Abstract
Objectives
Macroprolactin (macro-PRL) mostly comprises a complex of PRL with IgG. The aim of this study was to clarify whether IgA-type macro-PRL exists and, if so, to elucidate the prevalence of and differences in laboratory data from IgG-type.
Methods
One hundred thirty patients with macroprolactinemia who were diagnosed through screening via the polyethylene glycol precipitation method followed by confirmation using gel filtration chromatography (GFC) were examined. IgA-type and IgG-type macro-PRLs were identified via Jacalin column/SDS‒PAGE and protein G columns, respectively.
Results
SDS‒PAGE under nonreducing conditions followed by western blotting with an IgA antibody revealed that the fraction bound to the Jacalin column was actually IgA. The PRL band was detected at the same position as the IgA band, which was purified with a Jacalin column, suggesting that PRL was bound to IgA. The finding that the PRL band was observed not only at the same position as IgA but also at the same position as the 23 kDa PRL reference suggested that some PRL dissociated from IgA during SDS‒PAGE. The prevalence rates of macro-PRL of only IgA, IgA plus IgG, only IgG, and non-IgA/non-IgG types were 7.7, 3.1, 83.8, and 5.4 %, respectively. Neither the PEG precipitation ratios of PRL nor the macro-PRL ratios on GFC differed between IgA- and IgG-type macro-PRLs, whereas both ratios were significantly lower in non-IgA/non-IgG-type macro-PRL.
Conclusions
IgA-type macro-PRL was demonstrated to exist. IgG-type macro-PRL was most prevalent, followed by IgA, non-IgA/non-IgG and IgA plus IgG-type macro-PRLs.
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Research ethics: This study was approved by the Clinical Research Review Board of the Hamada Obstetrics and Gynecology Hospital and the Research Ethics Review Board of the Kansai Medical University. This research was completed in accordance with the Declaration of Helsinki.
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Informed consent: Informed consent was obtained from the participants included in this study.
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Author contributions: Masayuki Ishihara and Naoki Hattori conceived and performed the experiments, and wrote the manuscript in consultation with Takanori Saito. Kohozo Aisaka contributed to clinical sample collection and the analysis of the clinical data. Norito Nishiyama and Takashi Adachi carried out the experiments. All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
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Use of Large Language Models, AI and Machine Learning Tools: None declared.
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Conflict of interest: The authors state no conflict of interest.
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Research funding: None declared.
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Data availability: The raw data can be obtained on request from the corresponding author.
References
1. Fahie-Wilson, MN, Soule, SG. Macroprolactinaemia: contribution to hyperprolactinaemia in a district general hospital and evaluation of a screening test based on precipitation with polyethylene glycol. Ann Clin Biochem 1997;34:252–8. https://doi.org/10.1177/000456329703400305.Search in Google Scholar PubMed
2. Leslie, H, Courtney, CH, Bell, PM, Hadden, DR, McCance, DR, Ellis, PK, et al.. Laboratory and clinical experience in 55 patients with macroprolactinemia identified by a simple polyethylene glycol precipitation method. J Clin Endocrinol Metab 2001;86:2743–6. https://doi.org/10.1210/jcem.86.6.7521.Search in Google Scholar PubMed
3. Vallette-Kasic, S, Morange-Ramos, I, Selim, A, Gunz, G, Morange, S, Enjalbert, A, et al.. Macroprolactinemia revisited: a study on 106 patients. J Clin Endocrinol Metab 2002;87:581–8. https://doi.org/10.1210/jcem.87.2.8272.Search in Google Scholar PubMed
4. Gibney, J, Smith, TP, McKenna, TJ. Clinical relevance of macroprolactin. Clin Endocrinol 2005;62:633–43. https://doi.org/10.1111/j.1365-2265.2005.02243.x.Search in Google Scholar PubMed
5. Hattori, N, Ishihara, T, Saiki, Y. Macroprolactinaemia: prevalence and aetiologies in a large group of hospital workers. Clin Endocrinol 2009;71:702–8. https://doi.org/10.1111/j.1365-2265.2009.03570.x.Search in Google Scholar PubMed
6. Fahie-Wilson, MN, John, R, Ellis, AR. Macroprolactin; high molecular mass forms of circulating prolactin. Ann Clin Biochem 2005;42:175–92. https://doi.org/10.1258/0004563053857969.Search in Google Scholar PubMed
7. Fahie-Wilson, MN, Cobbaert, CM, Horvath, AR, Smith, TP. Interference by macroprolactin in assays for prolactin: will the in vitro diagnostics regulation lead to a solution at last? Clin Chem Lab Med 2022;60:1350–5. https://doi.org/10.1515/cclm-2022-0460.Search in Google Scholar PubMed
8. Soh, NAAC, Yaacob, NM, Omar, J, Jelani, AM, Shafii, N, Ismail, TST, et al.. Global prevalence of macroprolactinemia among patients with hyperprolactinemia: a systematic review and meta-analysis. Int J Environ Res Publ Health 2020;17:8199. https://doi.org/10.3390/ijerph17218199.Search in Google Scholar PubMed PubMed Central
9. Hattori, N, Inagaki, C. Anti-prolactin (PRL) autoantibodies cause asymptomatic hyperprolactinemia: bioassay and clearance studies of PRL-immunoglobulin G complex. J Clin Endocrinol Metab 1997;82:3107–10. https://doi.org/10.1210/jcem.82.9.4250.Search in Google Scholar PubMed
10. Hattori, N, Nakayama, Y, Kitagawa, K, Ishihara, T, Saiki, Y, Inagaki, C. Anti-prolactin (PRL) autoantibodies suppress PRL bioactivity in patients with macroprolactinaemia. Clin Endocrinol 2008;68:72–6. https://doi.org/10.1111/j.1365-2265.2007.03001.x.Search in Google Scholar PubMed
11. Leaños-Miranda, A, Cárdenas-Mondragón, G, Rivera-Leaños, R, Ulloa-Aguirre, A, Goffin, V. Application of new homologous in vitro bioassays for human lactogens to assess the actual bioactivity of human prolactin isotypes in hyperprolactinaemic patients. Clin Endocrinol 2006;65:146–53.10.1111/j.1365-2265.2006.02548.xSearch in Google Scholar PubMed
12. Schiettecatte, J, De Schepper, J, Velkeniers, B, Smitz, J, Van Steirteghem, A. Rapid detection of macroprolactin in the form of prolactin-immunoglobulin G complexes by immunoprecipitation with anti-human IgG-agarose. Clin Chem Lab Med 2001;39:1244–8. https://doi.org/10.1515/cclm.2001.200.Search in Google Scholar PubMed
13. De Schepper, J, Schiettecatte, J, Velkeniers, B, Blumenfeld, Z, Shteinberg, M, Devroey, P, et al.. Clinical and biological characterization of macroprolactinemia with and without prolactin-IgG complexes. Eur J Endocrinol 2003;149:201–7. https://doi.org/10.1530/eje.0.1490201.Search in Google Scholar PubMed
14. Lippi, G, Plebani, M. Macroprolactin: searching for a needle in a haystack? Clin Chem Lab Med 2016;54:519–22. https://doi.org/10.1515/cclm-2015-1283.Search in Google Scholar PubMed
15. Mills, F, Jeffery, J, Mackenzie, P, Cranfield, A, Ayling, RM. An immunoglobulin G complexed form of thyroid-stimulating hormone (macro thyroid-stimulating hormone) is a cause of elevated serum thyroid-stimulating hormone concentration. Ann Clin Biochem 2013;50:416–20. https://doi.org/10.1177/0004563213476271.Search in Google Scholar PubMed
16. Yamada, A, Hattori, N, Matsuda, T, Nishiyama, N, Shimatsu, A. Clearance of macro-TSH from the circulation is slower than TSH. Clin Chem Lab Med 2022;60:e132–5. https://doi.org/10.1515/cclm-2022-0131.Search in Google Scholar PubMed
17. Biondi, B, Cooper, DS. The clinical significance of subclinical thyroid dysfunction. Endocr Rev 2008;29:76–131. https://doi.org/10.1210/er.2006-0043.Search in Google Scholar PubMed
18. Spitz, IM, Le Roith, D, Hirsch, H, Carayon, P, Pekonen, F, Liel, Y, et al.. Increased high-molecular-weight thyrotropin with impaired biologic activity in a euthyroid man. N Engl J Med 1981;304:278–82. https://doi.org/10.1056/nejm198101293040506.Search in Google Scholar PubMed
19. Hattori, N, Ishihara, T, Yamagami, K, Shimatsu, A. Macro TSH in patients with subclinical hypothyroidism. Clin Endocrinol 2015;83:923–30. https://doi.org/10.1111/cen.12643.Search in Google Scholar PubMed
20. Nkuna, X, Dire, Z, Khoza, S. A macro-TSH: a clinical diagnostic dilemma. J Int Fed Clin Chem Lab Med 2022;33:317–24.Search in Google Scholar
21. Fukushita, M, Watanabe, N, Noh, JY, Yoshihara, A, Matsumoto, M, Suzuki, N, et al.. A case of macro-TSH consisting of IgA-bound TSH. Endocr J 2021;68:1241–6.10.1507/endocrj.EJ21-0021Search in Google Scholar PubMed
22. Hattori, N, Aisaka, K, Shimatsu, A. A possible cause of the variable detectability of macroprolactin by different immunoassay systems. Clin Chem Lab Med 2016;54:603–8. https://doi.org/10.1515/cclm-2015-0484.Search in Google Scholar PubMed
23. Roque-Barreira, MC, Campos-Neto, A. Jacalin: an IgA-binding lectin. J Immunol 1985;134:1740–3. https://doi.org/10.4049/jimmunol.134.3.1740.Search in Google Scholar
24. Bonhoff, A, Vuille, JC, Gomez, F, Gellersen, B. Identification of macroprolactin in a patient with asymptomatic hyperprolactinemia as a stable PRL-IgG complex. Exp Clin Endocrinol Diabetes 1995;103:252–5. https://doi.org/10.1055/s-0029-1211358.Search in Google Scholar PubMed
25. Hattori, N. The frequency of macroprolactinemia in pregnant women and the heterogeneity of its etiologies. J Clin Endocrinol Metab 1996;81:586–90. https://doi.org/10.1210/jcem.81.2.8636272.Search in Google Scholar PubMed
26. Nguyen, KQN, Langevin, RH, McPhaul, MJ, Hashim, IA. Circulating macroprolactin exhibits molecular heterogeneity and is not exclusively an antibody complex. Clin Chim Acta 2021;514:90–5.10.1016/j.cca.2020.12.018Search in Google Scholar PubMed
27. Carlson, HE, Markoff, E, Lee, DW. On the nature of serum prolactin in two patients with macroprolactinemia. Fertil Steril 1992;58:78–87. https://doi.org/10.1016/s0015-0282(16)55140-1.Search in Google Scholar
28. Gleeson, PJ, Camara, NOS, Launay, P, Lehuen, A, Monteiro, RC. Immunoglobulin A antibodies: from protection to harmful roles. Immunol Rev 2024;328:171–91. https://doi.org/10.1111/imr.13424.Search in Google Scholar PubMed PubMed Central
29. Chi, X, Li, Y, Qiu, X. V(D)J recombination, somatic hypermutation and class switch recombination of immunoglobulins: mechanism and regulation. Immunology 2020;160:233–47. https://doi.org/10.1111/imm.13176.Search in Google Scholar PubMed PubMed Central
© 2025 Walter de Gruyter GmbH, Berlin/Boston
Articles in the same Issue
- Frontmatter
- Editorial
- Macroprolactinaemia – some progress but still an ongoing problem
- Review
- Understanding the circulating forms of cardiac troponin: insights for clinical practice
- Opinion Papers
- New insights in preanalytical quality
- IFCC recommendations for internal quality control practice: a missed opportunity
- Genetics and Molecular Diagnostics
- Evaluation of error detection and treatment recommendations in nucleic acid test reports using ChatGPT models
- General Clinical Chemistry and Laboratory Medicine
- Pre-analytical phase errors constitute the vast majority of errors in clinical laboratory testing
- Improving the efficiency of quality control in clinical laboratory with an integrated PBRTQC system based on patient risk
- IgA-type macroprolactin among 130 patients with macroprolactinemia
- Prevalence and re-evaluation of macroprolactinemia in hyperprolactinemic patients: a retrospective study in the Turkish population
- Defining dried blood spot diameter: implications for measurement and specimen rejection rates
- Screening primary aldosteronism by plasma aldosterone-to-angiotensin II ratio
- Assessment of serum free light chain measurements in a large Chinese chronic kidney disease cohort: a multicenter real-world study
- Beyond the Hydrashift assay: the utility of isoelectric focusing for therapeutic antibody and paraprotein detection
- Direct screening and quantification of monoclonal immunoglobulins in serum using MALDI-TOF mass spectrometry without antibody enrichment
- Effect of long-term frozen storage on stability of kappa free light chain index
- Impact of renal function impairment on kappa free light chain index
- Standardization challenges in antipsychotic drug monitoring: insights from a national survey in Chinese TDM practices
- Potential coeliac disease in children: a single-center experience
- Vitamin D metabolome in preterm infants: insights into postnatal metabolism
- Candidate Reference Measurement Procedures and Materials
- Development of commutable candidate certified reference materials from protein solutions: concept and application to human insulin
- Reference Values and Biological Variations
- Biological variation of serum cholinesterase activity in healthy subjects
- Hematology and Coagulation
- Diagnostic performance of morphological analysis and red blood cell parameter-based algorithms in the routine laboratory screening of heterozygous haemoglobinopathies
- Cancer Diagnostics
- Promising protein biomarkers for early gastric cancer: clinical performance of combined detection
- Infectious Diseases
- The accuracy of presepsin in diagnosing neonatal late-onset sepsis in critically ill neonates: a prospective study
- Corrigendum
- The Unholy Grail of cancer screening: or is it just about the Benjamins?
- Letters to the Editor
- Analytical validation of hemolysis detection on GEM Premier 7000
- Reconciling reference ranges and clinical decision limits: the case of thyroid stimulating hormone
- Contradictory definitions give rise to demands for a right to unambiguous definitions
- Biomarkers to measure the need and the effectiveness of therapeutic supplementation: a critical issue
Articles in the same Issue
- Frontmatter
- Editorial
- Macroprolactinaemia – some progress but still an ongoing problem
- Review
- Understanding the circulating forms of cardiac troponin: insights for clinical practice
- Opinion Papers
- New insights in preanalytical quality
- IFCC recommendations for internal quality control practice: a missed opportunity
- Genetics and Molecular Diagnostics
- Evaluation of error detection and treatment recommendations in nucleic acid test reports using ChatGPT models
- General Clinical Chemistry and Laboratory Medicine
- Pre-analytical phase errors constitute the vast majority of errors in clinical laboratory testing
- Improving the efficiency of quality control in clinical laboratory with an integrated PBRTQC system based on patient risk
- IgA-type macroprolactin among 130 patients with macroprolactinemia
- Prevalence and re-evaluation of macroprolactinemia in hyperprolactinemic patients: a retrospective study in the Turkish population
- Defining dried blood spot diameter: implications for measurement and specimen rejection rates
- Screening primary aldosteronism by plasma aldosterone-to-angiotensin II ratio
- Assessment of serum free light chain measurements in a large Chinese chronic kidney disease cohort: a multicenter real-world study
- Beyond the Hydrashift assay: the utility of isoelectric focusing for therapeutic antibody and paraprotein detection
- Direct screening and quantification of monoclonal immunoglobulins in serum using MALDI-TOF mass spectrometry without antibody enrichment
- Effect of long-term frozen storage on stability of kappa free light chain index
- Impact of renal function impairment on kappa free light chain index
- Standardization challenges in antipsychotic drug monitoring: insights from a national survey in Chinese TDM practices
- Potential coeliac disease in children: a single-center experience
- Vitamin D metabolome in preterm infants: insights into postnatal metabolism
- Candidate Reference Measurement Procedures and Materials
- Development of commutable candidate certified reference materials from protein solutions: concept and application to human insulin
- Reference Values and Biological Variations
- Biological variation of serum cholinesterase activity in healthy subjects
- Hematology and Coagulation
- Diagnostic performance of morphological analysis and red blood cell parameter-based algorithms in the routine laboratory screening of heterozygous haemoglobinopathies
- Cancer Diagnostics
- Promising protein biomarkers for early gastric cancer: clinical performance of combined detection
- Infectious Diseases
- The accuracy of presepsin in diagnosing neonatal late-onset sepsis in critically ill neonates: a prospective study
- Corrigendum
- The Unholy Grail of cancer screening: or is it just about the Benjamins?
- Letters to the Editor
- Analytical validation of hemolysis detection on GEM Premier 7000
- Reconciling reference ranges and clinical decision limits: the case of thyroid stimulating hormone
- Contradictory definitions give rise to demands for a right to unambiguous definitions
- Biomarkers to measure the need and the effectiveness of therapeutic supplementation: a critical issue