section 31.2
Pituitary Gland (Hypophysis)
and liver and is responsible for the proportionate growth
of visceral organs and lean body mass during puberty. Lin-
ear growth during childhood requires the presence of GH.
GH acts directly on cartilage tissue to promote the endo-
chondral growth that results in skeletal growth; however
although GH has a direct effect on chondrocyte stem cells,
the growth-promoting effect of GH is due to its stimula-
tion of the chondrocytes to produce insulin-like growth
factor I (IGF-I, discussed later), which then acts locally
to stimulate cellular replication in the distal proliferative
zone of the epiphyseal plate. Thus, the growth-promoting
effect of GH can be abolished by blocking the IGF-I re-
ceptor and can be duplicated by exogenous IGF-I treat-
ment in the absence of GH. The importance of GH is in
its ability to stimulate IGF-I production within bone car-
tilage, an ability that is unique to GH. This explains why
GH deficiency results in growth retardation despite the
fact that bone cartilage has the ability to produce IGF-I.
GH exerts a “protein-sparing” effect by mobilizing the
body’s energy substrates, such as glucose, free fatty acids,
and ketone bodies, in the same tissues in which it stim-
ulates protein synthesis. GH inhibits glucose uptake by
skeletal muscle by inhibiting hexokinase activity and by
desensitizing the tissue to the actions of insulin; the ef-
fect is to elevate the blood glucose level. GH promotes
lipolysis in adipocytes, possibly by increasing the syn-
thesis of hormone-sensitive lipase (HSL), and ketogene-
sis in the liver. In addition, GH increases the activity of
hepatic glucose-
-phosphatase, increasing glucose secre-
tion. These protein-sparing effects of GH are diabetogenic
and explain how GH functions as an insulin antagonist
(Chapter 22).
Regulation of GH Release
The protein-anabolic and protein-sparing actions of GH
require the metabolic effects of insulin, glucagon, cortisol,
and thyroid hormone in the unstressed individual. These
actions depend on fine-tuned control of GH release, which
is achieved mainly by substrate feedback to the hypotha-
lamus (Figure 31-5).
A fall in blood glucose level stimulates GH release,
whereas a rise inhibits GH release. GH release also occurs
in response to certain amino acids, the most potent being
L-arginine, but with a latency period of about 30 minutes.
Circulating hormones exert their effects at the level of the
hypothalamus or the pituitary. GH influences its own se-
cretion by way of IGFs that exert a negative feedback effect
at the median eminence. However, whether this feedback
involves a decrease in GHRH, an increase in somatostatin,
or both is not known. Other hormones promote the synthe-
sis and release of GH at the level of the anterior pituitary.
F I G U R E 3 1 -5
R egulation of grow th horm one secretion in hum ans.
Estrogen promotes an increase in somatotroph numbers
and GH mRNA levels, while androgens increase, and IGF-
I decreases, the somatotroph response to GHRH. Gluco-
corticoids and thyroid hormone act in concert to stimulate
GH gene expression; however, pharmacological concen-
trations of glucocorticoids strongly inhibit GH release in
response to GHRH (Figure 31-5).
Superimposed on this fine regulation of GH secretion by
substrates and hormones is the coarse regulation by higher
brain centers that operate on an open-loop, substrate-
independent basis. These influences are dramatic and re-
sult in the several-fold increase in GH levels during stress
and during deep sleep. GH is one of several hormones re-
leased in response to stress (see below); it is also one of
the few released during deep sleep (EEG stages III and IV)
irrespective of the time of day. The amount of GH released
during deep sleep is substantial, accounting for about 75%
of the daily output of GH. In children who are unable to
achieve deep sleep because of emotional disturbances, the
absence of sleep-induced GH results in growth retardation.
Insulin-like Growth Factors (IGFs)
Insulin-like growth factors (IGFs) are GH-dependent
polypeptide hormones that promote cell replication in
most mesenchymally derived tissues and are responsi-
ble for the growth-promoting effects of GH. There are
two IGFs, I and II, both of which are 7 kDa proteins that
resemble proinsulin in structure. The IGFs exert insulin-
like biological effects when tested in insulin bioassay sys-
in vitro,
and account for the “nonsuppressible insulin-
like activity” (NSILA) in plasma that had been described
before the discovery of the IGFs. The similarities and
previous page 771 Bhagavan Medical Biochemistry 2001 read online next page 773 Bhagavan Medical Biochemistry 2001 read online Home Toggle text on/off