Prostaglandin E2 Via Steroidogenic Factor-1 Coordinately Regulates Transcription of Steroidogenic Genes Necessary for Estrogen Synthesis in Endometriosis

Attar, Erkut; Tokunaga, Hideki; İmir, Gonca; Yılmaz, Mehmet; Redwine, David B.; Putman, Michael; Gürateş, Bilgin; Attar, Rükset; Yaegashi, Nobuo; Hales, Dale B.; Bulun, Serdar E.

doi:10.1210/jc.2008-1180

Cited by 169 publications

(103 citation statements)

References 26 publications

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“…Recently, ERβ gain-of-function was shown to contribute to endometriotic lesion establishment and progression by evading the immune cell surveillance in mice (41). Furthermore, the inflammatory milieu of the disease, which is characterized by elevated PGE2, activates E2 synthesis in ectopic endometriotic stromal cells via SF1 and CYP19A1 activation (25, 36, 42, 43). In this study, we demonstrated that ERβ and PGE2 activate SGK1, leading to inhibition of pro-apoptotic factors that may support increased survival of endometriotic stromal cells.…”

Section: Discussionmentioning

confidence: 99%

Estrogen receptor β regulates endometriotic cell survival through serum and glucocorticoid–regulated kinase activation

Monsivais

Dyson

Yin

et al. 2016

Fertility and Sterility

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OBJECTIVE To determine the expression and biological roles of SGK1 in tissues and cells from patients with endometriosis and from healthy controls. DESIGN Case-control. SETTING University research setting. PATIENTS Premenopausal women. INTERVENTIONS Endometriotic tissues (E-Osis) were obtained from women with ovarian endometriosis and normal endometrial tissues (NoEM) were obtained from women undergoing hysterectomy for benign conditions. MAIN OUTCOMES MEASURES Expression levels of serum and glucocorticoid regulated kinase (SGK1), the role of SGK1 in E-Osis pathology, and the regulation of SGK1 by ERβ. RESULTS Transcript and protein levels of SGK1 were significantly higher in endometriotic tissues and cells compared to normal endometrium. SGK1 mRNA and protein levels were stimulated by estradiol, by the ERβ-selective agonist, diarylpropionitrile, and by prostaglandin E2. SGK1 was transcriptionally regulated by ERβ based on siRNA knockdown and chromatin immunoprecipitation of ERβ followed by quantitative PCR (ChIP-qPCR). SGK1 knockdown led to increased cleavage of PARP, and SGK1 activation was correlated with the phosphorylation of FOXO3a, a pro-apoptotic factor. CONCLUSIONS ERβ leads to SGK1 overexpression in endometriosis, which contributes to the survival of endometriotic lesions through inhibition of apoptosis.

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Section: Discussionmentioning

confidence: 99%

Estrogen receptor β regulates endometriotic cell survival through serum and glucocorticoid–regulated kinase activation

Monsivais

Dyson

Yin

et al. 2016

Fertility and Sterility

Self Cite

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“…181 Here, the COX-2-derived eicosanoid PGE 2 , as a potent inducer of aromatase and Steroidogenic acute regulatory protein expression, has a pivotal role. 182 Furthermore, estrogen degradation is regulated by progesterone and defective in progesterone resistance. 183 Estrogen may be pro-inflammatory in endometriosis 184 and contributes to the pathophysiology of the disease as a mitogen causing aberrant proliferation 185 and inhibition of apoptosis, 186 decreasing the tumor-suppressor phosphatase and tensin homolog deleted on chromosome 10 via NF-κB dependent pathways.…”

Section: Endometriosis: a Complex Disease For Which Improved Treatmenmentioning

confidence: 99%

The role of Lipoxin A4 in endometrial biology and endometriosis

Canny

Lessey

2013

Mucosal Immunology

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Lipoxin A4 (LXA4), an endogenous anti-inflammatory and immunomodulatory mediator studied in many disease states, is recently appreciated as a potentially significant player in the endometrium. This eicosanoid, synthesized from arachidonic acid via the action of lipoxygenase enzymes, is likely regulated in endometrial tissue during the menstrual cycle. Recent studies revealed that LXA4 acts as an estrogen receptor agonist in endometrial epithelial cells, antagonizing some estrogen-mediated activities in a manner similar to the weak estrogen estriol, with which it shares structural similarity. LXA4 may also be an anti-inflammatory molecule in the endometrium, though its precise function in various physiological and pathological scenarios remains to be determined. The expression patterns for LXA4 and its receptor in the female reproductive tract suggest a role in pregnancy. The present review provides an oversight of its known and putative roles in the context of immuno-endocrine crosstalk. Endometriosis, a common inflammatory condition and a major cause of infertility and pain, is currently treated by surgery or anti-hormone therapies that are contraceptive and associated with undesirable side effects. LXA4 may represent a potential therapeutic and further research to elucidate its function in endometrial tissue and the peritoneal cavity will undoubtedly provide valuable insights.

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“…STAR mRNA is reported to be expressed at low levels in ESCs but not in epithelial cells (Hukkanen et al 1998, Rhee et al 2003, Aghajanova et al 2009). However, STAR protein levels in total endometrial tissue homogenates detected by western blotting analysis were reported to be low to undetectable (Tsai et al 2001, Aghajanova et al 2009, Attar et al 2009), and to our knowledge, there are no studies reporting CYP11A1 or CYP17A1 protein expression or enzymatic activity in the endometrium. Androgen:oestrogen balance and regulation of the endometrial microenvironment.…”

Section: Androgen Biosynthesis and Expression Of Steroidmetabolisingmentioning

confidence: 81%

Regulation of androgen action during establishment of pregnancy

Gibson¹,

Simitsidellis²,

Saunders³

2016

Journal of Molecular Endocrinology

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During the establishment of pregnancy, the ovarian-derived hormones progesterone and oestradiol regulate remodelling of the endometrium to promote an environment that is able to support and maintain a successful pregnancy. Decidualisation is characterised by differentiation of endometrial stromal cells that secrete growth factors and cytokines that regulate vascular remodelling and immune cell influx. This differentiation process is critical for reproduction, and inadequate decidualisation is implicated in the aetiology of pregnancy disorders such as foetal growth restriction and preeclampsia. In contrast to progesterone and oestradiol, the role of androgens in regulating endometrial function is poorly understood. Androgen receptors are expressed in the endometrium, and androgens are reported to regulate both the transcriptome and the secretome of endometrial stromal cells. In androgen-target tissues, circulating precursors are activated to mediate local effects, and recent studies report that steroid concentrations detected in endometrial tissue are distinct to those detected in the peripheral circulation. New evidence suggests that decidualisation results in dynamic changes in the expression of androgen biosynthetic enzymes, highlighting a role for pre-receptor regulation of androgen action during the establishment of pregnancy. These results suggest that such enzymes could be future therapeutic targets for the treatment of infertility associated with endometrial dysfunction. In conclusion, these data support the hypothesis that androgens play a beneficial role in regulating the establishment and maintenance of pregnancy. Future studies should be focussed on investigating the safety and efficacy of androgen supplementation with the potential for utilisation of novel therapeutics, such as selective androgen receptor modulators, to improve reproductive outcomes in women.

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Prostaglandin E2 Via Steroidogenic Factor-1 Coordinately Regulates Transcription of Steroidogenic Genes Necessary for Estrogen Synthesis in Endometriosis

Abstract: Endometriotic cells contain the full complement of steroidogenic genes for de novo synthesis of estradiol from cholesterol, which is stimulated by PGE2 via enhanced binding of SF1 to promoters of StAR and aromatase genes in a synchronous fashion.

Cited by 169 publications

References 26 publications

Estrogen receptor β regulates endometriotic cell survival through serum and glucocorticoid–regulated kinase activation

Estrogen receptor β regulates endometriotic cell survival through serum and glucocorticoid–regulated kinase activation

The role of Lipoxin A4 in endometrial biology and endometriosis

Regulation of androgen action during establishment of pregnancy

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