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

II. Anterior Lobe and Intermediate Lobe
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projecting to higher brain centers remains to be elucidated.
Distribution patterns have been reported for the cat ( Rao
et al. , 1986 ). The C-terminal fragment of ACTH (18-39),
called corticotropin-like intermediate lobe peptide (CLIP),
has been found a potent stimulator of in vitro adrenal DNA
synthesis ( Wulffraat et al. , 1987 ).
Nowadays five different receptors for the melanocortins
have been cloned with variable affinities for ACTH(1-39),
α -MSH, and γ -MSH and related peptides. The MC2
receptor is unique because only ACTH(1-39) activates
this receptor. The receptor is present in the adrenal cortex
of many species and is also shown in adipocytes of mice.
The other receptors, MC1R and MC3R, have been found
to be expressed throughout the body, whereas MC4R is
only found within many brain regions and MC5R only in
peripheral tissues. Through these five receptors, the melanocortins
play a role in many biological functions such as
skin physiology, pain and nerve regeneration, behavior,
obesity and energy metabolism, and inflammatory and
immune processes ( Getting, 2006 ). The melanocortin system
plays a role in regulating feeding behavior and energy
balance ( Bertile and Raclot, 2006 ).
In the dog a single mutation in the MC1R gene results
in a premature stop codon and is associated with the yellow
coat color in Labrador retrievers ( Everts et al. , 2000 ).
f . Disease
Lesions at the hypothalamic and pituitary level may result
in altered synthesis and release of POMC-derived peptides.
There have been no reports of the occurrence of isolated
ACTH deficiency in domestic animals. There are a few
reports of dogs with tumorous (supra)hypophyseal lesions,
with indirect evidence for multiple adenohypophyseal
and neurohypophyseal deficits ( Eigenmann et al. , 1983b ;
Rijnberk, 1971 ), and one dog reported to have secondary
hypoadrenocorticism without information about other pituitary
functions ( Peterson et al. , 1992 ).
In contrast to the few descriptions of ACTH deficiency,
pituitary-dependent hyperadrenocorticism is a common
disorder in the dog ( Hanson et al. , 2005 ; Meij et al. , 2002 ;
Peterson, 1987 ) and rare in the cat ( Meij et al. , 2001 ). The
adenomas producing the ACTH excess may originate in
the AL or IL ( Peterson et al. , 1986 ). Cats with pituitarydependent
hyperadrenocorticism usually have concurrent
insulin-resistant diabetes mellitus. Various pituitary
neoplasm’s have been described in cats such as AL and IL
corticotropic adenomas ( Meij et al. , 2001 ), corticotropic
and somatotropic adenoma (double adenoma) ( Meij et al.
2004 ), and melanotropic adenoma ( Meij et al. , 2005 ).
Dogs with pituitary-dependent hyperadrenocorticism had
significantly lower CRH concentrations in cerebrospinal
fluid compared to control dogs indicating that the excessive
ACTH secretion is not caused by chronic hyperstimulation
with CRH ( Van Wijk et al. , 1992 ). The ACTH secretion
appeared also to be less sensitive to stimulation with CRH
than with LVP ( van Wijk et al. , 1994 ). The expansion of
pituitary corticotroph adenomas in dogs is correlated with
insensitivity to glucocorticoid feedback ( Kooistra et al. ,
1997b ) and plasma concentrations of ACTH precursors
( Bosje et al. , 2002 ). Evidence for a genetic involvement in
tumorigenesis was found in a family of Dandie Dinmont
terriers ( Scholten-Sloof et al. , 1992 ). In the horse, the disease
originates primarily in the IL ( Heinrichs et al. , 1990 ;
Orth et al. , 1982 ; van der Kolk et al. , 2004 ; Wilson et al. ,
1982 ). In agreement with the characteristics described earlier
for the secretion of POMC-derived peptides by the IL,
ACTH release by tumors of IL origin in both the dog and
the horse tends to be strongly resistant to suppression by
dexamethasone ( Orth et al. , 1982 ; Peterson et al. , 1986 ).
In dogs, the highest plasma α -MSH concentrations are
found in individuals with dexamethasone-resistant ACTH
secretion ( Meij et al. , 1997b ). This suggests an IL origin
of the disease, although there is evidence that the pituitary
lesions do not always maintain the characteristics of the
lobe of origin ( Rijnberk et al. , 1988b ). A dog with diabetes
insipidus has been described, in which the pituitary
tumor released primarily biologically inactive POMCderived
peptides ( Goossens et al. , 1995 ). In contrast
with the equine IL tumors, these tumors in dogs respond
poorly to administration of dopamine agonists in terms of
diminished ACTH secretion ( Rijnberk et al. , 1988b ). A
dog has been described that had dexamethasone-resistant
hyperadrenocorticism and elevated ACTH secretion resulting
from multiple endocrine neoplasia—that is, a pituitary
corticotropic tumor, bilateral adrenocortical tumors, and
pheochromocytoma ( Thuroczy et al. , 1998 ).
For details on clinical manifestations, laboratory findings,
diagnostics, and treatment of these diseases, including
iatrogenic hypoadrenocorticism resulting from corticosteroid
therapy, refer to textbooks by Feldman and Nelson
(2004) and Rijnberk (1996) and Chapter 19 on adrenocortical
function in this volume.
g . Tests
Basal levels of circulating POMC-derived peptides are
measured for diagnostic purposes in situations of suspected
hypo- as well as hypersecretion. ACTH values
below or just within the reference range ( Table 18-3 ) may
be found in cases of hypothalamus-pituitary disease, as
well as in situations where endogenous or exogenous glucocorticoid
excess suppresses hormone synthesis in the
corticotropic cells. This makes the measurement of basal
ACTH levels a useful tool in the differentiation between
pituitary-dependent hyperadrenocorticism and hyperadrenocorticism
resulting from adrenocortical tumor ( Feldman,
1983 ; Peterson, 1986 ). In pituitary-dependent hyperadrenocorticism,
ACTH values exceeding the reference range
may be found, but there is considerable overlap ( Meij
et al. , 1997a ). Basal MSH concentrations have been found
to be elevated in horses ( Orth et al. , 1982 ) and dogs ( Meij