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Original Studies |
Institut National de la Santé et de la Recherche Médicale U460, Centre Hospitalo-Universitaire Xavier Bichat, 75018 Paris Cedex, France
Address correspondence and requests for reprints to: Martine Perrot-Applanat, M.D., INSERM U554, Hôpital St. Louis/Bát INSERM, 1 Avenue Claude Vellefaux, 75475 Paris Cedex 10, France. E-mail: applanat{at}bichat.inserm.fr
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Abstract |
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in the endometrial functional zone.
Using immunocytochemistry with well characterized polyclonal antibodies
against ERß, we have detected specific ERß expression in all
endometrial compartments (glandular, stromal, and vascular); the
specificity of the immunostaining is confirmed by lack of staining of
the uterine sections with anti-ERß antibodies previously incubated
with peptide preparation. The highest levels of ERß expression are
observed in epithelial cells during the periovulatory period (days 14
and 15), as well as in stromal cells and cells of the vascular wall in
the late-secretory phase; both smooth muscle cells and endothelial
cells express ERß, as deduced from immunocytochemistry and RT-PCR
analysis. ERß staining is usually low compared with that of ER,
except at days 24–26. The presence of ERß in decidualized stromal
cells is deduced from immunocytochemistry using antismooth -actin
and anti-ERß antibodies or from RT-PCR analysis of ERß and
insulin-like growth factor-BP transcripts in the same cells; the
presence of ERß-positive stromal cells located close to vascular
smooth muscle cells during this period suggests some specific role of
this receptor during decidualization. ER is also present in the
cells of the endometrial vascular wall, in addition to the nuclei of
glandular epithelial and stromal cells. Vascular ER expression is
highest during the periovulatory period, suggesting a regulation by
estradiol, and a role in vascular function. Moreover, different
variations of ERß and ER in arterioles might have implications for
the modulation of vascular function, possibly of vascular tone, during
the menstrual cycle. Finally, these data suggest that ERß may have
important roles in endometrial function, in addition to the well known
role of ER in endometrial proliferation and differentiation. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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) and has been shown to stimulate
transcription of an ER target gene (7). The most
significant disparity between the two receptors lies in their tissue
distribution; ER messenger RNAs (mRNAs) are predominant in the
uterus, mammary gland, testis, pituitary, liver, kidney, heart, and
skeletal muscle, whereas ERß mRNAs are significantly expressed in the
ovary and prostate (8, 9). These studies lead to the
conclusion that there is a low to absent expression of ERß in the
uterus, at least in the mouse (8), in agreement with some
studies reporting insensitivity to estradiol (E2), with
respect to its effects on water imbibition, RNA and DNA synthesis, and
mitosis of the glandular and stromal compartment in ER knockout mice
(ERKO) (10, 11). However, the reported preservation of
other selective estrogen actions in the ERKO uterus, such as
induction of secretory products by the cateholestrogen
4-hydroxyestradiol (12), reinforces the need for studies
about the exact endometrial distribution of the two distinct ERs.
Few studies have reported the presence of ERß transcripts in the
human endometrium (13, 14), whereas immunocytochemical
detection in the uterine compartments has proven difficult in the past
owing to the lack of available antibodies against ERß. In the present
study, we investigated the expression of ERß in the human cyclic
endometrium, using immunocytochemistry with previously characterized
polyclonal anti-ERß antibodies (15, 16), and determined
the relative expression of ER and ERß in each cell
compartment.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Endometrial biopsies were obtained from 35 cycling women (age, 22–45 yr) undergoing routine gynecological investigations in Bari University Hospital in Italy. The selected patients had no evident endocrinological problems and had normal endometrial histology; none of the patients had taken hormonal medication for at least 6 months before surgery. Informed consent was obtained from each patient, and the study was approved by the local ethical commitee. Specimens of endometrium were obtained in the proliferative (n = 13), secretory (n = 18), and menstrual (n = 4) phases of the cycle. Endometrial dating criteria and independent histological examination were used to assess the phase of menstrual cycle (17). All tissues were fixed in 4% buffered paraformaldehyde and embedded in paraffin.
Immunocytochemistry
Paraffin sections of 5-µm thickness were routinely processed
and mounted on Superfrost+ glass slides. Immunocytochemistry of
E2 receptor(s) was performed as described previously
(17, 18), with the following modifications. Previous to
immunocytochemical staining, antigen retrieval was performed on the
paraffin sections by microwaving for 15 min in 0.1 M glycine-EDTA
buffer (pH 3.15). The immunocytochemical staining included overnight
incubation at 4 C with a mouse monoclonal antibody raised against the
67-kDa polypeptide chain of ER (clone 1D5; Immunotech, Marseille,
France) or affinity-purified sheep anti-ERß receptor antibodies (a
generous gift from P. Saunders; Ref. 15), followed by incubation with
biotinylated antimouse or antisheep IgG and streptavidin-peroxidase
(LSAB+ immunostaining kit; Dakopatts, Glostrup, Denmark). Peroxidase
reaction was performed using amino-ethylcarbazole substrate
(Sigma, St. Louis, MO), as described previously
(18). Some sections were lightly counterstained with
Meyer’s hematoxylin. Each immunoreaction was performed twice in
triplicate. A commercially available goat anti-ERß antibody
(Santa Cruz Biotechnologies, Santa Cruz, CA) was also used
in some experiments with comparable results in ERß distribution.
The following controls were performed: preincubation of anti-ERß
antibody with increasing amounts of purified recombinant peptide (a
gift from P. Saunders; 1–100 µg/µL diluted antibody) for 12 h
at 4 C before immunostaining; omission of the first antibody, and
finally incubation of tissue sections with nonimmune mouse (DAKO Corp.) or sheep IgG (Serotec, Oxford, UK).
Tissue sections of ERß-positive prostatic adenoma and of an
ER-positive mammary adenocarcinoma were used as positive
controls.
Adjacent sections were incubated with a marker of vascular endothelial
cells, the polyclonal anti-Von Willebrand factor antibody (DAKO A/S, Glostrup, Denmark), or with a monoclonal antismooth
-actin antibody (Sigma) to identify smooth muscle cells
of the vascular wall and decidualized stromal cells, as described
previously (19, 20).
Evaluation of immunostaining and nuclear counting
Both staining intensity and number of stained cells in the endometrial functional zone were evaluated. The relative intensity of the immunoreaction product on the whole section was graded blindly by three independent observers (G.L., G.M., and M.P.-A.) using a light microscope Axiophot (Zeiss, Oberkochen, Germany) at a x100 and x200 magnification; it was estimated semiquantitatively on a scale of 0–3+ as: -, no detectable stain; -/+, faint; +, moderate; ++, strong; and +++, very intense staining, as described previously (18, 20, 21). To quantify the number of immunopositive cells, immunostained nuclei were counted separately in glandular, stromal, and vascular cells of the functional zone, using a microscope (Leitz, Orthoplan) equipped with a color CDD video camera. Five different fields in each section (x16 objective, 0.322 mm2 per field) were digitized by image analysis and computerized using the Histolab program (Microvision, Evry, France), as described previously (18). Nuclear counts were assessed blindly for each section. Values were expressed as means/per unit area ± SEM. Measurements were tested by ANOVA with Fisher’s test. Comparisons were made using the mean values for each biopsy; Student’s t test was used to compare the ER levels of each group of cells in the proliferative phase with the levels seen in luteal phase. For all statistical analysis, P less than 0.05 was considered significant.
Isolation of human endometrial cells
Isolation of stromal cells from endometrial tissue was performed using dissociation with 0.1% collagenase and 0.02% DNAse I, as described previously (22, 23). Purity of the stromal cell preparation obtained at passage 3–4 was verified as described previously (22), by staining with anti-vimentin (clone V9; (DAKO Corp.) and antileucocyte common antigen (DAKO Corp.) antibodies. Cells were treated with epidermal growth factor (EGF; 20 ng/mL) plus E2 (10-8 M) and progesterone (10-6 M) (23) for various lengths of time (1–14 days). Decidual cells were characterized by expression of PRL and insulin-like growth factor binding protein (IGFBP) (24) demonstrated by immunocytochemistry with specific antibodies (Eurodiagnostica, Upjohn Pharmacia).
Extraction of RNA from cells and reverse transcription (RT)-PCR analysis
Total RNA was isolated from cultures of stromal cells using a modified guanidium isothiocyanate method (Trizol; Life Technologies) (22). A semiquantitative RT-PCR method was established [as described previously (26) and modified (25)] to determine the amount of RNA and the number of cycles to be used in order that the quantity of PCR products is proportional to the quantity of total RNA and increases linearly as a function of the number of cycles. Amplification of ERß complementary DNA (cDNA) was carried out in a DNA thermal cycler at 94, 59, and 72 C for 30 sec, 1 min, and 1 min, respectively, for 39 cycles using 50 pmol of each ERß primer. Oligonucleotide primers were chosen from homologous parts of the coding region of the human ERß gene. The sense primer for human ERß was 5'-TAGTGGTCCATCGCCAGTTAT-3', and the antisense primer was 5'-GGGAGCACACTTCACCAT-3'. Amplification of the constitutive glyceraldehyde-3-phosphate dehydrogenase (GAPDH) cDNA was performed as an internal control for cDNA quantity and integrity, using 10 pmol of each primer of GAPDH, as described previously (25), for 28 cycles at 94, 55, and 72 C for 30 sec, 1 min, and 1 min, respectively. The PCR fragments were analyzed by 8% polyacrylamide gel electrophoresis, visualized by ethidium bromide staining, and the radioactivity was counted by Instant imager.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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labeling.
ERß expression in the endometrial functional zone is usually weaker
than in the positive control prostatic adenoma, and endometrial
immunolabeling of ERß is less intense than that of ER. No
immunostaining is seen in proliferative or secretory endometrium when
the primary antibody is replaced by sheep IgG. Preincubation of the
anti-ERß antibody with the immunogen recombinant peptide (100
µg/mL) considerably reduces the intensity of staining (Fig. 1
, A and
B).
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ERß immunostaining patterns were consistent in all specimens
examined. Glandular, stromal, and vascular cells all express ERß
(
Figs. 1–4
).
ERß expression in a particular cellular compartment varies according
to the phase of the cycle (Table 1), as
deduced from analysis of both staining intensity and number of
immunostained nuclei with computerized image analysis (see
Materials and Methods and Ref. 18). ERß immunostaining
intensity is low in every compartment during the menstrual phase (Table 1).
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) or per glandular unit area (data not shown);
the glandular labeling intensity increases in the late-proliferative
and early-secretory phases with a peak at days 14 and 15 (Fig. 1, A and
D) and decreases again during the secretory phase. Stromal ERß
immunostaining is low during the menstrual cycle, except for the
late-secretory phase (Fig. 1F and Table 1).
Vascular ERß immunolabeling is low throughout most of the menstrual
cycle; however, it increases during the late-secretory phase both in
intensity (Figs. 2D and 4, B and D) and number of stained nuclei (Table 1) (x3.3 and x2.5; P < 0.05, as compared with the
mid- and late-proliferative periods, respectively). Vascular ERß is
predominantly expressed in parietal smooth muscle cells (CML) and
occasionally in endothelial cells (Fig. 4, B and D). Thus, while
epithelial ERß immunolabeling is higher on days 14 and 15,
interstitial and vascular ERß staining peaks in the late-secretory
phase.
Simultaneous or differential expression of ER and ERß during
the cycle
It has been suggested that cell-specific effects of estrogenic
action could vary according to the respective expression of ER and
ERß and to the potential for the formation of homodimers of each ER
type, as well as of ER/ERß heterodimers (27). To
understand the cell-specific effects of estrogens in the human
endometrium, we have analyzed the endometrial expression of ER and
ERß in serial sections throughout the menstrual cycle. Our main
findings concern the stronger immunolabeling of ER compared with
that of ERß and the variations of expression of both receptors
observed in the glandular, stromal, and vascular compartments according
to the phase of the cycle (Table 1).
Proliferative phase.Glandular epithelial, stromal, and
vascular cells of the functional zone express both ER and ERß
(Table 1). ERß immunolabeling is, however, less intense than that of
ER, especially in the glands (Fig. 1, A, C, and D). ERß labeling
in epithelial cells peaks in the periovulatory period (days 14 and 15),
and glandular ER staining is stronger during the midproliferative
and periovulatory period, leading to their significant coexpression in
the periovulatory period (Fig. 1, C and D).
Secretory phase. During the progression from early to
late-secretory phase, glandular expression of ER in the endometrial
functional zone becomes markedly lower than in the proliferative phase,
as described previously (1, 2) and confirmed in this study
(Table 1). A similar pattern of immunolabeling is observed for
glandular ERß, leading to a low coexpression of ER and ERß in
the mid- and late-secretory phase (Fig. 1, E and F). In contrast, ERß
immunolabeling in some stromal cells increases during the
late-secretory period (days 25–27; Fig. 1F).
ERß is present in stromal decidual cells of the functional zone
Stromal cells positive for ERß during the late-secretory period
(days 25–27) have a particular morphology and are mostly situated
around spiral arterioles (Fig. 2); they have a round shape and the
general aspect of decidual stromal cells (Fig. 2, A and D). To better
characterize these cells, adjacent sections were incubated with a
monoclonal antismooth actin antibody, as decidual stromal cells
have been shown to express this microfilament (19). As
shown in Fig. 2, B and D, ERß-positive cells are also -actin
positive, but not ER positive (Fig. 2C).
RT-PCR analysis of human endometrial cells was used to confirm the
expression of ERß in decidual stromal cells. As shown in Fig. 3, it
allows the detection of specific products having the expected size of
392 bp (ERß). To compare ERß transcripts in different hormonal
conditions, we developed a semiquantitative RT-PCR assay (see
Materials and Methods; Refs. 25, 26). Stromal cells
incubated with E2, progesterone, and EGF for 10 days
produce more ERß mRNA in contrast with control cells or cells
incubated for a shorter period (Fig. 3); these cells also express
IGFBP, a marker of decidualization (data not shown).
Modulation of ER and ERß in cells of the vascular wall from
the functionalis
In addition to glandular and stromal cells labeling described
previously (see Refs. 1, 2 for ER) and reported in this study
(for ERß), nuclear ER and ERß immunolabeling is also present in
vascular smooth muscle cells and occasionally in endothelial cells of
the vascular wall (Fig. 4); a semiquantitative analysis of the
immunostaining demonstrates that the expression of receptors changes
during the menstrual cycle (Table 1). ER staining of CML is
restricted to the late-proliferative and early-secretory phases, when
it is markedly high both in staining intensity and in number of labeled
nuclei (Fig. 4A). ERß is present in the wall of arterioles at a lower
concentration than that of ER during these periods, as deduced from
the lower staining intensity (Fig. 4E). In contrast, ERß markedly
increases in vascular cells (mainly smooth muscle cells of spiral
arteries) in the late-secretory period (day 25; Fig. 4, B and D), both
in terms of staining intensity and number of labeled cells, whereas
ER is absent during this period (Fig. 4F and Table 1).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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; ERß expression, however, is
usually less prominent, and its cyclic changes are less evident than
those of ER, especially in epithelial cells (1, 2).
Moreover, ERß is the predominant form of vascular ER in the
late-secretory period (days 24–26), whereas vascular ER is mainly
observed during the late follicular phase, suggesting different
regulations and functions of these two ER subtypes in the vessels.
Available data on the expression of ERß protein are restricted to
animal species (8, 15, 16, 28, 29), and studies in the
human endometrium have only reported the expression of the
corresponding mRNAs (13, 14). Using previously
characterized (15, 16) polyclonal antibodies that
cross-react with human ERß antigen, we demonstrated the
immunolocalization of ERß protein in the human endometrium; the
specificity of the immunostaining was confirmed by its decrease after
preincubation of the anti-ERß antibody with the recombinant immunogen
peptide, but not with the recombinant ER protein (30);
the presence of ERß was also deduced from RT-PCR analysis in isolated
endometrial and vascular cells (25). The relative levels
of ERß transcripts in uterine cells, as deduced from semiquantitative
RT-PCR analysis, correlated with differences at the protein level. This
simple method, which is based on the exponential nature of the PCR
reaction and the use of a stable endogenous internal standard, has
previously been validated using mathematical analysis and Northern blot
experiments (26); however, it only permits an estimation
of relative rather than absolute amounts of nucleic acids, and the
results should be confirmed by quantitative methods. Compared with the
presence of ERß in human and rat uteri (13, 15), the
reported absence of uterine ERß in the mouse (8) could
be related to species differences, or to the phase of the cycle of the
animals used in these experiments. The presence of ERß in glandular
epithelial and stromal cells also agrees with a previous study of the
human uterus using in situ hybridization (13).
Our results demonstrate that ERß mRNAs are, indeed, translated into
proteins in these cell types. Comparison of both the staining intensity
and the number of immunolabeled nuclei for each ER within each
compartment using computerized image analysis allows the analysis of
relative ER and ERß expression in each cell type during the
menstrual cycle; this methodology has been previously used for the
analysis of expression of vascular endothelial growth factor and its
receptors in the human endometrium (21).
Our results indicate that glandular ERß expression predominantly
occurs during the follicular phase and the early secretory period and
is usually lower than that of ER, although potential differences in
the affinity characteristics of the two antibodies cannot be excluded.
These findings extend and complete previous data based on mRNAs studies
(13). The higher epithelial expression of ERß and ER
on days 14–18 could modulate estrogen action in these cells at this
period. The finding of the presence of ERß in the human endometrial
glands is not unexpected, although the expression of this receptor in
the uterus has been reported to be low or absent (8).
Disruption of the ER gene results in some studies (11)
in insensitivity to the effects of E2 on oedema, hyperemia,
RNA and DNA synthesis, mitosis, and cellular hyperplasia, whereas
recent studies have shown the preservation of selective estrogen
actions in the ERKO uterus (12, 31), including water
retention and induction of secretory products (such as lactoferrin;
Ref. 12). The maintenance of these actions by the catecholestrogen
4-hydroxyestradiol, but not by E2, and the lack of
inhibition of those effects by the pure estrogen antagonist ICI 182780
suggest the possibility of a non-ER-mediated signaling pathway
(12), possibly through activation of ERß. Estrogenic
effects, such as epithelial growth and stimulation of secretory
products, have also been previously described in wild-type uterine
epithelial cells lacking ER (10, 32). Thus,
preservation of selective estrogenic effects in the ERKO mouse
uterus could also result from estrogenic action in ERß-positive
epithelial cells.
An important finding of our study is the presence of both ER and
ERß in human uterine vessels, mainly in smooth muscle cells of the
vascular wall and occasionally in endothelial cells, and the fact that
these receptors undergo different cyclic variations. The vascular
ER increase in the late-proliferative and early-secretory phases,
which has not been described before, can be explained as an effect of
the estrogen preovulatory surge, similarly to the
E2-induced ER increase observed in the rabbit uterine
vessels (20). Abundant evidence in the literature shows
that steroid hormones play an active role in regulating cyclic
endometrial vascular changes, vascular permeability, and blood flow
(see Refs. 20, 24, 33) that are essential for endometrial
physiology and for successful nidation and reproduction. Endometrial
vessels regenerate at the beginning of the ovarian cycle, proliferate
and branch during the follicular phase, then coil into thick-walled
spiral arteries in the luteal period to undergo collapse and sloughing
at menses (24). The observation of the presence of ERs at
relatively high concentrations in smooth muscle cells of the vascular
wall of uterine vessels (18, 20) has led to the conclusion
of a direct action of this steroid on endometrial vasculature.
Activation of vascular ER receptors during the periovulatory period
could be related to vasodilation, the production of paracrine factors
in the vascular smooth muscle cells and their permeabilizing action on
the vessels (20, 22, 34).
In the mid-late secretory phase (days 24–26), the finding that
ERß is the predominant form of vascular ER, while vascular ER
levels are very low, suggests that ERß might play a role in the
regulation of vascular function in this specific phase of the cycle.
Vascular ERß is expressed both when the coiling of the spiral
arterioles reaches its maximal level and when the decidual changes of
the stromal cells surrounding those same arterioles occur
(24); also ERß increases in late-proliferative decidual
stromal cells and in decidual cells during pregnancy (unpublished
data), suggesting some specific role of this receptor during the
process of decidualization. Mice lacking ERß have been reported to be
fertile, but have fewer and smaller litters than wild-type mice
(35); this result was interpreted as the consequence of a
direct loss of ERß-mediated actions in the ovary. However, the
ability of progesterone to induce a decidual response in the absence of
ER in endometrial stromal cells of ERKO mice with high
E2 levels (36) is a finding that could be
explained through activation of the ERß in addition to activation of
the progesterone receptor. The reasons for the appearance of
substantial levels of ERß in human vascular and stromal cells during
the mid-late luteal transition (days 24–26) and the disappearance of
the receptor during hormonal withdrawal (days 27–28) remain to be
elucidated.
Differences in tissue distribution of ERß and ER during the
menstrual cycle suggest the presence of analogous or distinct roles
fulfilled by each receptor. ERß may, therefore, play a role in the
modulation of estrogenic action, either in combination with ER or by
itself. It has been suggested that the potential for the formation of
homodimers of each ER type, as well as heterodimers, can have
differential effects on gene activation (27). Moreover,
ERß has been demonstrated to exert opposite transcriptional effects
in comparison to ER, after binding to estrogens and antiestrogens in
some promoter context (37). The transcriptional activity
in estrogen-responsive tissues may, therefore, be modulated by the
ER-type and the relative content of each receptor. ERß may modulate
the activity of ER in glandular cells and possibly in cells of the
vascular wall, especially during the lateproliferative and
early-secretory phases when these cells coexpress the two receptors.
Differences in the ER/ERß ratio among different hormonal
conditions and in pathological disorders (38, 39) could
have important functional implications, because these ERs have
different binding characteristics (7) and different levels
of expression are found in pathological conditions such as
endometriosis (38, 39). We also postulate that a decrease
in the ER/ERß ratio in stromal and vascular cells at day 25 could
influence endogenous gene expression during the decidualization
process.
In summary, this study indicates the presence of ERß receptors
in epithelial, stromal, and vascular cells of the human endometrium and
describes their cyclic changes during the menstrual cycle. Our findings
may explain the preservation of selective actions of estrogens in the
-ERKO mouse uterus, and provide a basis for the reinvestigation of
specific actions of E2 that are not mediated by ER in
the human endometrium. Further investigations into the ERß-mediated
signaling pathway, by which physiological estrogens or xeno-estrogens
may activate nuclear processes, are needed to better elucidate the role
of this receptor in endometrial cyclic functional changes.
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Acknowledgments |
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Footnotes |
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Received May 23, 2000.
Revised October 4, 2000.
Revised November 3, 2000.
Accepted November 9, 2000.
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References |
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R. K. Vadlamudi, S. Balasenthil, R. R. Broaddus, J.-A. Gustafsson, and R. Kumar Deregulation of Estrogen Receptor Coactivator Proline-, Glutamic Acid-, and Leucine-Rich Protein-1/Modulator of Nongenomic Activity of Estrogen Receptor in Human Endometrial Tumors J. Clin. Endocrinol. Metab., December 1, 2004; 89(12): 6130 - 6138. [Abstract] [Full Text] [PDF]
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U. A. Kayisli, J. Luk, O. Guzeloglu-Kayisli, Y. Seval, R. Demir, and A. Arici Regulation of Angiogenic Activity of Human Endometrial Endothelial Cells in Culture by Ovarian Steroids J. Clin. Endocrinol. Metab., November 1, 2004; 89(11): 5794 - 5802. [Abstract] [Full Text] [PDF]
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 R. Pilka, H. Domanski, S. Hansson, P. Eriksson, and B. Casslen Endometrial TIMP-4 mRNA is high at midcycle and in hyperplasia, but down-regulated in malignant tumours. Coordinated expression with MMP-26 Mol. Hum. Reprod., September 1, 2004; 10(9): 641 - 650. [Abstract] [Full Text] [PDF]
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V. Unfer, M. L. Casini, L. Costabile, M. Mignosa, S. Gerli, and G. C. Di Renzo High Dose of Phytoestrogens Can Reverse the Antiestrogenic Effects of Clomiphene Citrate on the Endometrium in Patients Undergoing Intrauterine Insemination: A Randomized Trial Reproductive Sciences, July 1, 2004; 11(5): 323 - 328. [Abstract] [PDF]
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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]
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F. Amant, E. Huys, A. Geurts-Moespot, B. G. Lindeque, I. Vergote, F. Sweep, and E. F. P. M. Schoenmakers Ethnic Variations in Uterine Leiomyoma Biology Are Not Caused By Differences in Myometrial Estrogen Receptor Alpha Levels Reproductive Sciences, February 1, 2003; 10(2): 105 - 109. [Abstract] [PDF]
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H. O. D. Critchley, T. A. Henderson, R. W. Kelly, G. S. Scobie, L. R. Evans, N. P. Groome, and P. T. K. Saunders Wild-Type Estrogen Receptor (ER{beta}1) and the Splice Variant (ER{beta}cx/{beta}2) Are Both Expressed within the Human Endometrium throughout the Normal Menstrual Cycle J. Clin. Endocrinol. Metab., November 1, 2002; 87(11): 5265 - 5273. [Abstract] [Full Text] [PDF]
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 H. Buteau-Lozano, M. Ancelin, B. Lardeux, J. Milanini, and M. Perrot-Applanat Transcriptional Regulation of Vascular Endothelial Growth Factor by Estradiol and Tamoxifen in Breast Cancer Cells: A Complex Interplay between Estrogen Receptors {alpha} and {beta} Cancer Res., September 1, 2002; 62(17): 4977 - 4984. [Abstract] [Full Text] [PDF]
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 S. Vanzulli, A. Efeyan, F. Benavides, L. A. Helguero, G. Peters, J. Shen, C. J. Conti, C. Lanari, and A. Molinolo p21, p27 and p53 in estrogen and antiprogestin-induced tumor regression of experimental mouse mammary ductal carcinomas Carcinogenesis, May 1, 2002; 23(5): 749 - 758. [Abstract] [Full Text] [PDF]
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 M. Ancelin, H. Buteau-Lozano, G. Meduri, M. Osborne-Pellegrin, S. Sordello, J. Plouet, and M. Perrot-Applanat A dynamic shift of VEGF isoforms with a transient and selective progesterone-induced expression of VEGF189 regulates angiogenesis and vascular permeability in human uterus PNAS, April 30, 2002; 99(9): 6023 - 6028. [Abstract] [Full Text] [PDF]
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N. R. Nayak and R. M. Brenner Vascular Proliferation and Vascular Endothelial Growth Factor Expression in the Rhesus Macaque Endometrium J. Clin. Endocrinol. Metab., April 1, 2002; 87(4): 1845 - 1855. [Abstract] [Full Text] [PDF]
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S. Hague, I.Z. MacKenzie, R. Bicknell, and M.C.P. Rees In-vivo angiogenesis and progestogens Hum. Reprod., March 1, 2002; 17(3): 786 - 793. [Abstract] [Full Text] [PDF]
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 R. Soares, J. S. Reis-Filho, F. Gartner, F. C. Schmitt, L. Iruela-Arispa, and M. D. Graubert Vascular Endothelial Growth Factor, Transforming Growth Factor-{alpha}, and Estrogen Receptors: Possible Cross-Talks and Interactions Am. J. Pathol., January 1, 2002; 160(1): 381 - 383. [Full Text] [PDF]
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M. Ancelin, H. Buteau-Lozano, G. Meduri, M. Osborne-Pellegrin, S. Sordello, J. Plouet, and M. Perrot-Applanat A dynamic shift of VEGF isoforms with a transient and selective progesterone-induced expression of VEGF189 regulates angiogenesis and vascular permeability in human uterus PNAS, April 30, 2002; 99(9): 6023 - 6028. [Abstract] [Full Text] [PDF]
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