What causes elevated prolactin (hyperprolactinemia) levels?

Causes of Elevated Prolactin (Hyperprolactinemia)

Elevated prolactin results from five main categories: prolactinomas (most common pathological cause), medications that block dopamine, primary hypothyroidism, chronic kidney or liver disease, and pituitary stalk compression by mass lesions. 1

Prolactinomas (Most Common Pathological Cause)

• Prolactinomas are the most common pathological cause of chronic hyperprolactinemia, with prolactin levels typically exceeding 4,000 mU/L in children and adolescents, and the degree of elevation generally correlating with tumor size. 1
• These tumors represent the most common pituitary adenoma type, occurring in approximately 0.1 per million children annually, with 93% presenting after age 12. 2
• Prolactinomas show a strong female predominance, being 3-4.5 times more common in females than males. 2

Medication-Induced Hyperprolactinemia

• Medications are one of the most common causes of hyperprolactinemia, acting either through direct stimulation of prolactin secretion or by antagonizing dopamine's inhibitory effect on lactotroph cells. 1, 3
• The most common offending medications are antipsychotic agents (particularly typical antipsychotics), though some newer atypical antipsychotics do not cause this effect. 4
• Other medication classes include antidepressants, antihypertensive agents, and drugs that increase bowel motility. 4
• Estrogens may induce hyperprolactinemia, though the role of synthetic oral contraceptives in causing mild elevation remains controversial. 3

Primary Hypothyroidism

• Primary hypothyroidism causes hyperprolactinemia in 43% of women and 40% of men with frank disease, and in 36% of women and 32% of men with subclinical hypothyroidism. 1
• The mechanism involves compensatory hypersecretion of thyrotropin-releasing hormone (TRH), which stimulates prolactin release. 1
• Prolonged hypothyroidism may produce pituitary hyperplasia that must be distinguished from a true prolactinoma on imaging. 1
• While prolactin elevation in hypothyroidism is generally modest (rarely exceeding 100 ng/mL), exceptional cases with markedly elevated levels have been reported, particularly when combined with macroprolactinemia. 5

Chronic Kidney and Liver Disease

• Chronic kidney disease is associated with hyperprolactinemia in 30-65% of adult patients, due to both increased prolactin secretion and reduced renal clearance. 1, 3
• Severe liver disease is also associated with hyperprolactinemia in adults, though the exact prevalence is less well-defined. 1, 3

Pituitary Stalk Compression (Stalk Effect)

• Compression of the pituitary stalk by mass lesions interrupts the inhibitory dopaminergic tone to lactotroph cells, resulting in elevated prolactin levels. 1
• This typically causes mild to moderate elevation (<100 μg/L or <2000 mU/L) with non-functioning pituitary adenomas or other sellar/parasellar masses. 1

Other Causes

• Macroprolactinemia accounts for 10-40% of all hyperprolactinemia cases, representing biologically inactive prolactin-immunoglobulin complexes that are detected by standard assays but have minimal clinical significance. 1, 3
• Stress can elevate prolactin levels up to five times the upper limit of normal, necessitating repeat measurements for modestly elevated levels. 1, 2
• Pregnancy is a physiological cause of hyperprolactinemia that must always be excluded. 1
• Rare causes include intracranial hypotension and tetrahydrobiopterin deficiency. 1

Critical Diagnostic Pitfalls to Avoid

• The "high-dose hook effect" occurs in approximately 5% of macroprolactinomas, where extremely high prolactin concentrations saturate the immunoassay, producing falsely low or normal measurements despite large pituitary tumors—manual serial dilutions should be requested when this is suspected. 1, 2
• Always exclude hypothyroidism, renal or hepatic insufficiency, and medication causes before attributing hyperprolactinemia to a prolactinoma. 1, 3
• Screen for macroprolactinemia in cases of mild or incidental elevation, especially in asymptomatic patients, as 20% of those with macroprolactinemia still have galactorrhea, 45% have oligo-amenorrhea, and 20% have pituitary adenomas, indicating possible concurrent true hyperprolactinemia. 1

Clinical Consequences

• Hyperprolactinemia inhibits gonadotropin secretion through suppression of hypothalamic kisspeptin, leading to hypogonadism. 1
• In women, this manifests as amenorrhea/oligomenorrhea, anovulation, galactorrhea, and infertility. 1, 3
• In men, this causes decreased libido, erectile dysfunction, and gynecomastia. 1, 3
• Large tumors may cause visual field defects (from optic chiasm compression), headaches, and rarely pituitary apoplexy. 1