Article

Involvement of estrogen receptor-related receptors in human ovarian endometriosis

Laboratory of Biochemistry, National Institute for Digestive Diseases, I.R.C.C.S. Saverio de Bellis, Castellana Grotte, Bari, Italy.
Fertility and sterility (Impact Factor: 4.3). 05/2011; 96(1):102-6. DOI: 10.1016/j.fertnstert.2011.04.032
Source: PubMed

ABSTRACT To determine whether decreased estrogen receptor alpha (ER-α) expression in endometriotic lesions could be balanced by an increased expression of estrogen receptor-related receptors (ERRs). To evaluate whether ERR-α expression is influenced by hormonal change in fertile and menopausal women.
Prospective controlled study.
University Hospital, Department of Gynecology.
Twenty-five women: 20 women of reproductive age with (n = 10) and without (control; n = 10) endometriosis and 5 menopausal women.
Real-time polymerase chain reaction (qPCR). Immunohistochemistry.
The ER and ERR expression levels were studied by reverse transcriptase-qPCR, ELISA, and immunohistochemistry using endometriotic and normal endometrial tissues. The ERR-α protein distribution was performed by immunohistochemistry in fertile and menopausal women.
Increased levels of ER-β were associated with ER-α, ERR-α, and ERR-γ reductions in ectopic tissue but not in eutopic and normal endometria. Similar levels of ERR-β were found in women with and without endometriosis. The ERR-α expression was similar in proliferative and secretory endometrial samples, whereas a down-regulation of this receptor was found in atrophic tissue.
Our data confirm the up-regulation of ER-β as the principal receptor involved in the progression of human endometriosis. In addition, we found that ERR-α seems to be unresponsive to hormonal changes during the menstrual cycle.

0 Followers
 · 
113 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Context: Endometriosis is an estrogen-dependent disease, and estrogen is overproduced by abnormally elevated aromatase in endometriotic tissues. Peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC-1α) is a transcriptional coactivator-modulating steroid hormone. Objective: To investigate the effect of PGC-1α on aromatase activity in endometriosis. Design: Specimens from ovarian endometrioma (OE), endometrium with endometriosis (EE), and normal endometrium (NE) were analyzed for PGC-1α and aromatase expression. PGC-1α-dependent changes in aromatase expression in primary cultured stromal cells (SCs) were identified using luciferase and enzymatic assays, exon I-specific RT-PCR, and real-time PCR. Environmental stimulus-induced changes in PGC-1α were also examined. Results: PGC-1α was more highly expressed in OE than in EE and NE (P < 0.01). In OE, PGC-1α was coexpressed with aromatase, and their mRNAs expressions were also correlated (r = 0.56, P = 0.02). PGC-1α was recruited to the nuclear receptor half-site between PI.3 and II in the aromatase promoter. PGC-1α overexpression enhanced aromatase promoter activity (P < 0.01), mRNA expression (P < 0.05), and enzymatic activity (P < 0.01) in OESCs, but not in EESCs or NESCs. The levels of PI.3, II, and exon II mRNA increased and transcriptional enhancement was abolished by mutation of the PGC-1α-interacting site. PGC-1α expression was enhanced in OESCs by TNF-α (P < 0.05) but not by hypoxia or estradiol-17β. Conclusions: PGC-1α stimulated by TNF-α regulates aromatase expression and activity to promote local estrogen biosynthesis in OE, suggesting that PGC-1α is a promising candidate for novel targeted therapies in endometriosis treatment.
    The Journal of Clinical Endocrinology and Metabolism 03/2014; 99(7):jc20132525. DOI:10.1210/jc.2013-2525 · 6.31 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Endometriosis is an estrogen-dependent inflammatory disease defined by the growth of endometrial stroma and glands outside of the uterus. Epidemiological and clinical studies show that estrogen is essential for the growth of endometriosis. There are several molecular links between estrogen production and inflammation in endometriosis. The enzyme aromatase P450 is expressed aberrantly in endometriosis and is stimulated by prostaglandin E2 , resulting in production of estrogen that induces prostaglandin E2 expression within endometriotic lesions. Furthermore, estrogen promotes the secretion of several inflammatory cytokines and growth factors, which contribute to the progression of endometriosis and stimulate estrogen production. On the basis of the local estrogen biosynthesis in endometriotic implants, nonsteroidal aromatase inhibitors have been successfully used to treat pain symptoms caused by endometriosis. These agents do not cause the disappearance of endometriosis; they cannot be considered routine treatment and should only be administered in adequately controlled clinical studies.
    Annals of the New York Academy of Sciences 04/2014; DOI:10.1111/nyas.12411 · 4.31 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Endometriosis is a complex and challenging disease that involves aberrant adhesion, growth, and progression of endometrial tissues outside of the uterine cavity, and there is evidence to suggest that estrogen plays a key role in its development and progression. Numerous in vivo clinical studies have described the ectopic expression and regulation of estrogen receptor (ER) and progesterone receptor (PR) in the different types of endometriosis compared to normal or eutopic endometrium. However, we have noticed that conflicting and contradictory results have been presented in terms of ER subtype (ERα and ERβ) and PR isoform (PRA and PRB) expression. Both ER and PR are transcription factors and ER/PR-mediated responses depend on the coordinated, opposing, and compensatory functions of ER subtypes and PR isoforms. Moreover, analysis of the uterine phenotypes of ERα/ERβ and PRA/PRB knockout mice indicates that different ER subtypes and PR isoforms mediate distinct responses to steroid hormones and play different roles in uterine function. In this review, we outline studies that have elucidated the molecules and signaling pathways that are linked to ER and/or PR signaling pathways in the development and progression of endometriosis.
    American Journal of Translational Research 01/2014; 6(2):104-113. · 3.23 Impact Factor