Glucocorticoids increase serum glucose levels and thus stimulate insulin release but inhibit the uptake of glucose by muscle cells, while they stimulate hormone-sensitive lipase and thus lipolysis. The increased insulin secretion stimulates lipogenesis and to a lesser degree inhibits lipolysis, leading to a net increase in fat deposition combined with increased release of fatty acids and glycerol into the circulation.
The net results of these actions are most apparent in the fasting state, when the supply of glucose from gluconeogenesis, the release of amino acids from muscle catabolism, the inhibition of peripheral glucose uptake, and the stimulation of lipolysis all contribute to maintenance of an adequate glucose supply to the brain.
D. Catabolic and Antianabolic Effects
Although glucocorticoids stimulate RNA and protein synthesis in the liver, they have catabolic and antianabolic effects in lymphoid and connective tissue, muscle, peripheral fat, and skin. Supraphysiologic amounts of glucocorticoids lead to decreased muscle mass and weakness and thinning of the skin. Catabolic and antianabolic effects on bone are the cause of osteoporosis in Cushing’s syndrome and impose a major limitation in the long-term therapeutic use of glucocorticoids. In children, glucocorticoids reduce growth. This effect may be partially prevented by administration of growth hormone in high doses, but this use of growth hormone is not recommended.
E. Anti-Inflammatory and Immunosuppressive Effects
Glucocorticoids dramatically reduce the manifestations of inflammation. This is due to their profound effects on the concentration, distribution, and function of peripheral leukocytes and to their suppressive effects on inflammatory cytokines and chemokines and on other mediators of inflammation. Inflammation, regardless of its cause, is characterized by the extravasation and infiltration of leukocytes into the affected tissue. These events are mediated by a complex series of interactions of white cell adhesion molecules with those on endothelial cells and are inhibited by glucocorticoids. After a single dose of a short-acting glucocorticoid, the concentration of neutrophils in the circulation increases while the lymphocytes (T and B cells), monocytes, eosinophils, and basophils decrease. The changes are maximal at 6 hours and are dissipated in 24 hours. The increase in neutrophils is due both to increased influx into the blood from the bone marrow and to decreased migration from the blood vessels, leading to a reduction in the number of cells at the site of inflammation. The reduction in circulating lymphocytes, monocytes, eosinophils, and basophils is primarily the result of their movement from the vascular bed to lymphoid tissue.
Glucocorticoids also inhibit the functions of tissue macrophages and other antigen-presenting cells. The ability of these cells to respond to antigens and mitogens is reduced. The effect on macrophages is particularly marked and limits their ability to phagocytose and kill microorganisms and to produce tumor necrosis factor α, interleukin 1, metalloproteinases, and plasminogen activator. Both macrophages and lymphocytes produce less interleukin 12 and interferon-γ, important inducers of Th1 cell activity, and cellular immunity.
In addition to their effects on leukocyte function, glucocorticoids influence the inflammatory response by inhibiting phospholipase A2 and thus reduce the synthesis of arachidonic acid, the precursor of prostaglandins and leukotrienes, and of platelet-activating factor. Finally, glucocorticoids reduce expression of cyclooxygenase 2, the inducible form of this enzyme, in inflammatory cells, thus reducing the amount of enzyme available to produce prostaglandins (see Chapters 18 and 36).