Molecular Human Reproduction, Vol. 8, No. 11, 998-1004,
November 2002
© 2002 European Society of Human Reproduction and Embryology
Uterine physiology |
The effect of mifepristone on the expression of insulin-like growth factor binding protein-1, prolactin and progesterone receptor mRNA and protein during the implantation phase in human endometrium
Division of Obstetrics and Gynecology, Department of Woman and Child Health, Karolinska Hospital, S-171 76 Stockholm, Sweden
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Abstract |
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Insulin-like growth factor binding protein-1 (IGFBP-1) and prolactin are recognized as crucial signals for the initiation and maintainance of decidualization. The purpose of the study was to investigate the effect of mifepristone on the expression of IGFBP-1, prolactin and progesterone receptors (PR) during the implantation phase in human endometrium. Eight fertile women were studied during control and treatment cycles. Treatment with 200 mg of mifepristone was administered on day LH +2. Endometrial samples were collected on day LH +6 to +8. Expression of IGFBP-1, prolactin and PR was identified using immunohistochemistry, and mRNA levels were determined with RT–PCR. In control specimens, IGFBP-1 and prolactin were localized to the cytoplasm of the endometrial glandular and to a lesser extent in stromal cells. In the same samples, PR immunoreactivity was detected in the nucleus of the endometrial stromal cells, and was absent from the glandular cells. After mifepristone treatment, there was a significant increase in the immunostaining and mRNA expression for IGFBP-1 and PR. Prolactin expression increased only slightly after treatment. These results support the view that administration of mifepristone in the early luteal phase does not simply retard endometrial development. Our findings provide further insight into the regulation of IGFBP-1 and prolactin by PR in the human endometrium in vivo.
endometrium/IGFBP-1/mifepristone/progesterone receptor/prolactin
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Introduction |
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Human endometrium is a target organ for ovarian steroids. Estrogen is mitogenic for the endometrium, whereas progesterone blocks and modifies the action of estrogen and changes the proliferating endometrium into a secretory one. Secretion peaks on day 21 of the cycle and coincides with the date of implantation of the blastocyst in the event of fertilization. This period has been called the implantation window and is the short period during which implantation is possible (Bergeron, 2000
). Classical and contemporary studies have shown that progesterone induces protein secretion during the luteal phase to permit implantation. It acts through progesterone receptors (PR) that are regulated by estrogen (Bell et al., 1987; Hustin et al., 1994; Seppala et al., 1994; Oehler et al., 2000). Nevertheless, increasing evidence demonstrates that growth factors and related peptides mediate and modulate the actions of hormones at their target tissues through autocrine/paracrine mechanisms (Simon et al., 2000). A number of such local regulators have been identified in the human endometrium. Among these, one group [insulin-like growth factor binding protein-1 (IGFBP-1), prolactin] is considered to represent paracrine parameters of differentiation, and another one (leukaemia inhibitory factor, epidermal growth factor, and transforming growth factors) consists of factors involved in implantation. These regulators are recognized as crucial signals for the initiation and maintainance of decidualization in the endometrium during the peri-implantation period (Licht et al., 2001). IGFBP-1 and prolactin have been shown to be produced by endometrial stromal cells in the secretory phase endometrium and in the decidua (Irwin et al., 1993; Telgmann and Gellersen, 1998).
The insulin-like growth factor family consists of the structurally related peptides insulin-like factor-I (IGF-I) and factor-II (IGF-II), their receptors (Type I and Type II IGF receptor) and a group of seven structurally homologous binding proteins (IGFBP-1–7) (Rinderknecht and Humbel, 1978a,b; Ghahary and Murphy, 1989; Oh et al., 1996). Members of the IGF family undergo specific changes in expression in human endometrium throughout the menstrual cycle (Rutanen, 1998). IGFBP-1 was formerly known as placental protein-12 (Koistinen et al., 1986) and 
l-progesterone-dependent endometrial globulin (l-PEG) (Bell, 1986). In humans, IGFBP-1 is a major product of the secretory endometrium, and is abundantly produced by the maternal decidua and is not a placental protein at all (Rutanen et al., 1986). Immunoreactive IGFBP-1 is expressed in a cyclic fashion in endometrial stromal cells, with the highest expression seen in the mid-to-late secretory phase (Waites et al., 1988). In addition, the IGFBP-1 mRNA is expressed similarly in both intra- and extrauterine pregnancies, indicating that the local physical stimulus from an implanting fetus is not necessary to induce or maintain decidual IGFBP-1 gene expression (Zygmunt et al., 2000). IGFBP-1 is believed to play a major role in endometrial development in the process of implantation.
Prolactin is one of the major proteins synthesized and secreted during decidualization of the human endometrium (Maslar and Riddick, 1979). Prolactin synthesis is detected between the mid-secretory phase and menses, and coincides with the first histological signs of decidualization. In the event of pregnancy, decidual prolactin secretion increases steadily after implantation. Prolactin, synthesized de novo by decidual cells, is indistinguishable from pituitary prolactin by chemical, immunological and biological criteria (Tomita et al., 1982). Moreover, the amino acid encoding sequence is identical for pituitary and decidual prolactin (Takahashi et al., 1984). The temporal and spatial expression of prolactin in the human endometrium suggests a role in the preparation for implantation and subsequent placentation (Bryant-Greenwood et al., 1993; Jabbour and Critchley, 2001). Indeed, prolactin expression is now commonly used as a marker for functional decidualization.
Mifepristone is a synthetic steroid that blocks the biological effects of progesterone at the receptor level (Spitz et al., 2000). We have previously reported that once-a-month treatment with a single dose of 200 mg of mifepristone on day LH +2 is an effective contraceptive method (Gemzell-Danielsson et al., 1993). The contraceptive effect seems to be primarily due to inhibition of endometrial development and function (Gemzell-Danielsson et al., 1994). On the other hand, mifepristone inhibits secretory activity but has no obvious effect on the predecidual reaction of the human endometrium during the secretory phase (Li et al., 1988). Whether the development of endometrial receptivity is simply delayed is still a matter of controversy (Sarantis et al., 1988).
In the present study, our aim was to examine the influence of early luteal phase administration of mifepristone, at a dose of 200 mg, on the expression of IGFBP-1, prolactin and PR during the implantation stage in the human endometrium of fertile women. Endometrial samples were collected on days 6–8 after ovulation from cycles with or without mifepristone treatment on day LH +2. For comparison, decidual biopsies were obtained from patients undergoing surgery because of ectopic tubal pregnancies. The expression of IGFBP-1, prolactin and PR protein and mRNA was analysed by immunohistochemistry and RT–PCR.
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Materials and methods |
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Subjects
A total of eight healthy women, 22–40 years of age, with regular menstrual cycles (25–35 days) volunteered for the study. The women served as their own controls. None of them had used a steroid contraceptive or an intrauterine device for a minimum of 3 months prior to the study. Gynaecological examination was performed on admission. The volunteers were advised to use a barrier method for contraception. In addition, decidual biopsies were obtained from patients undergoing surgery because of extrauterine tubal pregnancies. The ethics committee of the Karolinska Hospital approved the study. Informed consent was obtained from each volunteer or patient before inclusion in this study.
The study included one control and one treatment cycle. A single dose of 200 mg mifepristone was administered on cycle day LH +2 during treatment cycles. Endometrial biopsies were performed on the corresponding day LH +6 to LH +8 of control and treatment cycles. The biopsies were obtained from the uterine fundus using a Randall curette without prior cervical dilatation or anaesthesia. All specimens were frozen immediately and stored in liquid nitrogen until analysed.
Hormone assessment
During the control and treatment cycles, daily morning urine samples were collected and analysed for estrone- and pregnanediol-glucuronide and LH using enzyme immunoassays (Cekan et al., 1986). The homones were expressed in nmol per mmol creatinine for estrone- and pregnanediol-glucuronide and per mmol creatinine for LH (Metcalf and Hunt, 1976). For creatinine analysis, a commercial kit (Sigma Diagnostics, St Louis, MO, USA) was used.
In addition, all subjects determined the LH peak in urine samples collected twice daily from approximately cycle day 10 to LH +2 by using a rapid self-test (Clearplan, Searle Unipath Ltd, Bedford, UK).
Preparation of mRNA and RT–PCR
The procedure for mRNA preparation has been described previously in detail (Christow et al., 2002). Briefly, total tissue RNA was isolated using ULTRASPES-RNA Isolation reagent (Biotech Laboratories, Houston, TX, USA) according to the manufacturer’s instructions.
Reverse transcription (RT) was carried out on 2 µg of total RNA using the First-Strand cDNA Synthesis kit (Pharmacia Biotech AB, Uppsala, Sweden). For cDNA amplification, 1 µl RT product was amplified in a volume of 25 µl, containing 10xPCR buffer (100 mmol/l Tris–HCl, pH 8.4, 500 mmol/l KCl), 1.5 mmol/l MgCl2, 200 µmol/l of each deoxynucleotide, 0.4 umol/l of each primer and 2.5 IU Tag DNA polymerase. The sequences of the oligonucleotide primers used for RT and PCR reactions are given in Table I.
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The amplifications were performed in the following steps: 95°C for 30 s, annealing at 58–68°C for 30–60 s, depending upon specific primers, and extension at 72°C for 1 min. The optimal PCR cycle number for each message was chosen to yield product levels at the linear portion of the serial dilution curve (curves not shown). Thus 25 cycles for 28S, 30 cycles for PR, 32 cycles for IGFBP-1 and 32 cycles for prolactin were chosen. The PCR products were electrophoresed through a 1.5% agarose gel and visualized with ethidium bromide. A 100 bp ladder (Pharmacia Biotech AB, Uppsala, Sweden) was used as a molecular weight standard for each gel. All PCR conditions were optimized for quantification of relative message contents with respect to human ribosomal protein 28S product levels.
The films were scanned for measurements of integrated optical density using Scion Image version 1.62 (Wayne Rasband, National Insitutes of Health, USA). The arbitrary densitometric level of signals was determined in each case. The relative mRNA amounts of IGFBP-1, prolactin and PR were expressed as a ratio of specific mRNA to 28S mRNA.
Immunohistochemical analyses
IGFBP-1
The staining procedure used in this study has been described previously (Marchini et al., 2001). The frozen sections were fixed in 2% buffered formaldehyde for 20 min and then immersed in EBSS supplemented with 1% HEPES buffer solution 1 mol/l (Life Technologies Ltd, Paisley, UK) dissolved in 0.1% Quillaja Bark Saponin (Sigma, St Louis, MO, USA), adjusted to pH 7.4. Endogenous peroxidase activity was destroyed with 3% hydrogen peroxide at room temperature. Blocking of non-specific binding was performed with 1.5% horse serum 30 min. IGFBP-1 was localized using an affinity-purified goat polyclonal antibody [raised against a peptide mapping near the carboxy terminus of IGFBP-1 of human origin (SDS Systems, Santa Cruz Biotechnology, Inc., Falkenberg, Sweden)] at a dilution of 1:160 in the EBSS–saponin buffer supplemented with 0.02% sodium nitride incubated overnight at 4°C in a humid chamber. Prior to primary antibody binding, an avidin–biotin Blocking Kit was utilized (Vector Laboratories, Inc. Burlingame, CA, USA). Binding was visualized using a horse anti-goat biotinylated antibody for 30 min at room temperature. The slides were incubated with the avidin–biotin–peroxidase detection system (Vector) for a further 45 min at room temperature and then developed with diaminobenzidine (DAB Kit; Vector) for 10 min, and counterstained in Mayer’s 10% haematoxylin prior to mounting. Negative controls were incubated similarly but EBSS replaced the primary antibody. To check for primary antibody specificity, the primary antibody was replaced with non-immune serum of the equivalent concentration from the same species.
Prolactin
A similar protocol was used for prolactin immunolocalization, with the exception that an affinity-purified goat polyclonal antibody [raised against a peptide mapping near the carboxy terminus of prolactin of human origin (SDS Systems)] was used at a dilution of 1:320.
PR
The consecutive sections of each specimen were fixed in acetone for 3 min. Sections were washed with PBS and then incubated in 3% hydrogen peroxide in PBS for 30 min at room temperature. Blocking of non-specific binding was performed with 1.5% horse serum in PBS 30 min. PR was localized using a mouse monoclonal antibody PR (NCL-PGR-312, common for both the A and B isoforms; Novocastra Laboratories Ltd, Balliol Business Park West, Benton Lane, UK) at a dilution of 1:1600 for 2 h at room temperature. Specific binding of the primary antibody was detected using a horse anti-mouse biotinylated antibody for 30 min at room temperature. An avidin–biotin–peroxidase detection system (Vector) was applied for a further 45 min incubation at room temperature. Finally, the sections were developed with diaminobenzidine (DAB Kit; Vector) for 4 min. For negative controls, the primary antibody was omitted.
Morphometric analyses
The occurrence of specific staining for IGFBP-1, prolactin or PR was characterized as absent (–, 0%), weak (+, 1–30%), moderate (++, 31–60%), or strong (+++, 61–100%). Immunohistochemical staining was evaluated blindly by two independent persons, using a Zeiss light microscope at x200 magnifications.
Statistics
Differences in immunohistochemical staining were analysed by using the Wilcoxon signed ranks test. Specific mRNA levels were evaluated by Student’s t-test. Analyses were performed using the statistical package StatView (SAS Institute Inc., SAS Campus Drive, Cary, NC, USA). P < 0.05 was considered as statistically significant.
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All control and treatment cycles were ovulatory with an LH peak. Urinary concentrations of estrone- and pregnanediol-glucuronide and LH were not significantly affected by the administration of mifepristone (data not shown).
Immunohistochemistry
IGFBP-1, prolactin and PR were detected by immunohistochemistry in the samples from decidua and endometrium of controls and after treatment with mifepristone (Figure 1). The results are summarized in Figure 2 and Table II. Immunostaining was mainly present in the cytoplasm of the glandular epithelial cells and to a lesser extent in stromal cells for IGFBP-1 and prolactin. High staining intensity was observed in the glandular cells from decidua of extrauterine pregnancy which was used as a positive control for IGFBP-1 and prolactin. Intense immunoreactivity for PR was detected in the nucleus of the stromal cells, and in glandular cells after treatment (Table II). Controls were performed by omitting the primary antibody and were found to be negative.
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IGFBP-1
Significant increases were found in staining intensity of the glandular and stromal cells between controls and treatment with mifepristone (P < 0.05). Compared with the staining in the glandular cells, weaker immunoreactivity was identified in the stroma.
Prolactin
Strong prolactin immunostaining was detected in the endometrial glandular cells in all groups. There were clear increases in staining intensity for prolactin in both the glandular and stromal cells following mifepristone treatment, although these did not reach statistical significance.
PR
Different staining patterns for PR were observed between the three groups. In the controls and in decidua of extrauterine pregnancy, no glandular staining was discernible, whereas staining in glands from mifepristone-treated endometrium was clearly detectable. The difference between these groups was highly significant (P < 0.0005). Immunostaining in the endometrial stroma also increased significantly following treatment with mifepristone in comparison with control cycles (P < 0.05).
RT–PCR analysis
RT–PCR assays were established for IGFBP-1, prolactin, PR and 28S using species-specific oligonucleotide primers. Messenger RNA for all IGFBP-1, prolactin and PR was detected by RT–PCR in total RNA extracted from each sample (Figure 3). As shown in Figure 4, the administration of mifepristone increased the IGFBP-1, prolactin and PR mRNA expression. The expression of IGFBP-1 and PR mRNA increased significantly during the implantation phase in the human endometrium after treatment with mifepristone compared with the controls (P < 0.01 or P < 0.05 respectively) (Figure 4).
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Discussion |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionAcknowledgementsReferences |
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We have previously demonstrated that administration of the antiprogestin mifepristone in the early luteal phase is an effective contraceptive method (Gemzell-Danielsson et al., 1993
). The contraceptive effect seems to be primarily due to inhibition of endometrial development and function (Gemzell-Danielsson et al., 1994). Treatment with low intermittent or daily doses of mifepristone disturbs endometrial maturation and secretory activity without inhibiting ovulation and the normal rhythm of the menstrual cycle (Gemzell-Danielsson et al., 1996). The present study was designed to investigate the effect of mifepristone on the expression of IGFBP-1 and prolactin during the implantation phase. IGFBP-1 and prolactin are products of the cyclic endometrium and of the pregnant decidua. Both of these proteins are thought to function independently in endometrium or decidua as local mediators within the uterus without reaching the systemic circulation. The precise role of IGF-II in embryo implantation is not known but its abundance at the invading front of the trophoblast and the proximity of decidual cells expressing IGFBP-1 are suggestive of a role for this protein and its inhibitor in invasion (Han et al., 1996). Prolactin has been shown to have an immunosuppressive function and to be involved in the maintenance of T-cell immunocompetence in the endometrium (Bernton et al., 1988). It could be speculated that an effect on IGFBP-1 and/or prolactin may mediate the anti-nidatory action of mifepristone.
IGFBP-1 and prolactin have been separately immunolocalized previously in endometrium and decidua (Bryant-Greenwood et al., 1993). Prolactin appears first in the glandular epithelium and then in the stroma. IGFBP-1 is expressed later in the secretory phase. IGFBP-1 and prolactin mRNA are also present in non-pregnant endometrium in the secretory phase of the menstrual cycle (Huang et al., 1987; Julkunen et al., 1988). In the present study, IGFBP-1 and prolactin immunostainings were observed in the cytoplasm of the glandular and stromal cells in human endometrium during the mid-secretory phase. The glandular cell staining intensity detected for both IGFBP-1 and prolactin was more pronounced than that of the stroma. Following treatment with 200 mg of mifepristone on cycle day LH +2, IGFBP-1 and prolactin immunostaining intensity increased markedly in both glandular and stromal cells during the peri-implantation period, although this increase was only significant for IGFBP-1. Consistent with the observations for immunoreactive IGFBP-1 and prolactin, relative expression levels of IGFBP-1 and prolactin mRNA were also highest in endometrium from mifepristone-treated cycles.
Prolactin expression is now commonly used as a marker of functional decidualization. Administration of mifepristone in the early luteal phase seems to induce a delay in glandular secretory differentiation in the human endometrium (Gemzell-Danielsson et al., 1994). However, in the present study, administration of mifepristone on day LH +2 failed to prevent expression of prolactin mRNA and protein. Thus the administration of mifepristone in the early luteal phase does not simply retard endometrial development. The results of the present study support an earlier observation that administration of mifepristone has no demonstrable effect on the predecidual reaction (Li et al., 1988). This earlier study investigated the effect on endometrial development following various doses of mifepristone administered on day LH +2 to +6. It was observed that while glandular secretory activity appeared retarded, glandular mitotic count remained unchanged, while still other parameters such as stromal extravasation appeared advanced. In an in-vitro study, the concentration of prolactin was found to be decreased in the incubation media, while the decidual tissue concentration of prolactin was significantly increased, by mifepristone (Bischof et al., 1986).
In the present study, mifepristone increased the expression of endogenous IGFBP-1, prolactin and PR mRNA and protein during implantation phase in human endometrium in vivo. The increase in PR is consistent with the antagonistic action of mifepristone and confirms our previous findings in the implantation phase endometrium. The observed effect on IGFBP-1 and prolactin is more surprising. Both proteins seemed to increase, particularly in the glands, although this was significant only for IGFBP-1. A stimulating effect of an antiprogesterone is unexpected since accumulating evidence has suggested that progesterone is responsible for the production of these two proteins in the human endometrium (Rosenberg et al., 1980; Rutanen et al., 1986). The secretion of IGFBP-1 and prolactin increases dramatically when the serum progesterone level rapidly rises during the first trimester of pregnancy (Tulchinsky et al., 1972). In vitro, both proteins have been shown to be extensively induced when human endometrial stromal cells are decidualized by progestin in a long-term primary culture system (Bell et al., 1991; Tseng et al., 1992). Mifepristone has proved to be a remarkably active antiprogesterone in humans. At the molecular level, mifepristone binds with high affinity to the progesterone receptor. Upon binding, mifepristone induces transconformation in the ligand-binding domain. These peculiarities have consequences at different steps of the receptor function as compared with agonists (Cadepond et al., 1997). However, agonist-like proliferative effects have been reported with the progesterone antagonist mifepristone in cultured breast cancer cell lines and in post-menopausal women under conditions in which inhibition would be expected (Gravanis et al., 1985; Bowden et al., 1989). Furthermore, an in-vitro study has shown that mifepristone causes a transient superinduction of IGFBP-1 and prolactin secretion in human endometrial stromal cells (Tseng et al., 1992). Functional analysis of the promoter has indicated that PR activates the IGFBP-1 promoter via a progesterone-response element (PRE) sequence specifically in decidualized stromal cells (Gao et al., 1999). In contrast, stromal cells with no or only low PR expression do not show responsiveness of IGFBP-1. Thus, the increase in IGFBP-1 synthesis could, at least in part, be directly linked to the increase in PR. A subsequent study has demonstrated that ligand-activated PRA is a stronger transactivator than PRB to increase the promoter activity as well as the induction of the endogenous IGFBP-1 gene in endometrial stromal cells (Gao et al., 2000). The high transactivation capacity of PRA was activated by progesterone and mifepristone, but not by cortisol. Interestingly, preliminary data have shown that PRA is also a strong transactivator for the production of prolactin (Gao et al., 2000). However, these activating effects of PR on IGFBP-1 and prolactin would require mifepristone to be acting as an agonist rather than as an antagonist.
There is the possibility that mifepristone switches from antagonistic property to agonist activity, depending on the intervention of other signalling pathways. It has been shown that elevation of cAMP levels in a human breast cancer cell line leads to the functional reversal of progesterone antagonist action. cAMP amplifies the transcriptional signals of agonist-occupied steroid receptors. Additionally, in the case of progesterone antagonists at least, cAMP can switch the transcriptional phenotype to render them potent agonists (Sartorius et al., 1993; Brosens et al., 1999). A possible explanation could be that treatment with mifepristone alters the signalling mechanisms that may affect cAMP activation in vivo leading to the unexpected observation of stimulation as opposed to suppression by the PR antagonist.
In conclusion, the results from the present and previous studies indicate that endometrial IGFBP-1 may play an important role in human implantation. The administration of mifepristone in the early luteal phase does not simply retard endometrial development but has complex effects on the endometrium. Our findings provide further insight into the regulation of IGFBP-1 and prolactin mRNA and protein by the PR in human endometrium in vivo.
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The authors would like to thank research nurses Lena Elffors-Söderlund and Margareta Hellborg for taking good care of the patients. This investigation was supported by grants from the Karolinska Institute and the Swedish medical research council (project no. A0855).
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1 To whom correspondence should be addressed. E-mail: kristina.gemzell{at}kbh.ki.se
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References |
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Submitted on May 14, 2002; accepted on August 16, 2002.
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