What is the initial step in the workup for a patient with hyperprolactinemia?

Initial Workup for Elevated Prolactin

The initial step in evaluating hyperprolactinemia is to confirm the diagnosis with a single serum prolactin measurement (collected at any time of day), followed immediately by excluding the three most common secondary causes: medication use (particularly dopamine antagonists), primary hypothyroidism (TSH and free T4), and macroprolactinemia. 1, 2

Step 1: Confirm Hyperprolactinemia

• Obtain a single serum prolactin measurement at any time of day—timing is not critical for diagnosis 2
• Use age-specific and sex-specific reference ranges, as prolactin levels vary by age and sex (higher in first 2 years of life, lowest in mid-childhood, rising again in adolescence with higher levels in females) 1, 2
• For modestly elevated levels, consider serial measurements taken 20-60 minutes apart using an indwelling cannula to exclude stress-related transient elevation 1, 2
• Note that stress alone can elevate prolactin up to five times the upper limit of normal 3

Step 2: Exclude Secondary Causes (Before Any Imaging)

Medication Review

• Review all medications thoroughly, as drugs are among the most common causes of hyperprolactinemia 1, 3, 4
• Specifically identify dopamine antagonists (antipsychotics, antiemetics like prochlorperazine), antidepressants, antihypertensives, and prokinetic agents 1, 3, 4
• Medication-induced hyperprolactinemia is commonly symptomatic, causing galactorrhea, menstrual disturbances, and sexual dysfunction 4

Thyroid Function Testing

• Measure TSH and free T4 to exclude primary hypothyroidism, which causes hyperprolactinemia in 43% of women and 40% of men with frank hypothyroidism 1, 2
• Hypothyroidism causes compensatory hypersecretion of thyrotropin-releasing hormone, which stimulates prolactin release and can produce pituitary hyperplasia mimicking a prolactinoma 3

Macroprolactin Assessment

• Screen for macroprolactinemia when prolactin is mildly or incidentally elevated, as it accounts for 10-40% of all hyperprolactinemia cases 1, 3
• Macroprolactin represents biologically inactive prolactin complexes with low clinical significance 1
• Among adults with macroprolactinemia, 20% still have galactorrhea and 20% have pituitary adenomas, indicating some may have concurrent true hyperprolactinemia 3

Additional Secondary Causes to Consider

• Assess for chronic kidney disease (associated with hyperprolactinemia in 30-65% of adult patients) and severe liver disease 3
• Consider pregnancy as a physiologic cause in women of reproductive age 5

Step 3: Determine Need for Pituitary Imaging

When to Proceed with MRI

• Order MRI of the pituitary (without and with IV contrast) when prolactin levels are significantly elevated (typically >4,000 mU/L or 188 μg/L, approximately >100 ng/mL) after excluding secondary causes 2
• The degree of prolactin elevation correlates with tumor size: levels around 125 ng/mL typically indicate either a microprolactinoma or small macroadenoma 1
• Perform MRI regardless of prolactin level if the patient has visual symptoms, signs of mass effect, or other pituitary hormone deficiencies 2
• MRI is indicated even for mild elevations when unexplained, as pituitary adenomas can present with modestly elevated prolactin levels 2

Critical Pitfall: The "Hook Effect"

• If a large pituitary mass is found on MRI but prolactin seems disproportionately low for tumor size (normal or mildly elevated), request serial dilutions of the serum sample 1, 3
• The "hook effect" occurs in approximately 5% of macroprolactinomas, where extremely high prolactin concentrations saturate the immunoassay, producing falsely low measurements 1, 3

Step 4: Additional Diagnostic Considerations

• Measure luteinizing hormone (LH) levels to help establish the etiology of hyperprolactinemia and assess for hypogonadotropic hypogonadism 2
• If a macroadenoma is confirmed, perform visual field testing to assess for optic chiasm compression 1
• Prolactinomas are the most common pathological cause of chronic hyperprolactinemia once pregnancy, hypothyroidism, and medications are excluded 5

Common Pitfalls to Avoid

• Do not assume hyperprolactinemia is related to other conditions without excluding medications, macroprolactinemia, and stress first 1
• Do not start dopamine agonist therapy for mild, asymptomatic hyperprolactinemia without completing the diagnostic workup 1
• Do not order MRI before excluding hypothyroidism and medication causes, as these are more common and easily treatable 2
• Treatment is only indicated if macroprolactinemia is excluded, medication causes are ruled out, and the patient develops symptomatic hyperprolactinemia or prolactin levels rise significantly 1