G protein-coupled estrogen receptor in GtoPdb v.2021.3

The G protein-coupled estrogen receptor (GPER, nomenclature as agreed by the NC-IUPHAR Subcommittee on the G protein-coupled estrogen receptor [25]) was identified following observations of estrogen-evoked cyclic AMP signalling in breast cancer cells [2], which mirrored the differential expression of an orphan 7-transmembrane receptor GPR30 [6]. There are observations of both cell-surface and intracellular expression of the GPER receptor [28, 33]. Selective agonist/ antagonists for GPER have been characterized [25]. Antagonists of the nuclear estrogen receptor, such as fulvestrant [11], tamoxifen [28, 33] and raloxifene [24], as well as the flavonoid 'phytoestrogens' genistein and quercetin [17], are agonists of GPER. A complete review of GPER pharmacology has been published [25]. The roles of GPER in physiological systems throughout the body (cardiovascular, metabolic, endocrine, immune, reproductive) and in cancer have also been reviewed [25, 26, 19, 16, 9]. The GPER-selective agonist G-1 is currently in Phase I/II clinical trials for cancer (NCT04130516).

Reduced Vitellogenesis and Female Fertility in Gper Knockout Zebrafish

The role G-protein coupled estrogen receptor (GPER) plays in vertebrate reproduction remains controversial. To investigate GPER’s reproductive role, we generated a gper zebrafish mutant line (gper−/−) using TALENs. Gper mutant females exhibited reduced fertility with a 40.85% decrease in embryo production which was associated with a significant decrease in the number of Stage V (730–750 μm) ovulated oocytes. Correspondingly, the number of early vitellogenic follicles (Stage III, 400–450 µm) in gper−/− ovaries was greater than that in wildtypes (wt), suggesting that subsequent follicle development was retarded in the gper−/− fish. Moreover, plasma vitellogenin levels were decreased in gper−/− females, and epidermal growth factor receptor (Egfr) expression was lower in Stage III vitellogenic oocytes than in wt counterparts. However, hepatic nuclear estrogen receptor levels were not altered, and estrogen levels were elevated in ovarian follicles. These results suggest that Gper is involved in the control of ovarian follicle development via regulation of vitellogenesis and Egfr expression in zebrafish.

G protein-coupled estrogen receptor (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

The G protein-coupled estrogen receptor (GPER, nomenclature as agreed by the NC-IUPHAR Subcommittee on the G protein-coupled estrogen receptor [24]) was identified following observations of estrogen-evoked cyclic AMP signalling in breast cancer cells [2], which mirrored the differential expression of an orphan 7-transmembrane receptor GPR30 [5]. There are observations of both cell-surface and intracellular expression of the GPER receptor [27, 32]. Selective agonist/ antagonists for GPER have been characterized [24]. Antagonists of the nuclear estrogen receptor, such as fulvestrant [10], tamoxifen [27, 32] and raloxifene [23], as well as the flavonoid 'phytoestrogens' genistein and quercetin [16], are agonists of GPER. A complete review of GPER pharmacology has been recently published [24]. The roles of GPER in physiological systems throughout the body (cardiovascular, metabolic, endocrine, immune, reproductive) and in cancer have also been reviewed [24, 25, 18, 15, 8].

Endometrial cell apoptosis impairment associated with hormonal imbalance as a key factor in the development of endometriosis

The review describes the effect of certain hormones and their imbalance on apoptosis of retrogradely refluxed endometrial cells in the abdominal cavity and the effects of estrogen, progesterone, anti-Mullerian hormone, and gonadotropin-releasing hormone on the internal and external apoptotic pathways of various cell populations in endometriotic foci. The nuclear estrogen receptor (ER-) is shown to inhibit TNF receptors that trigger the external apoptotic pathway, but the effects of estrogens do not play a key role in the pathogenesis of endometriosis. The role of progesterone and changes in the receptor status towards prevalence of PR-A with a decreased response of endometrial tissue to progesterone and inhibition of apoptosis are described. We discuss the role of the anti-Mllerian hormone and gonadotropin-releasing hormone II (GnRH II) as activators of apoptosis in normal endometrial tissue and in endometriosis. Investigation of endocrine effects on apoptosis of parenchymal and stromal cells of endometriotic foci may provide a theoretical basis for searching for new therapeutic targets in this hormone-dependent pathology.