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chapter32
Endocrine Metabolism III: Adrenal Glands
Cortisol is an important modulator of the renin-
angiotensin system. It stimulates the synthesis of an-
giotensinogen (renin substrate) by the liver, probably by
prolonging the half-life of the angiotensinogen mRNA;
it also stimulates the synthesis of angiotensin-converting
enzyme (ACE) in vascular endothelial cells by promoting
the expression of the
ACE
gene. By these actions, cortisol
increases the magnitude of the renin-angiotensin response.
Concurrently, however, cortisol promotes the expression
of the atrial natriuretic peptide (
ANP
) gene in cardiac mus-
cle cells and thus allows for better modulation of a renin-
angiotensin overshoot.
Cortisol maintains the reactivity of the reticular acti-
vating system, the limbic system, and areas of the thala-
mus and hypothalamus to sensory “distress” signals and
to endogenous opiates. Cortisol thus has an important role
in behavioral and neuroendocrine responses to stress. The
presence of glucocorticoids appears to be necessary for the
stress analgesia that is attributed to endogenous opiates.
Cortisol promotes tissue responsiveness to catecholamines
and induces adrenal medullary phenylethanol amine-
N-methyltransferase
(PNMT),
which
converts
nore-
pinephrine to epinephrine (see below). Thus, even before
it reaches the general circulation, cortisol promotes car-
diovascular performance by promoting the formation of a
cardiotropic hormone.
These central, metabolic, and cardiovascular effects of
cortisol are accentuated when large amounts of cortisol
are released in response to severe stress. Although the
plasma cortisol concentration attained during stress of-
ten increases
1 0
-fold, this hypercortisolism is relatively
acute and ephemeral, and the effects do not resemble
those seen after chronic excesses of cortisol or synthetic
glucocorticoids.
Pharmacological Effects o f Glucocorticoids
When the plasma glucocorticoid levels are chronically
elevated, whether because of hyperactivity of the adrenal
cortex or administration or consumption of synthetic
glucocorticoids, some of the “physiological” effects be-
come exaggerated, while other effects not normally seen
appear. Protein catabolism is enhanced in skeletal muscle,
skin, bone matrix, and lymphoid tissues by inhibition
of protein synthesis and of cellular proliferation (DNA
synthesis). Glucose utilization is severely inhibited and
hepatic gluconeogenesis enhanced, which can lead to
muscle weakness and atrophy, thinning and weakening
of the skin, osteoporosis, diminished immunocompe-
tence (from destruction of lymphocytes in lymphoid
tissues), increased susceptibility to infections, and poor
wound healing. These are classical features of
Cushing’s
syndrome
and
Cushing’s disease,
in which the adrenal
cortex secretes supraphysiological amounts of cortisol.
Chronic excess of glucocorticoids leads to elevated lev-
els of glucose and free fatty acids in blood. Because these
effects indicate inadequate counteraction by insulin, they
are diabetogenic and are associated with an abnormal glu-
cose tolerance test. Although glucocorticoid excess stim-
ulates lipolysis, which leads to hyperlipemia, body fat is
not depleted; in fact, a form of obesity (“central obesity”)
involving redistribution of body fat to the abdomen, upper
back, and face appears to be characteristic of glucocorti-
coid toxicity.
Chronic glucocorticoid excess during the period of
growth (e.g., peripubertal period) leads to suppression
of cellular proliferation and of production of growth-
promoting hormones and results in stunting. Proliferation
of fibroblasts and other cell types required for longitudinal
bone growth and for somatic growth in general is severely
affected. The function of these cell types is also inhibited,
and adequate formation of tissue matrices is not possi-
ble. Release of GH and formation of IGFs, 5'-deiodinase
activity, and release of TSH and ACTH all are inhibited.
Synthetic glucocorticoids can exert a long-lasting repres-
sion of POMC synthesis in the anterior pituitary. After
cessation of chronic glucocorticoid treatment, ACTH lev-
els do not return to normal before 2-3 months, and corti-
sol secretion resumes only after an additional
6
months.
Thus, withdrawal of exogenous steroids results in a state
of adrenocortical deficiency for 8-9 months, during which
time the imposition of stressful stimuli may have undesir-
able consequences.
High local concentrations of glucocorticoids inhibit
or diminish inflammatory and allergic reactions. Cell-
mediated inflammation (of joints, bursae, etc.) and allergic
reactions (IgE-induced) are caused by release of agents de-
signed to combat infection (see Chapter 35). Thus, chemo-
taxis of neutrophils and other invasive cells to the affected
area is followed by release of lysosomal enzymes (e.g.,
collagenase), histamine, prostaglandin E
2
(PGE2), super-
oxide anion radicals, and other mediators of inflamma-
tion that cause tissue destruction and vascular permeability
changes (see Chapters 15 and 18). Glucocorticoids coun-
teract the inflammatory response by
1. Inhibiting phospholipase A
2
activity, thereby
decreasing the synthesis of PGE
2
and of the potent
chemotactic substance leukotriene B
4
2. Stabilizing membranes of the lysosomes and
secretory granules, thereby inhibiting the release of
their contents, and
3. Acting directly on the capillary endothelium to render
it less permeable.
