# Adrenal Insufficiency

Adrenal insufficiency requires rapid recognition of crisis, physiologic glucocorticoid replacement, etiologic localization with ACTH, and assay-aware cortisol interpretation. Distinguish primary disease from central and glucocorticoid-induced suppression because mineralocorticoid replacement, testing strategy, and long-term management differ.

**Clinical question:** How should physicians diagnose, localize, treat, and monitor adrenal insufficiency while preventing adrenal crisis?

Updated: 2026-08-21T00:40:04.816581+00:00

## What matters in practice
- In suspected adrenal crisis or high-probability adrenal insufficiency, draw diagnostic samples when feasible but do not delay glucocorticoid treatment. [17]
- Plasma ACTH is the principal test for localizing adrenal insufficiency to primary versus central hypothalamic-pituitary disease. [9]
- Interpret cosyntropin-stimulated cortisol against the laboratory assay: modern immunoassays can yield lower values than historic 18 μg/dL cutoffs. [6][8]
- Primary adrenal insufficiency requires both glucocorticoid and mineralocorticoid replacement; central and glucocorticoid-induced disease generally do not require mineralocorticoid replacement. [4][15]
- Adrenal suppression may follow oral, parenteral, inhaled, topical, intra-articular, or epidural glucocorticoid exposure. [15]

## When to suspect adrenal insufficiency

Clinical urgency depends on physiologic stress and hemodynamic status.

Adrenal insufficiency may evolve insidiously with nonspecific fatigue and weakness, delaying recognition until an acute adrenal crisis. Primary adrenal insufficiency is suggested by hyperpigmentation, hypotension or orthostasis, and salt craving; its presentation reflects combined glucocorticoid and mineralocorticoid deficiency. [2][4]

Consider central adrenal insufficiency in pituitary or hypothalamic disease and glucocorticoid-induced adrenal insufficiency (GIAI) after exogenous steroid exposure. GIAI is often missed when the exposure is nonsystemic, including inhaled, topical, intra-articular, and epidural formulations. [15]
- Treat suspected crisis as a time-critical endocrine emergency, particularly with acute illness, trauma, surgery, vomiting, hypotension, or unexplained clinical deterioration in a patient at risk for hypothalamic-pituitary-adrenal suppression. [3][17]
- Patients receiving long-term corticosteroids for Duchenne muscular dystrophy should be assumed to have adrenal suppression and have an emergency steroid plan. [3]
- Autoimmune adrenalitis is the most common cause of primary adrenal insufficiency in developed countries; other reported causes include tuberculosis, HIV infection, trauma, and immune checkpoint inhibitor use. [15]

*Clinical distinctions that direct initial localization and replacement strategy. [2][4][9][15]*

| Feature | Primary adrenal insufficiency | Central or glucocorticoid-induced adrenal insufficiency |
| --- | --- | --- |
| Anatomic defect | Adrenal cortex destruction or dysfunction. [2] | Reduced pituitary ACTH, hypothalamic stimulation, or suppression from exogenous glucocorticoids. [2][15] |
| Localizing test | ACTH is used to establish adrenal versus central localization. [9] | ACTH is used to establish adrenal versus central localization. [9] |
| Mineralocorticoid replacement | Required lifelong with glucocorticoid replacement. [4] | Not routinely indicated; the deficit is principally glucocorticoid production. [15] |
| Useful clinical clues | Hyperpigmentation, hypotension or orthostasis, and salt craving support suspicion. [4] | History of pituitary-hypothalamic disease or systemic and nonsystemic glucocorticoid exposure supports suspicion. [15] |

## How to test and localize adrenal insufficiency

Use biochemical confirmation when the patient is stable; preserve treatment priority in suspected crisis.

Obtain serum cortisol with plasma ACTH when adrenal insufficiency is suspected and the patient's condition permits. ACTH is the principal test for localization within the hypothalamic-pituitary-adrenal axis. A low cortisol with elevated ACTH supports primary adrenal insufficiency, whereas an inappropriately low or non-elevated ACTH supports central disease; interpretation should account for the clinical setting and exogenous glucocorticoid exposure. [9][15]

The ACTH stimulation test is the definitive confirmatory test for early primary adrenal insufficiency. Dynamic testing may also include insulin tolerance, metyrapone, glucagon, or corticotropin-releasing hormone testing, but specialized tests should be selected and interpreted with endocrinology support. [4][8][17]
- For a standard test, the cited contemporary study evaluated cortisol at baseline and 30 and 60 minutes after 250 μg ACTH 1-24. [6]
- Do not apply a universal stimulated cortisol threshold without knowing the assay. Proposed modern-assay cutoffs range from approximately 12.7 to 16 μg/dL, versus the historic 18 μg/dL threshold. [6]
- With the Roche Cortisol II assay, a 350 nmol/L stimulated cortisol threshold had 91% sensitivity and 97% specificity in one study; using an older cutoff would have approximately doubled classification as adrenal insufficient. [8]
- Morning cortisol is a triage tool rather than a replacement for clinical judgment and dynamic testing. In one retrospective cohort, morning cortisol of 285 nmol/L had 90.6% sensitivity and 93.3% negative predictive value for excluding adrenal insufficiency; 306 nmol/L increased sensitivity to 95.3%, and 362 nmol/L had 100% sensitivity. [7]

### Assay-aware interpretation

Cortisol immunoassay calibration materially changes diagnostic thresholds. Newer assays may report values about 30% lower than older immunoassays, creating false-positive diagnoses if historic cutoffs are used without assay-specific validation. Confirm the local laboratory's recommended decision limit and sampling protocol before labeling a patient with lifelong adrenal insufficiency. [8]
- A basal cortisol greater than 13.1 μg/dL predicted a normal ACTH-stimulation response in one contemporary cohort, while a basal cortisol below 1.5 μg/dL was always associated with pathology; these are study findings, not universal assay-independent rules. [6]

*Testing sequence for a stable patient with suspected adrenal insufficiency. [4][6][7][8][9][17]*

| Step | Action | Interpretation or next action |
| --- | --- | --- |
| 1 | Obtain serum cortisol and plasma ACTH. [9] | Use ACTH to localize primary versus central hypothalamic-pituitary disease. [9] |
| 2 | Perform ACTH stimulation testing when confirmation is needed. [4][17] | Interpret the peak against the assay-specific laboratory threshold rather than automatically using 18 μg/dL. [6][8] |
| 3 | Refer for specialized dynamic testing when results remain equivocal or central disease is suspected. [17] | Metyrapone, insulin tolerance, low-dose cosyntropin, or other dynamic testing requires expert selection and interpretation. [8][17] |
| 4 | Define etiology after biochemical localization. [15] | Review glucocorticoid exposures, evaluate pituitary-hypothalamic disease when indicated, and investigate causes of primary adrenal destruction or dysfunction. [15] |

## Management of suspected adrenal crisis

Treat immediately after obtaining samples if this does not delay therapy.

When clinical suspicion is high, initiate glucocorticoid therapy once diagnostic samples have been drawn; treatment should not await confirmatory results. [17] Hydrocortisone administered intramuscularly or intravenously should be considered during physiologic stress, including illness, trauma, surgery, or suspected adrenal crisis. [3]

Acute care should simultaneously address the precipitating illness and complications of cortisol and, in primary disease, mineralocorticoid deficiency. The supplied sources support urgent parenteral hydrocortisone but do not provide a source-supported adult adrenal-crisis dose or fluid regimen; use current institutional emergency protocols while arranging endocrine follow-up. [3][17]
- Document the suspected subtype, recent glucocorticoid exposure, vomiting or impaired oral absorption, intercurrent infection, trauma, and perioperative status. [3][15]
- After stabilization, establish an emergency steroid plan and ensure the patient and caregivers understand stress dosing during illness. [3][15]

*Immediate priorities in high-probability adrenal crisis. [3][17]*

| Priority | Action |
| --- | --- |
| Do not delay treatment | Draw diagnostic samples when feasible, then start glucocorticoid therapy without waiting for results. [17] |
| Use parenteral therapy when stressed or unable to rely on oral dosing | Consider intramuscular or intravenous hydrocortisone during illness, trauma, surgery, or suspected crisis. [3] |
| Plan for recurrence prevention | Provide an emergency steroid plan including oral stress dosing for mild-to-moderate illness. [3] |

## Chronic replacement and monitoring

Aim for adequate physiologic replacement while avoiding chronic glucocorticoid excess.

Patients with confirmed primary adrenal insufficiency require lifelong glucocorticoid and mineralocorticoid replacement. Once the diagnosis is established, glucocorticoid treatment should not be delayed. [4][17] Both excessive and inadequate glucocorticoid replacement cause harm; follow patients for symptoms suggesting either underreplacement or overtreatment and use the lowest replacement dose that is sufficient. [17]

For mineralocorticoid replacement in primary adrenal insufficiency, a cited review recommends fludrocortisone 50 to 100 μg orally daily as a starting dose, titrated within 50 to 300 μg daily according to clinical response. Monitor for salt craving, dizziness, orthostatic hypotension, hyperkalemia, and hyperreninemia as features of underreplacement. [17]
- Monitor blood pressure and orthostatic symptoms during fludrocortisone titration. [17]
- Assess serum potassium and renin when mineralocorticoid adequacy is uncertain; hyperkalemia or hyperreninemia can indicate underreplacement. [17]
- Patients on immunosuppressive glucocorticoid doses should not receive live or live-attenuated vaccines; corticosteroid labeling also warns of infection risk, masked infection manifestations, hypertension, fluid retention, hypokalemia, behavioral effects, gastrointestinal bleeding or perforation, and ophthalmic adverse effects. [1]

### Stress-dose planning

Patients at risk for adrenal suppression require explicit instructions for intercurrent illness. An emergency plan should include oral stress dosing for mild-to-moderate illness, with intramuscular or intravenous hydrocortisone considered for major physiologic stress or suspected crisis. [3]
- Review stress-dose instructions at routine visits and after changes in chronic glucocorticoid exposure. [3][15]
- Ensure patients and caregivers can communicate the diagnosis during emergency care and perioperative encounters. [3]

*Monitoring targets after establishing primary adrenal insufficiency replacement. [17]*

| Domain | What to assess | Finding that suggests action |
| --- | --- | --- |
| Glucocorticoid replacement | Symptoms of insufficient or excessive replacement; pursue the lowest sufficient replacement dose. [17] | Clinical evidence of underreplacement or glucocorticoid excess warrants reassessment of replacement strategy. [17] |
| Mineralocorticoid replacement | Salt craving, dizziness, orthostatic blood pressure, potassium, and renin. [17] | Salt craving, orthostasis, hyperkalemia, or hyperreninemia suggest underreplacement. [17] |
| Emergency preparedness | Illness and procedure stress-dose plan. [3] | Absent or unclear plan requires education and documented rescue instructions. [3] |

## Glucocorticoid-induced adrenal insufficiency

Exposure history is a diagnostic test and a prevention opportunity.

GIAI results from hypothalamic-pituitary-adrenal suppression by exogenous glucocorticoids and may be overlooked outside conventional oral or parenteral regimens. Specifically ask about inhaled, topical, intra-articular, and epidural products as well as systemic therapy. [15]

During glucocorticoid tapering, distinguish recurrent inflammatory disease, glucocorticoid withdrawal syndrome, and true adrenal insufficiency. The 2024 joint Endocrine Society-European Society of Endocrinology guideline addresses diagnosis and therapy of GIAI, but the provided search excerpt does not contain its detailed tapering or testing recommendations; consult the full guideline for regimen-specific management. [15][16]
- Patients receiving chronic corticosteroids should have an adrenal action plan; failures in patient education and home injectable glucocorticoid use contribute to preventable gaps in care. [15]
- For patients on long-term corticosteroids, account for stress-dose coverage during illness, trauma, surgery, or suspected crisis. [3]

*Practical GIAI assessment domains. [3][15][16]*

| Domain | Clinical action |
| --- | --- |
| Medication reconciliation | Identify systemic and nonsystemic glucocorticoid exposures, including inhaled, topical, intra-articular, and epidural formulations. [15] |
| Stress coverage | Provide an emergency steroid plan and consider parenteral hydrocortisone during substantial physiologic stress or suspected crisis. [3] |
| Taper evaluation | Use the 2024 Endocrine Society-ESE GIAI guideline for current testing and tapering recommendations; detailed recommendations are not available in the supplied excerpt. [16] |

## Common questions

### Should glucocorticoids be withheld until cosyntropin testing is completed?

No. In a patient with high clinical suspicion for adrenal insufficiency or crisis, obtain diagnostic samples if feasible, then start glucocorticoid therapy without awaiting results. [17]

### Is a stimulated cortisol of 18 μg/dL always required to exclude adrenal insufficiency?

No. Historic 18 μg/dL thresholds may overdiagnose adrenal insufficiency with newer assays. Use the local assay-specific cutoff; contemporary studies cite proposed thresholds approximately 12.7 to 16 μg/dL, with assay-dependent performance. [6][8]

### Which patients with adrenal insufficiency require fludrocortisone?

Patients with primary adrenal insufficiency require mineralocorticoid replacement. A cited review uses fludrocortisone 50 to 100 μg daily initially, titrating according to symptoms, orthostasis, potassium, and renin. [4][17]

### Can inhaled or joint-injected glucocorticoids cause adrenal insufficiency?

Yes. GIAI can follow nonsystemic glucocorticoid exposure, including inhaled, topical, intra-articular, and epidural formulations. [15]

## References
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## Editorial note

Prepared from cited clinical literature using Astra's research workflow. Verify recommendations against current guidance and patient-specific factors.