corticosteroid induced adrenal insufficiency

Last edited 07/2021 and last reviewed 08/2021

Glucocorticoid induced adrenal insufficiency (GI-AI)

Glucocorticoids are steroid hormones produced by the zona fasciculata of the adrenal cortex

  • these molecules are secreted into the peripheral blood under the control of the hypothalamic-pituitary-adrenal axis (HPAA) in an ultradian, circadian and stress-related fashion
  • iatrogenic, tertiary adrenal insufficiency induced by chronic administration of high doses of glucocorticoids (GCs) is the most common cause of adrenal insufficiency (1)
  • been reported that the inhibition of the HPAA function induced by exogenous GCs may persist for 6 to 12 months after treatment is withdrawn (1)

Synthetic glucocorticoids are widely used for their anti-inflammatory and immunosuppressive actions

  • a possible unwanted effect of glucocorticoid treatment is suppression of the hypothalamic-pituitary-adrenal axis (HPAA), which can lead to adrenal insufficiency
  • factors affecting the risk of glucocorticoid induced adrenal insufficiency (GI-AI) include:
    • the duration of glucocorticoid therapy,
    • mode of administration,
    • glucocorticoid dose and potency,
    • concomitant drugs that interfere with glucocorticoid metabolism,
    • individual susceptibility
  • patients with exogenous glucocorticoid use:
    • may develop features of Cushing's syndrome and,
    • subsequently, glucocorticoid withdrawal syndrome when the treatment is tapered down
    • symptoms of glucocorticoid withdrawal can overlap with those of the underlying disorder, as well as of GI-AI. A careful approach to the glucocorticoid taper and appropriate patient counseling are needed to assure a successful taper
    • glucocorticoid therapy should not be completely stopped until recovery of adrenal function is achieved

Glucocorticoid mode of administration and risk of GI-AI (2)

Systemic administration (including oral, intravenous, intramuscular)

Factors increasing the risk of GI-AI:

  • daily administration for >2-4 weeks
  • multiple daily split doses
  • bedtime administration

Factors reducing the risk of GI-AI:

  • alternate day administration
  • pulse systemic therapy (intermittent intravenous administration of very high doses of glucocorticoids over a few days or weeks)
  • whenever possible, use the lowest effective dose of glucocorticoids for the shortest period of time
  • whenever possible, favor once daily dosing when using intermediate and long acting glucocorticoids (eg, prednisone, prednisolone,
    dexamethasone)
  • whenever possible, avoid bedtime administration of glucocorticoids (excluding modified release formulations (eg, modified release prednisone))
  • do not taper down glucocorticoids if the treatment course is <2 weeks. The risk of HPAA axis suppression in such cases is low, and glucocorticoids can be discontinued abruptly. If treatment is prolonged beyond 2 weeks, the risk of HPAA suppression increases

 

Inhaled glucocorticoids

Factors increasing the risk of GI-AI:

  • high daily doses given for >6-12 months
  • treatment with fluticasone propionate
  • concomitant use of oral glucocorticoids (including intermittent use - eg, in chronic obstructive pulmonary disease)
  • lower body mass index (children)
  • higher compliance with treatment (children)

Advice to reduce the risk of GI-AI:

Inhaled glucocorticoids

  • whenever possible, use the lowest effective dose of glucocorticoids for the shortest period of time
  • use spacers and mouth rinsing to reduce systemic absorption through the gastrointestinal tract

 

Intra-articular glucocorticoids

Factors increasing the risk of GI-AI:

  • repeated injections with high doses of glucocorticoids
  • inflammatory arthropathies

Advice to reduce risk of GI-AI:

Intra-articular glucocorticoids

  • whenever possible, reduce the number of injections and space out the administration of intra-articular glucocorticoids (advice based on very low quality evidence and personal experience, the risk of sustained glucocorticoid induced adrenal insufficiency is higher in patients receiving multiple glucocorticoid injections)
  • whenever possible, avoid simultaneous injections of multiple joints
  • wue the lowest effective dose of glucocorticoids
  • favor triamcinolone hexacetonide over triamcinolone acetonide because of its higher residence time in the joint (lower risk of systemic absorption)

 

Percutaneous glucocorticoids

Factors increasing the risk of GI-AI:

  • long term and frequent use of large amounts of high potency glucocorticoids
  • prolonged use on inflamed skin or with impaired barrier function
  • occlusive dressings
  • use on mucous membranes, eyelids, and scrotum
  • larger body surface area to body weight ratio (children)

Weaning patients from glucocorticoid (GC) therapy:

  • seek expert advice
  • in general, patients taking any steroid dose for less than 2 weeks are not likely to develop HPAA suppression and can stop therapy suddenly without tapering (1)
    • possible exception to this is the patient who receives frequent "short" steroid courses e.g. in asthma

If glucocorticoid therapy > 2 weeks or frequent "short" steroid courses then seek expert advice.

Where there has been chronic therapy, the objective is to rapidly reduce the therapeutic dose to a physiological level (equivalent to 7.5mg/d prednisolone) e.g. by reducing 2.5mg every 3-4 days over a few weeks, and then proceed with slower withdrawal in order to permit the HPAA to recover (1)

  • after the initial reduction to physiological levels, doses should be reduced by 1mg/d of prednisolone or equivalent every 2-4 weeks depending upon patient's general condition, until the medication is discontinued
    • as an alternative, after the initial reduction to 5-7.5mg of prednisolone, the clinician can switch the patient to HC 20mg/d and reduce by 2.5mg/d every week until the dose of 10mg/d is achieved
    • after 2-3 months on the same dose, the HPAA function should be assessed through a Corticotropin (ACTH-Synachten) test or through an Insulin Tolerance test (ITT)
      • a pass response to these tests indicates adequate function of the axis and GCs can be safely withdrawn
      • if the axis has not fully recovered, treatment should be continued and the axis function should be reassessed

  • irrespectively of the tapering regimen used, if GC withdrawal syndrome, adrenal insufficiency's symptomatology, or exacerbation of the underlying disease appears, the dose being given at the time should be elevated or maintained for a longer period of time

  • in the absence of evidence of HPAA full recovery in patients who have been treated with GCs for prolonged periods (1)
    • supplementation equivalent to 100-150mg of HC is recommended during situations of severe stress such as major surgery, fractures, severe systemic infections, major burns, etc.
    • wear medical alert bracelet/necklace (2)
    • carry steroid card/letter outlining GC-AI management (2)

Reference:

  • Nicolaides NC, Pavlaki AN, Maria Alexandra MA, et al. Glucocorticoid Therapy and Adrenal Suppression. [Updated 2018 Oct 19]. In: Feingold KR, Anawalt B, Boyce A, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-.
  • Prete A, Bancos I. Glucocorticoid induced adrenal insufficiency. BMJ. 2021 Jul 12;374:n1380.