Autocrine actions of prolactin contribute to the regulation of lactotroph function in vivo

Abstract

Prolactin (PRL), whose principal role is regulation of lactation, is mainly synthesized and secreted by lactotroph anterior pituitary cells. Its signaling is exerted via a transmembrane PRL receptor (PRLR) expressed in a wide variety of tissues, including the anterior pituitary. Dopamine, which is secreted by tuberoinfundibular hypothalamic neurons, is the major inhibitory regulator of prolactin secretion. Although PRL is well established to stimulate hypothalamic dopamine secretion, thereby exerting a negative feedback regulation on its own release, autocrine or paracrine actions of PRL on lactotroph cells have also been suggested. Within the pituitary, PRL may inhibit both lactotroph proliferation and secretion, but in vivo evaluation of these putative functions is limited. To determine whether the autocrine actions of prolactin have a significant role in the physiologic function of lactotrophs in vivo, we examined the consequences of conditional deletion of Prlr in lactotroph cells using a novel mouse line with loxP sites flanking the Prlr gene ( Prlr) and Cre-recombinase (Cre) expressed under the control of the pituitary-specific Prl promoter. Prlr/Prl-Cre mice have normal PRL levels and did not develop any pituitary lactotroph adenoma, even at 20 mo of age. Nevertheless, Prlr/Prl-Cre mice displayed an increased dopaminergic inhibitory tone compared with control Prlr mice. These results elegantly confirm an autocrine/paracrine feedback of PRL on lactotroph cells in vivo, which can be fully compensated by an intact hypothalamic feedback system.-Bernard, V., Lamothe, S., Beau, I., Guillou, A., Martin, A., Le Tissier, P., Grattan, D., Young, J., Binart, N. Autocrine actions of prolactin contribute to the regulation of lactotroph function in vivo.

Association of prolactin receptor (PRLR) variants with prolactinomas

“…For example, deletion of Prlr in different subtypes of TIDA neurons (i.e. GABAergic versus dopaminergic) of the arcuate nucleus and lactotroph-specific Prlr knockout in mice have revealed that the PRLR may have distinct physiological outputs in these different cell types (16,26). Thus, the Akt pathway may mediate PRL-specific responses in one cell type, while having no function or a different function in another cell type and the local expression of different PRLR isoforms may also impact on whether Akt signaling is activated by the PRLR (9).…”

“…Support for this mechanism is provided by studies of mice lacking the dopamine D2 receptor, which are hyperprolactinaemic due to loss of dopaminergic inhibition at the pituitary gland (15). Interestingly, PRLR has also been reported to be expressed on lactotrophs of the pituitary gland where it may provide an autocrine loop to regulate lactotroph function (16). Moreover, human and rodent studies have reported roles for the PRLR in reproduction and development of breast and prostate tumors (17–19).…”

“…Thus, Prlr +/− and Prlr −/− female mice have been reported to have impaired mammary gland development, while Prlr −/− female and male mice also developed hyperprolactinemia, with pituitary hyperplasia and tumors, and infertility (18). Furthermore, neuron-specific conditional Prlr knockout mice have also been reported to develop hyperprolactinemia and abnormalities of the estrous cycle (26), with lactotroph-specific conditional Prlr knockout mice having normal circulating prolactin levels and estrous cycles, but impaired dopaminergic tone (16). Prolactin has been reported to have proapoptotic and antiproliferative effects in rats (27), and investigations of Prlr −/− mice have indicated that it is the chronic downregulation of PRLR signaling in these pathways that may cause pituitary hyperplasia and prolactinoma development (28).…”

Molecular Pathways in Prolactinomas: Translational and Therapeutic Implications

“…PRL secretion is mainly under inhibitory stimuli, via tuberoinfundibular dopamine (TIDA) neurons in the hypothalamus binding to Type 2 Dopamine Receptor (D2R) and GABA (gamma aminobutyric acid), the latter playing a minor role [21]. PRL also controls its own secretion through a short loop negative feedback, stimulating TIDA cells [22] and in the own lactotroph cell by an autocrine loop [23] (Figure 2). There are also prolactinreleasing factors (PRFs) such as thyrotropin-releasing hormone, vasoactive intestinal peptide, serotonin, histamine, oxytocin and oestrogens [24].…”

“…PRLR is expressed on TIDA cells (a short-loop feedback circuit) and also on lactotrophs of the pituitary gland where it may provide an autocrine loop to regulate lactotroph function [23]. The PRLR is a member of the cytokine receptor superfamily that signals via Janus kinase-2-signal transducer and activator of transcription-5 (JAK2-STAT5), phosphoinositide 3-kinase-Akt (PI3K-Akt-mTOR) or the MAPK pathways to mediate changes in transcription, differentiation and proliferation [36] (Figure 3).…”