Causes of High Prolactin
Hyperprolactinemia results from five major categories: prolactinomas (most common pathological cause), medications (most common overall cause), secondary endocrine/systemic disorders, pituitary stalk compression, and physiological/artifactual causes. 1, 2
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, and the degree of elevation generally correlates with tumor size. 2
- Microprolactinomas (<10mm) and macroprolactinomas (≥10mm) produce excessive prolactin directly or disrupt normal dopamine delivery from the hypothalamus. 3
- These tumors account for approximately 0.1 per million children annually and show a 3-4.5 times female predominance. 4
Medication-Induced Hyperprolactinemia
Medications are one of the most common causes of hyperprolactinemia and must be ruled out first. 1, 2
High-Risk Medications:
- Antipsychotics (typical neuroleptics and risperidone among atypicals) are the most frequent culprits, acting by antagonizing dopamine's inhibitory effect on prolactin secretion. 5, 6
- Antidepressants with serotonergic activity, including SSRIs, MAO inhibitors, and some tricyclics. 6
- Prokinetic agents (metoclopramide, prochlorperazine/Stemetil) that block dopamine receptors. 2, 7
- Antihypertensives (methyldopa, reserpine, verapamil). 7
- Other agents: H2-receptor antagonists, opiates, estrogens, anti-androgens, anticonvulsants. 6, 7
Key Clinical Point:
- Medication-induced hyperprolactinemia typically causes mild elevation, rarely exceeding 100 ng/mL (2,000 mU/L), though exceptions exist with combination therapy. 2, 8
- Women are more sensitive than men to the hyperprolactinemic effects of antipsychotics. 6
Secondary Endocrine and Systemic Causes
Primary Hypothyroidism:
- Occurs in 43% of women and 40% of men with frank primary hypothyroidism, and 36% of women and 32% of men with subclinical hypothyroidism. 2
- Mechanism involves compensatory hypersecretion of thyrotropin-releasing hormone (TRH), which stimulates prolactin release. 2
- Can produce pituitary hyperplasia that must be distinguished from true prolactinoma. 2
Chronic Kidney Disease:
- Associated with hyperprolactinemia in 30-65% of adult patients due to increased prolactin secretion and reduced renal clearance. 2
Severe Liver Disease:
- Also causes hyperprolactinemia in adults through impaired clearance mechanisms. 2
Pituitary Stalk Compression (Stalk Effect)
- Mass lesions compressing the pituitary stalk interrupt dopamine's inhibitory tone, resulting in elevated prolactin levels typically in the mild-to-moderate range (<100 μg/L or <2,000 mU/L). 2
- This occurs with non-functioning pituitary adenomas, craniopharyngiomas, or other sellar/suprasellar masses. 2
Physiological and Artifactual Causes
Macroprolactinemia:
- Accounts for 10-40% of all hyperprolactinemia cases and represents biologically inactive prolactin-antibody complexes. 1, 2
- Should be assessed in cases of mild or incidental elevation, especially in asymptomatic patients. 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. 2
Stress-Related Elevation:
- Stress can elevate prolactin levels up to five times the upper limit of normal. 2
- Serial measurements 20-60 minutes apart using an indwelling cannula help differentiate stress-related from organic disease. 1
Other Physiological Causes:
Critical Diagnostic Pitfall: The "Hook Effect"
In approximately 5% of macroprolactinomas, extremely high prolactin concentrations saturate the immunoassay, producing falsely low or normal measurements. 4, 2
- Suspect when a large pituitary mass on MRI shows paradoxically normal or mildly elevated prolactin levels. 4, 2
- Request manual serial dilutions of the serum sample to unmask the true prolactin level. 1, 2