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).”
Citations
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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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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