Assessment of Macroprolactin Persistence in a Large Clinical Population
Authors: Delaney Sarah , Algeciras-Schimnich Alicia , Bornhorst Joshua 
Published: September 2019

Abstract

Background
Pathologic causes of hyperprolactinemia include prolactin-secreting pituitary adenoma (prolactinoma), diseases of the hypothalamus, primary hypothyroidism, and renal failure. Another cause of hyperprolactinemia is the presence of macroprolactin, a high-molecular-mass complex of prolactin and immunoglobulins, which constitutes a biologically inactive form of prolactin. Detection of macroprolactin is important to avoid misdiagnosis and inappropriate treatment; however, relatively little is known about the persistence of macroprolactin in patients over time or how macroprolactin concentrations evolve within patients. The objective of this study was to examine the changes in macroprolactin and prolactin over time in a large clinical population.

Methods
All physician-ordered macroprolactin tests from December 2011 to October 2018 (n = 5,318 unique patients) were examined. Data were extracted from patients with repeat collections (≥2 timepoints) during this 7-year period (n = 269). Macroprolactin testing was performed using the Roche Elecsys Prolactin II assay. Prior to analysis, an equal volume of 25% polyethylene glycol (PEG) was added to patient serum, causing macroprolactin to precipitate. Following centrifugation, unprecipitated prolactin was measured in the supernatant, as well as an aliquot of the native sample (measuring total prolactin). Macroprolactin (precipitated prolactin) was calculated by subtracting the unprecipitated prolactin from the total prolactin concentration. For this study, a specimen was considered positive for macroprolactin if the percentage of precipitated prolactin was ≥60%.

Results
A total of 14% (37/269) of patients tested positive for macroprolactin in at least one of the sequential determinations. For all patients with two or more timepoints, the mean interdetermination change in percent macroprolactin was +0.6% and the mean interdetermination change in total prolactin was –11.6 ng/mL. The mean time between determinations in these patients was 303 days. For the 37 patients that had a positive macroprolactin determination, 25 remained positive across all sample collections (mean interdetermination change of +0.5% macroprolactin, mean interdetermination change in total prolactin of +0.4 ng/mL), seven samples went from positive to negative (mean interdetermination change of –10% macroprolactin, mean change in total prolactin of +0.2 ng/mL), and two samples went from negative to positive (mean interdetermination change of +5.5% macroprolactin, mean change in total prolactin of +1.3 ng/mL). The remaining 3 of the 37 specimens had more than two determinations that fluctuated above and below the predefined cutoff.

Conclusions
The results from this study suggest that the presence of macroprolactin largely but not exclusively persists over time. Additionally, macroprolactin rarely appears after a previously negative assessment (2/235 patients). Furthermore, only small increases in sequential percent macroprolactin determinations were observed in this data set. The prevalence of the persistence of macroprolactin protein over time might have important implications for patient prolactin monitoring.