Macroprolactinemia Is Clinically Important

Adebayo O. Olukoga

East Didsbury, Manchester M20 5QD, United Kingdom

Address correspondence to: Adebayo O. Olukoga, M.D., 9 Jayton Avenue, East Didsbury, Manchester M20 5QD, United Kingdom. E-mail: aolukoga{at}hotmail.com.

To the editor:

The study by Vallette-Kasic et al. (1), published in a recent issue of JCEM, found that a sizable proportion of women with macroprolactinemia presented with clinical symptoms usually associated with hyperprolactinemia, such as menstrual disorders, galactorrhea, or infertility, even when such women have had previous uneventful pregnancies. The authors also noted that dopamine agonist therapy may sometimes have beneficial effects on both serum prolactin (PRL) concentrations and symptoms. Considering that the clinical relevance of macroprolactinemia is still controversial, these results are significant not only because the study was prospective and involved the largest number of patients to be so investigated to date, but also because they provide the strongest indication yet that macroprolactinemia can be a direct cause of morbidity. Interestingly, the results also confirm findings in a previous retrospective, systematic clinical study of a smaller number of patients (2). The earliest reports of macroprolactinemia were isolated cases discovered as incidentalomas in patients being investigated for nonreproductive endocrine problems or healthy research volunteers who had no symptoms of hyperprolactinemia (3, 4). Subsequently, the condition was suspected mainly when unexplained hyperprolactinemia was found without recognized symptoms of PRL excess; this situation may have helped perpetuate the notion that macroprolactinemia is essentially asymptomatic. However, findings in more recent clinical studies indicate that some patients do, indeed, present with such symptoms (2, 5, 6, 7, 8). The balance of evidence, therefore, would favor the view that macroprolactinemia may be associated with reproductive symptoms of PRL excess in some patients but not in others. In addition to the potential for clinical symptoms, macroprolactinemia can cause diagnostic confusion in different ways. For example, macroprolactinemia is often the unrecognized factor in cases of the so-called idiopathic hyperprolactinemia and can mimic a PRL-secreting pituitary tumor (9). Moreover, when macroprolactinemia coexists with an imaging evidence of a pituitary microadenoma, as observed by Vallette-Kasic et al. (1), it is sometimes difficult to resolve whether the tumor is nonfunctioning or PRL-secreting (and hence, contributing to raised serum PRL concentration; Ref. 2). Furthermore, macroprolactinemia may be the unexplained cause of persistent hyperprolactinemia after an otherwise successful pituitary microsurgery for (micro)prolactinoma (7). Finally, variable recognition of macroprolactin by PRL immunoassays (10) can contribute to method-dependent bias and make interpretation and transferability of PRL results difficult. Although this capability to cause diagnostic uncertainty is in itself of some clinical relevance, it is the fact that patients can suffer from symptoms of hyperprolactinemia that really makes macroprolactinemia clinically important, worth detecting, and therefore eligible for recognition as a distinct cause of hyperprolactinemia.

The presence of symptoms of PRL excess in patients with macroprolactinemia has implications for our understanding of the condition and how it is perceived clinically and analytically. Firstly, we are provided with evidence that macroprolactin has some bioactivity in vivo, therefore it could be regarded as a circulating store of potentially bioactive PRL. In this context, it is noteworthy that elevated serum concentrations of free PRL (as determined in the polyethylene glycol precipitation test; Ref. 11) or monomeric PRL (as assessed by gel filtration chromatography; Ref. 2) have been found in some patients with macroprolactinemia. It is, therefore, possible that increasing bioavailability of monomeric PRL due, perhaps, to intermittent dissociation from the low affinity, high capacity IgG antibody to which it is bound in macroprolactin, and/or influence of macroprolactin in PRL secretion, may be a contributory factor to development of symptoms of PRL excess.

Secondly, indication is given that hyperprolactinemia caused by macroprolactin is neither completely harmless nor apparent. Therefore, macroprolactin cannot be dismissed simply as an analytical artifact as it is currently regarded by some workers, in obvious analogy to other macroanalyte phenomena such as macroamylase and macro-CK type 1. These phenomena, like macroprolactinemia, have antibody-bound analytes in circulation, cause elevated measured concentrations of the relevant analytes, and hence can create diagnostic confusion; but unlike macroprolactinemia, they are never associated directly with any metabolic consequences or clinical symptoms. Strictly speaking, therefore, it would be inappropriate to equate macroprolactinemia with any of these harmless macro-analyte phenomena. Instead, macroprolactinemia should be seen as one of those macro-analyte phenomena with a potential to cause morbidity; a prime example is the autoimmune insulin syndrome, a condition in which the majority of circulating insulin is bound to autoantibodies, causing elevated immunoassayable insulin and intermittent hypoglycemic symptoms. This distinction is more than just academic, because it enables macroprolactinemia to be viewed from the proper perspective.

Thirdly, there arises the question of whether or not immunoassays for PRL should ideally be reactive to macroprolactin, as do all those currently available for routine use, albeit to varying degrees. Some authors have called for the development of PRL assays that react with only monomeric PRL and are blind to macroprolactin as a means of neutralizing its effect. Although such blind assays should largely prevent any diagnostic confusion that may be caused by the presence of macroprolactin, they will fail to identify macroprolactin-related hyperprolactinemia as the cause of (unexplained) symptoms of PRL excess in some individuals. Therefore, evidence that macroprolactinemia can cause clinical symptoms would appear to establish the case for embracing PRL assays that react with macroprolactin.

Finally, the issue of how patients should be managed, especially if symptoms ascribable to hyperprolactinemia are present, becomes pertinent. This requires knowledge of the natural history of macroprolactinemia; but at the moment, there is paucity of information on this aspect. It is unknown, for example, whether or not patients who are asymptomatic at diagnosis will later develop symptoms or whether the few who experience spontaneous resolution of symptoms (2) will become symptomatic again at some point. Moreover, in symptomatic patients who may benefit from dopamine agonist therapy, as shown by Vallette-Kasic et al. (1) and other studies (2, 6), the treatment strategy to adopt is unclear. More evidence and discussion are needed to enable informed decisions to be made.

Received July 17, 2002.

References

  1. Vallette-Kasic S, Morange-Ramos I, Selim A, Gunz G, Morange S, Enjalbert A, Martin P, Jaquet P, Brue T 2002 Macroprolactinemia revisited: a study on 106 patients. J Clin Endocrinol Metab 87:581–588[Abstract/Free Full Text]
  2. Olukoga AO, Kane JW 1999 Macroprolactinemia: validation and application of the polyethylene glycol precipitation test and clinical characterisation of the condition. Clin Endocrinol (Oxf) 51:119–126[CrossRef][Medline]
  3. Rogol A, Rosen SW 1974 Prolactin of apparent large molecular size: the major immunoreactive prolactin component in plasma of a patient with a pituitary tumor. J Clin Endocrinol Metab 38:714–717[Medline]
  4. Whittaker PG, Wilcox T, Lind T 1981 Maintained fertility in a patient with hyperprolactinemia due to big, big prolactin. J Clin Endocrinol Metab 53: 863–866
  5. Leite V, Cosby H, Sobrinho LG, Fresnoza A, Amparo Santos MA, Friesen HG 1992 Characterisation of big, big prolactin in patients with hyperprolactinemia. Clin Endocrinol 37:365–372[Medline]
  6. Brue T, Rossi E, Enzo C, Morange I, Gunz G, Prou A, Jaquet P 1993 Hyperprolactinemia with predominant high molecular weight immuno-reactive prolactin variants: a study of 20 patients and review of literature. Exp Clin Endocrinol (Life Sci Adv) 12:201–213
  7. Olukoga AO, Dornan TL, Kane JW 1999 Three cases of macroprolactinemia. J R Soc Med 92:342–344[Abstract]
  8. Cattaneo F, Kappeler D, Müller B 2001 Macroprolactinemia, the major unknown in the differential diagnosis of hyperprolactinemia. Swiss Med Wkly 131:122–126[Medline]
  9. Jackson RD, Worstman J, Malarkey WB 1985 Macroprolactinaemia presenting like a pituitary tumor. Am J Med 78:346–350[Medline]
  10. Cavaco B, Prazeres S, Santos MA, Sobrinho LG, Leite V 1999 Hyperprolactinaemia due to big, big prolactin is differently detected by commercially available immunoassays. J Endocrinol Invest 22:203–208[Medline]
  11. Sapin R, Gasser F, Grucker D 2002 Free prolactin determinations in hyperprolactinemic men with suspicion of macroprolactinemia. Clin Chim Acta 316:33–41[CrossRef][Medline]