The G-Protein-Coupled Estrogen Receptor (GPER) is Expressed in Normal Human Ovaries and is Upregulated in Ovarian Endometriosis and Pelvic Inflammatory Disease Involving the Ovary

Abstract

Estrogens play a crucial role in maintaining ovarian function. Deregulation of estrogen signals is associated with fertility-impairing disorders. The aim of this study was to investigate whether the G-protein-coupled estrogen receptor (GPER) is present in the human ovary. Additionally, we analyzed the folliculogenesis and ovarian endometriosis in GPER expression. Seventy-nine patients (ovarian endometriosis, n = 26; ovarian pelvic inflammatory disease [PID], n = 10; normal ovaries/endometrium, n = 30/13) were analyzed by immunohistochemistry. Normal ovaries were also assessed by real-time polymerase chain reaction and double immunofluorescence. The most intense expression of GPER was noted in the ovarian surface epithelium. Theca cells and oocytes were also significantly positive. Expression of GPER was more frequent in mature follicles/oocytes than in primordial ones, implying that GPER could be a selector during folliculogenesis. Moreover, GPER was upregulated in ovarian endometriosis and PID. Overexpression of GPER in both inflammation and endometriosis affecting the ovary may prove useful in explaining/predicting the main endometriosis-related symptoms.

Chronic Niche Inflammation in Endometriosis-Associated Infertility: Current Understanding and Future Therapeutic Strategies

“…GPER is a transmembrane receptor that participates in nongenomic estrogen signaling pathway and is upregulated in endometriotic lesion and eutopic endometrium of endometriosis patients [60,61]. GPER signaling plays an important role in follicular maturation, and the lower follicular expression of GPER could explain the lower follicular count in endometrioma patients [60,62]. In moderate/severe endometriosis patients, the follicular environment was also characterized by increased oxidative stress and leukocyte activation marker myeloperoxidase, and this increase was correlated with decreased oocyte quality and fertility [63].…”

The G-Protein Coupled Estrogen Receptor (GPER/GPR30) in ovarian granulosa cell tumors

“…Ovarian stroma, as well as adjacent tumor stroma did not show GPER positivity (marked by stars). The ovarian surface epithelium presented strong GPER immunostaining (arrowhead (C)), as described before [18]. Representative Ki67 immunostaining is shown in (E,F).…”

“…GPER was detected by immunohistochemistry, as described before [9,10,18], and Ki67 immunohistochemistry was performed on a Ventana Benchmark XT autostainer, as explained elsewhere [26]. Normal ovarian tissue (GPER) and palatine tonsil tissue (Ki67) were used as positive controls.…”

“…GPER immunoreactivity in GCTs was assessed by applying a semi-quantitative scoring system (immuno-reactive score (IRS)) by two independent observers by consensus. The IRS has been initially established for the assessment of estrogen and progesterone receptor positivity in breast cancer within routine histopathological diagnostics [27] and has been extensively used for assessing the immunoreactivity of numerous receptors, so far [18,[28][29][30]. In brief, the IRS quantifies the intensity (1 = low, 2 = moderate, 3 = strong) and percentage of stained cells (0 = no, 1 = less than 10%, 2 = 10%-50%, 3 = 51%-80%, 4 = 81%-100%).…”

International Union of Basic and Clinical Pharmacology. XCVII. G Protein–Coupled Estrogen Receptor and Its Pharmacologic Modulators

“…A role for GPER in mammalian primordial follicle formation has been reported (Wang et al, 2008b), and in nonmammalian vertebrates, G-1 has also been shown to reduce both spontaneous and progestin-induced oocyte maturation, suggesting a role for GPER in maintaining oocyte meiotic arrest (Pang et al, 2008;Peyton and Thomas, 2011). In terms of female pathophysiology, increased GPER expression has been associated with endometriosis (Heublein et al, 2012;Plante et al, 2012;Samartzis et al, 2012;Yuguchi et al, 2013) and is more frequent in malignant versus benign ovarian endometriotic cysts (Long et al, 2012). GPER expression and its activity have also been demonstrated to be of importance in endometrial and ovarian cancers (see section III.F).…”