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

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Chapter | 19 Adrenocortical Function
peripheral blood of horses, higher cortisol/corticosterone
ratios (16.0:0.5 and 7.0:0.5) have been reported ( James
et al ., 1970 ; Zolovick et al ., 1966 ).
In birds, corticosterone, a glucocorticoid with minor
mineralocorticoid properties, is by far the main adrenal
secretory product. In the peripheral blood of adult birds,
no cortisol could be demonstrated with radioimmunoassay
( Walsh et al ., 1985 ; Zenoble et al ., 1985 ) or HPLC analysis
( Lumeij et al ., 1987 ). In chickens, the 17 α-hydrolyase
activity is present in embryonic life but decreases after
hatching ( Carsia et al ., 1987 ; Nakamura et al ., 1978 ).
C . Regulation of Secretion
The steroidogenic activity of the two inner zones of the
adrenal cortex is predominantly controlled by the pituitary
hormone ACTH. The production of aldosterone in the zona
glomerulosa is adapted to the sodium and potassium status
of the organism by a complex, multifactorial, and mainly
extrapituitary control system. For details on the secretion of
ACTH by the pituitary and its regulation, refer to Chapter
18 . In puppies, the feedback control of the hypothalamicpituitary-adrenal
axis is already operative at the time of birth
(Muelheims et al ., 1969 ), although up to the age of 8 weeks
basal plasma cortisol concentrations are lower than in
mature dogs. There is indirect evidence that this is related to
low binding to transport proteins ( Randolph et al ., 1995 ).
The action of ACTH on the adrenal gland is rapid;
within minutes of its release, the concentration of steroids
in the adrenal venous blood increases. The most likely
mechanism by which ACTH stimulates steroidogenesis is
via activation of membrane-bound adenylate cyclase. This
increases the level of cyclic adenosine 3 ,5-monophosphate
(cAMP), which activates adrenocortical protein kinases.
This results in the phosphorylation of enzymes that enhance
the rate of conversion of cholesterol to pregnenolone.
Within the adrenal gland, a crosstalk exists with the adrenal
medulla ( Schinner and Bornstein, 2005 ). In vitro coculture
of adrenocortical cells with chromaffin cells results in a
10-fold increase of steroidogenic activity ( Haidan et al .,
1998 ). Also, many intra-adrenal produced cytokines and
growth factors play an important role in the regulation of
steroidogenesis ( Ehrhart-Bornstein et al ., 1998 ). In adrenal
tumors, a variety of ectopic and abnormal hormone receptors
may stimulate adrenal corticoid release ( Lacroix et al .,
2001 ) (see also the section on adrenocortical diseases).
In the regulation of aldosterone secretion, the two most
important effectors are the peptide hormone angiotensin II
(ANG II) and the extracellular potassium concentrations.
Regulation of aldosterone secretion by the potassium status
is direct and rather simple ( Fig. 19-3 ). The second loop,
which adapts aldosterone secretion to the sodium balance,
is much more complex. These two systems are regulated by
negative feedback loops. In contrast, ACTH is a representative
of other factors that may stimulate aldosterone release
FIGURE 19-3 Physiological control of aldosterone secretion (Müller,
1986 ).
without a link to negative feedback ( Williams, 2005 ). From
all factors known to regulate aldosterone production in vitro ,
the stimulation is probably confined under physiological
conditions to stimulation by ANG II, K , and ACTH and
inhibition by the atrial natriuretic hormone (ANP) ( Spat and
Hunyady, 2004 ).
Apart from these factors, other intra-adrenal factors
(Ehrhart-Bornstein et al ., 1998 ) and environmental factors
may regulate aldosterone production not only at the level
of conversion of cholesterol to pregnenolone but also at the
level of aldosterone synthase (CYP11B2) ( Williams, 2005 ).
D . Transport
At normal concentrations, only about 10% of the total blood
cortisol and corticosterone is in the free form (i.e., susceptible
to ultrafiltration). At body temperature, 70% of the
plasma cortisol is bound to a globulin called transcortin or
corticosteroid-binding globulin (CBG). Transcortin has a
high affinity for cortisol and corticosterone, but its binding
capacity is limited. Another 20% of plasma cortisol is bound
to albumin although its affinity for cortisol is much less than
that of transcortin. In line with these percentages, in the dog
the free fraction has been estimated to range from 5% to 12%
(Kemppainen et al ., 1991 ; Meyer and Rothuizen, 1993 ).
Transcortin is ubiquitous in mammals, but plasma
concentrations vary considerably, resulting in species differences
in total cortisol concentration. Most domestic
animals have little corticosteroid-binding activity compared
to humans ( Rosner, 1969 ). As the free rather than
the protein-bound steroid is biologically active, methods
have been developed to measure free cortisol. By employing
the combination of ultrafiltration and equilibrium dialysis,
it was demonstrated that in dogs with portosystemic
encephalopathy the associated hyperadrenocorticism is not
only characterized by an increased total cortisol concentration
in plasma but also by an increase in the free fraction
of plasma cortisol ( Meyer and Rothuizen, 1994 ). Between
various pig breeds, a two-fold difference in plasma CBG
binding capacity was found and related to increased drip
loss in the Meishan breed ( Geverink et al ., 2006 ).