Glucocorticoid-induced adrenal insufficiency is suppression of the hypothalamic-pituitary-adrenal (HPA) axis caused by exogenous glucocorticoid administration, resulting in deficient endogenous cortisol production.
It is the most common form of adrenal insufficiency, affecting a substantial portion of the estimated 1-3% of adults prescribed glucocorticoid therapy.
Its pathophysiology involves negative feedback suppression of the HPA axis.
Receiving supraphysiological doses of glucocorticoids, exceeding the equivalent of 15-25 mg hydrocortisone daily for 3-4 weeks or longer, suppresses hypothalamic corticotropin-releasing hormone (CRH) and pituitary corticotropin (ACTH) production.
≥ 5 mg prednisone/day (or equivalent) for ≥3–4 weeks Long-acting or potent steroids (e.g., dexamethasone > prednisone > hydrocortisone) Daily dosing is greater thanalternate-day dosing Evening/bedtime dosing has greater HPA suppression Repeated steroid bursts or frequent intra-articular/epidural injections High-dose inhaled, topical, or ocular steroids (especially with CYP3A4 inhibitors)
Prolonged exposure leads to atrophy of both pituitary corticotrophs and the adrenal cortex, impairing the body’s ability to produce endogenous cortisol and adrenal androgens, while aldosterone production remains intact since it is regulated independently by the renin-angiotensin system.
Adrenal insufficiency risk varies by route, dose, and duration of glucocorticoid exposure.
Oral glucocorticoids carry approximately 49% risk of biochemical adrenal insufficiency, while inhaled formulations show 7.8% overall risk that increases to 21% with high doses (≥500 µg fluticasone daily) or 27% with treatment exceeding 12 months.
Intra-articular injections repeated within 3 months can also cause HPA suppression.
The condition typically manifests when glucocorticoids are tapered below physiologic replacement levels or discontinued entirely.
Patients may experience nonspecific symptoms including fatigue, nausea, anorexia, and weight loss.
During tapering from supraphysiological doses, patients often develop glucocorticoid withdrawal syndrome with overlapping symptoms of myalgias, arthralgias, fatigue, which can be distinguished from true adrenal insufficiency by occurring at doses still above physiologic levels.
Diagnosis requires biochemical testing, typically with early-morning cortisol and corticotropin measurements or ACTH stimulation testing, showing low or intermediate cortisol levels (5-10 µg/dL) with low or low-normal corticotropin.
Often nonspecific; symptoms may appear during tapering or after abrupt cessation:
Fatigue, weakness Anorexia, weight loss Nausea, vomiting, abdominal pain Myalgias, arthralgias Dizziness, orthostasis Hypoglycemia Hyponatremia (from ↑ ADH) No hyperkalemia or hyperpigmentation
Adrenal Crisis with stress, infection, surgery
Hypotension, shock Severe hypoglycemia Altered mental status Requires immediate IV hydrocortisone
Diagnosis of glucocorticoid induced adrenal insufficiency:
8 AM serum cortisol
>15–18 µg/dL (414–500 nmol/L): HPA axis intact <3–5 µg/dL (83–138 nmol/L): adrenal insufficiency likely Intermediate → dynamic testing
Dynamic testing ACTH (cosyntropin) stimulation test Peak cortisol <18 µg/dL (or assay-specific cutoff) = impaired adrenal reserve May be normal early in secondary AI → consider insulin tolerance test if uncertainty.
Management
1. Do not stop glucocorticoids abruptly Gradual taper allows HPA recovery
2. Tapering strategy Reduce to physiologic dose (~5 mg prednisone/day or 15–20 mg hydrocortisone/day) Then taper slowly: Decrease prednisone by 1 mg every 2–4 weeks Monitor symptoms and morning cortisol
Stress-dose steroids Required for illness, surgery, trauma Example: Hydrocortisone 50–100 mg IV q6–8h for major stres
Recovery HPA axis recovery is variable: Weeks to months Sometimes >1 year after long-term therapy Reassess periodically with AM cortisol or ACTH stimulation
e guidelines
Symptoms of glucocorticoid withdrawal syndrome include: myalgia, arthralgias, fatigue, weakness, and mood changes, and can be reduced by slowing the pace of taper by using taper that has smaller decrements in the daily glucocorticoid dose.
Glucocorticoid withdrawal syndrome is more likely than adrenal insufficiency if the glucocorticoid dose is super physiological.
Patient with glucocorticoid induced adrenal insufficiency can recover normal adrenoocortical function, and discontinue the use of corticosteroids.
The discontinuance of glucocorticoids in patients with glucocorticoid induced adrenal insufficiency can occur when morning serum cortisol is 10 µg per dL or higher.