What causes elevated prolactin levels?

Causes of Elevated Prolactin

Elevated prolactin results from prolactinomas, medications that block dopamine, primary hypothyroidism, chronic kidney or liver disease, pituitary stalk compression, pregnancy, macroprolactinemia, and stress. 1

Pathological Causes

Prolactinomas

• Prolactinomas are the most common pathological cause of chronic hyperprolactinemia, with prolactin levels typically exceeding 4,000 mU/L in children and adolescents and generally correlating with tumor size. 1
• In adults, prolactin levels around 125 ng/mL typically indicate either a microprolactinoma or small macroadenoma. 2
• Prolactinomas show a strong female predominance, occurring 3-4.5 times more commonly in females than males. 2

Pituitary Stalk Compression

• Mass lesions that compress the pituitary stalk interrupt the inhibitory dopaminergic tone on lactotroph cells, resulting in elevated prolactin levels. 1
• Mild elevation of prolactin (<100 μg/L or <2000 mU/L) can occur with non-functioning pituitary adenomas causing stalk compression. 1

Medication-Induced Hyperprolactinemia

Medications are one of the most common causes of hyperprolactinemia, acting through direct prolactin stimulation or by antagonizing dopamine's inhibitory effect. 1, 3

Common Offending Medications

• Antipsychotic agents, particularly dopamine antagonists, are the most frequent medication cause. 3, 4
• Risperidone elevates prolactin levels and the elevation persists during chronic administration, with risperidone associated with higher levels of prolactin elevation than other antipsychotic agents. 5
• Antidepressants, antihypertensive agents, and drugs that increase bowel motility can also cause hyperprolactinemia. 4
• Estrogens may induce hyperprolactinemia, though the role of synthetic oral contraceptives in causing mild prolactin elevation remains controversial. 3

Endocrine and Metabolic Causes

Primary Hypothyroidism

• Primary hypothyroidism causes hyperprolactinemia in 43% of women and 40% of men with frank hypothyroidism, and in 36% of women and 32% of men with subclinical hypothyroidism. 1
• The mechanism is likely compensatory hypersecretion of thyrotropin-releasing hormone, which may produce pituitary hyperplasia that must be distinguished from a true prolactinoma. 1

Chronic Kidney 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

• Severe liver disease is associated with hyperprolactinemia in adults. 1, 3

Physiological and Benign Causes

Pregnancy

• Pregnancy is a physiological cause of elevated prolactin and must always be excluded when evaluating hyperprolactinemia. 1

Macroprolactinemia

• Macroprolactinemia accounts for 10-40% of all hyperprolactinemia cases and represents biologically inactive prolactin complexes (>150 kDa) that circulate in the blood. 1, 3, 6
• Among adults with macroprolactinemia, 20% still have galactorrhea, 45% have oligo-amenorrhea, and 20% have pituitary adenomas, indicating some may have concurrent true hyperprolactinemia. 1
• Patients with macroprolactinemia are typically symptom-free despite marked hyperprolactinemia, and pregnancy is possible. 6
• Anti-prolactin autoantibodies are a leading cause of macroprolactinemia. 6

Stress

• Stress can elevate prolactin levels up to five times the upper limit of normal. 1

Critical Diagnostic Pitfalls

High-Dose Hook Effect

• The "high-dose hook effect" causes falsely low prolactin measurements in approximately 5% of macroprolactinomas when extremely high prolactin concentrations saturate the immunoassay. 1, 2
• Manual serial dilutions should be requested when large pituitary lesions show paradoxically normal or mildly elevated prolactin levels. 1, 2

Other Rare Causes

• Intracranial hypotension and tetrahydrobiopterin deficiency are uncommon causes of hyperprolactinemia. 1

Diagnostic Algorithm

Before attributing hyperprolactinemia to any single cause, systematically exclude:

1. Pregnancy (always first) 1
2. Medications, particularly dopamine antagonists 1, 3
3. Primary hypothyroidism 1, 3
4. Chronic kidney disease 1, 3
5. Severe liver disease 1, 3
6. Macroprolactinemia (especially if mildly or incidentally elevated) 1, 3
7. Pituitary stalk compression or prolactinoma (via MRI if above causes excluded) 1