What are the causes of hyperprolactinemia?

Causes of Hyperprolactinemia

Hyperprolactinemia results from prolactinomas, medications that block dopamine, primary hypothyroidism, chronic kidney or liver disease, and pituitary stalk compression by mass lesions. 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
• These tumors represent the most frequent pituitary adenoma type, occurring in approximately 0.1 per million children annually, with 93% presenting after age 12. 2
• The degree of prolactin elevation directly correlates with tumor size—levels around 125 ng/mL suggest either a microprolactinoma or small macroadenoma, while macroprolactinomas typically produce much higher levels. 2

Pituitary Stalk Compression

• Mass lesions that compress the pituitary stalk interrupt the inhibitory dopaminergic tone on lactotroph cells, resulting in elevated prolactin levels (typically mild elevation <100 μg/L or <2,000 mU/L). 1
• This "stalk effect" must be distinguished from true prolactinomas, as the mechanism and treatment differ fundamentally. 1

Medication-Induced Hyperprolactinemia

• Medications are one of the most common causes of hyperprolactinemia, acting either through direct prolactin stimulation or by antagonizing dopamine's inhibitory effect on lactotroph cells. 1, 3
• Antipsychotic agents, particularly dopamine antagonists like risperidone and prochlorperazine (Stemetil), are the most frequent medication culprits. 1, 4
• Risperidone elevates prolactin levels persistently during chronic administration and is associated with higher prolactin elevation than other antipsychotic agents. 4
• Other medications include antidepressants, antihypertensive agents (particularly methyldopa, reserpine, verapamil), metoclopramide, and drugs that increase bowel motility. 5, 6
• Estrogens may induce hyperprolactinemia, though the role of synthetic oral contraceptives in causing mild elevation remains controversial. 3

Endocrine Disorders

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 involves compensatory hypersecretion of thyrotropin-releasing hormone (TRH), which stimulates prolactin release. 1
• Hypothyroidism may produce pituitary hyperplasia that must be distinguished from a true prolactinoma—this is a critical diagnostic pitfall. 1

Systemic Diseases

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, though the exact prevalence and mechanism are less well-defined than with renal disease. 1, 3

Physiological and Other Causes

• Pregnancy is a physiological cause of elevated prolactin and must always be excluded first. 1, 7
• Stress can elevate prolactin levels up to five times the upper limit of normal—this is why serial measurements are recommended for modestly elevated levels. 1, 2
• Intracranial hypotension and tetrahydrobiopterin deficiency are rare causes. 1

Macroprolactinemia (Diagnostic Consideration)

• Macroprolactinemia accounts for 10-40% of all hyperprolactinemia cases and represents biologically inactive prolactin complexes that circulate but have minimal clinical significance. 1, 2
• 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
• Assessment for macroprolactin should be performed in cases of mild or incidental elevation, especially in asymptomatic patients, before pursuing further workup. 1, 2

Critical Diagnostic Pitfall: The Hook Effect

• Approximately 5% of patients with macroprolactinomas show paradoxically normal or mildly elevated prolactin due to assay saturation at very high concentrations—this is called the "high-dose hook effect." 1, 2
• When a large pituitary mass is found on MRI but prolactin levels seem disproportionately low, manual serial dilutions of the serum sample must be requested to avoid missing a giant prolactinoma. 1, 2