What is the algorithm for managing hyperprolactinemia?

Algorithm for Managing Hyperprolactinemia

The management of hyperprolactinemia follows a systematic approach: first exclude physiologic and medication-induced causes, then assess for macroprolactinemia in mild cases, followed by imaging to identify prolactinomas or stalk compression, and finally initiate dopamine agonist therapy with cabergoline as first-line treatment for confirmed prolactinomas. 1, 2

Step 1: Initial Diagnostic Workup

Confirm Hyperprolactinemia

• Measure serum prolactin in a single blood sample collected at any time of day 3
• For modestly elevated levels, obtain serial measurements to exclude stress-related elevation (stress can elevate prolactin up to five times the upper limit of normal) 4, 3
• Use age-specific and sex-specific reference ranges, as prolactin levels are higher in the first 2 years of life, decrease in mid-childhood, increase again in adolescence, and are higher in girls than boys 4

Exclude Secondary Causes

• Medications: Review all medications, as drug-induced hyperprolactinemia is one of the most common causes through dopamine antagonism or direct prolactin stimulation 1, 4
• Primary hypothyroidism: Check TSH and free T4, as hypothyroidism causes hyperprolactinemia in 43% of women and 40% of men with frank primary hypothyroidism, and 36% of women and 32% of men with subclinical hypothyroidism 1, 4
• Chronic kidney disease: Assess renal function, as 30-65% of patients with chronic kidney disease develop hyperprolactinemia due to increased secretion and reduced renal clearance 1, 4
• Severe liver disease: Evaluate hepatic function 1, 4
• Pregnancy: Exclude pregnancy in women of reproductive age 1

Step 2: Assess for Macroprolactinemia

• Perform polyethylene glycol (PEG) precipitation testing when serum prolactin is mildly or incidentally elevated, especially in asymptomatic patients 2, 3
• Macroprolactinemia accounts for 10-40% of all hyperprolactinemia cases and has low biological activity 2
• Most patients with isolated macroprolactinemia are asymptomatic, though some may present with headache, menstrual disturbances, short stature, increased hair growth, or early puberty 1, 2
• If macroprolactinemia is confirmed but the patient has symptoms or coexisting monomeric hyperprolactinemia, proceed with imaging 2

Step 3: Pituitary Imaging

When to Order MRI

• Obtain pituitary MRI for all patients with confirmed hyperprolactinemia after excluding secondary causes 3
• MRI is particularly indicated in patients with macroprolactinemia who have symptoms suggestive of a pituitary mass 2
• Approximately 20% of patients with macroprolactinemia have coexisting pituitary adenomas 2

Interpret Prolactin Levels in Context of Tumor Size

• Prolactin levels directly correlate with prolactinoma size: levels generally exceed 4,000 mU/L (approximately 200 ng/mL) in children and adolescents with prolactinomas 4
• Check for "hook effect" in large pituitary lesions: Perform serial dilutions of serum for prolactin measurement when large pituitary lesions are present with normal or mildly elevated prolactin levels 1, 3
• The hook effect occurs in approximately 5% of macroprolactinomas, where extremely high prolactin concentrations saturate the immunoassay, producing falsely low measurements 1, 3

Assess for Mass Effects

• Perform visual field testing if a macroadenoma is found, as compression of the optic chiasm can occur 3
• Evaluate for other cranial nerve compression 5

Step 4: Treatment Based on Etiology

For Secondary Hyperprolactinemia

• Treat the underlying condition (hypothyroidism, renal disease) to manage hyperprolactinemia 3
• For medication-induced hyperprolactinemia: If the causative medication cannot be withdrawn, check for absence of pituitary adenoma and consider sex steroid replacement to ensure satisfactory hormonal impregnation and avoid osteoporosis; administering a dopamine agonist is often pointless and possibly dangerous in these cases 6

For Prolactinomas

First-Line Medical Therapy

• Cabergoline is the preferred dopamine agonist due to superior effectiveness and better tolerability compared to bromocriptine 2, 7, 8
• Cabergoline has a long duration of action and is given once or twice weekly, while bromocriptine is given once or twice daily 7
• Dopamine agonists induce normal prolactinemia and ovulatory cycles in over 80% of cases 6
• Dopamine agonists are efficacious in about 80-90% of patients with prolactinoma, leading to reduction of serum prolactin levels and tumor dimensions 9

Cabergoline Dosing and Monitoring

• Cabergoline undergoes extensive first-pass metabolism with an elimination half-life of 63-69 hours 10
• The prolonged prolactin-lowering effect is related to slow elimination and long half-life 10
• Cabergoline is moderately bound (40-42%) to plasma proteins 10
• For patients on dopamine agonist therapy, measure prolactin levels 1-3 months after initiating treatment and every 3-6 months until stabilized 2
• For patients on standard doses of cabergoline (≤2 mg/week), perform echocardiographic surveillance every 6-12 months to monitor for cardiac valvulopathy 2

Bromocriptine as Alternative

• Bromocriptine is a dopamine receptor agonist that significantly reduces plasma prolactin levels 5
• Bromocriptine should be taken with food due to high percentage of subjects who vomit under fasting conditions 5
• Bromocriptine is 90-96% bound to serum albumin and undergoes extensive first-pass biotransformation 5
• Bromocriptine remains the treatment of choice in hyperprolactinemic women wishing to conceive due to more safety data during pregnancy 8

Imaging Follow-Up During Treatment

• For macroprolactinomas: Perform MRI after 3 months of treatment to verify tumor size reduction, then after 1 year, yearly for the next 5 years, and once every 5 years if adenoma size is stable 6
• For microprolactinomas: MRI control under treatment is pointless initially; may be performed after 1 year and then after 5 years 6

Treatment Duration and Discontinuation

• Once normal prolactin levels have been achieved, attempts may be made to stop treatment 6
• When prolonged treatment is interrupted, especially with cabergoline, progressive increase in serum prolactin and return of symptoms occur in only 20-30% of cases, particularly when residual adenoma exists 6
• Prolactin levels should continue to be monitored after discontinuation, possibly with MRI monitoring, since levels may rise again after months or years 6
• Another option is reducing the dose or dosing frequency to the lowest effective dose consistent with maintenance of normal prolactin levels and stable adenoma size 6

Resistant Cases

• In resistant cases, change to a different dopamine agonist 6
• In cases of intolerance to a given dopamine agonist, try another agent 6

Surgical Intervention

• Neurosurgery (transsphenoidal route) is indicated for:
  • Patients intolerant of or resistant to dopamine agonists 8, 9
  • Hyperprolactinemia caused by non-prolactin-secreting tumors compressing the pituitary stalk 8
  • Failure of medical therapy with evidence of mass effect despite medical therapy 7
• For microprolactinomas, dopamine agonist treatment offers a good first-line option, but surgery may also be useful 6
• At present, there is no evidence to suggest that prior treatment with dopamine agonists can modify the outcome of surgery 6

Radiotherapy and Other Treatments

• Radiotherapy is rarely used because of side effects and low efficacy 9
• The alkylating agent temozolomide has shown efficacy for treatment of aggressive and resistant prolactinomas 9

Step 5: Special Considerations

Pregnancy Management

• Withdraw dopamine agonists when pregnancy is diagnosed in patients being treated for hyperprolactinemia 5
• If bromocriptine is reinstituted to control a rapidly expanding macroadenoma during pregnancy, the benefit must be weighed against possible risk during hypertensive disorders of pregnancy 5
• Prolactin-secreting adenomas may expand during pregnancy with compression of optic or other cranial nerves, potentially requiring emergency pituitary surgery 5
• In most cases, nerve compression resolves following delivery 5
• Reinitiation of dopamine agonist treatment has produced improvement in visual fields when nerve compression occurred during pregnancy 5

Monitoring for Adverse Effects

• Monitor blood pressure, particularly during the first weeks of therapy 5
• Symptomatic hypotension can occur; decreases in supine systolic and diastolic pressures of greater than 20 mm and 10 mm Hg have been observed in almost 30% of patients 5
• Dopamine agonists have been associated with somnolence and episodes of sudden sleep onset; patients must be informed and advised not to drive or operate machines if affected 5
• Monitor for pleural and pericardial effusions, pleural and pulmonary fibrosis, and constrictive pericarditis, particularly with long-term and high-dose treatment 5
• Monitor for retroperitoneal fibrosis manifestations (back pain, edema of lower limbs, impaired kidney function) in patients on long-term and high-dose treatment 5

Drug Interactions

• Avoid concomitant use of bromocriptine with other ergot alkaloids 5
• CYP3A4 inhibitors or potent substrates might inhibit clearance of bromocriptine and lead to increased levels 5

Common Pitfalls to Avoid

• Do not dismiss all patients with macroprolactinemia as requiring no treatment without evaluating for coexisting monomeric hyperprolactinemia or pituitary adenomas 2
• Do not miss the hook effect: Always perform serial dilutions when large pituitary masses have disproportionately low prolactin levels 1, 3
• Do not overlook stress-related elevation: Obtain serial measurements for modestly elevated levels 4, 3
• Do not forget to exclude pregnancy as a physiologic cause 1
• Do not use dopamine agonists for prevention of physiological lactation or in patients with uncontrolled hypertension 5