Physiologic and Pharmacologic Effects of Corticosteroids
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).
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.
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
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
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
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
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,63 symptoms 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
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.
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.
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
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
Author: Lorraine I. McKay, PhD and John A. Cidlowski, PhD.