Cross reactivity with high molecular weight complexes of prolactin known as macroprolactin is a common cause of positive interference in assays for serum prolactin. All prolactin assays currently available are affected with 5–25% of results indicating hyperprolactinaemia falsely elevated due to macroprolactinaemia – hyperprolactinaemia due to macroprolactin with normal concentrations of bioactive monomeric prolactin. Macroprolactinaemia has no pathological significance but, if it is not recognised as the cause, the apparent hyperprolactinaemia can lead to clinical confusion, unnecessary further investigations, inappropriate treatment and waste of healthcare resources. Macroprolactinaemia cannot be distinguished from true hyperprolactinaemia on clinical grounds alone but can be detected by a simple laboratory test based on the precipitation of macroprolactin with polyethylene glycol. Laboratory screening of all cases of hyperprolactinaemia to exclude macroprolactinaemia has been advised as best practice but has not been implemented universally and reports of clinical confusion caused by macroprolactinaemia continue to appear in the literature. Information provided by manufacturers to users of assays for prolactin regarding interference by macroprolactin is absent or inadequate and does not comply with the European Union Regulation covering in vitro diagnostic medical devices (IVDR). As the IVDR is implemented notified bodies should insist that manufacturers of assays for serum prolactin comply with the regulations by informing users that macroprolactin is a source of interference which may have untoward clinical consequences and by providing an estimate of the magnitude of the interference and a means of detecting macroprolactinaemia. Laboratories should institute a policy for excluding macroprolactinaemia in all cases of hyperprolactinaemia.
Research funding: None declared.
Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
Competing interests: Michael Fahie-Wilson has served as consultant and provided advice to manufacturers of assays referred to in this work. All other authors state no conflict of interest.
Informed consent: Not applicable.
Ethical approval: Not applicable.
1. Wauthier, L, Plebani, M, Favresse, J. Interferences in immunoassays: review and practical algorithm. Clin Chem Lab Med 2022;60:808–20. https://doi.org/10.1515/cclm-2021-1288.Search in Google Scholar
3. Jones, AM, Honour, JW. Unusual results from immunoassays and the role of the clinical endocrinologist. Clin Endocrinol 2006;64:234–44. https://doi.org/10.1111/j.1365-2265.2006.02439.x.Search in Google Scholar
4. Smith, TP, Kelly, S, Fahie-Wilson, MN. Cross-reactivity in assays for prolactin and optimum screening policy for macroprolactinaemia. Clin Chem Lab Med 2022;60:1365–72.10.1515/cclm-2022-0459Search in Google Scholar
8. Whittaker, PG, Wilcox, T, Lind, T. Maintained fertility in a patient with hyperprolactinaemia due to big, big prolactin. J Clin Endocrinol Metab 1981;53:863–6. https://doi.org/10.1210/jcem-53-4-863.Search in Google Scholar
10. Fahie-Wilson, MN, Smith, TP. Determination of prolactin: the macroprolactin problem. Best Pract Res Clin Endocrinol Metabol 2013;27:25–42. https://doi.org/10.1016/j.beem.2013.07.002.Search in Google Scholar PubMed
11. Shimatsu, A, Hattori, N. Macroprolactinaemia: diagnostic, clinical, and pathogenic significance. Clin Dev Immunol 2012;2012:167132. https://doi.org/10.1155/2012/167132.Search in Google Scholar PubMed PubMed Central
12. Wallace, IR, Satti, N, Courtney, CH, Leslie, H, Bell, PM, Hunter, SJ, et al.. Ten-year clinical follow-up of a cohort of 51 patients with macroprolactinaemia establishes it as a benign variant. J Clin Endocrinol Metab 2010;95:3268–71. https://doi.org/10.1210/jc.2010-0114.Search in Google Scholar PubMed
13. Glezer, A, D’Alva, CB, Salgado, LR, Musolino, NR, Serafini, P, Vieira, JC, et al.. Pitfalls in pituitary diagnosis: peculiarities of three cases. Clin Endocrinol 2002;57:135–9. https://doi.org/10.1046/j.1365-2265.2002.01567.x.Search in Google Scholar PubMed
14. Beltran, L, Fahie-Wilson, M, McKenna, T, Kavanagh, L, Smith, T. Serum total prolactin and monomeric prolactin reference intervals determined by precipitation with polyethylene glycol: evaluation and validation on common immunoassay platforms. Clin Chem 2008;54:1673–81. https://doi.org/10.1373/clinchem.2008.105312.Search in Google Scholar PubMed
15. Henry, RK, Bowden, SA. A macroprolactin level today may keep health care cost and the surgical knife at bay. Clin Pediatr 2015;54:283–5. https://doi.org/10.1177/0009922814529017.Search in Google Scholar PubMed
16. Gautam, K, Cherian, KE, Jose, A, Aleyamma, TK, Kapoor, N, Paul, TV. Persistent idiopathic prolactin elevation merits macroprolactin estimation: a case report and review of the literature. J Hum Reprod Sci 2021;14:206–10. https://doi.org/10.4103/jhrs.jhrs_168_20.Search in Google Scholar PubMed PubMed Central
17. Vilar, L, Vilar, C, Albuquerque, JL, The, AC, Gadelha, P, Borges, T, et al.. Importance of routine screening for macroprolactin in symptomatic patients with idiopathic hyperprolactinaemia. An Fac Med Olinda, Recife 2018;1:2–7. https://doi.org/10.56102/afmo.2018.6.Search in Google Scholar
18. Melmed, S, Casanueva, FE, Hoffman, AR, Kleinberg, DL, Montori, VM, Schlechte, JA, et al.. Diagnosis and treatment of hyperprolactinaemia: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2011;96:273–88. https://doi.org/10.1210/jc.2010-1692.Search in Google Scholar PubMed
19. Fahie-Wilson, MN, Bieglmayer, C, Kratzsch, J, Nusbaumer, C, Roth, HJ, Zaninotto, M, et al.. Roche Elecsys prolactin II assay: reactivity with macroprolactin compared with eight commercial assays for prolactin and determination of monomeric prolactin by precipitation with polyethylene glycol. Clin Lab 2007;53:485–92.Search in Google Scholar
20. Whitehead, SJ, Cornes, MP, Ford, C, Gama, R. Reference ranges for serum total and monomeric prolactin for the current generation Abbott Architect assay. Ann Clin Biochem 2015;52:61–6. https://doi.org/10.1177/0004563214547779.Search in Google Scholar PubMed
21. Smith, T, Stern, E, Enqing, T, Vacic, A, Fahie-Wilson, M. Macroprolactin detection by magnetically assisted polyethylene glycol precipitation: potential for automation. J App Lab Med 2020;5:495–505. https://doi.org/10.1093/jalm/jfaa015.Search in Google Scholar PubMed
22. Ellis, MJ, Livesey, JH, Soule, SG. Macroprolactin, big-prolactin and potential effects on the misdiagnosis of hyperprolactinaemia using the Beckman Coulter Access prolactin assay. Clin Biochem 2006;39:1028–34. https://doi.org/10.1016/j.clinbiochem.2006.06.003.Search in Google Scholar PubMed
23. Overgaard, M, Pedersen, SM. Serum prolactin revisited: parametric reference intervals and cross platform evaluation of polyethylene glycol precipitation-based methods for discrimination between hyperprolactinaemia and macroprolactinaemia. Clin Chem Lab Med 2017;55:1744–53. https://doi.org/10.1515/cclm-2016-0902.Search in Google Scholar PubMed
24. Jassam, NF, Paterson, A, Lippiatt, C, Barth, JH. Macroprolactin on the Advia Centaur: experience with 409 patients over a three-year period. Ann Clin Biochem 2009;46:501–4. https://doi.org/10.1258/acb.2009.009059.Search in Google Scholar PubMed
25. European Union. Directive 98/79/EC of the European Parliament and of the Council of 27 October 1998 on in vitro diagnostic medical devices. Annex I. Essential requirements. Section B. Design and manufacturing requirements 8.7(h). Available from: https://eur-lex.europa.eu/legal-content/EN/ALL/?uri=CELEX%3A31998L0079 [Accessed 2 Mar 2022].Search in Google Scholar
26. European Union. Directive 98/79/EC of the European Parliament and of the Council of 27 October 1998 on in vitro diagnostic medical devices. Annex I. Essential Requirements. Section A: General requirements 1. Available from: https://eur-lex.europa.eu/legal-content/EN/ALL/?uri=CELEX%3A31998L0079 [Accessed 2 Mar 2022].Search in Google Scholar
27. Medical device coordination Group document MDCG 2022-2, guidance on general principles of clinical evidence for In Vitro diagnostic medical devices (IVDs). Available from: https://ec.europa.eu/health/system/files/2022-01/mdcg_2022-2_en.pdf [Accessed 2 Mar 2022].Search in Google Scholar
28. Vogeser, M, Bruggeman, M, Lennerz, J, Stenzinger, A, Gassner, UM. Laboratory-developed tests in the new European Union 2017/746 regulation: opportunities and risks. Clin Chem 2022;68:40–2. https://doi.org/10.1093/clinchem/hvac048.Search in Google Scholar PubMed
29. Cobbaert, C, Capoluongo, ED, Vanstapel, FJ, Bossuyt, PM, Bhattoa, HP, Nissen, PH, et al.. Implementation of the new EU IVD regulation - urgent initiatives are needed to avert impending crisis. Clin Chem Lab Med 2022;60:33–43. https://doi.org/10.1515/cclm-2021-0975.Search in Google Scholar PubMed
30. Vogeser, M, Bruggeman, M, Lennerz, J, Stenzinger, A, Gassner, UM. Partial postponement of the application of the In Vitro diagnostic medical devices regulation in the European union. Clin Chem 20 May 2022. https://doi.org/10.1093/clinchem/hvac048 [Epub ahead of print].Search in Google Scholar
31. Fahie-Wilson, MN, McKenna, TJ, Ahlquist, JA, Smith, TP. Macroprolactin and the Pituitary Society guidelines for the diagnosis and management of prolactinomas. Clin Endocrinol 2007;67:638–9. https://doi.org/10.1111/j.1365-2265.2007.02940.x.Search in Google Scholar PubMed
© 2022 Walter de Gruyter GmbH, Berlin/Boston