Endometriosis is defined as the presence of endometrial glands and stroma outside the uterus, which are commonly found in the peritoneal cavity and ovaries [1–3]. Endometriosis is the leading cause of chronic and cyclic pelvic pain in reproductive age women, affecting 10–15% of women worldwide; pain symptoms include dysmenorrhea, dyspareunia, dysuria and dyschezia [4,5]. Infertility is commonly associated with this disease mainly due to physical and molecular disruption in the uterus which in turn reduces implantation capacity, and finally increases the risk of pregnancy loss [6]. Moreover, endometriosis negatively impacts women’s quality of life by deteriorating their physical, mental, and social wellbeing [7]. The gold standard for the diagnosis of endometriosis is made by laparoscopic inspection with histologic confirmation after biopsy [8]. The aim of endometriosis treatment is to mitigate the symptoms associated with the disease and includes pharmacological therapy with non-steroidal anti-inflammatory drugs, progestins, oral contraceptives, and gonadotropin-releasing hormone agonists, as well as surgical removal of endometrial implants and the affected tissue; however, endometriosis recurs in at least 5–15% of the cases after most invasive surgeries [8,9]. The etiology of this disease is far from being elucidated; however, altered estrogen signaling and progesterone resistance have been identified as the most common hallmarks of this disease [10].
Progesterone resistance in endometriosis has been attributed in part to a decrease in the expression of the B isoform of its intracellular receptor (PR-B) in the endometriotic lesions (ectopic endometrium) of women with the disease [11]. Furthermore, it has been proposed that progesterone resistance leads to an altered eutopic endometrium function in women with endometriosis, which in turn has been associated with pregnancy loss [6]. There is controversy about the alteration in the expression of PR in eutopic endometrium, suggesting that other mechanisms should be involved in progesterone resistance in this tissue [12].
Progesterone induces the decidualization of the endometrium, which is essential for embryo implantation and maintenance of pregnancy [13]. It has been demonstrated that progesterone exerts its actions by activating genomic and non-genomic mechanisms [14,15]. Genomic action mechanisms are mediated by the PR, which acts as a ligand-dependent transcription factor that regulates the expression of progesterone responsive genes [16–18]. Besides, non-genomic action mechanisms are mediated in part by specific receptors localized in the plasma membrane that are not related to PR, and are divided into two major groups: the membrane progesterone receptors (mPRs) that belong to the class II members of the progesterone and adipoQ receptor (PAQR) family, and the progesterone receptor membrane components (PGRMCs) [19].
mPRs are G protein-coupled receptors that are encoded by five different genes: PAQR7 (mPRα), PAQR8 (mPRβ), PAQR5 (mPRγ), PAQR6 (mPRδ) and PAQR9 (mPRε) [19,20]. The activation of mPRs is necessary to achieve full effects of progesterone in some responsive tissues or cells to this hormone in which those effects are only partially explained by PR activation [21–23]. Importantly, we and others have demonstrated that the content and activity of these receptors are altered in many diseases, including cancer [24–27]. The expression pattern of mPRs is tissue-specific and their activation by progesterone or by the mPRs specific agonist 10-ethenyl-19-norprogesterone (Org OD 02 − 0) regulates signaling pathways involved in mammary gland development, sexual behavior, ovulation, maintenance of pregnancy and other processes [19,21,28–32]. mPRs are expressed in female reproductive and embryonic tissues, mainly in the endometrium, myometrium, ovaries, and placenta [19,30,33,34]. Particularly, it has been demonstrated that PAQR7, PAQR8, PARQ5, and PAQR9 are expressed in the endometrium. PAQR7 expression is induced during the secretory phase of the menstrual cycle, whereas the expression of PAQR5 and PAQR9 is decreased during that phase [30]. In addition, PAQR7 and PAQR8 expression and the respective protein content are decreased in endometrial cancer compared to adjacent non-affected endometrium, whereas mPRγ protein content is increased in endometrial cancer tissue [35]. To the best of our knowledge, it has not been demonstrated whether gene expression and protein content of mPRs are altered in ectopic lesions and eutopic endometrium of patients with endometriosis.
We hypothesized that the expression of mPRs is decreased in both eutopic and ectopic endometrium of patients with endometriosis compared with the endometrium of women without the disease, similar to that reported in PR. Therefore, the aim of the present study was to evaluate the mRNA expression and protein content of mPRs in eutopic and ectopic endometrium of women with endometriosis and endometrium in control subjects.