Aetiology

Exogenous glucocorticoids are cited as the most frequent cause of adrenal suppression, probably because the diseases for which they are often used (e.g., asthma, chronic obstructive pulmonary disease, and arthritis) are fairly common.[3][7] Systemically administered glucocorticoids are well-known causes of adrenal suppression.[1][3][4][7][8] Less commonly recognised is that local administration of glucocorticoids (such as intra-articular, epidural, inhaled, intranasal, or topical routes) can also cause adrenal suppression.[9][10][11][12][13][14][15] Medications that act on the glucocorticoid receptor, such as megestrol and medroxyprogesterone, are also reported causes.[1][16][17] In addition, as CYP3A4 is the primary pathway for the metabolism of most prescribed glucocorticoids, concomitant medications that are CYP3A4 inhibitors will increase exposure to glucocorticoids.[1] For example, the antiretroviral drug ritonavir is a CYP3A4 inhibitor, and is known to increase plasma concentrations of prednisone metabolites (prednisolone).[1] Other strong CYP3A4 inhibitors include antifungals such as itraconazole and ketoconazole, and cancer treatments such as ceritinib and idelalisib.[1] More recently, the anaesthetic induction agent etomidate was recognised as a drug that can interfere with adrenal steroid synthesis and was noted to increase the risk of adrenal insufficiency and mortality in patients with sepsis.[18]

Excess glucocorticoid secretion from an adrenal adenoma or carcinoma causing Cushing's syndrome can cause suppression of the contralateral adrenal gland, with adrenal insufficiency resulting if the autonomous adenoma or carcinoma is removed without glucocorticoid supplementation.[19][20] In addition, after removal of a pituitary tumour in Cushing's disease (Cushing's syndrome secondary to an adrenocorticotropic hormone [ACTH]-secreting pituitary tumour), the remaining ACTH-secreting cells in the pituitary gland may be sluggish in their recovery, resulting in a period of adrenal suppression necessitating glucocorticoid supplementation.

Susceptibility to corticosteroid-induced adrenal suppression may be linked to a specific genetic variation in the PDGFD gene locus.[21] However, universal testing is not currently recommended.

Pathophysiology

Exposure to excess glucocorticoids, whether exogenously administered or endogenously produced, results in negative feedback on the hypothalamic-pituitary-adrenal axis.[1] The result is decreased production of corticotropin-releasing hormone from the hypothalamus and adrenocorticotropic hormone from the pituitary gland, leading to a decrease in blood cortisol levels.[1] Suppression may persist even after the inciting medication or excess glucocorticoid condition ceases. In the case of excess glucocorticoid administration, patients may have signs and symptoms of Cushing's syndrome. When the inciting medication or condition is suddenly removed, especially in the setting of stress, symptoms of adrenal insufficiency may occur because the adrenal(s) are unable to produce sufficient cortisol.

There are no studies directly comparing adult versus paediatric corticosteroid-induced adrenal suppression, but the pathophysiology is the same in both populations. The risk is greater with higher doses and longer durations of therapy.[2]

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