What is the workup for hyperprolactinemia?

Workup for Hyperprolactinemia

Confirm hyperprolactinemia with a single blood sample collected at any time of day, exclude hypothyroidism and medication causes, then proceed to MRI imaging if prolactin remains elevated after excluding secondary causes. 1

Initial Laboratory Evaluation

Prolactin Measurement

• Obtain a single serum prolactin level at any time of day—timing is not critical for diagnosis. 1
• Use age-specific and sex-specific reference ranges, as normal values vary (typical upper limit ~20 μg/L or ~425 mU/L in non-pregnant adults, though women have higher baseline levels than men). 1, 2
• For modestly elevated prolactin levels, consider serial measurements taken 20-60 minutes apart using an indwelling cannula to differentiate stress-related elevation from organic disease. 1
• If the initial level is elevated, repeat the measurement in the morning with the patient fasting to confirm the diagnosis. 3

Exclude Secondary Causes

• Measure TSH to exclude primary hypothyroidism, which causes hyperprolactinemia in 43% of women and 40% of men with frank hypothyroidism. 1, 2
• Review all medications, particularly dopamine antagonists (antipsychotics, antiemetics like prochlorperazine, metoclopramide), as these are among the most common causes of hyperprolactinemia. 2
• Assess renal function (BUN, creatinine) since chronic kidney disease causes hyperprolactinemia in 30-65% of adult patients due to increased secretion and reduced clearance. 2
• Evaluate liver function in cases of severe liver disease, which is associated with hyperprolactinemia. 2
• Confirm the patient is not pregnant, as this is a physiologic cause of elevated prolactin. 3, 4

Special Laboratory Considerations

• Screen for macroprolactinemia when prolactin is mildly or incidentally elevated, as 10-40% of hyperprolactinemia cases are due to biologically inactive macroprolactin complexes. 1, 2
• For patients with large pituitary lesions but paradoxically normal or mildly elevated prolactin, request serial dilutions to detect the "high-dose hook effect," which occurs in approximately 5% of macroprolactinomas when extremely high concentrations saturate the immunoassay. 1, 5, 2
• Measure luteinizing hormone (LH) levels to help establish the etiology of hyperprolactinemia. 1

Imaging Evaluation

MRI Indications

• Perform MRI of the pituitary when prolactin levels are significantly elevated, typically >4,000 mU/l (or >188 μg/l), as this suggests a prolactinoma. 1
• MRI should be performed regardless of prolactin level if the patient has visual symptoms or signs of mass effect. 1
• MRI is indicated even with mild prolactin elevations when unexplained, as pituitary adenomas can present with only modestly elevated prolactin levels, and early detection impacts treatment outcomes. 1
• The degree of prolactin elevation correlates with tumor size: levels around 125 ng/ml typically indicate either a microprolactinoma or small macroadenoma. 5

MRI Protocol

• Use MRI without and with IV contrast for optimal visualization of pituitary lesions. 1
• MRI is preferred over CT due to better definition of very small lesions and superior anatomical detail. 6

Clinical Assessment

Symptom Evaluation

• In women: assess for menstrual irregularities (amenorrhea, oligomenorrhea), galactorrhea, infertility, and decreased libido. 5, 2
• In men: evaluate for decreased libido, erectile dysfunction, gynecomastia, and infertility. 5, 2
• In prepubertal children: look for headache, visual disturbances, growth failure, or delayed puberty. 5
• In adolescents: assess for delayed puberty, menstrual irregularities in girls, and gynecomastia in boys. 5
• If visual symptoms are present or a macroadenoma is found on MRI, perform visual field testing to assess for optic chiasm compression. 5

Interpretation of Prolactin Levels

Degree of Elevation

• Mild elevation (<100 μg/L or <2,000 mU/L) suggests non-functioning pituitary adenomas with stalk compression, medications, stress, or other secondary causes. 2
• Prolactin levels generally correlate with tumor size in prolactinomas, typically exceeding 4,000 mU/l in children and adolescents with prolactinomas. 2
• Stress alone can elevate prolactin levels up to five times the upper limit of normal. 2

Common Pitfalls

• Do not assume a large pituitary mass rules out hyperprolactinemia if prolactin appears normal or mildly elevated—always consider the hook effect and request manual dilutions. 1, 5, 2
• Among adults with macroprolactinemia, 20% still have galactorrhea, 45% have oligo-amenorrhea, and 20% have pituitary adenomas, indicating some may have concurrent true hyperprolactinemia requiring further evaluation. 2
• Pituitary stalk compression by mass lesions interrupts inhibitory dopaminergic tone, resulting in elevated prolactin levels even without a prolactinoma. 2