Molecular Human Reproduction, Vol. 5, No. 1, 17-21,
January 1999
© 1999 European Society of Human Reproduction and Embryology
Expression of oestrogen receptor 
and ß mRNA in corpus luteum of human subjects
Department of Obstetrics and Gynecology, Gifu University School of Medicine, Gifu City, 40 Tsukasamachi, Gifu 500-8705, Japan
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Abstract |
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To investigate the role of oestrogen receptor ß (ERß) in the function of human ovarian corpus luteum, the levels of luteal ER
and ERß mRNA were determined using competitive reverse transcription–polymerase chain reaction-Southern blot analysis. The expression of ER and ERß mRNA was detected in all luteal samples analysed. Luteal ER and ERß mRNA levels were significantly lower (P < 0.01 and P < 0.05 respectively) at the late secretory phase than those at the early and mid-secretory phases of the endometrium. The ratio of ER to ERß mRNA levels showed no change during the secretory phase of the endometrium. This study demonstrates that ERß is co-expressed with ER in human corpus luteum and is likely to play a biological role in the regulation of steroidal action of the corpus luteum with ER.
ER/ERß/human corpus luteum/mRNA
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Introduction |
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After ovulation, a pre-ovulatory dominant follicle is transformed into another ovarian structure, the corpus luteum, which synthesizes and secretes both oestrogen and progesterone (Ohara et al., 1987
). Oestrogen is involved in the local regulation of luteal cell function (Bogdanove, 1966; Keyes and Nalbandov, 1967). Steroid action is mediated by specific intracellular receptors which, following ligand binding, are shifted to a transcriptionally active state. The oestrogen receptor (ER) has been detected in human ovary including corpus luteum (Revelli et al., 1996).
Since the cloning of the ER (Green et al., 1986), there has been the general acceptance that only one ER existed. However, the discovery of a new member of the nuclear receptor superfamily with ligand and specificity for oestrogens in the rat (Kuiper et al., 1996), mouse (Tremblay et al., 1997) and human (Mosselman et al., 1996), has prompted a re-examination of the oestrogen signalling system. A novel ER, ERß, is highly homologous to the classical ER, termed ER, particularly in the DNA-binding and the ligand binding domains (Kuiper et al., 1996; Mosselman et al., 1996; Tremblay et al., 1997). ERß has been shown to stimulate transcription of an ER target gene in an oestrogen-dependent manner (Kuiper et al., 1996, 1997). The distribution and the relative levels of ER and ERß expressions are different (Mosselman et al., 1996; Kuiper et al., 1997; Tremblay et al., 1997). Moreover, the differences between the ER subtypes in relative ligand binding affinity and transcriptional activation have been described (Mosselman et al., 1996; Kuiper et al., 1997; Paech et al., 1997; Tremblay et al., 1997). These findings suggest functional differences in the two ER subtypes.
In the present study, we investigated the expression of ER and ERß genes in human ovarian corpora lutea.
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Materials and methods |
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Materials
The specimens of corpus luteum were obtained from 22 patients (aged 38–45 years) undergoing hysterectomy at the Department of Obstetrics and Gynecology, Gifu University School of Medicine, Japan, from October 1996 to July 1997. They had regular menstrual cycles (26–34-day cycle judged by basal body temperature) and had received no previous therapy. All subjects gave informed consent, and this study was approved by the Research Committee of Gifu University School of Medicine and Institutional Review Board. The cycle date of each woman was further estimated by endometrial biopsy (Noyes et al., 1950
). The specimens were grouped into three categories, early secretory (ES, n = 8), mid-secretory (MS, n = 8), and late secretory (LS, n = 6) phases of the menstrual cycle. Serum progesterone concentrations were 6.1 ± 2.3 pg/ml in the ES, 16.6 ± 4.1 pg/ml in the MS, and 5.8 ± 2.2 pg/ml in the LS respectively. Part of the luteal specimen was submitted for histological diagnosis, and the remainder was immediately frozen in liquid nitrogen and later prepared for RNA isolation.
Preparation of internal standard recombinant RNA (rcRNA)
Following the procedures described in previous studies (Misao et al., 1995a,b), the synthesis of internal standard rcRNA was performed. DNA construction of the internal standard was originated and synthesized by polymerase chain reaction (PCR) from a BamH/EcoRI fragment of v-erbB (Clontech Laboratories, Palo Alto, CA, USA) with two sets of oligonucleotide primers containing T7 promoter and ER- or ERß-specific primer sequences. The sequence of the first set of primers for the first PCR was as follows: ER, 5'-ACAAGGGAAGTATGGCTATGCGCAAGTGAAATCTCCTCC-G-3', and 5'-CATCTCTCTGGCGCTTGTGTTCTGTCAATGCAGTTTGTAG-3'; ERß, 5'-TGTTACTGGTCCAGGTTCAACGCAAGTGAAATCTCCTCCG-3', and 5'-TTCTCTGTCTCCGCACAAGGTCTGTCAATGCAGTTTGTAG-3' (Green et al., 1986; Venden Heuvel et al., 1993; Mosselman et al., 1996). The sequences of the second set of primers for the secondary PCR were as follows: ER, 5'TAATACGACTCACTATAGGACAAGGGAAGTATGGCTATG-3', and 5'-CATCTCTCTGGCGCTTGTGT-3'; ERß, 5'-TAATACGACTCACTATAGGTGTTACTGGTCCAGGTTCAA-3', and 5'-TTCTCTGTCTCCGCACAAGG-3'. The described two sets of primers were synthesized by Rikaken Co Ltd (Nagoya, Japan). The first PCR reaction was conducted in a final volume of 50 µl containing PCR buffer (50 mM KCl, 10 mM Tris–HCl, pH 8.3, 1.5 mM MgCl2), 0.2 mM deoxyribonucleoside triphosphates (dNTP), 2 ng BamH/EcoRI DNA fragment of v-erbB, 10 pmol each of the first set of PCR primers and 2.5 IU of Amplitaq DNA polymerase (Perkin-Elmer Cetus, Norwalk, CT, USA). The second PCR reaction was conducted in a final volume of 100 µl containing PCR buffer, 0.2 mM dNTP, 20 pmol each of the second set of PCR primers and 5 IU of Amplitaq DNA polymerase. The mixture was amplified in 28 cycles of PCR at 95°C for 45 s for denaturing, 60°C for 45 s for annealing, and 72°C for 90 s for extension in a DNA Thermal Cycler (Perkin-Elmer Cetus).
The second PCR product was purified by a Gene Clean II Kit (BIO 101 Inc, La Jolla, CA, USA), and transcribed using 100 IU of T7 RNA polymerase (Gibco BRL, Gaithersburg, MD, USA) containing T3/T7 buffer [40 mM Tris–HCl, pH 8.0, 8 mM MgCl2, 2 mM spermidine-(HCl)3, 25 mM NaCl], 0.1M dithiothreitol (DTT), 10 mM ribonucleoside triphosphates, 40 IU of RNAase inhibitor (Promega, Madison, WI, USA), 20 nM template DNA, and 10 µCi of [-32P]-UTP (New England Nuclear Co, Boston, MA, USA) as a tracer in 100 µl vol. The reaction was incubated at 37°C for 1 h, treated with 70 IU of RNase-free DNase (Takara Shuzo Co Ltd, Kyoto, Japan) at 37°C for 5 min to remove the DNA template. Subsequently, the products were extracted with water-saturated phenol/chloroform, and passed through a Sephadex G50 column (Boehringer Mannheim, Mannheim, Germany). The amount of transcribed internal marker RNA was calculated with the total radioactivity of the transcribed RNA.
Competitive reverse transcription-polymerase chain reaction (RT–PCR)
Total RNA was isolated from the cells by the acid guanidinium thiocyanate-phenol-chloroform extraction method (Chomczynski and Sacchi, 1987). To obtain a standard curve each time, the total RNA (3 µg) and a series of diluted recombinant RNA (10–103 fmol) were reverse-transcribed with Moloney murine leukaemia virus reverse transcriptase (MMLV–RT, 200 IU, Gibco BRL) in 50 mM Tris–HCl, pH 8.3, 75 mM KCl, 3 mM MgCl2, 40 IUof RNAsin (Toyobo, Osaka, Japan), 10 mM DTT, 0.5 mM dNTP, and 30 pmol 3' end-specific primers (ER-3' and ERß-3') at 37°C for 1 h. The reaction was incubated for 5 min at 95°C to inactivate MMLV–RT.
The sequences of primers which were used to amplify the ER and ERß genes were as follows: 5'-ACAAGGGAAGTATGGCTATG-3' (ER-5'; 740–759, exon 2), 5'-CCAGAAGAGAACACCACCTT-3' (ER-3'; 1030–1049, exon 4), 5'-TGTTACTGGTCCAGGTTCAA-3' (ERß-5'; 267–286, exon 2), 5'-TTCTCTGTCTCCGCACAAGG-3' (ERß-3'; 540–559, exon 4) synthesized by Rikaken Co Ltd (Figure 1). The sizes of PCR products for rcRNA, and ER and ERß mRNA are 440, 309 and 293 bp respectively. PCR with reverse-7 transcribed RNA as templates (1 µl) and 5 pmol of each specific primer was carried out using a DNA Thermal Cycler (Perkin-Elmer Cetus) with 0.5 IU of Amplitaq DNA polymerase (Perkin-Elmer Cetus) in a buffer containing 50 mM KCl, 10 mM Tris–HCl, pH 8.3, 1.5 mM MgCl2, and 0.2 mM dNTP. Amplification was performed for 38 cycles at 94°C for 45 s for denaturing, 55°C for 45 s for annealing, and 72°C for 90 s for extension.
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Southern blot analysis
Amplified PCR products were applied to 1.2% agarose gel for electrophoresis performed at 100 V, and capillary-transferred to a nylon membrane (Immobilon-S; Millipore, Burlington, MA, USA) for 20 h using 10x standard sodium citrate/sodium chloride solution (SSC; 1.5 M NaCl, 0.15 M sodium citrate, pH 7.0). After blotting, the membrane was dried at 75°C and then cross-linked by UV irradiation (33 000 µJ/cm2 at 254 nm). The membrane was prehybridized in hybridization buffer (1 M NaCl, 50 mM Tris–HCl, pH 7.6, 1% sodium dodecyl sulphate) at 42°C for 2 h, and then in the same solution with the biotinylated ER
- or ERß-gene-specific oligonucleotide probe (ER probe; 5'-TGCTTCAGGCTACCATTATG-3'; ERß probe; 5'-TAGGCATCGGGATATCACTA-3') and biotinylated internal standard gene-specific oligonucleotide probe (5'-TGTTATACAGGGAGTGAAA-3') simultaneously to detect specific genes, or hybridized with biotinylated ER- or ERß-5' (10 pmol/µl, Rikaken Co Ltd) to detect their precise intensities at 42°C for 24 h (Figure 1
). The membrane was washed with 2x SSC for 15 min at room temperature, then with 2x SSC for 15 min at 42°C, and finally with 0.5x SSC for 15 min at 42°C. The detection reaction for hybridized biotin was performed using a Plex Chemiluminescent Kit (New England BioLabs, Beverly, MA, USA). Kodak XAR-5 film (Eastman Kodak, Rochester, NY, USA) was exposed to the membrane for 15 min. The strength of the recorded signal on film was analysed densitometrically, using BioImage (Millipore).
Statistical analysis
Statistical analysis was performed with one-way analysis of variance (ANOVA), followed by Fisher's test for multiple comparisons. P < 0.05 was considered to be significant. Data were expressed as the mean ± SD.
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Results |
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In the competitive RT–PCR/Southern blot analysis for ER
and ERß mRNA, only two predicted PCR products were detected without non-specific products. The level of ER and ERß mRNA was determined using a standard curve of a serial dilution of rcRNA by competitive RT–PCR/Southern blot analysis, as detailed in our previous studies (Misao et al., 1995a,b) (Figure 2). We performed total RNA isolation and competitive RT–PCR/Southern blot analysis in three different parts of each individual sample.
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The expression of ER
and ERß mRNA was detected in all luteal samples analysed. Luteal ER and ERß mRNA levels were significantly lower (P < 0.01 and P < 0.05 respectively) at the LS than those at the ES and MS of the endometrium. ER mRNA levels were as follows: 24.16 ± 14.43 fmol/µg total RNA in the ES, 29.93 ± 10.24 fmol/µg total RNA in the MS, and 6.85 ± 3.16 fmol/µg total RNA in the LS. ERß mRNA levels were as follows: 22.13 ± 12.89 fmol/µg total RNA in the ES, 28.38 ± 15.09 fmol/µg total RNA in the MS, and 6.83 ± 1.47 fmol/µg total RNA in the LS (Figure 3). The ratio of ER to ERß mRNA levels showed no change during the secretory phases of the endometrium (0.94 ± 0.36 in the ES, 0.96 ± 0.42 in the MS, and 1.12 ± 0.55 in the LS) (Figure 4).
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Discussion |
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The discovery of a new member of the nuclear receptor superfamily with ligand specificity for oestrogens (Kuiper et al., 1996
, 1997; Mosselman et al., 1996), termed ERß, has increased the potential range of target tissues for oestrogen action beyond those in which ER is expressed. Several studies of ER knock-out mice indicate that ERß could not compensate for the function of ER completely (Lubahn et al., 1993; Korach et al., 1996). Therefore, the function of ERß is considered to be, in part, independent from that of ER. Steroid secretory function in the corpus luteum is governed not only by the central endocrine drive of luteinizing hormone, but also by autocrine and paracrine intraovarian regulation, such as by oestrogen or progesterone (Ohara et al., 1987). The expression of ER and ERß mRNA in the corpus luteum, as shown in the present study, suggests the possibility of autocrine and paracrine actions of the corpus luteum, mediated via receptors and/or steroid-linked local factors.
Species differences in the expression of ER and ERß mRNA are shown in some tissues. The most striking difference between the human and the rodent is seen in the prostate, where the expression of ERß is high in the rat, but is relatively low in the human (Enmark et al., 1997; Kuiper et al., 1997). The high gastrointestinal tract level of ERß in the human contrasts with the much lower level in the rat (Kuiper et al., 1997; Enmark et al., 1997). In the rat, while ERß mRNA is expressed preferentially in granulosa cells of small, growing, and pre-ovulatory follicles, the weak expression of ERß mRNA was observed in a subset of corpora lutea (Byers et al., 1997). In this study, ERß mRNA was detected in the human ovarian corpus luteum. Several studies indicate that the relative level of ER and ERß mRNA differs in different tissues. In the rat, the ER mRNA is highly expressed in epididymis, testis, pituitary, kidney and adrenal in comparison with ERß mRNA, while a relatively high expression ratio of ERß to ER mRNA is found in the prostate, bladder and various brain sections (Kuiper et al., 1997; Enmark et al., 1997). On the other hand, ovary and uterus have equal levels of both ER subtypes (Kuiper et al., 1997; Enmark et al., 1997). In the human corpus luteum, there was no difference between the levels of ER and ERß mRNA.
The function of the corpus luteum is terminated by the process of luteolysis, which induces a marked decrease of progesterone and oestrogen production, resulting ultimately in formation of the corpus albicans. Oestrogen is luteotropic in the rabbit (Yuh and Keyes, 1981). In contrast, luteolytic effects of oestrogens have been observed in the domestic ungulate (Cook et al., 1974), the monkey (Stouffer et al., 1980) and the human (Gore et al., 1973) and might be one important component of the mechanisms regulating the corpus luteum during its life span. In the present study, ER and ERß mRNA levels were significantly lower at the LS than those at the ES and MS of the endometrium, which might be consistent with the life span of the corpus luteum. During pregnancy, ER mRNA level in the rat corpus luteum shows alteration as a peak at mid-pregnancy, whereas the ERß mRNA level remains constant throughout pregnancy (Telleria et al., 1998). In human corpus luteum, alteration of ER and ERß expression during pregnancy is as yet unknown.
Several studies indicates that degeneration of the corpus luteum occurs by apoptosis (Shikone et al., 1996; Yuan and Giudice, 1997). Moreover, recent studies have proposed a role for oestradiol in corpus luteum apoptosis. In human and baboon, the expression of connexin-43, a gap junction protein, is hormonally regulated by locally produced factors such as oestradiol and progesterone and is involved in the process of luteolysis through luteal cell apoptosis (Khan-Dawood et al., 1996). In pigs, oestradiol is a strong luteotrophic factor and tumour necrosis factor that not only exerts direct apoptotic effects resulting in luteolysis but also prevents the luteotrophic effects of oestradiol (Wuttke et al., 1997). In humans, the high expression of ER subtypes at ES and MS might induce the luteolytic effects of oestrogen in the direction of luteolysis at LS, whereas the down-regulation of ER subtypes at LS might conversely prevent luteolysis. Therefore, the expression of ER subtypes might interact in a complex fashion with other apoptotic and anti-apoptotic factors when the corpus luteum is undergoing apoptosis. However, it is impossible to state definitively whether the decrease in both ER subtype mRNA levels merely reflects the down-regulation of luteal functions or whether it affects luteolysis; although oestrogens might play a role in modulating luteal life span and function via both ER and ERß.
In human ovarian granulosa cell lines, a functional ER was confirmed by a transfection study (Hurst and Leslie, 1997). Identification of ER mRNA is indirect evidence that ER itself is present. Functional ER expression in human corpora lutea needs to be demonstrated in future studies.
In conclusion, this study demonstrates that ERß co-expresses with ER in the human corpus luteum and might play a biological role in the regulation of steroidal action of the corpus luteum in collaboration with ER.
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1 To whom correspondence should be addressed
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Submitted on July 1, 1998; accepted on September 23, 1998.
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