Role of GPER in the anterior pituitary gland focusing on lactotroph function

Abstract

Ovarian steroids control a variety of physiological functions. They exert actions through classical nuclear steroid receptors, but rapid non-genomic actions through specific membrane steroid receptors have been also described. In this study, we demonstrate that the G-protein-coupled estrogen receptor (GPER) is expressed in the rat pituitary gland and, at a high level, in the lactotroph population. Our results revealed that ~40% of the anterior pituitary cells are GPER positive and ~35% of the lactotrophs are GPER positive. By immunocytochemical and immuno-electron-microscopy studies, we demonstrated that GPER is localized in the plasmatic membrane but is also associated to the endoplasmic reticulum in rat lactotrophs. Moreover, we found that local Gper expression is regulated negatively by 17β-estradiol (E2) and progesterone (P4) and fluctuates during the estrus cycle, being minimal in proestrus. Interestingly, lack of ovarian steroids after an ovariectomy (OVX) significantly increased pituitary GPER expression specifically in the three morphologically different subtypes of lactotrophs. We found a rapid estradiol stimulatory effect on PRL secretion mediated by GPER, both in vitro and ex vivo, using a GPER agonist G1, and this effect was prevented by the GPER antagonist G36, demonstrating a novel role for this receptor. Then, the increased pituitary GPER expression after OVX could lead to alterations in the pituitary function as all three lactotroph subtypes are target of GPER ligand and could be involved in the PRL secretion mediated by GPER. Therefore, it should be taken into consideration in the response of the gland to an eventual hormone replacement therapy.

The Importance of G-protein Coupled Estrogen Receptor in Patients With Fibromyalgia

“…Increased GPER activity with age may be attributed to the decreased amount of E2 with advanced age. Camilletti et al 30 have found that local GPER expression is regulated negatively by E2, progesterone, and lack of ovarian steroids after an ovariectomy significantly increases pituitary GPER expression. They have also shown a rapid E2 stimulatory effect on PRL secretion mediated by GPER.…”

“…They have also shown a rapid E2 stimulatory effect on PRL secretion mediated by GPER. 30,31 The GPER mediates the rapid effects of estrogen and aldosterone. Current studies indicate that GPER activation regulates blood pressure.…”

Pituitary Hyperplasia, Hormonal Changes and Prolactinoma Development in Males Exposed to Estrogens—An Insight From Translational Studies

“…However, the estradiol-mediated effect on proliferation of lactotropic cells in primary culture seems not to be due to GPER signaling [83]. The physiological roles of GPER in the pituitary are still not completely understood, but it seems to be involved in modulation of secretion of gonadotropins [84] and PRL [70] (Figure 3). At the same time, expression of the GPER gene is under estrogen-mediated genomic signaling [70] (Figure 3).…”

“…Physiological and pathophysiological mechanisms of estrogen (E) action on proliferation, growth and secretion of lactotropic (PRL) cells are probably largely mediated by nuclear estrogen receptor (ER) α. Membrane G-protein-coupled estrogen receptor 1 (GPER)-mediated estrogen signaling seems to be more involved in antiproliferative and apoptotic actions in the pituitary and may contribute to rapid secretion of PRL under physiological conditions. Its expression is under ERα-mediated nuclear signaling[15,59,[68][69][70].…”

G-protein Coupled Estrogen Receptor Expression in Growth Hormone Secreting and Non-Functioning Adenomas

“…The genomic effects of estrogen are relatively slow and take place in hours while some 'pregenomic' or rapid actions involving second messenger activation have also been described [13,23,24]. A membrane-bound G-protein coupled ER (GPER1) belonging to G-protein coupled receptor (GPCR) superfamily has recently been defined [13,25,26]. This receptor was shown to be rapidly activated upon estrogen binding and induce stimulation of adenylyl cyclase pathway [13,24].…”