What are the causes of hyperprolactinemia (elevated prolactin levels)?

Causes of Raised Prolactin

Hyperprolactinemia results from prolactinomas (most common pathological cause), medications that antagonize dopamine, primary hypothyroidism, chronic kidney or liver disease, pituitary stalk compression by mass lesions, and physiological states like pregnancy 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 (approximately 200 ng/mL) in children and adolescents. 1
• Prolactin levels directly correlate with tumor size—levels around 125 ng/mL suggest either a microprolactinoma or small macroadenoma. 2
• These tumors are the most frequent pituitary adenomas, showing a strong female predominance (3-4.5 times more common in females). 2

Pituitary Stalk Compression

• Mass lesions that compress the pituitary stalk interrupt the inhibitory dopaminergic tone on lactotroph cells, resulting in elevated prolactin levels (stalk effect). 1
• When large pituitary masses present with disproportionately low prolactin levels, the "hook effect" must be considered—extremely high prolactin concentrations saturate the immunoassay, producing falsely low measurements in approximately 5% of macroprolactinomas. 2

Medication-Induced Hyperprolactinemia

Medications are one of the most common causes of hyperprolactinemia, acting through direct stimulatory pathways or by antagonizing dopaminergic tone. 1

Key offending agents include:

• Antipsychotic agents (most common), though newer atypical antipsychotics may not cause this effect 3
• Antidepressants 1, 3
• Antihypertensive agents (methyldopa, reserpine, verapamil) 4, 3
• Gastrointestinal motility agents (metoclopramide, prochlorperazine/Stemetil) 1, 3
• Opiates and cocaine 4

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 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. 1

Chronic Kidney Disease

• Hyperprolactinemia occurs in 30-65% of adult patients with chronic kidney disease due to both increased prolactin secretion and reduced renal clearance. 1, 5

Severe Liver Disease

• Hepatic impairment is associated with hyperprolactinemia, though the mechanism is less well-defined than renal disease. 1, 5

Physiological and Other Causes

Pregnancy

• Pregnancy is a physiological cause of hyperprolactinemia and must be excluded in all women of reproductive age before pursuing other diagnoses. 5

Stress

• Stress can elevate prolactin levels up to five times the upper limit of normal, necessitating serial measurements for modestly elevated levels to exclude stress-related elevation. 1, 5

Macroprolactinemia

• Macroprolactinemia accounts for 10-40% of all hyperprolactinemia cases and represents prolactin bound to immunoglobulins with low biological activity. 5
• Most patients with isolated macroprolactinemia are asymptomatic, though approximately 20% have coexisting pituitary adenomas. 5

Other Rare Causes

• Intracranial hypotension 1
• Tetrahydrobiopterin deficiency 1
• Neurogenic stimulation (chest wall lesions, herpes zoster) 4
• Adrenal insufficiency 4

Critical Diagnostic Pitfalls to Avoid

• Always perform polyethylene glycol (PEG) precipitation testing when prolactin is mildly or incidentally elevated to exclude macroprolactinemia before extensive workup. 5
• Perform serial serum dilutions in patients with large pituitary lesions and unexpectedly normal or slightly elevated prolactin to detect the hook effect. 1, 5
• Review all medications thoroughly, as drug-induced hyperprolactinemia is frequently overlooked and is one of the most common causes. 5
• Exclude hypothyroidism, renal insufficiency, and hepatic impairment before attributing hyperprolactinemia to a pituitary adenoma. 1, 5