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

II. Physiology of Adrenocortical Hormones
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regions of genes. However, apart from this direct interaction,
the GR may also bind to other transcription factors and
thus regulate gene expression of genes devoid of a classical
glucocorticoid responsive element (GRE) . Next osmolytes,
small molecules that promote protein folding during
metabolic extremes, may also contribute to protein:protein
interactions at the genomic level ( Kumar and Thompson,
2005 ). A splicing variant of the classical GR α is called
GR β and may act as a dominant-negative inhibitor of GR α
(Charmandari et al ., 2005 ). Glucocorticoids may also act
in a way that does not directly and initially influence gene
expression, referred to as “ nongenomic. ” These pathways
involve the production of second messengers and activation
of signal transduction pathways by either the classical GR
or by a membrane glucocorticoid receptor. Apart from “ nongenomic
” effects, glucocorticoids may also predominantly
inhibit the synthesis of a variety of proteins by decreasing
their mRNA stability ( Dallman, 2005 ; Stellato, 2004 ).
The overall effect of glucocorticoids on metabolism is
to supply glucose to the organism by the transformation of
proteins. This occurs via the above-mentioned induction
of gluconeogenic enzymes in the liver. Thus, glucocorticoids
divert metabolism from a phase of growth and storage
toward increased physical activity and energy consumption,
whereas chronic excess leads to catabolic effects such as
muscle wasting, skin atrophy, and osteoporosis. The tendency
to hyperglycemia is opposed by increased secretion
of insulin, which in turn tends to enhance fat synthesis. This
along with the increased food intake owing to central appetite
stimulation ( Debons et al ., 1986 ) explains the (centripetal)
fat deposition, manifested by abdominal enlargement.
In situations of glucocorticoid deficiency, water excretion
is impaired, whereas glucocorticoid excess may result in
polyuria, being most pronounced in the dog. This is in part
due to antagonism of cortisol to the action of vasopressin. In
addition, glucocorticoid excess causes loss of the sensitivity
of the osmoregulation of vasopressin release ( Biewenga et al .,
1991 ). Even physiological increases in cortisol may inhibit
basal vasopressin release in dogs ( Papanek and Raff, 1994 ).
Glucocorticoids have long been known to have effects
on blood cells, including a reduction in the numbers of
eosinophils and lymphocytes and an increase in the number
of neutrophils and hence in the total number of leukocytes.
Glucocorticoid deficiency leads to normochromic,
normocytic anemia.
As far as effects on other endocrine glands are concerned,
it is shown that canine hyperadrenocorticism results in reversible
suppression of growth hormone secretion ( Peterson and
Altszuler, 1981 ). The frequently observed lowering of circulating
thyroxine concentrations has been ascribed to changes
in the thyroid hormone binding capacity of the plasma and
to inhibition of lysosomal hydrolysis of colloid in the thyroid
follicular cell ( Kemppainen et al ., 1983 ; Woltz et al .,
1983 ). Glucocorticoids have multiple effects on peripheral
transfer, distribution, and metabolism ( Kaptein et al .,
1992 ), but thyroid function does not seem to be affected
( Rijnberk, 1996 ). The glucocorticoid prednisone was found
to inhibit LH secretion in male dogs, leading to reduced
testosterone concentrations ( Kemppainen et al ., 1983 ).
2 . Adrenal Androgens
In health, adrenocortical production of androgens is trivial
in comparison with the production of these hormones
by the gonads. However, a pathological excess of adrenal
androgens might induce virilization (i.e., the development
of masculine secondary sex characteristics), which would
be most noticeable in the female or immature male. So far,
no virilization as a consequence of enzyme deficiency has
been reported in domestic animals, but in equine hyperadrenocorticism,
hirsutism is a common feature ( Pauli
et al ., 1974 ; Van der Kolk et al ., 1993 ).
3 . Mineralocorticoids
The widespread MR has equal affinity for aldosterone and
the glucocorticoids cortisol and corticosterone, whereas
the latter two hormones circulate at much higher concentrations
than aldosterone. However, in the classical aldosterone
targets (kidney, colon, and salivary gland), the
enzyme 11 β -hydroxysteroid dehydrogenase (11 β HSD)
converts cortisol and corticosterone (but not aldosterone!)
to the 11-keto analogues. These analogues cannot bind to
MR, thereby enabling aldosterone to occupy this receptor
( Funder, 2005 ). Thus, not the receptor but a prereceptor
modification provides the tissue specificity.
The synthetic steroid 9 α -fluorocortisone ( Table 19-1 )
binds tightly to mineralocorticoid receptors and is used
for mineralocorticoid replacement therapy because it is
more stable than aldosterone after oral administration.
Mineralocorticoid antagonists such as spironolactone bind
to these receptors and in this way block aldosterone action.
Aldosterone controls the volume and the cationic composition
of the extracellular fluid by regulating sodium and
potassium balance. Its main action is on the tubular apparatus
of the kidneys, but aldosterone receptors are also found
in the gut, the salivary glands, and the sweat glands. In the
kidney, the effect of aldosterone on the distal tubule consists
almost entirely of an exchange of sodium with potassium
and hydrogen ions. Aldosterone also promotes the
excretion of magnesium and ammonium ions.
G . Physiological Variation, Stress, and
the Immune System
In the absence of extraordinary stress, the plasma cortisol
concentration of healthy animals varies within certain limits,
although adrenocortical secretion does not occur evenly
throughout the day but rather in bursts. In humans, most
of the secretory bursts occur between midnight and early