The DOI matches its Crossref record; 34 of the 37 references it cites were found in a registry or an index; 4 of the 35 sources its claims cite were checked for support.
Prostaglandin E2 Via Steroidogenic Factor-1 Coordinately Regulates Transcription of Steroidogenic Genes Necessary for Estrogen Synthesis in Endometriosis
Open accessAbstract
Context: Products of at least five specific steroidogenic genes, including steroidogenic acute regulatory protein (StAR), which facilitates the entry of cytosolic cholesterol into the mitochondrion, side chain cleavage P450 enzyme, 3β-hydroxysteroid-dehydrogenase-2, 17-hydroxylase/17-20-lyase, and aromatase, which catalyzes the final step, are necessary for the conversion of cholesterol to estrogen. Expression and biological activity of StAR and aromatase were previously demonstrated in endometriosis but not in normal endometrium. Prostaglandin E2 (PGE2) induces aromatase expression via the transcriptional factor steroidogenic factor-1 (SF1) in endometriosis, which is opposed by chicken-ovalbumin upstream-transcription factor (COUP-TF) and Wilms’ tumor-1 (WT1) in endometrium. Objective: The aim of the study was to demonstrate a complete steroidogenic pathway leading to estrogen biosynthesis in endometriotic cells and the transcriptional mechanisms that regulate basal and PGE2-stimulated estrogen production in endometriotic cells and endometrium. Results: Compared with normal endometrial tissues, mRNA levels of StAR, side chain cleavage P450, 3β-hydroxysteroid-dehydrogenase-2, 17-hydroxylase/17-20-lyase, aromatase, and SF1 were significantly higher in endometriotic tissues. PGE2 induced the expression of all steroidogenic genes; production of progesterone, estrone, and estradiol; and StAR promoter activity in endometriotic cells. Overexpression of SF1 induced, whereas COUP-TFII or WT1 suppressed, StAR promoter activity. PGE2 induced coordinate binding of SF1 to StAR and aromatase promoters but decreased COUP-TFII binding in endometriotic cells. COUP-TFII or WT1 binding to both promoters was significantly higher in endometrial compared with endometriotic cells. Conclusion: 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.
Overview
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Written from the paper’s full text.
TL;DR
This study shows that endometriotic stromal cells express the complete enzymatic machinery needed to convert cholesterol to estradiol and that prostaglandin E2 (PGE2) coordinately stimulates this pathway through steroidogenic factor-1 (SF1). The same promoters are suppressed in normal endometrial cells by inhibitory factors such as COUP-TFII and WT1.
Key findings
- Endometriotic tissues had significantly higher mRNA levels of StAR, P450scc, HSD3B2, P450c17, P450arom, and SF1 than normal endometrium; LRH1 mRNA was slightly lower. StAR and P450arom showed the largest differences, and SF1 was reported at 0.7 attomoles/g 18S RNA in endometriotic tissue.
- In endometriotic stromal cells, PGE2 (10^-7 M) increased StAR mRNA 2.3-fold and P450arom mRNA 4.3-fold, with smaller but significant increases (1.4–1.9 fold) in P450scc, P450c17, and HSD3B2. PGE2 also raised progesterone, estrone, and estradiol levels in culture media.
- SF1 overexpression activated the StAR promoter, whereas COUP-TFII or WT1 suppressed it. Chromatin immunoprecipitation showed that PGE2 increased SF1 binding to both StAR and P450arom promoters and reduced binding of COUP-TFII and WT1; inhibitory factor binding was higher in endometrial than endometriotic cells.
- The authors conclude that endometriotic cells can synthesize estradiol de novo from cholesterol and that PGE2 acts through SF1 to synchronously regulate StAR and aromatase transcription.
Methods
- Primary stromal cells were cultured from ovarian endometriomas (n = 17) and eutopic endometrium (n = 16); extraovarian endometriotic tissue (n = 13) and endometrium from disease-free women (n = 13) were used for mRNA comparisons. Subjects were aged 23–45 years, and tissues were collected with IRB approval and consent.
- The study used real-time RT-PCR, ELISA for progesterone/estrone/estradiol, immunoblotting, transient transfection luciferase assays with a −885 bp StAR promoter and transcription-factor expression plasmids, and ChIP assays for SF1, COUP-TFII, and WT1 binding.
- Statistical comparisons used one-way ANOVA with Tukey tests or Student’s t tests, with significance set at α = 0.05 and β = 0.20; data are reported as mean ± SEM.
Limitations
- The paper does not include a dedicated limitations section. It acknowledges that its findings differ from an earlier study by Tsai et al. and suggests possible explanations: different patient populations (Taiwan vs. U.S.), greater sensitivity of real-time RT-PCR compared with semiquantitative PCR, and differences in surgical tissue excision.
- Evident from the text: some experiments relied on small samples (e.g., n = 3 for steroid measurements, n = 6 for stromal-cell mRNA experiments), and the work is primarily in vitro with primary stromal cells at passage 1.
- The study infers de novo cholesterol-to-estradiol synthesis from gene expression and steroid measurements rather than directly tracing the full flux; HSD17B1 was not re-examined because the authors relied on prior evidence of its expression.
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Claims the paper makes
49 Own result · 17 Own interpretation · 14 No full text of the sources · 3 Partly supported · 3 No basis given · 2 Not checked yet · 2 Own method · 1 Supported · accuracy not yet measured
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Previously, we demonstrated that in vitro overexpression studies reflected the in vivo effects of these factors on differential P450arom expression (16,17,22).”
§ Prostaglandin E 2 Via Steroidogenic Factor-1 Coordinately Regulates Transcription of Steroidogenic Genes Necessary for Estrogen Synthesis in Endometriosis > Transcriptional regulation of StAR in endometriotic cells
What the sources say
- Not checked — no full text of the sourcecites [16] Zeitoun, 1999, Stimulation of aromatase P450 promoter (II) activity in endometriosis and its inhibition in endometrium are regulated by competitive binding of SF-1 and COUP-TF to the same cis-acting element., Mol Endocrinol source
- Partly supportedcites [17] Gurates, 2002, WT1 and DAX-1 inhibit aromatase P450 expression in human endometrial and endometriotic stromal cells., J Clin Endocrinol Metab sourceExperimental — accuracy not yet measured
The Results (p. 5) show that overexpressed WT1 and DAX-1 inhibit P450arom promoter activity in cultured stromal cells. In vivo measurements (Endometriosis, pp. 7–8) show lower WT1 in endometriotic stroma, consistent with that finding, but no significant difference in DAX-1 levels between the tissues. The paper therefore does not show that the in vitro results reflected in vivo effects of both factors on differential P450arom expression. (LLM, conf=0.86)
- Not checked — no full text of the sourcecites [22] Yang, 2002, Regulation of aromatase P450 expression in endometriotic and endometrial stromal cells by CCAT/enhancer binding proteins: decreased C/EBPβ in endometriosis is associated with overexpression of aromatase., J Clin Endocrinol Metab source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We found that StAR, P450scc, P450c17, and P450arom mRNA levels were significantly higher in endometriotic tissue than in normal endometrium.”
§ Prostaglandin E 2 Via Steroidogenic Factor-1 Coordinately Regulates Transcription of Steroidogenic Genes Necessary for Estrogen Synthesis in Endometriosis > Expression of steroidogenic genes in eutopic and ectopic endometrium
plaincorrelationaln = 13- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“COUP-TFII or WT1 binding to both promoters was significantly higher in endometrial compared with endometriotic cells.”
§ Prostaglandin E 2 Via Steroidogenic Factor-1 Coordinately Regulates Transcription of Steroidogenic Genes Necessary for Estrogen Synthesis in Endometriosis > Abstract
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Time-dependent PGE 2 induction of both StAR mRNA and protein started as early as 1 h after treatment.”
§ Prostaglandin E 2 Via Steroidogenic Factor-1 Coordinately Regulates Transcription of Steroidogenic Genes Necessary for Estrogen Synthesis in Endometriosis > Regulation of StAR mRNA and protein levels by PGE 2 in endometriotic stromal cells
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“PGE 2 induced coordinate binding of SF1 to StAR and aromatase promoters but decreased COUP-TFII binding in endometriotic cells.”
§ Prostaglandin E 2 Via Steroidogenic Factor-1 Coordinately Regulates Transcription of Steroidogenic Genes Necessary for Estrogen Synthesis in Endometriosis > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The most striking differences, however, were observed for StAR and P450arom mRNA levels (Fig. 1, A and E).”
§ Prostaglandin E 2 Via Steroidogenic Factor-1 Coordinately Regulates Transcription of Steroidogenic Genes Necessary for Estrogen Synthesis in Endometriosis > Expression of steroidogenic genes in eutopic and ectopic endometrium
plaincorrelationaln = 13- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The differences in P450scc, HSD3B2, and P450c17 mRNA levels were apparent but less significant (Fig. 1, B-D).”
§ Prostaglandin E 2 Via Steroidogenic Factor-1 Coordinately Regulates Transcription of Steroidogenic Genes Necessary for Estrogen Synthesis in Endometriosis > Expression of steroidogenic genes in eutopic and ectopic endometrium
hedgedcorrelationaln = 13- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The addition of 22(R)-OH-cholesterol (10 M), which can pass directly through the mitochondrial membrane (independent of StAR) (31), did not stimulate the production of these steroids to the same extent as PGE 2 treatment, suggesting that StAR up-regulation by PGE 2 is necessary for steroid production in endometriotic cells (Fig. 3).”
§ Prostaglandin E 2 Via Steroidogenic Factor-1 Coordinately Regulates Transcription of Steroidogenic Genes Necessary for Estrogen Synthesis in Endometriosis > Progesterone and estradiol production by stromal cells
hedged- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Interestingly, LRH1 mRNA levels were slightly but significantly lower in endometriotic cells vs. endometrial cells (Fig. 1G).”
§ Prostaglandin E 2 Via Steroidogenic Factor-1 Coordinately Regulates Transcription of Steroidogenic Genes Necessary for Estrogen Synthesis in Endometriosis > Expression of steroidogenic genes in eutopic and ectopic endometrium
plaincorrelationaln = 13- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“PGE 2 induced coordinate binding of SF1 to StAR and aromatase promoters but decreased COUP-TFII binding in endometriotic cells.”
§ Prostaglandin E 2 Via Steroidogenic Factor-1 Coordinately Regulates Transcription of Steroidogenic Genes Necessary for Estrogen Synthesis in Endometriosis > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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- Probably not a substantial claim. 8
- It may state two separate claims as one. 15
- The quote only partly states this claim. 1
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Conversely, the transcription factors chicken ovalbumin upstream promoter-transcription factor (COUP-TF) and Wilms' tumor-1 (WT1) bind to and inhibit the P450arom promoter in endometrial stromal cells (16,17).”
§ Prostaglandin E 2 Via Steroidogenic Factor-1 Coordinately Regulates Transcription of Steroidogenic Genes Necessary for Estrogen Synthesis in Endometriosis > Abstract
What the sources say
- Not checked — no full text of the sourcecites [16] Zeitoun, 1999, Stimulation of aromatase P450 promoter (II) activity in endometriosis and its inhibition in endometrium are regulated by competitive binding of SF-1 and COUP-TF to the same cis-acting element., Mol Endocrinol source
- Partly supportedcites [17] Gurates, 2002, WT1 and DAX-1 inhibit aromatase P450 expression in human endometrial and endometriotic stromal cells., J Clin Endocrinol Metab sourceExperimental — accuracy not yet measured
The Discussion (p. 8) reports that COUP-TF inhibits aromatase expression in endometrium and competes with SF-1 for binding to the P450arom promoter. The Results (pp. 5–6) show that WT1 inhibits promoter activity in endometrial stromal cells, but do not show that WT1 itself binds the promoter; they instead describe inhibition of activity mediated by SF-1 binding. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“P450c17 catalyzes the conversion of progesterone to androstenedione, which is the primary substrate for P450arom in ovarian granulosa cells (6,7).”
§ Prostaglandin E 2 Via Steroidogenic Factor-1 Coordinately Regulates Transcription of Steroidogenic Genes Necessary for Estrogen Synthesis in Endometriosis > Abstract
What the sources say
- Partly supportedcites [6] Auchus, 1998, Cytochrome b5 augments the 17,20-lyase activity of human P450c17 without direct electron transfer., J Biol Chem sourceExperimental — accuracy not yet measured
The Results section (page unavailable) reports that human P450c17 converts progesterone to 17α-hydroxyprogesterone and can then convert that intermediate to androstenedione, although the second step is inefficient. The Discussion says human androgen biosynthesis predominantly follows a different route via DHEA. The paper does not establish that androstenedione is the primary P450arom substrate in ovarian granulosa cells. (LLM, conf=0.88)
- Not checked — no full text of the sourcecites [7] Lee-Robichaud, 1995, Modulation of the activity of human 17 α-hydroxylase-17,20-lyase (CYP17) by cytochrome b5: endocrinological and mechanistic implications., Biochem J source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“We used the minus KTS splice isoform of WT1, which is a more potent transcriptional regulator compared with the plus KTS isoform (17).”
§ Prostaglandin E 2 Via Steroidogenic Factor-1 Coordinately Regulates Transcription of Steroidogenic Genes Necessary for Estrogen Synthesis in Endometriosis > Transcriptional regulation of StAR in endometriotic cells
What the sources say
- Supportedcites [17] Gurates, 2002, WT1 and DAX-1 inhibit aromatase P450 expression in human endometrial and endometriotic stromal cells., J Clin Endocrinol Metab source
The Results (p. 5) directly compare the isoforms and find WT1(−KTS) much more potent than WT1(+KTS) at suppressing SF-1-induced aromatase promoter activity. The introduction (p. 2) also reports greater potency of the −KTS isoform in stimulating the MIS gene promoter. (LLM, conf=0.88)
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“On the other hand, SF1 mRNA was barely detectable in endometrium and expressed at strikingly high levels in endometriotic tissue (0.7 attomoles/g 18S RNA; Fig. 1F).”
§ Prostaglandin E 2 Via Steroidogenic Factor-1 Coordinately Regulates Transcription of Steroidogenic Genes Necessary for Estrogen Synthesis in Endometriosis > Expression of steroidogenic genes in eutopic and ectopic endometrium
plaincorrelationaln = 13- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Administration of physiological quantities of PGE 2 (10 Ϫ7 or 10 Ϫ8 M) significantly stimulated StAR mRNA expression, whereas this stimulatory effect was not observed at higher concentrations (Fig. 4A).”
§ Prostaglandin E 2 Via Steroidogenic Factor-1 Coordinately Regulates Transcription of Steroidogenic Genes Necessary for Estrogen Synthesis in Endometriosis > Regulation of StAR mRNA and protein levels by PGE 2 in endometriotic stromal cells
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Peak levels were observed at 24 h for mRNA and 48 h for protein.”
§ Prostaglandin E 2 Via Steroidogenic Factor-1 Coordinately Regulates Transcription of Steroidogenic Genes Necessary for Estrogen Synthesis in Endometriosis > Regulation of StAR mRNA and protein levels by PGE 2 in endometriotic stromal cells
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The PGE 2 -dependent binding pattern of these three factors was remarkably similar with respect to both the StAR and P450arom promoters, but distinct in endometriotic and endometrial stromal cells.”
§ Prostaglandin E 2 Via Steroidogenic Factor-1 Coordinately Regulates Transcription of Steroidogenic Genes Necessary for Estrogen Synthesis in Endometriosis > Binding of key regulatory transcription factors to StAR and P450arom promoters in a synchronized manner
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Our current results regarding PGE 2 induction of StAR expression and progesterone production are in general consistent with the previously published data by Tsai et al. (10) regarding StAR expression.”
§ Prostaglandin E 2 Via Steroidogenic Factor-1 Coordinately Regulates Transcription of Steroidogenic Genes Necessary for Estrogen Synthesis in Endometriosis > Discussion
What the sources say
- Not checked — no full text of the sourcecites [10] Tsai, 2001, Regulation of steroidogenic acute regulatory protein expression and progesterone production in endometriotic stromal cells., J Clin Endocrinol Metab source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“and PGE 2 significantly enhanced SF1 binding in both cell types.”
§ Prostaglandin E 2 Via Steroidogenic Factor-1 Coordinately Regulates Transcription of Steroidogenic Genes Necessary for Estrogen Synthesis in Endometriosis > Binding of key regulatory transcription factors to StAR and P450arom promoters in a synchronized manner
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The quote only partly states this claim.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“and SF1 is bound to the StAR and P450arom promoters, whereas the corepressors are not recruited.”
§ Prostaglandin E 2 Via Steroidogenic Factor-1 Coordinately Regulates Transcription of Steroidogenic Genes Necessary for Estrogen Synthesis in Endometriosis > Discussion
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In endometriotic (E-OSIS) stromal cells, PGE 2 induced binding of SF1 to both StAR and P450arom promoters, whereas very low SF1 binding was observed in endometrial (E-IUM) stromal cells.”
§ Prostaglandin E 2 Via Steroidogenic Factor-1 Coordinately Regulates Transcription of Steroidogenic Genes Necessary for Estrogen Synthesis in Endometriosis > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“PGE 2 stimulated the activity of the Ϫ885 bp StAR promoter fused to the luciferase (LUC) reporter gene in both endometriotic and endometrial cells, whereas it did not stimulate luciferase activity of the empty vector.”
§ Prostaglandin E 2 Via Steroidogenic Factor-1 Coordinately Regulates Transcription of Steroidogenic Genes Necessary for Estrogen Synthesis in Endometriosis > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“On the other hand, WT1 or COUP-TFII inhibited StAR promoter activity.”
§ Prostaglandin E 2 Via Steroidogenic Factor-1 Coordinately Regulates Transcription of Steroidogenic Genes Necessary for Estrogen Synthesis in Endometriosis > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
In the paper
“Because we previously demonstrated constitutive expression of HSD17B1, which catalyzes the conversion of weakly estrogenic estrone to biologically potent estradiol in both endometrial and endometriotic tissues, this experiment was not repeated here (11).”
§ Prostaglandin E 2 Via Steroidogenic Factor-1 Coordinately Regulates Transcription of Steroidogenic Genes Necessary for Estrogen Synthesis in Endometriosis > Discussion
What the sources say
- Not checked — no full text of the sourcecites [11] Zeitoun, 1998, Deficient 17β-hydroxysteroid dehydrogenase type 2 expression in endometriosis: failure to metabolize 17β-estradiol., J Clin Endocrinol Metab source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“P450arom is responsible for the conversion of androstenedione to estrone, which is further converted to the biologically active estradiol by the enzyme HSD17B1 (4).”
§ Prostaglandin E 2 Via Steroidogenic Factor-1 Coordinately Regulates Transcription of Steroidogenic Genes Necessary for Estrogen Synthesis in Endometriosis > Abstract
What the sources say
- Not checked — no full text of the sourcecites [4] Tremblay, 1989, Regulation of the gene for estrogenic 17-ketosteroid reductase lying on chromosome 17cen–q25., J Biol Chem source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“In addition to, or perhaps as a consequence of, immune, environmental, and genetic factors, endometriotic lesions show high estradiol biosynthesis and low estradiol inactivation compared with normal endometrium (4,5).”
§ Prostaglandin E 2 Via Steroidogenic Factor-1 Coordinately Regulates Transcription of Steroidogenic Genes Necessary for Estrogen Synthesis in Endometriosis > Abstract
What the sources say
- Not checked — no full text of the sourcecites [4] Tremblay, 1989, Regulation of the gene for estrogenic 17-ketosteroid reductase lying on chromosome 17cen–q25., J Biol Chem source
- Not checked — no full text of the sourcecites [5] Bulun, 2006, Progesterone resistance in endometriosis: link to failure to metabolize estradiol., Mol Cell Endocrinol source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“P450arom expression in endometriosis and peripheral tissues was shown to be critical because its inhibitors have been used successfully to treat postmenopausal endometriosis (14).”
§ Prostaglandin E 2 Via Steroidogenic Factor-1 Coordinately Regulates Transcription of Steroidogenic Genes Necessary for Estrogen Synthesis in Endometriosis > Abstract
What the sources say
- Not checked — no full text of the sourcecites [14] Attar, 2006, Aromatase inhibitors: the next generation of therapeutics for endometriosis?, Fertil Steril source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“StAR facilitates the first step of steroidogenesis, the entry of cholesterol into the mitochondrion, where cholesterol is converted by the mitochondrial enzyme P450scc to pregnenolone, which is then converted to progesterone via HSD3B2 (8,9).”
§ Prostaglandin E 2 Via Steroidogenic Factor-1 Coordinately Regulates Transcription of Steroidogenic Genes Necessary for Estrogen Synthesis in Endometriosis > Abstract
What the sources say
- Not checked — no full text of the sourcecites [8] Stocco, 2001, StAR protein and the regulation of steroid hormone biosynthesis., Annu Rev Physiol source
- Not checked — no full text of the sourcecites [9] Miller, 1999, Molecular pathology and mechanism of action of the steroidogenic acute regulatory protein, StAR., J Steroid Biochem Mol Biol source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In vivo and in vitro demonstration of synchronous regulation of StAR and a complete set of steroidogenic enzymes including P450arom by the same complement of transcription factors in endometriotic cells shows that estrogen production in endometriosis is up-regulated by a distinct mechanism.”
§ Prostaglandin E 2 Via Steroidogenic Factor-1 Coordinately Regulates Transcription of Steroidogenic Genes Necessary for Estrogen Synthesis in Endometriosis > Discussion
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Primary cultured endometrial and endometriotic stromal cells retain the transcriptional characteristics of the corresponding tissues in vivo.
In the paper
“This is mediated by a positive feedback cycle that favors overexpression of key steroidogenic genes, most notably aromatase, overexpression of COX2, and continuous local production of estradiol and prostaglandin E 2 (PGE 2 ) in endometriotic tissue (4).”
§ Prostaglandin E 2 Via Steroidogenic Factor-1 Coordinately Regulates Transcription of Steroidogenic Genes Necessary for Estrogen Synthesis in Endometriosis > Abstract
What the sources say
- Not checked — no full text of the sourcecites [4] Tremblay, 1989, Regulation of the gene for estrogenic 17-ketosteroid reductase lying on chromosome 17cen–q25., J Biol Chem source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The association of the control protein, nonacetylated histone H3, to chromatin did not vary with cell type or treatment.”
§ Prostaglandin E 2 Via Steroidogenic Factor-1 Coordinately Regulates Transcription of Steroidogenic Genes Necessary for Estrogen Synthesis in Endometriosis > Discussion
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“No binding activity was observed after chromatin was immunoprecipitated with nonspecific IgG.”
§ Prostaglandin E 2 Via Steroidogenic Factor-1 Coordinately Regulates Transcription of Steroidogenic Genes Necessary for Estrogen Synthesis in Endometriosis > Discussion
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper relies on this without support.
SF1 is elevated in endometriotic tissue and mediates the stimulatory action of PGE2 via binding to the P450arom promoter.
“The transcription factor steroidogenic factor-1 (SF1), which is elevated in endometriotic tissue, mediates the stimulatory action of PGE 2 via binding to the P450arom promoter.”
The authors state this as an assumption.
The transcriptional mechanisms responsible for the PGE2 induction of StAR in endometriotic cells are unknown.
“Although the transcriptional factors that mediate LH-, ACTH-, or cAMP-dependent regulation of StAR in gonadal or adrenal cells have been well characterized (19 -22), the transcriptional mechanisms responsible for the PGE 2 induction of StAR in endometriotic cells are unknown.”
The paper relies on this without support.
PGE2 regulates steroidogenic genes through cAMP.
“the PGE 2 -cAMP-SF1 pathway as the key regulator of steroidogenesis”
The paper relies on this without support.
22(R)-OH-cholesterol can diffuse into mitochondria without a requirement for StAR.
“22(R)-OH-cholesterol can diffuse into the mitochondria without a requirement for StAR.”
The paper relies on this without support.
Primary cultured endometrial and endometriotic stromal cells retain the transcriptional characteristics of the corresponding tissues in vivo.
“Using ChIP, we demonstrated differential binding of key transcription factors and coregulators (SF1, COUP-TFII, and WT1) to the StAR and P450arom promoters in intact endometrial and endometriotic stromal cells in primary culture.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The cited source doesn’t support the claim as written.
In the citing paper
“For example, the first studies reporting the overexpression of StAR, HSD3β2, aromatase, HSD17β1, ERβ, and GPER all used OE or AD tissue samples (Brandenberger et al., 1999; Fujimoto et al., 1999; Attar et al., 2009; Mehasseb et al., 2011; Samartzis et al., 2012), due, likely, to less prevalent occurrence and thus the difficulty in getting DE samples.”
From Progressively diminished estrogen signaling concordant with increased fibrosis in ectopic endometrium (2025) · cites this paper as Attar et al., 2009
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“In the endometriotic stromal cells, NR5A1 is essential for supporting high levels of proteins and enzymes that drive the serial conversion of cholesterol to estradiol”
From Endometriosis and nuclear receptors (2019) · cites this paper as Attar et al., 2009
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Additionally, 3β-hydroxysteroid dehydrogenase type 2 (HSD3β2), which converts dehydroepiandrosterone to androstenedione, that can be further converted to estrone (E1) by aromatase, and HSD17β1, which converts E1 into E2, a more potent estrogen, are also aberrantly upregulated (Attar et al., 2009; Smuc et al., 2009).”
From Progressively diminished estrogen signaling concordant with increased fibrosis in ectopic endometrium (2025) · cites this paper as Attar et al., 2009
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“In particular, the prevailing view holds that prostaglandin E2 plays a vital role in facilitating estrogen biosynthesis and the upregulation of ERβ, positioning itself in the central nexus in a feed-forward loop linking hyperestrogenism and inflammation in all ectopic endometria.”
From Progressively diminished estrogen signaling concordant with increased fibrosis in ectopic endometrium (2025) · cites this paper as Attar et al., 2009
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“NR5A1 binds the promoters and stimulates the expression of steroidogenic acute response protein (StAR), side chain cleavage enzyme (CYP11A1), 3β-hydroxysteroid dehydrogenase type 2 (HSD3B2), 17β-hydroxylase/17,20-lyase (CYP17A1) and aromatase (CYP19A1)”
From Endometriosis and nuclear receptors (2019) · cites this paper as Attar et al., 2009
Experimental — accuracy not yet measured
The cited source says what the claim attributes to it.
In the citing paper
“In addition to estrogen dependence, another striking feature of endometriosis is the availability of the full set of steroidogenic enzymes enabling de-novo synthesis of estradiol”
From Endometriosis and nuclear receptors (2019) · cites this paper as Attar et al., 2009
The cited source says what the claim attributes to it.
In the citing paper
“PGE2 in turn stimulates the production of cyclic AMP (cAMP), which, together with steroidogenic factor 1 (SF1), whose expression is aberrantly upregulated in endometriotic tissue compared to endometrial tissue, induces expression of mRNAs that encode enzymes that play a critical role in the steroidogenic enzyme machinery, including STAR, 17-hydroxylase/17,20-lyase, 3β-HSD and aromatase, which may”
From Endometrial Intracrinology: Oestrogens, Androgens and Endometrial Disorders (2018) · cites this paper as [74]
In the citing paper
“Even when stimulated with PGE2, the expression of most genes involved in estrogen biosynthesis, including StAR, SF-1, and aromatase, are still negligibly low, concomitant with the very low production of estradiol in normal endometrial stromal cells [70].”
From The Pathogenesis of Adenomyosis vis-à-vis Endometriosis (2020) · cites this paper as [70]
In the citing paper
“The difference in E2 production between HESCs and ESCLs is consistent with what have been documented previously41–45.”
From Platelets induce increased estrogen production through NF-κB and TGF-β1 signaling pathways in endometriotic stromal cells (2020) · cites this paper as [45]
In the citing paper
“endometriotic stromal cells, in contrast, do produce a much higher level of estrogens, due to demethylated aromatase42, and overexpression of StAR, HSD3B2 and HSD17B112,43,45,47.”
From Platelets induce increased estrogen production through NF-κB and TGF-β1 signaling pathways in endometriotic stromal cells (2020) · cites this paper as [45]
In the citing paper
“The similarity of the molecular biology of TIAR in various tissues with that described in endometriosis [39–41, 59–62] strongly suggests that this represents the common underlying mechanisms of both processes”
From The pathophysiology of endometriosis and adenomyosis, tissue injury and repair (2009) · cites this paper as [62]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Prostaglandin E 2 Via Steroidogenic Factor-1 Coordinately Regulates Transcription of Steroidogenic Genes Necessary for Estrogen Synthesis in Endometriosis > Progesterone and estradiol production by stromal cells
“These findings indicate that PGE 2 stimulates the expression of StAR, P450scc, and HDS3B2 to catalyze the conversion of cholesterol to progesterone in endometrial stromal cells.”
§ Prostaglandin E 2 Via Steroidogenic Factor-1 Coordinately Regulates Transcription of Steroidogenic Genes Necessary for Estrogen Synthesis in Endometriosis > Expression of steroidogenic genes in eutopic and ectopic endometrium
“Eutopic endometrial stromal cells from diseasefree women contained extremely low levels of steroidogenic genes, which could not be stimulated by PGE 2 (except for a 3-fold increase in StAR; Fig. 2).”
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BackgroundRole of Estrogen Receptor-β in Endometriosis
Bulun, S., Monsavais, D., Pavone, M., Dyson, M., Xue, Q., Attar, E., Tokunaga, H., & Su, E. (2012) · Seminars in Reproductive Medicine · doi:10.1055/s-0031-1299596 · Cited by 321
“36 We recently used real-time polymerase chain reaction (RT-PCR) to compare tissue mRNA levels of these key nuclear receptors in endometriosis and eutopic endometrium ( ► Fig.”
MethodSelf-citationEndometriosis and nuclear receptors
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“orphan NRs, steroidogenic factor-1 (NR5A1) and chicken ovalbumin upstream promoter-transcription factor II (NR2F2) also play critical roles in regulating local estrogen concentrations in endometriosis (Zeitoun et al., 1999; Attar et al., 2009; Bernardi et al., 2018).”
BackgroundInfluentialSelf-citationEndometriosis and adenomyosis: shared pathophysiology
Bulun, S. E., Yildiz, S., Adli, M., Chakravarti, D., Parker, J. B., Milad, M., Yang, L., Chaudhari, A., Tsai, S., Wei, J. J., et al. (2023) · Fertility and Sterility · doi:10.1016/j.fertnstert.2023.03.006 · Cited by 216
Self-citationRegulation of Inflammation Pathways and Inflammasome by Sex Steroid Hormones in Endometriosis
García-Gómez, E., Vázquez-Martínez, E. R., Reyes-Mayoral, C., Cruz-Orozco, O., Camacho‐Arroyo, I., & Cerbón, M. A. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2019.00935 · Cited by 202
“For example, it is involved in activation of cyclooxygenase 2 (COX2), which in turn elevates prostaglandin E2 (PGE2) levels that contribute to activation of aromatase and other members of steroidogenic pathway, through an increased binding of steroidogenic factor 1 (SF-1) to promoter of aromatase gene (85).”
BackgroundPathogenesis of Endometriosis: The Origin of Pain and Subfertility
Gruber, T. M., & Mechsner, S. (2021) · Cells · doi:10.3390/cells10061381 · Cited by 237
“Besides, local hyperestrogenism may explain the high comorbidity rates of AM and endometrial polyps, endometrial hyperplasia, and myomas that also influence fertility rates [74].”
BackgroundHuhtinen, K., Desai, R., Ståhle, M., Salminen, A., Handelsman, D. J., Perheentupa, A., & Poutanen, M. (2012) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2012-1154 · Cited by 195
Peritoneal immune microenvironment of endometriosis: Role and therapeutic perspectives
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“IL-1b is involved in the activation of COX2 and the enhancement of PGE2 levels, contributing to the synthesis of estradiol through the binding of steroidogenic factor 1 (SF-1) to promoters of steroidogenic genes and aromatase genes (119).”
BackgroundLin, B. C., Suzawa, M., Blind, R. D., Tobias, S. C., Bulun, S. E., Scanlan, T. S., & Ingraham, H. A. (2009) · Cancer Research · doi:10.1158/0008-5472.can-08-1622 · Cited by 157
“Indeed, profiling studies comparing human ectopic and eutopic endometrium confirm that SF-1 and estradiol biosynthesis are amplified in ectopic disease tissue (38, 39).”
Self-citationThe Pathogenesis of Adenomyosis vis-à-vis Endometriosis
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“Even when stimulated with PGE2, the expression of most genes involved in estrogen biosynthesis, including StAR, SF-1, and aromatase, are still negligibly low, concomitant with the very low production of estradiol in normal endometrial stromal cells [70].”
BackgroundProgesterone Resistance in Endometriosis: an Acquired Property?
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“Indeed, studies have shown that while in normal endometrial cells, chicken-ovalbumin upstream-transcription factor (COUP-TF) and WT1 bind to the promoter region of CYP19 to inhibit its expression, in endometriotic stromal cells, the presence of SF-1 expression competes with these two transcription factors to induce st…”
BackgroundA new concept of endometriosis and adenomyosis, tissue injury and repair (TIAR)
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BackgroundInfluentialAromatase inhibitors for the treatment of endometriosis
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“SF1, whose expression depends on the presence of prostaglandin E2 in endometriotic cells, assembles enhancer transcriptional complexes, which then bind to the promoters of STAR and aromatase genes to induce their expression (1, 11, 28, 29).”
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“Unlike the eutopic endometrium, endometriotic stromal cells possess exceptionally high levels of P450arom (aromatase) and steroidogenic acute regulatory protein (StAR) that are induced by PGE2 to produce estradiol de novo [84].”
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“It has been demonstrated that endometriotic tissues have significantly increased levels of mRNA encoding through steroidogenic genes, including StAR, CYP17, and CYP19A1, which may contribute to estrogen levels [156].”
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“Numerous studies have shown that the mechanism underlying such effects involves competition between COUPTFII and SF-1 for binding to an overlapping response element in the promoter region of genes encoding steroidogenic enzymes [18,19,20,21,23,30,31,32,33,34,35,36,37,38], as proposed for the present studies in fetal r…”
BackgroundMonsivais, D., Dyson, M. T., Yin, P., Coon, J. S., Navarro, A., Feng, G., Malpani, S. S., Ono, M., Ercan, C. M., Wei, J. J., et al. (2014) · Molecular Endocrinology · doi:10.1210/me.2013-1421 · Cited by 91
Self-citationHypoxia: The force of endometriosis
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Absence of aromatase protein and mRNA expression in endometriosis
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“…et al., 2002; Ishihara et al., 2003; Heilier et al., 2006a, b; Matsuzaki et al., 2006; Dassen et al., 2007; Kyama et al., 2007; Smuc et al., 2007; Attar et al., 2008; Smuc et al., 2008; Aghajanova et al., 2009) in both eutopic and ectopic endometrium from endometriosis patients, but not in…”
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“COUP-TFII is a versatile transcription repressor, which has been shown to regulate the expression of aromatase (24), COX-2 (15), and angiogenin (18) in endometriotic stromal cells.”
BackgroundThe non-human primate model of endometriosis: research and implications for fecundity
Braundmeier, A. G., & Fazleabas, A. T. (2009) · Molecular Human Reproduction · doi:10.1093/molehr/gap057 · Cited by 85
“The ability of these lesions to regulate their own steroid hormone production within their local environment renders them hormonally independent from the eutopic endometrium (Attar et al., 2009; Bulun et al., 2009).”
BackgroundAromatase and endometriosis: estrogens play a role
Ferrero, S., Remorgida, V., Maganza, C., Venturini, P. L., Salvatore, S., Papaleo, E., Candiani, M., & Maggiore, U. L. R. (2014) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.12411 · Cited by 84
The role of prostaglandin E 2 in endometriosis
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“ectopic endometrial cells and competes with chicken ovalbumin upstream-transcription factor (COUP-TF) and Wilm’s tumor-1, both of which acts as inhibitors of the P450arom promoter [29].”
BackgroundRole of nuclear receptors in blastocyst implantation
Vasquez, Y. M., & DeMayo, F. J. (2013) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2013.08.004 · Cited by 82
Local estrogen formation and its regulation in endometriosis
Mori, T., Ito, F., Koshiba, A., Kataoka, H., Takaoka, O., Okimura, H., Khan, K. N., & Kitawaki, J. (2019) · Reproductive Medicine and Biology · doi:10.1002/rmb2.12285 · Cited by 84
Kim, S., Wairkar, Y. P., Daniels, R. W., & DiAntonio, A. (2010) · Journal of Cell Biology · doi:10.1083/jcb.200911126 · Cited by 82
Bakhtiarizadeh, M. R., Hosseinpour, B., Shahhoseini, M., Korte, A., & Gifani, P. (2018) · Frontiers in Genetics · doi:10.3389/fgene.2018.00453 · Cited by 78
MAP kinases and the inflammatory signaling cascade as targets for the treatment of endometriosis?
Santulli, P., Marcellin, L., Tosti, C., Chouzenoux, S., Cerles, O., Borghese, B., Batteux, F., & Chapron, C. (2015) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.2015.1090974 · Cited by 75
“2 Inflammation and stimulation of steroidogenesis It has been shown that endometriotic stromal cells exhibit an abnormal level of estrogen production [34,51,52].”
BackgroundInfluentialGenome-wide DNA methylation profiling in cultured eutopic and ectopic endometrial stromal cells
Yamagata, Y., Nishino, K., Takaki, E., Sato, S., Maekawa, R., Nakai, A., & Sugino, N. (2014) · PLoS ONE · doi:10.1371/journal.pone.0083612 · Cited by 70
“Remarkably high mRNA expression and DNA hypomethylation in the NR5A1 gene, encoding SF-1, was found in the choESC and chocolate cysts in this study, which is consistent with the previous reports [2,24].”
ResultCollins, F., Macpherson, S., Brown, P., Bombail, V., Williams, A. R. W., Anderson, R. A., Jabbour, H. N., & Saunders, P. T. K. (2009) · BMC Cancer · doi:10.1186/1471-2407-9-330 · Cited by 70
“In addition there is evidence that PGE2 can up-regulate expression of steroidogenic genes including CYP19A1 and thereby contribute to increased local concentrations of oestrogenic ligands that could bind ERα and/or ERβ [58].”
Eaton, J. L., Unno, K., Caraveo, M., Lu, Z., & Kim, J. J. (2013) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2013-1661 · Cited by 67
Liu, M.-H., Liu, X., Zhang, Y., & Guo, S. (2012) · Reproductive Sciences · doi:10.1177/1933719111424453 · Cited by 68
Konings, G. F. J., Brentjens, L. S., Delvoux, B., Linnanen, T., Cornel, K. M. C., Koskimies, P., Bongers, M. Y., Kruitwagen, R. F. P. M., Xanthoulea, S., & Romano, A. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.00940 · Cited by 66
“Also 3βHSD2, whose expression was initially considered to be restricted to endocrine tissues, is detected peripherally in recent reports (Stoffel-Wagner, 2001; Tsai et al., 2001; Attar et al., 2009; Huhtinen et al., 2014; Osinski et al., 2018).”
BackgroundMendoza-Villarroel, R. E., Robert, N. M., Martin, L. J., Brousseau, C., & Tremblay, J. J. (2014) · Biology of Reproduction · doi:10.1095/biolreprod.113.115790 · Cited by 48
“NR2F2 was reported to inhibit Star expression in the endometriotic cells [66].”
BackgroundEndometrial Intracrinology: Oestrogens, Androgens and Endometrial Disorders
Gibson, D. A., Simitsidellis, I., Collins, F., & Saunders, P. T. K. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19103276 · Cited by 70
“role in the steroidogenic enzyme machinery, including STAR, 17-hydroxylase/17,20-lyase, 3β-HSD and aromatase, which may be consistent with the synthesis of E2 from cholesterol within lesions [72,74].”
BackgroundMonsivais, D., Dyson, M. T., Yin, P., Navarro, A., Coon, J. S., Pavone, M. E., & Bulun, S. E. (2016) · Fertility and Sterility · doi:10.1016/j.fertnstert.2016.01.012 · Cited by 62
Self-citationEndometriosis, leiomyoma and adenomyosis: the risk of gynecologic malignancy.
Verit, F., & Yucel, O. (2013) · Asian Pacific Journal of Cancer Prevention · doi:10.7314/apjcp.2013.14.10.5589 · Cited by 63
“SF-1 binding activity was higher in endometriotic cells whereas the inhibitory COUP-TF and WT-1 was absent or minimal in endometriotic cells when compared with normal endometrium (Attar et al., 2009).”
BackgroundInfluentialAnuka, E., Gal, M., Stocco, D. M., & Orly, J. (2013) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2013.02.003 · Cited by 60
Shen, L., Yang, S., Huang, W., Xu, W., Wang, Q., Song, Y., & Liu, Y. (2013) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2012-3010 · Cited by 57
Braundmeier, A. G., Jackson, K. S., Hastings, J. M., Koehler, J., Nowak, R. A., & Fazleabas, A. T. (2012) · Human Reproduction · doi:10.1093/humrep/des083 · Cited by 58
Functional Expression of FSH Receptor in Endometriotic Lesions
Ponikwicka‐Tyszko, D., Chruściel, M., Stelmaszewska, J., Bernaczyk, P., Sztachelska, M., Sidorkiewicz, I., Doroszko, M., Tomaszewski, J., Tapanainen, J. S., Huhtaniemi, I. T., et al. (2016) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2016-1014 · Cited by 54
Lin, S.-C., Li, Y.-H., Wu, M.-H., Chang, Y.-F., Lee, D.-K., Tsai, S. Y., Tsai, M.-J., & Tsai, S.-J. (2014) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2013-3717 · Cited by 52
Gołąbek-Grenda, A., & Olejnik, A. M. (2022) · Cellular Signalling · doi:10.1016/j.cellsig.2022.110375 · Cited by 53
Shi, J., Xu, Q., Yu, S., & Zhang, T. (2025) · Seminars in Immunopathology · doi:10.1007/s00281-025-01040-1 · Cited by 55
“Both endometriosis and adenomyosis are characterized by elevated estrogen levels in the endometriotic lesions [124–126].”
Endometriosis Treatment: Role of Natural Polyphenols as Anti-Inflammatory Agents
Tassinari, V., Smeriglio, A., Stillittano, V., Trombetta, D., Zilli, R., Tassinari, R., Maranghi, F., Frank, G., Marcoccia, D., & Renzo, L. D. (2023) · Nutrients · doi:10.3390/nu15132967 · Cited by 55
“Moreover, the over-expression of COXs and the increased synthesis of PGs is influenced by over-expression of ERβ [59,66].”
BackgroundLu, J., Ling, X., Liu, L., Jiang, A., Ren, C., Lü, C., & Yu, Z. (2022) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2022.119381 · Cited by 48
Epigenetic Factors in Eutopic Endometrium in Women with Endometriosis and Infertility
Adamczyk, M., Wender-Ożegowska, E., & Kędzia, M. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23073804 · Cited by 51
“It has been found that the endometrium of endometriosis patients shows the increased activity or aromatase P450 that metabolizes androgens to estrogens [27].”
BackgroundQi, Q., Liu, X., Zhang, Q., & Guo, S.-W. (2020) · Scientific Reports · doi:10.1038/s41598-020-57997-6 · Cited by 44
Regulation of androgen action during establishment of pregnancy
Gibson, D. A., Simitsidellis, I., & Saunders, P. T. K. (2016) · Journal of Molecular Endocrinology · doi:10.1530/jme-16-0027 · Cited by 42
Zhou, Y., Zeng, C., Li, X., Wu, P., Yin, L., Yu, X., Zhou, Y., & Xue, Q. (2016) · Journal of Molecular Medicine · doi:10.1007/s00109-016-1396-1 · Cited by 44
“[11], StAR facilitates the entry of cholesterol into the mitochondrion, while aromatase catalyzes the final step of estrogen production by converting C19 steroids to estrogens.”
BackgroundInfluence of AKT on Progesterone Action in Endometrial Diseases
Lee, I. I., & Kim, J. J. (2014) · Biology of Reproduction · doi:10.1095/biolreprod.114.119255 · Cited by 45
“Endometriotic tissues synthesize and secrete estradiol [116], which can also activate AKT in a nongenomic manner [117, 118].”
BackgroundThe Estrogen–Immune Interface in Endometriosis
Greygoose, E., Metharom, P., Kula, H., Seckin, T. K., Seckin, T. A., Ayhan, A., & Yu, Y. (2025) · Cells · doi:10.3390/cells14010058 · Cited by 50
“A unique known challenge in endometriosis, P4 resistance, stems from the deficiency of P4 in the stromal cells of endometriotic tissue, complicating the hormonal and immune interplay characteristic of the condition [63,64].”
Xu, J., Zeng, C., Zhou, Y., Peng, C., Zhou, Y.-F., & Xue, Q. (2014) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2014-1593 · Cited by 44
Increased circulating miR-370-3p regulates steroidogenic factor 1 in endometriosis
Hu, Z., Mamillapalli, R., & Taylor, H. S. (2018) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00244.2018 · Cited by 38
“Previous studies have reported aberrant SF-1 expression in endometriotic tissues and stromal cells compared with eutopic endometrial tissues and stromal cells (3, 5, 7, 9, 49, 53).”
BackgroundWaters, S. M., Coyne, G. S., Kenny, D. A., MacHugh, D. E., & Morris, D. G. (2012) · Physiological Genomics · doi:10.1152/physiolgenomics.00065.2011 · Cited by 36
“Following the catabolic conversion of PGE2 to the less-active 15-keto-PGE2 by 15-hydroxyprostaglandin dehydrogenase (15-PGDH) (76), this PGE2 intermediate metabolite is further catabolized to 13, 14-dihydro-15-keto-PGE2 in a reaction catalyzed by PTGR2 (9, 93).”
BackgroundInfluentialThe Essential Role of GATA6 in the Activation of Estrogen Synthesis in Endometriosis
Bernardi, L. A., Dyson, M. T., Tokunaga, H., Sison, C., Oral, M., Robins, J. C., & Bulun, S. E. (2019) · Reproductive Sciences · doi:10.1177/1933719118756751 · Cited by 40
“05).(7,29) The steroid-producing capacity of endometriotic stromal cells is comparable to ovarian granulosa cells.”
BackgroundSelf-citationPrather, G. R., MacLean, J. A., Shi, M., Boadu, D., Paquet, M., & Hayashi, K. (2016) · Biology of Reproduction · doi:10.1095/biolreprod.116.140236 · Cited by 40
“While systemic estrogen can be a player for endometriosis, local estrogen production by aromatase and development of an inflammatory environment in the presence of prostaglandins and cytokines are hallmarks of the progression of endometriosis [7, 12, 16, 55].”
BackgroundXue, Q., Xu, Y., Yang, H., Zhang, L., Shang, J., Zeng, C., Yin, P., & Bulun, S. E. (2013) · Reproductive Sciences · doi:10.1177/1933719113497283 · Cited by 40
“Bulun and others demonstrated that abundant expression of steroidogenic genes including StAR gave rise to local estrogen production in endometriotic tissue.(3,5,6) Aromatase and StAR are regulated by a nuclear receptor termed steroidogenic factor 1 (SF-1) in endometriotic stromal cells, which is a member of the nuclea…”
BackgroundSelf-citationClinical impact of scavenger receptor class B type I gene polymorphisms on human female fertility
Yates, M., Kolmakova, A., Zhao, Y., et al. (2011) · Human Reproduction · doi:10.1093/humrep/der124 · Cited by 40
“little progesterone following stimulation (Attar et al., 2009).”
BackgroundFerroptosis and oxidative stress in endometriosis: A systematic review of the literature
Ni, C., & Li, D. (2024) · Medicine · doi:10.1097/md.0000000000037421 · Cited by 45
“[92,93] One of the mevalonate products, CoQ10, acts as an endogenous antioxidant that protects endometriotic cells against ferroptosis.”
BackgroundIlluminating the “Black Box” of Progesterone-Dependent Embryo Implantation Using Engineered Mice
Maurya, V. K., DeMayo, F. J., & Lydon, J. P. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.640907 · Cited by 39
“…levels is linked to increased proinflammatory cytokine levels (Li et al., 2013; Lin et al., 2014), angiogenesis (Fu et al., 2018), and local estrogen synthesis (Zeitoun et al., 1999; Zeitoun and Bulun, 1999; Attar et al., 2009), all of which markedly promote the pathogenesis of endometriosis.”
BackgroundActivated glucocorticoid and eicosanoid pathways in endometriosis
Monsivais, D., Bray, J. D., Su, E. J., Pavone, M. E., Dyson, M. T., Navarro, A., Kakinuma, T., & Bulun, S. E. (2012) · Fertility and Sterility · doi:10.1016/j.fertnstert.2012.03.030 · Cited by 37
“Relative to normal endometrium, the elevated expression of P450aromatase (CYP19A1), steroidogenic acute regulatory protein (StAR), and 17βhydroxysteroid dehydrogenase type 1 (HSD17B1) in endometriosis facilitate de novo steroid hormone synthesis (7).”
BackgroundMethodSelf-citationKim, S. O., Harris, S. M., & Duffy, D. M. (2014) · Endocrinology · doi:10.1210/en.2013-2096 · Cited by 37
“PGE2 has been reported to regulate expression of these key enzymes in nonovarian cells (40, 41), and PGE2 regulation of steroid hormone production by primate luteal cells is well established (42).”
BackgroundLee, J., Banu, S. K., Rodriguez, R., Starzinski‐Powitz, A., & Arosh, J. A. (2010) · Fertility and Sterility · doi:10.1016/j.fertnstert.2010.01.038 · Cited by 37
Current Knowledge on Endometriosis Etiology: A Systematic Review of Literature
Михалева, Л. М., Radzinsky, V. E., Orazov, M. R., Николаевна, Х. Т., Sorokina, A. V., Александрович, М. С., Владимировна, В. С., Shustova, V. B., & Sinelnikov, M. Y. (2021) · International Journal of Women s Health · doi:10.2147/ijwh.s306135 · Cited by 37
Lebovic, D. I., Kavoussi, S. K., Lee, J., Banu, S. K., & Arosh, J. A. (2013) · Endocrinology · doi:10.1210/en.2013-1168 · Cited by 36
The role of Lipoxin A4 in endometrial biology and endometriosis
Canny, G., & Lessey, B. A. (2013) · Mucosal Immunology · doi:10.1038/mi.2013.9 · Cited by 35
“Here, the COX-2-derived eicosanoid PGE2, 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.”
BackgroundBanu, S. K., Lee, J., Speights, V. O., Starzinski‐Powitz, A., & Arosh, J. A. (2009) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.94.7.9993 · Cited by 35
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Khankari, N. K., Bradshaw, P. T., Steck, S. E., He, K., Olshan, A. F., Shen, J., Ahn, J., Chen, Y., Ahsan, H., Terry, M. B., et al. (2015) · Annals of Epidemiology · doi:10.1016/j.annepidem.2015.09.003 · Cited by 31
The Effects and Possible Mechanisms of Puerarin to Treat Endometriosis Model Rats
Yu, J., Zhao, L., Zhang, D., Zhai, D., Shen, W., Bai, L., Liu, Y., Cai, Z., Li, J., & Yu, C. (2015) · Evidence-based Complementary and Alternative Medicine · doi:10.1155/2015/269138 · Cited by 31
Urata, Y., Osuga, Y., Akiyama, I., Nagai, M., Izumi, G., Takamura, M., Hasegawa, A., Harada, M., Hirata, T., Hirota, Y., et al. (2013) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2012-3475 · Cited by 30
Lewis, S. R., Hedman, C. J., Ziegler, T. E., Ricke, W. A., & Jorgensen, J. S. (2013) · Endocrinology · doi:10.1210/en.2013-1583 · Cited by 28
Aromatase inhibitor treatment limits progression of peritoneal endometriosis in baboons
Langoi, D., Pavone, M. E., Gürateş, B., Chai, D. C., Fazleabas, A. T., & Bulun, S. E. (2012) · Fertility and Sterility · doi:10.1016/j.fertnstert.2012.11.021 · Cited by 31
“High levels of aromatase mRNA have been found in extraovarian endometriotic lesions and endometriomas when compared to normal endometrium (10).”
BackgroundMethodSelf-citationEndometrial Expression of Steroidogenic Factor 1 Promotes Cystic Glandular Morphogenesis
Vasquez, Y. M., Wu, S., Anderson, M. L., Hawkins, S. M., Creighton, C. J., Ray, M., Tsai, S. Y., Tsai, M., Lydon, J. P., & DeMayo, F. J. (2016) · Molecular Endocrinology · doi:10.1210/me.2015-1215 · Cited by 26
Chen, Y., Cai, S., Wang, J., & Xu, M. (2015) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2015.2263 · Cited by 27
“The CYP19 gene encodes P450 aromatase, and cyclo-oxegenase-2 (COX2) increases the expression of P450 aromatase (17-19).”
BackgroundZhou, Y., Xu, J., Zeng, C., Li, X., Zhou, Y., Qi, Y., & Xue, Q. (2015) · Reproductive Sciences · doi:10.1177/1933719115590664 · Cited by 26
“In addition, metformin interacted with the FSH-stimulated cAMP/PKA/CREB pathway, which is the primary signaling pathway for the regulation of CYP19A1 gene expression in the ovary.55 These findings suggest that therapeutic effects of metformin might also be mediated by the suppression of ovarian estrogen production thr…”
BackgroundInfluentialSuppression of COUP-TFII upregulates angiogenin and promotes angiogenesis in endometriosis
Fu, J.-L., Hsiao, K., Lee, H.-C., Li, W.-N., Chang, N., Wu, M., & Tsai, S. (2018) · Human Reproduction · doi:10.1093/humrep/dey220 · Cited by 26
Are aromatase inhibitors effective in endometriosis treatment?
Colette, S., & Donnez, J. (2011) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.2011.581226 · Cited by 26
“Indeed, from the end of the 1990s until very recently, aromatase was widely believed to be expressed at the transcriptional [20-48], protein [21,23,27,29,33,37,49-55] and activity levels [21,22,26,33,41,56-58].”
Background
Metadata
- Authors
- Attar, E., Tokunaga, H., Imir, G., Yilmaz, M. B., Redwine, D., Putman, M., Gurates, B., Attar, R., Yaegashi, N., Hales, D. B., & Bulun, S. E.
- Affiliations
- Northwestern University (US)
- Division of Reproductive Biology Research (E.A., H.T., G.I., M.B.Y., S.E.B.), Department of Obstetrics and Gynecology, Feinberg School of Medicine at Northwestern University, Chicago, Illinois 60611
- St. Charles Medical Center (US)
- Baylor University Medical Center (US)
- Department of Obstetrics and Gynecology (B.G.), Firat University School of Medicine, Elazig, Turkey
- Department of Obstetrics and Gynecology (R.A.), Yeditepe University Hospital, Kozyatagi, Istanbul, Turkey
- Tohoku University (JP)
- University of Illinois Chicago (US)
- Corresponding author
- Bulun, Serdar E.
- ORCID
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2009-02-01
- Volume
- 94
- Issue
- 2
- Pages
- 623-631
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- PMC
- PMC2646521
- OpenAlex
- W1973817527
- Cited by
- 207
- References
- 37
- Citations by year
- 2026: 9 · 2025: 15 · 2024: 7 · 2023: 7 · 2022: 7 · 2021: 15 · 2020: 16 · 2019: 13 · 2018: 12 · 2017: 5 · 2016: 13 · 2015: 12 · 2014: 12 · 2013: 14 · 2012: 11
- FWCI
- 15.09
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DSpace - FIRAT (Fırat University) (submittedVersion, cc-by-nc-nd)
- Funders
- GlaxoSmithKline
- Northwestern University
- National Institutes of Health (HD40093)
- Feinberg School of Medicine
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD040093, HD-38691, HD 40093, R01HD038691, R37HD038691)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Endometriosis Research and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Estrogen and related hormone effects
- Health Sciences › Medicine › Reproductive Medicine › Ovarian function and disorders
- Keywords
- endometriosis, prostaglandin E2, steroidogenic factor 1, aromatase, steroidogenic acute regulatory protein, estrogen synthesis, steroidogenic genes, COUP-TFII, Wilms tumor 1, transcriptional regulation, endometriotic cells, endometrium, estradiol, progesterone, estrone
- MeSH terms
- Steroidogenic Acute Regulatory Protein, Adult, Cells, Cultured, Cytochrome P-450 Enzyme System, Endometriosis, Endometrium, Estradiol, Female, Humans, Middle Aged, Ovarian Diseases, Phosphoproteins, Progesterone, Promoter Regions, Genetic, Transcription, Genetic, Dinoprostone, Gene Expression Regulation, Enzymologic, Steroidogenic Factor 1, Young Adult
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