Objective: Macroprolactinemia, which can be detected by a polyethylene glycol (PEG) precipitation test, is a clinically and biologically heterogeneous condition. In this study, we analyzed whether the clinical presentation, the hormonal findings and the in vitro lactogenic activity differed between macroprolactinemic patients with and without circulating prolactin (PRL) -IgG complexes. Design: Clinical data were reviewed and additional hormonal studies were performed in 50 hyperprolactinemic patients with macroprolactinemia. Methods: Macroprolactinemia was identified by a PRL recovery after PEG precipitation of ,50%, as measured by an automated commercial immunoassay system and circulating PRL -IgG complexes by an abnormal PRL binding to anti-IgG agarose. Results: PRL -IgG complexes were found in 46 patients. The origin of hyperprolactinemia in these 46 patients was idiopathic in 33 patients, while a pituitary lesion or stalk magnetic resonance imaging or computed tomography scan was detected in 13 patients found compression. Galactorrhea was found in 11 of these 46 patients, while this condition was present in three of the four patients without circulating PRL -IgG complexes. The median free PRL concentration was significantly lower in patients with PRL -IgG complexes than in the group without complexes (243 vs 969 mIU/l; P , 0.005), whereas median total PRL immunoreactivity and median PRL bioactivity in the Nb2 assay were not significantly different. In patients with circulating PRL -IgG complexes, Nb2 bioassay results correlated significantly with total PRL immunoreactivity (r ¼ 0.64; P , 0.0001), but not with free PRL results (r ¼ 0.24; P , 0.17). Conclusions: These results indicate that PRL -IgG complexes (i) account for most cases of macroprolactinemia -as identified by PEG precipitation -in hyperprolactinemic patients presenting with a variety of diagnoses, (ii) are not associated with a specific clinical presentation, (iii) can be found in patients with diverse pituitary pathologies, and (iv) possess an in vitro lactogenic activity in the Nb2 bioassay in relation to their immunoreactivity.
We previously reported that prolactin gene expression in the T-leukemic cell line Jurkat is stimulated by PGE2 and that cAMP acts synergistically with Ca2+ or protein kinase C on the activation of the upstream prolactin promoter. Using the transcription inhibitor actinomycin D, we now show that PGE2-induced prolactin expression requires de novo prolactin mRNA synthesis and that PGE2 does not influence prolactin mRNA stability. Furthermore, PGE2-induced prolactin expression was inhibited by protein kinase inhibitor fragment 14–22 and BAPTA-AM, which respectively, inhibit protein kinase A- and Ca2+-mediated signaling cascades. Using specific PGE2 receptor agonists and antagonists, we show that PGE2 induces prolactin expression through engagement of E-prostanoid (EP) 3 and EP4 receptors. We also found that PGE2 induces an increase in intracellular cAMP concentration as well as intracellular calcium concentration via EP4 and EP3 receptors, respectively. In transient transfections, 3000 bp flanking the leukocyte prolactin promoter conferred a weak induction of the luciferase reporter gene by PGE2 and cAMP, whereas cAMP in synergy with ionomycin strongly activated the promoter. Mutation of a C/EBP responsive element at −214 partially abolished the response of the leukocyte prolactin promoter to PGE2, cAMP, and ionomycin plus cAMP.
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