Frequent Misdiagnosis and Mismanagement of Hyperprolactinemic Patients before the Introduction of Macroprolactin Screening: Application of a New Strict Laboratory Definition of Macroprolactinemia

Abstract

Abstract Background: Macroprolactin (big big prolactin) has reduced bioactivity and is measured by immunoassays for prolactin when it accumulates in the plasma of some individuals. We applied normative data for serum prolactin after treatment of sera to remove macroprolactin to elucidate the contribution of macroprolactin to misleading diagnoses, inappropriate investigations, and unnecessary treatment. Methods: We reviewed records of women attending a tertiary referral center who had prolactin >1000 mIU/L. Application of a reference interval to polyethylene glycol (PEG)-treated hyperprolactinemic sera identified 21 patients in whom hyperprolactinemia was accounted for entirely by the presence of macroprolactin. Presenting clinical features, diagnoses, and treatment were compared in these patients and 42 age-matched true hyperprolactinemic patients. Results: Prolactin concentrations in sera of 110 healthy individuals ranged from 78 to 564 mIU/L. The range of values for the sera after PEG treatment was 70–403 mIU/L. For macroprolactinemic samples, PEG treatment decreased mean (SD) prolactin from 1524 (202) mIU/L to 202 (27) mIU/L but decreased it only from 2096 (233) mIU/L to 1705 (190) mIU/L in true hyperprolactinemic patients (P <0.01 between groups). Oligomenorrhea or amenorrhea and galactorrhea were the most common clinical features in both groups, although they occurred more frequently in true hyperprolactinemic patients (P <0.05). Serum estradiol and luteinizing hormone concentrations were significantly higher in participants with macroprolactinemia than in those with true hyperprolactinemia (P <0.05). Among participants with retrospectively identified macroprolactinemia, pituitary imaging was performed in 93% and treatment with dopamine agonist was prescribed in 87%. Conclusions: Macroprolactin is a significant cause of misdiagnosis, unnecessary investigation, and inappropriate treatment. The use of an appropriate reference interval for the PEG immunoprecipitation procedure may be of particular importance in those patients who have an excess of both macroprolactin and monomeric prolactin.