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

II. Anterior Lobe and Intermediate Lobe
581
Plasma IGF-I exerts a negative feedback of GH release
both at the hypothalamic level where it stimulates SS release
and inhibits GHRH release, as well as at the pituitary level.
As the majority of plasma IGF-I is bound to specific binding
proteins, in plasma predominantly IGFBP3, the free rather
than the protein-bound IGF-I determines these feedback
regulations ( Chen et al. , 2005 ). The elevated GH concentrations
in fasting dogs have also been explained as the result
of impaired feedback inhibition caused by low IGF-I plasma
levels ( Eigenmann et al. , 1985 ).
Finally thyroid hormone, sex steroids, and glucocorticoids
modulate GH synthesis and release. In contrast to
humans and rats where low plasma thyroid hormone concentrations
result in attenuated GH secretion, hypothyroidism
in the dog is associated with enhanced basal plasma GH
concentrations and reduced pulsatility ( Lee et al. , 2001 ). In
dogs with pituitary-dependent hyperadrenocorticism, no differences
exist in the basal plasma GH secretion, but less GH
is secreted in pulses in comparison to control dogs ( Hanson
et al. , 2006a ; Lee et al. , 2003 ). In dogs, endogenous and
exogenous progestins may induce considerable rises in
plasma growth hormone concentrations, resulting in acromegalic
changes and insulin resistance ( Rijnberk et al. , 2003 ;
Selman et al. , 1994a ; Selman et al. , 1994b ).
e . Action
The effects of GH can be divided into two main categories:
rapid or metabolic actions and slow or hypertrophic
actions. The (acute) metabolic responses are due
to direct interaction of growth hormone with the target
cell, whereas the slow hypertrophic effects or those on
cartilage, bone, and other tissues are indirect. The direct
effects of GH result in differentiation of prechondrocytes,
enhanced lipolysis in adipose tissue, increased gluconeogenesis,
and restricted glucose transport caused by insulin
resistance ( Eigenmann, 1984 ; Renaville et al. , 2002 ;
Veldhuis et al. , 2006 ). The GH responsiveness of adipose
tissue is less dependent on nutrition than that of the liver,
which may explain the reduced adiposity in the absence
of growth enhancement in GH-treated ruminants ( Breier
et al. , 1986 ). In vitro GH has also a direct positive effect
on the maturation of bovine oocytes ( Bevers and Izadyar,
2002 ) and human hematolymphopoiesis ( Hanley et al. ,
2005 ).
In contrast to these direct catabolic effects, the indirect
actions are anabolic and mediated by the insulin-like
growth factors IGF-I and IGF-II ( Daughaday et al. , 1987 ).
In their chemical structure the IGFs have approximately
50% homology with insulin/proinsulin, suggesting they
have evolved from a common ancestral molecule. The IGFs
are bound to a family of six different high-affinity IGFbinding
proteins ( Firth and Baxter, 2002 ). The main
IGFBP in plasma is IGFBP3, which forms together with
an acid-labile subunit a ternary complex of 150 kDa. As a
consequence, IGFs have a long plasma half-life, which is
consistent with their long-term growth promoting action.
Specific proteolysis may increase free IGF concentration
locally and modulates the IGF receptor signaling ( Bunn
and Fowlkes, 2003 ).
Dogs have an extreme variation of body size between
breeds. It has been shown that a large body size is associated
with GH excess at a young age ( Favier et al. , 2001 ).
In adult dogs, circulating IGF-I concentrations were
found to correlate with body size in different dog breeds
( Eigenmann et al. , 1988 ). By studying genetic subgroups
within one breed (i.e., standard, miniature, and toy poodles),
plasma IGF-I concentrations, and not GH secretory
reserve, did parallel body size ( Eigenmann et al. , 1984a ).
f . Disease
Inadequate growth hormone secretion at a young age retards
growth. Apart from occasional reports on dwarfism in dogs
and cats, GH-deficiency dwarfism seems to occur primarily
as a genetically transmitted condition in the German
Shepherd ( Andresen et al. , 1974 ) and in the Carelian bear
dog ( Andresen and Willeberg, 1977 ). In the German shepherd,
the GH deficiency is associated with TSH and prolactin
deficiency and impaired LH and FSH release without disturbances
in ACTH secretion ( Kooistra et al. , 2000c ). This
indicates that at a defect in the organogenesis of the pituitary
resulting from mutation in an essential transcription
factor may have occurred. So far the involvement of mutations
in Pit-1 ( Lantinga-van Leeuwen et al. , 2000b ), Prop1
(Lantinga-van Leeuwen et al. , 2000a ), LHX4 ( van Oost et al. ,
2002 ), and the LIF receptor ( Hanson et al. , 2006b ) has been
excluded as candidate genes for pituitary dwarfism.
In adults, growth hormone deficiency causes much less
impressive changes. The clinical features remain confined
to the skin and coat. Affected dogs are presented with
alopecia and hyperpigmentation of the skin. In contrast
to dogs with congenital hyposomatotropism, these dogs
may have low but detectable plasma GH concentrations,
a blunted response to a clonidine or GHRH stimulation
test, but plasma IGF-I concentrations within the reference
range. This may be caused by a mild and fluctuating
hyperadrenocorticism ( Rijnberk et al. , 1993 ). In some dogs
the alopecia was explained by an adrenal androgen imbalance.
Among other treatments, administration of GH has
been associated with hair regrowth ( Frank, 2005 ).
Syndromes resulting from GH excess are known to
occur in the dog and the cat. In both species, the GH excess
gives rise to outgrowth of bone and soft tissues (acromegaly),
as well as to insulin resistance with the possibility
of development of frank diabetes mellitus. However, the
pathogenesis of the excessive GH secretion in these species
is completely different. GH-producing canine pituitary
adenomas are extremely rare and only reported once
( Fracassi, 2007 ). A physiological, reversible form of extrapituitary
GH secretion is found to be stimulated during