Prolactin Control of Growth and Prolactin Autoregulation in Cultured Human Pituitary Cells

Hosojima, Hiroyuki; Wyche, James H.

doi:10.1159/000180056

Cited by 13 publications

(6 citation statements)

References 7 publications

(7 reference statements)

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“…The inhibitory growth response of lactotrophs to PRL is quite different from the proliferative effect exhibited in nonpituitary cell types (14)(15)(16)(17)(18)(19)(21)(22)(23)(24)(25), in human prolactinoma cells (44), and in a transformed rat lactotroph cell line (20). It is, however, consistent with models of PRL effects on EGF and TGF-α signaling cascades.…”

Section: Discussionsupporting

confidence: 62%

Lack of prolactin receptor signaling in mice results in lactotroph proliferation and prolactinomas by dopamine-dependent and -independent mechanisms

Schuff¹,

Hentges²,

Kelly³

et al. 2002

J. Clin. Invest.

103

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Hypothalamic dopamine inhibits pituitary prolactin secretion and proliferation of prolactin-producing lactotroph cells by activating lactotroph dopamine D2 receptors (D2Rs). Conversely, prolactin (PRL) stimulates hypothalamic dopamine neurons via PRL receptors (PRLRs) in a short-loop feedback circuit. We used Drd2(-/-) and Prlr(-/-) mutant mice to bypass this feedback and investigate possible dopamine-independent effects of PRL on lactotroph function. The absence of either receptor induced hyperprolactinemia and large prolactinomas in females. Small macroadenomas developed in aged Prlr(-/-) males, but only microscopic adenomas were found in Drd2(-/-) male mice. Pharmacologic studies in Prlr(-/-) mice with D2R agonists and antagonists demonstrated a significant loss of endogenous dopamine tone, i.e., constitutive inhibitory signaling by the D2R, in the pituitary. However, Prlr(-/-) mice exhibited more profound hyperprolactinemia and larger tumors than did age-matched Drd2(-/-) mice, and there were additive effects in compound homozygous mutant male mice. In vitro, PRL treatment markedly inhibited the proliferation of wild-type female and male Drd2(-/-) lactotrophs, but had no effect on female Drd2(-/-) lactotrophs, suggesting a downregulation or desensitization of PRLR in response to chronic hyperprolactinemia. We conclude that PRL inhibits lactotrophs by two distinct mechanisms: (a) indirectly by activation of hypothalamic dopamine neurons and (b) directly within the pituitary in a dopamine-independent fashion.

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Section: Discussionsupporting

confidence: 62%

Lack of prolactin receptor signaling in mice results in lactotroph proliferation and prolactinomas by dopamine-dependent and -independent mechanisms

Schuff¹,

Hentges²,

Kelly³

et al. 2002

J. Clin. Invest.

103

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supporting

confidence: 62%

Lack of prolactin receptor signaling in mice results in lactotroph proliferation and prolactinomas by dopamine-dependent and -independent mechanisms

Schuff¹,

Hentges²,

Kelly³

et al. 2002

J. Clin. Invest.

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IntroductionHuman lactotroph adenomas (prolactinomas) are the most frequent functioning pituitary tumors (1), but their pathogenesis remains elusive. The primary regulation of prolactin (PRL) secretion is mediated by the inhibitory effects of dopamine released from the median eminence of the hypothalamus and acting at the dopamine D2 receptor subtype (D2R) (2). Mice deficient in the D2R receptor (Drd2 -/-mice) have previously been shown to develop hyperprolactinemia, lactotroph hyperplasia, and prolactinomas (3, 4), confirming a critical role of hypothalamic dopamine and dopamine receptor activation in the physiologic regulation of lactotroph proliferation and PRL secretion. However, the involvement of a number of other regulatory factors has been postulated, including PRL itself (5). PRL increases hypothalamic-pituitary dopamine tone, i.e., constitutive inhibitory signaling by the D2R, and decreases PRL secretion (6-8) by altering the expression (9) and activity (7) of tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine synthesis.In addition to its indirect effects, mediated by changes in hypothalamic dopamine, we hypothesize that PRL might have direct effects on the pituitary gland. PRL receptors (PRLRs) have been demonstrated in the anterior pituitary in several species, including mouse (10, 11), and have been found specifically on lactotrophs in rats (12) and humans (13). Its effects on proliferation of other cell types are varied, but are predominantly stimulatory (14-25) except in the ovary (26, 27), adrenal gland (28), and vascular endothelium (29). Although it has been postulated that PRL may play an autocrine or paracrine role in lactotroph proliferation (11), there is limited empirical evidence supporting this theory. Experiments to evaluate a direct pituitary effect of PRL in vivo are difficult because of its concurrent effects on hypothalamic dopamine. By Hypothalamic dopamine inhibits pituitary prolactin secretion and proliferation of prolactin-producing lactotroph cells by activating lactotroph dopamine D2 receptors (D2Rs). Conversely, prolactin (PRL) stimulates hypothalamic dopamine neurons via PRL receptors (PRLRs) in a short-loop feedback circuit. We used Drd2 -/-and Prlr -/-mutant mice to bypass this feedback and investigate possible dopamine-independent effects of PRL on lactotroph function. The absence of either receptor induced hyperprolactinemia and large prolactinomas in females. Small macroadenomas developed in aged Prlr -/-males, but only microscopic adenomas were found in Drd2 -/-male mice. Pharmacologic studies in Prlr -/-mice with D2R agonists and antagonists demonstrated a significant loss of endogenous dopamine tone, i.e., constitutive inhibitory signaling by the D2R, in the pituitary. However, Prlr -/-mice exhibited more profound hyperprolactinemia and larger tumors than did age-matched Drd2 -/-mice, and there were additive effects in compound homozygous mutant male mice. In vitro, PRL treatment markedly inhibited the proliferation of wild-type female and male Drd2 -/-l...

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“…PRL acts as a proliferative factor in some tissues, such as mammary gland, prostate, and lymphoid cells (11), but exerts proapoptotic actions in others, such as luteal cells (12) and hair follicles (10). Although older studies using in vitro cell cultures suggested that PRL could act as a growth factor for anterior pituitary cells (15,17), more recent investigations involving genetically modified mouse models actually achieved opposite conclusions because lack of PRL activity in PRL-knockout mice (PRL Ϫ/Ϫ ) and PRLR knockout-mice (PRLR Ϫ/Ϫ ) was shown to lead to pituitary hyperplasia and tumor development (8,27). Also, it has been shown that exogenous PRL decreases in vitro lactotrope proliferation in D2R-knockout mice (D2R Ϫ/Ϫ ) (27), suggesting that PRL may regulate the size of the population of anterior pituitary cells, particularly lactotropes.…”

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confidence: 99%

Prolactin receptor antagonism in mouse anterior pituitary: effects on cell turnover and prolactin receptor expression

Ferraris

Boutillon

Bernadet

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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Since anterior pituitary expresses prolactin receptors, prolactin secreted by lactotropes could exert autocrine or paracrine actions on anterior pituitary cells. In fact, it has been observed that prolactin inhibits its own expression by lactotropes. Our hypothesis is that prolactin participates in the control of anterior pituitary cell turnover. In the present study, we explored the action of prolactin on proliferation and apoptosis of anterior pituitary cells and its effect on the expression of the prolactin receptor. To determine the activity of endogenous prolactin, we evaluated the effect of the competitive prolactin receptor antagonist Δ1-9-G129R-hPRL in vivo, using transgenic mice that constitutively and systemically express this antagonist. The weight of the pituitary gland and the anterior pituitary proliferation index, determined by BrdU incorporation, were higher in transgenic mice expressing the antagonist than in wild-type littermates. In addition, blockade of prolactin receptor in vitro by Δ1-9-G129R-hPRL increased proliferation and inhibited apoptosis of somatolactotrope GH3 cells and of primary cultures of male rat anterior pituitary cells, including lactotropes. These results suggest that prolactin acts as an autocrine/paracrine antiproliferative and proapoptotic factor in the anterior pituitary gland. In addition, anterior pituitary expression of the long isoform of the prolactin receptor, measured by real-time PCR, increased about 10-fold in transgenic mice expressing the prolactin receptor antagonist, whereas only a modest increase in the S3 short-isoform expression was observed. These results suggest that endogenous prolactin may regulate its own biological actions in the anterior pituitary by inhibiting the expression of the long isoform of the prolactin receptor. In conclusion, our observations suggest that prolactin is involved in the maintenance of physiological cell renewal in the anterior pituitary. Alterations in this physiological role of prolactin could contribute to pituitary tumor development.

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Prolactin Control of Growth and Prolactin Autoregulation in Cultured Human Pituitary Cells

Cited by 13 publications

References 7 publications

Lack of prolactin receptor signaling in mice results in lactotroph proliferation and prolactinomas by dopamine-dependent and -independent mechanisms

Lack of prolactin receptor signaling in mice results in lactotroph proliferation and prolactinomas by dopamine-dependent and -independent mechanisms

Lack of prolactin receptor signaling in mice results in lactotroph proliferation and prolactinomas by dopamine-dependent and -independent mechanisms

Prolactin receptor antagonism in mouse anterior pituitary: effects on cell turnover and prolactin receptor expression

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