Editorial: Is macroprolactinemia just a diagnostic pitfall?

Abstract

As hyperprolactinemia is involved in the impairment of the gonadotropic axis, serum prolactin (PRL) assessment is often required in the clinical scenario of menstrual disturbances, infertility, loss of libido, galactorrhea, osteoporosis, and bone fractures [1–3]. Nevertheless, the excessive requirement of PRL determination led to an important laboratory pitfall: the find of hyperprolactinemia in subjects with few or no symptoms related to such condition. Human PRL in circulation has marked size heterogeneity, mainly with three forms: 23 kDa (monomeric or little PRL), 50 kDa (dimeric or big PRL), and 150–170 kDa (big–big prolactin or macroprolactin, the three forms being indistinguishable by routine assays [4]. Nevertheless, monomeric PRL, the most common form, is considered to be the biological active one, whereas molecular aggregates as macroprolactin are regarded to have low biologic activity. Therefore, the predominance of macroprolactin, associated with normal levels of monomeric PRL, may lead to the laboratorial diagnosis of hyperprolactinemia in subjects with no symptoms, ending up in unnecessary treatment approaches. The gel-filtration chromatography is the goldstandard method to confirm the presence of big–big PRL, but is a costly and time-consuming process. For routine purposes, precipitation with polyethylene glycol (PEG) is an excellent screening method [5]. The predominant molecular form recovered (i.e., assayed after precipitation) is the highly biologically active monomeric PRL. Usually considering macroprolactin [60% of total PRL, macroprolactinemia has been shown as a common finding, occurring in 8–42% of all cases of hyperprolactinemia. The reason for such large range can be attributed both to selection bias and the use of diverse assays, which differently recognize the amount of big–big PRL in each sample [6]. Macroprolactin biologic activity is still controversial in the literature. Studies in vitro with rat Nb2 cell bioassays show either its presence or absence. To explain the presence of activity in vitro but not in vivo, it was hypothesized that its high molecular weight impairs capillary barrier crossing and its action on target cells. Moreover, the Nb2 cells are a PRL-dependent rat immune cell line expressing a mutant form of PRL receptor, so a bioassay using cells harboring human PRL receptors which addresses the biologic activity of macroprolactin should be more reliable. In fact, a study by Glezer et al. [7] showed that sera of individuals with macroprolactinemia presented lower biological activity in a bioassay using a mouse cell transfected with the long form of human PRL receptor as compared to the rat Nb2 bioassay. Moreover, Hattori et al. [8] assume that the bioactivity of macroprolactin in the Nb2 bioassay is due to dissociation of monomeric PRL from the autoantibodies as a result of the longer incubation than in a bioassay using human breast cancer cells. Despite these controversies in the literature concerning the biologic activity of PRL aggregates, most patients with macroprolactinemia do not manifest clinical features related to hyperprolactinemia. This Endocrine issue brings two publications from Turkey addressing the macroprolactin matter. In one study, Isik et al. [9] enrolled 337 hyperprolactinemic individuals, and found that in 26.1% of them macroprolactinemia prevailed, based on a percentage of PRL in the serum supernatant \40% after PEG precipitation. Subjects with PRL recover value of C40% were considered with absence of M. D. Bronstein (&) Neuroendocrine Unit, Division of Endocrinology and Metabolism, Hospital das Clinicas, University of Sao Paulo, Sao Paulo, SP, Brazil e-mail: mdbronstein@uol.com.br