What's the next step in testing and management for a patient with low adrenocorticotropic hormone (ACTH) levels, normal cortisol levels, normal luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels, a controlled microprolactinoma on cabergoline (dopamine agonist), and normalized prolactin levels?

Next Steps in Testing and Management

The next step is to perform an ACTH stimulation test (cosyntropin 0.25 mg) to definitively confirm or exclude secondary adrenal insufficiency, as the combination of low ACTH with normal cortisol is indeterminate and requires dynamic testing to establish whether the patient has true adrenal insufficiency or intact adrenal reserve. 1

Diagnostic Rationale

The clinical scenario presents a diagnostic challenge:

• Low ACTH with normal cortisol is not diagnostic of secondary adrenal insufficiency—it represents an indeterminate result that requires confirmatory testing 1, 2
• The patient has a known pituitary lesion (microprolactinoma), which can cause secondary adrenal insufficiency through ACTH deficiency, even when controlled on cabergoline 1
• Morning cortisol levels alone cannot distinguish between adequate adrenal reserve and partial ACTH deficiency 1, 2

ACTH Stimulation Test Protocol

Perform the standard high-dose cosyntropin stimulation test: 2

• Administer 0.25 mg (250 mcg) cosyntropin IV or IM 2
• Measure baseline serum cortisol before administration 2
• Measure cortisol at exactly 30 and 60 minutes post-administration 2
• Peak cortisol <500 nmol/L (<18 mcg/dL) confirms adrenal insufficiency 1, 2
• Peak cortisol >550 nmol/L (>18-20 mcg/dL) excludes adrenal insufficiency 1, 2

The high-dose test is preferred over the low-dose (1 mcg) test due to easier practical administration, comparable diagnostic accuracy, and FDA approval 2

Additional Pituitary Hormone Evaluation

Assess for other pituitary hormone deficiencies beyond what has already been tested: 3, 1

• TSH and free T4 to evaluate for central hypothyroidism 3, 1
• IGF-1 to screen for growth hormone deficiency 3
• Morning testosterone (in men) or estradiol (in premenopausal women) if not already done, to fully characterize hypogonadotropic hypogonadism 3, 1
• Serum and urine osmolality with electrolytes to screen for diabetes insipidus 3

While LH and FSH are reported as normal, the presence of a pituitary lesion warrants comprehensive evaluation for hypopituitarism, as multiple hormone deficiencies can coexist 3, 1

Neuroimaging Considerations

Obtain MRI of the brain with pituitary/sellar cuts if not recently performed: 3, 1

• Evaluate for interval change in the microprolactinoma size despite cabergoline therapy 3
• Assess for compression of the normal pituitary gland or stalk, which could explain ACTH deficiency 3
• Rule out other pituitary pathology (e.g., additional adenomas, hypophysitis, infiltrative disease) 3, 1

This is particularly important given the low ACTH, as pituitary lesions can cause progressive hormone deficiencies over time 3, 1

Management Based on Test Results

If ACTH Stimulation Test Confirms Secondary Adrenal Insufficiency:

Initiate glucocorticoid replacement therapy: 1

• Hydrocortisone 15-20 mg in the morning and 5-10 mg in early afternoon (preferred regimen to mimic diurnal rhythm) 3, 1
• Alternative: Prednisone 4-5 mg daily if hydrocortisone is not tolerated 1
• Do NOT add mineralocorticoid replacement (fludrocortisone), as the renin-angiotensin-aldosterone system remains intact in secondary adrenal insufficiency 1, 4

Critical management principles: 3, 1

• If concurrent central hypothyroidism is present, start corticosteroids several days before initiating thyroid hormone replacement to prevent precipitating adrenal crisis 3, 1
• Provide mandatory patient education on stress dosing (doubling or tripling doses during illness, surgery, or significant stress) 3, 1
• Prescribe emergency injectable hydrocortisone 100 mg IM kit with self-injection training 1
• Ensure patient obtains a medical alert bracelet indicating adrenal insufficiency 3, 1
• Arrange endocrine consultation for optimization of therapy and long-term management 3, 1

If ACTH Stimulation Test Excludes Adrenal Insufficiency:

• The low ACTH likely represents physiologic variation or mild HPA axis suppression without clinical significance 1
• Continue cabergoline for the microprolactinoma as currently managed 5
• Monitor prolactin levels and repeat MRI as per standard prolactinoma surveillance 5
• Reassess pituitary function annually or if new symptoms develop 1

Critical Pitfalls to Avoid

• Never delay treatment if the patient develops symptoms of acute adrenal crisis (hypotension, collapse, severe vomiting)—immediately administer IV hydrocortisone 100 mg and 0.9% saline infusion without waiting for test results 3, 1, 2
• Do not rely on electrolyte abnormalities to make or exclude the diagnosis—hyponatremia without hyperkalemia is characteristic of secondary adrenal insufficiency, but normal electrolytes do not rule it out 2, 4
• Do not diagnose SIADH in a patient with hyponatremia without first excluding adrenal insufficiency, as the clinical presentations can be nearly identical 2, 4
• Avoid checking morning cortisol levels while the patient is on glucocorticoid therapy, as this will yield false-positive results showing "adrenal insufficiency" that simply reflects expected HPA suppression 2

Cabergoline Considerations

The patient's microprolactinoma is well-controlled on cabergoline with normalized prolactin levels:

• Continue current cabergoline therapy as it is effective and well-tolerated 5, 6
• Cabergoline does not directly cause adrenal insufficiency, but the underlying pituitary lesion may 5
• After 6 months of normal prolactin levels, consider whether cabergoline can be discontinued with periodic monitoring, though this decision should be deferred until the adrenal axis is fully evaluated 5
• Monitor for impulse control disorders (pathological gambling, hypersexuality, compulsive spending) as rare but important adverse effects of dopamine agonists 5