Editorial: The Macroprolactin Problem

Human prolactin (PRL) is synthesized as a prehormone with a molecular weight of 26,000 kDa. When the preprolactin is cleaved, the resulting polypeptide has a molecular weight of 23,000 kDa, and this monomeric form accounts for the majority of total PRL. Serum also contains a 50,000-kDa form that is termed big PRL and another species with a molecular weight of greater than l00,000 kDa, which is termed big big PRL. In general, big big PRL consists of an antigen antibody complex of monomeric PRL and IgG (1). When the serum of a patient with hyperprolactinemia contains mostly big big PRL the condition is termed macroprolactinemia. Macroprolactinemia has been recognized for many years and is suspected when a patient with hyperprolactinemia lacks typical symptoms and/or has no radiographic evidence of a pituitary tumor (2, 3). Macroprolactinemia is seen in both sexes and in children, and increases in big big PRL occur during pregnancy due to binding of PRL to specific autoantibodies. The incidence of macroprolactinemia in patients with hyperprolactinemia ranges from l8–42% when samples from reference laboratores are assayed (4–6). In contrast, the incidence of macroprolactinemia in patients from an endocrinology practice is closer to l0% (7). Because reference laboratories routinely analyze samples for confirmation of unexpectedly high PRL levels, it is not surprising that macroprolactinemia is more frequent in that situation. Whereas the incidence of macroprolactinemia is not known precisely, the condition is more common than previously recognized. Whether macroprolactin is biologically active is controversial. The earliest studies showed no activity in the NB2 lymphoma cell bioassay, but more recent studies have demonstrated normal bioactivity of big big PRL in the NB2 assay. If big big PRL is biologically active, the effects may be blunted because of decreased bioavailability. The large PRL-Ig complex may fail to reach receptors because of limited capacity to cross-vascular endothelium. Although many patients with macroprolactinemia lack typical symptoms of an elevated PRL, there are multiple reports of patients with macroprolactinemia who present with amenorrhea, galactorrhea, and infertility (5). In a recent prospective analysis, roughly one third of women with macroprolactinemia had amenorrhea and infertility (7). Hauache et al. (8) showed that the presence of macroprolactin does not totally exclude the possibility of a pituitary adenoma, but asymptomatic patients with macroprolactin usually have normal radiographic studies. Recognizing the presence of macroprolactin may help define the etiology in patients with idiopathic hyperprolactinemia, and in some cases recognition of macroprolactinemia might eliminate the need for extensive diagnostic tests or pituitary imaging. This is especially important because 10% of healthy subjects have radiographic evidence of a pituitary adenoma (9). Smith et al. (10), in this issue of JCEM, emphasize the difficulty of detecting macroprolactin with commonly used PRL immunoassays. These authors sent sera from patients with macroprolactinemia to l8 clinical laboratores in the United States and Europe. In nine assay systems, the differences in PRL varied from 2.3to 7.8-fold, and in each case PRL measured after removal of macroprolactin was consistently lower than PRL reported by the immunoanalyzer (10). Schneider et al. (11) also noted that PRL assays vary remarkably in reactivity for macroprolactin. These and other studies (5) suggest that there is no single PRL assay that will give a normal level of monomeric PRL in the presence of big big PRL, but that some assays are better than others. It is surprising that the results from different assays are so discrepant. It is possible that the differences in cross-reactivity are due to the nature of the macroprolactin autoantibody complex, which may mask epitopes that are recognized by the antibodies in the assay. There is no simple method for detection of big big PRL, and clinicians may not be aware that many commercial assays do not provide a procedure for detection of macroprolactin. Gel filtration chromatography is time consuming, expensive, and not used in clinical laboratories. Polyethylene glycol (PEG) precipitates macroprolactin, leaving reduced levels in the supernatant. PEG precipitation is a relatively simple and inexpensive technique but is not specific or quantitative. A percentage recovery of greater than 60% confirms the presence of monomeric PRL whereas a percentage recovery of 40% or less is very sensitive for detecting significant amounts of macroprolactin (5, 6). Recovery between 40% and 60% indicates a sample may contain macroprolactin and oligomeric PRL, in addition to the monomeric form. In these cases, gel filtration chromatography would be necessary to confirm the presence of macroprolactinemia. Equipment manufacturers and clinical laboratories need to clearly characterize their assays with respect to macroprolactin and provide a procedure for detection of big big PRL. Whereas PEG precipitation is simple and could be widely used, not all instrumented assays may be compatible with serum treated in this fashion. It is also vital that laboratories publicize their assay characteristics and that clinicians understand the limitations and variability of the assays. Cavaco et al. (12) have suggested that PRL should be measured by assays that are only minimally affected by macroprolactinemia; however, there are only a few assays that have minimal cross-reactivity with macroprolactin, and it is unlikely that all PRL determinations will be done using only those assays. It would be better for laboratories to develop a method for detecting macroprolactin to screen all samples with elevated PRL for the presence of macroprolactin and to communicate this information to the physicians. With knowledge of the presence of big big PRL, a clinician can determine which patients need further diagnostic studies or radiographs. The presence of macroprolactinemia in a paAbbreviations: PEG, Polyethylene glycol; PRL, prolactin. 0013-7227/02/$15.00/0 The Journal of Clinical Endocrinology & Metabolism 87(12):5408–5409 Printed in U.S.A. Copyright © 2002 by The Endocrine Society doi: 10.1210/jc.2002-021617