Molecular Human Reproduction, Vol. 5, No. 6, 559-564,
June 1999
© 1999 European Society of Human Reproduction and Embryology
Oestrogen receptor 
and ß mRNA expression in human endometrium throughout the menstrual cycle
1 Department of Obstetrics & Gynecology and 2 Department of Pathology, Tohoku University School of Medicine, 1–1, Seiryo-machi, Aoba-ku, Sendai, 980–8574, Japan
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Abstract |
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We examined the localization of oestrogen receptor (ER) ß mRNA in the human endometrium throughout the menstrual cycle using non-radioactive in-situ hybridization with Brigati-tailed oligonucleotides. The findings were compared with those of ER
in order to examine the possible biological significance of ERß in the human endometrium. Both ER and ERß mRNA expression were detected in all major human uterine cell types, including glandular epithelial cells, stromal cells and smooth muscle cells of the uterine wall, at every menstrual cycle stage. However, ER mRNA expression was more prominent than that of ERß in all cell types throughout the menstrual cycle. In proliferative phase endometrium, ER mRNA was expressed in both glandular epithelial and stromal cells, while ERß mRNA was expressed predominantly in glandular epithelial cells. Although the same pattern was observed in the secretory phase, both the ER and ERß mRNA expression was relatively weaker. These results suggest that oestrogenic effects occur predominantly through ER, but that ERß may also play a role in the modulation of oestrogenic action, especially on glandular epithelial cells in the human endometrium throughout the menstrual cycle.
endometrium/ER/ERß/in-situ hybridization
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Introduction |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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Oestrogens play important roles in the regulation of the menstrual cycle in human endometrium and these oestrogenic effects were thought to act via a single oestrogen receptor (ER)
. Since the cloning of classical ER (or ER) cDNA (Greene et al., 1986
) and the production of specific monoclonal antibodies against the ER protein, numerous studies have demonstrated the expression of ER mRNA (Parl et al., 1987; Koji and Brenner, 1993) and protein (Press et al., 1984; Bergerone et al., 1988; Lessey et al., 1988) in human uterus throughout the menstrual cycle. However, with the recent cloning of a novel oestrogen receptor ERß (Kuiper et al., 1996; Mosselman et al., 1996; Tremblay et al., 1997), some of these oestrogenic effects may occur through this newly identified receptor. ERß mRNA in uterine tissues has been studied by several groups using reverse transcription –polymerase chain reaction (RT–PCR) and/or Northern blot analysis (Kuiper et al., 1996; Mosselman et al., 1996; Enmark et al., 1997; Tremblay et al., 1997), which demonstrated that ERß mRNA concentrations were much lower than those of ER mRNA. A recent study has demonstrated ERß mRNA in the human endometrium, regardless of the cycle phase, using RT–PCR analysis (Rey et al., 1998). As the endometrium is composed of both glandular epithelial and stromal cells, it is very important to study the localization of ERß mRNA expression in the endometrium to clarify its possible biological roles. The localization of ERß expression has not been examined in human endometrium. In this study we examined the localization of the ER and ERß mRNA expression in the human uterus at different phases of the menstrual cycle by non-radioactive in-situ hybridization technique using Brigati-tailed oligonucleotides. Findings for ER and ERß were compared to obtain a better understanding of oestrogenic effects in the human endometrium. In addition, we evaluated the localization of ER protein by immunohistochemistry and compared the findings with those of ER mRNA expression. |
Materials and methods |
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Human uterine tissue
We retrieved hysterectomy specimens of cervical carcinoma from surgical pathology files of Tohoku University Hospital and Tohoku Rosai Hospital, Sendai, Japan. Patient clinical charts were reviewed and patients selected on the basis of history of regular menstrual cycles, and no use of any intra-uterine device or hormone therapies for at least 6 months prior to hysterectomy. Histological slides of the endometrium were subsequently reviewed and cases were further selected on the basis of consistent histological findings and serum oestradiol and progesterone concentrations. After these reviews, 16 cases were available for examination. Endometrial dating criteria were used to assess the phase of menstrual cycle (Noyes et al., 1950
). Results of these histological classifications were as follows; eight proliferative phase, two early secretory phase, three mid-secretory phase and three late secretory phase. All tissues had been fixed in 4% paraformaldehyde and embedded in paraffin. Sections of 3 µm thickness were routinely prepared and mounted on 3-aminopropyltrie thoxysilane-coated glass slides (Dako, Kyoto, Japan) for immunohistochemistry, or on Probe-On glass slides (Fisher Scientific, Philadelphia, PA, USA) for mRNA in-situ hybridization.
Oligonucleotide probes
The sequence of antisense ER oligonucleotide probes employed for mRNA in-situ hybridization were; ER: 5'-CAG CTC GTT CCC TTG GAT CTG ATG CAG TAG-3' and ERß: 5'-TGT TGG CCA CAA CAC ATT TGG GCT TGT GGT-3', which correspond to nucleotides 332–361 (Greene et al., 1986) and 76–105 (Mosselman et al., 1996) of ER and ERß sequences respectively. The probes had similar GC-contents and were selected from the N-terminal A/B domain (Sasano et al., 1998). Sense oligonucleotides, complementary to the antisense probes, were used as negative control probes; ER: 5' -CTA CTG CAT CAG ATC CAA GGG AAC GAG CTG-3' and ERß: 5'-ACC ACA AGC CCA AAT GTG TTG TGG CCA ACA-3'. All oligonucleotide probes were synthesized with a 3'-biotinylated tail [Brigati tail (Iino et al., 1997; Sasano et al., 1997); 5'-probe-biotin-biotin-biotin-TAG-TAG-biotin-biotin-biotin-3'].
Both the ER and ERß probes demonstrated no significant sequence similarity to each other, or to other known human gene sequences, including glucocorticoid, mineralcorticoid or progesterone receptors as assessed by a Genbank database search.
In-situ hybridization
In-situ hybridization was performed using of a manual capillary action system (MicroProbe staining system, Fisher Scientific, Pittsburgh, PA, USA) with a modification of previously reported methods (Iino et al., 1997; Sasano et al., 1997). Tissue sections were rapidly dewaxed, cleared, with alcohol, rehydrated with a Tris-based buffer, pH 7.4 (Universal Buffer; Research Genetics, Huntsville, AL, USA), and digested with pepsin (2.5 mg/ml; Research Genetics) for 4 min at 105°C. The probe was applied in formamide-free diluent, slides heated to 105°C for 3 min, cooled for ~1 min at room temperature and allowed to hybridize at 45°C for 45 min. The sections were then washed three times with 2x sodium chloride/sodium citrate (SSC) solution at room temperature and incubated with alkaline phosphatase-conjugated streptavidin (Research Genetics). After washing three times in alkaline phosphatase chromogen buffer, pH 9.5 (Research Genetics), at room temperature, hybridization signals were visualized using fast red salt. Slides were counterstained with haematoxylin, air-dried, and covered with coverslips for microscopic examination. Negative control experiments were performed using sense probes. As positive control tissues for ERß, fetal kidney tissues were used, in which moderate expression of ERß mRNA had been previously demonstrated by RT–PCR (Brandenberger et al., 1997).
The relative strengths of mRNA hybridization signals were independently evaluated by two of the authors (S.M. and H.S.) and classified as (–); no hybridization signal, (±); very weak, (+); weak, (++); moderate, (+++); strong. Discordant cases were re-evaluated together (S.M. and H.S.).
Immunohistochemistry
Immunohistochemical staining was performed using the monoclonal antibody, ER1D5 (Immunotech, Marseille, France), which was generated against the A/B domain of ER (Al Saati et al., 1993). Immunohistochemical procedures were as previously reported (Sasano et al., 1994, 1996). Autoclave treatment in citric acid buffer at 120°C for 5 min was employed for tissue antigen retrieval. Negative controls were performed by replacing primary antibody with normal mouse immunoglobulin (Ig)G diluted at the same concentration as the primary antibody and no specific immunoreactivity was detected. As positive controls, tissue sections of ER-positive breast cancer were used. To quantify immunopositivity, immunoreacted cells were counted separately in the functionalis and basalis of the endometrium, using a semi-automatic computerized image analysis system. The computerized image analysis system consisted of a light microscope (Zeiss, Göttingen, Germany) (x40 objective, x10 ocular) with a colour charge coupling device camera (Zeiss) connected to a Macintosh 9500/120 computer. For each section, the number of positive glandular and stromal cells was counted, regardless of the staining intensity, in a total of 10 non-overlapping areas. Results were expressed as (–); no positive cells, (±); 0–5%, (+); 5–25%, (++); 25–50%, (+++); 50–75%, (++++); >75% of positive cells.
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Results |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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Results are summarized in Tables I (in-situ hybridization) and II (immunohistochemistry for ER
).
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Proliferative phase
Both glandular epithelial and stromal cells demonstrated marked expression of ER
mRNA (Figure 1a). ERß mRNA expression, however, was predominantly detected in glandular epithelial cells and weakly in stromal cells (Figure 1b). Patterns of ER and ERß mRNA localization were not different between the functionalis and basalis. The lowermost layer of the endometrium is the basalis and the overlying one the functionalis. The basalis is a zone of weakly proliferative glands and associated dense spindled stroma immediately adjacent to the myometrium (Hendrickson and Kempson, 1991). ERß mRNA expression in glandular epithelial cells was weak compared with that of ER.
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Secretory phase
From early to late secretory phase, ER
mRNA concentrations in the glandular epithelial cells became markedly low in the functionalis, whereas ER mRNA concentrations in the basalis remained similar to those observed in the proliferative phase. ER mRNA hybridization signals in the stromal cells also became less prominent than those during the proliferative phase, but stromal cells adjacent to the secretory glands and in the basalis retained the same hybridization signal intensity (Figure 1d,g
). ERß mRNA expression in glandular epithelial and stromal cells was also markedly decreased in the functionalis with the progression of the secretory phase. In the late secretory phase, ERß mRNA concentrations in the glandular epithelial and stromal cells became barely discernible or absent in the functionalis (Figure 1e) and retained very weakly in the basalis (Figure 1h). Throughout the menstrual cycle, ERß mRNA expression in the glandular epithelial cells remained much weaker than that of ER.
Myometrium
In the myometrium, relatively weak ER and ERß mRNA hybridization signals were detected in smooth muscle cells, and no change in their relative intensities and localization patterns were observed throughout the menstrual cycle. However, at every stage, ER mRNA expression was more prominent than that of ERß.
Immunohistochemistry for ER
During the proliferative phase, both glandular epithelial and stromal cells demonstrated marked nuclear immunoreactivity and intensity of staining was not different between functionalis and basalis (Figure 2a,b). During the secretory phase, the number of ER-positive cells decreased markedly in both glandular epithelial and stromal cells of the functionalis but remained similar in the basalis (Figure 2c,d). ER nuclear immunoreactivity was detected in smooth muscle cells of the myometrium at each stage of the menstrual cycle.
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Controls
No significant hybridization signals were detected when sections were hybridized with either ER
or ERß sense probes (Figure 1c,f,i). Significant hybridization signals were detected when sections of fetal kidney were hybridized with the ERß antisense probe, whereas no significant hybridization signals were detected when they were hybridized with the ER antisense probe. |
Discussion |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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Our results demonstrated the localization of ER
and ERß mRNA expression in the human endometrium in agreement with previous study using RT–PCR, which demonstrated the presence of both ER and ERß mRNAs (Rey et al., 1998). ER mRNA expression was localized in glandular epithelial and stromal cells with marked cyclic change, which is consistent with another previous study (Koji and Brenner, 1993). ERß mRNA expression was detected in glandular epithelial and stromal cells as well as in myometrial smooth muscle cells. Cyclic change of ERß mRNA expression was less evident compared with that of ER mRNA expression. In addition, ERß mRNA was expressed predominantly in glandular epithelial cells. Although both ER and ERß mRNA expression patterns in glandular epithelial and stromal cells of the endometrium were similar throughout the menstrual cycle, ER mRNA expression was more prominent than that of ERß. The intensity of ERß mRNA hybridization signals in stromal cells was always much weaker than that of ER. In-situ hybridization has some unavoidable limitations in terms of quantification and comparison of signal intensities between different genes and may, therefore, be difficult. Various technical factors such as duration of fixation, types of fixatives employed (Koji and Brenner, 1993) and probe labelling efficiency may affect the intensity of mRNA hybridization signals. To minimize the possible technical problems, we performed in-situ hybridization for ER and ERß mRNA on serial sections at the same time in the same manner. We verified the labelling efficiency for ER and ERß, using fetal kidney tissues as positive controls for ERß. Results of these studies suggested that there were only minimal differences of the probe labelling efficiency between ER and ERß. The present findings suggest that oestrogenic effects occur predominantly through ER, but ERß may also play some role in the modulation of oestrogenic action, especially on glandular epithelial cells in human uterine tissues. In the present study we demonstrated that the expression of ER mRNA parallels that of ER protein. Further investigations are required to examine ER and ERß in protein concentrations in various cell types.
ERß is thought to be functional in vitro as it interacts with both oestrogens and anti-oestrogens, and activates transcription of oestrogen response element (ERE)-containing promoters (Mosselman et al., 1996). In addition, ERß protein has a high affinity for oestradiol, as does the ER (Kuiper et al., 1997). However, the uterus of the oestrogen receptor knock-out (ERKO) mice, in which the ER but not the ERß gene was disrupted (Couse et al., 1997), demonstrated no response to oestradiol treatment (Lubahn et al., 1993; Couse et al., 1995). One possible explanation for this lack of oestradiol responsiveness is that heterodimerization of ER and ß is required for transcription activation in uterine tissues. ER and ERß can form heterodimers upon binding to the oestrogen response elements both in vitro and in vivo (Pace et al., 1997; Ogawa et al., 1998). We demonstrated that ER and ERß are co-expressed in glandular epithelial cells with similar marked cyclic changes in the uterus, suggesting that both ERs may be involved in the regulation of oestrogen-responsive gene expression. It will be important to examine whether ER and ERß proteins are co-expresed in a single cell. Another possible explanation is that signalling from an ERß-dependent AP-1 element may occur in ERKO mouse uterus. A recent study demonstrated that ER and ERß signal in different ways depending on ligands and response elements (Paeh et al., 1997). Both in Ishikawa cells (a human uterine cell line) and in human breast cancer cells, synthetic anti-oestrogens, including tamoxifen, raloxifen and ICI164384, activated an ERß-dependent AP-1 site. In contrast, oestrogens (including 17ß-oestradiol and diethylstilboestrol) inhibited the ERß-dependent AP-1 site (Paeh et al., 1997). If signalling from an ERß-dependent AP-1 site occurs in uterine tissues, ERß may play an important role in mechanism to control ER-mediated effects.
In conclusion, our findings suggest that ERß may play some functional role in human endometrium throughout the menstrual cycle. However, further studies, including the analysis using quantitative PCR, are required to clarify the biological roles of ERß in human endometrium.
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Notes |
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3 To whom correspondence should be addressed
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Submitted on November 12, 1998; accepted on March 10, 1999.
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