What is the diagnosis and treatment for hyperprolactinemia (elevated prolactin levels)?

Diagnosis and Management of Hyperprolactinemia

Initial Diagnostic Approach

Confirm hyperprolactinemia with a single blood sample collected at any time of day, as timing is not critical for diagnosis. 1

Confirmatory Testing

• For modestly elevated prolactin levels, obtain serial measurements 20-60 minutes apart using an indwelling cannula to differentiate stress-related elevation from organic disease 1
• Use age-specific and sex-specific reference ranges, as prolactin concentrations vary significantly with age and sex 1
• Consider repeat sampling on a different day if initial elevation is modest to exclude stress-induced elevation 2

Exclude Secondary Causes Before Confirming Diagnosis

• Rule out pregnancy - essential first step in all women of reproductive age 2, 3
• Exclude primary hypothyroidism - can cause hyperprolactinemia and must be tested before confirming diagnosis 1, 4, 3
• Review all medications - dopamine antagonists are among the most common causes of hyperprolactinemia 4, 2
• Assess for renal failure - chronic kidney disease causes hyperprolactinemia in 30-65% of adult patients 4, 3
• Evaluate for severe liver disease - associated with hyperprolactinemia in adults 4

Screen for Macroprolactinemia

• Screen for macroprolactin in cases of mild or incidental elevation, as 10-40% of hyperprolactinemia in adults is due to macroprolactin 1, 3
• Up to 40% of macroprolactinemic patients may present with hypogonadism symptoms, infertility, and/or galactorrhea, so screening is indicated even in symptomatic patients 3

Interpret Prolactin Levels to Guide Diagnosis

• Prolactin >4,000 mU/L (>188 μg/L) strongly suggests a prolactinoma in pediatric populations 1, 2
• Prolactin >250 ng/mL is highly suggestive of prolactinomas and virtually excludes nonfunctioning pituitary adenomas 3
• Prolactin <100 ng/mL is most consistent with nonfunctioning adenomas, drug-induced hyperprolactinemia, macroprolactinemia, or systemic diseases, though up to 25% of microprolactinomas or cystic macroprolactinomas may present with these levels 3

Check for Hook Effect

• For patients with large pituitary lesions (≥3 cm) but paradoxically normal or mildly elevated prolactin (≤250 ng/mL), perform serial dilutions (1:100 serum sample dilution) to detect the "high-dose hook effect" 1, 3

Imaging Guidelines

Obtain pituitary MRI when prolactin levels are significantly elevated (typically >4,000 mU/L or 188 μg/L) suggesting a prolactinoma, or when visual symptoms or signs of mass effect are present regardless of prolactin level. 1, 2

• MRI is preferred over CT due to better definition of very small lesions and superior anatomical detail 5
• MRI of the pituitary is indicated even with mild elevations of unexplained hyperprolactinemia, as pituitary adenomas can present with only modestly elevated prolactin levels 1

Additional Laboratory Testing

• Measure luteinizing hormone (LH) levels in all patients with confirmed hyperprolactinemia to help establish etiology 1, 2
• Patients with significantly low hormone levels combined with low or low-normal LH should undergo pituitary MRI regardless of prolactin levels 1

Medical Treatment

Dopamine agonists are the first-line treatment for hyperprolactinemia, with cabergoline being superior to bromocriptine in both efficacy and tolerability. 6, 7

Cabergoline (Preferred Agent)

• More effective and better tolerated than bromocriptine, with once or twice weekly dosing due to long duration of action 6, 7
• Normalizes prolactin levels and restores ovulatory cycles in over 80% of cases 8
• Use the lowest effective dose and periodically reassess the need for continuing therapy 9

Monitoring Requirements for Cabergoline

• Baseline cardiovascular evaluation including echocardiogram to assess for valvular disease before initiating treatment 9
• Routine echocardiographic monitoring every 6-12 months or as clinically indicated with signs/symptoms such as edema, new cardiac murmur, dyspnea, or congestive heart failure 9
• Discontinue cabergoline if echocardiogram reveals new valvular regurgitation, valvular restriction, or valve leaflet thickening 9
• Risk of cardiac valvulopathy is primarily associated with high doses (>2 mg/day) used for Parkinson's disease; persons with hyperprolactinemia treated with cabergoline did not have elevated risk of cardiac valvular regurgitation 9

Fibrotic Complications Warning

• Monitor for pleural, pericardial, and retroperitoneal fibrosis with clinical and diagnostic monitoring (chest x-ray, CT scan, erythrocyte sedimentation rate, serum creatinine) at baseline and as necessary 9
• Watch for manifestations including dyspnea, persistent cough, chest pain, back pain, lower limb edema, and impaired kidney function 9
• Discontinue if fibrotic changes are diagnosed or suspected 9

Bromocriptine (Alternative Agent)

• Usually given once or twice daily 7
• Remains the treatment of choice in hyperprolactinemic women wishing to conceive due to more extensive safety data during pregnancy 6
• Less well-tolerated than cabergoline, with higher rates of nausea and vomiting 8, 7
• Should be taken with food due to high percentage of subjects who vomit under fasting conditions 10

Monitoring Requirements for Bromocriptine

• Periodic blood pressure monitoring, particularly during the first weeks of therapy 10
• Monitor for symptomatic hypotension, which can occur in almost 30% of patients 10
• Watch for severe, progressive, or unremitting headache (with or without visual disturbance) or evidence of CNS toxicity 10
• Monitor for pleural and pericardial effusions, pulmonary fibrosis, constrictive pericarditis, and retroperitoneal fibrosis, particularly with long-term and high-dose treatment 10

Contraindications and Warnings for Bromocriptine

• Should not be used in patients with uncontrolled hypertension or for prevention of physiological lactation 10
• Rare but serious adverse events including hypertension, myocardial infarction, seizures, and stroke have been reported in postpartum women 10
• Withdraw when pregnancy is diagnosed in patients being treated for hyperprolactinemia 10

Treatment Resistance

• In resistant cases (failure to normalize prolactin or restore gonadal function), switch to a different dopamine agonist 8
• In cases of intolerance to one dopamine agonist, try another agent 8

MRI Monitoring During Treatment

For Macroprolactinomas

• Perform MRI after 3 months of treatment to verify tumor size reduction 8
• Repeat MRI after 1 year, then yearly for the next 5 years 8
• If adenoma size is stable, perform MRI once every 5 years thereafter 8

For Microprolactinomas

• MRI monitoring under treatment is not necessary 8
• May perform MRI after 1 year and then after 5 years 8

Treatment Duration and Discontinuation

• Once normal prolactin levels are achieved, attempts may be made to stop treatment 8
• After prolonged treatment interruption (especially with cabergoline), progressive increase in serum prolactin and return of symptoms occur in only 20-30% of cases, particularly when residual adenoma exists 8
• Continue monitoring prolactin levels after discontinuation of dopamine agonists, as levels may rise again after months or years 8
• Alternative approach: reduce the dose or dosing frequency in steps to the lowest effective dose that maintains normal prolactin levels and stable adenoma size 8

Surgical Considerations

• Transsphenoidal surgery is reserved for patients who are intolerant of or resistant to dopamine agonists, or when hyperprolactinemia is caused by non-prolactin-secreting tumors compressing the pituitary stalk 6
• For macroprolactinomas, medical therapy with dopamine agonists is first-line treatment 8
• For microprolactinomas, dopamine agonists offer good first-line therapy, but surgery may also be useful 8

Special Populations

Drug-Induced Hyperprolactinemia

• When the causative medication cannot be withdrawn, administering a dopamine agonist is often pointless and possibly dangerous 8
• Check for absence of pituitary adenoma 8
• Begin treatment with sex steroids to ensure satisfactory hormonal impregnation and avoid osteoporosis 8

Postmenopausal Women

• Dopamine agonists for microprolactinoma may be withdrawn after menopause 8

Referral Criteria

Refer to an endocrinologist for:

• Persistently elevated prolactin levels after excluding common causes 2
• Men with total testosterone <150 ng/dL and low/low-normal LH 2
• Confirmed pituitary adenomas 2