What is the next step in managing a patient with chronic fatigue, low testosterone, and lab results suggesting possible adrenal insufficiency, including a low Adrenocorticotropic hormone (ACTH) level?

Management of Suspected Secondary Adrenal Insufficiency with Low ACTH

The immediate next step is to perform a cosyntropin (ACTH) stimulation test to confirm the diagnosis of adrenal insufficiency before initiating treatment or further imaging. 1

Diagnostic Priority: Confirm Adrenal Insufficiency First

The low ACTH level with chronic fatigue strongly suggests secondary adrenal insufficiency (central origin), not primary adrenal disease. 1 This is a critical distinction because:

• Low ACTH with low cortisol indicates a pituitary or hypothalamic problem, not an adrenal gland problem 1
• The planned adrenal MRI is not the appropriate next imaging study - if imaging is needed after confirmation, it should be pituitary MRI, not adrenal imaging 1
• Secondary adrenal insufficiency requires only glucocorticoid replacement, not mineralocorticoid replacement 1

Perform the Cosyntropin Stimulation Test

Administer 0.25 mg (250 mcg) cosyntropin intramuscularly or intravenously, then measure serum cortisol at 30 and 60 minutes post-administration. 1 The high-dose test is preferred over low-dose testing due to easier administration, comparable diagnostic accuracy, and FDA approval. 1

Interpretation:

• Peak cortisol <500 nmol/L (<18 μg/dL) is diagnostic of adrenal insufficiency 1, 2
• Peak cortisol >550 nmol/L (>20 μg/dL) is normal 1

Critical timing consideration: This test should be performed in the morning, preferably before 9 AM, though not strictly mandatory. 1 Obtain a baseline cortisol and ACTH sample before administering cosyntropin. 1

Important Pitfall to Avoid

Do NOT order an adrenal MRI as the next step. 3 The low ACTH indicates the problem originates in the brain (pituitary or hypothalamus), not the adrenal glands. The adrenal glands are likely atrophied from chronic understimulation, not diseased. If imaging is warranted after confirming the diagnosis, order a pituitary MRI to evaluate for pituitary adenoma, empty sella, or other structural lesions causing ACTH deficiency. 1

Management Based on Test Results

If Adrenal Insufficiency is Confirmed (Peak Cortisol <500 nmol/L):

Initiate glucocorticoid replacement therapy immediately:

• Hydrocortisone 15-25 mg daily in divided doses (typical regimen: 10 mg at 7 AM, 5 mg at noon, 2.5-5 mg at 4 PM) 1
• Alternative: Prednisone 4-5 mg daily in select patients 1
• Do NOT add fludrocortisone - secondary adrenal insufficiency does not cause mineralocorticoid deficiency because the renin-angiotensin-aldosterone system remains intact 1

Mandatory patient education:

• Provide stress-dosing instructions (double or triple dose during illness, fever, or physical stress) 1
• Prescribe hydrocortisone 100 mg IM injection kit with self-injection training 1
• Medical alert bracelet indicating adrenal insufficiency 1, 2

Refer to endocrinology for:

• Pituitary MRI to identify the underlying cause of ACTH deficiency 1
• Evaluation of other pituitary hormone deficiencies (TSH, LH, FSH, prolactin, growth hormone) 4
• Long-term management and monitoring 1

If Test is Normal (Peak Cortisol >550 nmol/L):

Consider alternative diagnoses for chronic fatigue, though note that some patients with chronic fatigue syndrome demonstrate mild central adrenal insufficiency with attenuated ACTH responses despite normal stimulation testing. 5 The low ACTH in this patient makes true adrenal insufficiency more likely than chronic fatigue syndrome alone.

Addressing the Low Testosterone

Defer testosterone replacement until the adrenal insufficiency workup is complete. 1 This is appropriate because:

• Low testosterone may be secondary to pituitary dysfunction (same cause as low ACTH) 1
• Treating hypothyroidism or initiating testosterone before addressing adrenal insufficiency can precipitate adrenal crisis 1
• Once glucocorticoid replacement is established, reassess testosterone and consider replacement if it remains low 1

Timeline for Follow-Up

• Return for cosyntropin test when schedule permits (should be prioritized within 1-2 weeks given significant fatigue impacting function)
• If confirmed adrenal insufficiency: Start treatment immediately and schedule endocrinology referral within 2-4 weeks 1
• Follow-up in 1 month to review endocrinology recommendations and assess treatment response 2

Red Flags Requiring Emergency Treatment

If the patient develops any of the following before testing, treat immediately with IV hydrocortisone 100 mg and do not delay for diagnostic procedures: 1

• Unexplained collapse or severe hypotension
• Persistent vomiting or diarrhea
• Altered mental status
• Fever with hemodynamic instability

In emergency situations where you need to treat but still want diagnostic testing later, use dexamethasone 4 mg IV instead of hydrocortisone, as dexamethasone does not interfere with cortisol assays. 1