Abstract
Anterior pituitary cell turnover occurring during female sexual cycle is a poorly understood process that involves complex regulation of cell proliferation and apoptosis by multiple hormones. In rats, the prolactin (PRL) surge that occurs at proestrus coincides with the highest apoptotic rate. Since anterior pituitary cells express the prolactin receptor (PRLR), we aimed to address the actual role of PRL in the regulation of pituitary cell turnover in cycling females. We showed that acute hyperprolactinemia induced in ovariectomized rats using PRL injection or dopamine antagonist treatment rapidly increased apoptosis and decreased proliferation specifically of PRL producing cells (lactotropes), suggesting a direct regulation of these cell responses by PRL. To demonstrate that apoptosis naturally occurring at proestrus was regulated by transient elevation of endogenous PRL levels, we used PRLR-deficient female mice (PRLRKO) in which PRL signaling is totally abolished. According to our hypothesis, no increase in lactotrope apoptotic rate was observed at proestrus, which likely contributes to pituitary tumorigenesis observed in these animals. To decipher the molecular mechanisms underlying PRL effects, we explored the isoform-specific pattern of PRLR expression in cycling wild type females. This analysis revealed dramatic changes of long versus short PRLR ratio during the estrous cycle, which is particularly relevant since these isoforms exhibit distinct signaling properties. This pattern was markedly altered in a model of chronic PRLR signaling blockade involving transgenic mice expressing a pure PRLR antagonist (TGΔ1–9-G129R-hPRL), providing evidence that PRL regulates the expression of its own receptor in an isoform-specific manner. Taken together, these results demonstrate that i) the PRL surge occurring during proestrus is a major proapoptotic signal for lactotropes, and ii) partial or total deficiencies in PRLR signaling in the anterior pituitary may result in pituitary hyperplasia and eventual prolactinoma development, as observed in TGΔ1–9-G129R-hPRL and PRLRKO mice, respectively.
Highlights
Prolactin (PRL) is a hormone secreted mainly by lactotropes in the anterior pituitary gland
Using a specific prolactin receptors (PRLR) antagonist able to partially block PRLR signaling in biological systems where both the ligand and the receptor are expressed, we recently demonstrated that unlike what happens in most other tissues, PRL induced apoptosis and reduced proliferation of anterior pituitary cells from male rats, acting through an autocrine/paracrine mechanism [24]
To evaluate if the antiproliferative effect of PRL is implied in the control of the proliferation rate that occurs at proestrus, we studied the effects of PRLR signaling on pituitary cell proliferation in wild type (WT) and PRLR knockout (PRLRKO) mice sacrificed at diestrus or proestrus
Summary
Prolactin (PRL) is a hormone secreted mainly by lactotropes in the anterior pituitary gland This hormone is involved in several physiological functions, including mammopoiesis, lactogenesis and reproduction [1] it has been implicated in the development of various peripheral tumors. It has been proposed that prolactinomas have a monoclonal origin and that alterations in cell cycle regulation lead to expansion of an original mutated cell [8,9]. Considering that the anterior pituitary is a gland with considerable plasticity [10], alterations in the mechanisms that physiologically regulate anterior pituitary cell turnover can be involved in the pathogenesis of pituitary tumors. Since all endocrine pituitary cells, including lactotropes, express prolactin receptors (PRLR) [11,12], PRL is assumed to participate in the regulation of anterior pituitary functions including tissue homeostasis. Alterations of PRLR signaling may play a role in anterior pituitary tumor development
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