What is the role of PEG (Polyethylene Glycol) testing in evaluating mildly elevated prolactin levels?

PEG Testing for Elevated Prolactin Levels

Direct Recommendation

PEG (polyethylene glycol) precipitation testing should be performed when serum prolactin is found to be mildly or incidentally elevated, particularly in asymptomatic patients, to identify macroprolactinemia and avoid unnecessary treatment and imaging. 1, 2

Rationale for PEG Testing

Why It Matters

• Macroprolactinemia accounts for 10-40% of all hyperprolactinemia cases, making it the third most common cause after medications and prolactinomas 2
• Macroprolactin is a large polymeric form (>100 kDa) with low biological activity that is measured by standard immunoassays but does not cause true hyperprolactinemic symptoms 1
• Identifying macroprolactinemia prevents unnecessary pituitary imaging, dopamine agonist therapy, and patient anxiety 3

When to Order PEG Testing

• Mild hyperprolactinemia (typically <100 ng/mL) without clear symptoms 1, 2
• Incidental hyperprolactinemia discovered during routine testing 1
• Asymptomatic patients with elevated prolactin 2
• Discordance between prolactin level and clinical presentation 3

Interpreting PEG Test Results

Recovery Percentage Thresholds

• ≤40% recovery: Macroprolactinemia is present 4
• 40-50% recovery: Indeterminate zone, consider gel filtration chromatography for confirmation 4
• >50% recovery: Macroprolactinemia unlikely; true monomeric hyperprolactinemia present 4

Test Performance

• The PEG precipitation test demonstrates good reproducibility with within-batch CV of 2.8-7.3% and between-batch CV of 3.4-9.7% 4
• Intra-individual variability over five months is approximately 10% 4

Critical Pitfalls to Avoid

False-Positive PEG Results

• Elevated serum globulins (IgG myeloma, HIV-related polyclonal hypergammaglobulinemia) can cause false-positive PEG precipitation tests by co-precipitating monomeric prolactin with immunoglobulins 5
• In patients with known or suspected elevated globulins, interpret PEG results cautiously and consider gel filtration chromatography for confirmation 5
• Gamma globulin concentrations correlate inversely with PRL recovery (r = -1.000, P < 0.005), leading to underestimation of true monomeric prolactin 5

Coexisting Conditions

• Do not dismiss all macroprolactinemia as benign: Approximately 20% of patients with macroprolactinemia have coexisting pituitary adenomas 2
• Some patients with macroprolactinemia can have genuine symptoms including headache, menstrual disturbances, or galactorrhea 1, 2
• In one pediatric series, 2 of 6 patients with macroprolactinemia had microadenomas on MRI 1

The "Hook Effect" Consideration

• In patients with large pituitary lesions but paradoxically normal or mildly elevated prolactin, perform serial dilutions rather than PEG testing 1
• The high-dose hook effect occurs in approximately 5% of macroprolactinomas when extremely high prolactin concentrations saturate the immunoassay, producing falsely low measurements 1, 6

Clinical Management Algorithm

Step 1: Confirm True Hyperprolactinemia

• Repeat prolactin measurement in morning while resting to exclude stress-related elevation 6
• Rule out medications (dopamine antagonists, antipsychotics), hypothyroidism, pregnancy, chronic kidney disease, and severe liver disease 1, 6

Step 2: Order PEG Testing

• Perform PEG precipitation on confirmed hyperprolactinemia samples 1, 2
• Calculate both recovery percentage and absolute monomeric prolactin concentration 7

Step 3: Act on Results

• If macroprolactinemia confirmed (≤40% recovery):

  • Reassure asymptomatic patients; no treatment needed 2
  • If symptomatic or imaging shows adenoma, consider dopamine agonist therapy 2
  • Pituitary MRI only if symptoms suggest mass effect 2

• If true hyperprolactinemia (>50% recovery):

  • Proceed with standard hyperprolactinemia workup including pituitary MRI 2, 8
  • Initiate cabergoline if prolactinoma confirmed 2, 6

Step 4: Special Considerations

• In patients with elevated globulins, request gel filtration chromatography if PEG results seem discordant with clinical picture 5
• Monitor patients with macroprolactinemia who have symptoms, as some may benefit from treatment despite the traditional view that it is asymptomatic 2, 4

Assay-Specific Considerations

Different prolactin immunoassays vary in their reactivity with macroprolactin 3, 9. The PEG precipitation method requires:

• Use of a PEG-modified prolactin reference interval derived from PEG-precipitated reference sera 3
• Treatment of calibration standards with PEG when using certain analyzers (e.g., Abbott AxSYM) 7
• The Roche Elecsys Prolactin II assay has reduced reactivity with macroprolactin compared to earlier versions 9