Detection of Macroprolactin Causing Hyperprolactinemia in Commercial Assays for Prolactin

John et al. (1) presented two clinical cases demonstrating the diagnostic confusion created by cases of hyperprolactinemia that are attributable to the presence of macroprolactin. The authors urged manufacturers of prolactin (PRL) reagents to (a) indicate in their product literature the extent to which macroprolactin interferes in their assays, and (b) have available a validated method to confirm the presence of macroprolactin. Considerable progress has been made in both of these issues since the distribution of serum from one of the cases presented by John et al. (1) by the United Kingdom National External Quality Assessment Scheme (UKNEQAS) (2); however, most of the data have been presented only in preliminary form. A more recent UKNEQAS distribution of a serum containing macroprolactin (2) provided data on more recently introduced assays, as well as on a wider range of assays (Table 1 ), and showed a pattern of reactivity in PRL assays similar to that presented by John et al. (1). The Roche Elecsys PRL assay (2) reacted strongly with macroprolactin in this sample, as indicated by product literature. Polyethylene glycol (PEG) precipitation has been validated as a technique for detection of macroprolactin with the Elecsys PRL assay (3). PEG precipitation has also been validated for use with the Bayer Immuno-1 PRL assay (4). These data have been presented at user group meetings, and guidance has been issued to users in the United Kingdom. The recently introduced Abbott Architect PRL assay reacts strongly with macroprolactin, and PEG precipitation has also been validated with this assay (5). PEG interferes in the Abbott AxSYM PRL assay, but preliminary communications (6)(7) have described detection of macroprolactin by centrifugal ultrafiltration with this assay, and a full publication is in preparation. In the Wallac Delfia assay, macroprolactin has been identified as the cause of hyperprolactinemia in 15–17% of patient samples with increased serum PRL (8). In the Elecsys and Architect assays, macroprolactin has been identified as the cause of hyperprolactinemia in 16–17% of patient samples with increased serum PRL (3)(5). Preliminary results indicate a similar prevalence with the Immuno-1 (4), and it seems probable that this can be expected with all of the relatively strongly reacting assays in Table 1 . The Bayer/Chiron PRL assays on the ACS:180 and Centaur analyzers have been considered low-reacting assays with regard to the presence of macroprolactin, as illustrated by the serums distributed through UKNEQAS (1)(2). The differences between the results of relatively high- and low-reacting assays have been taken as an indication of the presence of macroprolactin in samples. Inspection of estimates of monomeric PRL by gel-filtration chromatography in these samples suggests that although the Bayer/Chiron PRL assays react with the macroprolactin present, these assays generally react to a lesser extent than others. The structure of macroprolactin is variable (9), and the reaction of PRL assays with macroprolactin is also variable (4)(10). The Bayer/Chiron PRL assays may react strongly with the macroprolactin in some patient samples, and concordance of results with other assays does not exclude macroprolactin as a cause of hyperprolactinemia. PEG interferes in the Bayer/Chiron PRL assays, and further work is needed to (a) establish the prevalence of macroprolactin as a cause of hyperprolactinemia with these assays, and (b) develop a method for detecting macroprolactin in these assays. The distribution of specimens containing macroprolactin through UKNEQAS has provided valuable information on the response of PRL assays to macroprolactin. This distribution has also heightened awareness of macroprolactin and encouraged laboratories to consider and investigate macroprolactin as a possible cause of hyperprolactinemia. In the most recent distribution, 49% of respondents considered macroprolactin as a potential cause of hyperprolactinemia, and 5% of respondents who used assays that reacted strongly with the macroprolactin investigated and detected the presence of macroprolactin. Greater awareness of the problem is still required, but considerable progress has been made. Method mean PRL results for PRL serum containing 93% macroprolactin and 7.1 μg/L monomeric PRL distributed through the UKNEQAS.1 Macroprolactin and monomeric PRL were determined by gel-filtration chromatography and the Wallac Delfia PRL assay. n = number of laboratories contributing results to method men. Method mean PRL results for PRL serum containing 93% macroprolactin and 7.1 μg/L monomeric PRL distributed through the UKNEQAS.1 Macroprolactin and monomeric PRL were determined by gel-filtration chromatography and the Wallac Delfia PRL assay. n = number of laboratories contributing results to method men.