Glucocorticoid Therapy

David M. Slovik

The therapeutic potency of glucocorticoids has led to their widespread use. Although benefits can be substantial, adverse effects are numerous, including serious metabolic derangements and suppression of the hypothalamic-pituitary-adrenal (HPA) axis. To maximize the therapeutic response and minimize the risks, a number of questions must be addressed before steroid therapy is initiated: (a) Is the underlying disorder of such severity that the benefits of therapy outweigh the risks? (b) Will prolonged treatment be required, or will a brief, limited course suffice? (c) Have alternative, less morbid therapies been maximally utilized? (d) Does the patient have any underlying condition that will worsen on steroid therapy or predispose to druginduced complications? (e) Can a less suppressive regimen (e.g., alternate-day therapy or inhaled steroids) be utilized?

The primary physician must decide when and how to institute steroid therapy, whether to use daily or alternate-day treatment, and how to withdraw long-term glucocorticoid treatment safely.

ADVERSE EFFECTS (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16)

Most adverse effects of glucocorticoids are a function of the degree of systemic absorption, dose, and duration of use. A few effects are irreversible; fortunately, most resolve within several months of termination of therapy.

Suppression of the Hypothalamic-Pituitary-Adrenal Axis

Suppression compromises the physiologic response to major stress (e.g., surgery, injury), putting the patient at risk for hypotension and hypoglycemia. Symptoms and signs include lightheadedness, nausea, postural hypotension, and hypoglycemia.

Risk of Suppression and Its Determinants

Risk correlates with the dose and duration of therapy, but it is hard to predict HPA responsiveness accurately on the basis of dose and duration alone. Other factors are believed to be operative also.

Dose and Duration of Steroid Therapy.

Any patient who has received a glucocorticoid in a dose equivalent to 20 to 30 mg/d of prednisone for more than 5 days may begin to manifest some degree of HPA suppression; by 3 weeks, suppression is likely to be significant. Prednisone at doses of 5 mg or less given once daily in the morning is generally not associated with HPA
suppression. Doses greater than 5 mg/d are usually suppressive over time, but this also depends on the dose and the duration of therapy. Even the so-called physiologic dose of 5.0 to 7.5 mg of prednisone that supposedly corresponds to daily endogenous glucocorticoid synthesis is suppressive in some patients, especially the elderly and if given for long periods of time. Moreover, individual patients vary widely.

Dose Scheduling.

Dose scheduling has some effect on the degree of HPA suppression. Daily physiologic doses of glucocorticoids (e.g., 5 to 7.5 mg of prednisone) given in the morning may not cause suppression of any consequence, but if the same doses are given at night, normal diurnal cortisol secretion is inhibited. Doses just greater than the physiologic range are suppressive after about 1 month of use. Alternate-day therapy, in which short- or intermediate-acting preparations are taken at 8 am every other day generally, does not induce clinically significant HPA suppression, nor does a cyclic program of 5 days of daily therapy followed by 2 to 4 weeks off therapy. However, cycles of 2 weeks on and 2 weeks off do lead to HPA suppression. A single daily pharmacologic dose of glucocorticoid produces less HPA suppression than does the same dose divided and taken at intervals during the course of the day.

Other Factors.

The renal clearance of glucocorticoids decreases with age, and thus, a given dose will have greater effects in older persons.

Recovery from HPA Suppression

Recovery from HPA suppression can take up to 12 months, depending on the dose and duration of treatment. Hypothalamic-pituitary function returns first, reappearing 2 to 5 months after the cessation of suppressive therapy, and is manifested by appropriate plasma adrenocorticotropic hormone (ACTH) levels, which demonstrate a normal diurnal pattern. Signs of adrenal recovery become evident at 6 to 9 months, with a return of the baseline serum cortisol level to normal. Maximal adrenal response to ACTH may not reappear until 9 to 12 months after the cessation of therapy. There is no proven method for accelerating the restoration of normal HPA function once it has been inhibited. The administration of ACTH does not seem to speed adrenal recovery.

Metabolic and Endocrinologic Side Effects

Protein and Fat

A negative nitrogen balance (the result of inhibition of protein synthesis and enhancement of protein catabolism) is believed to be partially responsible for reduced muscle mass, weakness, thinning of the skin, and striae formation. Fat redistribution accounts for the characteristic truncal obesity and cushingoid appearance. Both fat redistribution and negative nitrogen balance are minimized by using alternate-day therapy or giving no more than a physiologic dose each morning, but not by using ACTH or daily pharmacologic glucocorticoid doses. Acne is seen, more often with ACTH than with glucocorticoid use, because of stimulation of adrenal androgen production.

TABLE 105-1 Commonly Used Glucocorticoids

Duration of Action		Glucocorticoid Potency^a	Equivalent Glucocorticoid Dose (mg)	Mineralocorticoid Activity
Short-Acting
	Cortisol (hydrocortisone)	1	20	Yes^b
	Cortisone	0.8	25	Yes^b
	Prednisone	4	5	No
	Prednisolone	4	5	No
	Methylprednisolone	5	4	No
Intermediate-Acting
	Triamcinolone	5	4	No
Long-Acting
	Betamethasone	25	0.60	No
	Dexamethasone	30	0.75	No
^aThe values given for glucocorticoid potency are relative. Cortisol is arbitrarily assigned a value of 1. ^bMineralocorticoid effects are dose related. At doses close to or within the basal physiologic range for glucocorticoid activity, no such effect may be detectable.
Adapted from Axelrod L. Glucocorticoid therapy. Medicine (Baltimore) 1976;55:39, with permission. Copyright (c) 1976 Lippincott Williams & Wilkins.

Glucose

Glucose intolerance is common. Mechanisms include increases in peripheral insulin resistance, gluconeogenesis, glucagon secretion, and substrate availability. Usually, the glucose intolerance is mild, does not lead to ketosis, and resolves when therapy is stopped. When carbohydrate intolerance develops, the effect appears to be dose-related.

Hypertension and Fluid Retention

Hypertension and fluid retention with peripheral edema are more common when agents with mineralocorticoid effects are used, and they are not dependent on any prior elevation of blood pressure (Table 105-1). Again, the dose and duration of therapy are important factors. Pure glucocorticoids should not produce electrolyte abnormalities, but those with mineralocorticoid properties may produce electrolyte abnormalities especially hypokalemia.

Enhanced Susceptibility to Infection

Enhanced susceptibility to infection results from the antiinflammatory and immunosuppressive actions of corticosteroids. Bacterial infections are common. Candidiasis and aspergillosis sometimes develop. Herpes zoster, varicella, and cytomegalovirus infection are the principal viral infections encountered in patients on steroids. Reactivation of tuberculosis is a well-recognized risk (see Chapter 38).

Osteoporosis

Osteoporosis develops when steroids are used for prolonged periods. The exact incidence of clinically significant bone loss is unknown, but estimates are around 50%. Bone loss is most rapid within the first 3 to 6 months of therapy. Higher doses for prolonged duration increase the risk for osteoporosis, but even as little as 5 mg of prednisone per day over time, especially in older individuals, can result in bone loss. Although bone loss
occurs with alternate-day and inhaled therapy, it is less than with daily oral therapy. Patients with a predisposition to osteoporosis, such as menopausal women and immobilized persons, appear to be among the most susceptible. The axial skeleton is affected more than the limbs, and vertebral compression fractures may result. Aseptic necrosis of the femoral head and other bones is a well-recognized and serious, but relatively rare, skeletal complication. Sometimes, it may be a manifestation of the underlying illness for which corticosteroids are being given, such as rheumatoid arthritis or systemic lupus.

Gastrointestinal Effects

Gastritis, peptic ulceration, and gastrointestinal bleeding have all been attributed to steroid use. Multiple randomized, controlled trials have produced conflicting results, as have major meta-analyses examining pooled data from such trials (see Chapter 68). Hotly debated is the degree to which ulcer risk is a function of the dose and duration of exposure. The risk appears to be small until doses greater than the equivalent of 30 mg of prednisone per day are reached and continued for more than 1 month. Even then, the increase in rate of peptic ulceration is in the range of only 1% to 2%. Most peptic ulceration is caused by the concurrent use of nonsteroidal anti-inflammatory agents. Antacids and food do not interfere with the absorption of oral steroid preparations.

Acute pancreatitis is noted with increased frequency in patients taking corticosteroids. Panniculitis is unique to iatrogenic Cushing syndrome.

Myopathy

Myopathy may result from the prolonged intake of large doses. Proximal muscle wasting and weakness of the lower extremities are characteristic. Patients have difficulty climbing stairs and rising from a seated position. The average time of onset is 5 months into treatment. Muscle enzymes are normal. The complication is reversible, and exercise may help to minimize it. Sometimes, it is difficult to distinguish between steroid myopathy and the myopathy associated with the underlying disorder it is being used to treat, for example, polymyositis.

Psychological and Behavioral Changes

Psychological and behavioral changes are particularly common in the elderly. The reported incidence ranges from 25% to 40%, mostly among patients receiving high doses. Increased appetite, mild euphoria, and insomnia are rather common at the beginning of treatment, especially with higher doses. Psychoses, which are not predictably related to dose or duration of therapy, can occur; they slowly respond to reduction or cessation of steroid use. The patient’s premorbid personality may play a role. Steroid therapy can exacerbate previous psychiatric disease.

Cataracts

Cataracts of the posterior subcapsular type are reported in 10% to 35% of cases and are predominantly dose- and durationdependent. A few require removal; most do not.

Adverse Effects of Inhaled Glucocorticoids

The inhaled topically active steroid preparations used for asthma are usually well-tolerated and not associated with significant adverse effects, even when used daily for months at a time. However, the growing appreciation of the need for long-term therapy with inhaled steroids and the development of increasingly potent preparations (e.g., fluticasone) have raised concerns about the potential for systemic effects. There is some systemic absorption with the inhaled steroids, especially at high doses. Meta-analytic study finds that the risk for HPA suppression is greatest when the dose of most inhaled steroids exceeds 1.5 mg/d (>0.75 mg/d for fluticasone). Fluticasone demonstrates greater biologic activity and confers a greater risk on a milligram-per-milligram basis than beclomethasone, budesonide, and triamcinolone. Similar relationships and dose thresholds have been noted with regard to the risks for osteoporosis and posterior subcapsular cataracts. A lesser risk for ocular hypertension and glaucoma has been observed, but no evidence has been found of permanent growth retardation in children. Skin bruising parallels HPA suppression.

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