Bioactivity and Glycosylation of Circulating Prolactin in Various Physiological and Pathological Conditions
Tóm tắt
Multiple posttranslational processes modify native PRL and result in the secretion of several PRL isoforms with different bioactivity. Since we observed that serum samples contain non-lactogenic substances able to interfere in Nb2 cell bioassay, in this study we extracted PRL molecules from sera of pregnant and non-pregnant normal adults, fetuses and patients with prolactinoma and evaluated the ability of partially purified PRL to stimulate Nb2 cell proliferation. The preliminary immunopurification of PRL samples, conferred good sensitivity and specificity to PRL biological assay. Whenever possible, bioactivity values were correlated with glycosylated-PRL levels (G-PRL), the major posttranslational modification known to reduce PRL bioactivity. The ratio of bioactive (B-) vs immunoreactive PRL (I-PRL) (B/I) in normal subjects was 0.9 ± 0.1 (mean±SD), and not affected by TRH and sulpiride administration. PRL B/I ratio did not change during pregnancy, both in maternal (0.8 ± 0.1) and fetal circulation (1.0 ± 0.01). In patients with prolactinoma PRL B/I ratios (0.8 ± 0.18) were in the normal range. However, in 2 women with microprolactinoma, with a clear discrepancy between high I-PRL levels and mild clinical features, a significantly reduced PRL B/I ratio was observed (0.51 ± 0.08 and 0.52 ± 0.1 respectively). Conversely, a woman with clear clinical features of hyperprolactinemia, but border-line elevated I-PRL levels had a PRL B/I ratio in the upper limit of normal range. No variation in G-PRL vs NG-PRL percentages was observed in all the cases studied. In conclusion, our data show that physiological and pathological conditions of hyperprolactinemia, including fetal life, are associated in the majority of cases, with the secretion of PRL molecules with unchanged mitogenic activity on Nb2 cells. Nb2 PRL bioassay may be an useful tool to explain the discrepancies between clinical features and immunoreactive PRL levels in some particular cases.
Tài liệu tham khảo
De Vlaming V. Actions of Prolactin among the Vertebrates. New York: Academic Press, 1979:561–642.
Sinha Y. Structural variants of prolactin: Occurrence and physiological significance. Endocr Rev 1995;16:354–369.
Sinha Y, Gilligan T, Lee D, Hollingsworth D, Markoff E. Cleaved prolactin: Evidence for its occurrence in human pituitary gland and plasma. J Clin Endocrinol Metab 1985; 60:239–243.
Oetting W, Tuazon P, Traugh J, Walker A. Phosphorylation of prolactin. J Biol Chem 1986;261:1649–1652.
Kohli R, Chadha N, Muralidhar K. Are sheep and buffalo prolactin sulfated? Biochem Biophys Res Comm 1987;149: 515–522.
Lewis U, Singh R, Sinha Y, VanderLaan W. Glycosylated human prolactin. Endocrinology 1985;116:359–363.
Markoff E, Sigel M, Lacour N, Seavey B, Friesen H. Glycosylation selectively alters the biological activity of prolactin. Endocrinology 1988;123:1303–1306.
Pellegrini I, Gunz G, Ronin C, Fenouillet E, Peyrat J, Delori P, Jaquet P. Polymorphism of prolactin secreted by human prolactinoma cells: immunological, receptor binding and biological properties of the glycosylated and nonglycosyated forms. Endocrinology 1988;122:2667–2674.
Hoffmann T, Gunz G, Brue T, Jaquet P, Ronin C. Prolactin isoforms secreted by human prolactinomas. Horm Res 1992; 38:164–170.
Postel-Vinay M, Belair L, Kaiser C, Kelly P, Djiane J. Identification of prolactin and growth hormone binding proteins in milk. Proc Natl Acad Sci USA 1991;84:1237–1243.
Heffner LJ, Gramatos LS, Yuan RW. A glycosylated prolactin species covalently bound to immunoglobulin in human amniotic fluid. Biochem Biophys Res Commun 1989;165: 299–305.
Hattori N, Ishihara T, Ikekubo K, Moridera K, Hino M, Kurahachi H. Autoantibody to human prolactin in patients with idiopatic hyperprolactinemia. J Clin Endocrinol Metab 1992;75:1226–1229.
Jackson RD, Wortsman J, Malarkey WB. Characterization of a large molecular weight prolactin in women with idiopathic hyperprolactinemia and normal menses. J Clin Endocrinol Metab 1985;61:258–264.
Sinha Y. Prolactin variants. Trends Endocrinol Metab 1992; 3:100–106.
Noble R, Beer C, Gout P. Evidence in vivo and in vitro of a role for the pituitary in the growth of malignant lymphoma s in Nb rats. Cancer Res 1980;40:2437–2440.
Lebrun J, Ali S, Sofer L, Ullrich A, Kelly P. Prolactin-induced proliferation of Nb2 cells involves tyrosine phosphorylation of the prolactin receptor and its associated tyrosine kinase JAK2. J Biol Chem 1994;269:14021–14026.
Ihle J. Signaling by the cytokine receptor superfamily. Trends Endocrinol Metab 1994;5:137–143.
Kelly P, Djiane J, Postel-Vinay M, Edery M. The prolactin/ growth hormone receptor family. Endocr Rev 1991;12:235–251.
Ali S, Edery M, Pellegrini I, Lesueur L, Paly J, Djiane J, Kelly P. The Nb2 form of prolactin receptor is able to activate a milk protein gene promoter. Mol Endocrinol 1992; 6:1242–1248.
Tanaka T, Shiu R, Gout P, Beer C, Noble R, Friesen H. A new sensitive and specific bioassay for lactogenic hormones: Measurement of prolactin and growth hormone in human serum. J Clin Endocrinol Metab 1980;51:1058–1063.
McNeilly A, Friesen H. Presence of a nonlactogenic factor in human serum which synergistically enhances prolactinstimulated growth of Nb2 rat lymphoma cells in vitro. J Clin Endocrinol Metab 1985;61:408–411.
Moy J, Lawson D. Serum specifically potentiates the mitogenic response of Nb2 lymphoma cells to rat prolactin. Endocrinology 1988;123:1314–1319.
Walker A, Croze F, Friesen H. A serum-free medium for culturing lactogen dependent and autonomous Nb2 lymphoma cells. Endocrinology 1987;120:2389–2397.
Persani L, Tonacchera M, Beck-Peccoz P, Vitti P, Mammoli C, Chiovato L, Elisei R. Faglia G, Ludgate M, Vassart G, Pinchera A. Measurement of cAMP accumulation in chinese hamster ovary cells transfected with recombinant human TSH receptor (CHO-R): A new bioassay for human thyrotropin. J Endocrinol Invest 1993;16:511–519.
Pellegrini I, Gunz G, Jaquet P. Different pathways of secretion for glycosylated and nonglycosylated human prolactin. Endocrinology 1990;126:1087–1095.
Daffos F, Capella-Pavloski M, Forester F. Fetal blood sampling during pregnancy with use of a needle guided by ultrasound: A study of 606 consecutive cases. Am J Obst Gynec 1985;153:655–656.
Beck-Peccoz P, Padmanabhan V, Baggiani A, Cortelazzi D, Buscaglia M, Medri G, Marconi A, Pardi G, Beitins I. Maturation of hypothalamic-pituitary-gonadal function in normal human fetuses: Circulating levels of gonadotrophins, their common a-subunit and free testosterone, and discrepancy between immunological and biological activities of circulating follicle-stimulating hormone. J Clin Endocrinol Metab 1991;73:525–532.
Gout P, Beer C, Noble R. Prolactin-stimulated growth of cell cultures established from malignant Nb rat lymphomas. Cancer Res 1980;40:2433–2436.
Brue T, Caruso E, Morange I, Hoffmann T, Evrin M, Gunz G, Benkirane M, Jaquet P. Immunoradiometric analysis of circulating human glycosylated and nonglycosylated prolactin forms: Spontaneous and stimulated secretions. J Clin Endocrinol Metab 1992;75:1338–1344.
Chappel S. Editorial: Biological to immunological ratios: reevaluation of a concept. J Clin Endocrinol Metab 1990;70: 1494–1495.
Rowe R, Cowden E, Faiman C, Friesen H. Correlation of Nb2 bioassay and radioimmunoassay values for human serum prolactin. J Clin Endocrinol Metab 1983;57:942–946.
Markoff E, Lee D, Hollingsworth D. Glycosylated and nonglycosylated prolactin serum during pregnancy. J Clin Endocrinol Metab 1988;67:519–523.
Ajika K, Krulich L, Fawcett C, McCann S. Effect of estrogen on plasma and pituitary gonadotropins and prolactin and on hypotalamic releasing and inhibiting factors. Neuro Endocrinology 1972;9:304–308.
Arosio M, Nissim M, Ballabio M, Orefice R, Bazzoni N, Faglia G. Size heterogeneity of circulating growth hormone. Big-big forms are associated with inappropriately low IGF-I levels. Acta Endocrinol (Copenh) 1991;125:150–159.
Beck-Peccoz P, Brucker-Davies F, Persani L, Smallridge RC, Weintraub BD. Thytotropin secreting pituitary tumors. Endocr Rev 1996;17:610–638.
Borgato S, Persani L, Romoli R, Cortelazzi D, Spada A, Beck-Peccoz P. Serum FSH bioactivity and inhibin levels in patients with gonadotropin secreting and nonfunctioning pituitary adenomas. J Endocrinol Invest 1998;21:372–379.
Hashim I, Lee D, Butler J, McGregor A, Smith C, Norman M. The proportion of glycosylated prolactin in serum is decreased in hyperprolactinemic states. J Clin Endocrinol Metab 1990;71:111–115.
Walker A. Phosphorylated and nonphosphorylated prolactin isoforms. Trends Endocrinol Metab 1994;5:195–200.