What is the initial step in the workup of a patient with hyperprolactinemia (elevated prolactin levels)?

Initial Workup of Elevated Prolactin

The initial step in evaluating hyperprolactinemia is to confirm the elevation with a repeat measurement (preferably morning, fasting), then immediately rule out secondary causes including medications (especially dopamine antagonists), pregnancy, primary hypothyroidism, and assess for macroprolactinemia before proceeding to pituitary imaging. 1

Step 1: Confirm the Elevation

• Repeat the prolactin measurement to exclude stress-induced or pulsatile elevation, ideally collected in the morning while fasting 1
• For modestly elevated levels, consider serial measurements 20-60 minutes apart using an indwelling cannula to differentiate stress-related hyperprolactinemia from organic disease 1, 2
• Use age-specific and sex-specific reference ranges, as prolactin concentrations vary significantly with age and sex 3, 2

Step 2: Rule Out Secondary Causes (Critical First Step)

Medication Review

• Review all medications, particularly antipsychotics and dopamine antagonists, which are among the most common causes of hyperprolactinemia 1, 3
• Common culprits include antipsychotics, metoclopramide, domperidone, and certain antidepressants 4

Screen for Medical Conditions

• Exclude pregnancy in all women of reproductive age 1
• Measure TSH to rule out primary hypothyroidism, which causes hyperprolactinemia in 40-43% of patients with frank hypothyroidism 3, 2
• Screen for chronic kidney disease and severe liver disease 1, 3
• Consider intracranial hypotension as a rare cause 1

Step 3: Assess for Macroprolactinemia

• Test for macroprolactinemia in patients with mildly or incidentally elevated prolactin, especially if asymptomatic 4, 1
• This is critical because macroprolactinemia accounts for 10-40% of hyperprolactinemia cases and represents biologically inactive prolactin complexes that do not require treatment 4, 3
• No routine assays distinguish monomeric from macroprolactin, so request secondary analysis specifically 4

Step 4: Additional Laboratory Testing

• Measure luteinizing hormone (LH) in all patients with confirmed hyperprolactinemia to help establish etiology 1, 2
• Evaluate IGF-1 levels to rule out mixed prolactin and growth hormone hypersecretion (acromegaly), particularly if clinical features suggest this diagnosis 1, 5
• In males with breast symptoms or gynecomastia, measure estradiol 1

Step 5: Assess Clinical Symptoms

Document specific symptoms that guide urgency and further workup:

• Hypogonadal symptoms: menstrual irregularities, amenorrhea, infertility, erectile dysfunction 1, 6
• Galactorrhea (though absence does not exclude prolactinoma) 1
• Mass effect symptoms: headache, visual field disturbances (require urgent imaging) 1, 2
• In children/adolescents: delayed or arrested puberty, growth failure 3

Step 6: Pituitary Imaging (When Indicated)

Indications for MRI

• Significantly elevated prolactin levels (generally >4,000 mU/L or 188 μg/L) suggesting prolactinoma 2
• Any visual symptoms or signs of mass effect, regardless of prolactin level 2
• Men with total testosterone <150 ng/dL combined with low/low-normal LH 1
• Unexplained hyperprolactinemia after excluding secondary causes, even with mild elevations 2

MRI Protocol

• MRI with and without gadolinium contrast is the imaging modality of choice, superior to CT for detecting microadenomas 2, 7, 5

Critical Pitfalls to Avoid

The "Hook Effect"

• In patients with large pituitary lesions but paradoxically normal or mildly elevated prolactin, request serial dilutions of the serum sample 4, 1
• This "high-dose hook effect" occurs in approximately 5% of macroprolactinomas when extremely high prolactin concentrations saturate the immunoassay, producing falsely low measurements 4, 3

Macroprolactinemia

• Do not initiate treatment for mild, asymptomatic hyperprolactinemia without first excluding macroprolactinemia 3
• Even though 20% of patients with macroprolactinemia may have galactorrhea or menstrual irregularities, most do not require dopamine agonist therapy 4

Premature Treatment

• Do not start dopamine agonists until secondary causes are excluded and the diagnosis is confirmed 3
• For drug-induced hyperprolactinemia where the causative medication cannot be withdrawn, dopamine agonists are often unnecessary and potentially dangerous; instead, check for absence of pituitary adenoma and consider sex steroid replacement to prevent osteoporosis 8

When to Refer to Endocrinology

• Persistently elevated prolactin of unknown etiology after initial workup 1, 3
• Confirmed prolactinoma requiring dopamine agonist therapy 1
• Men with total testosterone <150 ng/dL and low/low-normal LH 1
• Any patient with visual symptoms or large pituitary mass 1