Physiologic and Pharmacologic Effects of Corticosteroids

Lorraine I. McKay, PhD and John A. Cidlowski, PhD.

Corticosteroids are key regulators of whole-body homeostasis that provide an organism with the
capacity to resist environmental changes and invasion of foreign substances. The effects of
corticosteroids are widespread, including profound alterations in carbohydrate, protein, and lipid
metabolism, and the modulation of electrolyte and water balance. Corticosteroids affect all of the
major systems of the body, including the cardiovascular, musculoskeletal, nervous, and immune
systems, and play critical roles in fetal development including the maturation of the fetal lung.
Because so many systems are sensitive to corticosteroid levels, tight regulatory control is exerted
on the system. The direct effects of corticosteroids are sometimes difficult to separate from their
complex relationship with other hormones, in part due to the permissive action of low levels of
corticosteroid on the effectiveness of other hormones, including catecholamines and glucagon.
Nevertheless, the effects of corticosteroids can be classified into two general categories:
glucocorticoid (intermediary metabolism, inflammation, immunity, wound healing, myocardial,
and muscle integrity) and mineralocorticoid (salt, water, and mineral metabolism). Although the
following section discusses the separate effects of glucocorticoids and mineralocorticoids, it
must be emphasized that natural steroids possess both glucocorticoid and mineralocorticoid
activity to some extent. The ratio between the two activities ranges from all glucocorticoid and
almost no mineralocorticoid activity (cortisol) to all mineralocorticoid and almost no
glucocorticoid activity (aldosterone).
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Intermediary Metabolism
Glucocorticoids stimulate the conversion of protein to carbohydrate through gluconeogenesis and
promote the storage of carbohydrate as glycogen. The increase in urinary nitrogen after an
increase in glucocorticoids is the result of amino acid mobilization from protein and its
subsequent breakdown as a source of carbon during gluconeogenesis. Adrenalectomized animals
are able to function normally as long as food (ie, free amino acids) is available. Upon starvation,
however, these animals cannot mobilize amino acids from muscle or serum protein, indicating
that cortisol plays a role in the mobilization process.33 Glucocorticoids stimulate the process of
hepatic gluconeogenesis, resulting in elevated plasma glucose, which, in turn, promotes the
deposition of liver glycogen.34 Increased hepatic gluconeogenesis/glycogenesis is due to direct
effects of glucocorticoids on the hepatic expression of genes that code for enzymes required for
glucose and glycogen biosynthesis. Prolonged exposure to glucocorticoids leads to a diabetic-
like state due to the increase in plasma glucose, while low glucocorticoid concentrations lead to
hypoglycemia, decreased glycogen stores, and hypersensitivity to insulin. Glucocorticoids also
decrease facilitated uptake of glucose in peripheral tissues to provide more glucose for glycogen
formation in the liver. This effect is particularly prevalent in leukocytes and may be a major
contributing factor to the rapid elevation in blood glucose after steroid administration. The
complex mechanisms for the peripheral effects of glucocorticoids are still unclear, but chronic
administration can result in the atrophy of lymphatic tissue and muscle, osteoporosis, and
thinning of the skin.
There are two established effects of glucocorticoids on lipid metabolism. One is the
redistribution of body fat in hypercorticism; the other is facilitation of effects of lipolytic agents.
Large doses of glucocorticoids lead to redistribution of fat to the upper trunk and face, with a
concomitant loss of fat in the extremities.35 The mechanism for this effect is not understood,
although these apparently paradoxical responses may result from differences in the number of
glucocorticoid receptors in different types of fat cells.36 By this hypothesis, cells with fewer
receptors would be spared the effects of glucocorticoids on glucose transport. Therefore, glucose
and triglyceride accumulation would occur in response to the rise in insulin levels. Fat cells
containing higher levels of receptor (perhaps in the periphery) would respond to the high
glucocorticoid level by decreasing glucose uptake and would not accumulate triglycerides.
Alternatively, cells in the extremities may be less sensitive to insulin.37 The mobilization of fat
from peripheral depots by epinephrine and other lipolytics is severely blunted in the absence of
glucocorticoids.38 Cortisol facilitates the response of adipocytes to the rise in cAMP induced by
these agents rather than creating a larger increase in the amount of cAMP.
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Electrolyte and Water Balance

The major effect of mineralocorticoids is the regulation of electrolyte excretion in the
kidney.39 Aldosterone treatment results in increased sodium reabsorption and an increase in
excretion of potassium and hydrogen in the renal tubule. Similar effects on cation transport in
most other tissues account for all the systemic activity of mineralocorticoids. The primary
features of mineralocorticoid excess are positive sodium balance, increased extracellular fluid
volume, normal or slightly high plasma sodium, hypokalemia, and alkalosis. Hypocorticism
results in renal loss of sodium, hyponatremia, hyperkalemia, and a decrease in extracellular fluid
volume and cellular hydration. The 1% decrease in sodium reabsorption that occurs in
hypocorticism is enough to cause profound cardiovascular changes, resulting in circulatory
collapse, renal failure, and, ultimately, death. Aldosterone modulates sodium levels by activating
mineralocorticoid receptors in the distal tubules of the kidney, leading to increased permeability
of the apical membrane of the cells lining the cortical collecting tube. However, there is also
evidence for a rapid (within minutes) upregulation of sodium-hydrogen exchange by aldosterone
that is independent of traditional mineralocorticoid receptors.40 Aldosterone also increases the
activity of the sodium/potassium-adenosine triphosphatase (ATPase) in the serosal
membrane.41 These changes increase sodium reabsorption and generate a higher negative
potential in the lumen, which is the driving force for increased potassium and hydrogen
excretion. Mineralocorticoids also increase calcium and magnesium excretion, probably due to
volume expansion. Prolonged aldosterone treatment results in sodium “escaping,” a cessation of
sodium changes, while potassium and hydrogen loss continues to occur. The mechanism for this
effect is unknown but may involve mineralocorticoid receptor downregulation and subsequent
cessation of hormonal responsiveness.
Glucocorticoid effects on the kidney differ from mineralocorticoid effects. Glucocorticoids
increase water diuresis, glomerular filtration rate, and renal plasma flow. Although increases in
sodium retention and potassium excretion occur with cortisol, there seems to be no increase in
hydrogen excretion. The major renal complications of glucocorticoid therapy are
nephrocalcinosis, nephrolithiasis, and increased stone formation as a result of increased urinary
calcium and uric acid.42
Electrolyte changes also occur outside the kidney in response to mineralocorticoid treatment, in
the gastrointestinal mucosa,43 salivary and sweat glands,44 and exocrine pancreas. In these tissues,
a longer onset period is required to detect significant responses to aldosterone, and no sodium
“escape” occurs after prolonged hormone administration. In the intestine, aldosterone does not
cause changes in intestinal electrolyte absorption,45 but glucocorticoids increase sodium and
water absorption and potassium secretion. Both glucocorticoid and mineralocorticoid receptors
are present in the mucosa, but dexamethasone can bind to both receptor types whereas
aldosterone can only bind to its own receptor. Cortisol also increases gastric acid secretion and
blood flow to the gastric mucosa, while decreasing the rate of gastric cell proliferation. High
doses of glucocorticoids may cause peptic ulceration or aggravate preexisting ulcers.46
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Endocrine System
In addition to effects on ACTH secretion, corticosteroids influence the action of several other
hormones. Cortisol increases growth hormone secretion in patients with acromegaly.47 In
contrast, the spontaneous secretion of growth hormone is inhibited in hypercorticism.48 Growth
failure is observed with prolonged glucocorticoid treatment in children. This response is
apparently a result of decreased maturation of the epiphyseal plates and a decrease in long bone
growth.49 Corticosteroids depress the secretion of thyroid-stimulating hormone in patients with
myxedema,50 and reduce the physiologic effectiveness of thyroxine.51 High doses of steroid
decrease luteinizing hormone release in response to luteinizing hormone-releasing
hormone.52 Corticosteroids potentiate the adrenergic effects of catecholamines and stimulate the
synthesis of epinephrine from norepinephrine.53 Other systemic effects of high doses of
glucocorticoids include adrenocortical insufficiency upon glucocorticoid removal, steroid-
induced diabetes, hyperlipidemia, elevated glucagon, and hypocalcemia.54
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Cardiovascular System
The major effects of corticosteroids on the cardiovascular system are a result of their influence
on plasma volume, electrolyte retention, epinephrine synthesis, and angiotensin levels, which
together result in the maintenance of normal blood pressure and cardiac output. However, the
hypotension that occurs from corticosteroid deficiency cannot be totally explained by these
factors. Corticosteroids have effects on myocardial responsiveness, arteriolar tone, and capillary
permeability. Hypocorticism leads to increased capillary permeability, inadequate vasomotor
response, and decrease in cardiac output and cardiac size. Hypercorticism leads to chronic
arterial hypertension,55 an effect probably due to prolonged, excessive sodium retention and
specific to mineralocorticoids. Aldosterone affects ion transport in the vascular smooth muscle
and the central nervous system,56 possibly altering sympathetic output by influencing the
periventricular area of the hypothalamus, where information about cardiovascular status,
electrolyte and fluid balance are integrated. Hypertension can also be induced by glucocorticoids.
Although the mechanism for this response is unknown, glucocorticoids influence many factors
that modulate blood pressure. For example, they increase filtration fraction and glomerular
hypertension, as well as the synthesis of angiotensinogen and atrial natriuretic peptide. They
decrease prostaglandin synthesis, which leads to decreased vasodilation, and simultaneously
increase responsiveness to vasopressors. They modulate vascular tone by decreasing expression
of calcium-activated potassium channels, and there is evidence that glucocorticoids potentiate
atherosclerosis and thromboembolic complications.57
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Musculoskeletal System
Normal corticosteroid levels are required for muscle maintenance, but altered glucocorticoid or
mineralocorticoid levels can lead to muscle abnormalities.58 Elevated aldosterone causes muscle
weakness because of hypokalemia, while high glucocorticoid levels cause muscle wasting
because of their catabolic effects on protein metabolism. Corticosteroid insufficiency results in
decreased work capacity of striated muscle, weakness, and fatigue. This response reflects an
inadequacy of the circulatory system rather than electrolyte and carbohydrate imbalances.
Chronic glucocorticoid administration results in induction of osteoporosis, a serious limiting
factor in the clinical use of steroids. Glucocorticoid-induced bone loss is a multifaceted process.
Glucocorticoids reduce bone remodeling by directly modulating osteoclast, osteoblast, and
osteocyte function. They increase renal calcium excretion and decrease gastrointestinal calcium
absorption, resulting in reduced serum calcium. Reduced serum calcium causes increased
secretion of parathyroid hormone (PTH), and glucocorticoids increase PTH sensitivity. PTH
action in turn stimulates osteoclast activity.59 Other effects of high doses of glucocorticoids on
the musculoskeletal system include aseptic or avascular necrosis of bone and spontaneous tendon
rupture, presumably through an effect on collagen metabolism.57,60,61
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Central Nervous System

Corticosteroids affect the nervous system indirectly in a number of ways, by maintaining normal
plasma glucose levels, adequate circulation, and normal electrolyte levels. Direct effects of
corticosteroids on the central nervous system occur, but are not well defined. Corticosteroid
levels influence mood, behavior, electroencephalograph patterns, memory consolidation, and
brain excitability. Chronic glucocorticoid treatment causes cell death in hippocampal neurons in
rats, and elevated glucocorticoid in the hippocampus is thought to play a role in altered
cognition, dementia, and depression in aging humans.62 Patients with Addison disease are subject
to apathy, depression, irritability, and psychosis,63symptoms that are alleviated by glucocorticoid,
but not mineralocorticoid, therapy. Cushing disease patients sometimes develop neuroses and
psychoses that are reversible with the removal of excess hormone.64 Increases in brain
excitability in hypercorticism and after mineralocorticoid treatment are a result of electrolyte
imbalances. However, increased brain excitability induced by cortisol is not due to changes in
sodium concentration. Chronic glucocorticoid treatment can also result in pseudotumor cerebri,
primarily in children.65
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Hematologic Effects
Corticosteroids increase hemoglobin and red cell content of blood, possibly by retarding
erythrophagocytosis. This effect is demonstrated by the occurrence of polycythemia in Cushing
disease and mild normochromic anemia in Addison disease. Corticosteroids also affect
circulating white cells. Glucocorticoid treatment results in increased polymorphonuclear
leukocytes in blood as a result of increased rate of entrance from marrow and a decreased rate of
removal from the vascular compartment. In contrast, the lymphocytes, eosinophils, monocytes,
and basophils decrease in number after administration of glucocorticoids. A single dose of
cortisol results in a 70% decrease in lymphocytes and a 90% decrease in monocytes, occurring 4
to 6 h after treatment and persisting for about 24 h. Cell numbers then rise 24 to 72 h after
treatment.66 The decrease in lymphocytes, monocytes, and eosinophils is generally thought to be
a consequence of redistribution of these cells, although certain lymphocytes also undergo
glucocorticoid-induced apoptosis.67 T lymphocytes are more sensitive to glucocorticoid-induced
apoptosis than are B lymphocytes, and T-cell subpopulations differ in their glucocorticoid
sensitivity. A decrease in basophils occurs by an unknown mechanism.
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Antiinflammatory Effects
Glucocorticoids prevent or suppress the full inflammatory reaction to infectious, physical, or
immunologic agents, inhibiting early inflammatory events such as edema, cellular exudation,
fibrin deposition, capillary dilatation, migration of leukocytes into the area, and phagocytic
activity. Later events, such as capillary and fibroblast proliferation, deposition of collagen, and
cicatrization, are also inhibited. The antiinflammatory mechanism of glucocorticoids, while not
completely understood, is of great therapeutic relevance and is the subject of intense scientific
investigation.
A major effect of glucocorticoids on the inflammatory process is inhibition of recruitment of
neutrophils and monocytes.68 Glucocorticoids dampen the ability of neutrophils to adhere to
capillary endothelial cells by a dual mechanism. They block the normal increase in expression of
endothelial adhesion molecules (ie, ELAM-1) and intercellular adhesion molecules (ie, ICAM-
1), and they induce lipocortin, a protein inhibitor of phospholipase A2(PLA2). Because PLA2 is
an enzyme involved in prostaglandin synthesis, glucocorticoids ultimately decrease the synthesis
and release of prostaglandin mediators of cell adhesion. Glucocorticoids also inhibit synthesis of
plasminogen activator and migration inhibitory factor,69,70 stabilize lysosomes (thereby
decreasing the release of hydrolytic enzymes and histamine71), and decrease binding of
chemokines that attract white blood cells.72 Glucocorticoids slow wound healing by blocking the
normal inflammatory reaction of breaking down and disorganizing collagen.
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Immune System
It is well known that hypocorticism results in hypertrophy of lymphoid tissue (ie, thymus, spleen,
lymph nodes) and hypercorticism leads to dimunition or total loss of these tissues.
Glucocorticoids induce rapid apoptosis in lymphatic tissue in rats and mice, but these effects
seem to occur only at pharmacologic doses in man. The effects seen in humans, therefore, may
be due to changes in the rate of formation or destruction of lymphoid cells that become evident
over a longer period of time. More acute effects of glucocorticoid on lymphoid cells in man are
probably caused by sequestration of the cells rather than by cell lysis, although there is evidence
that certain types of activated T lymphocytes are susceptible to glucocorticoid-induced
apoptosis.67 In contrast to normal human lymphocytes, acute lymphocytic leukemias and other
malignancies respond to glucocorticoid treatment by apoptosis, as is seen in rodents.
Glucocorticoids decrease the secretion of interleukin 1 and other mediators of immune response,
inhibit lymphocyte participation in delayed hypersensitivity reactions, and interfere with the
rejection of immunologically incompatible graft tissue.73 This is probably a consequence of
decreases in leukocyte recruitment. High doses of glucocorticoids inhibit immunoglobulin
synthesis, kill B cells,74 and decrease production of components of the complement system.75
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Other Effects
Other effects of prolonged glucocorticoid therapy include ophthalmologic (posterior subcapsular
cataracts,76 increased intraocular pressure77) and dermatologic (redistribution of subcutaneous fat,
hirsutism, alopecia, impaired wound healing, purpura, purple striae, and acneiform eruptions78)
problems. Long-term glucocorticoid treatment, with the concomitant immunosuppression, also
leaves patients susceptible to invasive diseases such as Kaposi sarcoma79 and fungal infections.80