| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Original Studies |
Departments of Obstetrics-Gynecology (K.Z., K.T., N.M., S.A., A.J., L.M., M.P., B.C., S.E.B.) and Biochemistry (N.M., S.A.), University of Texas Southwestern Medical Center, Dallas, Texas 75235; and the Department of Pathology, Tohoku University School of Medicine (T.S.), Sendai, Japan
Address all correspondence and requests for reprints to: Serdar E. Bulun, M.D., Department of Obstetrics-Gynecology, 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 |
|---|
It was previously demonstrated that progesterone stimulates the inactivation of 17ß-estradiol through conversion to estrone in eutopic endometrial epithelial cells. Subsequently, 17ßHSD type 2 was shown to catalyze this reaction, and its transcripts were detected in the epithelial cell component of the eutopic endometrium in secretory phase. Because 17ß-estradiol plays a critical role in the development and growth of endometriosis, we studied 17ßHSD-2 expression in endometriotic tissues and eutopic endometrium. We demonstrated, by Northern blotting, 17ßHSD-2 messenger ribonucleic acid (RNA) in all RNA samples of secretory eutopic endometrium (n = 12) but not in secretory samples of endometriotic lesions (n = 10), including paired samples of endometrium and endometriosis obtained simultaneously from eight patients. This messenger RNA was not detectable in any samples of proliferative eutopic endometrium or endometriosis (n = 4) as expected. Next, we confirmed these findings by demonstration of immunoreactive 17ßHSD-2 in epithelial cells of secretory eutopic endometrium in 11 of 13 samples employing a monoclonal antibody against 17ßHSD-2, whereas 17ßHSD-2 was absent in paired secretory endometriotic tissues (n = 4). Proliferative eutopic endometrial (n = 8) and endometriotic (n = 4) tissues were both negative for immunoreactive 17ßHSD-2, except for barely detectable levels in 1 eutopic endometrial sample. Finally, we sought to determine whether deficient 17ßHSD-2 expression in endometriotic tissues is due to impaired progesterone action in endometriosis. We determined by immunohistochemistry the expression of progesterone and estrogen receptors in these paired samples of secretory (n = 4) and proliferative (n = 4) eutopic endometrium and endometriosis, and no differences could be demonstrated. In conclusion, inactivation of 17ß-estradiol is impaired in endometriotic tissues due to deficient expression of 17ßHSD-2, which is normally expressed in eutopic endometrium in response to progesterone. The lack of 17ßHSD-2 expression in endometriosis is not due to alterations in the levels of immunoreactive progesterone or estrogen receptors in this tissue and may be related to an inhibitory aberration in the signaling pathway that regulates 17ßHSD-2 expression.
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Both circumstantial and laboratory evidence indicate that endometriosis is an estrogen-dependent disease. The formation of estrogens from C19 steroids is catalyzed by aromatase P450, which is expressed in significant levels in endometriotic tissues and stromal cells in culture, but not in the eutopic endometrium (5, 10, 13, 14). This was suggestive of a role of estrogen formed in situ in addition to circulating estrogens in the development and growth of endometriotic implants. The primary C19 substrate for aromatase in extraglandular tissues such as adipose and endometriotic tissues is circulating androstenedione that is converted to estrone. Estrone itself, however, is only weakly estrogenic and must be reduced by 17ß-hydroxysteroid dehydrogenase (17ßHSD) type 1 to the potent estrogen, 17ß-estradiol, for attainment of full estrogenic effect (15, 16). Another 17ßHSD isozyme, 17ßHSD type 2, catalyzes the conversions of 17ß-estradiol to estrone and testosterone to androstenedione in a number of human tissues, including the placenta and liver (17). Additionally, very high levels of 17ßHSD type 2 messenger ribonucleic acid (mRNA) have been demonstrated in the glandular epithelial cell fraction of the human endometrium during the secretory phase, suggesting that progesterone stimulates this enzyme (18, 19). In fact, estradiol dehydrogenase activity (oxidation of 17ß-estradiol to estrone) in the endometrium has been shown to be stimulated by progesterone in earlier reports (20, 21, 22). The inactivation of 17ß-estradiol to estrone by the secretory phase endometrium has been viewed as an important protective mechanism in this estrogen-responsive tissue. The expression of 17ßHSD type 2 protein in the eutopic endometrium, however, has not been demonstrated to date. Additionally, the presence or absence of any type of 17ßHSD expression in endometriotic tissues has not been investigated.
It should be noted that a third 17ßHSD isozyme (type 3) catalyzes the reduction of androstenedione to testosterone in the microsomes of testicular Leydig cells (23, 24). Type 3 isozyme can also catalyze the reduction of estrone to 17ß-estradiol. The mRNAs for these three proteins with aforementioned 17ßHSD enzyme activities are encoded by three separate genes (16, 17, 18, 24). Because they play vital roles in 17ß-estradiol biosynthesis or metabolism, we studied herein endometriotic and eutopic endometrial tissues to address the following questions. 1) As aberrant aromatase expression in endometriotic stromal cells gives rise to formation of primarily estrone, is there a 17ßHSD isozyme in endometriosis that can catalyze the conversion of estrone to 17ß-estradiol? 2) Is the protective mechanism of 17ß-estradiol inactivation by 17ßHSD type 2 in the secretory eutopic endometrium impaired in endometriotic tissues to give rise to increased local 17ß-estradiol levels? Thus, we determined the transcript and protein levels of 17ßHSD isozymes using RT-PCR, Northern blotting, and immunohistochemistry in the eutopic endometrium and endometriosis. We also report, for the first time in the literature, the localization of 17ßHSD type 2 protein to secretory eutopic endometrial glandular cells.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
At the time of laparoscopy or laparotomy the following types of samples were obtained: 1) extraovarian endometriotic implants from patients with endometriosis, 2) eutopic endometrial tissues from patients with endometriosis, 3) eutopic endometrial tissues from disease-free patients, 4) normal peritoneum from patients with endometriosis. Patients were between 24–38 yr of age with regular cycles. All specimens were confirmed histologically, and the phase of the cycle was determined by histological examination of the endometrium. Tissue samples were frozen instantly in liquid nitrogen in the operating room and stored at -80 C. Total RNA was isolated from tissues by the guanidium thiocyanate-cesium chloride method (25). Samples for immunohistochemistry were transported in 10% formalin and embedded in paraffin. Written informed consent was obtained before surgical procedures, including a consent form, and the protocol was approved by the institutional review board for human research of the University of Texas Southwestern Medical Center.
RT-PCR/Southern Hybridization
RT-PCR amplification of sequences in the coding regions of
17ßHSD type 1, 2, and 3 mRNA species was performed using specific
oligonucleotides (Table 1
). The
oligonucleotide primers were designed to flank at least three exons in
each complementary DNA (cDNA; Table 1). This procedure involved
synthesizing initially a cDNA by reverse transcription of 5 µg total
RNA using Superscript II reverse transcriptase (BRL, Gaithersburg, MD)
and random primers. Specific regions in the coding sequences of
17ßHSD-1, -2, and -3 cDNAs were then amplified by PCR. The reaction
was carried out in a 50-µl volume using Amplitaq DNA polymerase
(Perkin Elmer/Cetus, Norwalk, CT), 1 mmol/L deoxy
(d)-NTPs, 10 µmol/L sense and antisense primers, and PCR buffer
(Perkin Elmer/Cetus) for 35 amplification cycles.
Denaturing was performed at 94 C for 40 s, annealing at 58 C for
40 s, and extension at 72 C for 40 s. The generated PCR
products were then size-fractionated on 1.8% agarose gel and
transferred to nylon membranes for Southern blot analysis. The
membranes were hybridized for 16 h at 42 C using specific cDNA
probes radiolabeled with [
-32P]dCTP. They were then
exposed to x-ray film at -80 C for varying lengths of time.
|
Total RNA (20 µg/lane) was size-fractionated by
electrophoresis on 1% formaldehyde-agarose gels and transferred
electrophoretically to a nylon membrane. The RNA was cross-linked to
the nylon membranes by UV irradiation. The membranes were prehybridized
for 24 h at 42 C in prehybridization buffer comprised of formamide
(50%, vol/vol), NaH2PO4 (250 mmol/L; pH 7.2),
NaCl (250 mmol/L), SDS (7%, wt/vol), and denatured sheared salmon
sperm DNA (100 µg/mL). Hybridizations were conducted for 16 h at
42 C in the same buffer by adding 17ßHSD type 1, 17ßHSD type 2, or
17ßHSD type 3 full-length cDNA probes (2 x 106
cpm/mL) radiolabeled with [-32P]dCTP using random
hexanucleotide primers and Klenow. After hybridization, the blots were
washed with varying concentrations of SSC (standard saline citrate) and
SDS at varying temperatures. The membranes were exposed to film with
intensifying screens at -80 C for varying lengths of time. The
presence of comparable amounts of total RNA in each lane was verified
by visualization of 18S and 28S ribosomal RNA subunits or by
hybridization of membranes with a ß-actin cDNA probe
(Clontech Laboratories, Inc., Palo Alto, CA).
Immunohistochemistry
Immunohistochemistry for 17ßHSD type 2, estradiol receptors
(ER), and progesterone receptors (PR) in eutopic
endometrial and endometriotic tissues was performed using monoclonal
antibodies. The monoclonal antibody, mAb-C2-12, against 17ßHSD type 2
was produced as previously described (26). Monoclonal antibodies
against ER (ERIDS) and PR (both A and B, MAB429) were purchased from
Immunotech (Marseille, France) and Chemiron International,
Inc. (Temecula, CA), respectively. The immunohistochemical procedures
were performed as previously described on 2.5-µm-thick sections
mounted on silane-coated slides using the biotin-streptavidin-amplified
technique with a Histofine immunostaining system (Nichirei, Tokyo,
Japan). Briefly, the staining procedure was performed as follows: 1)
routine deparaffinization; 2) inactivation of endogenous peroxidase
with 0.3% H2O2 in methyl alcohol for 20 min at
23 C; 3) blocking with 1% goat serum for 20 min at 23 C; 4) incubation
with the primary antibody at 4 C for 18 h; 5) incubation with
biotinylated goat antirabbit antibody for 20 min at 23 C; 6) incubation
with peroxidase-conjugated streptavidin for 20 min at 23 C; 7)
immersion in a solution containing 0.05% Tris-HCl (pH 7.6), 0.001
mol/L 3.3'-diaminobenzidine, and 0.006% H2O2;
and 8) counterstaining with hematoxylin. For negative controls, normal
mouse IgG was used instead of the primary antibodies. As positive
controls, tissue sections of ER- and PR-positive breast cancer were
used for ER and PR, and those of placenta were used for 17ßHSD type 2
(27, 28, 29).
The dilutions of the primary antibodies are as follows: ER, 1:1; PR, 1:50; and 17ßHSD type 2, 1:5. The dilution of the secondary antibody was 1:1. The semiquantification of ER and PR immunoreactivity was performed using labeling index as previously described (29).
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Initially using RT-PCR, mRNAs for 17ßHSD types 1, 2, and 3 were detected in the majority of extraovarian endometriotic and eutopic endometrial tissue samples (data not shown). Type 1 17ßHSD mRNA was detected in all eutopic endometrial (n = 6) and endometriotic (n = 10) tissue samples. Type 2 17ßHSD mRNA was detected in all 8 eutopic endometrial and in 7 of 8 endometriotic tissues. Type 3 17ßHSD mRNA was detected in 30 of 33 eutopic endometrial samples and in all endometriotic samples (n = 10). Both proliferative and secretory endometriotic and eutopic endometrial tissues were included in this study, and no differences were noted between tissues in various phases of the cycle. Because RT-PCR is sufficiently sensitive to detect physiologically insignificant quantities of mRNA, we decided to use Northern blotting to demonstrate the presence or absence of significant quantities of mRNA.
Detection of mRNAs of 17ßHSD types 1, 2, and 3 in eutopic endometrial and endometriotic tissues by Northern analysis
Type 1 17ßHSD mRNA was detected by Northern analysis in both
eutopic endometrial (12 secretory and 4 proliferative) and
endometriotic (10 secretory and 4 proliferative) tissues after exposure
of the film for 80 h at -80 C (Figs. 1 and 2).
There were no apparent differences in the steady state levels of
17ßHSD type 1 mRNA between eutopic endometrial and endometriotic
samples in different cycle phases.
|
|
and 2. Included among these samples were eight pairs
of eutopic endometrial and endometriotic tissues that were
simultaneously acquired from eight patients undergoing laparoscopy
during the secretory phase. All secretory eutopic endometrial samples
(n = 8) contained 17ßHSD type 2 mRNA, whereas all simultaneously
biopsied endometriotic tissues were negative (n = 8) for 17ßHSD
type 2 mRNA using Northern blotting (Figs. 1 and 2). Type 3 17ßHSD
mRNA was not detected by Northern analysis in any of the eutopic
endometrial (n = 16) or endometriotic (n = 14) tissues even
after prolonged exposure (Fig. 1). Normal-appearing peritoneal samples
from patients with endometriosis (n = 6) biopsied during
laparoscopy were negative for 17ßHSD type 2 by Northern analysis
(Fig. 1). No differences were detected between eutopic endometrial
samples from patients with endometriosis and those from disease-free
women. Immunohistochemistry for 17ßHSD type 2
Type 2 17ßHSD was detected in eutopic endometrial glandular
epithelial cells in 11 of 13 secretory phase eutopic endometrial
samples. One of the negative endometrial samples was in the very early
secretory phase, and the other had evidence of chronic endometritis.
Immunoreactive 17ßHSD type 2 became detectable in the early secretory
phase and increased during the midsecretory phase, and the intensity of
staining was the highest in the late secretory phase. Immunoreactive
17ßHSD type 2 was detected in only 1 of 8 proliferative eutopic
endometrial samples. In this 1 sample, however, intensity of
immunostaining with 17ßHSD type 2 antibody was very low. In addition
to these, we also performed immunohistochemistry on simultaneously
biopsied samples of eutopic endometrium and pelvic extraovarian
endometriosis (n = 8). In these paired samples, no 17ßHSD type 2
was detected in proliferative phase eutopic endometrial or
endometriotic tissues (n = 4 pairs; Fig. 3). In secretory phase samples, however,
17ßHSD type 2 was detected in the glandular cells of all eutopic
endometrial specimens (n = 4), whereas the paired secretory phase
endometriotic tissues were negative for immunoreactive 17ßHSD type 2
(Fig. 3).
|
We hypothesized that deficient 17ßHSD type 2 expression in
the secretory endometriotic tissue may be due to deficient
progesterone action, as progesterone was
demonstrated to induce this enzyme in the eutopic endometrium (18, 21, 22). Thus, we determined immunoreactive PR and ER in simultaneously
obtained paired samples (n = 8) of eutopic endometrium and
endometriosis that were previously stained for 17ßHSD type 2.
Immunoreactive ER and PR were demonstrated in both glandular epithelial
and stromal cells regardless of the cycle phase in all samples of
eutopic endometrium and endometriosis (Fig. 4). No obvious differences in ER and PR
expression were observed between eutopic endometrial and endometriotic
tissues. Thus, it appears that differences in ER and PR expression do
not account for the differential expression of 17ßHSD type 2
expression in our samples.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
We also sought to demonstrate the presence or absence of a reductive-type 17ßHSD in the eutopic endometrium and endometriosis. To this end, we used RT-PCR and Northern analysis to detect mRNA species of two well defined reductive 17ßHSDs, namely type 1 and type 3, both of which are capable of catalyzing the conversion of estrone to 17ß-estradiol. RT-PCR gave rise to amplification of mRNAs for all three types of 17ßHSDs in both tissues regardless of the cycle phase. As mRNA levels detected by PCR may not be physiologically relevant, we resorted to Northern blotting, which demonstrated 17ßHSD type 1 mRNA in both eutopic endometrium and endometriosis during the proliferative and secretory phases. We concluded that the presence of a reductive enzyme, which catalyzes the conversion of locally produced estrone to the potent estrogen 17ß-estradiol, might be an important pathophysiological complement to aberrant aromatase expression in endometriosis for local estrogen production (5). The primary cell type that expresses 17ßHSD type 1 in the eutopic endometrium or endometriosis is not known yet. Studies are under way to address this question.
The most exciting finding was the absence of progesterone-induced 17ßHSD type 2 expression in epithelial cells of endometriotic tissues in contrast to those of the eutopic endometrium. This was demonstrated by Northern blotting and immunohistochemistry. Deficient expression of an enzyme that inactivates 17ß-estradiol in endometriosis is supportive of a model in which a number of aberrations (e.g. aromatase expression) in this tissue serve to maintain maximal local concentrations of 17ß-estradiol for prolonged periods.
The role of progesterone in the induction of 17ßHSD type 2 in the eutopic endometrium is evident from previous studies on estradiol dehydrogenase activity and 17ßHSD type 2 mRNA and protein expression, which were demonstrated only during the secretory phase (18, 19, 20, 21, 22). Thus, one may speculate that the absence of induction of 17ßHSD type 2 in secretory endometriotic samples may result from defective progesterone exposure or action in endometriosis. For example, very low levels of progesterone reaching the endometriotic lesions because of poor blood supply may give rise to a relative progesterone deficiency. However, histological changes in response to progesterone are routinely noted in endometriotic lesions, indicative of at least a partial response to progesterone. Thus, poor circulation in endometriotic implants is not a likely cause of progesterone deficiency in endometriosis. Impaired progesterone action on endometriosis may also be explicable in terms of selective defects in the signaling pathway, such as the quantity of PRs. In fact, several investigators have previously reported decreased ER and PR contents in endometriotic glandular cells compared with those in the eutopic endometrium, whereas others found the opposite (30, 31, 32, 33, 34, 35, 36). Moreover, a group of investigators found that the ER and PR contents of endometriotic implants do not undergo predictable changes in response to endogenous hormones (11). To determine whether deficient 17ßHSD type 2 expression in endometriotic epithelial cells is due to alterations in the ER/PR content, we localized these receptors by immunohistochemistry in simultaneously biopsied, paired samples of endometriosis and eutopic endometrium, which were previously used to study 17ßHSD type 2 expression. No apparent differences in ER and PR expression between these two groups were observed. This, however, did not exclude defective receptors or altered ratios of PR subtypes in endometriosis. The absence or presence of a PR coregulator that gives rise to inhibition of progesterone action on selected target genes in endometriotic epithelial cells is another exciting possibility. We would like to point out, however, that the number of samples used was small, and immunohistochemistry is not a suitable quantitative method to compare small differences between tissues. In summary, 17ßHSD type 2 deficiency in endometriotic tissues may give rise to higher local concentrations of 17ß-estradiol. Because progesterone inhibits and estrogen stimulates the growth of endometriotic implants, partial progesterone resistance in endometriosis may be a key event that is responsible for the growth properties and molecular aberrations in this tissue. This does not, however, preclude the response of the tissue to pharmacological or continuous levels of progesterone during treatment of endometriosis with progestins.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
Received June 2, 1998.
Revised August 27, 1998.
Accepted August 28, 1998.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
-hydroxysteroid dehydrogenase activity. J Biol
Chem. 268:12964–12969.-dihydroprogesterone dehydrogenase activities in human endometrium
during the menstrual cycle. Endocrinology. 94:419–423.-dihydroprogesterone dehydrogenase activities in human endometrial
glands and stroma: progestin induction of steroid dehydrogenase
activities in vitro is restricted to the glandular
epithelium. Endocrinology. 111:743–749.This article has been cited by other articles:
 |
|
 |
|
  A.G. Braundmeier and A.T. Fazleabas The non-human primate model of endometriosis: research and implications for fecundity Mol. Hum. Reprod., October 1, 2009; 15(10): 577 - 586. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. J. P. Jones, I. M. Inuwa, L. G. Nardo, P. Litta, and A. T. Fazleabas Eutopic Endometrium From Women With Endometriosis Shows Altered Ultrastructure and Glycosylation Compared to That From Healthy Controls--A Pilot Observational Study Reproductive Sciences, June 1, 2009; 16(6): 559 - 572. [Abstract] [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]
|
|
|
|
 |
|
 S. E. Bulun Endometriosis N. Engl. J. Med., January 15, 2009; 360(3): 268 - 279. [Full Text] [PDF]
|
|
|
|
|
|
S. A. Salama, M. W. Kamel, C. R. Diaz-Arrastia, X. Xu, T. D. Veenstra, S. Salih, S. K. Botting, and R. Kumar Effect of Tumor Necrosis Factor-{alpha} on Estrogen Metabolism and Endometrial Cells: Potential Physiological and Pathological Relevance J. Clin. Endocrinol. Metab., January 1, 2009; 94(1): 285 - 293. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. J. P. Jones, L. G. Nardo, P. Litta, and A. T. Fazleabas Ultrastructure of Ectopic Peritoneal Lesions From Women With Endometriosis, Including Observations on the Contribution of Coelomic Mesothelium Reproductive Sciences, January 1, 2009; 16(1): 43 - 55. [Abstract] [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]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
G. Hudelist, K. Czerwenka, J. Keckstein, C. Haas, A. Fink-Retter, D. Gschwantler-Kaulich, E. Kubista, and C.F. Singer Expression of Aromatase and Estrogen Sulfotransferase in Eutopic and Ectopic Endometrium: Evidence for Unbalanced Estradiol Production in Endometriosis Reproductive Sciences, December 1, 2007; 14(8): 798 - 805. [Abstract] [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]
|
|
|
|
|
|
A. Yuge, K. Nasu, H. Matsumoto, M. Nishida, and H. Narahara Collagen gel contractility is enhanced in human endometriotic stromal cells: a possible mechanism underlying the pathogenesis of endometriosis-associated fibrosis Hum. Reprod., April 1, 2007; 22(4): 938 - 944. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Husen, K. Huhtinen, T. Saloniemi, J. Messinger, H. H. Thole, and M. Poutanen Human Hydroxysteroid (17-{beta}) Dehydrogenase 1 Expression Enhances Estrogen Sensitivity of MCF-7 Breast Cancer Cell Xenografts Endocrinology, November 1, 2006; 147(11): 5333 - 5339. [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]
|
|
|
|
|
|
Y.-H. Cheng, A. Imir, T. Suzuki, V. Fenkci, B. Yilmaz, H. Sasano, and S. E. Bulun SP1 and SP3 Mediate Progesterone-Dependent Induction of the 17beta Hydroxysteroid Dehydrogenase Type 2 Gene in Human Endometrium Biol Reprod, October 1, 2006; 75(4): 605 - 614. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Grummer Animal models in endometriosis research Hum. Reprod. Update, September 1, 2006; 12(5): 641 - 649. [Abstract] [Full Text] [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]
|
|
|
|
|
|
I. Gashaw, J. M. Hastings, K. S. Jackson, E. Winterhager, and A. T. Fazleabas Induced Endometriosis in the Baboon (Papio anubis) Increases the Expression of the Proangiogenic Factor CYR61 (CCN1) in Eutopic and Ectopic Endometria Biol Reprod, June 1, 2006; 74(6): 1060 - 1066. [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]
|
|
|
|
 |
|
 S P Renner, R Strick, P Oppelt, P A Fasching, S Engel, R Baumann, M W Beckmann, and P L Strissel Evaluation of clinical parameters and estrogen receptor alpha gene polymorphisms for patients with endometriosis Reproduction, January 1, 2006; 131(1): 153 - 161. [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.-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]
|
|
|
|
|
|
K. Shazand, S. Baban, C. Prive, B. Malette, P. Croteau, M. Lagace, J.-B. Racine, and P. Hugo FOXO1 and c-jun transcription factors mRNA are modulated in endometriosis Mol. Hum. Reprod., December 1, 2004; 10(12): 871 - 877. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Kasai, M. Shozu, K. Murakami, T. Segawa, K. Shinohara, K. Nomura, and M. Inoue Increased Expression of Type I 17{beta}-Hydroxysteroid Dehydrogenase Enhances in Situ Production of Estradiol in Uterine Leiomyoma J. Clin. Endocrinol. Metab., November 1, 2004; 89(11): 5661 - 5668. [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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
L. C. Kao, A. Germeyer, S. Tulac, S. Lobo, J. P. Yang, R. N. Taylor, K. Osteen, B. A. Lessey, and L. C. Giudice Expression Profiling of Endometrium from Women with Endometriosis Reveals Candidate Genes for Disease-Based Implantation Failure and Infertility Endocrinology, July 1, 2003; 144(7): 2870 - 2881. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. L. Bruner-Tran, E. Eisenberg, G. R. Yeaman, T. A. Anderson, J. McBean, and K. G. Osteen Steroid and Cytokine Regulation of Matrix Metalloproteinase Expression in Endometriosis and the Establishment of Experimental Endometriosis in Nude Mice J. Clin. Endocrinol. Metab., October 1, 2002; 87(10): 4782 - 4791. [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]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 S. Yang, Z. Fang, B. Gurates, M. Tamura, J. Miller, K. Ferrer, and S. E. Bulun Stromal PRs Mediate Induction of 17{beta}-Hydroxysteroid Dehydrogenase Type 2 Expression in Human Endometrial Epithelium: A Paracrine Mechanism for Inactivation Of E2 Mol. Endocrinol., December 1, 2001; 15(12): 2093 - 2105. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Utsunomiya, T. Suzuki, C. Kaneko, J. Takeyama, J. Nakamura, K. Kimura, M. Yoshihama, N. Harada, K. Ito, R. Konno, et al. The Analyses of 17{beta}-Hydroxysteroid Dehydrogenase Isozymes in Human Endometrial Hyperplasia and Carcinoma J. Clin. Endocrinol. Metab., July 1, 2001; 86(7): 3436 - 3443. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Ito, T. Suzuki, T. Moriya, H. Utsunomiya, A. Sugawara, R. Konno, S. Sato, and H. Sasano Retinoid Receptors in the Human Endometrium and Its Disorders: A Possible Modulator of 17{beta}-Hydroxysteroid Dehydrogenase J. Clin. Endocrinol. Metab., June 1, 2001; 86(6): 2721 - 2727. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Kitawaki, H. Koshiba, H. Ishihara, I. Kusuki, K. Tsukamoto, and H. Honjo Progesterone Induction of 17{beta}-Hydroxysteroid Dehydrogenase Type 2 during the Secretory Phase Occurs in the Endometrium of Estrogen-Dependent Benign Diseases But Not in Normal Endometrium J. Clin. Endocrinol. Metab., September 1, 2000; 85(9): 3292 - 3296. [Abstract] [Full Text]
|
|
|
|
|
|
G. R. ATTIA, K. ZEITOUN, D. EDWARDS, A. JOHNS, B. R. CARR, and S. E. BULUN Progesterone Receptor Isoform A But Not B Is Expressed in Endometriosis J. Clin. Endocrinol. Metab., August 1, 2000; 85(8): 2897 - 2902. [Abstract] [Full Text]
|
|
|
|
|
|
G. Leyendecker Redefining endometriosis: Endometriosis is an entity with extreme pleiomorphism Hum. Reprod., January 1, 2000; 15(1): 4 - 7. [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 |
