Aberrant activation of signal transducer and activator of transcription-3 (STAT3) signaling in endometriosis

Kim, Byung Gak; Yoo, Jeong-Eun; Kim, Tae Hoon; Shin, Jung Hoon; Langenheim, John F.; Ferguson, Susan D.; Fazleabas, Asgerally T.; Young, Steven L.; Lessey, Bruce A.; Jeong, Jae Wook

doi:10.1093/humrep/dev050

Cited by 95 publications

(89 citation statements)

References 54 publications

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“…Endometriosis is a systemic and reversible inflammatory condition that alters endometrial function (13, 14). Clinical and animal studies support this association between endometriosis and infertility, including: 1) early prospective studies that show endometriosis patients are infertile (15, 16); 2) a recent large retrospective study demonstrating increased risk of infertility was associated with endometriosis (8), 3) reduced success rates in women with endometriosis in the setting of intrauterine insemination (IUI) has been repeatedly demonstrated (17-19), and 4) IUI results, in general, that find decreased fecundity comparing endometriosis to other diagnoses (20).…”

Section: Endometriosis and Infertility – What Is The Evidence?mentioning

confidence: 99%

“…We have reported that endometriosis is associated with sustained activation of STAT3 in eutopic endometrium, that is driven by IL-6 (13) and exacerbated by down-regulation of its primary inhibitor, protein-inhibitor of STAT3 (PIAS3) in women with endometriosis (84). STAT3 phosphorylation stabilizes hypoxia-induced factor 1-alpha (HIF1A)⍰(13) and stimulates expression of BCL6 expression (99).…”

Section: Endometriosis and Inflammationmentioning

confidence: 99%

“…STAT3 phosphorylation stabilizes hypoxia-induced factor 1-alpha (HIF1A)⍰(13) and stimulates expression of BCL6 expression (99). STAT3 activation appears to contribute to progesterone resistance and is central to inflammatory responses, including stimulation of these downstream effectors leading to the hallmark changes seen in endometriosis: proliferation, cell-survival and angiogenesis.…”

Section: Endometriosis and Inflammationmentioning

confidence: 99%

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Endometrial receptivity in the eutopic endometrium of women with endometriosis: it is affected, and let me show you why

Lessey¹,

Kim²

2017

Fertility and Sterility

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216

158

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The endometrium maintains complex controls on proliferation and apoptosis as part of repetitive menstrual cycles that prepare the endometrium for the window of implantation and pregnancy. The reliance on inflammatory mechanisms for both implantation and menstruation, creates the opportunity in the setting of endometriosis for the establishment of chronic inflammation that is disruptive to endometrial receptivity, causing both infertility and abnormal bleeding. Clinically, there can be little doubt that the endometrium of women with endometriosis is less receptive to embryo implantation, and strong evidence exists to suggests that endometrial changes are associated with decreased cycle fecundity as a result of this disease. Here we provide unifying concepts regarding those changes and how they are coordinated to promote progesterone resistance and estrogen dominance through aberrant cell signaling pathways and reduced expression of key homeostatic proteins in eutopic endometrium of women with endometriosis.

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Section: Endometriosis and Infertility – What Is The Evidence?mentioning

confidence: 99%

Section: Endometriosis and Inflammationmentioning

confidence: 99%

Section: Endometriosis and Inflammationmentioning

confidence: 99%

See 1 more Smart Citation

Endometrial receptivity in the eutopic endometrium of women with endometriosis: it is affected, and let me show you why

Lessey¹,

Kim²

2017

Fertility and Sterility

Self Cite

216

158

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“…Alterations in eutopic endometrial metabolism of estrogen in endometriosis is regulated by complex changes in autocrine and paracrine signaling associated with inflammation (36, 94, 101–104), driven in part by prostaglandin E2 (PGE2) (105, 106), produced in response to estrogen-regulated cycylooyxgenase 2 (COX-2) (107) and hypoxia induced factor-1 (HIF1α) (108). HIF1α is stabilized by activation of STAT3 that we recently showed are both over-expressed in women with endometriosis and infertility (109). COX-2 and STAT3 expression have been linked to inflammatory cytokines such as IL-17 and IL-6 (109–111), which are also elevated in women with endometriosis (109, 112).…”

Section: Impaired Expression Of Endometrial Factors Correlates With Rmentioning

confidence: 99%

“…HIF1α is stabilized by activation of STAT3 that we recently showed are both over-expressed in women with endometriosis and infertility (109). COX-2 and STAT3 expression have been linked to inflammatory cytokines such as IL-17 and IL-6 (109–111), which are also elevated in women with endometriosis (109, 112). Inhibitors of aromatase can reverse the negative effects of endometriosis in general (113) and improves outcomes in IVF for patients with suspected defects in endometrial receptivity (68).…”

Section: Impaired Expression Of Endometrial Factors Correlates With Rmentioning

confidence: 99%

Local and systemic factors and implantation: what is the evidence?

Fox

Morin

Jeong

et al. 2016

Fertility and Sterility

Self Cite

142

124

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Significant progress has been made in the understanding of embryonic competence and endometrial receptivity since the inception of Assisted Reproductive Technologies (ART). The endometrium is a highly dynamic tissue that plays a crucial role in the establishment and maintenance of normal pregnancy. In response to steroid sex hormones, the endometrium undergoes marked changes during the menstrual cycle that are critical for acceptance of the nascent embryo. There is also a wide body of literature on systemic factors that impact ART outcomes. Patient prognosis is impacted by an array of factors that tip the scales in her favor or against success. Recognizing the local and systemic factors will allow clinicians to better understand and optimize the maternal environment at the time of implantation. This review will address the current literature on endometrial and systemic factors related to impaired implantation and highlight recent advances in this area of reproductive medicine.

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Genetic overlap between endometriosis and endometrial cancer: evidence from cross‐disease genetic correlation and GWAS meta‐analyses

et al. 2018

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Epidemiological, biological, and molecular data suggest links between endometriosis and endometrial cancer, with recent epidemiological studies providing evidence for an association between a previous diagnosis of endometriosis and risk of endometrial cancer. We used genetic data as an alternative approach to investigate shared biological etiology of these two diseases. Genetic correlation analysis of summary level statistics from genomewide association studies (GWAS) using LD Score regression revealed moderate but significant genetic correlation (r g = 0.23, P = 9.3 × 10−3), and SNP effect concordance analysis provided evidence for significant SNP pleiotropy (P = 6.0 × 10−3) and concordance in effect direction (P = 2.0 × 10−3) between the two diseases. Cross‐disease GWAS meta‐analysis highlighted 13 distinct loci associated at P ≤ 10−5 with both endometriosis and endometrial cancer, with one locus (SNP rs2475335) located within PTPRD associated at a genomewide significant level (P = 4.9 × 10−8, OR = 1.11, 95% CI = 1.07–1.15). PTPRD acts in the STAT3 pathway, which has been implicated in both endometriosis and endometrial cancer. This study demonstrates the value of cross‐disease genetic analysis to support epidemiological observations and to identify biological pathways of relevance to multiple diseases.

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Aberrant activation of signal transducer and activator of transcription-3 (STAT3) signaling in endometriosis

Abstract: This work was supported by NIH R01 HD067721 (to S.L.Y and B.A.L) and NIH R01 HD057873 and American Cancer Society Research Grant RSG-12-084-01-TBG (to J.-W.J.). There are no conflicts of interest.

Cited by 95 publications

References 54 publications

Endometrial receptivity in the eutopic endometrium of women with endometriosis: it is affected, and let me show you why

Endometrial receptivity in the eutopic endometrium of women with endometriosis: it is affected, and let me show you why

Local and systemic factors and implantation: what is the evidence?

Genetic overlap between endometriosis and endometrial cancer: evidence from cross‐disease genetic correlation and GWAS meta‐analyses

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