Prolactinomas are increasingly viewed as a “problem of signal transduction.” Consequently, the identification of factors and signaling pathways that control lactotrope cell turnover is needed in order to encourage new therapeutic developments. We have previously shown that prolactin (PRL) acts as a proapoptotic and antiproliferative factor on lactotropes, maintaining anterior pituitary cell homeostasis, which contrasts with the classical antiapoptotic and/or proliferative actions exerted by PRL in most other target tissues. We aimed to investigate the PRLR-triggered signaling pathways mediating these nonclassical effects of PRL in the pituitary. Our results suggest that (i) the PRLR/Jak2/STAT5 pathway is constitutively active in GH3 cells and contributes to PRL-induced apoptosis by increasing the Bax/Bcl-2 ratio, (ii) PRL inhibits ERK1/2 and Akt phosphorylation, thereby contributing to its proapoptotic effect, and (iii) the PI3K/Akt pathway participates in the PRL-mediated control of lactotrope proliferation. We hypothesize that the alteration of PRL actions in lactotrope homeostasis due to the dysregulation of any of the mechanisms of actions described above may contribute to the pathogenesis of prolactinomas.

Prolactin (PRL) is a hormone principally secreted by lactotrophs of the anterior pituitary gland. Although the synthesis and exocytosis of this hormone are mainly under the regulation of hypothalamic dopamine (DA), the possibility that the anterior pituitary synthesizes this catecholamine remains unclear. In this study, our aim was to determine if the anterior pituitary produces DA from the precursor L-Dopa. To this purpose, we studied the expression of aromatic L-amino acid decarboxylase (AADC) enzyme and the transporter VMAT2 in the anterior pituitary, AtT20 and GH3 cells by immunofluorescence and western blot. Moreover, we investigated the production of DA Accepted Article This article is protected by copyright. All rights reserved from L-Dopa and its release in vitro. Then, we explored the effects of L-Dopa in the secretion of PRL from anterior pituitary fragments. We observed that the anterior pituitary, AtT20 and GH3 cells express both AADC and VMAT2. Next, we detected an increase in DA content after anterior pituitary fragments were incubated with L-Dopa. Also, the presence of L-Dopa increased DA levels in incubation media and reduced PRL secretion. Likewise, the content of cellular DA increased after AtT20 cells were incubated with L-Dopa. In addition, L-Dopa reduced CRH-stimulated ACTH release from these cells after AADC activity was inhibited by NSD-1015. Moreover, DA formation from L-Dopa increased apoptosis and decreased proliferation. However, in the presence of NSD-1015, L-Dopa decreased apoptosis and increased proliferation rates. These results suggest that the anterior pituitary synthesizes DA from L-Dopa by AADC and this catecholamine can be released from this gland contributing to the control of PRL secretion. In addition, our results suggest that L-Dopa exerts direct actions independently from its metabolization to DA.

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