Abstract
Purpose
Macroprolactinemia is characterized by predominance of macroprolactin molecules in circulation and generally has extra-pituitary origin. Macroprolactin is viewed as biologically inactive, therefore asymptomatic, and thus may not require any treatment or prolonged follow-up. In addition, data on prevalence of macroprolactinemia and its clinical manifestation are also rare. Therefore, the present study was aimed to find out prevalence of macroprolactinemia and its association, if any, with reproductive manifestations.
Material and methods
Macroprolactin was measured in 102 hyperprolactinemia cases (>100 ng/ml prolactin level), 135 physiological hyperprolactinemia cases (50 pregnant and 85 lactating females; >100 ng/ml prolactin level) and 24 controls. Poly ethylene glycol (PEG) precipitation method was carried out to screen macroprolactin. Prolactin recovery of <25% was considered overt macroprolactinemia. Detailed clinical data was recorded which included complete medical history, physical examination and hormone measurements besides CT/MRI for pituitary abnormalities.
Results
Prevalence of macroprolactinemia was 21.57% (22/102) in hyperprolactinemia (prolactin >100 ng/ml). There was no case of macroprolactinemia in physiological hyperprolactinemia, or healthy control females. Reproductive manifestations were present in 72.73% (16/22) macroprolactinemia cases, out of which macroprolactinemia was the sole cause of associated reproductive manifestations in 68.7% (11/16) cases. Reversal of reproductive dysfunction/s was observed in five cases with appropriate treatment for high macroprolactin.
Conclusion
Macroprolactinemia prevalence was found to be 21.5%, out of which 72.73% cases had associated reproductive dysfunctions.
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References
M.N. Fahie-Wilson, R. John, A.R. Ellis, Macroprolactin; high molecular mass forms of circulating prolactin. Ann. Clin. Biochem. 42, 175–192 (2005). https://doi.org/10.1258/0004563053857969
J.G.H. Vieira, Macroprolactinemia. Arq. Bras. Endocrinol. Metab. 46, 45–50 (2002)
T.S. Morteza, A.E. Hossein, K.D. M, Evaluating the prevalence of macroprolactinemia and hyperprolactinemia and comparing their clinical and radiological signs in infertile women. J. Reprod. Infertil. 8, 128–134 (2007)
A. Gezer, T. Atasü, C. Hekim, U.H. Stenman, N. Hekim, Hyperprolactinaemia does not always mean’hyperprolactinaemia’! Eur. J. Obstet. Gynecol. Reprod. Biol. 118, 206–208 (2005). https://doi.org/10.1016/j.ejogrb.2004.06.020
K.M. Genesio Ceratto, M.M. Zitta, P. Avalos, M.H. Gomez, C. Avendano, C. Sanchez Sarmiento, Prevalence of macroprolactin (mprl) in infertile female patients: frequent misdiagnosis and mismanagement of hyperprolactinemia. Fertil. Steril. 106, 373 (2016)
K. Thirunavakkarasu, P. Dutta, S. Sridhar, L. Dhaliwal, G.R.V. Prashad, S. Gainder, N. Sachdeva, A. Bhansali, Macroprolactinemia in hyperprolactinemic infertile women. Endocrine 44, 750–755 (2013). https://doi.org/10.1007/s12020-013-9925-y
L. Vilar, E. Moura, V. Canadas, A. Gusmão, R. Campos, E. Leal, L. Teixeira, V. Santos, B. Gomes, M. Lima, R. Paiva, J.L. Albuquerque, C.S. Egito, C.A. Botelho, M. Azevedo, L.A. Casulari, L.A. Naves, Prevalence of macroprolactinemia among 115 patients with hyperprolactinemia]. Arq. Bras. Endocrinol. Metabol. 51, 86–91 (2007)
S. Vallette-Kasic, I. Morange-Ramos, A. Selim, G. Gunz, S. Morange, A. Enjalbert, P.-M. Martin, P. Jaquet, T. Brue, Macroprolactinemia revisited: a study on 106 patients. J. Clin. Endocrinol. Metab. 87, 581–588 (2002). https://doi.org/10.1210/jcem.87.2.8272
T. Bjøro, E. Johansen, H.H. Frey, A. Turter, P.A. Torjesen, Different responses in little and bigbig prolactin to metoclopramide in subjects with hyperprolactinemia due to 150-170 kD (bigbig) prolactin. Acta Endocrinol. 128, 308–312 (1993)
P.G. Whittaker, T. Wilcox, T. Lind, Maintained fertility in a patient with hyperprolactinemia due to big, big prolactin. J. Clin. Endocrinol. Metab. 53, 863–866 (1981). https://doi.org/10.1210/jcem-53-4-863
A.N. Andersen, H. Pedersen, H. Djursing, B.N. Andersen, H.G. Friesen, Bioactivity of prolactin in a woman with an excess of large molecular size prolactin, persistent hyperprolactinemia and spontaneous conception. Fertil. Steril. 38, 625–628 (1982)
N. Hattori, Y. Nakayama, K. Kitagawa, T. Ishihara, Y. Saiki, C. Inagaki, Anti-prolactin (P. R. L.) autoantibody-binding sites (epitopes) on PRL molecule in macroprolactinemia. J. Endocrinol. 190, 287–293 (2006). https://doi.org/10.1677/joe.1.06871
A. Glezer, C.R.J. Soares, J.G. Vieira, D. Giannella-Neto, M.T.C.P. Ribela, V. Goffin, M.D. Bronstein, Human macroprolactin displays low biological activity via its homologous receptor in a new sensitive bioassay. J. Clin. Endocrinol. Metab. 91, 1048–1055 (2006). https://doi.org/10.1210/jc.2005-1831
A. Leaños-Miranda, G. Cárdenas-Mondragón, R. Rivera-Leaños, A. Ulloa-Aguirre, V. Goffin, Application of new homologous in vitro bioassays for human lactogens to assess the actual bioactivity of human prolactin isoforms in hyperprolactinaemic patients. Clin. Endocrinol. 65, 146–153 (2006). https://doi.org/10.1111/j.1365-2265.2006.02548.x
I.R. Wallace, N. Satti, C.H. Courtney, H. Leslie, P.M. Bell, S.J. Hunter, D.R. McCance, B. Sheridan, A.B. Atkinson, Ten-year clinical follow-up of a cohort of 51 patients with macroprolactinemia establishes it as a benign variant. J. Clin. Endocrinol. Metab. 95, 3268–3271 (2010). https://doi.org/10.1210/jc.2010-0114
R. Krysiak, A. Drosdzol-Cop, V. Skrzypulec-Plinta, B. Okopien, Sexual function and depressive symptoms in young women with elevated macroprolactin content: a pilot study. Endocrine 53, 291–298 (2016). https://doi.org/10.1007/s12020-016-0898-5
V.S. Fang, S. Refetoff, Heterogeneous human prolactin from a giant pituitary tumor in a patient with panhypopituitarism. J. Clin. Endocrinol. Metab. 47, 780–787 (1978). https://doi.org/10.1210/jcem-47-4-780
N.H. Farkouh, M.G. Packer, A.G. Frantz, Large molecular size prolactin with reduced receptor activity in human serum: high proportion in basal state and reduction after thyrotropin-releasing hormone. J. Clin. Endocrinol. Metab. 48, 1026–1032 (1979). https://doi.org/10.1210/jcem-48-6-1026
O.M. Hauache, A.J. Rocha, A.C.M. Maia, R.M.B. Maciel, J.G.H. Vieira, Screening for macroprolactinaemia and pituitary imaging studies. Clin. Endocrinol. 57, 327–331 (2002)
M. Overgaard, S.M. Pedersen, Serum prolactin revisited: parametric reference intervals and cross platform evaluation of polyethylene glycol precipitation-based methods for discrimination between hyperprolactinemia and macroprolactinemia. Clin. Chem. Lab. Med. 55, 1744–1753 (2017). https://doi.org/10.1515/cclm-2016-0902
M.W.J. Strachan, W.L. Teoh, A.C. Don-Wauchope, J. Seth, M. Stoddart, G.J. Beckett, Clinical and radiological features of patients with macroprolactinaemia. Clin. Endocrinol. 59, 339–346 (2003)
M.N. Fahie-Wilson, S.G. Soule, 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(Pt3), 252–258 (1997). https://doi.org/10.1177/000456329703400305
C. Theunissen, J. De Schepper, J. Schiettecatte, P. Verdood, E.L. Hooghe-Peeters, B. Velkeniers, Macroprolactinemia: clinical significance and characterization of the condition. Acta Clin. Belg. 60, 190–197 (2005). https://doi.org/10.1179/acb.2005.034
E. Toldy, Z. Löcsei, I. Szabolcs, M.I. Góth, P. Kneffel, D. Szöke, G.L. Kovács, Macroprolactinemia: the consequences of a laboratory pitfall. Endocrine 22, 267–273 (2003). https://doi.org/10.1385/ENDO:22:3:267
J. Gibney, T.P. Smith, T.J. McKenna, The impact on clinical practice of routine screening for macroprolactin. J. Clin. Endocrinol. Metab. 90, 3927–3932 (2005). https://doi.org/10.1210/jc.2004-2234
N. Hattori, K. Ikekubo, T. Ishihara, K. Moridera, M. Hino, H. Kurahachi, Correlation of the antibody titers with serum prolactin levels and their clinical course in patients with anti-prolactin autoantibody. Eur. J. Endocrinol. 130, 438–445 (1994)
N. Hattori, T. Ishihara, K. Ikekubo, K. Moridera, M. Hino, H. Kurahachi, Autoantibody to human prolactin in patients with idiopathic hyperprolactinemia. J. Clin. Endocrinol. Metab. 75, 1226–1229 (1992). https://doi.org/10.1210/jcem.75.5.1430082
M. Guclu, S. Cander, S. Kiyici, E. Vatansever, A.B. Hacihasanoğlu, G. Kisakol, Serum macroprolactin levels in pregnancy and association with thyroid autoimmunity. BMC Endocr. Disord. 15, 31 (2015). https://doi.org/10.1186/s12902-015-0025-2
D. Pascoe-Lira, G. Duran-Reyes, I. Contreras-Hernández, L. Manuel-Apolinar, F. Blanco-Favela, A. Leaños-Miranda, Frequency of macroprolactinemia due to autoantibodies against prolactin in pregnant women. J. Clin. Endocrinol. Metab. 86, 924–929 (2001). https://doi.org/10.1210/jcem.86.2.7183
N. Hattori, The frequency of macroprolactinemia in pregnant women and the heterogeneity of its etiologies. J. Clin. Endocrinol. Metab. 81, 586–590 (1996). https://doi.org/10.1210/jcem.81.2.8636272
S. Radavelli-Bagatini, F.L. Lhullier, E.S. Mallmann, P.M. Spritzer, Macroprolactinemia in women with hyperprolactinemia: a 10-year follow-up. Neuro. Endocrinol. Lett. 34, 207–211 (2013)
R.D. Jackson, J. Wortsman, W.B. Malarkey, Characterization of a large molecular weight prolactin in women with idiopathic hyperprolactinemia and normal menses. J. Clin. Endocrinol. Metab. 61, 258–264 (1985). https://doi.org/10.1210/jcem-61-2-258
N. Hattori, C. Inagaki, Anti-prolactin (P. R. L.) autoantibodies cause asymptomatic hyperprolactinemia: bioassay and clearance studies of PRL-immunoglobulin G complex. J. Clin. Endocrinol. Metab. 82, 3107–3110 (1997). https://doi.org/10.1210/jcem.82.9.4250
I.S. Fraser, Z.G. Lun, J.P. Zhou, A.C. Herington, G. McCarron, I. Caterson, K. Tan, R. Markham, Detailed assessment of big big prolactin in women with hyperprolactinemia and normal ovarian function. J. Clin. Endocrinol. Metab. 69, 585–592 (1989). https://doi.org/10.1210/jcem-69-3-585
C.R. McCudden, J.L. Sharpless, D.G. Grenache, Comparison of multiple methods for identification of hyperprolactinemia in the presence of macroprolactin. Clin. Chim. Acta 411, 155–160 (2010). https://doi.org/10.1016/j.cca.2009.10.020
G. Lippi, M. Plebani, Macroprolactin: searching for a needle in a haystack? Clin. Chem. Lab. Med. 54, 519–522 (2016). https://doi.org/10.1515/cclm-2015-1283
J.G. Vieira, T.T. Tachibana, L.H. Obara, R.M. Maciel, Extensive experience and validation of polyethylene glycol precipitation as a screening method for macroprolactinemia. Clin. Chem. 44, 1758–1759 (1998)
J. Gibney, T.P. Smith, T.J. McKenna, Clinical relevance of macroprolactin. Clin. Endocrinol. 62, 633–643 (2005). https://doi.org/10.1111/j.1365-2265.2005.02243.x
A.M. Suliman, T.P. Smith, J. Gibney, T.J. McKenna, 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 (2003)
H. Leslie, C.H. Courtney, P.M. Bell, D.R. Hadden, D.R. McCance, P.K. Ellis, B. Sheridan, A.B. Atkinson, Laboratory and clinical experience in 55 patients with macroprolactinemia identified by a simple polyethylene glycol precipitation method. J. Clin. Endocrinol. Metab. 86, 2743–2746 (2001). https://doi.org/10.1210/jcem.86.6.7521
A. Elenkova, Z. Abadzhieva, N. Genov, V. Vasilev, G. Kirilov, S. Zacharieva, Macroprolactinemia in a patient with invasive macroprolactinoma: a case report and minireview. Case Rep. Endocrinol. 2013, 634349 (2013). https://doi.org/10.1155/2013/634349
F.D. Dellal, D. Ozdemir, C. Aydin, G. Kaya, R. Ersoy, B. Cakir, Gigantomastia and macroprolactinemia responding to cabergoline treatment: a case report and minireview of the literature. Case Rep. Endocrinol. 2016, 3576024 (2016). https://doi.org/10.1155/2016/3576024
Acknowledgements
We thank Department of Obstetrics and Gynecology, All India Institute of Medical Sciences, New Delhi, India for providing their support in recruiting pregnant and lactating females for the study. We are grateful to our patients for their invaluable cooperation during the study.
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This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector. The PhD student was receiving CSIR-UGC JRF.
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All procedures performed in the study involving human participants were in accordance with the ethical standards of the institutional ethical committee.
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Informed consent was obtained from all individual participants included in the study.
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Kalsi, A.K., Halder, A., Jain, M. et al. Prevalence and reproductive manifestations of macroprolactinemia. Endocrine 63, 332–340 (2019). https://doi.org/10.1007/s12020-018-1770-6
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DOI: https://doi.org/10.1007/s12020-018-1770-6