# Adrenal Insufficiency Diagnostic Testing

Test promptly when otherwise unexplained hypotension, volume depletion, hyponatremia, hyperkalemia, abdominal pain, fever, or hypoglycemia raises concern. Draw cortisol and ACTH when feasible, but treat suspected crisis immediately, then use cosyntropin testing and ACTH-directed classification to define primary versus central disease.

**Clinical question:** How should clinicians test for adrenal insufficiency while avoiding delay in treatment of adrenal crisis?

Updated: 2026-09-15T22:07:07.675647+00:00

## What matters in practice
- In suspected adrenal crisis or severe adrenal insufficiency, give parenteral hydrocortisone immediately; do not await diagnostic results. [14][22][23]
- Obtain early-morning serum cortisol and plasma ACTH concurrently when the patient is stable enough for testing; ACTH greater than twice the assay upper limit supports primary adrenal insufficiency. [18][19]
- Use the standard 250-mcg cosyntropin stimulation test as confirmatory testing when clinical circumstances permit; a normal stimulated cortisol threshold depends on assay and sampling method. [20][23]
- A cosyntropin test documents impaired adrenal reserve but does not independently distinguish primary from chronic central adrenal insufficiency; classify with ACTH and assess renin and aldosterone when primary disease is suspected. [18][19][23]
- Do not use a reassuring cosyntropin response to exclude newly acquired secondary or tertiary adrenal insufficiency without considering timing and pretest probability. [20]

## When suspected adrenal crisis overrides diagnostic sequencing

Stabilize first when the presentation suggests cortisol-deficient shock or severe illness.

Test acutely ill patients for primary adrenal insufficiency when otherwise unexplained volume depletion, hypotension, hyponatremia, hyperkalemia, fever, abdominal pain, hyperpigmentation, or—particularly in children—hypoglycemia is present. [14][22][23]

For severe symptoms or suspected adrenal crisis, administer hydrocortisone before diagnostic results return. The recommended emergency regimen is 100 mg hydrocortisone intravenously or intramuscularly immediately, with fluid resuscitation, then 200 mg hydrocortisone over 24 hours by continuous intravenous infusion or 50 mg intravenously or intramuscularly every 6 hours. [22][24]

If doing so does not delay therapy, obtain serum cortisol and plasma ACTH before the first glucocorticoid dose. Once initial samples are drawn, high clinical suspicion warrants steroid treatment even before confirmatory testing; defer dynamic testing until the patient is clinically stable. [19][22]
- Admit patients unable to absorb oral glucocorticoid during prolonged vomiting or diarrhea; give 100 mg intravenous or intramuscular hydrocortisone. [24]
- In severe illness such as sepsis or intensive-care admission, continue 200 mg intravenous hydrocortisone per 24 hours after the initial emergency dose. [24]

*Emergency testing and treatment sequence for suspected adrenal crisis. [22][24]*

| Clinical state | Immediate action | Testing implication |
| --- | --- | --- |
| Severe symptoms or suspected adrenal crisis | Hydrocortisone 100 mg IV or IM immediately; give fluid resuscitation. [22] | Draw cortisol and ACTH first only if this does not delay treatment. [19][22] |
| Persistent severe illness after initial dose | Hydrocortisone 200 mg IV over 24 hours or 50 mg IV/IM every 6 hours. [22][24] | Perform confirmatory adrenal-axis testing after stabilization. [22][23] |
| Prolonged vomiting or diarrhea preventing oral absorption | Hospitalize and give hydrocortisone 100 mg IV or IM. [24] | Oral replacement cannot be relied on during this interval. [24] |

## How to use morning cortisol and ACTH

Interpret basal cortisol in context, then use ACTH to localize the defect.

In a hemodynamically stable patient with suspected adrenal insufficiency, measure an early-morning serum cortisol with plasma ACTH collected concurrently. ACTH is the key discriminator after low or inappropriately low cortisol: an ACTH concentration greater than twice the upper limit of normal at any time of day is consistent with primary adrenal insufficiency, whereas low or inappropriately normal ACTH indicates secondary or tertiary disease. [18][19][20]

Basal cortisol can triage the need for dynamic testing, but cutoffs are assay- and center-dependent. In an observational cohort of 804 patients undergoing cosyntropin testing, basal cortisol at least 450 nmol/L had a 98.7% negative predictive value for adrenal insufficiency; basal cortisol values of 100 nmol/L or lower and 450 nmol/L or higher had high diagnostic accuracy in that cohort. [10]

Do not apply a single basal cortisol threshold as a universal exclusion rule. Current diagnostic strategy still recommends corticotropin stimulation testing for patients with symptoms or signs suggesting primary adrenal insufficiency when their condition permits, and contemporary commentary emphasizes limitations of single cortisol measurements. [7][23]
- Order ACTH with—not after—the initial morning cortisol, because delayed ACTH sampling can obscure primary versus central classification. [18][19]
- For suspected primary adrenal insufficiency, obtain plasma renin and aldosterone simultaneously to identify mineralocorticoid deficiency. [23]
- Elevated renin with low aldosterone increases suspicion for primary adrenal insufficiency in the appropriate clinical setting. [19]

*Initial biochemical patterns and the next diagnostic action. [10][18][19][23]*

| Pattern | Interpretation | Next action |
| --- | --- | --- |
| Morning cortisol ≥450 nmol/L | In one 804-patient cohort, negative predictive value for adrenal insufficiency was 98.7%. [10] | If pretest probability remains high, do not rely on a single value; proceed according to clinical context and dynamic-test strategy. [7][23] |
| Morning cortisol ≤100 nmol/L | Had high diagnostic accuracy for adrenal insufficiency in the observational cohort. [10] | Measure concurrent ACTH and promptly establish the etiologic branch; treat without delay when clinical suspicion is high. [19] |
| Low cortisol with ACTH >2× upper limit of normal | Consistent with primary adrenal insufficiency. [18][19] | Measure renin and aldosterone and pursue primary adrenal etiologic evaluation. [23] |
| Low cortisol with low or inappropriately normal ACTH | Suggests secondary or tertiary adrenal insufficiency. [20] | Evaluate the central hypothalamic-pituitary axis; recognize that acute central disease may have a falsely reassuring cosyntropin response. [20] |

## When and how to interpret cosyntropin stimulation testing

Use dynamic testing to confirm impaired adrenal reserve in stable patients.

Use a corticotropin stimulation test to confirm suspected primary adrenal insufficiency when the patient is clinically stable enough to undergo testing. The Endocrine Society guideline recommends the standard 250-mcg test for most patients and reserves the 1-mcg low-dose test for primary adrenal insufficiency when standard corticotropin is in short supply. [20][23]

A standard 250-mcg cosyntropin test can be performed at any time of day. In the cited clinical review, a cortisol value greater than 18 to 20 mcg/dL after intravenous cosyntropin excluded adrenal insufficiency; after intramuscular administration, a 30-minute value greater than 16 to 18 mcg/dL excluded adrenal insufficiency. These thresholds require alignment with the local assay and protocol. [20]

A blunted cosyntropin response confirms deficient adrenal reserve but does not establish adrenal versus central pathology. Chronic ACTH deficiency can produce adrenal hyporesponsiveness, so an abnormal response occurs in secondary disease as well as primary disease; use ACTH rather than the cosyntropin result alone to classify the disorder. [18][19]
- Do not infer primary adrenal insufficiency solely from an abnormal cosyntropin test. [18][19]
- Do not use a standard cosyntropin test to exclude acute secondary or tertiary adrenal insufficiency, because adrenal responsiveness may still be preserved early after central ACTH deficiency develops. [20]
- Low-dose and high-dose corticotropin tests had comparable results in the primary adrenal insufficiency workup in the Endocrine Society guideline evidence review; low-dose testing may be more sensitive for secondary disease, but is not the routine primary-adrenal-insufficiency test. [22][23]

### When to consider specialized central-axis testing

When clinical suspicion for secondary adrenal insufficiency remains high despite non-diagnostic testing, insulin tolerance testing or overnight metyrapone testing may identify central adrenal insufficiency. These tests should be selected and interpreted with endocrinology involvement. [11][19]
- Use specialized testing particularly when recent-onset central ACTH deficiency is plausible and standard cosyntropin testing may not exclude it. [20]
- Interpret insulin tolerance and metyrapone tests in a setting able to manage test-specific risk and assay-dependent thresholds. [11][19]

*Dynamic-test selection and limitations in suspected adrenal insufficiency. [18][19][20][22][23]*

| Test | Best use | Key interpretation or limitation |
| --- | --- | --- |
| Standard 250-mcg cosyntropin stimulation test | Confirm suspected primary adrenal insufficiency in stable patients. [20][23] | Post-IV cortisol >18–20 mcg/dL excluded adrenal insufficiency in the cited review; use assay-appropriate local thresholds. [20] |
| Low-dose 1-mcg corticotropin test | Alternative for primary adrenal insufficiency only when standard corticotropin is unavailable. [23] | May have greater sensitivity for secondary adrenal insufficiency, but is not the guideline-preferred routine test for primary disease. [22][23] |
| Insulin tolerance test | Evaluate selected suspected central cases. [11][19] | Requires endocrinology-supervised selection and interpretation. [19] |
| Overnight metyrapone test | Evaluate selected suspected central cases. [11][19] | Requires endocrinology-supervised selection and interpretation. [19] |

## What changes after abnormal testing

Use ACTH and mineralocorticoid testing to separate adrenal failure from central ACTH deficiency.

After documenting adrenal insufficiency, classify primary versus central disease immediately because mineralocorticoid evaluation and replacement apply to primary disease. Primary adrenal insufficiency requires lifelong glucocorticoid and mineralocorticoid replacement, whereas secondary adrenal insufficiency reflects impaired pituitary ACTH secretion and tertiary disease impaired hypothalamic corticotropin-releasing hormone signaling. [19][20]

For the primary pattern—low cortisol with elevated ACTH—measure renin and aldosterone to determine mineralocorticoid deficiency. Confirmed aldosterone deficiency is an indication for fludrocortisone replacement, in addition to glucocorticoid replacement. [23]

For the central pattern—low cortisol with low or inappropriately normal ACTH—evaluate for pituitary or hypothalamic structural causes when clinically indicated; adrenal imaging and pituitary imaging can identify structural etiologies in their respective branches. [7]
- Hyperkalemia, elevated renin, and low aldosterone reinforce a primary-adrenal pattern. [19][23]
- A cosyntropin result cannot replace ACTH for primary-versus-central classification. [18][19]
- Initiate glucocorticoid therapy without delay once adrenal insufficiency is established, or earlier after diagnostic samples when suspicion is high. [19]

*Primary and central adrenal insufficiency: classification tests that alter management. [18][19][20][23]*

| Feature | Primary adrenal insufficiency | Secondary or tertiary adrenal insufficiency |
| --- | --- | --- |
| ACTH with low cortisol | ACTH >2× upper limit of normal supports primary disease. [18][19] | ACTH is low or inappropriately normal. [20] |
| Mineralocorticoid evaluation | Measure plasma renin and aldosterone; confirmed aldosterone deficiency supports fludrocortisone replacement. [23] | The cited guideline specifically directs renin and aldosterone testing for primary disease. [23] |
| Role of cosyntropin result | Confirms impaired reserve but does not by itself prove adrenal pathology. [18][19] | Chronic central ACTH deficiency may yield an abnormal response; acute central disease may not be excluded by testing. [18][20] |
| Structural evaluation | Adrenal imaging may elucidate structural causes when indicated. [7] | Pituitary imaging may elucidate structural causes when indicated. [7] |

## Common testing traps and operational follow-up

Interpret results against illness severity, timing, and the suspected anatomic level of disease.

Do not postpone emergency hydrocortisone for a technically ideal stimulation test. In severe suspected adrenal insufficiency, the clinical priority is immediate stress-dose therapy, with diagnostic confirmation and etiologic classification pursued after stabilization. [14][22][23]

Avoid interpreting a delayed ACTH result as if it were paired with the original cortisol. Concurrent early-morning cortisol and ACTH sampling gives the most reliable primary-versus-central distinction, while dynamic testing assesses reserve rather than disease location. [18][19][20]

In patients receiving exogenous corticosteroids or with concern for treatment-related suppression, recognize that systemic corticosteroid exposure is associated with adrenal insufficiency and that inhaled fluticasone has been associated with impaired adrenal responses in bronchiectasis cohorts. A medication history should therefore precede interpretation of a suspected central pattern. [4][15]
- Refer for endocrinology-guided insulin tolerance or metyrapone testing when standard testing is discordant with a high-probability central presentation. [11][19]
- For a confirmed primary pattern, complete renin-aldosterone assessment rather than assuming glucocorticoid deficiency alone. [23]
- For future vomiting, diarrhea, sepsis, or inability to take oral glucocorticoids, patients with established adrenal insufficiency need parenteral hydrocortisone rather than routine oral dosing. [24]

*Pitfalls that should change the next diagnostic step. [4][18][19][20][24]*

| Pitfall | Why it misleads | Correct next step |
| --- | --- | --- |
| Waiting for testing in shock | Adrenal crisis requires immediate parenteral hydrocortisone. [22][24] | Treat immediately; collect cortisol and ACTH only if treatment is not delayed. [19][22] |
| Using cosyntropin to label disease as primary | Chronic secondary disease can also produce a suboptimal response. [18][19] | Classify with concurrent ACTH; add renin and aldosterone for a primary pattern. [19][23] |
| Using a normal cosyntropin test to exclude recent central disease | Acute secondary or tertiary adrenal insufficiency may retain adrenal responsiveness. [20] | Consider endocrinology-supervised insulin tolerance or metyrapone testing when suspicion persists. [11][19] |
| Ignoring corticosteroid exposure | Systemic corticosteroids are associated with adrenal insufficiency; inhaled fluticasone has been associated with impaired adrenal response. [4][15] | Reconstruct systemic, inhaled, and interacting drug exposure before assigning idiopathic central disease. [4][15] |

## References
1. invasive diagnostic test for patients with adrenal insufficiency using — bmjopen.bmj.com — https://bmjopen.bmj.com/content/bmjopen/16/2/e112708.full.pdf
2. Consensus-based disease definitions for endocrine immune-related ... — jitc.bmj.com — https://jitc.bmj.com/content/jitc/13/10/e011865.full.pdf
3. the STARLIT-3 study protocol | BMJ Open — bmjopen.bmj.com — https://bmjopen.bmj.com/content/16/2/e112708
4. British Thoracic Society Guideline for bronchiectasis in adults - Thorax — thorax.bmj.com — https://thorax.bmj.com/content/74/Suppl_1/1
5. The diagnosis and treatment of adrenal insufficiency during ... — adc.bmj.com — https://adc.bmj.com/content/early/2016/04/15/archdischild-2015-308799?versioned=true
6. Hydrocortisone Dosing for Adrenal Insufficiency | NEJM Clinician — clinician.nejm.org — https://clinician.nejm.org/hydrocortisone-dosing-adrenal-insufficiency-nejm-jw.NA42734
7. Nature Index Adrenal Insufficiency Diagnosis and Management — www.nature.com — https://www.nature.com/nature-index/topics/l4/adrenal-insufficiency-diagnosis-and-management
8. Management of Primary Adrenal Insufficiency and Overt ... — onlinelibrary.wiley.com — https://onlinelibrary.wiley.com/doi/10.1002/ccr3.71401
9. Adrenal Insufficiency During Treatment With Immune‐Checkpoint ... — onlinelibrary.wiley.com — https://onlinelibrary.wiley.com/doi/pdf/10.1111/cen.70023
10. Diagnostic Accuracy of Basal Cortisol Level to Predict Adrenal Insufficiency in Cosyntropin Testing: Results from an Observational Cohort Study with 804 Patients — www.sciencedirect.com — https://www.sciencedirect.com/science/article/abs/pii/S1530891X20358511
11. Diagnostic Predicament of Secondary Adrenal Insufficiency - ScienceDirect — www.sciencedirect.com — https://www.sciencedirect.com/science/article/abs/pii/S1530891X20408171
12. ACTH Stimulation Test - an overview — www.sciencedirect.com — https://www.sciencedirect.com/topics/agricultural-and-biological-sciences/acth-stimulation-test
13. Secondary Adrenal Insufficiency: Recent Updates and New Directions for Diagnosis and Management — www.sciencedirect.com — https://www.sciencedirect.com/science/article/abs/pii/S1530891X21012428
14. Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline — academic.oup.com — https://academic.oup.com/jcem/article/101/2/364/2810222
15. Long‐term corticosteroid use, adrenal insufficiency and the need for ... — onlinelibrary.wiley.com — https://onlinelibrary.wiley.com/doi/full/10.1111/joim.13273
16. Adrenal Tuberculosis Presenting as Adrenal Crisis: A Rare ... — onlinelibrary.wiley.com — https://onlinelibrary.wiley.com/doi/10.1155/crie/9086526
17. Diagnosis and Treatment of Primary Adrenal Insufficiency — www.ccjm.org — https://www.ccjm.org/lookup/external-ref?access_num=10.1210%2Fjc.2015-1710&link_type=DOI
18. Primary adrenal insufficiency in adults: When to suspect, how to ... — www.ccjm.org — https://www.ccjm.org/content/91/9/553
19. [PDF] Abdominal pain without physical findings is not always without ... — www.ccjm.org — https://www.ccjm.org/content/ccjom/91/9/local/complete-issue.pdf
20. A 71-year-old woman with shock and a high INR | Cleveland Clinic Journal of medicine — www.ccjm.org — https://www.ccjm.org/content/85/4/303/tab-figures-data
21. Clinical Management of Adrenocortical Carcinoma - Endocrine Society — www.endocrine.org — https://www.endocrine.org/-/media/endocrine/files/endo-annual-meetings/2012endoabstracts.html
22. Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline - PMC — www.ncbi.nlm.nih.gov — https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4880116?term=%22J+Clin+Endocrinol+Metab%22%5Bjour%5D
23. Primary Adrenal Insufficiency Guideline Resources | Endocrine Society — support.endocrine.org — https://support.endocrine.org/clinical-practice-guidelines/primary-adrenal-insufficiency
24. Adrenal insufficiency: identification and management - NCBI Bookshelf — www.ncbi.nlm.nih.gov — https://www.ncbi.nlm.nih.gov/books/NBK609655

## Editorial note

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