Clinical Biochemistry of Domestic Animals (Sixth Edition) - UMK ...

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Chapter | 18 Pituitary Function
GH-GHBP
Hypothalamus
GHRH
ghrelin
Pituitary
GH
Somatostatin
ALS
IGFBP-3
IGF-I
Protease
Lipolysis
IGFBP-1
IGFBP-2
IGFBP-3
Amino acid transport
IGF-I
IGFBP-4
protein synthesis
IGFBP-5
IGFBP-6
Anabolism
FIGURE 18-12 Regulation of pituitary GH release, peripheral actions,
and feedback.
5 peaks/12 h ( Kooistra et al. , 2000a ). The higher basal concentration
and diminished pulsatility in early luteal phase
may be caused by a direct or indirect inhibition of pituitary
GH release by GH secretion from the mammary glands
stimulated by progesterone.
Pituitary somatotropes are not only stimulated by the
GH-releasing hormone (GHRH), which was first isolated
from human pancreas islet tumors in 1982 and next found in
the hypothalamus, but also by the more recently discovered
GH-releasing hormone ghrelin, which was originally isolated
from rat and human gut. In the pituitary, two GHRH-R
isoforms exist generated by alternative splicing. The predominant
short form activates somatotropes through the
adenylate cyclase/cAMP/PKA pathway. The pituitary
contains also two splice variants of a distinct seven-transmembrane
helix, G protein coupled receptor for ghrelin,
called the GH secretagogue receptor (GHS-R). Only the
long type 1a isoform activates pituitary somatotropes
via the phospholipase C/IP 3 /PKC pathway. The expression
of both receptors is down-regulated by exposure to GHRH
as well as ghrelin in porcine pituitary cell cultures ( Luque
et al. , 2004 ). The release of GH is generally inhibited by somatostatin
(SS). In the pituitary all five SS receptors (SST1-5)
are expressed. In porcine pituitary cells low SS concentrations
may, however, also stimulate GH release. It has been
found that the inhibitory effects are mediated by SST1 and
SST2 receptors, whereas SST5 mediates the stimulatory
effect of SS on GH release in vitro (Luque et al. , 2006 ).
In young beagle dogs, 13 to 17 months of age, ghrelin
was shown to a more potent GH secretagogue in comparison
to GHRH. With aging, 7 to 12 year of age, the GH
response to ghrelin was significantly lower, whereas only
a moderate decrease in the sensitivity toward GHRH was
noticed and GHRH appeared to be at higher age a more
potent stimulator of GH release ( Bhatti et al. , 2006b ). In
contrast to humans, in the dog ghrelin has hardly any stimulatory
effect on ACTH and prolactin release ( Bhatti et al. ,
TABLE 18-5 Putative Factors Modulating GH Release
Stimulating
Inhibiting
Hormones GHRH Somatostatin (SS)
Ghrelin
IGF-I, IGF-II
Glucagon
Corticosteroid excess
Pentagastrin
Enkephalin
Biogenic amines
α -Adrenergic
agonists
β -Adrenergic
antagonists
Dopamine
α -Adrenergic
antagonists
β-Adrenergic agonists
Serotonin antagonists
Others Hypoglycemia Hyperglycemia
Fall in free fatty acids Rise in free fatty acids
Amino acids
(arginine)
Sleep
Stress (emotional)
Exercise
2006b ; van der Lely et al. , 2004 ). Plasma concentrations
of acylated ghrelin, which is the biologically active form,
are higher after fasting and lower after food intake, suggesting
a role in feeding control and energy homeostasis
also in the dog ( Bhatti et al. , 2006c, 2006d ). No clear relation
was found of plasma GH and ghrelin in the study by
Bhatti et al. , in agreement with a previous study in which
also no close relation was found between plasma GH and
ghrelin concentrations during the juvenile period in dogs
( Yokoyama et al. , 2005 ).
Next to the direct and selective effects of the hypophysiotropic
hormones on GH secretion at the pituitary level, there
are indirect neuronal influences that modulate GH secretion
(see also Table 18-3 ) ( McMahon et al. , 2001 ). In general, the
main physiological stimuli of GH secretion are sleep, physical
exercise, stress, fasting, catecholamines, hypoglycemia,
and certain amino acids. However, this does not apply in
every respect to all species. For example, GH secretion in
dogs is not related to sleep or day-night cycles, although GH
peaks may occur after forced wakefulness at the onset of
sleep ( Takahashi et al. , 1981 ). Insulin-induced hypoglycemia
and arginine administration do not consistently result in GH
release in the dog ( Eigenmann and Eigenmann, 1981 ). Of
the neurotransmitter systems involved, adrenergic systems
seem to play a major role. α -Adrenergic agonists promote
GH secretion, whereas β -adrenergic agonists are inhibitory.
Thus, clonidine, a central α 2 -adrenergic agonist, is an effective
stimulator of GH secretion in the dog ( Eigenmann and
Eigenmann, 1981 ; Selman et al. , 1994a ). The dopaminergic
D2 receptor is important for stimulating GH release, as
can be concluded from the dwarfism in the D2 KO mouse
(Garcia-Tornadu et al. , 2006 ).