humans (260). In dwarf mice with transgenic over-
expression of human GH to sites of tyrosine-hydroxylase
synthesis in the brain, plasma endogenous GH, IGF-1, and
GHRH are nearly undetectable and the duration of NREM
sleep and total sleep time are reduced while wakefulness is
increased (595). Similarly, the lit/lit mouse with nonfunc-
tional GHRH receptors displays reduced NREM sleep (and
slightly decreased REM sleep as well) during the light period
and sc GHRH infusion restores NREM sleep values similar to
those observed in wild-type mice (383). In spontaneous dwarf
rats with a recessive abnormality that decreases GHRH-R and
GH levels (dw/dw), reduced NREM sleep during the light and
dark cycles and reduced REM sleep during the light period is
observed (384). In contrast, transgenic mice over-expressing
GH show increased NREM (and REM) sleep during the light
period (188).
Growth hormone secretagogues (GHS) and ghrelin are
also modulators of the sleep-wake cycle. In healthy young
men, 1-week oral treatment with the GHS MK-0677 increased
SWS and decreased wakefulness (103). In elderly subjects,
GHS does not appear to affect the sleep-promoting effects of
GHRH (103). When GHRP-6, another GHS, is administered
intravenously in a pulsatile manner (four injections during
the night), NREM sleep stage 2 increases as well as nocturnal
GH secretion (157). In another study by the same group,
after pulsatile intranasal, oral and sublingual administration
of the same GHS, the effect on sleep architecture was not
as pronounced, suggesting that the observed effects depend
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Comprehensive Physiology
on the route of administration (156). Furthermore, the mode
of administration (pulsatile versus single injection) could be
an important determinant of the effects of GHS on sleep,
as a single injection of GHRP-2 during the third period of
REM sleep does not affect sleep (355). Hexarelin, in contrast,
decreased the amount of SWS and increased GH secretion
(155). Possible negative feedback of GH on GHRH may have
induced a reduction in SWS in this latter study.
Ghrelin, after four repeated injections every hour at
the beginning of the dark cycle, increases NREM sleep
and decrease REM sleep in young men, but not young
women, when administered alone or coadministered with
GHRH (270) (271,272), reaffirming potential sex-differences
between sleep and GH release. Ghrelin also increases SWS
and decreases REM sleep in elderly men but not in elderly
women, although it triggers the same GH effect in both
sexes, indicating sexual dimorphism in the sleep promoting
but not GH-releasing effects of ghrelin (269). However, four
repeated injections of ghrelin in the early morning increase
GH secretion without affecting sleep (271,272). As with GH,
an increase in endogenous ghrelin secretion is observed before
sleep onset in men but not in women (462). In young adult
male rats, repeated administration of ghrelin at 3- to 4-h inter-
vals (one during lights-on and two during lights-off periods)
decreased REM sleep duration (529). In ghrl−/− mice, basic
sleep-wake regulatory mechanisms are not impaired (499)
but restricted feeding-induced arousal is attenuated (135).
Altogether, interaction between endogenous ghrelin and sleep
appear to be gender and species dependent and still needs to
be clarified.
In GH-deficient (GHD) patients, sleep-wake cycles
are characterized only in a few controversial studies
(21, 235, 359, 382, 408, 460). These studies are often difficult
to interpret due to the small number of subjects, the lack of
proper controls or GHD of different origin (pituitary versus
hypothalamic). In a placebo-controlled study, 4 months of GH
therapy seem to partly reverse sleep disturbances previously
observed in untreated patients (359). GHRH induced NREM
sleep is a hypothalamic mechanism involving GABAergic
neurons in the medial preoptic area and neither GH not
IGF-1 are involved (386). Thus, as GH stimulates REM
sleep in both rodents and humans (20, 335) while GHRH
rather promotes NREM sleep, excess of high-intensity SWS
associated with decreased REM sleep in some untreated
GH-deficient subjects of pituitary origins (235) has been
interpreted as an upregulated hypothalamic GHRH release
secondary to the lack of negative GH feedback (104). In
GHD with hypothalamic disorders, defect in both GHRH and
GH are associated with both reduced NREM and REM sleep
(519).
GH regulation and stress
Impaired bone growth is observed in children exposed to
stress (457). In animal models, maternal immobilization stress
during lactation results in low body weight in the offspring.
Volume 6, April 2016
Growth Hormone Axis
GH expression in the pups pituitary is reduced. In addition,
maternal malnutrition induced by stress is associated with a
reduction in serum IGF-1 levels in the dams and the pups
(165).
The physiological effects of stress can be mediated
through many different mechanisms, including increased
serum concentrations of proinflammatory cytokines and glu-
cocorticoids (GCs), as well as impaired actions of the GH-
IGF-1 axis. Neuroendocrine responses to stress involve the
activation of the HPA axis with increase in hypothalamic CRH
mRNA and serum GCs level. Data concerning the actions of
GCs on GH secretion are contradictory: GCs increasing or
reducing GH secretion depending on the experimental con-
ditions. Dexamethasone stimulates GH release from soma-
totroph cells (392) and increases the sensitivity to GHRH in
rats (371,538) and humans (370). In vivo, acute administration
of dexamethasone increases the amplitude of GH secretory
peaks (562) and potentiates GH response to GHRH (562).
Some studies also reported elevated IGF-1 levels in subjects
exposed to dexamethasone on the short term (341, 419). In
contrast, GCs administered on the long term or with supra-
physiological doses inhibit growth and GH secretion in the
rat (387). Direct GCs stimulatory effects in the pituitary gland
are mediated through an increase in the transcriptional activity
of the somatotrophs (524) or by a higher affinity or receptor
density for GHRH on the cell (464, 465) associated with a
decrease in the number of somatostatin receptors but not their
affinity (461). At the hypothalamic level, GCs stimulatory
effects may be the consequence of altered synthesis or release
of somatostatin and a reduction of the negative feedback from
IGF-1 on GH secretion (523). In contrast, GCs inhibitory
effects seem to be the consequence of an increase in the
somatostatin tone. Indeed, inhibition of GHRH-induced GH
release by high doses of dexamethasone is totally absent after
antisomatostatin pretreatment (565). In patients with Cush-
ing syndrome, a decrease in GH secretion is observed (490),
accompanied by growth retardation in children (491). Chronic
stress that impairs hippocampal function in rats leads to a
reduction in hippocampal GH levels and restoration of hip-
pocampal GH by viral gene transfer reverses stress-related
alterations (544).
Ghrelin is involved in both neuroendocrine and behavioral
responses to stress through activation of the HPA axis (includ-
ing increases in hypothalamic CRH mRNA and serum cor-
ticosterone). However some of the effects of ghrelin appear
independent of the HPA axis; rats repeatedly exposed to a
stressor display, a model of posttraumatic stress disorder,
heighten fear learning following auditory Pavlovian fear con-
ditioning through ghrelin stimulation of GH receptor in the
amygdala, independently of the HPA axis (339). In humans,
however, posttraumatic stress is associated with a reduction
in nocturnal GH secretion, possibly secondary to sleep frag-
mentation in response to stress (543). Behavioral responses
to stress may preclude anxiodepressive disorders and ghrelin
has been shown to mediate metabolic-induced anxiety and
depression (282).
715
Growth Hormone Axis Comprehensive Physiology

Old age and somatopause GH Axis and Longevity

This section will briefly discuss considerations pertinent to
Growth Hormone and IGF-1 levels decline during advanc-
the role of GH in ageing. For a more comprehensive overview
ing years of life. These changes (somatopause) are associ-
of the effects of ageing on GH output, the role of GH
ated with loss of vitality, muscle mass, physical function,
on accelerated ageing, and therapeutic strategies, and side
together with the occurrence of frailty, central adiposity, car-
effects of GH treatment, please consult recent comprehen-
diovascular complications, and deterioration of mental func-
sive reviews (110, 170, 557). The progressive decline of GH
tion. This phenomenon has led to recombinant human GH
release with age (16, 108, 363) culminates in levels of GH
being widely promoted and abused as an antiageing drug,
resembling that seen in adult GHD (240), and corresponds to
despite lack of evidence of efficacy and possible deleterious
decreased lean body mass, increased body fat mass, reduced
effects as indicated in the consensus statement by the Growth
bone mass, and reduced aerobic capacity. This may contribute
Hormone Research Society on the GH/IGF-I Axis in Extend-
to the development of a number of pathologies, including
ing Health Span (527). By contrast, evolutionarily conserved
increased frailty and frequency of fractures, muscle atrophy,
mutations that decrease the tone of the GH/IGF-1 axis are
and obesity (240). Despite considerable evidence from ani-
associated with extended longevity from worms to mice with
mal studies suggesting that increased GH release may accel-
some homologies extending to unicellular yeast (403). How-
erate ageing (28-30, 217), it is thought that reduced GH
ever, while mutations in IGF-1-Insulin-like receptor (Daf-
output, and an acceleration in reduced GH output with age
2) often result in a twofold to threefold lifespan extension
might accelerate the ageing process. This has spurred a num-
in Caenorhabditis elegans, corresponding mutations in mice
ber of trials wherein GH administration was considered as
are much less efficient. Such mutations and genetic models
an effective mean for slowing the ageing process [includ-
affecting the GH axis are listed on Table 3, according to their
ing (149, 211, 286, 402, 447)]. While generally promoting an
primary effect with their human counterparts.
increase in lean muscle mass at the expense of adipose tis-
Natural mutations in two genes involved in pituitary devel-
sue (149,211,286,402,447), studies often report adverse side
opment (Pou1f1, the gene encoding for the pituitary transcrip-
effects including edema (149, 211, 286, 402), fluid retention
tion factor Pit-1 in Snell mice, and Prop1, a homeobox protein
(402), hypertension (447), carpal tunnel syndrome (211,286),
involved in the transcriptional regulation of Pit-1 in Ames
and to some extent, hyperglycemia (149, 447). The efficacy
mice) are the two most potent mutations in terms of dwarfism
and risks associated with GH treatment relative to age is still
and life span extension. On both strains of mice insulin sen-
under debate, and considerable attention needs to be directed
sitivity is increased despite increased body fat. Tumor inci-
toward the mode and dosage of GH or GH secretagogues
dence is decreased and oxidative stress resistance increased.
delivery.
A homozygous PROP1 mutation has been described in 25
While still under investigation, proposed mechanisms for
patients with dwarfism originating from the Island of Krk in
impaired GH output in old-age mostly converge at the level of
Croatia. These short-statured individuals (106-152 cm) are
the hypothalamus, and it is believed that reduced GH output is
obese but they do not develop type 2 diabetes with increasing
largely due to enhanced somatostatin release, and diminished
age and do not seem to die prematurely (280).
GHRH secretion (372). In men, treatment of pyridostigmine,
A third natural mutation, a single amino acid substi-
to withdraw somatostatin and therefore to enhance GHRH
tution in the extracellular domain of the GHRH receptor,
release, recovers peripheral GH output. This results in the
induces GHRH resistance and life span extension in little
near normalization of mean 24-h serum GH and IGF-1 con-
dwarf mice. As the Snell and Ames mice, the little mice phe-
centrations in older men, when compared to young men (97).
notype includes higher insulin sensitivity despite increased
Regarding GHRH deficiency, measures are somewhat con-
body fat, lower tumor incidence, and increased stress resis-
tradicting. For example, pulsatile-GHRH infusion over three
tance. Two cohorts of patients with homozygous mutations
consecutive days failed to enhance GH output in older men
in the GHRH receptor have been reported, originating from
(173). Similarly, daily treatment of GHRH alone, or in com-
Pakistan (317) or Brazil (3, 451) with very similar heights
bination with L-arginine (to suppress endogenous somato-
(105-135 cm) and mild obesity. A reduced mean life span
statin tone), failed to normalize GH output in elderly patients
compared with the unaffected population was reported for the
(169). In this regard, impaired GH release in old age may
later (48 vs. 63 years) but no data is yet available for the for-
occur as a further consequence of impaired GHRH action.
mer. Reduced longevity relative to that of unaffected brothers
These observations stem from initial investigations that con-
and sisters (males, 56 vs. 75 year; females, 46 vs. 80 year)
sidered the effects of ageing on GH output in dogs (77-79),
has also been reported in untreated patients with isolated GH
wherein the combined roles of somatostatin and GHRH were
deficiency linked to a 6.7 kb deletion in the GH1 gene (45).
well defined. In Man, there is evidence of an age-dependent
Major GH deficiency is also observed in the Ghrh knock-
decline in circulating acyl-ghrelin levels, with ghrelin/GH
out mice on a mixed genetic background with remarkably
association more than threefold lower in the 62- to 74-year-
increased longevity accompanied by major shifts in the
old group compared with the young 18- to 28-year-old adults
expression of genes related to xenobiotic detoxification, stress
(376).
resistance, and insulin signaling (493).

716 Volume 6, April 2016

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Table 3 Effects of Genetic Alterations in the GH/IGF-1 Axis on Longevity in Human Diseases or Genetic Variants and Mouse Models

Human diseases Lifespan Lifespan (days)

or genetic Size (% of changes Genetic Body Insulin Tumour Stress
variants Mouse models control) (%) Mutant Control background fat sensitivity incidence resistance

Pituitary Krk cohort Snella 25-33 F + 42 F 1148 ± 39 F 811 ± 80 DWC3F1 ⇑ ⇑ ⇓ ⇑

developmental M + 26 M 1037 ± 33 M 822 ± 34
defect
Amesb 33-50 F + 68 F 1206 ± 32 F 718 ± 45 heterogenous ⇑ ⇑ ⇓ ⇑
M + 49 M 1076 ± 56 M 723 ± 54
GH deficiency Itabaianinha lit/litc 50-67 F + 25 F 1070 ± 127 F 857 ± 169 C57BL/6J ⇑ nd ⇓ ⇑
Sindh M + 23 M 1093 ± 186 M 886 ± 148
Sammaun
cohorts Ghrh−/−d 55-60 F + 43 F 956 ±? F 666 ± ? C57BL/6J x ⇑ ⇑ nd ⇑
M + 51 M 928 ±? M 614 ± ? 129SV/E
GH resistance Laron syndrome Ghr−/−e 50 F + 21 F 921 ± 41 F 759 ± 41 Ola-BALB/cj ⇑ ⇑ ⇓ ⇑
M + 40 M 917 ± 55 M 656 ± 67
GH antagonism GHAf 70 F+9 F 839 ± 25 F 771 ± 26 C57BL/6J ⇑ ⇑ nd
M+4 M 790 ± 41 M 758 ± 40
GH excess Acromegaly bGH transgeneg 150 F? F? F? C57BL/6J ⇓ ⇓ ⇑ nd
M - 45 M 425 ± 22 M 773 ± ?
Decreased IGF-1 Pappa−/−h 40 F + 41 F&M F & M 698 ± 23 C57BL/6J x nd = ⇓ nd
availability in M+3 960 ± 28 F 672 ± ? 129SV/E
pericellular F + 33 F 882 ±? M 679 ± ?
environment M + 20 M 812 ± ?
Decreased LID−/−i 90 F+4 F 1087 ± 38 F 1043 ± 30 C57BL/6J ⇑ ⇓ ⇓ nd
circulating M - 18 M 836 ± 50 M 1014 ± 55
IGF-1 levels
LI-Igf1−/−j 88 F + 16 F 812 ± 33 F 700 ± 21 C57BL/6J ⇓ ⇓ nd nd
M+6 M 714 ± 24 M 672 ± 21

(continued)

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718
Growth Hormone Axis

Table 3 (Continued)

Human diseases Lifespan Lifespan (days)

or genetic Size (% of changes Genetic Body Insulin Tumour Stress
variants Mouse models control) (%) Mutant Control background fat sensitivity incidence resistance

50% IGF-1 IGFR variants Igf1r+/−k 90 F + 33 F 756 ± 46 F 568 ± 49 129J nd ⇓ nd ⇑

receptor activity M + 16 M 679 ± 80 M 585 ± 69
Igf1r+/−l 90 F+5 F 967 ± 29 F 923 ± 21 C57BL/6J nd ⇓ = ⇑F
M-5 M 939 ± 24 M 983 ± 21
Igf1r+/−m 90 F + 11 F 896 ± 23 F 805 ± 26 C57BL/6J nd ⇓ nd ⇑
M-3 M 803 ± 20 M 831 ± 22
BIGFRKO+/−n 90 F+8 F 888 ± 27 F 821 ± 36 C57BL/6J x ⇑ ⇓ ⇓ =
(brain specific) M + 13 M 966 ± 28 M 853 ± 43 129SV/E
Alterations in IRS2 variants Klotho 100 F1 + 19
IGF-1/Insulin transgeneo F2 + 19
signalling
M1 + 20 F1 829 ± 32 F 697 ± 45 C57BL/6J × nd ⇓M Nd ⇑
M2 + 31 F2 830 ± 29 M 715 ± 44 C3H
M1 858 ± 40
M2 936 ± 47
Irs1−/−p 70 F + 17 F 891 ± 39
M + 14
M 897 ± 41 F 763 ± 21 C57BL/6J ⇓ ⇓ nd Nd
M 786 ± 21
Irs2 +/−q 100 F + 16 F 918 ± 21 F 790 ± 14 C57BL/6J nd ⇑ nd nd
M + 18 M 900 ± 34 M 761 ± 13
Irs2 +/−r 100 F&M + 4 F&M 788 ± 17 F&M 755 ± 22 C57BL/6J nd = nd nd
Irs2−/−s 90 F - 26 F 560 ± 63 F 755 ± 23 C57BL/6J nd ⇓ nd nd
M - 84 M123 ± 20 M 767 ± 40
Comprehensive Physiology

Volume 6, April 2016

 NesCreIrs2+/−t 100 F&M + 18 F&M 936 F&M 791 C57BL/6J ⇑ ⇓ nd nd
NesCreIrs2−/−t 100 F&M + 14 F&M 901
(brain specific)

P66shc+/−u 100 F&M + 7 F&M 815 ± 37 F&M 761 ± 19 129SV/Ev ⇓ = nd ⇑

P66shc−/−u F&M + 28 F&M 973 ± 37
S6K1−/−v 70 F + 20 F 950 ± 38 F 789 ± 42 C57BL/6J = nd

Volume 6, April 2016

⇓ ⇑
M+5 M 841 ± 47 M 801 ± 39
Comprehensive Physiology

Modified from Junnila, 2013 and Berryman et al., 2008.

Abreviations: F, females; M, males; nd, not determined.
a, (8) g, (1) m, (21) s, (20)
b, (4) h, (5, 6) n, (11) t, (19)
c, (8) i, (9) o, (12) u, (13)
d, (17) j, (18) p, (14, 15) v, (16)
e, (2, 7) k, (10) q, (19)
f, (2, 7) l, (3) r, (14)

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5. Conover CA. Role of PAPP-A in aging and age-related disease. Exp Gerontol 48: 612-613, 2013.
6. Conover CA, and Bale LK. Loss of pregnancy-associated plasma protein A extends lifespan in mice. Aging Cell 6: 727-729, 2007.
7. Coschigano KT, Holland AN, Riders ME, List EO, Flyvbjerg A, and Kopchick JJ. Deletion, but not antagonism, of the mouse growth hormone receptor results in severely decreased body weights,
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and Kuro-o M. Suppression of aging in mice by the hormone Klotho. Science 309: 1829-1833, 2005.
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IC, Thornton JM, Gems D, Partridge L, and Withers DJ. Evidence for lifespan extension and delayed age-related biomarkers in insulin receptor substrate 1 null mice. FASEB J 22: 807-818, 2008.
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19-28, 2014.

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Growth Hormone Axis
Two dwarf mouse lines with decreased GH action exhibit
strikingly different phenotypes in term of life span extension:
the GH receptor-invalidated (Ghr−/−) mouse is completely
resistant to GH action and long-lived while another dwarf
mouse line expressing a GH-R antagonist (GHA) transgene
is only partially resistant to GH. Compared to the Ghr−/−, life
span extension in this mouse is not as significant. Circulating
IGF-1 levels are less reduced in the GHA when compared
to the GH-R-/- mouse, and if glucose homeostasis is mod-
estly improved in young GHA animals, it deteriorates with
age. In humans, GH resistance corresponds to the Laron syn-
drome (182,290,291,443), caused by homozygous mutations
in GHR or GHR-signaling molecules. Laron adult heights
vary from 106 to 142 cm and they are obese. Protection from
diabetes is observed in a large Ecuatorian cohort but not in
the original Mediterranean one. No change in lifespan in this
population has been reported as yet.
Growth hormone excess in GH overexpressing transgenic
mice (29,398,421), as is seen in acromegalic patients bearing
GH hypersecreting adenomas (85), induces gigantism, lean-
ness, insulin resistance and shortens life span. Decreasing
GH and normalizing IGF-1 levels, by surgery, radiotherapy
or pharmacological treatment with somatostatin analogues
or the GH antagonist pegvisomant, reduces the mortality
rate of acromegalic patients to that of the normal population
(37, 124, 209).
In contrast to mice lacking GHRH, GH or the GH
receptor which are viable, neonatal deaths often occur in
IGF-1 knockout (Igf1−/−) dwarf (60% of normal size)
mice. Neonatal death ratio depends on the mouse genetic
background (90% in 129SVX 129SV to 32% in MF1x129SV
crosses). Null mutants for the Igf1r gene invariably die at
birth as a consequence of respiratory failure, with a more
severe growth deficiency (45% of normal birth weight)
(307). Therefore, several strategies were designed to assess
the effects of IGF-1 deficiency in nonlethal mouse mutants.
Pregnancy-associated plasma protein A (PAPP-A) is a
metalloproteinase that degrade inhibitory IGF-Binding
Proteins (IGFBP), particularly IGFBP4, in the pericellular
environment; thereby increasing IGF-1 bioavailability
without changing IGF-I levels. Genetic deletion of PAPP-A
extends mean and maximum lifespans by 30% to 40%, with
no reduction in food intake or secondary endocrine abnor-
malities and reduced incidence of spontaneous tumors (101).
In contrast, when 75% decreases in circulating IGF-1 levels
were achieved by liver-specific invalidation of IGF-1 in two
mouse strains (LID−/− (180) and LI-Igf1−/− (497) mice),
modest (<20%), sex-dependent and contradictory modifica-
tions in life spans were reported. Contradictory reports also
exist for constitutive IGF-1r heterozygous (Igf1r+/−) mice,
which display a 50% or no reduction in circulating IGF-1
levels (52,217,585). The effects on life span appear to depend
on the conditions in which these mice are kept and crossed.
However, human IGF1R variants with a higher frequency in
centenarians (2.3%) than controls (0.3%) have been reported
to suppress IGF1 signaling and female carriers have slightly
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Comprehensive Physiology
short stature and elevated IGF-1, suggesting IGF-1 resistance
(492, 522).
Post IGF-1 and insulin receptor signaling has also been
targeted on insulin receptor substrates (IRS), which are dock-
ing proteins between the membrane receptors and their mul-
tiple intracellular pathways. Out of the 4 IRS, IRS1, and
IRS2 are the major insulin receptor substrates leading to glu-
cose homeostasis, and have distinct and overlapping roles in
diverse organs. The majority of the published literature in
this field suggests that IRS1 is the major substrate leading to
stimulation of glucose transport in muscle and adipose tis-
sues, whereas in liver, IRS1 and IRS2 have complementary
roles in insulin signaling and metabolism. Constitutive dele-
tion of IRS1 extends lifespan in IRS-1 knockout (Irs1−/−)
mice (467, 468) while IRS-2 knockout (Irs2−/−) mice are
diabetic and considerably short lived (467). Lifespan is not
affected in Irs1 heterozygous (Irs1+/−) mice (467) while Irs2
heterozygous (Irs2+/−) mice (which have normal to improved
insulin sensitivity (500,580) display extended (500) or normal
(467) longevity. In Humans, one study of an Italian popula-
tion revealed that individuals heterozygous or homozygous
for a common IRS2 gene variant, Gly1057Asp, present in
about a third of the population, have a higher probability of
reaching old age (96-104 years) than bearers of the wild-
type allele (27). When tested together with two other com-
mon alleles, G/A-IGF1R and the mitochondrial uncoupling
protein 2 Ala/Val-UCP2, the AAV allele combination was
associated with a decrease in all-cause mortality risk and a
higher probability to reach extreme old age as well as lower
homeostatic model assessment ratio (HOMA-R), a measure
of insulin resistance, higher respiratory quotient, and resting
metabolic rate (27).
Taken altogether, this complex set of data raises the ques-
tion of the tissue targets for IGF-1 in extending life span. In
this respect, cardiac-specific overexpression of IGF-1 posi-
tively affected mouse median but not maximal lifespan (298).
Conversely, neuron-specific reduction of the IGF-1/insulin
receptor ortholog Daf-2 in C. elegans (581) and brain-specific
reduction of IGF1-R1 (248) or IRS2 (500) in mice were
reported to increase maximal life span (again with a much
bigger effect in worms than mammals). Moreover, the invali-
dation of Surfeit locus protein 1 (SURF1), a 30 kDa hydropho-
bic protein embedded in the inner membrane of mitochon-
dria, also results in markedly prolonged median lifespan, and
complete protection from calcium-dependent neurotoxicity
induced by kainic acid (125). However, the brain is not the
only target organ involved since extended longevity is also
observed in mice lacking the insulin receptor in adipose tissue
(50). The kidney may also be involved since Klotho protein,
a transmembrane protein with homology to B-glycosidases,
is principally expressed in the distal tubules (and the choroid
plexus). Klotho may also acts as a hormone and may bind and
repress IGF-1 and insulin intracellular signals (281). Klotho
overexpression in mice extends lifespan but in contrast to
previously discussed mouse models with increased lifespan,
Klotho transgenic mice are insulin resistant (281).
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Comprehensive Physiology
In summary, corresponding or similar mutations in the
GHRH/GH/IGF-1 pathway have been identified in mouse
and Man, but whether these mutations alter longevity has
yet to be confirmed in the latter species. At any rate, several
of these mouse and human mutations with reduced activity
of the GH/IGF-1 axis appear protective against cancer and
diabetes mellitus, two major ageing-related morbidities. The
activity of the GH-IGF-1 axis is also decreased by calorie
restriction (CR), a powerful intervention that slows the age-
ing process and decreases mortality in a range of organisms,
including rhesus monkeys (98). Deletion of ribosomal S6 pro-
tein kinase 1 (S6K1), a component of the nutrient-responsive
mTOR (mammalian target of rapamycin) signaling pathway,
downstream of IRS1 signaling, lead to increased life span and
resistance to age-related pathologies, such as bone, immune,
and motor dysfunction and loss of insulin sensitivity (469).
Life extension is also present in p66shc−/− mice (342). The
p66shc isoform of SHC-transforming protein 1 has been sug-
gested to couple IRS1 and the S6 kinase.
Conclusion
Assessment of the complex interactions that define GH release
has seen the evolution of models that predict and interpret
GH output under particular physiological or pathophysiolog-
ical conditions. Considerable insights now help to define the
actions of GH in growth, metabolism, and longevity, and the
role of the neuroendocrine system in sustaining these fun-
damental processes of life. These led to significant clinical
improvement for the therapy of acromegaly through long
acting somatostatin analogs (379) and GH receptor antag-
onism (277). More recently, a botulinum neurotoxin-derived
targeted secretion inhibitor has been designed to target pitu-
itary somatotroph cells and suppress GH secretion (476). This
recombinant protein contains a modified GHRH domain and
the endopeptidase domain of botulinum toxin serotype D, thus
targeting the GHRH receptor and depleting vesicle-associated
membrane protein 2 (VAMP2) a SNARE protein involved in
GH exocytosis. Beyond the GH axis, somatostatin receptor
imaging is also of interest for diagnosis and therapy of neu-
roendocrine tumors (542).
While significant progress was made in defining the neu-
ronal processes that govern GH output, a complete overview
of these interactions is still lacking. In this pursuit we
must direct our attention to the neurovascular unit of the
hypothalamo-pituitary complex, as has been done for the reg-
ulation of the gonadotropic axis. Development of a greater
understanding of the control and release of somatostatin and
GHRH will reveal the cause for the seemingly discordant
release of peripheral GH output relative to somatostatin and
GHRH content in pituitary portal vasculature. By making this
a research priority, we may perhaps extend our list of primary
regulators of GH release beyond somatostatin and GHRH.
As is detailed throughout this article, mechanisms that
control GH release are varied, and involve a very large
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Growth Hormone Axis
number of neuropeptides, neurohormones, and peripheral fac-
tors including gut hormones and energy substrates. While
impacting the amount of GH released, these factors also
determine the patterning of GH release, and this change in
patterning may affect the actions of GH more so than changes
in the amount of GH released. To this extent, future studies
must consider measures of irregularity and pulse frequency,
particularly in animal models for which these data are scarce.
In many regards, neuronal regulators that couple GH release
with food intake (including NPY) are emerging as suitable
candidates. Given the developing role of GH as a critical
regulator of long-term energy homoeostasis, and emerging
evidence of neuronal regulators of food intake in the con-
trol of GH release, studies that couple GH release with food
intake may further define mechanisms of GH action that pre-
dict the use of energy during metabolic extremes. We must
however acknowledge that the context under which GH mod-
ulates energy homeostasis in the various animal models often
used to define GH regulation and action differs according to
species; therefore, impacting our capacity to directly translate
observations into human physiology. There is much to gain
through recognizing these differences, and through the devel-
opment of a greater physiological understanding behind these
differences.
As listed throughout this article, the release of GH changes
considerably relative to metabolic demand. This is clearly
illustrated in female physiology, wherein altered metabolic
needs throughout the ovulatory cycle, in pregnancy and in
lactation may predict GH output (as detailed earlier). While
dramatic changes in the hormonal milieu specific to these dif-
ferent reproductive states contribute to increased (i.e., estra-
diol) or decreased (i.e., placental-derived GH) GH output, the
physiological context of increased or decreased GH release
remains mostly unknown. Should we hope to understand this,
current measures must be extended to define the mechanisms
of actions of GH under these and other metabolic extremes,
and through studying the interactions of GH with other crit-
ical regulators of energy homoeostasis (including insulin).
Indeed, an extension in lifespan following genetic alterations
that compromise GH signaling is often associated with an
improved capacity to tolerate life-long pressures on energy
homeostasis. Only by understanding the mechanisms that
predict GH release throughout life, and relative to other crit-
ical regulators of energy homeostasis, will we define strate-
gies for improving health-span and longevity. Indeed, our
emerging understanding of the role of GH in regulating long-
term energy homeostasis, and by proxy health-span, offers the
greatest incentive yet in defining mechanisms of GH release.
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