Exercise

Sleep

Hypothalamus

GHRH
+

DIRECT EFFECTS
Liver: gluconeogenesis and glycogenolysis

Stress

Adipose: lipolysis
Muscle: glycogenolysis and inhibition of glycogen synthesis

Somatostatin

Cartilage / Bone: chondrocyte and osteoblast differentiation

Energy expenditure: increased

Ghrelin
(mainly from
the stomach)

Pituitary

GH

Liver
IGF-I

Growth: long bones at epiphyseal plate

Muscle (and periphery): glucose uptake,
glycolysis, glycogen synthesis

Figure 5.5 Summary of the regulation and effects of growth hormone (GH). Some of the anabolic effects of GH are mediated by local
production of IGF-I acting in an autocrine or paracrine manner. In addition to the feedback loops shown, glucagon and free fatty acids
decrease GH secretion by increasing somatostatin release. GHRH, growth hormone-releasing hormone; IGF-I, insulin-like growth
factor I.

tall secretes GH at higher circulating

concentrations
than smaller peers. The consequence is faster
than
average growth and, year-by-year, height gain.
There
is a marked rise in circulating GH levels at
puberty.
The anabolic effects of GH on protein
metabolism are mainly mediated by IGF-I. This
promotes
growth of long bones at the epiphyseal plates,
where
there are actively proliferating cartilage cells.
This
growth spurt at and following puberty ceases
once
the epiphyses of the long bones fuse at the end
of

adolescence - the reason why too much GH

after
this time leads to the progressively
dysmorphic
growth of acromegaly compared to the
proportionate growth of gigantism (see Box 5.4). GH
also has

profound effects on bone turnover. It is likely

that these effects are largely indirect, as serum
IGF-I correlates well with estimates of bone
mineral density. In addition, GH and IGF-I may
modify intestinal calcium absorption and serum
levels of active vitamin D (see Chapter 9).
Acute administration of GH modestly stimulates muscle and whole-body protein synthesis,
leading to nitrogen retention and increased

lean
body mass. The converse effects are seen with
decline in GH secretion with ageing, features
of
which can be partially reversed by GH
administration. As well as GH, IGF-I concentration also
declines with advancing age. Accordingly, ageand

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abcd

76 / Chapter 5: The hypothalamus and pituitary

sex-matched
normal
ranges
are
necessary
for
the
appropriate interpretation of serum IGF-I
assays.
Without these details, there is a risk of
incorrectly
diagnosing overactivity or underactivity of
the
GHIGF-I axis.
Sodium and water homeostasis

The mechanisms enabling the body to

regulate
sodium and water homeostasis are
complex.
Although incompletely understood, there
is
evidence that GH induces sodium and fluid
retention,
possibly
by
increasing
glomerular
filtration
rate.
The main clinical implication of this
phenomenon
is the side-effect of swollen hands or feet
or pitting oedema reported by adults
receiving GH replacement therapy or
with acromegaly.
Mechanism of action of GH and IGFs
GH signals within the cell via the
JAK-STAT
pathway (see Figures 3.7 and 3.8). GH
receptors
have been detected within the first year
of
life
in
all
known target tissues. The number of
receptors
in
a
target tissue (e.g. the liver) is
changed
both
by
peripheral factors, such as sex hormones,
and
downregulated by GH itself. As suggested by
the
name,
the indirect effects of GH via IGF-I
are
often
insulin-like. They can be antagonized
by
cortisol

free
9

008

12

16

20
24
Clock time

04

08

Figure 5.6 A 24-h profile of serum growth hormone

(GH) in a normal 7-year-old child. Irregular pulses
occur, which are greatest during sleep.

Box 5.3 Assessing the GH-IGF-I

and are mediated intracellularly by
pathways
very
similar
to
those
for
insulin
signalling
(review
Chapter 3 and Figure 3.6).
Growth hormone regulation
Input from the hypothalamus and higher
brain centres
GH secretion is stimulated by sleep and
exercise
and
inhibited by food ingestion. During
deep
sleep,
bursts of secretion occur every 1-2 h
(Figure
5.6).
Stress
(e.g.
excitement,
cold,
anaesthesia,
surgery
or
haemorrhage)
produces
a
rapid

increase
in
serum
GH. Although negative feedback has been
proposed
for IGF-I (see Figure 5.5), the GH axis
lacks
a
single
end-organ secreting a hormone with a
clear
negative
feedback role. Contrast this with cortisol
from
the
adrenal
cortex,
which
suppresses
corticotrophicreleasing hormone (CRH) and ACTH
secretion.

axis
GH release is pulsatile (Figure 5.6):
andom serum GH is a poor marker of

clinical
R
GH status

ither dynamic testing (see later) or a

series
E
of serum measurements is
needed

Circulating

IGF-I

concentration

is

relatively

constant:
andom serum IGF-I is a useful marker

of
R clinical GH status

Instead, regulation of GH production

comes
from
the
dynamic,
opposing
interplay
between
hypothalamic GHRH (a positive influence) and
somato
statin (negative) (see Figure 5.5). GH
pulses
are
virtually simultaneous with peaks of
GHRH
and
low somatostatin secretion; conversely,
GH
falls
as somatostatin concentration rises.
The
pulsatile
release of GH and its relatively short
half-life
of
15 min mean that random serum
measurements
are
usually barely detectable [<0.4 ng/mL
(<1
mU/L)].
A circulating GH-binding protein slightly
increases
the half-life, but its physiological
significance
is
unclear. This intermittent nature of
circulating
GH,
compared to reasonably constant levels
of
serum
IGF-I, is important in assessing clinical
GH
status
(Box 5.3).

abcdfreeer 5: The hypothalamus and pituitary gland / 77

Input from other hypothalamic-anterior
pituitary-end-organ axes
GH production from somatotrophs is
dependent
upon an adequate supply of thyroid
hormone,
which
explains
why
hypothyroid
children
suffer
from stunted growth. Glucocorticoids,
as
either
endogenous
cortisol
or
synthetic
steroids
given
for
inflammatory disorders such as asthma
or
rheumatoid arthritis, suppress GH secretion.
Children
with
Cushing syndrome stop growing. By
contrast,
oestrogens sensitize the pituitary to the
action
of
GHRH, so that basal and stimulated GH
concentrations are slightly higher in women and
rise
earlier
during female puberty.
Metabolic regulation
In addition to the regulation of GH by
hypothalamic GHRH and somatostatin, ghrelin is
secreted mainly by the stomach and
acts as a potent GH secretagogue. It
also stimulates hunger, acting oppositely from leptin (see Chapter 15).
FFA and GH form a negative
feedback
loop;
GH induces lipolysis and a rise in FFA,
which,
in
turn, inhibits further GH secretion by
increasing
somatostatin.
FFA
also
increases
following
a
meal
and GH release is inhibited at the
same time as

insulin secretion rises, which suppresses

lipolysis.
As
the individual moves back into the
fasting
state,
FFA concentrations fall, GH secretion
returns
and
falling insulin concentration removes the
brake
on
lipolysis. Longer periods of fasting and
chronic
malnutrition are associated with increased
amplitude
and frequency of GH secretion. In
contrast,
obesity
is associated with increased GH
clearance
and
reduced GH secretion. The metabolic
regulation
of
GH secretion is utilized clinically in the
oral
glucose
tolerance test (OGTT) and insulin
tolerance
test
(ITT) for assessment of GH status
(Figure
5.7
and
Table 5.4).
Clinical disorders
Growth hormone excess - acromegaly and
gigantism
GH
excess
is
rare,
affecting
approximately 60 people per million (Box
5.4). It most commonly arises from
tumours of the pituitary somatotroph. In
line with all pituitary tumours, these are
virtually always benign adenomas
rather than carcinomas.
Symptoms and signs

The
phenotypic
appearance
of
excessive
bone
growth differs depending on whether
the patient

Normal

for academic only, not for sale

1
12

(a)

0
0

2
4
Hours

Glucose

(b)
Normal
6
3
0

Partial
deficiency
0

2
Hours

Insulin

GH (ng/mL)

Figure 5.7 Dynamic tests of growth hormone (GH)

status. (a) In an oral glucose tolerance test (OGTT)
GH release is normally suppressed, although it can
rebound as blood glucose returns to normal (as
shown at 2-3 h). In acromegaly, GH release does not
suppress and may even rise paradoxically. (b) In an
insulin tolerance test (ITT), insulin reduces blood

glucose, which stimulates GH release in normal

subjects. This response is blunted in partial GH
deficiency and lacking in patients with complete
deficiency; it is also diminished in some people with
longstanding type 1 diabetes. The precise diagnostic
values are shown in Table 5.4.