What are the causes and treatment options for hyperprolactinemia?

Causes and Treatment of Hyperprolactinemia

Hyperprolactinemia is most commonly caused by prolactinomas, medications (especially dopamine antagonists), primary hypothyroidism, renal or hepatic disease, and pituitary stalk compression, and should be treated with dopamine agonists like cabergoline or bromocriptine when symptomatic or caused by prolactinomas. 1

Etiology of Hyperprolactinemia

Physiologic Causes

• Prolactin levels naturally vary with age and sex, being higher in the first 2 years of life, decreasing in mid-childhood, and increasing again in adolescence (higher in girls than boys) 1
• Stress can elevate prolactin levels up to five times the upper limit of normal 1
• Pregnancy is a common physiologic cause of hyperprolactinemia 1

Pathologic Causes

• Prolactinomas are the most common pathological cause of chronic hyperprolactinemia, with prolactin levels typically correlating with tumor size (usually exceeding 4,000 mU/l in children and adolescents with prolactinomas) 1, 2
• Primary hypothyroidism can cause hyperprolactinemia in 43% of women and 40% of men, likely due to compensatory hypersecretion of thyrotropin-releasing hormone 1
• Chronic kidney disease is associated with hyperprolactinemia in 30-65% of adult patients due to increased secretion and reduced renal clearance 1
• Severe liver disease can also cause hyperprolactinemia in adults 1
• Pituitary stalk compression by mass lesions can interrupt dopaminergic inhibition of lactotroph cells, resulting in elevated prolactin 1
• Other causes include intracranial hypotension, tetrahydrobiopterin deficiency, and macroprolactinemia 1

Medication-Induced Causes

• Medications are among the most common causes of hyperprolactinemia, particularly those that antagonize dopamine 1, 3
• Common culprits include antipsychotics, antidepressants, and certain antihypertensives 1

Clinical Presentation

In Women

• Hyperprolactinemia inhibits gonadotropin secretion leading to hypogonadism, which manifests as amenorrhea/oligomenorrhea, anovulation, and galactorrhea 1, 4
• Infertility and decreased libido are common complaints 4

In Men

• Decreased libido, erectile dysfunction, and gynecomastia are typical presentations 1, 4
• Men often present later with larger prolactinomas and symptoms of mass effect (headaches, visual disturbances) 2

Diagnostic Approach

Initial Evaluation

• Confirm hyperprolactinemia with a single blood sample collected at any time of day 5
• For modestly elevated levels, consider serial measurements 20-60 minutes apart using an indwelling cannula to differentiate stress-related elevation from organic disease 5
• Use age-specific and sex-specific reference ranges for prolactin levels 5

Rule Out Confounding Conditions

• Exclude hypothyroidism, renal or hepatic impairment, and medication-induced hyperprolactinemia before confirming diagnosis 5, 1
• Consider macroprolactinemia in cases of mild or incidental hyperprolactinemia 1, 3
• Be aware of the "hook effect" in large pituitary adenomas (≥3 cm) with normal or mildly elevated prolactin levels, which can be unmasked by diluting the sample 3

Imaging

• MRI imaging of the pituitary should be performed when prolactin levels are significantly elevated (typically >4,000 mU/l or 188 μg/l in pediatric populations) 5
• For patients with visual symptoms or signs of mass effect, MRI imaging should be performed regardless of prolactin level 5

Treatment Options

Dopamine Agonists

• Dopamine agonists are the first-line treatment for prolactinomas and symptomatic hyperprolactinemia 6, 7, 8
• Cabergoline and bromocriptine are the FDA-approved options in the United States 8, 9
• These medications normalize prolactin levels and restore ovulatory cycles in over 80% of cases 8

Cabergoline

• Administered once or twice weekly due to its long duration of action 9
• Superior to bromocriptine in both efficacy (prolactin suppression, restoration of gonadal function) and tolerability 9, 2
• Requires cardiovascular evaluation including echocardiogram before initiation to assess for valvular disease 7
• Periodic echocardiographic monitoring (every 6-12 months) is recommended during treatment 7

Bromocriptine

• Usually given once or twice daily 9
• Indicated for treatment of dysfunctions associated with hyperprolactinemia including amenorrhea, galactorrhea, infertility, or hypogonadism 6
• Can reduce tumor size in patients with prolactin-secreting adenomas 6
• May cause more side effects than cabergoline, particularly somnolence, hypotension, and gastrointestinal symptoms 6, 8

Treatment Monitoring

• Monitor prolactin levels to assess treatment efficacy 5
• For macroprolactinomas, perform MRI after 3 months of treatment to verify tumor size reduction, then after 1 year, yearly for 5 years, and once every 5 years if adenoma size is stable 8
• For microprolactinomas, MRI may be performed after 1 year and then after 5 years 8

Treatment Duration and Discontinuation

• Once normal prolactin levels are achieved, treatment may be discontinued in some patients 8
• After prolonged treatment with cabergoline, only 20-30% of patients experience recurrence of hyperprolactinemia when treatment is stopped 8
• Continue monitoring prolactin levels after discontinuation of dopamine agonists 8
• An alternative approach is reducing the dose or frequency to the lowest effective dose that maintains normal prolactin levels and stable adenoma size 8

Special Considerations

• For drug-induced hyperprolactinemia where the causative medication cannot be withdrawn, it may be unnecessary and potentially dangerous to administer a dopamine agonist 8
• For macroprolactinomas, first-line treatment is dopamine agonist therapy 8, 2
• For microprolactinomas, dopamine agonist treatment is a good first-line option, but surgery may also be considered 8
• Surgery and/or radiotherapy are indicated for resistance to dopamine agonists or by patient preference 2

Pitfalls and Caveats

• The magnitude of prolactin elevation can help determine etiology, but exceptions exist 3
• Values >250 ng/mL suggest prolactinomas but can also occur with macroprolactinemia, drug-induced hyperprolactinemia, or chronic renal failure 3
• Up to 25% of patients with microprolactinomas may have prolactin levels <100 ng/mL 3
• Pregnancy and menopause may promote spontaneous prolactin decline and allow for earlier discontinuation of treatment in women 2