What is the likely diagnosis and recommended management for a patient with secondary adrenal insufficiency, elevated insulin‑like growth factor‑1, mild hyperprolactinemia, and a pituitary MRI that shows no discrete mass?

Likely Diagnosis: Pituitary Microadenoma with Stalk Effect

The most likely diagnosis is a pituitary microadenoma causing stalk compression ("stalk effect"), which explains the constellation of secondary adrenal insufficiency, elevated IGF-1, and mild hyperprolactinemia despite a normal MRI. 1, 2

Understanding the Clinical Picture

Why the MRI May Appear Normal

• Microadenomas (<10 mm) can be below MRI detection limits, particularly when standard imaging protocols are used rather than dedicated pituitary protocols with thin cuts and dynamic contrast enhancement 1
• Stalk compression from even small adenomas can cause mild hyperprolactinemia, typically below 2,000 mU/L (94 μg/L), which is a well-recognized phenomenon 1
• The absence of a visible mass does not exclude a functioning or non-functioning pituitary adenoma, especially in the context of biochemical hypopituitarism 1

The Biochemical Pattern Points to Pituitary Disease

• Secondary adrenal insufficiency indicates ACTH deficiency from hypothalamic-pituitary dysfunction 3, 4
• Elevated IGF-1 with mild hyperprolactinemia suggests either:
  • A mixed GH-prolactin secreting adenoma (plurihormonal tumor) 1
  • Separate microadenomas causing stalk compression 1
  • A GH-secreting adenoma with stalk effect causing the hyperprolactinemia 5

Immediate Diagnostic Steps

Critical Laboratory Testing

• Measure serum dilutions for prolactin to rule out the "hook effect," which occurs in ~5% of cases and produces falsely low prolactin readings when levels are extremely high 2, 6
• Assess for macroprolactinemia (accounts for 10-40% of hyperprolactinemia cases) through secondary analysis, as this represents biologically inactive prolactin complexes 2, 6
• Obtain oral glucose tolerance test (OGTT) with GH measurements to confirm GH excess, as elevated IGF-1 alone warrants evaluation for acromegaly 5
• Complete anterior pituitary axis assessment including TSH, free T4, LH, FSH, testosterone/estradiol, and morning cortisol with ACTH 1, 4

Exclude Secondary Causes

• Rule out primary hypothyroidism (causes hyperprolactinemia in 43% of women and 40% of men with frank hypothyroidism) 6, 7
• Review all medications, particularly antipsychotics, antidepressants, and dopamine antagonists 2, 6
• Assess for chronic kidney disease and severe liver disease as alternative causes 6

Advanced Imaging

• Repeat pituitary MRI with dedicated pituitary protocol: thin-slice (2-3 mm) imaging with dynamic contrast enhancement and coronal/sagittal views 1
• If second MRI remains normal but clinical suspicion is high, consider:
  • Repeat imaging in 3-6 months to detect interval growth 1
  • Inferior petrosal sinus sampling if ACTH-dependent Cushing's is in the differential 4

Management Algorithm

Step 1: Immediate Corticosteroid Replacement

• Initiate hydrocortisone replacement immediately for confirmed secondary adrenal insufficiency to prevent adrenal crisis 8, 9
• Standard dosing: hydrocortisone 15-25 mg daily in divided doses (typically 10 mg morning, 5 mg afternoon) 9
• Do not delay treatment while pursuing further diagnostic workup 9

Step 2: Address the Elevated IGF-1

• If OGTT confirms GH excess (failure to suppress GH <1 ng/mL), this represents acromegaly requiring treatment 5
• First-line therapy for GH-secreting adenomas: transsphenoidal surgery for microadenomas or somatostatin analogues if surgery is not feasible 1
• Monitor for tumor growth with serial MRI every 3-6 months initially 1, 7

Step 3: Manage Hyperprolactinemia

• If prolactin remains elevated after excluding macroprolactinemia and secondary causes:
  • Dopamine agonist therapy (cabergoline preferred over bromocriptine) is first-line treatment 2, 6
  • Cabergoline typically normalizes prolactin in 74% of cases and can shrink tumors 6
• Monitor prolactin levels every 3-6 months during the first year of treatment 6, 7

Step 4: Surveillance Protocol

• For confirmed pituitary pathology without visible mass:
  • Repeat MRI at 6-12 months, then annually if stable 1
  • Biochemical monitoring every 3-6 months (prolactin, IGF-1, cortisol, other deficient axes) 6, 7
  • Visual field testing if any mass becomes apparent 6

Critical Pitfalls to Avoid

The "Hook Effect" Trap

• Do not assume prolactin is only mildly elevated without requesting serial dilutions, especially if clinical features suggest a larger tumor burden 2, 6
• This assay artifact can mask macroprolactinomas by producing falsely low readings 2

Macroprolactinemia Misdiagnosis

• Do not initiate dopamine agonist therapy without excluding macroprolactinemia first 2, 6
• Macroprolactin is biologically inactive and generally does not require treatment 2

Delayed Diagnosis of Acromegaly

• Marginal IGF-1 elevations with hyperprolactinemia mandate evaluation for acromegaly, as mixed GH-prolactin tumors are well-described 5
• Early detection improves surgical cure rates 5

Inadequate Imaging Protocol

• Standard brain MRI is insufficient—dedicated pituitary protocol with thin cuts and dynamic contrast is essential 1
• Microadenomas are frequently missed on routine imaging 1

Special Considerations

If All Testing Remains Negative

• Consider idiopathic isolated ACTH deficiency, a rare but recognized entity that can present without identifiable pituitary pathology 8, 4
• Maintain high clinical suspicion and continue surveillance, as tumors may declare themselves over time 4, 5
• Genetic testing for familial pituitary adenoma syndromes (MEN1, AIP variants) should be considered even without family history 1, 6

Monitoring for Disease Progression

• Hypopituitarism can evolve—patients with one pituitary hormone deficiency are at risk for developing additional deficiencies 4
• Annual comprehensive pituitary function testing is warranted 1, 4