Review

Glucocorticoid-induced adrenal insufficiency and glucocorticoid withdrawal syndrome: Two sides of the same coin

Noura Nachawi, MD, Dingfeng Li, MD and M. Cecilia Lansang, MD, MPH
Cleveland Clinic Journal of Medicine April 2024, 91 (4) 245-255; DOI: https://doi.org/10.3949/ccjm.91a.23039

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  • TABLE 1

    Common causes of primary adrenal insufficiency

    Autoimmune
    Isolated
    Autoimmune polyglandular syndrome type 1
    Autoimmune polyglandular syndrome type 2
    Adrenal infection
    Tuberculosis
    Human immunodeficiency virus
    Cytomegalovirus
    Fungal infections: candidiasis, histoplasmosis, paracoccidioidomycosis
    Syphilis
    African trypanosomiasis
    Adrenal metastases
    Breast, lung, colon, stomach cancers or lymphoma
    Adrenal hemorrhage
    Trauma
    Anticoagulation
    Antiphospholipid syndrome
    Congenital adrenal hyperplasia
    21-hydroxylase deficiency
    11-hydroxylase deficiency
    3B-hydroxysteroid dehydrogenase II deficiency
    Drug-induced primary adrenal insufficiency
    Adrenal enzyme inhibitors: mitotane, ketoconazole, metyrapone, etomidate
    Drugs that accelerate cortisol metabolism: fluconazole, phenytoin, rifampin, barbiturates
    Immune checkpoint inhibitors
     Anti-PD-1 (programmed cell death protein 1) monoclonal antibodies: pembrolizumab, nivolumab
     CTLA-4 (cytotoxic T-lymphocyte antigen 4) inhibitor: ipilimumab
    Others
    Adrenoleukodystrophy and adrenomyeloneuropathy
    Familial glucocorticoid deficiency
    Familial glucocorticoid resistance
  • TABLE 2

    Common causes of secondary adrenal insufficiency

    Pituitary tumors
    Pituitary tumors replacing normal corticotropic cells
    Adrenocorticotropic hormone deficiency after tumor resection or radiation treatment
    Nonpituitary tumors
    Meningioma
    Craniopharyngioma
    Sellar or suprasellar metastases (lung, colon, and breast cancer)
    Pituitary infiltration
    Granulomatosis with polyangiitis
    Sarcoidosis
    Amyloidosis Hemochromatosis
    Lymphoma
    Autoimmune
    Lymphocytic hypophysitis
     Isolated (usually with pregnancy)
     Associated with other autoimmune disease (thyroid, vitiligo, type 1 diabetes, pernicious anemia)
    Sheehan syndrome
    Infarction in the pituitary gland due to excessive postpartum hemorrhage
    Pituitary apoplexy
    Acute hemorrhage in the pituitary adenoma
    Head trauma
    Severe head trauma leading to fracture of the skull base and injury in the pituitary gland
    Drug-induced central adrenal insufficiency
    See Figure 1
    Rare congenital causes
    Mutations of TBX19 (T-box transcription factor 19) and PCSK1 kexin (proprotein convertase subtilisin) genes
    Mutations of POMC (proopiomelanocortin) gene
  • TABLE 3

    Risk factors for glucocorticoid-induced adrenal insufficiency

    Route of administrationReported riskFactors that increase the riskFactors that decrease the risk
    InhaledDose- and duration-dependent41
    20.3% in patients treated for > 1 year19    		High doses (any glucocorticoid > 0.8 mg/day or fluticasone propionate > 0.75 mg/day)42
    Concurrent use of intranasal or oral glucocorticoids43,44
    Use of spacer device to deliver more medication to the lower airways45
    Higher lung volumes45    		Beclomethasone dipropionate, budesonide, and triamcinolone acetonide are less likely to suppress the HPAA compared with fluticasone propionate42
    Ciclesonide has the lowest risk of HPAA suppression46
    Lower lung volumes45
    IntranasalLow (≤ 4.2%)19,46,47Long-term use (> 12 months)46Short-term use46
    Intra-articular injections52.2%19
    GIAI usually occurs 1 to 8 weeks after injection48
    After single and repeated injections49    		Higher doses49
    Patients with inflammatory disease49
    Administration in bilateral joints simultaneously48    		Patients with degenerative disease49
    Epidural injections52.2%19Higher doses50
    Longer-acting glucocorticoids (eg, methylprednisolone, triamcinolone)51    		Lower doses50
    Shorter-acting glucocorticoids51
    Topical4.7%19,52
    Shampoo formulations are not linked to GIAI53    		Disruption of skin barrier52,54
    Long-term use (> 12 months)52,55
    Higher-potency topical glucocorticoids (eg, betamethasone dipropionate, clobetasol propionate)52,55,56
    Higher doses
    Application to larger body surface52,54
    Use of occlusive bandage52,54
    Application on the eyelids, scrotum, and mucosal surfaces52,54    		Lower-potency topical glucocorticoids (eg, dexamethasone cream 0.1%, hydrocortisone 0.5%, hydrocortisone 1%, hydrocortisone 2.5%, methylprednisolone 1%)55

    • GIAI = glucocorticoid-induced adrenal insufficiency; HPAA = hypothalamic-pituitary-adrenal axis

    • Based on information in references 19 and 41–56.

  • TABLE 4

    Adrenal insufficiency, glucocorticoid-induced adrenal insufficiency, and glucocorticoid withdrawal syndrome

    Adrenal insufficiencyGlucocorticoid-induced adrenal insufficiencyGlucocorticoid withdrawal syndrome
    DiagnosisClinical symptoms and biochemical testing:
     Low 8 AM cortisol (< 4.8 μg/dL)a
     Abnormal response to corticotropin stimulation test (cortisol peak < 12.6 μg/dL at 30 minutes and 60 minutes)a
     Variable adrenocorticotropic hormone (for primary adrenal insufficiency > 63.3 pg/mL, for secondary adrenalinsufficiency < 7.2 pg/mL)b    		After abrupt discontinuation or quick taper of exogenous glucocorticoid or Cushing syndrome:
     Low 8 AM cortisol (< 4.8 μg/dL)a
     Low adrenocorticotropic hormone (< 7.2 pg/mL)b
     Low dehydroepiandrosterone sulfatec
     Abnormal response to corticotropin stimulation test (cortisol peak < 12.6 μg/dL at 30 and 60 minutes)a    		Clinical symptoms of adrenal insufficiency with or without cushingoid features while gradually tapering or after abrupt discontinuation of glucocorticoid
    No laboratory test to diagnose
    MechanismLack of glucocorticoid secretion from adrenal cortex due to either adrenal etiology (primary adrenal insufficiency) or pituitary or hypothalamic etiology (secondary adrenal insufficiency)HPAA suppression due to excessive endogenous or exogenous glucocorticoid, leading to atrophy of adrenal cortexTolerance of and dependence on supraphysiologic doses of glucocorticoid
    PreventionReplace with physiologic doses of glucocorticoidGradually taper glucocorticoid until completely stoppedUse the lowest effective supraphysiologic glucocorticoid dose when indicated
    TreatmentReplace with physiologic doses of glucocorticoidGradually taper glucocorticoid until completely stopped
    Consider stress-dose glucocorticoid under stressors    		No effective treatment: empirically increase glucocorticoid to prolong
    HPAA suppression

    • ↵a Cortisol values per the Elecsys Cortisol II assay.

    • ↵b Adrenocorticotropic hormone values per the Electro Chemiluminescence Immunoassay.

    • ↵c Dehydroepiandrosterone sulfate normal values (μg/dL) per the Electro Chemiluminescence Immunoassay for females, by age:

      15–19 years 65.1–368.0; 20–24 years 148–407; 25–34 years 98.8–340; 35–44 years 60.9–337; 45–54 years 35.4–256; 55–64 years 18.9–205; 65–74 years < 247; 75–99 years 12–154.

      For males, by age:

      15–19 years 70.2–492; 20–24 years 211–492; 25–34 years 160–449; 35–44 years 88.9–427; 45–54 years 44.3–331; 55–64 years 51.7–295; 65–74 years 33.6–249; 75–99 years 16.2–123.

    • HPAA = hypothalamic-pituitary-adrenal axis

  • TABLE 5

    Approach to glucocorticoid taper in patients with glucocorticoid-induced adrenal insufficiency and after surgery for Cushing syndrome

    Average daily prednisone dose
    > 40 mg/day: decrease by 10 mg weekly until 40 mg daily
    20–40 mg/day: decrease by 5 mg weekly until 20 mg daily
    10–20 mg/day: decrease by 1–2.5 mg weekly until 10 mg daily
    5–10 mg/day: decrease by 1 mg weekly until < 5 mg daily
    < 5 mg/day: switch to equivalent dose of hydrocortisone (eg, 10 mg in the morning and 5 mg in the early afternoon); hold hydrocortisone for 24 hours and retest HPAA
    Testing for HPAA recovery
    If patient has been on prednisone 5 mg/day, switch to equivalent dose of hydrocortisone, wait for 2–4 weeks, and hold hydrocortisone for 24 hours before testing

    Check 8 am serum cortisol:
     If < 10 μg/dL,a continue current dose of hydrocortisone and retest in 4–8 weeks
     If ≥ 10 μg/dL, perform 250-μg corticotropin stimulation test:

    • If suboptimal (cortisol peak < 12.6 μg/dL at 30 minutes and 60 minutes), consider stopping daily glucocorticoid replacement if patient has no withdrawal symptoms, but continue the sick-day rule (using stress-dose glucocorticoid) until repeating corticotropin stimulation test

    • If optimal (peak cortisol ≥ 12.6 μg/dL), stop glucocorticoid if patient is comfortable


     If 8 am serum cortisol ≥ 12.6 μg/dL, consider stopping glucocorticoid if patient is ready in terms of withdrawal symptoms, or performing 250-μg corticotropin stimulation test or tapering glucocorticoid dose

    Frequency of testing:

    • If the results of tests are abnormal, recheck every 2–3 months

    • If no recovery within 1 year, reassess every 3–6 months

    Things to consider

    • If glucocorticoid withdrawal syndrome develops at any point, increase the glucocorticoid dose to the most recent dose on which the patient did not have glucocorticoid withdrawal syndrome; consider decrements every other week rather than weekly

    • If patient is on dexamethasone, consider switching to prednisone

    • If patient is on twice-daily prednisone dosing, consider switching to equivalent dose of prednisone in the morning once daily

    • ↵a Values per the Elecsys Cortisol II assay.

      HPAA = hypothalamic-pituitary-adrenal axis

      Based in part on information in reference 81.

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