| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Other Original Studies |
Departments of Obstetrics and Gynecology (K.I., H.U., R.K., S.S.), Pathology (T.S., T.M., H.S.), and Medicine II (A.S.), Tohoku University School of Medicine, Sendai 980-8557, Japan
Address all correspondence and requests for reprints to: Kiyoshi Ito, M.D., Department of Obstetrics and Gynecology, Tohoku University School of Medicine, 1-1 Seiryo-Machi, Aoba-ku, Sendai 980-8557, Japan. E-mail: kito{at}ob-gy.med.tohoku.ac.jp
Abstract
Retinoids have recently been proposed to modulate estrogenic actions in
various sex steroid-dependent neoplasms, but little has been studied in
human endometrial disorders. Therefore, in this study, we first
examined the immunolocalization of retinoic acid receptor 
, ß, and
, and retinoid X receptor (RXR) , ß, and in 20
normal cycling human endometria, 34 endometrial hyperplasia, and 46
endometrioid endometrial adenocarcinomas. We then correlated these
findings with other clinicopathological parameters, especially in the
correlation between retinoid receptor subtypes and the status of
steroid hormone receptors, 17ß-hydroxysteroid dehydrogenase
(17ß-HSD) and aromatase. We also then examined the effects of
retinoic acid on the expression of 17ß-HSD type 2 in cell lines
derived from endometrial carcinoma using Northern blotting analysis to
examine the possible roles of retinoids in in situ
endometrial estrogen metabolism. Among these six retinoid receptors
examined, RXR immunoreactivity was exclusively detected in the
epithelial cells of the secretory phase endometrium but not of the
proliferative phase, which was well correlated with 17ß-HSD type 2
immunolocalization. However, in endometrial hyperplasia, RXR was not
correlated with 17ß-HSD type 2. In endometrioid endometrial
adenocarcinoma, there was a statistically significant correlation
between 17ß-HSD type 2 immunoreactivity and RXR labeling index
(LI) (P < 0.001) and between RXR LI and
progesterone receptor LI (r = 0.501, P =
0.003).
A significant inverse correlation was also detected between RXR LI
and patient age (r = 0.449, P = 0.015). No
statistically significant correlation was obtained between LIs of
receptors and other clinicopathological parameters including the status
of intratumoral aromatase examined by immunohistochemistry. In the
endometrial carcinoma cell line, RL95–2, retinoic acid markedly
increased the level of 17ß-HSD type 2 messenger RNA in a time- and
dose-dependent manner. These results all suggest that retinoic acids
may be involved in modulation of in situ estrogen
metabolism in both normal and neoplastic human endometrium possibly
through RXR by stimulating the expression of 17ß-HSD type 2.
ENDOMETRIAL CARCINOMA IS one of the most common female pelvic malignancies in the world, and its incidence has recently increased (1, 2). Previous clinical, biological, and epidemiological findings all suggest that prolonged or unopposed estrogenic stimulation increased the risk of endometrial carcinoma, especially of the endometrioid type (3, 4). However, there has been no consistent evidence of increased serum estrogen concentrations in women with endometrial disorders (5, 6, 7). Recently, in situ estrogen metabolism and synthesis have been considered to play a very important role in the development and progression of various human steroid hormone-dependent epithelial neoplasms, including endometrial carcinoma (8). It therefore becomes very important to study the expression and/or regulation of the enzymes involved in in situ estrogen metabolism in human endometrial malignancy to understand its local hormonal involvement. Among these enzymes, aromatase, which catalyzes the conversion of androgens to estrogens, and 17ß hydroxysteroid dehydrogenase (17ß-HSD) isozymes, which catalyze the interconversion of E2 and estrone (E1), are two principal enzymes involved in the formation (9, 10, 11).
Retinoids, metabolites of vitamin A, have been recently demonstrated to
play very important roles in in situ estrogen metabolism
through the regulation of steroid hormone receptors and17ß-HSD. The
possible therapeutic implications related to this property have been
proposed in human breast cancer (12, 13, 14, 15, 16). Retinoids are
known to exert their effects through their binding to specific
receptors and subsequent modulation of specific gene expression in
their target tissues. Roma et al. (13) reported
that estrogen receptor (ER)-positive breast cancer cell lines
express significantly higher levels of retinoic acid receptors (RAR)
than ER-negative cell lines. They also reported a significant
correlation between RAR and ER in human breast cancer tissues
(13). Reed et al. (14) also
reported that retinoic acid increases the expression of 17ß-HSD type
1 messenger RNA (mRNA) and reductive activity in breast cancer cell
lines. Suzuki et al. (15) reported a
significant correlation between RAR and 17ß-HSD type 1 expression
in human breast carcinoma. These data all suggest that retinoids may
modulate in situ estrogen metabolism through their receptors
in estrogen receptor-positive human breast carcinomas, possibly through
RAR.
In the normal human endometrium, intracellular retinoic acid
concentrations in both epithelial and stromal cells are elevated during
the secretory phase (17). Kumarendran et al.
(18) also reported the presence of the mRNA expression of
RAR, RARß, RAR, and RXR (retinoid X receptor) using
Northern blotting in normal human endometrium. Siddiqui et
al. (19) then reported the presence of RAR and RXR
mRNA using Northern blotting in endometrioid endometrial carcinoma.
However, the details of the status of these retinoid receptors and the
correlation between retinoid receptors and local estrogenic metabolism
has not been studied in the human endometrium and its disorders.
Therefore, in this study we first examined the cellular localization of RARs and RXRs using immunohistochemistry. We then correlated these findings with clinicopathological parameters, including the status of steroid hormone receptors, 17ß-HSD type 2 and aromatase, in the human endometrium and its disorders to study the possible roles and regulatory mechanism of retinoids in in situ estrogen metabolism. Using endometrial cancer cell lines, we also examined the effects of retinoids on 17ß-HSD type 2 mRNA expression for further analysis.
Materials and Methods
Patients and tissues
Twenty normal-cycling human endometria (41 ± 3.7 yr old), 33 endometrial hyperplasias (42 ± 9.2 yr old), and 46 endometrial endometrioid adenocarcinomas (58 ± 9.8 yr old; grade 1: 23 cases; grade 2: 14 cases; grade 3: 9 cases) were retrieved from the surgical pathology files of Tohoku University Hospital, Sendai, Japan. None of these patients had received preoperative chemotherapy or pelvic radiation. The lesions were classified according to the Histological Typing of Female Genital Tract Tumors by the World Health Organization and staged according to the International Federation of Gynecology and Obstetrics system (20, 21). All specimens were routinely processed (i.e., 10% formalin fixed for 24–48 h), paraffin embedded, and thin sectioned (3 µm).
Antibodies
Polyclonal antibodies for RAR (sc-551), RARß (sc-552),
RAR (sc550) were purchased (Santa Cruz Biotechnology,
Santa Cruz, CA). Polyclonal antibodies for RXR, RXRß, and
RXR were raised against synthetic peptides containing the following
mouse RXR amino acid residues: RXR 92–109; RXRß 78–93; RXR
35–54. The characterization of the RXR antibodies was confirmed by
Western blotting and immunoprecipitation as described previously
(22), and utilization of these antibodies for
immunohistochemistry was also reported previously
(23).
The monoclonal antibody of 17ß-HSD type 2, mAB-C2–12, was produced by immunizing mice with a synthetic carboxyl-terminal peptide corresponding to amino acids 375–387 of 17ß-HSD type 2 and was provided by Dr. S. Andersson, University of Texas Southwestern Medical Center, Dallas, TX (24). Aromatase antibody was prepared against enzyme purified from human placenta and was provided by Dr. N. Harada, Fujita-Gakuen Health University, Toyoake, Japan (25).
The monoclonal antibody for progesterone receptor (PR)
(Chemicon, Temecula, CA) and the monoclonal antibody for
ER (Immunotech, Marseille, France) were used.
Immunohistochemistry
Immunohistochemical analysis was performed employing the streptavidin-biotin amplification method using a Histofine kit (Nichirei, Tokyo, Japan) and has been previously described in detail (26). Tissue sections of full-term placenta were used as positive controls for 17ß-HSD type 2. Human breast carcinoma was used as a positive control for retinoid and steroid receptors. As a negative control, normal rabbit or mouse IgG was used instead of the primary antibodies. In RXRs, immunohistochemical preabsorption tests were also performed. No specific immunoreactivity was detected in these tissue sections.
Semiquantitative analysis of immunohistochemical staining
In retinoid receptors, ERs, and PRs, more than 500 glandular or carcinoma cells were counted in each case by two of the authors (K.I. and T.S.) independently, after reviewing the slides and determining the areas of evaluation simultaneously, using a double-headed microscope. The percentage of immunoreactivity (i.e., labeling index [LI]) was subsequently determined. Cases with interobserver differences of more than 5%, which occurred in 3–7% of the cases examined were re-evaluated together using double-headed microscopy. Intraobserver differences were less than 5% when examining the same selected fields of representative cases. The mean value was obtained in cases with interobserver differences of less than 5%. For 17ß-HSD type 2 immunostaining, glandular or carcinoma cells were divided into the following three groups: 2+: more than 50% positive cells, +: 0–50% positive cells; -: no immunoreactivity, based on the report by Sasano et al. (23). For aromatase immunostaining, the findings were also classified as follows according to Watanabe et al. (9). The aromatase-positive stromal cells were divided into the following three groups: 1), 0–5%; 2), 5–25%; and 3) more than 25% of cells positive for aromatase. Evaluation of immunoreactivity of these steroidogenic enzymes was performed in the same manner as that of the nuclear antigen described above.
Statistical analysis
Statistical analyses among LIs of retinoid receptors, ERs, PRs, and KI-67, and patient age were performed by the correlation coefficient (r) and the regression equation. Association between LIs of retinoid receptors and 17ß-HSD immunoreactivity, stage, and histological grade were all evaluated using a Bonferroni test. P values less than 0.05 were considered significant. We corrected the data with a Bonfferoni post hoc test, and multiple correlations were performed among clinicopathological parameters.
Cell culture
We examined five human endometrial cancer cell lines in this study: RL95–2, HEC-1A, HEC1-B, and KLE, obtained from the American Type Culture Collection (Manassas, VA), and the Ishikawa cell line provided by Dr. Sakurada (Department of Thoracic Surgery, Institute of Development, Aging and Cancer, Sendai, Japan). The cells were cultured with Ham F12: DMEM (1:1, vol/vol) containing 10% FBS and passed at confluence to plastic culture dishes (100-mm diameter; Becton Dickinson and Co. Lincoln Park, NJ) for 17ß-HSD type 2 mRNA analyses.
RNA extraction and Northern blot analysis
Total cellular RNA was extracted with lithium chlolide/urea from cells grown in monolayers according to the method of Chirgwin et al. (27). Total RNA (10 µg/lane) was size fractionated by electrophoresis on formaldehyde-agarose (1%) gels and transferred electrophoretically to a nylon membrane. A P-32–labeled 17ß-HSD type 2 complementary DNA was employed as a probe provided by Dr. S. Anderson (University of Texas Southwestern Medical Center, Dallas, TX). An oligonucleotide probe of glyceraldehyde-3-phosphate dehydrogenase (G3PDH; 24-mer) was used as an internal standard. Specific radioactivity was assayed by AMBIS radioanalytic imaging system (AMBIS Inc., San Diego, CA). The mRNA level of 17ß-HSD type 2 was evaluated as the ratio of the radiointensity, compared with that of G3PDH and is expressed as percent change, compared with the control.
Total RNA (10 µg/lane) of nontreated RL95–2, HEC-1A, HEC-1B, KLE, and Ishikawa cells was evaluated by Northern analyses for 17ß-HSD type 2. Next, for checking the effects of RA derivatives and ligands for RA receptors on the level of 17ß-HSD type 2 mRNA in RL95–2 cells, cells were treated with three RA derivatives (t-RA, 13-cis-RA, and 9-cis-RA) and two RA receptor selective RA agonists (TTNPB for RAR and LG69 for RXR, 1 µM for each) for 32 h.
For evaluating the dose response to t-RA and 13-cis-RA on the levels of 17ß-HSD type 2 mRNA in RL95–2 cells, the cells were treated with t-RA (closed bars) or 13-cis-RA (open bar) in six different concentrations (0, 1 nM, 10 nM, 100 nM, 1 µM, and 10 µM) for 32 h. The levels of 17ß-HSD type 2 mRNA were evaluated as percent change, compared with the control (nontreatment for 32 h). Then for confirming time course of t-RA action on the level of 17ß-HSD type 2 mRNA in RL95–2 cells, the cells were treated with (closed circles) or without (open circles) t-RA (1 µM) for 0, 2, 4, 8, 16, 32, and 64 h. The levels of 17ß-HSD type 2 mRNA were evaluated as percent change, compared with those of nontreated cells.
Results
Normal cycling endometrium
RAR,ß, and RXR,ß, immunoreactivities were all
detected in the nuclei of some endometrial stromal cells throughout the
phases of the menstrual cycle. RAR and RXR, immunoreactivities
were detected in the nuclei of 60–70% of stromal cells, whereas
RARß, and RXRß immunoreactivities were present in the nuclei of
3–5% of stromal cells throughout the phases of the menstrual cycle.
RAR and RXRß immunoreactivity was not detected in any of the
epithelial cells examined. RAR, RARß, and RXR immunoreactivity
was detected in the nuclei of epithelial cells throughout all menstrual
phases. RXR immunoreactivity was detected in the nuclei of
epithelial cells of the secretory phase endometrium but not of the
proliferative phase (Fig. 1
, A and
B).
|
Endometrial hyperplasia
Results are summarized in Table 1.
Immunoreactivity for retinoid receptors was detected in the nuclei of
both epithelial and stromal cells. RAR,ß, and RXR,ß,
immunoreactivity was detected in all the nuclei of some stromal cells
in all the cases examined. RAR and RXR, immunoreactivities
were detected in the nuclei of 30–50% of stromal cells, whereas
RARß, and RXRß immunoreactivities were present in the nuclei of
3–5% of stromal cells. RAR, RARß, RXR, and RXR
immunoreactivity was detected in all the nuclei of hyperplastic glands.
17ß-HSD type 2 immunoreactivity was detected in 24/33 cases (72.7%).
17ß-HSD type 2 immunoreactivity tended to be correlated with RXR
LI, but the correlation did not reach statistical significance
(P = 0.2). No significant correlation was detected
between retinoid receptor immunoreactivity and ER LI; PR LI; age; or
histological classification including simple, complex, and atypical
endometrial hyperplasia (data not shown). Aromatase immunoreactivity
was undetected in all of the cases examined.
|
Results are summarized in Table 1
. RAR and RXR immunoreactivity
was not detected in stromal cells in all the cases examined. RAR,
RARß, RXR, and RXR immunoreactivity was detected in the nuclei
of carcinoma cells (Fig. 2A). Marked
aromatase immunoreactivity was detected in stromal cells in 50% of the
cases of endometrial carcinoma, especially at the sites of frank
invasion.
|
immunopositive carcinoma cells were also positive
for 17ß-HSD type 2 (Fig. 2, A and B). In addition, a statistically
significant correlation was detected between 17ß-HSD type 2
immunoreactivity and RXR LI (P < 0.001) (Fig. 3). A significant positive correlation
was also detected between RXR LI and PR LI (r = 0.501,
P = 0.003) (Fig. 4). A
significant inverse correlation was also detected between RXR LI and
patient age (r = 0.449, P = 0.015). No
statistically significant correlation was obtained between LIs of any
other retinoid receptor subtypes and other clinicopathological
parameters, including the status of aromatase immunoreactivity, ER LI,
clinical stage, and histological grade (data not shown).
|
|
Cell culture
17ß-HSD type 2 mRNA was detected in RL95–2 and HEC-1A cells but
not in the other endometrial cancer cell line. The level of 17ß-HSD
type 2 mRNA, as detected by densitometry in Northern blots, in RL95–2
cells was approximately 100 times more than that of HEC-1A cell. We
therefore evaluated the effects of RA on the level of 17ß-HSD type 2
mRNA in RL95–2 cells. Results of the effects of various RA derivatives
and ligands for RA receptors employed in this study on the level of
17ß-HSD type 2 mRNA in RL95–2 cells are shown in Fig. 5A. The relative level of induction of
17ß-HSD type 2 mRNA, compared with controls, determined by
densitometry was as follows: t-RA: 7.1, 13-cis-RA: 9.2,
9-cis-RA: 9.1, TTNPB: 7.9, LG69: 3.0 (Fig. 5B).
Dose-response experiments on the level of 17ß-HSD type 2 mRNA by t-RA
and 13-cis-RA in RL95–2 cells revealed that the level of
17ß-HSD type 2 mRNA was increased in a dose-dependent manner by t-RA
and 13-cis-RA (Fig. 6A). Time
course of t-RA on the level of 17ß-HSD type 2 mRNA is also summarized
in Fig. 6B. T-R- induced 17ß-HSD type 2 mRNA in a time-dependent
manner for up to 32 h. After 32 h of treatment, the level of
17ß-HSD type 2 mRNA was still 4.9-fold greater than that of
nontreated cells.
|
|
In this study, we examined the localization of all six subtypes of
retinoid receptors in human endometrium and its disorders. Among these
receptor subtypes, RAR, RARß, RXR, and RXR were widely
distributed, compared with other retinoid receptor subtypes, in both
neoplastic and nonneoplastic human endometrium. Especially,
immunoreactivity for RAR, RARß, and RXR was widely distributed
in both epithelial and stromal cells of endometrial tissues throughout
the menstrual cycle. The fact that these receptors were present in the
stromal cells of normal endometrium and hyperplasia but not in
endometrial carcinoma suggests possible alterations of characteristics
of stromal cells and/or fibroblasts because of stromal invasion. We
then examined the possible correlation between patterns of retinoid
receptor immunolocalization and in situ estrogen metabolism
and actions. In normal endometrium, Casey et al.
(28) and Zeitoun et al. (29)
reported that 17ß-HSD type 2 mRNA was markedly expressed in
endometrial glandural epithelial cells during the secretory phase but
not during the proliferative phase. Mustonen et al.
(30) also reported the same results using mRNA in
situ hybridization. On the other hand, 17ß-HSD type 1 mRNA was
reported to be expressed at very low levels, compared with 17ß-HSD
type 2 mRNA in normal endometrium (31). In our study,
17ß-HSD type 2 immunoreactivity was also detected only in the
cytoplasm of epithelial cells in the secretory phase endometrium and
not in the proliferative phase. Intracellular retinoic acid
concentrations in both epithelial and stromal cells of endometrial
mucosa are considered to be elevated during the secretory phase because
of a marked reduction of cellular retinoic acid-binding protein type II
mRNA (17). In normal endometrium, RXR was detected only
in the secretory phase among retinoid receptor subtypes examined. These
results all indicated that increased retinoic acid concentrations are
considered to exert their effects on secretory phase mucosa, possibly
through RXR.
We therefore further characterized the possible correlation between
retinoids and their receptors and 17ß-HSD type 2 in endometrial
disorders. Among retinoid receptor subtypes, the status of RXR
tended to be correlated with 17ß-HSD type 2 in endometrial
hyperplasia, although not statistically significant. A significant
positive correlation was, however, detected between RXR LI and
17ß-HSD type 2 immunoreactivity (P < 0.001) in
endometrial carcinoma. There were no correlations between the status of
retinoid receptor subtypes and aromatase and/or estrogen receptor
status in patients diagnosed with endometrial cancer. These findings
suggest that among the factors that influence in situ
estrogen metabolism and actions, the status of RXR was correlated
with that of 17ß-HSD type 2 at least in normal and neoplastic
endometrium. These results also suggest that the possible effects of
retinoids on in situ steroid metabolism in the human
endometrium and its disorders may be mediated through modulation of
17ß-HSD type 2 expression and/or activity.
We then examined the effects of retinoids on the expression of
17ß-HSD type 2 mRNA in cell lines derived from human endometrial
carcinoma based on these findings above. In our present study,
17ß-HSD type 2 mRNA was detected in RL95–2 and HEC-1A cell lines,
but its level was much greater in RL95–2. Variability in the
expression of 17ß-HSD type 2 by retinoic acid in endometrial
carcinoma cells may reflect the characteristics and differentiation of
endometrial epithelial cells from which the tumor arose. We therefore
examined the various effects of retinoids on 17ß-HSD type 2 mRNA
expression using this cell line. Retinoic acid derivatives and
selective RA receptor agonists increased the level of 17ß-HSD type 2
mRNA in RL95–2 cells in both a time- and dose-dependent manner.
However, the induction by LG69, a selective RXR agonist was
approximately 0.38 times that of TTNPB, a RAR agonist, which is not
necessarily consistent with the correlation between RXR and
17ß-HSD type 2 in endometrial carcinoma cases. These findings suggest
that retinoid actions through RXR alone may not be sufficient to
induce 17ß-HSD type2 mRNA. Retinoid actions through the RXR-RAR
complex may be important for this induction, but further investigations
are required to clarify these discrepancies.
No other correlations were detected between retinoid receptors and ER
and aromatase. These results all suggest that retinoids influence
in situ estrogen metabolism of both normal and neoplastic
human endometrium on the expression of 17ß-HSD type 2. A significant
correlation was also detected between RXR and PR LI
(P = 0.003) in endometrioid endometrial
adenocarcinomas. In the human breast cancer cell line, T-47D, RA
treatment induced a decrease in the cellular PR concentration by
decreasing the amounts of its receptor mRNA and protein, suggesting
that RA is capable of modulating sensitivity to progestins
(32). Savouret et al. (33)
demonstrated that transcriptional progesterone receptor gene expression
was induced by estrogens and decreased by progestins and RA. In our
study, a significant inverse correlation was also detected between
RXR LI and patient age (r = 0.449, P = 0.015);
RXR LI was markedly decreased in patients older than 50 yr old,
which may also be due to the decrement of progesterone following
menopause. Retinoids are considered to be effective as chemopreventive
and chemotherapeutic agents in a variety of human epithelial and
hematopoietic neoplasms (12, 34, 35). Kudelka et
al. (35) reported the favorable results obtained with
RA-based treatment of patients with cisplatin-resistant metastatic
endometrial adenocarcinoma. These clinical effects of retinoids may be
partly due to increased 17ß-HSD type 2 mRNA expression in carcinoma
cells, which results in the decreased in situ availability
of biologically active estrogen, and the stimulation of PR expression.
This may also reduce tumor cell proliferation through RXR, but it
awaits further investigation such as possible inhibition of other
subtypes of 17ß-HSD including type 1 and type 3 and the correlation
of the findings with percentage of body fat mass of individual patients
for clarification.
Footnotes
1 This work is supported in part by the grant-in-aid for Cancer
Research 7-1 from the Ministry of Health and Welfare, Japan; a
grant-in-aid for scientific area on priority area (A-11137301) from the
Ministry of Education, Science, and Culture, Japan; a grant-in-aid for
Scientific Research (B-11470047) from the Japan Society for the
Promotion of Science; and a grant from the Naitou Foundation and
Suzukenn Memorial Foundation. 
Received June 20, 2000.
Revised September 12, 2000.
Accepted February 12, 2001.
References
-hydroxysteroid dehydrogenase activity. J Biol
Chem. 268:12964–12969.This article has been cited by other articles:
 |
|
 |
|
  Z. Shen, T. Saloniemi, A. Ronnblad, P. Jarvensivu, P. Pakarinen, and M. Poutanen Sex Steroid-Dependent and -Independent Action of Hydroxysteroid (17{beta}) Dehydrogenase 2: Evidence from Transgenic Female Mice Endocrinology, November 1, 2009; 150(11): 4941 - 4949. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Terao, M. Kurosaki, M. M. Barzago, M. Fratelli, R. Bagnati, A. Bastone, C. Giudice, E. Scanziani, A. Mancuso, C. Tiveron, et al. Role of the Molybdoflavoenzyme Aldehyde Oxidase Homolog 2 in the Biosynthesis of Retinoic Acid: Generation and Characterization of a Knockout Mouse Mol. Cell. Biol., January 15, 2009; 29(2): 357 - 377. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y.-H. Cheng, P. Yin, Q. Xue, B. Yilmaz, M. I. Dawson, and S. E. Bulun Retinoic Acid (RA) Regulates 17{beta}-Hydroxysteroid Dehydrogenase Type 2 Expression in Endometrium: Interaction of RA Receptors with Specificity Protein (SP) 1/SP3 for Estradiol Metabolism J. Clin. Endocrinol. Metab., May 1, 2008; 93(5): 1915 - 1923. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Rantakari, L. Strauss, R. Kiviranta, H. Lagerbohm, J. Paviala, I. Holopainen, S. Vainio, P. Pakarinen, and M. Poutanen Placenta Defects and Embryonic Lethality Resulting from Disruption of Mouse Hydroxysteroid (17-{beta}) Dehydrogenase 2 Gene Mol. Endocrinol., March 1, 2008; 22(3): 665 - 675. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. J Su, Y.-H. Cheng, R. T Chatterton, Z.-H. Lin, P. Yin, S. Reierstad, J. Innes, and S. E Bulun Regulation of 17-Beta Hydroxysteroid Dehydrogenase Type 2 in Human Placental Endothelial Cells Biol Reprod, September 1, 2007; 77(3): 517 - 525. [Abstract] [Full Text] [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]
|
|
|
|
 |
|
 K. Ota, K. Ito, T. Suzuki, S. Saito, M. Tamura, S.-i. Hayashi, K. Okamura, H. Sasano, and N. Yaegashi Peroxisome Proliferator-Activated Receptor {gamma} and Growth Inhibition by Its Ligands in Uterine Endometrial Carcinoma. Clin. Cancer Res., July 15, 2006; 12(14): 4200 - 4208. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Ito, T. Suzuki, J.-i. Akahira, M. Sakuma, S. Saitou, S. Okamoto, H. Niikura, K. Okamura, N. Yaegashi, H. Sasano, et al. 14-3-3{sigma} in Endometrial Cancer-A Possible Prognostic Marker in Early-Stage Cancer Clin. Cancer Res., October 15, 2005; 11(20): 7384 - 7391. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Vienonen, S. Miettinen, M. Blauer, P. M. Martikainen, E. Tomas, P. K. Heinonen, and T. Ylikomi Expression of Nuclear Receptors and Cofacotrs in Human Endometrium and Myometrium Reproductive Sciences, February 1, 2004; 11(2): 104 - 112. [Abstract] [PDF]
|
|
|
|
|
|
X.-H. Li, H. Li, Z.-J. Xiao, and Y.-S. Piao Divergent Effects of Retinoic Acids on the Expression of ER{alpha} and 17{beta}-Hydroxysteroid Dehydrogenase Type 2 in Endometrial Carcinoma Cells (RL 95-2) J. Clin. Endocrinol. Metab., February 1, 2002; 87(2): 640 - 649. [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 |
