Hyperprolactinemia: new assay more specific for the monomeric form does not eliminate screening for macroprolactin with polyethylene glycol precipitation.

Prolactin presents important size heterogeneity in terms of circulating molecular forms. Besides the monomer (23kDa), which predominates in healthy subjects as well as in patients with prolactinoma, high molecular forms are also present in low concentrations (1). These high molecular forms include 50 kDa dimers (big prolactin) and also forms with even larger molecular weights (MW>150 kDa), known as big-big or macroprolactin. According to our current knowledge, the biological action of prolactin is almost exclusively associated with the monomeric form (2). Most of macroprolactin is related to the presence of endogenous anti-prolactin antibodies that, acting like a binding protein, prolong the half-life and block receptor binding (3). The practical implication of these facts stems from the observation that in some individuals macroprolactin is the main circulating form, and routine assays for prolactin do not distinguish between the different size forms. This phenomenon can lead to misdiagnosis, with important clinical implications, and have been reported by several authors to be present in more than 15% of the patients with hyperprolactinemia (4). Based on cumulative experience it is considered that best practice involves the screening for macroprolactinemia in all samples with hyperprolactinemia. The gold standard to define the presence of macroprolactinemia is gel filtration chromatography, but due to the expertise and costs involved, more simple alternatives have been developed, with polyethylene glycol (PEG) precipitation being the most used. The technique consists of measurement of prolactin in a serum sample and, when hyperprolactinemia is present, the sample is submitted to precipitation with PEG solution and the measurement is repeated in the supernatant that contains almost exclusively monomeric prolactin (5). Experience with screening of samples with hyperprolactinemia points to the conclusion that the best way to describe normal reference ranges for prolactin may be its definition in terms of monomeric values, based on PEG precipitation (6). One additional reason for this position is the fact that different assays (nowadays different automatic platforms) recognize macroprolactin differently (7). The ideal solution would be to have assays that do not recognize macroprolactin, so that in the case of hyperprolactinemia one could trust that it represents solely monomeric hyperprolactinemia. Several publications have recently described new commercial assays with low recognition of macroprolactin (8-10). 1 Endocrinology Sector, Grupo Fleury, São Paulo, SP, Brazil