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].