What is the appropriate workup and management for a patient with hyperprolactinemia (elevated prolactin levels)?

Workup for Elevated Prolactin

Confirm hyperprolactinemia with a repeat fasting morning measurement, then systematically exclude secondary causes (medications, pregnancy, hypothyroidism, renal/liver disease) before pursuing pituitary imaging and considering dopamine agonist therapy. 1

Initial Confirmation and Timing

• Obtain a repeat prolactin measurement in the morning while fasting to exclude stress-induced or pulsatile elevation, as stress alone can elevate prolactin up to five times the upper limit of normal. 1, 2

• For modestly elevated levels, consider serial measurements 20-60 minutes apart using an indwelling cannula to differentiate stress-related hyperprolactinemia from organic disease. 1

• Use age-specific and sex-specific reference ranges, as normal levels are approximately <20 μg/L (<425 mU/L) for non-pregnant adults, with women having higher baseline levels than men. 2, 3

Exclude Secondary Causes First

Medication Review

• Review all medications immediately, particularly antipsychotics and dopamine antagonists, as drug-induced hyperprolactinemia is one of the most common causes. 1, 2, 4

• Common culprits include antipsychotics, antidepressants, antihypertensives, and prokinetic agents (medications that increase bowel motility). 4

Physiologic and Systemic Causes

• Exclude pregnancy in all women of reproductive age before proceeding with further workup. 2, 3

• Screen for primary hypothyroidism with TSH measurement, as it causes hyperprolactinemia in 43% of women and 40% of men with frank hypothyroidism, and 36% of women and 32% of men with subclinical hypothyroidism. 2, 3

• Assess renal function, as chronic kidney disease causes hyperprolactinemia in 30-65% of patients due to increased secretion and reduced renal clearance. 2, 3

• Evaluate for severe liver disease, which is also associated with hyperprolactinemia. 2, 3

Screen for Macroprolactinemia

• Perform polyethylene glycol (PEG) precipitation testing when prolactin is mildly or incidentally elevated, especially in asymptomatic patients. 1, 3, 5

• Macroprolactinemia accounts for 10-40% of all hyperprolactinemia cases and represents biologically inactive prolactin complexes that may not require treatment. 1, 2, 5

• Do not dismiss macroprolactinemia as benign without further evaluation: 20% of patients with macroprolactinemia have coexisting pituitary adenomas, 20% have galactorrhea, 45% have oligo-amenorrhea, and 20% have pituitary adenomas. 2, 3

Assess Clinical Symptoms

• Evaluate for delayed or arrested puberty, visual field disturbances, menstrual irregularities or amenorrhea, hypogonadism, infertility, galactorrhea, and headaches. 1, 2

• Visual field defects occur when macroadenomas compress the optic chiasm. 2

Laboratory Testing

• Measure luteinizing hormone (LH) levels in all patients with confirmed hyperprolactinemia to assess for hypogonadotropic hypogonadism. 1

• Measure estradiol in male patients with breast symptoms or gynecomastia. 1

• Evaluate IGF-1 levels to rule out mixed prolactin and growth hormone hypersecretion. 1

Pituitary Imaging

• Obtain pituitary MRI with contrast after excluding secondary causes, particularly when prolactin levels are significantly elevated. 1, 3

• MRI is indicated in men with total testosterone <150 ng/dL combined with low/low-normal LH, regardless of prolactin level. 1

• Prolactin levels generally correlate with tumor size: levels >250 ng/mL (or >4,000 mU/L in children/adolescents) are highly suggestive of prolactinomas. 2, 3, 5

• Levels <100 ng/mL suggest non-functioning pituitary adenomas, drug-induced hyperprolactinemia, macroprolactinemia, or systemic diseases, though up to 25% of microprolactinomas or cystic macroprolactinomas may present with levels <100 ng/mL. 2, 5

Critical Pitfall: The Hook Effect

• Always check for the "hook effect" when large pituitary lesions (≥3 cm) show paradoxically normal or mildly elevated prolactin levels (≤250 ng/mL). 1, 2, 3, 5

• This occurs in approximately 5% of macroprolactinomas due to assay saturation at very high prolactin concentrations. 1, 2

• Request manual serial dilutions (1:100) of the serum sample to unmask falsely low prolactin levels. 1, 3, 5

Treatment Approach

First-Line Medical Therapy

• Dopamine agonists are first-line treatment for prolactinomas to reduce serum prolactin and induce tumor shrinkage. 1, 6

• Cabergoline is preferred over bromocriptine due to superior effectiveness (>80% normalization rate), better tolerability, and convenient dosing (once or twice weekly vs. daily). 1, 3, 6, 7, 8

• Bromocriptine remains an option but has more side effects and requires daily dosing. 9, 6

Monitoring During Treatment

• Measure prolactin levels 1-3 months after initiating treatment and every 3-6 months until stabilized. 1, 3

• For macroprolactinomas, repeat MRI 3-6 months after starting treatment; for microprolactinomas, re-imaging depends on clinical and biochemical follow-up. 1, 8

• Perform echocardiographic surveillance every 6-12 months for patients on cabergoline to monitor for cardiac valvulopathy, particularly at doses >2 mg/week. 3, 10

Important Safety Considerations

• All patients should undergo baseline cardiovascular evaluation including echocardiogram before starting cabergoline, as postmarketing cases of cardiac valvulopathy have been reported, particularly with high doses (>2 mg/day) for Parkinson's disease. 10

• Cabergoline should be discontinued if echocardiogram reveals new valvular regurgitation, restriction, or leaflet thickening. 10

• Monitor for extracardiac fibrotic reactions (pleural, pericardial, retroperitoneal fibrosis) with clinical and diagnostic monitoring including chest x-ray, erythrocyte sedimentation rate, and serum creatinine. 10, 9

Pregnancy Considerations

• Withdraw dopamine agonists when pregnancy is diagnosed unless managing a rapidly expanding macroadenoma. 9

• Bromocriptine has the most safety data for use in early pregnancy, while cabergoline and quinagolide have good safety profiles but less extensive evidence. 6, 8

• Do not initiate testosterone therapy until prolactinoma is excluded or treated, as it does not address underlying pituitary pathology. 1

Referral Indications

• Refer to endocrinology for persistently elevated prolactin levels of unknown etiology after excluding common causes. 1

• Refer men with total testosterone <150 ng/dL and low/low-normal LH. 1

• Consider neurosurgical evaluation for patients who refuse or fail medical therapy, or have evidence of mass effect despite treatment. 6, 7

Special Populations

Asymptomatic Microprolactinomas

• No treatment is required for asymptomatic microprolactinomas; organize regular follow-up with serial prolactin measurements and pituitary imaging, as growth is uncommon. 6, 7

Drug-Induced Hyperprolactinemia

• If the causative medication cannot be withdrawn, confirm absence of pituitary adenoma and consider sex steroid replacement to prevent osteoporosis rather than adding a dopamine agonist. 8