Causes of Hyperprolactinemia
Hyperprolactinemia results from prolactinomas (most common pathological cause), medications that block dopamine, primary hypothyroidism, chronic kidney or liver disease, pituitary stalk compression by mass lesions, and physiological states like pregnancy. 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 account for the majority of cases once physiological causes, medications, and systemic diseases are excluded 1
- In pediatric populations, 93% of prolactinomas present after age 12, with a 3-4.5 times higher prevalence in females 2
Non-Prolactin-Secreting Pituitary Lesions
- Pituitary stalk compression by mass lesions (non-functioning adenomas, craniopharyngiomas, or other sellar/suprasellar masses) interrupts the inhibitory dopaminergic tone to lactotroph cells, causing mild-to-moderate prolactin elevation 1
- These typically cause prolactin levels <100 μg/L (<2000 mU/L), distinguishing them from prolactinomas 1
Medication-Induced Hyperprolactinemia
- Medications are one of the most common causes, acting either through direct prolactin stimulation or by antagonizing dopamine's inhibitory effect 1, 3
- Dopamine antagonists (antipsychotics, antiemetics like metoclopramide and prochlorperazine) are the primary culprits 1, 3
- Estrogens may induce hyperprolactinemia, though the role of oral contraceptives in causing mild elevation remains controversial 3
- Always review medications first in the initial evaluation, as this is among the most common and reversible causes 2
Systemic Medical Conditions
Primary Hypothyroidism
- Hyperprolactinemia occurs in 43% of women and 40% of men with frank primary 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 is reported in 30-65% of adult patients with chronic kidney disease, due to both increased prolactin secretion and reduced renal clearance 1, 3
Severe Liver Disease
- Severe hepatic disease is associated with hyperprolactinemia in adults, though less commonly than renal disease 1, 3
Physiological and Other Causes
Stress
- Stress can elevate prolactin levels up to five times the upper limit of normal, making repeat measurement necessary for modestly elevated levels 1, 2
Macroprolactinemia
- 10-40% of patients with elevated prolactin have macroprolactinemia, a benign condition where large, biologically inactive prolactin-immunoglobulin complexes circulate 1, 3
- 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 1, 2
Other Causes
Critical Diagnostic Pitfalls
The "High-Dose Hook Effect"
- In approximately 5% of macroprolactinomas, extremely high prolactin concentrations saturate the immunoassay, producing falsely low or normal measurements 1, 2
- When a large pituitary mass is found on MRI but prolactin levels seem paradoxically normal or only mildly elevated, request manual serial dilutions of the serum sample 1, 2
Systematic Exclusion Required
- Before attributing hyperprolactinemia to any single cause, exclude hypothyroidism, renal or hepatic insufficiency, and medications 1, 3
- The degree of prolactin elevation helps narrow the differential: levels >4,000 mU/L strongly suggest prolactinoma, while levels <2,000 mU/L suggest secondary causes 1