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Technology Insight: measuring prolactin in clinical samples

Nature Clinical Practice Endocrinology & Metabolism volume 3, pages 279–289 (2007)Cite this article

Abstract

Measurement of prolactin is one of the most commonly undertaken hormonal investigations in evaluating patients with reproductive disorders. Hyperprolactinemia is found in up to 17% of such cases. Diagnostic evaluation of hyperprolactinemia is difficult but is facilitated by a logical approach where a thorough patient history is obtained, secondary causes of hyperprolactinemia are excluded, and the limitations of current prolactin assays are appreciated. Once hyperprolactinemia has been confirmed, attempts to establish the underlying cause can start. Given current workloads, laboratories rely on automated platforms to measure prolactin, most of which employ two-site immunoassay sandwich methods. Although generally robust and reliable, such immunoassays are susceptible to interference, and good collaboration between clinicians and the laboratory helps to minimize problems. A major challenge facing laboratories is correct differentiation of patients with true hyperprolactinemia from those with macroprolactinemia. Macroprolactin is a high-molecular-mass, biologically inactive form of prolactin that is detected to varying degrees by all prolactin immunoassays. Conservative estimates suggest that the presence of macroprolactin leads to misdiagnosis in as many as 10% of all reported instances of biochemical hyperprolactinemia. In the absence of specific testing, macroprolactin represents a diagnostic pitfall that results in the misdiagnosis and mismanagement of large numbers of patients.

Key Points

  • Prolactin levels are invariably measured in patients presenting with infertility

  • Although the etiology of hyperprolactinemia is complex, correct diagnosis is facilitated by a logical and systematic investigative approach

  • Immunoassay interference together with physiologic, pharmacologic, and secondary causes of hyperprolactinemia should be ruled out before embarking on pituitary imaging

  • The introduction of screening for macroprolactin has significantly reduced the extent of misdiagnosis and mismanagement of patients

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Figure 1: Known causes of hyperprolactinemia
Figure 2: Schematic illustrating the principle of a two-site immunometric assay for prolactin
Figure 3: Diagnostic algorithm for the investigation of hyperprolactinemia
Figure 4: Schematic illustrating potential sources of interference in immunometric assays for prolactin
Figure 5: Mean serum prolactin levels reported by nine different immunoanalyzer user groups in specimens collected from 10 subjects who had macroprolactinemia
Figure 6: Schematic illustration of a theoretical model to explain the variability in macroprolactin detection observed between different prolactin immunoassays

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References

  1. Jeffcoate SL et al. (1986) Assays for prolactin: guidelines for the provision of a clinical biochemistry service. Ann Clin Biochem 23: 638–651

    Article  CAS  PubMed  Google Scholar 

  2. Gibney J et al. (2005) The impact on clinical practice of routine screening for macroprolactin. J Clin Endocrinol Metab 90: 3927–3932

    Article  CAS  PubMed  Google Scholar 

  3. Fahie-Wilson MN and Soule SG (1997) Macroprolactinaemia: contribution to hyperprolactinaemia in a district general hospital and evaluation of a screening test based on precipitation with polyethylene glycol. Ann Clin Biochem 34: 252–258

    Article  CAS  PubMed  Google Scholar 

  4. Olukoga AO et al. (1999) Macroprolactinaemia: validation and application of the polyethylene glycol precipitation test and clinical characterization of the condition. Clin Endocrinol (Oxf) 51: 119–126

    Article  CAS  Google Scholar 

  5. Leslie H et al. (2001) Laboratory and clinical experience in 55 patients with macroprolactinemia identified by a simple polyethylene glycol precipitation method. J Clin Endocrinol Metab 86: 2743–2746

    Article  CAS  PubMed  Google Scholar 

  6. Strachan MW et al. (2003) Clinical and radiological features of patients with macroprolactinaemia. Clin Endocrinol (Oxf) 59: 339–346

    Article  Google Scholar 

  7. Fraser IS et al. (1989) Detailed assessment of big big prolactin in women with hyperprolactinemia and normal ovarian function. J Clin Endocrinol Metab 69: 585–592

    Article  CAS  PubMed  Google Scholar 

  8. Hattori N et al. (1997) Anti-prolactin (PRL) autoantibodies cause asymptomatic hyperprolactinemia: bioassay and clearance studies of PRL-immunoglobulin G complex. J Clin Endocrinol Metab 82: 3107–3110

    CAS  PubMed  Google Scholar 

  9. Larrea F et al. (1985) Further evidence that big, big prolactin is preferentially secreted in women with hyperprolactinemia and normal ovarian function. Fertil Steril 44: 25–30

    Article  CAS  PubMed  Google Scholar 

  10. Foglia G (2001) Prolactinomas and hyperprolactinemic syndromes. In Endocrinology, 329–342 (Eds De Groot LJ and Jameson JL) Philadelphia: WB Saunders

    Google Scholar 

  11. Bergh T et al. (2002) Hyperprolactinaemic anovulation. In Oxford Textbook of Endocrinology and Diabetes, 1130–1134 (Eds Wass J and Shalet S) Oxford: Oxford University Press

    Google Scholar 

  12. Mah PM et al. (2002) Hyperprolactinemia: etiology, diagnosis, and management. Semin Reprod Med 20: 365–374

    Article  PubMed  Google Scholar 

  13. Molitch ME (2002) Medical management of prolactin-secreting pituitary adenomas. Pituitary 5: 55–65

    Article  CAS  PubMed  Google Scholar 

  14. Luciano AA et al. (1985) Hyperprolactinemia and contraception: a prospective study. Obstet Gynecol 65: 506–510

    CAS  PubMed  Google Scholar 

  15. Luciano AA et al. (1984) Hyperprolactinemia in polycystic ovary syndrome. Fertil Steril 41: 719–725

    Article  CAS  PubMed  Google Scholar 

  16. Melmed S et al. (2002) Anterior pituitary. In Williams Textbook of Endocrinology, 177–279 (Eds Williams RH et al.) Philadelphia: WB Saunders

    Google Scholar 

  17. Thorner MO et al. (1998) The anterior pituitary. In Williams Textbook of Endocrinology, 249–340 (Eds Wilson et al.) Philadelphia: WB Saunders

    Google Scholar 

  18. Sinha YN (1995) Structural variants of prolactin: occurrence and physiological significance. Endocr Rev 16: 354–369

    Article  CAS  PubMed  Google Scholar 

  19. Hattori N et al. (1992) A normal ovulatory woman with hyperprolactinemia: presence of anti-prolactin autoantibody and the regulation of prolactin secretion. Acta Endocrinol (Copenh) 126: 497–500

    Article  CAS  Google Scholar 

  20. Leite V et al. (1992) Characterization of big, big prolactin in patients with hyperprolactinaemia. Clin Endocrinol (Oxf) 37: 365–372

    Article  CAS  Google Scholar 

  21. Rosato F et al. (2002) Hyperprolactinemia: from diagnosis to treatment. Minerva Pediatr 54: 547–552

    CAS  PubMed  Google Scholar 

  22. Sam S et al. (2005) The pituitary mass: diagnosis and management. Rev Endocr Metab Disord 6: 55–62

    Article  PubMed  Google Scholar 

  23. Smith T et al. (1998) Prevalence of macroprolactinemia in various hyperprolactinemic states [abstract]. Irish J Med Sci 167: 6

    Google Scholar 

  24. Klibanski A et al. (1988) Effects of prolactin and estrogen deficiency in amenorrheic bone loss. J Clin Endocrinol Metab 67: 124–130

    Article  CAS  PubMed  Google Scholar 

  25. Lewis UJ et al. (2000) Structure and properties of members of the hGH family: a review. Endocr J 47: S1–S8

    Article  CAS  PubMed  Google Scholar 

  26. Suliman AM et al. (2003) Frequent misdiagnosis and mismanagement of hyperprolactinemic patients before the introduction of macroprolactin screening: application of a new strict laboratory definition of macroprolactinemia. Clin Chem 49: 1504–1509

    Article  CAS  PubMed  Google Scholar 

  27. Freeman ME et al. (2000) Prolactin: structure, function, and regulation of secretion. Physiol Rev 80: 1523–1631

    Article  CAS  PubMed  Google Scholar 

  28. Bayrak A et al. (2005) Pituitary imaging is indicated for the evaluation of hyperprolactinemia. Fertil Steril 84: 181–185

    Article  PubMed  Google Scholar 

  29. Smith TP et al. (2002) Gross variability in the detection of prolactin in sera containing big big prolactin (macroprolactin) by commercial immunoassays. J Clin Endocrinol Metab 87: 5410–5415

    Article  CAS  PubMed  Google Scholar 

  30. Hattori N et al. (2006) Anti-prolactin (PRL) autoantibody-binding sites (epitopes) on PRL molecule in macroprolactinemia. J Endocrinol 190: 287–293

    Article  CAS  PubMed  Google Scholar 

  31. Rogol AD et al. (1974) Prolactin of apparent large molecular size: the major immunoactive prolactin component in plasma of a patient with a pituitary tumor. J Clin Endocrinol Metab 38: 714–717

    Article  CAS  PubMed  Google Scholar 

  32. Fahie-Wilson MN et al. (2005) Macroprolactin; high molecular mass forms of circulating prolactin. Ann Clin Biochem 42: 175–192

    Article  CAS  PubMed  Google Scholar 

  33. Tritos NA et al. (1998) Asymptomatic 'big' hyperprolactinemia in two men with pituitary adenomas. Eur J Endocrinol 138: 82–85

    Article  CAS  PubMed  Google Scholar 

  34. Ellis AR and Fahie-Wilson M (2005) Method recognition of big prolactin in serum and prolactin in amniotic fluid. In UK NEQAS for Peptide Hormones and Related Substances, Annual Review 2005, A1–A4 (Eds Ellis AR et al.) Edinburgh: United Kingdom National External Quality Assessment Service

    Google Scholar 

  35. Kavanagh L et al. (2006) Specificity and clinical utility of methods for the detection of macroprolactin. Clin Chem 52: 1366–1372

    Article  CAS  PubMed  Google Scholar 

  36. Schlechte JA (2002) The macroprolactin problem. J Clin Endocrinol Metab 87: 5408–5409

    Article  CAS  PubMed  Google Scholar 

  37. Fahie-Wilson M (2003) In hyperprolactinemia, testing for macroprolactin is essential. Clin Chem 49: 1434–1436

    Article  CAS  PubMed  Google Scholar 

  38. Olukoga AO et al. (1999) Three cases of macroprolactinaemia. J R Soc Med 92: 342–344

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Heaney AP et al. (1999) Misleading hyperprolactinaemia in pregnancy. Lancet 353: 720

    Article  CAS  PubMed  Google Scholar 

  40. Guay AT et al. (1996) Delayed diagnosis of psychological erectile dysfunction because of the presence of macroprolactinemia. J Clin Endocrinol Metab 81: 2512–2514

    CAS  PubMed  Google Scholar 

  41. Cattaneo FA et al. (2001) Concomitant occurrence of macroprolactin, exercise-induced amenorrhea, and a pituitary lesion: a diagnostic pitfall. Case report. J Neurosurg 95: 334–337

    Article  CAS  PubMed  Google Scholar 

  42. Gibney J et al. (2005) Clinical relevance of macroprolactin. Clin Endocrinol (Oxf) 62: 633–643

    Article  CAS  Google Scholar 

  43. Hattori N et al. (1992) Autoantibody to human prolactin in patients with idiopathic hyperprolactinemia. J Clin Endocrinol Metab 75: 1226–1229

    CAS  PubMed  Google Scholar 

  44. Vieira JG et al. (1998) Extensive experience and validation of polyethylene glycol precipitation as a screening method for macroprolactinemia. Clin Chem 44: 1758–1759

    CAS  PubMed  Google Scholar 

  45. Haller BL et al. (1992) Two automated prolactin immunoassays evaluated with demonstration of a high-dose hook effect in one. Clin Chem 38: 437–438

    CAS  PubMed  Google Scholar 

  46. Petakov MS et al. (1998) Pituitary adenomas secreting large amounts of prolactin may give false low values in immunoradiometric assays. The hook effect. J Endocrinol Invest 21: 184–188

    Article  CAS  PubMed  Google Scholar 

  47. St-Jean E et al. (1996) High prolactin levels may be missed by immunoradiometric assay in patients with macroprolactinomas. Clin Endocrinol (Oxf) 44: 305–309

    Article  CAS  Google Scholar 

  48. Frieze TW et al. (2002) “Hook effect” in prolactinomas: case report and review of literature. Endocr Pract 8: 296–303

    Article  PubMed  Google Scholar 

  49. Schofl C et al. (2002) Falsely low serum prolactin in two cases of invasive macroprolactinoma. Pituitary 5: 261–265

    Article  PubMed  Google Scholar 

  50. Ismail AA (2005) A radical approach is needed to eliminate interference from endogenous antibodies in immunoassays. Clin Chem 51: 25–26

    Article  CAS  PubMed  Google Scholar 

  51. Kircka L (2000) Interferences in immunoassay—still a threat. Clin Chem 46: 1037–1038

    Google Scholar 

  52. Preissner CM et al. (2005) Prevalence of heterophilic antibody interference in eight automated tumor marker immunoassays. Clin Chem 51: 208–210

    Article  CAS  PubMed  Google Scholar 

  53. Bjerner J et al. (2005) Human heterophilic antibodies display specificity for murine IgG subclasses. Clin Biochem 38: 465–472

    Article  CAS  PubMed  Google Scholar 

  54. Bjerner J et al. (2005) The war on heterophilic antibody Interference. Clin Chem 51: 9–11

    Article  CAS  PubMed  Google Scholar 

  55. Sapin R and Simon C (2001) False hyperprolactinemia corrected by the use of heterophilic antibody-blocking agent. Clin Chem 47: 2184–2185

    CAS  PubMed  Google Scholar 

  56. Kricka LJ et al. (1990) Interference by human anti-mouse antibody in two-site immunoassays. Clin Chem 36: 892–894

    CAS  PubMed  Google Scholar 

  57. Madry N et al. (1997) Measures to overcome HAMA interferences in immunoassays. Anticancer Res 17: 2883–2886

    CAS  PubMed  Google Scholar 

  58. Nussbaum S et al. (2000) Human anti-mouse antibodies: pitfalls in tumor marker measurement and strategies for enhanced assay robustness; including results with Elecsys CEA. Anticancer Res 20: 5249–5252

    CAS  PubMed  Google Scholar 

  59. Webster J et al. (1994) A comparison of cabergoline and bromocriptine in the treatment of hyperprolactinemic amenorrhea. Cabergoline Comparative Study Group. N Engl J Med 331: 904–909

    Article  CAS  PubMed  Google Scholar 

  60. Molitch ME et al. (1985) Bromocriptine as primary therapy for prolactin-secreting macroadenomas: results of a prospective multicenter study. J Clin Endocrinol Metab 60: 698–705

    Article  CAS  PubMed  Google Scholar 

  61. Biller BM et al. (1996) Treatment of prolactin-secreting macroadenomas with the once-weekly dopamine agonist cabergoline. J Clin Endocrinol Metab 81: 2338–2343

    CAS  PubMed  Google Scholar 

  62. Di Somma C et al. (1998) Bone marker and bone density responses to dopamine agonist therapy in hyperprolactinemic males. J Clin Endocrinol Metab 83: 807–813

    Article  CAS  PubMed  Google Scholar 

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Author information

Authors and Affiliations

  1. TP Smith is Lecturer in Clinical Chemistry in Trinity College Dublin and Principal Biochemist in the Department of Investigative Endocrinology, St Vincent's University Hospital, Elm Park, Dublin, Ireland,

    Thomas P Smith

  2. L Kavanagh is a postgraduate student in the Department of Endocrinology, University College Dublin, Belfield, Dublin,

    Lucille Kavanagh

  3. M-L Healy is Lecturer in Endocrinology at University College Dublin, Belfield ,

    Marie-Louise Healy

  4. and Consultant Endocrinologist in the Department of Endocrinology, TJ McKenna is Professor of Investigative Endocrinology, University College Dublin, Belfield, St Vincent's University Hospital.,

    T Joseph McKenna

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Correspondence to Thomas P Smith.

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Smith, T., Kavanagh, L., Healy, ML. et al. Technology Insight: measuring prolactin in clinical samples. Nat Rev Endocrinol 3, 279–289 (2007). https://doi.org/10.1038/ncpendmet0447

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