Adverse effects
Prolonged and/or high dose glucocorticoid therapy promotes gluconeogenesis, protein catabolism and lipolysis, reduces proliferation of actively dividing cells, promotes apoptosis, inhibits the synthesis of extracellular matrix proteins, has vasopressor effects and suppresses the hypothalamic pituitary axis [3]. Adverse effects of treatment therefore include weight gain, metabolic disorders, growth retardation and/or bone and muscle loss, poor wound healing, increased susceptibility to infection and adrenal insufficiency, as well as neuropsychiatric effects. Some toxicity from oral or injected glucocorticoids is inevitable, even with short courses of treatment. However, the adverse effects experienced by an individual depend on both the average and the cumulative dose of treatment, with harms experienced even at very low doses of glucocorticoids when given over long periods of time (figure 1). This means that long term inhaled or topical glucocorticoids also have potential to cause systemic adverse effects. This is more likely for inhaled or topical glucocorticoids with greater potency (table 1) and is dependent on systemic bioavailability, which may be increased by a wide range of factors including drug-drug interactions and severity of underlying disease (figure 2).
Adrenal insufficiency . The endogenous glucocorticoid, cortisol is secreted by the adrenal cortex at around 5.7 mg/m2/day [16], approximately equivalent to a therapeutic regimen of 15-25 mg hydrocortisone/day [17] or prednisolone 7.5 mg/day. Glucocorticoid release from the adrenal glands is regulated by the hypothalamic-pituitary-adrenal (HPA) axis. In the hypothalamus, the circadian oscillator in the suprachiasmatic nucleus controls secretion of corticotrophin-release hormone (CRH) into hypophyseal portal veins. CRH stimulates the anterior pituitary gland to release stored adrenocorticotrophic hormone (ACTH) into the circulation and promotes synthesis of new ACTH. ACTH simulates cortisol secretion by the adrenal glands with a pronounced diurnal rhythm. Plasma cortisol concentrations peak at 06.00 to 07.00 am and reach a nadir at around 24.00 hours. Physiological and emotional stress override this daily rhythm, stimulating a rapid increase in cortisol levels. Cortisol exerts negative feedback on the hypothalamus and anterior pituitary gland, regulating secretion of CRH and ACTH. Exogenous glucocorticoids suppress the HPA axis by reducing secretion and synthesis of CRH and ACTH, which in turn reduces endogenous cortisol production and secretion by the adrenal glands. After a short course of exogenous glucocorticoids these changes can reverse rapidly [18]. However if treatment is prolonged, atrophy of corticotrophin cells in the anterior pituitary [19] and of the adrenal glands [20] may occur and reversal may be prolonged over weeks [21], months or years [22].
In a systematic review of studies measuring adrenal function following systemic glucocorticoid exposure, Joseph and colleagues found that a median of 37% (interquartile range 13-63%) patients had adrenal insufficiency [22]. Adrenal insufficiency occurred even with low dose (<5 mg prednisolone equivalent) and short duration (<4 weeks) glucocorticoid treatment and following tapered withdrawal. It persisted in 15% patients retested 3 years after glucocorticoid withdrawal. In a separate review, Broersen and colleagues found that there was no administration form, dosage, treatment duration or underlying disease for which adrenal insufficiency could be excluded, although increased dose and duration of treatment were associated with increased risk [23].