Glucocorticoids are important in the treatment of many inflammatory, allergic, immunologic, and malignant disorders, and the toxicity of glucocorticoids is one of the commonest causes of iatrogenic illness associated with chronic inflammatory disease. Recognition of these toxicities, many of which are similar to the findings in spontaneous (endogenous) Cushing’s syndrome, is of value in their prevention and management. (See "Epidemiology and clinical manifestations of Cushing's syndrome".)
Numerous toxicities, or adverse effects (AEs), have been attributed to glucocorticoids (table 1). However, the attribution of causality to the glucocorticoids alone cannot always be clearly established. Other factors that may contribute to such AEs include the nature and severity of the underlying disease being treated and the other medications being administered concurrently. Estimates of the frequency and severity of AEs, as well as the respective dose and duration of therapy that may result in such AEs, are also limited by the modest number of prospective trials that address this question. The benefits of these medications in critical illness and the morbidity of some of the AEs make such prospective data acquisition in randomized trials of sufficient duration unlikely.
The AEs seen specifically with systemic (oral and parenteral) glucocorticoid therapy will be reviewed here. The AEs resulting from the use of inhaled, topical, and intraarticular glucocorticoids; glucocorticoid withdrawal; and the clinical manifestations of endogenous glucocorticoid excess are discussed in detail separately. (See "Major side effects of inhaled glucocorticoids" and "General principles of dermatologic therapy and topical corticosteroid use", section on 'Side effects' and "Joint aspiration or injection in adults: Complications" and "Glucocorticoid withdrawal" and "Epidemiology and clinical manifestations of Cushing's syndrome".)
MECHANISM OF ADVERSE EFFECTS
The adverse effects (AEs) of glucocorticoids are more common in patients receiving these drugs in high doses or over a long period of time. Glucocorticoids used in chronic disease (eg, prednisone or prednisolone) do not have significant mineralocorticoid, androgenic, or estrogenic activity; thus, their major AEs result from inhibition of hypothalamic-pituitary-adrenal function and the development of iatrogenic Cushing’s syndrome. The relative frequency of features of endogenous Cushing’s syndrome and the iatrogenic syndrome vary. (See "Pharmacologic use of glucocorticoids", section on 'Complications of chronic use' and "Epidemiology and clinical manifestations of Cushing's syndrome".)
The effects of glucocorticoids are mediated by cytosolic glucocorticoid receptors and result from both genomic and nongenomic mechanisms that also have a role in the therapeutic effects of these agents [1-3]. The AEs appear to result largely from transactivation that leads to increased expression of regulatory and antiinflammatory proteins ; by contrast, many of the clinically desirable effects appear to result primarily from transrepression, which results in the decreased production of proinflammatory proteins. Nongenomic effects of glucocorticoids include rapid, nonspecific interactions of glucocorticoids with cellular membranes, nongenomic effects medicated by cytosolic glucocorticoid receptors, and specific interactions with membrane-bound glucocorticoid receptors .