In an adult with an adrenocorticotropic hormone (ACTH) level of 5 pg/mL, what does this low result indicate and how should it be evaluated and managed?

Low ACTH Level of 5 pg/mL: Diagnostic Interpretation and Management

An ACTH level of 5 pg/mL is at the threshold of detectability and indicates either secondary (central) adrenal insufficiency or normal adrenal function, requiring immediate correlation with morning serum cortisol and clinical context to determine the next diagnostic step. 1

Immediate Diagnostic Interpretation

ACTH Level Context:

• Any ACTH level >5 pg/mL is considered detectable and typically suggests ACTH-dependent processes, whereas levels ≤5 pg/mL or undetectable indicate either secondary adrenal insufficiency or ACTH-independent conditions 2
• In the context of Cushing's syndrome evaluation, ACTH <5 pg/mL with elevated cortisol would indicate ACTH-independent disease (adrenal source), but this is not your scenario 2
• For adrenal insufficiency evaluation, low or inappropriately normal ACTH with low cortisol points to secondary (central) adrenal insufficiency 1

Critical First Step:

• Obtain a simultaneous morning (8:00-9:00 AM) serum cortisol measurement if not already done, as the ACTH-cortisol relationship is the definitive diagnostic factor 1, 2

Diagnostic Algorithm Based on Morning Cortisol

If Morning Cortisol <250 nmol/L (<9 µg/dL):

• This combination (low ACTH + low cortisol) is diagnostic of secondary adrenal insufficiency 1
• No further dynamic testing is required for diagnosis 1
• Proceed directly to treatment initiation and etiologic workup 1

If Morning Cortisol 250-400 nmol/L (9-14 µg/dL):

• Perform cosyntropin stimulation test to confirm or exclude adrenal insufficiency 1, 3
• This indeterminate range requires dynamic testing because basal values alone cannot establish the diagnosis 1

If Morning Cortisol >550 nmol/L (>18-20 µg/dL):

• Adrenal insufficiency is effectively ruled out 1
• No further adrenal testing is indicated 1

Cosyntropin Stimulation Test Protocol (When Indicated)

Standard High-Dose Protocol:

• Administer 0.25 mg (250 µg) cosyntropin IV or IM 1, 4
• Measure serum cortisol at baseline, 30 minutes, and 60 minutes post-administration 1, 5
• Peak cortisol <500 nmol/L (<18 µg/dL) at either 30 or 60 minutes confirms adrenal insufficiency 1, 6
• Peak cortisol >550 nmol/L (>18-20 µg/dL) excludes adrenal insufficiency 1, 6

Critical Testing Considerations:

• Measure both 30- and 60-minute cortisol levels, as 54% of patients peak at 60 minutes and 11% may pass only at 60 minutes 5
• Stop glucocorticoids on the day of testing; long-acting glucocorticoids require longer washout periods 1, 4
• Stop estrogen-containing drugs 4-6 weeks before testing, as elevated cortisol-binding globulin causes falsely elevated total cortisol 4
• Dexamethasone 4 mg IV can be used for emergency treatment if you need to preserve diagnostic testing capability, as it does not cross-react with cortisol assays 1

Etiologic Workup for Confirmed Secondary Adrenal Insufficiency

Pituitary Imaging:

• Obtain high-resolution 3-Tesla pituitary MRI with thin slices and gadolinium contrast to evaluate for pituitary adenoma, empty sella, or other structural lesions 1, 2

Assess Other Pituitary Axes:

• Measure TSH, free T4, LH, FSH, testosterone (males) or estradiol (females), prolactin, and IGF-1 to identify additional pituitary hormone deficiencies 1
• Isolated ACTH deficiency is rare; most cases of secondary adrenal insufficiency occur with other pituitary hormone deficits 3

Medication History:

• Review for exogenous glucocorticoid use (prednisone, dexamethasone, inhaled fluticasone) causing iatrogenic secondary adrenal insufficiency 1
• Patients taking ≥20 mg/day prednisone or equivalent for ≥3 weeks are at high risk for HPA axis suppression 1

Treatment Initiation

For Confirmed Secondary Adrenal Insufficiency:

• Initiate hydrocortisone 15-25 mg daily in divided doses (typically 10 mg at 7:00 AM, 5 mg at 12:00 PM, 2.5-5 mg at 4:00 PM) 1
• Alternative: cortisone acetate 25-37.5 mg daily or prednisone 3-5 mg daily 1
• Mineralocorticoid replacement (fludrocortisone) is NOT required in secondary adrenal insufficiency, as the renin-angiotensin-aldosterone system remains intact 1

Critical Safety Measures:

• If concurrent hypothyroidism exists, start glucocorticoids several days BEFORE initiating thyroid hormone replacement to prevent precipitating adrenal crisis 1
• Provide emergency injectable hydrocortisone 100 mg IM kit with self-injection training 1
• Issue medical alert bracelet indicating adrenal insufficiency 1
• Educate on stress-dosing: double or triple usual dose during illness, fever, or physical stress 1

Emergency Management (If Clinically Unstable)

Never delay treatment for diagnostic testing if the patient presents with:

• Unexplained hypotension or shock 1
• Severe vomiting, diarrhea, or inability to take oral medications 1
• Marked weakness, confusion, or altered mental status 1

Immediate Treatment Protocol:

• Administer 100 mg IV hydrocortisone bolus immediately 1
• Infuse 0.9% saline at 1 L/hour (at least 2L total) 1
• Draw blood for cortisol and ACTH before steroid administration if feasible, but do NOT delay treatment 1

Common Pitfalls to Avoid

• Do not rely on ACTH alone—the ACTH-cortisol relationship is what matters diagnostically 1
• Do not check cortisol levels in patients actively taking corticosteroids—the assay measures both endogenous and therapeutic steroids, yielding uninterpretable results 1
• Do not use only the 30-minute cortisol value on cosyntropin testing, as this misses 11% of patients who peak at 60 minutes 5
• Do not assume normal electrolytes exclude adrenal insufficiency—hyperkalemia occurs in only ~50% of primary adrenal insufficiency cases, and secondary adrenal insufficiency typically has normal potassium 1
• Do not attempt diagnostic testing immediately after stopping long-term glucocorticoids—wait 3 months for HPA axis recovery testing 1