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

Workup for Elevated Prolactin

Confirm hyperprolactinemia with a repeat fasting morning measurement, then systematically exclude secondary causes (medications, pregnancy, hypothyroidism, renal/hepatic disease) before proceeding to imaging and specialized testing. 1

Initial Confirmation and Timing

• Repeat prolactin measurement preferably in the morning while fasting to exclude stress-induced or pulsatile elevation 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 2
• Note that stress alone can elevate prolactin up to five times the upper limit of normal 3

Exclude Secondary Causes First

Before any imaging or specialized testing, systematically rule out these common causes:

• Pregnancy - must be excluded in all women of reproductive age 1
• Medications - particularly antipsychotics and dopamine antagonists, which are among the most common causes of hyperprolactinemia 1, 3
• Primary hypothyroidism - check TSH, as hypothyroidism causes hyperprolactinemia in 43% of women and 40% of men with primary hypothyroidism 3
• Chronic kidney disease - associated with hyperprolactinemia in 30-65% of adult patients 3
• Severe liver disease - can cause elevated prolactin 3

Clinical Assessment

Assess for specific symptoms that indicate the severity and impact:

• In women: amenorrhea/oligomenorrhea, galactorrhea, infertility, anovulation 1, 3
• In men: decreased libido, erectile dysfunction, infertility, gynecomastia 1, 3
• Mass effect symptoms: visual field disturbances, headaches, delayed/arrested puberty 1

Laboratory Testing

Measure the following hormones to establish etiology and assess for associated conditions:

• Luteinizing hormone (LH) - measure in all patients with confirmed hyperprolactinemia to help establish etiology 1, 2
• TSH - to exclude hypothyroidism before confirming diagnosis 2
• IGF-1 - to rule out mixed prolactin and growth hormone hypersecretion 1
• Estradiol - in male patients with breast symptoms or gynecomastia 1

Specialized Prolactin Testing

Screen for macroprolactinemia in patients with mildly or incidentally elevated prolactin, especially if asymptomatic 1, 4

• Macroprolactinemia accounts for 10-40% of all hyperprolactinemia cases and represents biologically inactive prolactin complexes 1, 3, 4
• Up to 40% of macroprolactinemic patients may still present with hypogonadism symptoms, infertility, or galactorrhea, so screening is indicated even in symptomatic patients 4

For large pituitary lesions with paradoxically normal or mildly elevated prolactin (<250 ng/mL), request serial dilutions (1:100) to rule out the "hook effect" 1, 4

• The hook effect occurs in approximately 5% of macroprolactinomas due to assay saturation at very high concentrations 3, 4
• This causes falsely low prolactin measurements in patients with very high actual levels 4

Imaging Guidelines

Obtain pituitary MRI with contrast when:

• Prolactin levels are significantly elevated (>4,000 mU/L or >188 μg/L), suggesting a prolactinoma 2
• Visual symptoms or signs of mass effect are present, regardless of prolactin level 2
• In men with total testosterone <150 ng/dL combined with low/low-normal LH 1
• After excluding common secondary causes in patients with persistently elevated prolactin 1

Interpreting prolactin levels in relation to imaging findings:

• Prolactin >250 ng/mL is highly suggestive of prolactinoma and virtually excludes non-functioning pituitary adenomas 4
• Most patients with non-functioning adenomas, drug-induced hyperprolactinemia, or macroprolactinemia have prolactin <100 ng/mL 4
• However, up to 25% of microprolactinomas or cystic macroprolactinomas may also have prolactin <100 ng/mL 4

Referral Indications

Refer to endocrinology when:

• Persistently elevated prolactin levels after excluding common causes 1
• Men with total testosterone <150 ng/dL and low/low-normal LH 1
• Confirmed prolactinoma requiring dopamine agonist therapy 1

Critical Pitfalls to Avoid

• Do not miss the hook effect - always request dilutions for large tumors with unexpectedly low prolactin 1, 4
• Do not overlook macroprolactinemia - present in 10-40% of cases and may not require treatment 1, 4
• Do not initiate testosterone therapy until prolactinoma is excluded or treated, as it does not address underlying pituitary pathology 1
• Do not forget fertility assessment - measure FSH and perform semen analysis before any treatment if fertility is desired, as testosterone therapy suppresses spermatogenesis 1