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Human Macroprolactin Displays Low Biological Activity via Its Homologous Receptor in a New Sensitive Bioassay

Neuroendocrine Unit (A.G., M.D.B.), Division of Endocrinology and Metabolism and Laboratory for Cellular and Molecular Endocrinology–LIM25 (D.G.-N.), Division of Endocrinology and Metabolism, Hospital das Clinicas, University of Sao Paulo Medical School, Sao Paulo 01406-100, Brazil; Biotechnology Department (C.R.J.S., M.T.C.P.R.), Instituto de Pesquisas Energeticas e Nucleares-Comissão Nacional de Energia Nuclear, Sao Paulo 05508-900, Brazil; Fleury Laboratory (J.G.V.), Section of Endocrinology, Soa Paulo 04344-070, Brazil; Institut National de la Santé et de la Recherche Médicale U584 (V.G.), F-75730 Paris Cedex 15, France; and Université Paris Descartes Faculté de Médecine, René Descartes-site Necker (V.G.), F-75015 Paris, France

Address all correspondence and requests for reprints to: Marcello D. Bronstein, M.D., Neuroendocrine Unit, Division of Endocrinology and Metabolism, Hospital das Clinicas, University of Sao Paulo Medical School, Avenida 9 de julho, 3858 Jardins CEP, 01406-100 São Paulo SP, Brazil. E-mail: mdbronstein{at}uol.com.br.

Context: Macroprolactinemia is a frequent finding in hyperprolactinemic individuals, usually without clinical impact. Data on biological activity of macroprolactin (bbPRL) are controversial and mostly based on a heterologous rat Nb2 cell bioassay. Biological activity of bbPRL observed in vitro but not in vivo may be due to its high molecular weight, preventing its passage through capillary barrier. Alternatively, bbPRL bioactivity may differ depending on the prolactin (PRL) receptor (PRLR) species specificity.

Objective: The objective of the study was to characterize the bioactivity of bbPRL in a homologous bioassay: Ba/F-3 cells stably expressing the human PRLR.

Design/Setting/Patients: Chromatography-purified bbPRL from macroprolactinemic individuals (group I, n = 18) and monomeric PRL from hyperprolactinemic patients without macroprolactinemia (group II, n = 5) were tested in Nb2 and Ba/F-LLP bioassays. Both groups were followed up at the neuroendocrinology outpatients’ clinic.

Main Outcome Measure: Biological activity of bbPRL presented in the two bioassays was measured.

Results: In group I, no patient had hypogonadism. Mean ratio bioactivity to immunoactivity of bbPRL in the Nb2 assay was 0.69. There was no dose-response in 15 of the 18 samples tested in Ba/F-LLP assay. In group II, three patients had galactorrhea and all five had hypogonadism. Mean ratio bioactivity to immunoactivity of monomeric PRL samples was 1.35 in Nb2 and 0.91 in Ba/F-LLP assay.

Conclusion: Whereas both bioassays achieve similar results with respect to monomeric PRL activity, our results indicate that the activity displayed by bbPRL toward the rat receptor may be inappropriate because it is not observed in the human PRLR-mediated assay, consistent with the apparent absence of bioactivity in vivo.

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