Glucocorticoids cause vasoconstriction when applied directly to the skin, possibly by suppressing mast cell degranulation. They also decrease capillary permeability by reducing the amount of histamine released by basophils and mast cells.
The anti-inflammatory and immunosuppressive effects of glucocorticoids are largely due to the actions described above. In humans, complement activation is unaltered, but its effects are inhibited. Antibody production can be reduced by large doses of steroids, although it is unaffected by moderate doses (eg, 20 mg/d of prednisone).
The anti-inflammatory and immunosuppressive effects of these agents are widely useful therapeutically but are also responsible for some of their most serious adverse effects (see text that follows).
F. Other Effects
Glucocorticoids have important effects on the nervous system. Adrenal insufficiency causes marked slowing of the alpha rhythm of the electroencephalogram and is associated with depression. Increased amounts of glucocorticoids often produce behavioral disturbances in humans: initially insomnia and euphoria and subsequently depression. Large doses of glucocorticoids may increase intracranial pressure (pseudotumor cerebri).
Glucocorticoids given chronically suppress the pituitary release of ACTH, growth hormone, thyroid-stimulating hormone, and luteinizing hormone.
Large doses of glucocorticoids have been associated with the development of peptic ulcer, possibly by suppressing the local immune response against Helicobacter pylori. They also promote fat redistribution in the body, with increase of visceral, facial, nuchal, and supraclavicular fat, and they appear to antagonize the effect of vitamin D on calcium absorption. The glucocorticoids also have important effects on the hematopoietic system. In addition to their effects on leukocytes, they increase the number of platelets and red blood cells.
Cortisol deficiency results in impaired renal function (particularly glomerular filtration), augmented vasopressin secretion, and diminished ability to excrete a water load.
Glucocorticoids have important effects on the development of the fetal lungs. Indeed, the structural and functional changes in the lungs near term, including the production of pulmonary surface-active material required for air breathing (surfactant), are stimulated by glucocorticoids.
Recently, glucocorticoids were found to have direct effects on the epigenetic regulation of specific target genes by altering the activities of DNA methyltransferases and other enzymes participating in epigenesis. This is of particular importance in the prenatal treatment of pregnant mothers or treatment of young infants and children, when the effects of glucocorticoids may be long-term or even permanent. These effects may predispose these patients to behavioral or somatic disorders, such as depression or obesity and metabolic syndrome.
Glucocorticoids have become important agents for use in the treatment of many inflammatory, immunologic, hematologic, and other disorders. This has stimulated the development of many synthetic steroids with anti-inflammatory and immunosuppressive activity.
Pharmaceutical steroids are usually synthesized from cholic acid obtained from cattle or steroid sapogenins found in plants. Further modifications of these steroids have led to the marketing of a large group of synthetic steroids with special characteristics that are pharmacologically and therapeutically important (Table 39–1; Figure 39–3).
The metabolism of the naturally occurring adrenal steroids has been discussed above. The synthetic corticosteroids (Table 39–1) are in most cases rapidly and completely absorbed when given by mouth. Although they are transported and metabolized in a fashion similar to that of the endogenous steroids, important differences exist.