| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Reproductive Endocrinology |
The Cecil H. and Ida Green Center for Reproductive Biology Sciences and the Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology, University of Texas Southwestern Medical Center, Dallas, Texas 75235
Address all correspondence and requests for reprints to: Serdar E. Bulun, M.D., The Cecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75235-9051. E-mail: bulun{at}grnctr.swmed.edu
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
, PGE2, estradiol, R5020,
dexamethasone, and dibutyryl cAMP (Bt2cAMP) on aromatase
activity in endometriosis-derived stromal cells were assessed. We chose
treatments with PGs and ILs because of the inflammatory nature of
endometriosis. PGE2 stimulated aromatase activity in
endometriosis-derived stromal cells by 19- to 44-fold (37–221 pmol/mg
protein·4 h), whereas Bt2cAMP induction was 26- to
60-fold the baseline level. No stimulation was observed by estradiol or
R5020 or by IL-1ß, IL-2, IL-6, IL-11, IL-15, or TNF in the
presence or absence of glucocorticoids. A modest induction of aromatase
activity (2-fold) was observed in dexamethasone- plus oncostatin
M-treated cells. These changes in aromatase activity were accompanied
by comparable changes in the levels of P450arom mRNA levels, determined
by a quantitative reverse transcription-PCR method. Promoter-specific
5'-ends of P450arom transcripts in total RNA from endometriosis-derived
stromal cells treated with PGE2 and Bt2cAMP
were amplified employing a novel modified rapid
amplification of cDNA 5'-ends/Southern hybridization method using
exon-specific oligonucleotide probes. The majority of P450arom
transcripts in these cells contained the gonadal-type promoter
II-specific sequences, whereas very few transcripts contained
adipose-type promoter I.3- and I.4-specific sequences. PGE2 appears to be the most potent known stimulator of aromatase in endometriosis. Aromatase expression in PGE2-stimulated stromal cells of endometriosis is regulated primarily by the classically located promoter II, which, in turn, is regulated by cAMP. As PGE2 is known to increase intracellular cAMP levels, estrogen biosynthesis in endometriosis may be primarily regulated by PGE2 that is locally produced. Consequent local estrogen production may promote the growth of endometriotic implants.
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
(18, 19, 20), and certain
cytokines, such as interleukin-6 (IL-6) (9, 12, 21) and IL-11 (12) are
locally produced in eutopic endometrium and endometriotic implants.
Cultured endometriosis-derived and eutopic endometrial stromal cells
from patients with endometriosis, however, produce much higher
quantities of IL-6 (9) than those from disease-free controls. Moreover,
the endometrium from patients with endometriosis exhibits higher
chemotactic activity for neutrophils and macrophages throughout the
menstrual cycle compared with disease-free controls (22). Estrogen is believed to play important roles in the establishment and maintenance of endometriosis (23). The formation of estrogens from C19 steroids is catalyzed by a specific form of P450, namely aromatase P450 (P450arom; the product of the CYP19 gene). Aromatase expression in various human cells is regulated by the use of alternative promoters in the placental syncytiotrophoblast (promoter I.1), ovarian granulosa and testicular Leydig cells (promoter II), adipose fibroblasts (promoters I.4, I.3, and II), and skin fibroblasts (promoter I.4) (24). This is accomplished by binding of specific trans-activating factors to defined genomic response elements upstream of the promoter used in that particular tissue (24). Tissue-specific promoter use is accomplished by alternative splicing mechanisms, which give rise to specific P450arom transcript populations with unique untranslated 5'-ends but with identical coding regions. Thus, the protein encoded is always identical regardless of the tissue site of expression, promoter use, or alternative splicing. In adipose fibroblasts in monolayer culture, aromatase expression is hormonally regulated (24). Aromatase activity and P450arom transcript levels in these cells can be markedly stimulated by cAMP analogs. This effect is potentiated by the addition of phorbol esters (25). Members of the IL-6 cytokine family [IL-6, IL-11, oncostatin-M (OSM), and leukemia inhibitory factor] (26) or serum (27) in the presence of glucocorticoids are also capable of inducing aromatase expression in adipose fibroblasts. As a further twist, the aforementioned hormones or cytokines stimulate aromatase expression in these cells by the use of alternative promoters (28). For example, serum or cytokines in the presence of glucocorticoids give rise to initiation of transcription primarily via promoter I.4. On the other hand, cAMP analogs (with or without phorbol esters) favor the use of promoters I.3 and II.
Aromatase is not expressed in endometrial or myometrial tissues of
disease-free women (12, 29). Aromatase expression, however, was
demonstrated in the neoplastic counterparts of these uterine tissues,
namely endometrial cancer and uterine leiomyomas (30, 31). This
suggests a role for estrogens formed in situ in the
regulation of growth of these neoplasms. Previously, we showed the
presence of P450arom transcripts in pelvic endometriotic implants and
eutopic endometrial tissues of patients with endometriosis, whereas
endometrial curettings from disease-free women and endometriosis-free
peritoneal biopsies did not contain P450arom transcripts (12). In the
current investigation, regulation of aromatase activity and levels of
P450arom transcripts in endometriosis-derived stromal cells in culture
were studied. The effects of PGE2, dibutyryl cAMP
(Bt2cAMP), estradiol, the progesterone analog R5020,
dexamethasone (DEX), tumor necrosis factor- (TNF), IL-1ß, IL-2,
IL-6, IL-11, OSM, and IL-15 on aromatase activity were determined.
P450arom transcript levels under these treatment conditions also were
analyzed using a quantitative reverse transcripton-PCR (RT-PCR) method.
Subsequently, promoter-specific transcripts were determined by a novel
modified rapid amplification of cDNA 5'-ends (5'-RACE)/exon-specific
Southern hybridization method.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
At the time of laparoscopy or laparotomy, the following samples were obtained from eight women: 1) ovarian endometriomas (n = 4), 2) eutopic endometrial tissues from patients with endometriosis (n = 2), and 3) eutopic endometrial tissues from disease-free patients (n = 3). All samples were histologically confirmed. Endometriotic implants were frozen in liquid nitrogen and stored at -70 C. Endometriomas and eutopic endometrial tissues were transported (in Hanks’ Balanced Salt Solution with HEPES and 2% antibiotic concentration) for cell culture and were immediately processed. Written consent was obtained before surgical procedures, including a consent form and protocol approved by the institutional review board for human research of the University of Texas Southwestern Medical Center.
Cell cultures
Endometriomas and eutopic endometrial tissues were cultured
using a modified protocol previously reported by Ryan et al.
with minor modifications (32). Tissues were rinsed with sterile saline
solution, minced finely, and digested with collagenase B (1 mg/mL) and
deoxyribonuclease I (0.1 mg/mL) at 37 C for 30–60 min. Epithelial
cells were separated from stromal cells by filtration through a 75-µm
sieve. Stromal cells were then suspended in Waymouth’s MB 752/1
enriched medium (Life Technologies, Grand Island, NY) containing 10%
FBS. Fresh suspensions of stromal cells were plated in 35-mm culture
dishes and kept in an incubator in a humidified atmosphere with 5%
CO2 at 37 C. Media were changed within 48 h and
thereafter at intervals until the cells became 75% confluent. Stromal
cells were then placed in serum-free Waymouth’s medium. The
fibroblast-like appearance of endometriosis-derived stromal cells in
culture under phase contrast microscopy was identical to that of
endometrial stromal cells (Fig. 1
).
|
(10 ng/mL), IL-1ß (1 ng/mL), IL-2 (2 ng/mL), IL-6 (2 ng/mL), IL-11 (2
ng/mL), OSM (2 ng/mL), IL-15 (2 ng/mL); 5) PGE2
(10-6-10-8 mol/L); 6) 17ß-estradiol
(10-7 mol/L); and 7) R5020 (5 x 10-7
mol/L). All treatments were continued for 24 h. Determination of aromatase activity
Aromatase activity was assayed in intact stromal cells after the
addition of [1ß-3H]androstenedione (150 nmol/L; DuPont,
Boston, MA) to the medium. Endometrial stromal cells from a
disease-free patient were used as negative controls. At the end of a
4-h incubation period, medium was removed, and the incorporation of
tritium from [1ß-3H]androstenedione into
[3H]water was assayed as described previously (33). The
cells were then scraped off the dishes, homogenized, and assayed for
protein using the BCA protein assay (Pierce, Rockford, IL). Results
were expressed as picomoles per mg of protein/4 h. Each bar
in Figs. 2 and 3 represents the mean of triplicate replicates
(±SEM).
|
|
Total RNA was isolated, using the method described by Chirgwin
et al. (34), from frozen tissues and cells in culture. PCR
amplification of a sequence in the coding region of P450arom
transcripts after RT was performed as previously described (35). This
procedure involved RT of 10 µg total RNA from cells or tissues using
a 3'-oligonucleotide specific for coding exon IV to synthesize a single
stranded complementary DNA (cDNA). These cDNA templates were amplified
separately using promoter-specific 5'-oligonucleotide primers.
5'-Untranslated sequences specific for promoters II, I.4, and I.3 as
well as a sequence in the common coding region were amplified,
size-fractionated in 1.8% agarose gels, and transferred to a blotting
nylon membrane by capillary elution. Southern hybridization with the
32P-labeled oligonucleotide probes specific for unique
5'-sequences was continued overnight (Figs. 4 and 5). The sequences of
these probes were published previously (12). X-Ray films were exposed
to blotting membranes for 1–16 h. Samples containing ovarian granulosa
cells (positive control for promoter II-specific transcripts) and
adipose stromal cells treated with Bt2cAMP (positive
control for promoters I.3-, II-, and I.4-specific transcripts) were
included in this experiment. Transcripts of the housekeeping gene,
glyceraldehyde-3-phosphate dehydrogenase (G3PDH), were amplified in
each sample as described previously (36). This ubiquitous marker was
used to normalize the quantity of RNA used. Radioactivity on blotting
membranes was quantified using the PhosphorImager System (Molecular
Dynamics, Sunnyvale, CA). A ratio of the value obtained from P450arom
coding sequence amplification products to that from G3PDH amplification
products in a total RNA sample was recorded as the arbitrary unit for
the total P450arom transcript level (Fig. 4).
|
|
Construction of cDNA by 5'-RACE was performed using total RNA from PGE2- and Bt2cAMP-treated endometriosis-derived stromal cells in culture. 5'-RACE was performed with minor modifications, as described by Frohman et al. (37, 38). First strand synthesis was performed using 10 µg total RNA, 2.5 pmol antisense primer that is complementary to a sequence in exon III located in the coding region (5'-ACTTGCTGATAATGAGTGTT-3'), reverse transcriptase buffer, 10 mmol/L dithiothreitol, 1 mmol/L final concentration of each deoxy-NTP, and 200 U Super-Script II reverse transcriptase in a 25-µL volume (5'RACE system, Life Technologies, Gaithersburg, MD). The primer extension was carried out at 42 C for 1 h, then the single stranded cDNA was tailed at the 3'-end with poly(C) using terminal transferase. Poly(C)-tailed cDNA template was then amplified by PCR using an amplification buffer system, a nested antisense primer that is complementary to an upstream sequence in coding exon III (5'ATTCCCATGCAGTAGCCAGG-3'), and a sense anchor primer that was provided in the kit. Amplification products were divided into four equal aliquots, which were separately size-fractionated in 1.8% agarose gels and transferred to blotting nylon membranes by capillary elution. Southern hybridization with 32P-labeled promoter-specific oligonucleotide probes was continued overnight. The sequences of these probes were previously published (12). X-Ray films were exposed to blotting membranes for 1–16 h.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Eutopic endometrial stromal cells from disease-free women (n = 3). These cells were used as negative controls. No detectable baseline or hormone-inducible aromatase activity was demonstrated (data not shown).
Eutopic endometrial stromal cells from women (n = 2) with
endometriosis. Although it was detectable, baseline aromatase
activity in eutopic endometrial stromal cells from a patient with
endometriosis (0.06 pmol/mg protein·4 h; Fig. 2A
) was
markedly lower than that in endometriosis-derived stromal cells (Fig. 2B). Bt2cAMP, in the absence of serum, stimulated aromatase
activity by 5-fold. The addition of PDA neither potentiated nor
suppressed Bt2cAMP stimulation. DEX in the presence of
serum or cytokines failed to stimulate aromatase activity, although a
marginal stimulation was noted in DEX- plus OSM-treated cells. The
progesterone agonist R5020 in the absence or presence of estradiol or
serum did not affect aromatase activity. Similar results were observed
in cultured endometrial cells from another subject with
endometriosis.
Endometriosis-derived stromal cells (n = 4). In a
representative experiment, the mean baseline aromatase activity of
endometriosis-derived stromal cells (0.65 pmol/mg protein·4 h; Fig. 2B) was approximately 11 times that of eutopic endometrial stromal
cells (Fig. 2A) from the same woman. In these cells, which were derived
from an endometrioma, Bt2cAMP treatment gave rise to a
26-fold increase over baseline activity. Again, the addition of PDA did
not modify Bt2cAMP stimulation. DEX induced aromatase
activity (2-fold over baseline) only in the presence of OSM, but not in
the presence of other cytokines or serum. No stimulation was observed
in R5020- or estradiol-treated cells. In cells from another patient
(Fig. 3), PGE2 (10-8 mol/L)
stimulated aromatase activity by 19-fold over the baseline value,
whereas Bt2cAMP induction was 32-fold. Moreover, increasing
concentrations of PGE2 showed stimulation in a
dose-dependent manner (data not shown). No stimulation was observed
with IL-1ß, IL-2, or IL-15 (Fig. 3). Additionally, TNF, IL-6, or
IL-11 treatment in the presence or absence of DEX had no effects on
aromatase activity (data not shown). PGE2 and
Bt2cAMP inductions of aromatase activity in
endometriosis-derived cells from two other women were up to 44-fold and
60-fold, respectively (data not shown).
Determination of P450arom transcript levels in
endometriosis-derived and eutopic endometrial stromal cells (Fig. 4)
We compared P450arom transcript levels in total RNA from eutopic
endometrial stromal cells and endometrioma-derived stromal cells, which
were treated with Bt2cAMP and DEX plus OSM. Total P450arom
transcript levels in RNA samples were determined by RT-PCR
amplification of a common coding sequence. Changes in transcript levels
were associated with comparable changes in aromatase activity (Fig. 4, lanes 3–5) in endometriosis-derived cells. Stromal cells originated
from eutopic endometrium of the same woman (lanes 1 and 2, Fig. 4)
contained detectable, but very low, levels of P450arom transcripts,
which remained below the linear range of the quantitative RT-PCR assay
(36). RNA samples of ovarian granulosa cells and
Bt2cAMP-treated adipose fibroblasts were included as
controls (lanes 6 and 7, Fig. 4).
Detection of promoter-specific P450arom transcripts in
endometriosis-derived and eutopic endometrial stromal cells (Fig. 5)
Total RNA samples shown in Fig. 4 were subjected to RT-PCR
followed by exon-specific Southern hybridization using
32P-labeled oligonucleotide probes specific for sequences
associated with transcription via promoters II, I.4, and I.3 (Fig. 5).
Bt2cAMP treatment was associated with promoter II- and
I.3-specific transcripts, whereas promoters II, I.4, and I.3 were used
in DEX- plus OSM-treated cells. It should be pointed out here that as
the amplification products of promoter-specific sequences (Fig. 5) were
also normalized to amplification products of G3PDH transcripts (Fig. 4), the intensity of the bands in Fig. 5 can be interpreted as relative
quantities of promoter-specific transcripts. It was apparent that,
under all incubation conditions, promoter II-specific transcripts
comprised the majority. In eutopic endometrial stromal cells from a
woman with endometriosis, amplified products of promoter-specific
5'-ends were not detected (Fig. 5, lanes 1 and 2), and in untreated
endometriosis-derived stromal cells (Fig. 5, lane 3), a faint band was
detected only for promoter II-specific amplification products with
prolonged exposure of the autoradiograph. The most likely explanation
is the presence of low messenger RNA (mRNA) copy numbers in these three
samples. [A sequence in the coding region of P450arom transcripts in
all of these cells was detected using RT-PCR (Fig. 4, lanes 1–3).]
Additionally, a novel modified RACE/exon-specific Southern
hybridization method was used to analyze 5'-ends of P450arom
transcripts in PGE2- and Bt2cAMP-treated
endometriosis-derived stromal cells. Almost all P450arom transcripts in
Bt2cAMP- and PGE2-treated cells contained
promoter II-specific 5'-ends, whereas very few promoter I.3- and
I.4-specific transcripts were found (Fig. 6). Although
some I.3- and I.4-specific bands cannot be seen in Fig. 6, they were
detected by longer exposure of the autoradiograph. PDA did not
potentiate or suppress Bt2cAMP or PGE2
stimulation of P450arom gene expression. This was consistent with
aromatase activity determinations after similar treatments (Figs. 2 and 3). P450arom transcript levels and the pattern of promoter use
were similar in endometriosis-derived stromal cells from all patients
studied (n = 4).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
PGE2 is the most potent known (patho)physiological
stimulator of estrogen biosynthesis in endometriosis. This prostanoid
was capable of inducing aromatase activity up to 44-fold the baseline
level. PGE2 can cause a diverse range of actions that are
mainly determined by the subtype of receptor used in that tissue. It
was observed that various prostanoids, whether natural or synthetic,
showed different effects on a variety of isolated tissues (40, 41). For
example, when applied to preparations of guinea pig trachea,
PGE2 can cause smooth muscle contraction, relaxation, or
both depending on the use of selective receptor antagonists (42). These
actions were later explained by the discovery of different PGE (EP)
receptor subtypes (EP1, EP2, EP3,
and EP4) that, in turn, are linked to different signal
transduction pathways. PGE2 interacts with several receptor
subtypes, one of which, EP2, is coupled to stimulation of
adenylate cyclase, whereas another, EP1, is coupled to
calcium uptake, inositol triphosphate formation, and protein kinase C
activation (41, 43). In endometriosis-derived stromal cells, it appears
that the stimulation of aromatase activity by PGE2 may be
mediated by a cAMP-dependent pathway (EP2 receptor
binding), as Bt2cAMP also induces aromatase expression in
these cells. PGE2 treatment of endometriosis-derived
stromal cells in culture was initially carried out based on our
observations involving incubation of adipose fibroblasts with various
prostanoids. PGE2 and PGD2 were capable of
markedly inducing aromatase activity of adipose fibroblasts, whereas
PGF2, PGI2, and PGJ2 treatments
failed to elicit a response (our unpublished observations). Studies
regarding the effects of prostanoids other than PGE2 and
their synthetic analogs and determination of the receptor types in
endometriotic stromal cells are currently underway. One may also
envision that differential expression of other genes besides P450arom
would take place in endometrial tissues of women with pelvic
endometriosis compared with those of disease-free women (9, 10, 12). In
fact, expression (or lack of expression) of some of these genes may
render endometriosis-derived stromal cells cAMP responsive and give
rise to activation of the gonadal-type P450arom promoter II.
The basis for the 11–70-fold difference between levels of aromatase expression in eutopic endometrium and pelvic endometriosis may be due to the transformation of endometrial stromal cells after implantation in pelvis in response to paracrine factors produced by the ovary and pelvic peritoneum. The aromatization capability of eutopic endometrial cells from women with endometriosis may facilitate their implantation in pelvic peritoneum and may promote the growth of these implants. Cytokines produced by blood-borne monocytes or local macrophages may induce PG synthesis in certain cell types of endometriosis, such as stromal, glandular, or vascular endothelial cells. This, in turn, may markedly stimulate estrogen production in pelvic endometriotic implants. The failure of GnRH analog treatment in a certain number of cases of pelvic endometriosis may be explained in part by local estrogen biosynthesis in these tissues. The final question is whether pathophysiologically sufficient quantities of estradiol are produced to sustain the maintenance and growth of these implants. This is dependent on the availability of the type of C19 substrate (testosterone vs. androstenedione), the presence of the reductive types of 17ß-hydroxysteroid dehydrogenase enzyme, and the ready availability of produced estradiol to estrogen receptors within the same cell type (intracrine effect). It should be emphasized here that aromatase activity in stimulated endometriosis-derived cells is extremely high and is comparable with that in placental trophoblasts or ovarian granulosa cells in culture. Thus, it is likely that local estrogen production makes an impact on the development and growth of pelvic endometriosis.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
Received August 19, 1996.
Revised October 11, 1996.
Accepted October 14, 1996.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
 |
|
 |
|
  S.-W. Guo Recurrence of endometriosis and its control Hum. Reprod. Update, July 1, 2009; 15(4): 441 - 461. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Carli, C. N. Metz, Y. Al-Abed, P. H. Naccache, and A. Akoum Up-Regulation of Cyclooxygenase-2 Expression and Prostaglandin E2 Production in Human Endometriotic Cells by Macrophage Migration Inhibitory Factor: Involvement of Novel Kinase Signaling Pathways Endocrinology, July 1, 2009; 150(7): 3128 - 3137. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Colette, J.C. Lousse, S. Defrere, M. Curaba, J.F. Heilier, A. Van Langendonckt, M. Mestdagt, J.M. Foidart, E. Loumaye, and J. Donnez Absence of aromatase protein and mRNA expression in endometriosis Hum. Reprod., June 2, 2009; (2009) dep199v1. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. J. Santen, H. Brodie, E. R. Simpson, P. K. Siiteri, and A. Brodie History of Aromatase: Saga of an Important Biological Mediator and Therapeutic Target Endocr. Rev., June 1, 2009; 30(4): 343 - 375. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Delvoux, P. Groothuis, T. D'Hooghe, C. Kyama, G. Dunselman, and A. Romano Increased Production of 17{beta}-Estradiol in Endometriosis Lesions Is the Result of Impaired Metabolism J. Clin. Endocrinol. Metab., March 1, 2009; 94(3): 876 - 883. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Attar, H. Tokunaga, G. Imir, M. B. Yilmaz, D. Redwine, M. Putman, B. Gurates, R. Attar, N. Yaegashi, D. B. Hales, et al. Prostaglandin E2 Via Steroidogenic Factor-1 Coordinately Regulates Transcription of Steroidogenic Genes Necessary for Estrogen Synthesis in Endometriosis J. Clin. Endocrinol. Metab., February 1, 2009; 94(2): 623 - 631. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Trukhacheva, Z. Lin, S. Reierstad, Y.-H. Cheng, M. Milad, and S. E. Bulun Estrogen Receptor (ER) {beta} Regulates ER{alpha} Expression in Stromal Cells Derived from Ovarian Endometriosis J. Clin. Endocrinol. Metab., February 1, 2009; 94(2): 615 - 622. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. E. Bulun Endometriosis N. Engl. J. Med., January 15, 2009; 360(3): 268 - 279. [Full Text] [PDF]
|
|
|
|
 |
|
 L. Aghajanova, A. Hamilton, J. Kwintkiewicz, K.C. Vo, and L.C. Giudice Steroidogenic Enzyme and Key Decidualization Marker Dysregulation in Endometrial Stromal Cells from Women with Versus Without Endometriosis Biol Reprod, January 1, 2009; 80(1): 105 - 114. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Demura, S. Reierstad, J. E. Innes, and S. E. Bulun Novel Promoter I.8 and Promoter Usage in the CYP19 (Aromatase) Gene Reproductive Sciences, December 1, 2008; 15(10): 1044 - 1053. [Abstract] [PDF]
|
|
|
|
|
|
O. Bukulmez, D. B. Hardy, B. R. Carr, R. J. Auchus, T. Toloubeydokhti, R. A. Word, and C. R. Mendelson Androstenedione Up-Regulation of Endometrial Aromatase Expression via Local Conversion to Estrogen: Potential Relevance to the Pathogenesis of Endometriosis J. Clin. Endocrinol. Metab., September 1, 2008; 93(9): 3471 - 3477. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C.-C. Hsu, C.-W. Lu, B.-M. Huang, M.-H. Wu, and S.-J. Tsai Cyclic Adenosine 3',5'-Monophosphate Response Element-Binding Protein and CCAAT/Enhancer-Binding Protein Mediate Prostaglandin E2-Induced Steroidogenic Acute Regulatory Protein Expression in Endometriotic Stromal Cells Am. J. Pathol., August 1, 2008; 173(2): 433 - 441. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Utsunomiya, Y.-H. Cheng, Z. Lin, S. Reierstad, P. Yin, E. Attar, Q. Xue, G. Imir, S. Thung, E. Trukhacheva, et al. Upstream Stimulatory Factor-2 Regulates Steroidogenic Factor-1 Expression in Endometriosis Mol. Endocrinol., April 1, 2008; 22(4): 904 - 914. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Ishikawa, V. Fencki, E. E. Marsh, P. Yin, D. Chen, Y.-H. Cheng, S. Reisterd, Z. Lin, and S. E. Bulun CCAAT/Enhancer Binding Protein {beta} Regulates Aromatase Expression via Multiple and Novel Cis-Regulatory Sequences in Uterine Leiomyoma J. Clin. Endocrinol. Metab., March 1, 2008; 93(3): 981 - 991. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Bukulmez, D. B. Hardy, B. R. Carr, R. A. Word, and C. R. Mendelson Inflammatory Status Influences Aromatase and Steroid Receptor Expression in Endometriosis Endocrinology, March 1, 2008; 149(3): 1190 - 1204. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Subbaramaiah, C. Hudis, S.-H. Chang, T. Hla, and A. J. Dannenberg EP2 and EP4 Receptors Regulate Aromatase Expression in Human Adipocytes and Breast Cancer Cells: EVIDENCE OF A BRCA1 AND p300 EXCHANGE J. Biol. Chem., February 8, 2008; 283(6): 3433 - 3444. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Purohit, L. Fusi, J. Brosens, L.W.L. Woo, B.V.L. Potter, and M.J. Reed Inhibition of steroid sulphatase activity in endometriotic implants by 667 COUMATE: a potential new therapy Hum. Reprod., February 1, 2008; 23(2): 290 - 297. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Dassen, C. Punyadeera, R. Kamps, B. Delvoux, A. Van Langendonckt, J. Donnez, B. Husen, H. Thole, G. Dunselman, and P. Groothuis Estrogen metabolizing enzymes in endometrium and endometriosis Hum. Reprod., December 1, 2007; 22(12): 3148 - 3158. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. Xue, Z. Lin, Y.-H. Cheng, C.-C. Huang, E. Marsh, P. Yin, M. P Milad, E. Confino, S. Reierstad, J. Innes, et al. Promoter Methylation Regulates Estrogen Receptor 2 in Human Endometrium and Endometriosis Biol Reprod, October 1, 2007; 77(4): 681 - 687. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Wieser, M. Cohen, A. Gaeddert, J. Yu, C. Burks-Wicks, S. L. Berga, and R. N. Taylor Evolution of medical treatment for endometriosis: back to the roots? Hum. Reprod. Update, September 1, 2007; 13(5): 487 - 499. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. Xue, Z. Lin, P. Yin, M. P. Milad, Y.-H. Cheng, E. Confino, S. Reierstad, and S. E. Bulun Transcriptional Activation of Steroidogenic Factor-1 by Hypomethylation of the 5' CpG Island in Endometriosis J. Clin. Endocrinol. Metab., August 1, 2007; 92(8): 3261 - 3267. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P.-C. Chuang, H. S. Sun, T.-M. Chen, and S.-J. Tsai Prostaglandin E2 Induces Fibroblast Growth Factor 9 via EP3-Dependent Protein Kinase C{delta} and Elk-1 Signaling Mol. Cell. Biol., November 15, 2006; 26(22): 8281 - 8292. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Ulukus, H. Cakmak, and A. Arici The Role of Endometrium in Endometriosis Reproductive Sciences, October 1, 2006; 13(7): 467 - 476. [Abstract] [PDF]
|
|
|
|
 |
|
 I. Velasco, J. Rueda, and P. Acien Aromatase expression in endometriotic tissues and cell cultures of patients with endometriosis Mol. Hum. Reprod., June 1, 2006; 12(6): 377 - 381. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. M. Becker, R. D. Wright, R. Satchi-Fainaro, T. Funakoshi, J. Folkman, A. L. Kung, and R. J. D'Amato A Novel Noninvasive Model of Endometriosis for Monitoring the Efficacy of Antiangiogenic Therapy Am. J. Pathol., June 1, 2006; 168(6): 2074 - 2084. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Einspanier, K. Lieder, A. Bruns, B. Husen, H. Thole, and C. Simon Induction of endometriosis in the marmoset monkey (Callithrix jacchus) Mol. Hum. Reprod., May 1, 2006; 12(5): 291 - 299. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Attar and S.E. Bulun Aromatase and other steroidogenic genes in endometriosis: translational aspects Hum. Reprod. Update, January 1, 2006; 12(1): 49 - 56. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Miljanovic, K. A Trivedi, M R. Dana, J. P Gilbard, J. E Buring, and D. A Schaumberg Relation between dietary n-3 and n-6 fatty acids and clinically diagnosed dry eye syndrome in women Am. J. Clinical Nutrition, October 1, 2005; 82(4): 887 - 893. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. E. Bulun, Z. Lin, G. Imir, S. Amin, M. Demura, B. Yilmaz, R. Martin, H. Utsunomiya, S. Thung, B. Gurates, et al. Regulation of Aromatase Expression in Estrogen-Responsive Breast and Uterine Disease: From Bench to Treatment Pharmacol. Rev., September 1, 2005; 57(3): 359 - 383. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.M. Wolfler, F. Nagele, A. Kolbus, S. Seidl, B. Schneider, J.C. Huber, and W. Tschugguel A predictive model for endometriosis Hum. Reprod., June 1, 2005; 20(6): 1702 - 1708. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.L. Hull, A. Prentice, D.Y. Wang, R.P. Butt, S.C. Phillips, S.K. Smith, and D.S. Charnock-Jones Nimesulide, a COX-2 inhibitor, does not reduce lesion size or number in a nude mouse model of endometriosis Hum. Reprod., February 1, 2005; 20(2): 350 - 358. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.-H. Wu, C.-A. Wang, C.-C. Lin, L.-C. Chen, W.-C. Chang, and S.-J. Tsai Distinct Regulation of Cyclooxygenase-2 by Interleukin-1{beta} in Normal and Endometriotic Stromal Cells J. Clin. Endocrinol. Metab., January 1, 2005; 90(1): 286 - 295. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Nishida, K. Nasu, T. Ueda, J. Fukuda, N. Takai, and I. Miyakawa Endometriotic cells are resistant to interferon-{gamma}-induced cell growth inhibition and apoptosis: a possible mechanism involved in the pathogenesis of endometriosis Mol. Hum. Reprod., January 1, 2005; 11(1): 29 - 34. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. E. Hardman (n-3) Fatty Acids and Cancer Therapy J. Nutr., December 1, 2004; 134(12): 3427S - 3430S. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Stocco In Vivo and in Vitro Inhibition of cyp19 Gene Expression by Prostaglandin F2{alpha} in Murine Luteal Cells: Implication of GATA-4 Endocrinology, November 1, 2004; 145(11): 4957 - 4966. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Matsuzaki, M. Canis, C. Vaurs-Barriere, J.L. Pouly, O. Boespflug-Tanguy, F. Penault-Llorca, P. Dechelotte, B. Dastugue, K. Okamura, and G. Mage DNA microarray analysis of gene expression profiles in deep endometriosis using laser capture microdissection Mol. Hum. Reprod., October 1, 2004; 10(10): 719 - 728. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. C Larsson, M. Kumlin, M. Ingelman-Sundberg, and A. Wolk Dietary long-chain n-3 fatty acids for the prevention of cancer: a review of potential mechanisms Am. J. Clinical Nutrition, June 1, 2004; 79(6): 935 - 945. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Absenger, H. Hess-Stumpp, B. Kreft, J. Kratzschmar, B. Haendler, N. Schutze, P.-A. Regidor, and E. Winterhager Cyr61, a deregulated gene in endometriosis Mol. Hum. Reprod., June 1, 2004; 10(6): 399 - 407. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Harada, A. Kaponis, T. Iwabe, F. Taniguchi, G. Makrydimas, N. Sofikitis, M. Paschopoulos, E. Paraskevaidis, and N. Terakawa Apoptosis in human endometrium and endometriosis Hum. Reprod. Update, January 1, 2004; 10(1): 29 - 38. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L.-Y. C. Wing, P.-C. Chuang, M.-H. Wu, H.-M. Chen, and S.-J. Tsai Expression and Mitogenic Effect of Fibroblast Growth Factor-9 in Human Endometriotic Implant Is Regulated by Aberrant Production of Estrogen J. Clin. Endocrinol. Metab., November 1, 2003; 88(11): 5547 - 5554. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. S. Sun, K.-Y. Hsiao, C.-C. Hsu, M.-H. Wu, and S.-J. Tsai Transactivation of Steroidogenic Acute Regulatory Protein in Human Endometriotic Stromal Cells Is Mediated by the Prostaglandin EP2 Receptor Endocrinology, September 1, 2003; 144(9): 3934 - 3942. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. de Ziegler Associate editor's commentary: The dawning of the non-cancer uses of aromatase inhibitors in gynaecology Hum. Reprod., August 1, 2003; 18(8): 1598 - 1602. [Full Text] [PDF]
|
|
|
|
|
|
M.-H. Wu, H.S. Sun, C.-C. Lin, K.-Y. Hsiao, P.-C. Chuang, H.-A. Pan, and S.-J. Tsai Distinct mechanisms regulate cyclooxygenase-1 and -2 in peritoneal macrophages of women with and without endometriosis Mol. Hum. Reprod., December 1, 2002; 8(12): 1103 - 1110. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. E. Hardman Omega-3 Fatty Acids to Augment Cancer Therapy J. Nutr., November 1, 2002; 132(11): 3508S - 3512. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Leyendecker, M. Herbertz, G. Kunz, and G. Mall Endometriosis results from the dislocation of basal endometrium Hum. Reprod., October 1, 2002; 17(10): 2725 - 2736. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Gurates, S. Sebastian, S. Yang, J. Zhou, M. Tamura, Z. Fang, T. Suzuki, H. Sasano, and S. E. Bulun WT1 and DAX-1 Inhibit Aromatase P450 Expression in Human Endometrial and Endometriotic Stromal Cells J. Clin. Endocrinol. Metab., September 1, 2002; 87(9): 4369 - 4377. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H.-J. Yang, M. Shozu, K. Murakami, H. Sumitani, T. Segawa, T. Kasai, and M. Inoue Spatially Heterogenous Expression of Aromatase P450 through Promoter II Is Closely Correlated with the Level of Steroidogenic Factor-1 Transcript in Endometrioma Tissues J. Clin. Endocrinol. Metab., August 1, 2002; 87(8): 3745 - 3753. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Fang, S. Yang, B. Gurates, M. Tamura, E. Simpson, D. Evans, and S. E. Bulun Genetic or Enzymatic Disruption of Aromatase Inhibits the Growth of Ectopic Uterine Tissue J. Clin. Endocrinol. Metab., July 1, 2002; 87(7): 3460 - 3466. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Shozu, H. Sumitani, T. Segawa, H.-J. Yang, K. Murakami, T. Kasai, and M. Inoue Overexpression of Aromatase P450 in Leiomyoma Tissue Is Driven Primarily through Promoter I.4 of the Aromatase P450 Gene (CYP19) J. Clin. Endocrinol. Metab., June 1, 2002; 87(6): 2540 - 2548. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Yang, Z. Fang, T. Suzuki, H. Sasano, J. Zhou, B. Gurates, M. Tamura, K. Ferrer, and S. Bulun Regulation of Aromatase P450 Expression in Endometriotic and Endometrial Stromal Cells by CCAAT/Enhancer Binding Proteins (C/EBPs): Decreased C/EBP{beta} in Endometriosis Is Associated with Overexpression of Aromatase J. Clin. Endocrinol. Metab., May 1, 2002; 87(5): 2336 - 2345. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-J. Tsai, M.-H. Wu, C.-C. Lin, H. S. Sun, and H.-M. Chen Regulation of Steroidogenic Acute Regulatory Protein Expression and Progesterone Production in Endometriotic Stromal Cells J. Clin. Endocrinol. Metab., December 1, 2001; 86(12): 5765 - 5773. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Ramachandran, M. Song, A. A. Murphy, and S. Parthasarathy Expression of Scavenger Receptor Class B1 in Endometrium and Endometriosis J. Clin. Endocrinol. Metab., August 1, 2001; 86(8): 3924 - 3928. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I.A. Brosens and J.J. Brosens Redefining endometriosis: Is deep endometriosis a progressive disease? Hum. Reprod., January 1, 2000; 15(1): 1 - 3. [Full Text] [PDF]
|
|
|
|
|
|
G. Leyendecker Redefining endometriosis: Endometriosis is an entity with extreme pleiomorphism Hum. Reprod., January 1, 2000; 15(1): 4 - 7. [Full Text] [PDF]
|
|
|
|
|
|
G. Kunz, D. Beil, P. Huppert, and G. Leyendecker Structural abnormalities of the uterine wall in women with endometriosis and infertility visualized by vaginal sonography and magnetic resonance imaging Hum. Reprod., January 1, 2000; 15(1): 76 - 82. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Zeitoun, K. Takayama, M. D. Michael, and S. E. Bulun Stimulation of Aromatase P450 Promoter (II) Activity in Endometriosis and Its Inhibition in Endometrium Are Regulated by Competitive Binding of Steroidogenic Factor-1 and Chicken Ovalbumin Upstream Promoter Transcription Factor to the Same cis-Acting Element Mol. Endocrinol., February 1, 1999; 13(2): 239 - 253. [Abstract] [Full Text]
|
|
|
|
|
|
K. Zeitoun, K. Takayama, H. Sasano, T. Suzuki, N. Moghrabi, S. Andersson, A. Johns, L. Meng, M. Putman, B. Carr, et al. Deficient 17{beta}-Hydroxysteroid Dehydrogenase Type 2 Expression in Endometriosis: Failure to Metabolize 17{beta}-Estradiol J. Clin. Endocrinol. Metab., December 1, 1998; 83(12): 4474 - 4480. [Abstract] [Full Text]
|
|
|
|
|
|
H. Sasano and N. Harada Intratumoral Aromatase in Human Breast, Endometrial, and Ovarian Malignancies Endocr. Rev., October 1, 1998; 19(5): 593 - 607. [Abstract] [Full Text]
|
|
|
|
 |
|
 L. Hilakivi-Clarke, R. Clarke, I. Onojafe, M. Raygada, E. Cho, and M. Lippman A maternal diet high in n - 6 polyunsaturated fats alters mammary gland development, puberty onset, and breast cancer risk among female rat offspring PNAS, August 19, 1997; 94(17): 9372 - 9377. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
