Since their identification nearly 80 years ago, steroids have played a prominent role in the treatment of many disease states. Many of the clinical roles of steroids are related to their potent antiinflammatory and immune-modulating properties…
Since their identification in 1935, steroids have served a wide range of uses. Initially, these isolates from adrenal glands were thought to be useful only in patients suffering from Addison disease.1 Today, many of the clinical roles of steroids are related to their potent antiinflammatory and immune-modulating properties. Clinically relevant side effects of steroids are common and problematic, ranging from a minor case of acne to Cushing syndrome that can result in diabetes mellitus and potentially life-threatening heart disease if untreated.2 Side effects can occur at a wide range of doses and vary depending on the route of administration.1
The term steroid applies to a wide range of molecules with varying physiological effects. More specifically, corticosteroids are a class of chemicals encompassing both laboratory-synthesized and naturally produced hormones. Glucocorticoids, in general, regulate metabolism and inflammation; mineralocorticoids regulate sodium and water levels. Corticosteroids fall along a spectrum from exclusively glucocorticoid effects to exclusively mineralocorticoid effects, and steroid compounds are selected based on their appropriateness for a given treatment. For example, although a compound may possess potent antiinflammatory properties, it may additionally have mineralocorticoid activity that adversely affects blood pressure.
Although corticosteroid metabolism is complicated by enzyme induction, protein binding, molecular interconversion, and interaction with endogenous cortisol, corticosteroids are generally metabolized by the hepatic P450 system.3 Direct application (eg, topical, intraarticular, inhaled, or epidural) of these agents to sites of inflammation bypasses the liver and its first-pass effect.
Chronic oral glucocorticoid use is common in patients with rheumatoid arthritis, chronic obstructive pulmonary disease, systemic lupus erythematosus, inflammatory bowel disease, and asthma.4 Side effects of chronic use include bruising, muscle weakness, weight gain, skin changes, sleep disturbances, cataracts, and pathologic fractures.4 Glucocorticoid administration can also have psychiatric side effects: mood disorders, anxiety, delirium, and panic disorder. Psychotropic medication may be required to treat these symptoms, but the prognosis is favorable once the glucocorticoids are reduced or discontinued.5–7 Adverse effects occur in up to 90% of patients who take glucocorticoids for >60 days.4 These side effects, including the more serious fractures and cataracts, occur even in patients taking low (≤7.5 mg/d) dosages.4,8
Glucocorticoids affect bone mineralization by inhibiting calcium absorption in the gastrointestinal tract and shifting signaling-molecule production to favor bone resorption.8 Recommendations for preventing glucocorticoid-induced osteopenia and its subsequent complications and comorbidities include supplementing calcium with vitamin D for glucocorticoid doses ≥5 mg/d and starting bisphosphonates when indicated by densiometric evaluation.8
Because of their effects on insulin resistance, glucocorticoids are the most common cause of drug-induced diabetes mellitus.9 Screening guidelines using a fasting glucose ≥126 mg/dL or HbA1c ≥6.5% are suitable for diagnosing steroid-induced diabetes; however, per American Diabetes Association guidelines, results should be confirmed via repeat testing.9 Management is similar to that of type 2 diabetes mellitus; treatment options progress from single agent to double agent to insulin ± another agent, based upon fasting glucose measurements and glucose control.9 In patients with preexisting diabetes, blood sugars should be measured more often than in patients without preexisting diabetes, and medications should be adjusted to maintain adequate control.9
Cushing syndrome and adrenal suppression have been observed in patients taking oral, intraarticular, epidural, inhaled, nasal, ocular, and topical glucocorticoid preparations.8,9 These side effects become more likely with longer durations of treatment and higher dosages.8,9
Mineralocorticoid activity causes the retention of sodium and free water and the excretion of potassium.2 Derangements in mineralocorticoid production can manifest with abnormalities in any of these areas. Hyponatremia, hyperkalemia, and hypotension are present to varying degrees in mineralocorticoid-deficient states (eg, various congenital adrenal hyperplasias and aldosterone synthase deficiency), whereas the inverse is present in mineralocorticoid-excess states (eg, Conn syndrome). Because endogenous glucocorticoids also have activity at mineralocorticoid receptors, signs and symptoms of mineralocorticoid excess can be seen in cases of excess glucocorticoid production (eg, Cushing syndrome).2
The antiinflammatory properties of steroids have been attributed to their inhibitory effects on the action of phospholipase A2, an enzyme critical to the production of inflammatory compounds.22 Research has shown that steroids are active in affecting gene expression, translation, and enzyme activity.23 In short, they bring about their physiologic effects through a multitude of biochemical pathways.23 One such pathway is through their induction of the production of proteins called lipocortins. Glucocorticoids stem the production of inflammatory mediators such as leukotrienes and prostaglandins and effectively halt the inflammatory cascade.22,24 As their wide-ranging side effects indicate, glucocorticoids can impact many systems throughout the body. Through negative feedback regulation of the hypothalamic-pituitary-adrenal (HPA) axis, exogenous glucocorticoids can directly induce hypopituitarism (Addison disease).2,25 Their actions on glucose metabolism can increase insulin resistance in tissues and increase fasting glucose levels.2,25 Glucocorticoids can act directly on osteoclasts to affect bone resorption and decrease calcium absorption in the gastrointestinal tract, resulting in osteopenia and osteoporosis.2,25 more »