Chapter
Regulation of Growth Hormone Secretion
8
Linear growth in humans is dependent on a complex
interplay of various endocrine factors including:
growth hormone (GH), insulin-like growth factors
(e.g., IGF-1), ghrelin, thyroid hormones, glucocorti-
coids (GCs), sex hormones and non-endocrine mod-
ulators such as nutritional status, familial growth
pattern, physical and psychosocial health. The pri-
mary determinants, however, are GH, GH-stimulated
IGF-1 production by the liver, plus ghrelin derived
from the stomach. Ghrelin also plays a major role in
the control of food intake (see Chapter 4). Its involve-
ment in GH secretion is covered in Section 8.1.
This chapter will focus on the regulation of pitui-
tary GH secretion and the pathophysiological impli-
cations of abnormal GH production. GH is secreted
from anterior pituitary somatotrophs, which make up
approximately 50% of the cell population of the gland
(Heaney and Melmed, 2004). At least five different
isoforms of GH exist, encoded by homologous genes,
Although only one, GH1, is expressed in somato-
trophs (Lim et al., 2014).
8.1 Regulation of GH Secretion
GH secretion is regulated through both central (GH-
releasing hormone [GHRH] and somatostatin
[SOM]) and peripheral (ghrelin and IGF-1) factors.
An overview of the orchestration of GH release is
shown in Figure 8.1. The hypothalamic neuropeptide
hormones – GHRH (stimulatory) and SOM (inhibi-
tory) – constitute the principal central factors of GH
regulation. However, the hormone ghrelin – released
from the stomach – exerts a powerful stimulatory
effect on GH secretion, whereas IGF-1, secreted
from the liver, inhibits GH secretion. Cell bodies of
the GHRH and SOM neurons are located in close
proximity to each other in the basal infundibulum/
median eminence region of the hypothalamus
(Proudan et al., 2015). Both peptides are released
from nerve terminals and are transported through
134 the hypophyseal portal system to reach the anterior
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pituitary where they control the secretion of GH.
Figure 8.1 illustrates the homeostatic feedback path-
ways involving GH, hypothalamic neuropeptides
(GHRH and SOM), ghrelin and IGF-1 from the
liver. Ghrelin is the most potent GH secretagogue
known. Ghrelin infusion, in men and women, syner-
gizes with GHRH to stimulate pulsatile release of GH
from somatotrophs, but likely exerts a positive feed-
back on GHRH neurons as well (Veldhuis et al., 2008).
In contrast, IGF-1 inhibits GHRH release but stimu-
lates SOM release, a combination that attenuates GH
secretion. Note that GH also controls its own release
via autocrine regulation exerted via GH receptors on
somatotrophs (Figure 8.1).
8.2 Pulsatile Secretion
Similar to various other pituitary hormones, GH is
secreted in an episodic manner. Typical GH secretion
consists of a minimal basal secretory rate where GH
levels drop to <0.04 mcg/L, interspersed by bursts or
pulses. Although the average frequency of GH pulses
in both men and women is similar (approx. 11 over 24
hours), the mean GH concentration is significantly
elevated in women (Veldhuis et al., 2011; Roelfsema
and Veldhuis, 2016). The pulse frequency is also
higher in prepubertal children and adolescents com-
pared to adult levels (Steyn et al., 2016). Evidence
from animal experiments confirm that GHRH and
SOM are released as pulses from the hypothalamus
into the hypophyseal blood circulation (Thomas et al.,
1991; Goldenberg and Barkan, 2007) and it is likely,
although unproven, that neuronal secretion of human
GHRH and SOM is also inherently pulsatile.
However, the overall pituitary output of GH is
achieved, not by increasing pulse frequency, but by
amplifying pulse, or burst, size. Pulse amplitude is
regulated by a combination of GHRH stimulation,
inhibition by SOM, plus a synergistic stimulation by
ghrelin. GH pulses are particularly evident at night
(Figure 8.2; Van Cauter et al., 1998).
 Chapter 8: Regulation of Growth Hormone Secretion

Figure 8.1 Regulation of GH secretion. Pituitary secretion of GH is stimulated by pulsatile secretion of hypothalamic GHRH. The amplitude
of the GH pulse is modulated by an inhibitory effect of SOM. GH stimulates synthesis of IGF-1 in the liver; about 85% of circulating IGF-1 is liver-
derived. IGF-1 inhibits GH secretion at both hypothalamic and pituitary levels by reducing GHRH, and by stimulating SOM secretion. GH also
acts as an autocrine factor to control its own secretion from the pituitary. Ghrelin, released from the stomach, potently increases GH release by
boosting hypothalamic GHRH secretion. It also synergizes with GHRH to modulate GH pulse amplitude, but its overall role in physiological GH
regulation remains incompletely defined. Reproduced with permission (Kargi and Merriam, 2013). Abbreviations: GH, growth hormone; GHRH,
GH releasing hormone; IGF-1, insulin-like growth factor 1.

This figure shows that sleep deprivation abolishes
GH secretion and that daytime sleep, several hours
later, restores the sleep-related surge of GH.
Nevertheless, despite the loss of the normal sleep-
induced peak of GH, daytime pulses of GH are
increased, so that the overall quantity of GH per 24
hours is not compromised by sleep deprivation
(Brandenberger and Weibel, 2004). This is also con-
firmed in studies where subjects were deprived of sleep
for 24 hours; that is, the sleep-associated peak of GH
was normal (Schüssler et al. 2006; see also Section 8.3).
A clear association of increases in ghrelin secretion
and GH surges is revealed when GH and ghrelin are
assayed in plasma from a group of fed young men
(Figure 8.3; Nass et al., 2011). The meal-associated
peaks of ghrelin are coincident with those of GH. In
addition, ghrelin and GH peaks are coincident during
the night when meals are not anticipated. It is thought
that ghrelin may act as a positive modifier of GH
pulsatile secretion. In fact, intravenous boluses of
ghrelin induced slow-wave sleep (SWS) and a signifi-
cant increase in GH secretion in young men (see also
Section 8.3; Weikel et al., 2003).
Clinical implications: Macimorelin is a ghrelin
receptor agonist that stimulates the production of
GH. This agent is used for testing of GH deficiency
(see later in this chapter).
Clinical relevance: The pulsatile nature of the GH
secretory pattern has profound diagnostic and therapeu-
tic implications. Not only does a single random measure-
ment of GH provide limited information on GH levels,
but targeting medical therapies in GH disorders also
cannot be reliably based on GH levels alone
(Goldenberg and Barkan, 2007). 135

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 Chapter 8: Regulation of Growth Hormone Secretion

Figure 8.2 Sleep-induced GH secretion and effect of sleep deprivation. Plasma GH in ten normal young men studied during a 52-hour period
including 8 hours of normal, nocturnal sleep, 28 hours of sleep deprivation and 8 hours of daytime sleep. GH secretion is abolished by sleep
deprivation, but is reinstated by a sleep period during the normal daytime. Figure is based on data obtained from Van Cauter et al. (1998).

Lunch

70
100

60
Dinner
; pg/mL)

Bkfst
50 10 GH (
; microgm/L)

40
Acyl-Ghrelin (

30 1

20

0.1
10

sleep
0
0800 1000 1200 1400 1600 1800 2000 2200 2400 0200 0400 0600 0800 1000
Clock time (hour)
Figure 8.3 Coincidence of ghrelin and GH secretion in the fed state. The figure illustrates that the meal-associated peaks of ghrelin are
coincident with those of GH. Ghrelin and GH peaks are also coincident during the night, when meals are not anticipated, emphasizing that
ghrelin may act as a modifier of GH secretion. Values are mean+/-SEM plasma acyl-ghrelin (picograms per milliliter) and serum GH levels
(micrograms per liter, shown on log scale); n=8 young men during the fed state. Reproduced with permission (Nass et al., 2011).

8.3 Other Factors Regulating GH whereas others are extrinsic, such as age, gender, sex
hormones, glucose, amino acids, sleep, feeding, exer-
Secretion cise, stress, illness, obesity and medication (Table 8.1;
In addition to GHRH, SOM and ghrelin, GH secre- Fanciulli et al., 2009). The effects of some of these
tion is sensitive to an array of other influences. Some regulatory factors form the underlying basis of clinical
136 of these are best described as neural (see Section 8.4), GH testing.

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 Chapter 8: Regulation of Growth Hormone Secretion

Table 8.1 Regulators of GH secretion in humans. Reproduced with permission (Fanciulli et al., 2009).

Effector Increases GH Reduces GH Notes

Alpha1-adrenergic receptors ✔
Alpha2-adrenergic receptors ✔
Beta-adrenergic receptors ✔
Amino acids ✔
Anorexia nervosa ✔
Bombesin ✔
Dopamine ✔
Muscarinic receptors ✔
Cortisol ✔ ✔ Dose dependent
Diabetes mellitus ✔
Estrogen ✔ Increases pulse
amplitude
Exercise ✔
Free fatty acids ✔
γ-aminobutyric acid ✔
Galanin ✔
Ghrelin ✔
GHRH ✔
GH-releasing peptide ✔
Glucose ✔
Histamine ✔
Hypoglycemia ✔
Hypothyroidism ✔
IGF-1 ✔
Leptin Inversely correlated with
GH levels
Neuropeptide Y ✔
Obesity ✔
Opiates ✔
Senescence ✔
Serotonin ✔
Starvation ✔
Stress ✔
Testosterone ✔
Thyrotropin ✔ Only in acromegaly

Gender and Sex Hormones In addition, detailed studies by Veldhuis et al

Young women have significantly higher blood levels (2011) revealed that total GH secretion per day, and
of GH throughout the day compared to young men the amount of GH released per pulse, was significantly
(Goldenberg and Barkan, 2007; Figure 8.4). However, higher in healthy adult women compared to men,
this is not the case in older men and post-menopausal whereas the number of pulses per 24 hours was not
women, especially during sleep when secretory epi- different. During the menstrual cycle, when sex hor-
mone levels fluctuate (see Figure 3.1), there is a 137
sodes in women disappear (Latta et al., 2005).
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 Chapter 8: Regulation of Growth Hormone Secretion

12 Figure 8.4 Women have higher GH levels than men. Sexual

dimorphism of GH secretion illustrated with data from a
young man (top) and a young woman (bottom). The
10 difference in secretory pattern is seen during sleep, but is
sleep also readily apparent in baseline states where larger
amplitude pulses of GH can be observed in the young
Plasma GH (ng/mL)

8 woman. Reproduced with permission (Goldenberg and

Barkan, 2007) and redrawn.

0
0600 noon 1800 2400 0600
14
sleep
12

10
Plasma GH (ng/mL)

0
0600 noon 1800 2400 0600
Clock time (hour)

significant increase in GH secretion during the luteal
phase, suggesting that progesterone, and possibly
estradiol, might be a stimulatory factor for GH secre-
tion in normal cycling women (Caufriez et al., 2009).
GH levels typically fall in post-menopausal women,
and secretion can be restored by estrogen treatment
(Kalleinen et al., 2008). These data indicate a role for
sex hormones in regulating GH secretion. This is also
evident in children, where there is strong evidence for
sex hormone stimulation of GH in boys and girls
during puberty (Meinhardt and Ho, 2006). For exam-
ple, GH secretion is restored in hypogonadal boys
treated with testosterone (Veldhuis et al., 1997;
138 Giustina et al., 1997). However, in adults, the
relationship holds for men, but is unconvincing for
women. For example, testosterone supplementation
in healthy men drives secretion of GH and IGF-1
(Veldhuis et al., 2005), although this action of testos-
terone is mediated by its conversion to estradiol (aro-
matization) in the brain (Weissberger and Ho, 1993;
Veldhuis et al., 1997). The mechanism by which estra-
diol regulates GH secretion in women is incompletely
understood. One possible explanation for estrogen-
induced GH release is that estrogen leads to reduced
hepatic production of IGF-1, which in turn exerts a
stimulatory effect on GH release; that is, estradiol
attenuates the IGF-1-mediated negative feedback,
thereby increasing GH release. Another possibility is

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 Chapter 8: Regulation of Growth Hormone Secretion

Figure 8.5 Increases in SWS coincident with GH secretion. (A) Profiles of sleep stages, (B) slow-wave activity (EEG spectral power in the 0.5–4 Hz
frequency range), (C) plasma GH concentrations and (D) GH secretory rates derived from plasma GH levels in a healthy young man. Note the
temporal coincidence between major episodes of slow-wave activity and GH secretory pulses. Reproduced with permission (Van Cauter et al.,
2004) and redrawn.

an enhanced stimulatory effect of ghrelin on GH levels
in the presence of estradiol (Norman et al., 2014a) or a
synergistic influence of estradiol on GHRH stimula-
tion of GH release (Norman et al., 2014b). In sum-
mary, although there are pronounced sex differences
in GH secretion, the precise role, and mechanism of
action, of gonadal hormones in men and women
remains unclear.
Clinical implications: The IGF-1 lowering effect of
estrogen has led to the use of estrogen as an additional
therapeutic option in patients with excessive GH pro-
duction (acromegaly).
Sleep
GH secretion is preferentially increased during
human sleep (Figures 8.2 and 8.3) and is closely asso-
ciated with slow wave sleep (SWS) (Figure 8.5; van
Cauter et al., 2004).
One of the few drugs known to increase SWS is γ-
hydroxybutyrate (GHB), and treatment of healthy
young men, as well as narcolepsy patients, with GHB,
significantly increased SWS and GH secretion (Van
Cauter et al., 1997; Donjacour et al., 2011). The neural
control underlying the association of SWS and GH is
unknown, although the principal factor driving noc-
turnal GH secretion is GHRH; that is, an overnight
infusion of a GHRH antagonist largely eliminated GH
release (Ocampo-Lim et al., 1996). This suggests that
GHB increases the release of endogenous GHRH.
Age
GH is present in human fetal pituitary from 8 weeks of
gestation and is measurable in fetal serum from 12
weeks (Kaplan et al., 1976). Pulsatile secretion of GH
is detectable in plasma immediately after birth, but
declines thereafter (Miller et al., 1993). GH levels are
higher than normal in preterm infants, leading to the
suggestion that this might be responsible for neuro-
cognitive deficits seen later in life (Scratch et al.,
2015). In normal children, however, GH levels 139

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 Chapter 8: Regulation of Growth Hormone Secretion
Figure 8.6 Age-dependent decrease in GH secretion during 24 hours.
Mean (+/-SEM) values for GH for each age group plotted as total GH
release in 24 hours (top) and as GH during sleep only (bottom).
Probability levels, by analysis of variance, revealed a significant effect
of age in both total secretion (p<0.02) and in sleep-related GH
(p<0.001). Data were grouped by age as follows: 16–25 years (n=42);
26–35 years (n=28); 36–50 years (n=26); 51–60 years (n=23); 61–70
years (n=18); 71–83 years (n=12). Figure is based on data obtained
from Van Cauter et al. (2000).
increase substantially through the process of puberty,
corresponding with the period of maximum height
velocity. In adolescents, the mass of GH per GH pulse
increases by up to ten-fold (Christoforidis et al., 2005;
Veldhuis et al., 2006). These pubertal increases in GH
output are driven by aromatization of testosterone to
estradiol in boys and by estradiol in girls (Veldhuis
et al., 1997). After puberty, GH secretion declines
steadily to reach very low levels as early as 50–60
years. The decline is observable as an attenuation of
pulse amplitude (Blackman, 2000) as well as total
secretion in 24 hours. This is especially notable during
sleep (Figure 8.6; van Cauter et al., 2000; Junnila et al.,
2013) where the day–night rhythm largely disappears
140
(Latta et al., 2005; Chertman et al., 2015).
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A deficiency of GH, either congenital or acquired, is
associated with distinct clinical outcomes. Childhood
onset GH deficiency (GHD) typically leads to short
stature, growth failure and delayed bone age, whereas
adult GHD is associated with loss of muscle mass,
increased adiposity, poor exercise capacity and dete-
rioration of mental function (Sattler, 2013; Bartke et al.,
2016; Milman et al., 2016). Although data on mortality
associated with GHD in humans are conflicting, mice
with mutational defects in somatotropic (GH/IGF-1)
action – and therefore with compromised growth and
body size – have remarkably extended lifespan, with
retention of physical and cognitive function and a
reduced incidence of age-related disease. Human stu-
dies on this phenomenon are limited (Milman et al.,
2016), although one large-scale investigation into
dwarf patients with mutations in the GHR (GH resis-
tance) revealed a highly significant reduction in the
incidence of cancer and diabetes compared to that in
normal relatives, although there was no observed
change in longevity (Guevara-Aguirre et al., 2011;
Guevara-Aguirre and Rosenbloom, 2015). In sum-
mary, age-related reductions in GH are regarded as
deleterious to human health and GH replacement as
an anti-aging therapy has been proposed (Kargi and
Merriam, 2013; Sattler, 2013). However, other evidence
indicates that GH replacement in adults may induce
unwanted consequences, such as increased insulin
resistance and possibly cancer.
Clinical implications: Smaller doses of GH replace-
ment are typically required in the elderly based on the
natural decline of GH with age. Section 8.8 will
describe an example of clinical GHD.
Glucose
Glucose administration has a profound effect on GH
secretion. Typically, glucose administration in normal
individuals is associated with a biphasic GH response –
an initial SOM-mediated GH suppression is followed,
3–5 hours later, by an increase in GH release. On the
other hand, hypoglycemia leads to release of GH, in
tandem with hormones such as cortisol, via a reduction
in SOM control (Giustina and Veldhuis, 1998). The
sensitivity of GH levels to glucose constitutes the basis
of clinical testing of GH disorders. For instance, failure
of GH to suppress after oral glucose administration is
regarded as the gold standard for the diagnosis of acro-
megaly (excessive GH production), whereas failure of
GH to rise after insulin-induced hypoglycemia suggests
GHD.
 Chapter 8: Regulation of Growth Hormone Secretion

Clinical implications: Acromegaly is confirmed by patients – the influence of GC on GH secretion is in

measuring GH after administering 75 g oral glucose.
GH levels suppress to <1 mcg/L (<0.4 mcg/L with sen-
sitive GH assay) in normal individuals. Failure to sup-
press GH suggests acromegaly. GHD is confirmed by
measuring GH after an insulin-induced hypoglycemia
of <2.2 mmol/L. GH levels typically rise to >5.0 mcg/L in
normal individuals. Failure of GH to rise to >5.0 mcg/L
suggests GHD.
Glucocorticoids
As described in Chapter 5, the GC cortisol is a major
influence on most cells of the body. However, negative
effects of GCs are well described and include impaired
growth in childhood, and altered body composition and
bone metabolism in adults and children. The common
view is that an excess of GCs, either endogenous or
exogenous, suppresses GH secretion. This inhibition
might be imposed at several sites, including inhibition
of GH production and secretion, inhibition of GHRH
and ghrelin action and stimulation of SOM activity (see
Figure 8.1).
Stimulatory Effects of GC on GH
Notwithstanding the view that GCs are inhibitory to
GH secretion – for example, in Cushing’s syndrome
fact biphasic; the biological activity of GC is depen-
dent on dose and time of exposure. For example, in
hypocortisolemic patients, physiological doses of GC
will restore GH secretion (Barkan et al., 2000). In this
study, patients with Addison’s disease were with-
drawn (24 hours) from cortisol treatment and then
given replacement doses of hydrocortisone to main-
tain physiological levels of cortisol. Withdrawal of GC
maintenance impaired spontaneous GH secretion
(Mazziotti and Giustina, 2013), but GH levels were
increased significantly following replacement cortisol
infusion due entirely to a doubling of pulse amplitude
(Figure 8.7). Patients with idiopathic adrenocortico-
tropin (ACTH) deficiency are also deficient in GH,
and respond to cortisol with increases in GH levels as
described for Addison’s patients (Giustina et al.,
1989). The authors concluded that cortisol stimulates
GH output by reducing the inhibitory influence of
hypothalamic SOM.
Inhibitory Effects of GC on GH
Both short term (1 hour) and long term (> 3 months)
treatment with pharmacological doses of GC reduce
GH secretion and inhibit the stimulatory effect of
GHRH on pituitary GH release (Mazziotti and

Figure 8.7 Cortisol-induced secretion of GH in patients with primary adrenal insufficiency (Addison’s disease). Figure shows data from two
patients (A and B) with long-standing Addison’s disease. Patients had received regular hydrocortisone replacement but were withdrawn from
treatment 24 hours prior to admission. Patients were then infused with either saline or hydrocortisone (19 mg/day) given in a pattern designed
to mimic the normal circadian rhythm in cortisol secretion (i.e., peaks in the early morning). Compared to saline infusions, cortisol induced a 141
significant increase in GH secretion. The graphs are based on data obtained from Barkan et al. (2000).
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 Chapter 8: Regulation of Growth Hormone Secretion

Figure 8.8 Biphasic effects of GCs on GH secretion. The figure outlines a model of the effect of circulating GCs on human GH secretion. The
ascending part of the curve (light blue) reveals the stimulatory effect of GCs observable in a GC-deficient state. At higher doses, the
well-described inhibition of GH becomes apparent. Data were extrapolated from studies in humans performed separately in patients with
hypoadrenalism and in those exposed to an excess of GCs, either endogenous or exogenous. Reproduced with permission (Mazziotti and
Giustina, 2013).

Giustina, 2013). Such effects are seen in patients with
hypercortisolism (Cushing’s syndrome) and in those
undergoing long-term immunosuppressive GC treat-
ment, for example, following organ transplants. In
summary, GCs represent a critical component of the
normal regulation of GH secretion. GC have both
stimulatory and inhibitory effects on GH secretion,
dependent on dose and time of exposure (Figure 8.8).
8.4 Neural Control of GH Secretion
Figure 8.1 illustrates that pituitary GH secretion is
primarily controlled by GHRH, SOM and ghrelin.
However, there are multiple stimulatory and inhibi-
tory signals, some described in Section 8.1, and
some of them of brain origin, that impose further
levels of regulation (see Table 8.1; Fanciulli et al.,
2009). Animal experiments have provided detailed
knowledge of the neural control systems (Steyn
et al., 2016), but evidence for such involvement in
man is limited (Giustina and Veldhuis,1998; Steyn
et al., 2016). Extensive immunohistochemical stu-
dies in human brain tissue revealed evidence for
possible neurotransmitter/neuropeptide synaptic
regulation of GHRH and/or SOM neurons, includ-
ing dopamine (inhibitory; Rotoli et al., 2011), neu-
ropeptide Y (inhibitory; Deltondo et al., 2008), SOM
(inhibitory; Proudan et al., 2015), enkephalin (sti-
mulatory; Olsen et al., 2014) and CRH (inhibitory;
142 Peroski et al., 2016). Complementary reports,
focused on drug-induced changes, implicate several
receptor types in controlling human GH secretion
(Table 8.1). For example, clonidine and the anti-
depressant reboxetine act as hypothalamic α2-adre-
nergic stimuli for GH secretion (Schüle et al., 2004;
Steyn et al., 2016). Baclofen, a γ-aminobutyric acidB
agonist, also stimulates GH secretion in women
(Orio et al., 2001). For serotonin, the evidence is
less convincing. Increased secretion of GH, follow-
ing insulin-induced hypoglycemia, is prevented by
the serotonin receptor antagonist cyproheptadine
(Bivens et al., 1973), but the selective serotonin
reuptake inhibitor citalopram, a drug designed to
increase synaptic serotonin, significantly increased
ACTH secretion but had no effect on GH levels
(Berardelli et al., 2010). On the other hand, acetyl-
choline has a profound stimulatory effect on GH
secretion in normal men and women. Inhibition of
central acetylcholinesterase, by physostigmine, or by
donepezil, markedly increased basal as well as
GHRH-stimulated GH secretion (Fedi et al., 2008;
Obermayr et al., 2005). In addition, arginine- or
exercise-induced GH secretion was blocked by pre-
treatment with the cholinergic antagonist atropine
(Casanueva et al., 1984). Inhibitory dopamine recep-
tors are thought to underlie the effects of the anti-
psychotic olanzapine. In this study, olanzapine
abolished the normal nocturnal secretion of GH in
schizophrenic patients (Mann et al., 2006). Opioid
receptors appear to be stimulatory for human GH

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 Chapter 8: Regulation of Growth Hormone Secretion

secretion (Vuong et al., 2010). For example, a met-
enkephalin analog elevated GH secretion in young
men (Giusti et al., 1992), and morphine stimulated
GH release in acromegalic patients (Bhansali et al.,
2005). In contrast, blockade of opioid receptors with
the antagonist naltrexone prevented GHRH induc-
tion of GH release (Villa et al., 1997). In summary,
the regulation of human GH secretion appears to be
under the control of the same neurotransmitters
and neuropeptides already implicated in experimen-
tal animals. It remains to be determined whether
these influences are imposed on GHRH or on SOM
neurons (or both). For example, opioids could
directly stimulate GHRH neurons or, alternatively,
SOM neurons could be inhibited by opioids to allow
GHRH secretion to occur.
8.5 Receptor Mechanisms that Control
GH Secretion from Somatotrophs
As noted in Section 8.1, the principal factors
that enable secretion of GH from somatotrophs
are GHRH, SOM and ghrelin, together with nega-
tive feedback from IGF-1. Somatotrophs possess
specific cell membrane receptors for each factor
(Figure 8.9).
Three of them are of the GPCR class (described in
Chapter 1). Receptors for GHRH and ghrelin are
stimulatory and are linked to cyclic adenosine mono-
phosphate (cAMP) and inositol triphosphate (IP3)
signals, respectively. GHRH and ghrelin act synergis-
tically to induce intracellular calcium ion mobiliza-
tion that, in turn, regulates GH secretion. In addition,

Figure 8.9 Receptor mechanisms

regulating GH secretion from
somatotrophs. Receptors for GHRH and
ghrelin are stimulatory G protein-
coupled, linked to cAMP and IP3
signals, respectively. GHRH and ghrelin
act synergistically to induce
intracellular calcium ion mobilization
that, in turn, regulates GH secretion.
These stimuli also induce GH gene
expression and GH synthesis in
somatotrophs. SOM binds to an
inhibitory G protein-coupled receptor
that reduces the accumulation of
cAMP, decreasing the release of GH
(Ben-Shlomo and Melmed, 2010).
Receptors for IGF-1 are inhibitory, but
not G protein-coupled, and consist of
four subunits: two alpha-subunits plus
two beta-subunits, held together by
covalent disulfide bonds (see Figure
8.10). Abbreviations: cAMP, cyclic
adenosine monophosphate; IP3,
inositol triphosphate; PLC,
phospholipase C; SOM, somatostatin.

143

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 Chapter 8: Regulation of Growth Hormone Secretion
Figure 8.10 Schematic representation of the IGF-1 signaling system.
IGF-1 receptors consist of four subunits: two alpha-subunits plus two
beta-subunits, held together by covalent disulfide bond. IGF-
1 receptors possess intrinsic tyrosine kinase activity; that is, following
IGF-1 binding, this kinase is activated, auto-phosphorylating
(activating) the beta-subunits. The activated beta-subunits then
phosphorylate intracellular signaling proteins (IRS-1).
Phosphorylated IRS-1 then induces other signaling cascades that
ultimately regulate gene transcription. In the case of somatotrophs
this involves inhibition of GH synthesis and release.
these stimuli induce GH gene expression and GH
synthesis in somatotrophs. SOM also binds to a
GPCR, but these receptors are inhibitory and prevent,
or reduce, the accumulation of cAMP, thus reducing
the release of GH (Ben-Shlomo and Melmed,
2010; see Figure 8.9). Receptors for IGF-1 are not G
protein-coupled and consist of four subunits: two
alpha-subunits plus two beta-subunits, held together
by covalent disulfide bonds, similar to the insulin
receptor (Figure 8.10; Schwartz et al., 2000). IGF-1
receptors (IGF-1 Rs) possess intrinsic tyrosine kinase
activity; that is, following IGF-1 binding, this kinase is
144 activated and auto-phosphorylates the beta subunits.
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These, in turn, activate intracellular signaling proteins
(insulin receptor substrate 1; IRS-1). Phosphorylated
IRS-1 then induces other signaling cascades that ulti-
mately regulate gene transcription. In the case of
somatotrophs this involves inhibition of GH synthesis
and release.
The human SOM receptor exists as five distinct
subtypes: SSTR1–SSTR5. All five subtypes are detect-
able in the human fetal pituitary, but adult pituitary
tissue contains only four of them (SSTR1, SSTR2,
SSTR3 and SSTR5). Of these, SSTR2 and SSTR5 are
most abundant on somatotrophs and are effective in
inhibiting secretion of GH. When activated simulta-
neously they induce a synergistic suppression of GH
release (Ren et al., 2003). Knowledge of these sub-
types has important implications for the therapeutic
use of synthetic SOM analogs, including the treat-
ment of neuroendocrine tumors (Theodoropoulou
and Stalla, 2013). SOM receptors are also found in
several human pituitary tumors; that is, GH-,
ACTH-, PRL- TSH-secreting adenomas and in
non-functioning pituitary tumors, suggesting that
these hormones may also be under inhibitory control
by SOM (Eigler and Ben-Shlomo, 2014). In addition,
SOM receptors are expressed in many peripheral
tissues, and influence secretion from the GI tract
(e.g., gastrin and secretin) and from the pancreas
(e.g., insulin and glucagon).
Clinical relevance: Short- and long-acting SOM
analogs such as octreotide, lanreotide and pasireo-
tide are used for suppression of GH and normal-
ization of IGF-1 in acromegaly (Melmed, 2016). In
addition, these agents are also used for treatment of
TSH adenomas (see Chapter 10). Both octreotide
and lanreotide have an affinity for SSTR2 and
SSTR5 whereas pasireotide has an affinity for
SSTR1, SSTR2, SSTR3 and SSTR5. Figure 8.11 illus-
trates the inhibitory effects of pasireotide treatment
on GH and IGF-1 levels in acromegalic patients
(Schmid et al., 2016).
8.6 Receptor Mechanism for GH
Stimulation of IGF-1 Production in
Liver Cells
Figure 8.1 reveals the liver as a major target for GH. In
contrast to the seven transmembrane domains of the
GHRH receptor, the GHR has only a single trans-
membrane domain. Binding of GH to the GHR
induces the formation of a dimer (Figure 8.12).

This type of receptor does not use cAMP as a
second messenger but possesses docking sites for
janus kinases (JAKs), a family of tyrosine kinases
(see Chapter 1). Thus, when GH binds to its receptor,
and following dimerization, JAK phosphorylates
other intracellular chemical signals that act as second
messengers. The most important of these is signal
transduction and activator of transcription (STAT).
Once phosphorylated, STAT dimerizes and travels
into the cell nucleus where it modulates gene expres-
sion for IGF-1 (Figure 8.12). Secretion of IGF-1 from
the liver stimulates bone and muscle growth (Reiter
and Rosenfeld, 2008; Rozario et al., 2015).
Clinical relevance: Acromegaly is characterized by
somatotroph adenomas and hypersecretion of GH,
which leads to elevated IGF-1. Pegvisomant is a
GHR antagonist that blocks the effect of GH at the
receptor and consequently reduces the production of
IGF-1. Pegvisomant is used for treatment of acrome-
galy (Franck et al., 2016; see Section 8.7).
8.7 GH Excess
Two distinct clinical syndromes – gigantism and acro-
megaly – are associated with excessive GH produc-
tion. Gigantism results from excessive prepubertal
GH secretion and is characterized by a rapid increase
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Chapter 8: Regulation of Growth Hormone Secretion
Figure 8.11 Inhibitory effect of
pasireotide on GH and IGF-1 secretion in
acromegalic patients. Patients were
treated with long-acting release
pasireotide (40 or 60 mg intramuscular,
every 28 days) for a period of 24 weeks.
Values of GH and IGF-1 in blood were
analyzed by immunoassay. Error bars
are presented as geometric means
(68% CI; n= numbers of patients in the
study at 24 weeks). Abbreviation: CON,
control. Data reproduced with the kind
permission of Dr. H. A. Schmid (Schmid
et al., 2016).
in skeletal growth. Acromegaly, on the other hand,
results from excessive GH production in postpubertal
individuals who have already achieved fusion of the
epiphyseal plates. These patients typically present
with growth of bone and soft tissue leading to enlar-
gement of hands, feet, skull and jaw; excessive sweat-
ing (due to the effect of GH on sweat glands);
visceromegaly and obstructive sleep apnea due to
enlargement of tongue and soft tissue. If left untreated
patients with acromegaly die early of cardiovascular
or respiratory complications and cancer. The com-
monest etiology of gigantism and acromegaly is an
underlying GH-producing pituitary adenoma.
Although mostly sporadic, these benign tumors can
also be familial in conditions such as multiple endo-
crine neoplasia type 1, familial isolated pituitary ade-
noma, McCune–Albright syndrome and Carney
complex. Acromegaly is suspected in patients with
typical clinical features and is confirmed by failure
of GH to suppress to <1 mcg/L (or <0.4 mcg/L with
sensitive GH assay) after administration of a 75 g oral
glucose challenge. Serum IGF-1 is elevated in patients
with excessive GH and is used as a marker of excessive
GH activity.
The primary management of acromegaly is trans-
sphenoidal surgical excision of the tumor. Patients
who are either unable to achieve a remission after 145
 Chapter 8: Regulation of Growth Hormone Secretion
Figure 8.12 GHR signaling in the production of IGF-1 by the liver.
The GHR, unlike those for GHRH and SOM, has only a single
transmembrane domain. Binding of GH to the GHR induces the
formation of a dimer that possesses docking sites for janus kinases
(JAKs), a family of tyrosine kinases. Thus, following GH-induced
dimerization, JAK phosphorylates other intracellular chemical
signals that act as second messengers. The most important of
these is signal transduction and activator of transcription (STAT).
Once phosphorylated, STAT dimerizes and travels into the cell
nucleus where it modulates gene expression for IGF-1. IGF-1 is
then secreted from the liver, binds to a binding protein (BP) and is
transported to target tissues such as bone and muscle.
Abbreviations: BP, binding protein; mRNA, messenger ribonucleic
acid. Reproduced with permission (Junnila et al., 2013).
surgery or cannot undergo surgery are treated with
medical therapy. The currently available pharmacolo-
gic options include: SOM analogs (octreotide, lanreo-
tide and pasireotide; see Figure 8.11), dopamine
agonists (bromocriptine and cabergoline) and the
146 GHR antagonist pegvisomant (Franck et al., 2016).
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In uncontrolled female acromegaly patients, estrogen
therapy can also be added to these agents to further
reduce IGF-1 (Shimon and Barkan, 2012).
Occasionally, radiation therapy is also used in patients
with residual tumor that fails to respond to medical
therapy. The aim of therapy is removal/shrinkage of
the tumor and normalization of GH and IGF-1 levels.
Unfortunately, several complications related to acro-
megaly are irreversible despite achieving biochemical
normalization.
8.7.1 A Case of Gigantism
A 15-year-old male was referred to the endocrinol-
ogy clinic for excessive fatigue and sleepiness. His
birth weight was 3.5 kg, and he had normal growth
until age 11, after which he experienced an acceler-
ated increase in his height and weight. About 6
months ago he developed pain in his left hip, tin-
gling in both hands and noticed deteriorating vision
for 2 months prior to presentation. His mother
mentioned that he snored heavily during sleep and
he slept on a semi-reclined couch because he was
unable to lay flat. His paternal aunt had undergone
surgery for a pituitary tumor of unknown etiology
17 years ago. On examination, his height was
198.12 cm (mid-parental height=172.3 cm) and
weight was 126.2 kg (BMI=32.2 kg/m2). His shoe
size was 16EEE (extra-wide). He had evidence of
scoliosis and had bilateral field of vision constriction
on confrontation.
Endocrine investigations were as follows:
Cortisol=298 nmol/L (184–512)
TSH=2.37 mIU/L (0.35–5.4)
Free thyroxine (fT4)=8.8 pmol/L (11–19)
PRL=15.4 mcg/L (2.1–17.7)
GH=13.4 mcg/L (<3.0)
IGF-1=1600 mcg/L (232–1077)
Testosterone=<0.3 nmol/L (8.0–32)
Follicle stimulating hormone (FSH)=0.5 IU/L
(1.5–9.3)
Luteinizing hormone (LH)=0.4 IU/L (1.4–18.1)
Ca=2.31 mmol/L (2.23–2.58)
Nadir GH after an oral glucose tolerance test=7.9
mcg/L
Figure 8.13A shows a magnetic resonance image
(MRI) confirming the presence of a macroadenoma
and Figure 8.13B reveals that a Goldmann visual field
test showed bilateral visual field defects.
A diagnosis of gigantism or early-onset acromegaly
was made on the basis of typical clinical features and
 Chapter 8: Regulation of Growth Hormone Secretion

A. MRI reveals a macroadenoma

B. Goldmann visual field test shows bilateral visual field defects

Figure 8.13 (A) MRI scans confirming the presence of a macroadenoma; (B) Goldmann visual field test results showing bilateral visual field defects.

elevated serum IGF-1 and non-suppressibility of GH to 8.8 GH Deficiency

<0.4 mcg/L after oral glucose. Based on the family
GHD can occur as a result of congenital pituitary
history, invasive macroadenoma, male gender and
defects, pituitary tumors and infiltrative disorders,
young age at presentation he was offered genetic test-
pituitary surgery or radiation therapy and head
ing. The test confirmed an aryl-hydrocarbon interact-
trauma. GHD in children typically presents with
ing receptor protein mutation associated with familial
growth failure and short stature, whereas adults
isolated pituitary adenomas (Imran et al., 2018). The
show decreased muscle and bone mass, increased
patient underwent trans-sphenoidal excision of the
cardiovascular risk factors and poor exercise reserve.
pituitary tumor followed by SOM analog therapy to
GHD is confirmed by failure of GH to rise in
achieve biochemical remission. Figure 8.14 shows the
response to provocative stimuli such as insulin-
patient with his mother 3 years following treatment.
induced hypoglycemia, L-Dopa, arginine, glucagon 147

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 Chapter 8: Regulation of Growth Hormone Secretion
Figure 8.14 Acromegalic patient, with his mother, shown 3 years
following trans-sphenoidal removal of pituitary macroadenoma.
Reproduced with permission.
and the ghrelin receptor agonist macimorelin.
Different cut-off levels of GH response to these tests
are reported in the literature. Typically, a failure of
GH to rise to >5 mcg/L in normal individuals after
insulin-induced hypoglycemia of <2.2 mmol/L, or
>2.8 mcg/L after macimorelin, confirms GHD.
Management of GHD is in the form of injectable
GH replacement, which has been shown to improve
height in children as well as bone and muscle mass,
exercise capacity and quality of life in adults (Ahmid
et al., 2016). The aim of therapy is to normalize serum
IGF-1.
Unfortunately, the abuse of GH is high among
professional athletes and bodybuilding enthusiasts
(Baumann, 2012). Chronic use of excessive doses of
GH are known to induce some features of acromegaly.
8.8.1 A Case of growth hormone deficiency
A 34-year-old athletic male presented with increasing
fatigue and inability to keep up with his running
group for the past 6 months. He was becoming fru-
strated because his routine investigations through his
family physician failed to show any concerning
148 abnormality. After searching the subject online, he
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asked his family physician to rule out GH deficiency
(GHD) and was referred to the endocrine clinic.
His past history was unremarkable, apart from a
head injury a year ago when he fell off his mountain
bike and briefly lost consciousness. He was admitted
to a local hospital where he underwent computed
tomography scans and was observed for a few days
and then discharged.
His pituitary investigations were as follows:
Cortisol=311 nmol/L (184–512)
TSH=1.17 mIU/L (0.35–5.4)
fT4=14.3 pmol/L (11–19)
PRL=7.7 mcg/L (2.1–17.7)
GH=1.08 mcg/L (<3.0)
IGF-1=88 mcg/L (175–288)
Testosterone=15.4 nmol/L (8.0–32)
FSH=2.2 IU/L (1.5–9.3)
LH=1.9 IU/L (1.4–18.1)
Peak GH after insulin-induced hypoglycemia=2.3
mcg/L
A diagnosis of GHD was made on the basis of low
IGF-1, and failure of GH to rise >5 mcg/L after insu-
lin-induced hypoglycemia. The most likely underly-
ing etiology was GHD due to head injury. GH-
replacement therapy was initiated and serum IGF-1
was normalized after 3 months (212 mcg/L). The
patient experienced significant improvement in exer-
cise capacity with complete resolution of the fatigue.
8.9 Chapter Summary
This chapter outlines the mechanisms by which GH
secretion is regulated to maintain GH homeostasis and
in those states of pathological GH secretion, such as
acromegaly. Human GH secretion appears to be under
the control of the same neurotransmitters and neuro-
peptides already implicated in experimental animals,
although it remains unknown whether these influences
are imposed on GHRH or SOM neurons (or both). GH
secretion from somatotrophs is regulated by opposing
hypothalamic releasing factors: GHRH is stimulatory
and SOM inhibitory. In addition, GH levels are subject
to peripheral feedback pathways from IGF-1 (negative)
and ghrelin (positive). Ghrelin is the most potent GH
secretagogue known, and synergizes with GHRH to
stimulate pulsatile release of GH from somatotrophs.
Somatotrophs possess specific cell membrane receptors
for each factor. Similar to other pituitary hormones,
GH is secreted in an episodic (pulsatile) manner, espe-
cially during SWS. GH secretion is sensitive to an array
of other influences such as age, gender, sex hormones,
 Chapter 8: Regulation of Growth Hormone Secretion

glucose, amino acids, feeding, exercise, stress, illness, a. Hypoglycemia

obesity and medication. For example, sex hormones b. Pasireotide
stimulate GH secretion in pubertal children, and tes- c. Somatostatin (SOM)
tosterone supplementation in men drives GH and IGF- d. Insulin-like growth factor 1 (IGF-1)
1 release, but the role of estradiol in women is unclear. e. Ghrelin
In normal children, GH levels increase substantially 2. Which of the following statements on GH are
through the process of puberty, corresponding with incorrect?
the period of maximum height velocity. After puberty,
a. Secretion is negatively regulated by a
GH secretion declines steadily to reach very low levels
hypothalamic releasing factor.
as early as 50–60 years, especially notable during sleep.
b. Blood levels are higher in children than in
A deficiency of GH, either congenital or acquired, is
older adults.
associated with distinct clinical outcomes. Childhood-
c. Pulses of GH occur during sleep.
onset GHD leads to short stature and delayed bone age,
d. GH modulates the secretion of IGF-1 from the
whereas adult GHD is associated with loss of muscle
liver.
mass, increased adiposity, poor exercise capacity and
e. SOM stimulates GH secretion.
deterioration of mental function. A case of clinical
GHD is provided. 3. A pituitary adenoma in an adult, secreting high
Glucose administration in normal individuals levels of GH, causes:
induces a biphasic GH response – an initial suppres- a. Gigantism
sion followed, 3–5 hours later, by an increase in GH b. Enlargement of the liver
release. Hypoglycemia leads to release of GH. The c. Elevated blood levels of glucose
sensitivity of GH levels to glucose constitutes the d. Reduced circulating levels of IGF-1
basis of clinical testing of GH disorders: failure of e. Acromegaly
GH to suppress after oral glucose administration is 4. Which of the following statements concerning GH
the gold standard for the diagnosis of acromegaly, are correct? Select all that apply.
whereas failure of GH to rise after insulin-induced
hypoglycemia suggests GHD. a. GH shows increased secretion during SWS
GCs are generally regarded as inhibitory to GH sleep.
secretion, but the GH response to GC is in fact bipha- b. The systemic actions of GH are mediated by
sic. Treatment with pharmacological doses of GC IGF-1.
reduces GH secretion and inhibits the stimulatory c. IGF-1 is synthesized mainly in the anterior
effect of GHRH on pituitary GH release. Such effects pituitary.
are seen in patients with hypercortisolism (Cushing’s d. GH is required for growth in stature from
syndrome) and in those undergoing long-term immu- birth to puberty.
nosuppressive GC treatment. e. An increase in serum SOM will inhibit GH
Two distinct clinical syndromes – gigantism and secretion.
acromegaly – are associated with excessive GH pro- 5. A 12-year-old boy presented with short stature
duction. Gigantism occurs due to excessive prepuber- and reduced height velocity over the past 6
tal GH secretion and is characterized by a rapid months. Which of the following factors suggest a
increase in skeletal growth. Acromegaly results from possibility of GH deficiency (GHD)?
excessive GH production in postpubertal individuals. a. Previous diagnosis of celiac disease
A case of gigantism is presented. GHD can occur as a b. Both parents are short
result of congenital pituitary defects, pituitary tumors c. Subnormal serum IGF-1 level
and infiltrative disorders, pituitary surgery or radia- d. Severe asthma requiring glucocorticoid
tion therapy and head trauma. A case of GHD due to therapy
head trauma is presented. e. Presence of 16 mm pituitary adenoma on a
magnetic resonance image
8.10 Review Questions 6. Which of the following therapeutic options are
1. Which of the following inhibit growth hormone used for management of acromegaly?
149
(GH) secretion from somatotrophs? a. Cabergoline
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 Chapter 8: Regulation of Growth Hormone Secretion

b. Lanreotide Blum W F, Alherbish A, Alsagheir A et al. (2018). The

c. Pasireotide growth hormone–insulin-like growth factor-1 axis in the
d. Estrogen diagnosis and treatment of growth disorders. Endocr
Connect 7, R212–R222.
e. Pegvisomant
Butler A A & le Roith D. (2001). Control of growth by the
7. Which of the following statements regarding somatropic axis: growth hormone and the insulin-like
GHD are correct? growth factors have related and independent roles. Annu
a. The diagnosis of GHD is based on the failure Rev Physiol 63, 141–164.
of GH to rise after an oral glucose load. Eigler T & Ben-Shlomo A. (2014). Somatostatin system:
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GHD. Nat Revs Endocr 12, 90–98.
d. GHD is associated with poor exercise tolerance Milman S, Huffman D M & Barzilai N. (2016). The
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