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.
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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.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
4 of 35 cited sources checked · 1 supported · 0 flagged · accuracy not yet measured
- Premisecitation
In vitro overexpression studies reflected the in vivo effects of these factors on differential P450arom expression.
“Previously, we demonstrated that in vitro overexpression studies reflected the in vivo effects of these factors on differential P450arom expression (16,17,22).”
Quote in the paperSubstantial claim1 of 3 sources checked- cites [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
- cites [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) 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)
Experimental — accuracy not yet measured - cites [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
- Findingown data
StAR, P450scc, P450c17, and P450arom mRNA levels were significantly higher in endometriotic tissue than in normal endometrium.
“We found that StAR, P450scc, P450c17, and P450arom mRNA levels were significantly higher in endometriotic tissue than in normal endometrium.”
Quote in the paperSubstantial claim - Findingown data
COUP-TFII and WT1 binding to both promoters is significantly higher in endometrial compared with endometriotic cells.
“COUP-TFII or WT1 binding to both promoters was significantly higher in endometrial compared with endometriotic cells.”
Quote in the paperNot a substantial claim - Findingown data
Time-dependent PGE2 induction of StAR mRNA and protein starts as early as 1 h after treatment.
“Time-dependent PGE 2 induction of both StAR mRNA and protein started as early as 1 h after treatment.”
Quote in the paperNot a substantial claim - Findingown data
PGE2 decreases COUP-TFII binding to StAR and aromatase promoters in endometriotic cells.
“PGE 2 induced coordinate binding of SF1 to StAR and aromatase promoters but decreased COUP-TFII binding in endometriotic cells.”
Quote in the paperSubstantial claim
- Findingown data
The most striking differences in mRNA levels between endometriotic and normal endometrium were observed for StAR and P450arom.
“The most striking differences, however, were observed for StAR and P450arom mRNA levels (Fig. 1, A and E).”
Quote in the paperSubstantial claim - Findingown data
HSD3B2 mRNA levels differ between endometriotic and normal endometrium but less significantly than other steroidogenic genes.
“The differences in P450scc, HSD3B2, and P450c17 mRNA levels were apparent but less significant (Fig. 1, B-D).”
Quote in the paperNot a substantial claim - Findingown data
Addition of 22(R)-OH-cholesterol does not stimulate production of progesterone, estrone, and estradiol to the same extent as PGE2 treatment in endometriotic cells.
“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).”
Quote in the paperSubstantial claim - Findingown data
LRH1 mRNA levels are slightly but significantly lower in endometriotic cells compared with endometrial cells.
“Interestingly, LRH1 mRNA levels were slightly but significantly lower in endometriotic cells vs. endometrial cells (Fig. 1G).”
Quote in the paperNot a substantial claim - Findingown data
PGE2 induces coordinate binding of SF1 to StAR and aromatase promoters in endometriotic cells.
“PGE 2 induced coordinate binding of SF1 to StAR and aromatase promoters but decreased COUP-TFII binding in endometriotic cells.”
Quote in the paperSubstantial claim - Findingown data
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 compared with normal endometrial tissues.
“Compared with normal endometrial tissues, mRNA levels of StAR, side chain cleavage P450, 3-hydroxysteroid-dehydrogenase-2, 17-hydroxylase/17-20-lyase, aromatase, and SF1 were significantly higher in endometriotic tissues.”
Quote in the paperSubstantial claim - Findingown data
PGE2 induces StAR promoter activity in endometriotic cells.
“PGE 2 induced the expression of all steroidogenic genes; production of progesterone, estrone, and estradiol; and StAR promoter activity in endometriotic cells.”
Quote in the paperSubstantial claim - Findingown data
Addition of LDL increases estrone formation by endometriotic cells.
“Addition of LDL increases the formation of estrone by endometriotic cells (Fig. 3B).”
Quote in the paperNot a substantial claim - Findingown data
Overexpression of LRH1, C/EBPα, and C/EBPβ modestly induces StAR promoter activity.
“Modest inductions were also observed with overexpression of LRH1 (an SF1 homolog), C/EBP␣, and C/EBP.”
Quote in the paperNot a substantial claim - Findingown data
The dose-dependent regulation of StAR mRNA by PGE2 is accompanied by similar changes in protein levels.
“The dose-dependent regulation of StAR mRNA by PGE 2 was accompanied by similar changes in protein levels (Fig. 4B).”
Quote in the paperSubstantial claim - Findingown data
Addition of LDL does not stimulate progesterone or estradiol production in endometriotic cells.
“We did not observe a stimulatory effect on progesterone or estradiol production with the addition of LDLs to the media (LDL, 50 g/ml) (Fig. 3, A and C).”
Quote in the paperNot a substantial claim - Findingown data
mRNA levels of tested genes are not significantly different between endometriotic or endometrial tissues collected during proliferative vs luteal phase.
“The mRNA levels of each of the tested genes were not significantly different between endometriotic or endometrial tissues collected during the proliferative vs. luteal phase of the menstrual cycle.”
Quote in the paperNot a substantial claim - Findingown data
PGE2 significantly induced the expression of each of P450scc, HSD3B2, and P450c17 in endometriotic stromal cells.
“Moreover, we found that PGE 2 significantly induced the expression of each gene in endometriotic stromal cells (Fig. 2).”
Quote in the paperSubstantial claim - Findingown data
PGE2 stimulated endometriotic stromal cells to produce progesterone, estrone, and estradiol.
“and PGE 2 stimulated these cells to produce progesterone, estrone, and estradiol.”
- Also stated in: § Discussion · plain
“PGE 2 stimulated the levels progesterone (A), estrone (B), and estradiol (C) in media from endometriosis-derived stromal cells.”
Quote in the paperSubstantial claim - Also stated in: § Discussion · plain
- Findingown data
Expression of all components of the complete steroidogenic cascade for estrogen biosynthesis was present in endometriotic stromal cells.
“First, expression of all components of the complete steroidogenic cascade for estrogen biosynthesis was present in endometriotic stromal cells”
Quote in the paperSubstantial claim - Findingown data
Significant binding of the SF1 corepressor WT1 to both StAR and P450arom promoters occurs in endometrial but not endometriotic stromal cells.
“Significant binding of the SF1 corepressor WT1 to both StAR and P450arom promoters in endometrial but not endometriotic stromal cells (Fig. 6)”
Quote in the paperSubstantial claim - Findingown data
Similar results were observed upon cotransfection of endometrial stromal cells with the StAR promoter-luciferase vector and these expression plasmids.
“Similar results were observed upon cotransfection of endometrial stromal cells with the StAR promoter-luciferase vector and these expression plasmids.”
Quote in the paperNot a substantial claim - Findingown data
PGE2 suppressed the binding activity of WT1 to either the StAR or P450arom promoter in endometrial cells.
“PGE 2 suppressed the binding activity of WT1, which functions as a corepressor of SF1, to either promoter in endometrial cells (Fig. 6).”
Quote in the paperSubstantial claim - Findingown data
Binding activity of the inhibitory transcription factor COUP-TFII was much higher in endometrial cells compared with endometriotic cells.
“On the other hand, binding activity of the inhibitory transcription factor COUP-TFII was much higher in endometrial cells compared with endometriotic cells”
Quote in the paperSubstantial claim - Findingnone given
Minimal levels of StAR and steroidogenic enzymes are expressed in endometrium despite practically absent SF1 in this tissue.
“Interestingly, minimal levels of StAR and steroidogenic enzymes are expressed in endometrium despite practically absent SF1 in this tissue.”
Quote in the paperNot a substantial claim - Findingnone given
Endometriotic cells express more endogenous SF1, StAR, P450arom, and other steroidogenic enzymes compared with normal cells.
“The endometriotic cells express more endogenous SF1, StAR, P450arom, and other steroidogenic enzymes compared with normal cells”
Quote in the paperSubstantial claim - Findingown data
ChIP 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.
“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.”
Quote in the paperSubstantial claim - Findingown data
Under basal conditions, SF1 bound to both the StAR and P450arom promoters in endometriotic but not in endometrial cells.
“Under basal conditions, SF1 bound to both promoters in endometriotic but not in endometrial cells (Fig. 6)”
Quote in the paperSubstantial claim - Findingown data
Endometriotic cells can produce a baseline level of estrogen even in the absence of PGE2 that is higher than in normal endometrial cells.
“Third, endometriotic cells do not only have the ability to produce estrogen, but they can also produce a baseline level of estrogen even in the absence of PGE 2 that is higher than in normal endometrial cells (Fig. 3).”
Quote in the paperSubstantial claim - Findingown data
WT1 binding activity was either minimal or absent in endometriotic cells.
“Similarly, WT1 binding activity was either minimal or absent in endometriotic cells.”
Quote in the paperSubstantial claim - Findingown data
SF1 binding activity was strikingly higher in PGE2-treated endometriotic cells.
“SF1 binding activity was strikingly higher in PGE 2 -treated endometriotic cells.”
Quote in the paperSubstantial claim - Findingown data
P450scc, HSD3B2, and P450c17 were strikingly higher in endometriotic vs. endometrial tissues in our hands.
“all of which were strikingly higher in endometriotic vs. endometrial tissues in our hands (Fig. 1).”
Quote in the paperSubstantial claim - Findingnone given
In normal endometrial cells, corepressors are bound to the target promoters to limit estrogen synthesis.
“This is the exact opposite of the normal endometrial cells, in which corepressors are bound to the target promoters to limit estrogen synthesis.”
Quote in the paperSubstantial claim - Findingown data
Addition of 22(R)-OH-cholesterol to endometriotic cells did not fully substitute PGE2 induction of progesterone production.
“In our hands, addition of 22(R)-OH-cholesterol to endometriotic cells did not fully substitute PGE 2 induction of progesterone production (Fig. 3A).”
Quote in the paperSubstantial claim - Findingown data
PGE2 treatment eliminated COUP-TFII binding to either the StAR or P450arom promoter.
“where PGE 2 treatment eliminated its binding to either promoter.”
Quote in the paperSubstantial claim - Findingown data
Our data differ significantly from Tsai et al. with respect to expression of P450scc, HSD3B2, and P450c17.
“Our data, however, differ significantly with respect to expression of P450scc, HSD3B2, and P450c17, all of which were strikingly higher in endometriotic vs. endometrial tissues in our hands (Fig. 1).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [10] Tsai, 2001, Regulation of steroidogenic acute regulatory protein expression and progesterone production in endometriotic stromal cells., J Clin Endocrinol Metab source
- Findingown data
The key steroidogenic genes StAR and P450arom are synchronously regulated via binding of identical transactivating factors to their promoters in response to PGE2.
“Second, we demonstrated the synchronized regulation of the key steroidogenic genes StAR and P450arom via binding of identical transactivating factors to their promoters in response to PGE 2 .”
Quote in the paperSubstantial claim - Findingown data
mRNA levels of the SF1 homolog gene LRH1 were higher in endometrial tissue.
“On the other hand, mRNA levels of the SF1 homolog gene, LRH1, were higher in endometrial tissue.”
Quote in the paperNot a substantial claim - Findingown data
The inhibitory transcription factors COUP-TFII and WT1 were associated with StAR and P450arom promoters more avidly in endometrial cells compared with endometriotic cells.
“On the other hand, the inhibitory transcription factors COUP-TFII and WT1 were associated with StAR and P450arom promoters more avidly in endometrial cells compared with endometriotic cells.”
Quote in the paperSubstantial claim - Findingown data
PGE2 reduced binding of COUP-TFII or WT1 in endometriotic or endometrial cells.
“Note that PGE 2 reduced binding of COUP-TFII or WT1 in endometriotic or endometrial cells.”
Quote in the paperSubstantial claim - Findingown data
PGE2 stimulated StAR mRNA and protein levels in a time- and dose-dependent manner in endometriotic stromal cells.
“PGE 2 stimulated StAR mRNA (A) and protein levels (B) in a time-and dose-dependent manner in endometriotic stromal cells.”
Quote in the paperSubstantial claim - Findingown data
mRNA levels of the steroidogenic genes StAR, P450scc, HSD3B2, P450c17, P450arom, and SF1 were strikingly higher in tissues of endometriosis (n=13) compared with endometrium (n=13).
“mRNA levels of the steroidogenic genes including the mitochondrial cholesterol transporter, StAR (STAR); the enzymes P450scc (CYP11A1), HSD3B2, P450c17 (CYP17A1), and P450arom (CYP19A1); and the transcription factor SF1 were found to be strikingly higher in tissues of endometriosis (n ϭ 13) compared with endometrium (n ϭ 13).”
Quote in the paperSubstantial claim - Findingown data
PGE2 significantly stimulated mRNA levels of each steroidogenic gene except for HSD3B1 in endometriotic stromal cells (n=6).
“PGE 2 significantly stimulated mRNA levels of each steroidogenic gene except for HSD3B1 in endometriotic stromal cells (E-OSIS; n ϭ 6).”
Quote in the paperSubstantial claim - Findingown data
C/EBPβ, C/EBPα, SF1, or LRH1 induced StAR promoter activity in both endometriotic and endometrial cells.
“C/EBP, C/EBP␣, SF1, or LRH1 induced StAR promoter activity in both cell types.”
Quote in the paperSubstantial claim - Findingown data
mRNA levels of steroidogenic genes in normal endometrium (n=6) were very low regardless of the absence or presence of PGE2.
“The mRNA levels of these genes in normal endometrium (E-IUM; n ϭ 6) were very low regardless of the absence or presence of PGE 2 .”
Quote in the paperSubstantial claim - Premisecitation
The regulation of StAR promoter by various transcription factors is very similar to that described for the P450arom promoter.
“The regulation of StAR promoter by various transcription factors was very similar to that described for the P450arom promoter (16).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [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
- Interpretationown data
All steroidogenic genes involved in estrogen production in endometriotic tissue are responsive to PGE2.
“Furthermore, when compared with normal endometrial tissue, all steroidogenic genes involved in estrogen production in endometriotic tissue are responsive to PGE 2 .”
Quote in the paperSubstantial claim - Interpretationown data
StAR up-regulation by PGE2 is necessary for steroid production in endometriotic cells.
“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).”
Quote in the paperSubstantial claim - Interpretationown data
PGE2 stimulates de novo synthesis of estradiol from cholesterol in endometriotic cells via enhanced binding of SF1 to promoters of StAR and aromatase genes in a synchronous fashion.
“Endometriotic cells contain the full complement of steroidogenic genes for de novo synthesis of estradiol from cholesterol, which is stimulated by PGE 2 via enhanced binding of SF1 to promoters of StAR and aromatase genes in a synchronous fashion.”
Quote in the paperSubstantial claim- Rests on an assumption: SF1 is elevated in endometriotic tissue and mediates the stimulatory action of PGE2 via binding to the P450arom promoter.
- Interpretationreasoning
PGE2 can stimulate the full conversion of cholesterol to estradiol within the endometriotic stromal cell.
“Taken together, our data suggest that PGE 2 can stimulate the full conversion of cholesterol to estradiol within the endometriotic stromal cell.”
Quote in the paperSubstantial claim - Interpretationown data
Endometriotic cells contain the full complement of steroidogenic genes necessary for de novo synthesis of estradiol from cholesterol.
“Endometriotic cells contain the full complement of steroidogenic genes for de novo synthesis of estradiol from cholesterol, which is stimulated by PGE 2 via enhanced binding of SF1 to promoters of StAR and aromatase genes in a synchronous fashion.”
Quote in the paperSubstantial claim - Interpretationown data
PGE2 stimulates the expression of StAR, P450scc, and HSD3B2 to catalyze the conversion of cholesterol to progesterone in endometriotic 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.”
Quote in the paperSubstantial claim - Interpretationown data
StAR and P450arom appear to be the key PGE2-induced genes in endometriotic tissue.
“These findings are consistent with the data shown in Fig. 1 and indicate that StAR and P450arom appear to be the key PGE 2 -induced genes in endometriotic tissue.”
Quote in the paperSubstantial claim - Interpretationown data
PGE2 stimulates estrone and estradiol formation through additional up-regulation of P450c17 and P450arom in endometriotic cells.
“PGE 2 also stimulated estrone and estradiol formation through additional up-regulation of P450c17 and P450arom.”
Quote in the paperSubstantial claim - Interpretationown data
WT1 binding to StAR and P450arom promoters likely represents one of the redundant mechanisms for the inhibition of estrogen synthesis in eutopic endometrium.
“likely represents one of these redundant mechanisms for the inhibition of estrogen synthesis in eutopic endometrium.”
Quote in the paperSubstantial claim - Interpretationown data
Endometriotic P450arom is not solely dependent for substrate on circulating androstenedione secreted by the adrenal or ovary.
“and that endometriotic P450arom is not solely dependent for substrate on cir- culating androstenedione secreted by the adrenal or ovary.”
Quote in the paperSubstantial claim - Premisecitation
PGE2 is the most potent known stimulator of P450arom in endometriotic stromal cells.
“PGE 2 is the most potent known stimulator of P450arom in endometriotic stromal cells (10,13,15).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [10] Tsai, 2001, Regulation of steroidogenic acute regulatory protein expression and progesterone production in endometriotic stromal cells., J Clin Endocrinol Metab source
- cites [13] Noble, 1997, Prostaglandin E2 stimulates aromatase expression in endometriosis-derived stromal cells., J Clin Endocrinol Metab
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [15] Attar, 2006, Aromatase and other steroidogenic genes in endometriosis: translational aspects., Hum Reprod Update source
- Premisecitation
These promoters remain quiescent under the influence of inhibitory transcription factors (e.g. COUP-TF) and corepressors (e.g. WT1) in normal endometrial stromal cells.
“These promoters remain quiescent under the influence of inhibitory transcription factors (e.g.COUP-TF) and corepressors (e.g.WT1) in normal endometrial stromal cells (4).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [4] Tremblay, 1989, Regulation of the gene for estrogenic 17-ketosteroid reductase lying on chromosome 17cen–q25., J Biol Chem source
- Interpretationcitation
SF1 possibly serves as a dominant activator for StAR by competing with COUP-TF for binding to its promoter in endometriotic stromal cells.
“As in the case of the P450arom gene, SF1 possibly serves as a dominant activator for StAR by competing with COUP-TF for binding to its promoter in endometriotic stromal cells (16).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [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
- Interpretationown data
PGE2 induction of progesterone production in endometriotic cells is not solely attributable to StAR activity.
“In our hands, addition of 22(R)-OH-cholesterol to endometriotic cells did not fully substitute PGE 2 induction of progesterone production (Fig. 3A).”
Quote in the paperSubstantial claim- Rests on an assumption: 22(R)-OH-cholesterol can diffuse into mitochondria without a requirement for StAR.
- Interpretationreasoning
The full enzymatic cascade for production of estradiol from cholesterol is present in the endometriotic stromal cell.
“Thus, the full enzymatic cascade for production of estradiol from cholesterol is present in the endometriotic stromal cell.”
Quote in the paperSubstantial claim - Premisecitation
PGE2 stimulates StAR expression in endometriotic stromal cells.
“PGE 2 also stimulates StAR expression in endometriotic stromal cells (10,18).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [10] Tsai, 2001, Regulation of steroidogenic acute regulatory protein expression and progesterone production in endometriotic stromal cells., J Clin Endocrinol Metab source
- cites [18] Sun, 2003, Transactivation of steroidogenic acute regulatory protein in human endometriotic stromal cells is mediated by the prostaglandin EP2 receptor., Endocrinology source
- Interpretationreasoning
Binding of SF1 to the promoter region of StAR may be the key event that brings the entire transcriptional complex to initiate StAR expression in endometriosis.
“Binding of SF1 to the promoter region of the StAR may be the key event that brings the entire transcriptional complex to initiate StAR expression in endometriosis.”
Quote in the paperSubstantial claim - Interpretationown data
The same transcriptional mechanism is responsible for silencing StAR and P450arom, leading to suppression of estrogen production in normal endometrial stromal cells.
“We also found that the same transcriptional mechanism is responsible for silencing the two genes, leading to suppression of estrogen production in normal endometrial stromal cells.”
Quote in the paperSubstantial claim - Premisecitation
StAR, P450arom, and HSD17B1 were demonstrated in stromal cells of endometriotic tissue.
“The products of some of these steroidogenic genes that catalyze the formation of estradiol from cholesterol, namely StAR, P450arom (CYP19A1), and HSD17B1 were demonstrated in stromal cells of endometriotic tissue (10 -13).”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [10] Tsai, 2001, Regulation of steroidogenic acute regulatory protein expression and progesterone production in endometriotic stromal cells., J Clin Endocrinol Metab source
- cites [11] Zeitoun, 1998, Deficient 17β-hydroxysteroid dehydrogenase type 2 expression in endometriosis: failure to metabolize 17β-estradiol., J Clin Endocrinol Metab source
- cites [12] Noble, 1996, Aromatase expression in endometriosis., J Clin Endocrinol Metab source
- cites [13] Noble, 1997, Prostaglandin E2 stimulates aromatase expression in endometriosis-derived stromal cells., J Clin Endocrinol Metab
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationown data
Steroid measurements and parallel gene expression data support the notion that estrogen is synthesized de novo from cholesterol in endometriosis.
“Moreover, steroid measurements and parallel gene expression data support the notion that estrogen is synthesized de novo from cholesterol”
Quote in the paperSubstantial claim- Rests on an assumption: Primary cultured endometrial and endometriotic stromal cells retain the transcriptional characteristics of the corresponding tissues in vivo.
- Interpretationreasoning
The PGE2-cAMP-SF1 pathway is the key regulator of steroidogenesis, particularly estradiol production, in endometriotic stromal cells.
“These two findings complement each other and support the notion that the PGE 2 -cAMP-SF1 pathway as the key regulator of steroidogenesis, particularly estradiol production, in endometriotic stromal cells.”
Quote in the paperSubstantial claim- Rests on an assumption: PGE2 regulates steroidogenic genes through cAMP.
- Premisecitation
High levels of StAR and P450arom have been demonstrated in endometriotic stromal cells.
“In particular, high levels of steroidogenic acute regulatory protein (StAR) and P450arom have been demonstrated in endometriotic stromal cells (4).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [4] Tremblay, 1989, Regulation of the gene for estrogenic 17-ketosteroid reductase lying on chromosome 17cen–q25., J Biol Chem source
- Premisecitation
Similar transcription factors (SF1, C/EBPs, and CREB) mediate PGE2-dependent regulation of both the StAR and aromatase promoters.
“Additionally, similar transcription factors (SF1, C/EBPs, and CREB) mediate PGE 2 -dependent regulation of both promoters (19 -22).”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [19] Manna, 2002, Regulation of steroidogenesis and the steroidogenic acute regulatory protein by a member of the cAMP response-element binding protein family., Mol Endocrinol source
- cites [20] Manna, 2003, Transcriptional regulation of the mouse steroidogenic acute regulatory protein gene by the cAMP response-element binding protein and steroidogenic factor 1., J Mol Endocrinol source
- cites [21] Christenson, 2001, Steroidogenic acute regulatory protein: an update on its regulation and mechanism of action., Arch Med Res source
- cites [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
- Classified as probably not a substantial claim. 8
- May combine two claims. 15
- The quote only partly states this claim. 1
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationCOUP-TF and WT1 bind to and inhibit the P450arom promoter in endometrial stromal cells.
“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).”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [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
- cites [17] Gurates, 2002, WT1 and DAX-1 inhibit aromatase P450 expression in human endometrial and endometriotic stromal cells., J Clin Endocrinol Metab source
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)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationP450c17 catalyzes the conversion of progesterone to androstenedione, which is the primary substrate for P450arom in ovarian granulosa cells.
“P450c17 catalyzes the conversion of progesterone to androstenedione, which is the primary substrate for P450arom in ovarian granulosa cells (6,7).”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [6] Auchus, 1998, Cytochrome b5 augments the 17,20-lyase activity of human P450c17 without direct electron transfer., J Biol Chem source
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)
Experimental — accuracy not yet measured - cites [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
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe minus KTS splice isoform of WT1 is a more potent transcriptional regulator compared with the plus KTS isoform.
“We used the minus KTS splice isoform of WT1, which is a more potent transcriptional regulator compared with the plus KTS isoform (17).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [17] Gurates, 2002, WT1 and DAX-1 inhibit aromatase P450 expression in human endometrial and endometriotic stromal cells., J Clin Endocrinol Metab source
May combine two claims.
Findingown dataSF1 mRNA is barely detectable in endometrium and expressed at strikingly high levels in endometriotic tissue.
“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).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataPhysiological quantities of PGE2 (10−7 or 10−8 M) significantly stimulate StAR mRNA expression, whereas higher concentrations do not.
“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).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataPeak levels of PGE2-induced StAR mRNA occur at 24 h and protein at 48 h.
“Peak levels were observed at 24 h for mRNA and 48 h for protein.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataThe PGE2-dependent binding pattern of SF1, COUP-TFII, and WT1 was remarkably similar with respect to both the StAR and P450arom promoters, but distinct in endometriotic and endometrial stromal cells.
“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.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
FindingcitationOur current results regarding PGE2 induction of StAR expression and progesterone production are in general consistent with previously published data by Tsai et al. regarding StAR expression.
“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.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [10] Tsai, 2001, Regulation of steroidogenic acute regulatory protein expression and progesterone production in endometriotic stromal cells., J Clin Endocrinol Metab source
The quote only partly states this claim.
Findingown dataPGE2 significantly enhanced SF1 binding to both the StAR and P450arom promoters in both endometriotic and endometrial cells.
“and PGE 2 significantly enhanced SF1 binding in both cell types.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataSF1 is bound to the StAR and P450arom promoters in endometriotic cells, whereas corepressors are not recruited.
“and SF1 is bound to the StAR and P450arom promoters, whereas the corepressors are not recruited.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn endometriotic stromal cells, PGE2 induced binding of SF1 to both StAR and P450arom promoters, whereas very low SF1 binding was observed in endometrial stromal cells.
“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.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataPGE2 stimulated the activity of the -885 bp StAR promoter fused to luciferase in both endometriotic and endometrial cells, whereas it did not stimulate luciferase activity of the empty vector.
“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.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataWT1 or COUP-TFII inhibited StAR promoter activity.
“On the other hand, WT1 or COUP-TFII inhibited StAR promoter activity.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationHSD17B1 is constitutively expressed and catalyzes the conversion of weakly estrogenic estrone to biologically potent estradiol in both endometrial and endometriotic tissues.
“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).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11] Zeitoun, 1998, Deficient 17β-hydroxysteroid dehydrogenase type 2 expression in endometriosis: failure to metabolize 17β-estradiol., J Clin Endocrinol Metab source
Classified as probably not a substantial claim. May combine two claims.
PremisecitationP450arom is responsible for the conversion of androstenedione to estrone, which is further converted to estradiol by HSD17B1.
“P450arom is responsible for the conversion of androstenedione to estrone, which is further converted to the biologically active estradiol by the enzyme HSD17B1 (4).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [4] Tremblay, 1989, Regulation of the gene for estrogenic 17-ketosteroid reductase lying on chromosome 17cen–q25., J Biol Chem source
May combine two claims.
PremisecitationEndometriotic lesions show high estradiol biosynthesis and low estradiol inactivation compared with normal endometrium.
“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).”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationP450arom expression in endometriosis and peripheral tissues is critical because its inhibitors have been used successfully to treat postmenopausal endometriosis.
“P450arom expression in endometriosis and peripheral tissues was shown to be critical because its inhibitors have been used successfully to treat postmenopausal endometriosis (14).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [14] Attar, 2006, Aromatase inhibitors: the next generation of therapeutics for endometriosis?, Fertil Steril source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationStAR facilitates the first step of steroidogenesis, the entry of cholesterol into the mitochondrion.
“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).”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
Interpretationown dataIn 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.
“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.”
Quote in the paperSubstantial claim- Rests on an assumption: Primary cultured endometrial and endometriotic stromal cells retain the transcriptional characteristics of the corresponding tissues in vivo.
May combine two claims.
PremisecitationA molecular link between inflammation and estrogen production in endometriotic tissue 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 PGE2 in endometriotic tissue.
“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).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [4] Tremblay, 1989, Regulation of the gene for estrogenic 17-ketosteroid reductase lying on chromosome 17cen–q25., J Biol Chem source
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataThe association of the control protein nonacetylated histone H3 to chromatin did not vary with cell type or treatment.
“The association of the control protein, nonacetylated histone H3, to chromatin did not vary with cell type or treatment.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataNo binding activity was observed after chromatin was immunoprecipitated with nonspecific IgG.
“No binding activity was observed after chromatin was immunoprecipitated with nonspecific IgG.”
Quote in the paperNot a substantial claim
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 first studies reporting overexpression of StAR, HSD3β2, aromatase, HSD17β1, ERβ, and GPER all used OE or AD tissue samples.
“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
The ‘Expression of steroidogenic genes in eutopic and ectopic endometrium’ section reports elevated StAR and aromatase, with an apparent but less significant HSD3B2 difference, using extraovarian (peritoneal) endometriosis tissues—not OE or AD tissues. ‘Tissue acquisition and processing’ says ovarian endometrioma cyst walls were also collected, but those supplied cells for culture rather than the reported tissue-expression comparison. Our copy provides no basis for judging which studies were first. (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredIn endometriotic stromal cells, NR5A1 is essential for supporting high levels of proteins and enzymes that drive the serial conversion of cholesterol to estradiol.
“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
The Discussion (page not available) says endometriotic stromal cells contain the full enzymatic cascade for producing estradiol from cholesterol and identifies the PGE2–SF1 pathway as a key regulator. The gene-expression results also show high SF1 and steroidogenic-gene mRNA levels in endometriotic tissue. The paper does not establish that SF1 is essential for maintaining those levels; it describes SF1 as a possible key regulator and shows that its overexpression activates a promoter. (LLM, conf=0.83)
Experimental — accuracy not yet measuredHSD3β2 and HSD17β1 are aberrantly upregulated in ectopic endometrium.
“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
In “Expression of steroidogenic genes in eutopic and ectopic endometrium” (page unavailable), HSD3B2 mRNA was higher in endometriotic tissue than in normal endometrium, though the difference was less significant than for some other genes. The copy describes HSD17B1’s role in converting estrone to estradiol but does not report that HSD17B1 is upregulated in ectopic endometrium. (LLM, conf=0.88)
Experimental — accuracy not yet measuredPGE2 plays a vital role in facilitating estrogen biosynthesis and upregulation of ERβ, positioning itself in a feed-forward loop linking hyperestrogenism and inflammation in all ectopic endometria.
“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
The Discussion reports that PGE2 stimulates estradiol production in endometriotic stromal cells, and the paper’s introductory passage describes a positive-feedback link between inflammation and local estrogen production. Our copy does not show that PGE2 upregulates ERβ, and the cell findings do not establish the mechanism in all ectopic endometria. Page numbers are unavailable in the indexed copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredNR5A1 binds promoters and stimulates expression of StAR, CYP11A1, HSD3B2, CYP17A1 and aromatase (CYP19A1).
“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
The Discussion (Fig. 6; page not given) reports SF1 binding to the StAR and aromatase promoters in endometriotic stromal cells, and the StAR transcriptional-regulation section reports that SF1 overexpression increased StAR promoter activity. The paper reports expression of CYP11A1, HSD3B2 and CYP17A1, but the cited passages do not establish SF1 binding to their promoters or directly stimulating each gene's expression. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Endometriosis has the full set of steroidogenic enzymes enabling de-novo synthesis of estradiol.
“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
PGE2 stimulates production of cyclic AMP, which together with steroidogenic factor 1 induces expression of mRNAs encoding steroidogenic enzymes including STAR, 17-hydroxylase/17,20-lyase, 3β-HSD and aromatase.
“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]
Even when stimulated with PGE2, expression of most genes involved in estrogen biosynthesis, including StAR, SF-1, and aromatase, remains negligibly low, with very low estradiol production in normal endometrial stromal cells.
“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]
The difference in E2 production between HESCs and ESCLs is consistent with what has been documented previously.
“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]
Endometriotic stromal cells produce a much higher level of estrogens, due to demethylated aromatase and overexpression of StAR, HSD3B2 and HSD17B1.
“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]
Similarity of molecular biology of TIAR in various tissues with that described in endometriosis strongly suggests that this represents the common underlying mechanisms of both processes.
“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.
Progesterone-pathway induction is assigned to the wrong cell type
MinorThe results attribute PGE2-induced expression of three progesterone-pathway genes to endometrial stromal cells, but the same section says PGE2 did not stimulate steroidogenic genes in those cells except StAR. The reported induction was in endometriotic 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.”
“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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The pathophysiology of endometriosis and adenomyosis, tissue injury and repair
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Mortality attributable to smoking in China.
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Hormonal treatments for endometriosis: The endocrine background
Vannuccini, S., Clemenza, S., Rossi, M., & Petraglia, F. (2022) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-021-09666-w · Cited by 336 · see citing works
“A feed-forward loop connects hyperestrogenic stimulation with inflammation: the overexpression of cyclooxygenase 2 (COX2) and CYP19A1 increases local production of prostaglandins and estrogen, causing a vicious circle [38].”
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 307 · see citing works
“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
Yilmaz, B. D., & Bulun, S. E. (2019) · Human Reproduction Update · doi:10.1093/humupd/dmz005 · Cited by 243 · see citing works
“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 · see citing works
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 198 · see citing works
“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 202 · see citing works
“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 · see citing works
Peritoneal immune microenvironment of endometriosis: Role and therapeutic perspectives
Chen, S., Liu, Y., Zhong, Z., Wei, C., Liu, Y., & Zhu, X. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1134663 · Cited by 172 · see citing works
“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 · see citing works
“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
Guo, S.-W. (2020) · Journal of Clinical Medicine · doi:10.3390/jcm9020485 · Cited by 165 · see citing works
“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?
McKinnon, B. D., Mueller, M. D., & Montgomery, G. W. (2018) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2018.05.006 · Cited by 153 · see citing works
Extra-adrenal glucocorticoid biosynthesis: implications for autoimmune and inflammatory disorders
Slominski, R. M., Tuckey, R. C., Manna, P. R., Jetten, A. M., Postlethwaite, A., Raman, C., & Slominski, A. T. (2020) · Genes & Immunity · doi:10.1038/s41435-020-0096-6 · Cited by 155 · see citing works
Plants as source of new therapies for endometriosis: a review of preclinical and clinical studies
Meresman, G. F., Götte, M., & Laschke, M. W. (2020) · Human Reproduction Update · doi:10.1093/humupd/dmaa039 · Cited by 158 · see citing works
Estrogen metabolism and action in endometriosis
Rižner, T. L. (2009) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2009.03.022 · Cited by 153 · see citing works
Meinsohn, M.-C., Smith, O. E., Bertolin, K., & Murphy, B. D. (2019) · Physiological Reviews · doi:10.1152/physrev.00019.2018 · Cited by 146 · see citing works
“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)
Leyendecker, G., & Wildt, L. (2011) · hmbci · doi:10.1515/hmbci.2011.002 · Cited by 147 · see citing works
Vinketova, К., Mourdjeva, M., & Oreshkova, T. (2016) · Journal of Pregnancy · doi:10.1155/2016/8689436 · Cited by 142 · see citing works
“Initially triggered by the oestrogen or/and progesterone, all components of the functional endometrial layer, that is, glandular epithelium, endometrial stromal cells (ESCs), and endothelium, respond by interrelated and simultaneous activation of multiple factors and mediators.”
BackgroundInfluentialAromatase inhibitors for the treatment of endometriosis
Pavone, M. E., & Bulun, S. E. (2012) · Fertility and Sterility · doi:10.1016/j.fertnstert.2012.08.053 · Cited by 138 · see citing works
“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).”
BackgroundSelf-citationKuijsters, N. P. M., Methorst, W., Kortenhorst, M. S. Q., Rabotti, C., Mischi, M., & Schoot, B. C. (2017) · Reproductive BioMedicine Online · doi:10.1016/j.rbmo.2017.03.019 · Cited by 131 · see citing works
“Ectopic endometrial cells are found to produce oestradiol when stimulated by prostaglandin E2 (Attar et al., 2009).”
BackgroundProstaglandin E 2 : the master of endometriosis?
Wu, M., Lu, C.-W., Chuang, P., & Tsai, S. (2010) · Experimental Biology and Medicine · doi:10.1258/ebm.2010.009321 · Cited by 135 · see citing works
Endometriosis: The Role of Iron Overload and Ferroptosis
Ng, S., Norwitz, S. G., Taylor, H. S., & Norwitz, E. R. (2020) · Reproductive Sciences · doi:10.1007/s43032-020-00164-z · Cited by 132 · see citing works
Drosophila Eggshell Production: Identification of New Genes and Coordination by Pxt
Tootle, T. L., Williams, D., Hubb, A. J., et al. (2011) · PLoS ONE · doi:10.1371/journal.pone.0019943 · Cited by 127 · see citing works
Banu, S. K., Lee, J., Speights, V. O., Starzinski‐Powitz, A., & Arosh, J. A. (2009) · Molecular Endocrinology · doi:10.1210/me.2009-0017 · Cited by 116 · see citing works
Eutopic endometrium in women with endometriosis: ground zero for the study of implantation defects
Lessey, B., Lebovic, D., & Taylor, R. (2013) · Seminars in Reproductive Medicine · doi:10.1055/s-0032-1333476 · Cited by 113 · see citing works
Role of inflammation in benign gynecologic disorders: from pathogenesis to novel therapies†
AlAshqar, A., Reschke, L. D., Kirschen, G. W., & Borahay, M. A. (2021) · Biology of Reproduction · doi:10.1093/biolre/ioab054 · Cited by 121 · see citing works
“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].”
BackgroundAndrogens and endometrium: new insights and new targets
Simitsidellis, I., Saunders, P. T. K., & Gibson, D. A. (2018) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2017.09.022 · Cited by 107 · see citing works
Estrogen biosynthesis and signaling in endometriosis
Huhtinen, K., Ståhle, M., Perheentupa, A., & Poutanen, M. (2012) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2011.08.022 · Cited by 107 · see citing works
Epithelial Mutations in Endometriosis: Link to Ovarian Cancer
Bulun, S. E., Wan, Y., & Matei, D. E. (2019) · Endocrinology · doi:10.1210/en.2018-00794 · Cited by 103 · see citing works
Self-citationLee, J., Banu, S. K., Subbarao, T., Starzinski‐Powitz, A., & Arosh, J. A. (2010) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2010.11.022 · Cited by 92 · see citing works
Genetic, Epigenetic, and Steroidogenic Modulation Mechanisms in Endometriosis
Zubrzycka, A., Zubrzycki, M., Perdas, E., & Zubrzycka, M. (2020) · Journal of Clinical Medicine · doi:10.3390/jcm9051309 · Cited by 97 · see citing works
“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].”
Backgroundvan den Driesche, S., Walker, M., McKinnell, C., Scott, H. M., Eddie, S. L., Mitchell, R. T., Seckl, J. R., Drake, A. J., Smith, L. B., Anderson, R. A., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0037064 · Cited by 90 · see citing works
“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 · see citing works
Self-citationHypoxia: The force of endometriosis
Wu, M., Hsiao, K., & Tsai, S. (2019) · Journal of Obstetrics and Gynaecology Research · doi:10.1111/jog.13900 · Cited by 88 · see citing works
Absence of aromatase protein and mRNA expression in endometriosis
Colette, S., Lousse, J. C., Defrère, S., Curaba, M., Heilier, J.-F., Langendonckt, A. V., Mestdagt, M., Foidart, J. M., Loumaye, E., & Donnez, J. (2009) · Human Reproduction · doi:10.1093/humrep/dep199 · Cited by 86 · see citing works
“…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…”
BackgroundLi, W.-N., Hsiao, K., Wang, C.-A., Chang, N., Hsu, P.-L., Sun, C.-H., Wu, S.-R., Wu, M., & Tsai, S. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1920037117 · Cited by 96 · see citing works
“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 · see citing works
“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 · see citing works
The role of prostaglandin E 2 in endometriosis
Sacco, K. A., Portelli, M., Pollacco, J., Schembri-Wismayer, P., & Calleja‐Agius, J. (2011) · Gynecological Endocrinology · doi:10.3109/09513590.2011.588753 · Cited by 88 · see citing works
“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 · see citing works
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 · see citing works
Kim, S., Wairkar, Y. P., Daniels, R. W., & DiAntonio, A. (2010) · Journal of Cell Biology · doi:10.1083/jcb.200911126 · Cited by 82 · see citing works
Bakhtiarizadeh, M. R., Hosseinpour, B., Shahhoseini, M., Korte, A., & Gifani, P. (2018) · Frontiers in Genetics · doi:10.3389/fgene.2018.00453 · Cited by 78 · see citing works
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 · see citing works
“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 · see citing works
“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 · see citing works
“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 · see citing works
Liu, M.-H., Liu, X., Zhang, Y., & Guo, S. (2012) · Reproductive Sciences · doi:10.1177/1933719111424453 · Cited by 68 · see citing works
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 65 · see citing works
“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. (2014) · Biology of Reproduction · doi:10.1095/biolreprod.113.115790 · Cited by 62 · see citing works
“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 · see citing works
“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 · see citing works
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 · see citing works
“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 · see citing works
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 · see citing works
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 · see citing works
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 53 · see citing works
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 · see citing works
Gołąbek-Grenda, A., & Olejnik, A. M. (2022) · Cellular Signalling · doi:10.1016/j.cellsig.2022.110375 · Cited by 48 · see citing works
Shi, J., Xu, Q., Yu, S., & Zhang, T. (2025) · Seminars in Immunopathology · doi:10.1007/s00281-025-01040-1 · Cited by 50 · see citing works
“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 49 · see citing works
“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 · see citing works
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 48 · see citing works
“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 · see citing works
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 · see citing works
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 · see citing works
“[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 · see citing works
“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 44 · see citing works
“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 43 · see citing works
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 · see citing works
“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 · see citing works
“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 · see citing works
“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 · see citing works
“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 · see citing works
“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 · see citing works
“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 44 · see citing works
“[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 · see citing works
“…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 · see citing works
“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 · see citing works
“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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
“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 · see citing works
Garzon, S., Laganà, A. S., Barra, F., Casarin, J., Cromi, A., Raffaelli, R., Uccella, S., Franchi, M. P., Ghezzi, F., & Ferrero, S. (2020) · Expert Opinion on Investigational Drugs · doi:10.1080/13543784.2020.1842356 · Cited by 36 · see citing works
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 · see citing works
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 30 · see citing works
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 · see citing works
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 · see citing works
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 29 · see citing works
“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 · see citing works
Chen, Y., Cai, S., Wang, J., & Xu, M. (2015) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2015.2263 · Cited by 26 · see citing works
“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 27 · see citing works
“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 · see citing works
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 · see citing works
“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
- 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 › Genetics › 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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