DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

chromosome 17 (17q22), which also contains three different
variants of placental lactogen and a GH variant,
chorionic somatotropin, expressed in the syncytiotrophoblast.
GH is secreted by somatotropes as a heterogeneous
mixture of peptides; the principal form is a
single polypeptide chain of 22 kDa that has two disulfide
bonds and is not glycosylated. Alternative splicing
deletes residues 32 to 46 of the larger form to produce a
smaller form (~20 kDa) with equal bioactivity that
makes up 5-10% of circulating GH. Recombinant
human GH consists entirely of the 22 kDa form, which
provides a way to detect GH abuse for sports performance
enhancement.
Additional GH species, differing in size or charge, are found
in serum, but their physiological significance is unclear. In the circulation,
a 55 kDa protein binds approximately 45% of the 22 kDa and
25% of the 20 kDa forms; this binding protein contains the extracellular
domain of the GH receptor and apparently arises from proteolytic
cleavage. A second protein unrelated to the GH receptor also
binds approximately 5-10% of circulating GH with lower affinity.
Bound GH is cleared more slowly and has a biological t 1/2
~10 times
that of unbound GH, suggesting that the bound hormone may provide
a GH reservoir that dampens acute fluctuations in GH levels
associated with its pulsatile secretion. Alternatively, the binding protein
may decrease GH bioactivity by preventing it from binding to its
receptor in target tissues. Obesity increases circulating levels of GH
binding proteins and thus may affect the clinical response to exogenous
GH.
Human prolactin is a 23 kDa protein with three
intramolecular disulfide bonds. It is synthesized by lactotropes,
and a portion of the secreted hormone is glycosylated
at a single Asn residue. In circulation, dimeric
and polymeric forms of prolactin also are found, as are
degradation products of 16 kDa and 18 kDa. As with
GH, the biological significance of these different forms
is not known.
Regulation of Secretion of the Somatotropic Hormones.
Daily GH secretion varies throughout life; secretion is
high in children, peaks during puberty, and then
decreases in an age-related manner in adulthood. GH is
secreted in discrete but irregular pulses. Between
these pulses, circulating GH falls to levels that are
undetectable with most assays. The amplitude of secretory
pulses is greatest at night, and the most consistent
period of GH secretion is shortly after the onset of deep
sleep.
GH secretion, as illustrated in Figure 38–2, incorporates
many of the classic features of endocrine regulation.
GHRH, produced by hypothalamic neurons
found predominantly in the arcuate nucleus, stimulates
GH secretion by binding to a specific GPCR on
Hypothalamus
Anterior
pituitary
Target
tissues
–
–
GHRH
–
+
+
Growth
hormone
IGF-1
SST
Liver Bone Adipocyte
Ghrelin
Stomach
Muscle
Secondary
target tissues
Figure 38–2. Growth hormone secretion and actions. Two hypothalamic
factors, growth hormone–releasing hormone (GHRH)
and somatostatin (SST) stimulate or inhibit the release of growth
hormone (GH) from the pituitary, respectively. Insulin-like
growth factor-1 (IGF-1), a product of GH action on peripheral
tissues, causes negative feedback inhibition of GH release by
acting at the hypothalamus and the pituitary. The actions of GH
can be direct or indirect (mediated by IGF-1). See text for discussion
of the other agents that modulate GH secretion and of the
effects of locally produced IGF-1. Inhibition, −; stimulation, +.
somatotropes that resembles most closely the receptors
for secretin, vasoactive intestinal polypeptide (VIP),
pituitary adenylyl cyclase-activating peptide (PACAP),
glucagon, glucagon-like peptide-1 (GLP-1), calcitonin,
and parathyroid hormone (PTH). Upon binding GHRH,
the GHRH receptor couples to G s
to raise intracellular
levels of cyclic AMP and Ca 2+ , thereby stimulating GH
synthesis and secretion. Loss-of-function mutations of
the GHRH receptor cause a rare form of short stature in
humans, thereby demonstrating its essential role in
normal GH secretion (Wajnrajch et al., 1996).
Typical of endocrine systems, GH and its major
peripheral effector, insulin-like growth factor 1 (IGF-1),
act in negative feedback loops to suppress GH secretion.
The negative effect of IGF-1 is predominantly
through direct effects on the anterior pituitary gland. In
contrast, the negative feedback action of GH is mediated
in part by SST, which is synthesized in more
widely distributed neurons.
–
–
+
–
1107
CHAPTER 38
INTRODUCTION TO ENDOCRINOLOGY: THE HYPOTHALAMIC-PITUITARY AXIS