In a patient with a 3 mm pituitary incidental microadenoma, low‑normal morning serum cortisol (~6 µg/dL) and normal ACTH (~18 pg/mL) awaiting prolactin results, what is the appropriate next step in evaluation and management?

Evaluation of Pituitary Microadenoma with Low-Normal Cortisol and Normal ACTH

Your patient's morning cortisol of 6.4 µg/dL and ACTH of 18 pg/mL do NOT indicate Cushing's disease or hypercortisolism—these values are actually low-normal to borderline low, and the next critical step is to obtain the prolactin level and perform a high-resolution pituitary MRI to characterize the microadenoma. 1

Understanding the Biochemical Picture

• A morning cortisol of ~6 µg/dL is at the lower end of normal (normal range typically 5-25 µg/dL), and this level does not suggest autonomous cortisol excess or Cushing's syndrome 2
• An ACTH level of 18 pg/mL is within the normal reference range (typically 10-60 pg/mL) and indicates the hypothalamic-pituitary-adrenal axis is functioning appropriately 1
• These values together rule out ACTH-dependent Cushing's disease, which would require both elevated cortisol (typically >15-20 µg/dL) and detectable/elevated ACTH 1
• A morning cortisol >13 µg/dL reliably rules out adrenal insufficiency, but your patient's level of 6.4 µg/dL falls below this threshold and warrants consideration of possible hypopituitarism rather than hypercortisolism 2

Diagnostic Algorithm for This Microadenoma

Immediate Next Steps

• Obtain the prolactin level to determine if this is a microprolactinoma, which accounts for 32-66% of all pituitary adenomas and is the most common functional adenoma type 3
• Order a high-resolution 3-Tesla pituitary MRI with thin slices (1 mm intervals) and gadolinium contrast to better characterize the 3 mm lesion 4, 1
• Complete a full pituitary hormone panel including: TSH, free T4, LH, FSH, testosterone (in men) or estradiol (in women), and IGF-1 to assess for other pituitary hormone deficiencies or excess 3, 5

Interpretation Based on Prolactin Results

If prolactin is elevated (>25 ng/mL in women, >20 ng/mL in men):

• This likely represents a microprolactinoma, and dopamine agonist therapy (cabergoline or bromocriptine) is the first-line treatment rather than surgery 3, 5
• Mild elevations (<100 ng/mL) may also represent "stalk effect" from any pituitary mass compressing the pituitary stalk 1

If prolactin is normal:

• This represents a clinically nonfunctioning microadenoma (incidentaloma), which accounts for 15-54% of pituitary adenomas 3
• For asymptomatic nonfunctioning microadenomas <10 mm, observation with repeat MRI in 6-12 months is appropriate rather than immediate intervention 3, 6

Addressing the Low-Normal Cortisol

• ACTH-secreting microadenomas causing Cushing's disease are paradoxically associated with a higher prevalence of central hypothyroidism (18%) due to glucocorticoid suppression of the thyroid axis 7
• However, your patient's cortisol is low, not high, making Cushing's disease extremely unlikely 1
• The combination of low-normal cortisol with normal ACTH suggests either:
  • Normal variation (cortisol was drawn at the lower end of the morning peak)
  • Early secondary adrenal insufficiency from pituitary dysfunction (though ACTH is not suppressed)
  • Need for dynamic testing if clinical suspicion for adrenal insufficiency exists 2

If Clinical Suspicion for Adrenal Insufficiency Exists

• Perform a cosyntropin stimulation test (250 mcg IV or IM) with cortisol measurements at 0,30, and 60 minutes 2
• A peak cortisol >18-20 µg/dL rules out adrenal insufficiency 2
• This is particularly important if the patient has symptoms of fatigue, weight loss, hypotension, or hyponatremia

Critical Pitfalls to Avoid

• Do not pursue Cushing's disease workup (dexamethasone suppression test, 24-hour urinary free cortisol, late-night salivary cortisol) in this patient—the biochemistry does not support hypercortisolism 4, 1
• Do not perform bilateral inferior petrosal sinus sampling (BIPSS), which is only indicated when ACTH-dependent Cushing's syndrome is confirmed biochemically and pituitary imaging is inconclusive 1
• Do not assume all pituitary microadenomas require surgery—microprolactinomas respond to medical therapy, and nonfunctioning microadenomas can be safely observed 3, 6
• Remember that tumor size does not correlate with degree of hormone secretion; even 2 mm microadenomas can cause significant Cushing's disease if they are ACTH-secreting, but this patient lacks biochemical evidence of hypercortisolism 4

Summary of Recommended Workup

1. Obtain prolactin level (most critical missing piece) 3
2. Order 3-Tesla pituitary MRI with thin slices and contrast 4, 1
3. Complete pituitary hormone panel (TSH, free T4, LH, FSH, sex hormones, IGF-1) 3, 5
4. Consider cosyntropin stimulation test if clinical features suggest adrenal insufficiency 2
5. Reassess in 6-12 months with repeat MRI and hormone testing if the adenoma is nonfunctioning and asymptomatic 6