Prolactin Levels in Children: Reference Ranges and Evaluation
Age- and Sex-Specific Reference Ranges
Prolactin levels in children vary dramatically by age and sex, with the highest values in the first 2 years of life, a nadir in mid-childhood, and a rise again during adolescence, with adolescent girls showing higher levels than boys. 1, 2
- Infancy (0–1 year): Prolactin is markedly elevated in the first year of life and declines sharply throughout this period 3
- Early childhood (1–5 years): Levels continue to decline until approximately 5 years of age, when concentrations stabilize 3
- Mid-childhood (5–12 years): Prolactin remains at a nadir with minimal sex differences 1, 3
- Adolescence (≥12 years): Levels rise again, with significant sex divergence—girls have higher values than boys starting at 13–17 years 3, 4
- Upper limit of normal in adolescents: Approximately <20 μg/L (<425 mU/L) for non-pregnant females and <18 μg/L for males, though assay-specific reference ranges must be used 2
The non-Gaussian distribution of prolactin across all pediatric age groups necessitates use of percentile-based reference intervals (2.5th to 97.5th percentile) rather than mean ± 2 SD 3, 4
Initial Diagnostic Approach
Measure serum prolactin in any child presenting with delayed or arrested puberty, menstrual disturbances, galactorrhea, visual field defects, growth failure, or headache. 1, 5
- Sampling technique: A single blood sample collected at any time of day is sufficient for initial assessment—specialized timing is unnecessary 1, 5
- Repeat sampling: For modestly elevated levels (≤5× the upper limit of normal), obtain 2–3 samples 20–60 minutes apart via an indwelling cannula on a separate day to exclude stress-related elevation 1, 5
- Stress effect: Transient stress can elevate prolactin up to 5-fold above the upper limit 2
Systematic Exclusion of Secondary Causes
Before attributing hyperprolactinemia to a prolactinoma, systematically rule out reversible etiologies:
- Medications: Review all current medications, particularly dopamine antagonists (e.g., prochlorperazine, risperidone, metoclopramide), which are among the most common causes of hyperprolactinemia in children 1, 2
- Primary hypothyroidism: Always measure TSH and free T4; hypothyroidism causes hyperprolactinemia in 43% of women and 40% of men with frank disease, and is fully reversible with thyroid hormone replacement 1, 2
- Chronic kidney disease: Associated with hyperprolactinemia in 30–65% of adult patients due to increased secretion and reduced renal clearance 2
- Severe liver disease: Can cause hyperprolactinemia 1, 2
- Macroprolactinemia: Assess for macroprolactin (biologically inactive prolactin-immunoglobulin complexes) when prolactin is mildly or incidentally elevated; this accounts for 10–40% of hyperprolactinemia cases and requires no treatment 1, 2
Correlation Between Prolactin Level and Tumor Size
Prolactin levels generally correlate with pituitary tumor size, with values >4,000 mU/L (≈188 μg/L) strongly suggesting a prolactinoma in pediatric populations. 1, 5
- Microprolactinomas: May present with lower prolactin values 1
- Macroprolactinomas: Typically show prolactin >4,000 mU/L 1, 5
- Giant prolactinomas: More common in children than adults, often with very high prolactin levels 1, 2
Critical Pitfall: The "Hook Effect"
- When a large pituitary mass is found on MRI but prolactin is paradoxically normal or only mildly elevated, request serial dilutions of the serum sample to rule out assay saturation. 1, 2
- This "high-dose hook effect" occurs in approximately 5% of macroprolactinomas when extremely high prolactin concentrations saturate the immunoassay, producing falsely low measurements 1, 2
Imaging Indications
Obtain high-resolution pituitary MRI with and without contrast when prolactin markedly exceeds age/sex norms, when visual or mass-effect symptoms are present, or after secondary causes have been excluded. 1, 5
- Visual field testing should be performed if a macroadenoma is found, as compression of the optic chiasm occurs in 73% of giant prolactinoma cases 1, 2
Additional Endocrine Testing
- Measure IGF-1 (age- and sex-adjusted) to exclude mixed prolactin-GH hypersecretion syndromes 1
- Assess remaining pituitary hormone axes (LH, FSH, cortisol, thyroid function) to identify concurrent hypopituitarism 5, 2
- Consider genetic testing for familial isolated pituitary adenoma (AIP) or MEN1-related syndromes, even without known family history, as approximately 14% of pediatric prolactinomas are hereditary 1, 6
Medical Management
Dopamine agonists (cabergoline first-line) constitute definitive medical therapy for both micro- and macroprolactinomas in children, including cases with visual field defects. 7, 1
- Efficacy: Prolactin normalizes in 74% of pediatric patients treated with dopamine agonists 6
- Tumor shrinkage: Visual field defects resolve in 67% of patients treated with dopamine agonists 2
- Monitoring: For macroprolactinomas, repeat MRI 3–6 months after starting cabergoline; for microprolactinomas, re-imaging depends on clinical and biochemical follow-up 7
- Long-term surveillance: Prolactin levels assessed at 3–6-month intervals initially can serve as markers of tumor relapse, though biochemical relapse does not always correlate with radiological change 7
Predictors of Dopamine Agonist Resistance
- Younger age at diagnosis 6
- Higher baseline prolactin levels 6
- Larger tumor volume 6
- Presence of a MEN1 mutation (but not AIP mutation) 6
Pediatric-Specific Considerations
- Age at presentation: 93% of pediatric prolactinomas are diagnosed after age 12 years 1, 2
- Sex distribution: Strong female predominance (3–4.5:1 female-to-male ratio) 1
- Presenting symptoms in prepubertal children: Headache, visual disturbances, growth failure, or delayed puberty 1
- Presenting symptoms in adolescent girls: Menstrual irregularities (primary or secondary amenorrhea) and galactorrhea 1
- Presenting symptoms in adolescent boys: Headache, gynecomastia, delayed puberty, or visual field defects 1
- Associated obesity: 46% of children with macroprolactinomas are overweight or obese at presentation, and 23% report recent weight gain 1, 2
- Bone health: Low bone mineral density is reported at diagnosis with modest recovery after 2 years of dopamine agonist therapy; assess BMD 2 years after diagnosis, though interpretation is confounded by delayed growth and puberty 7
Common Pitfalls to Avoid
- Do not overlook hypothyroidism: Always include thyroid function testing in the initial work-up, as this is a fully reversible cause of hyperprolactinemia 1
- Do not miss the hook effect: Request serial dilutions when clinical suspicion is high (large tumor, mass-effect symptoms) but prolactin is unexpectedly low 1, 2
- Do not forget genetic testing: Consider AIP and MEN1 testing in young patients, as hereditary pituitary adenomas can occur without obvious family history 1, 6
- Do not start dopamine agonist therapy for mild, asymptomatic hyperprolactinemia: First exclude macroprolactinemia, medications, and secondary causes 1, 2
- Do not assume hyperprolactinemia is related to precocious puberty: Exclude more common causes (medications, macroprolactinemia, stress) first 1