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Original Studies |
Department of Obstetrics-Gynecology, University of Texas Southwestern Medical Center (G.R.A., K.Z., A.J., B.R.C.), Dallas, Texas 75235; Department of Pathology, University of Colorado Health Sciences Center (D.E.), Denver, Colorado 80262; and Department of Obstetrics and Gynecology, University of Illinois at Chicago (S.E.B.), Chicago, Illinois 60612
Address correspondence and requests for reprints to: Serdar E. Bulun, M.D., Department of Obstetrics-Gynecology, University of Illinois at Chicago, 820 South Wood Street, M/C 808, Chicago, Illinois 60612. E-mail: sbulun{at}uic.edu
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Abstract |
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levels. Using RNase protection assay, we also demonstrated indirectly
that only PR-A transcripts were present in endometriotic tissue samples
(n = 8), whereas both PR-A and PR-B transcripts were readily
detectable in all eutopic endometrial samples (n = 8). This was
indicative that failure to detect PR-B protein in endometriotic tissues
is due to the absence of PR-B transcripts. We conclude that
progesterone resistance in endometriotic tissue from laboratory and
clinical observations may be accounted for by the presence of the
inhibitory PR isoform PR-A and the absence of the stimulatory isoform
PR-B. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The enzyme 17ß hydroxysteroid dehydrogenase (HSD) type 2 catalyzes the conversion of estradiol to the less biologically active estrone. We have demonstrated previously the expression of 17ß-HSD type 2 in luteal phase endometrium but not in endometriotic tissue simultaneously biopsied from the same patients (4). Furthermore, the activity of this enzyme has been shown to be stimulated by progesterone in endometrial glandular cells (5, 6). The lack of 17ß-HSD type 2 in endometriotic tissue during the luteal phase, despite histologically recognizable secretory changes, is suggestive of selective resistance of certain target genes to progesterone action. Moreover, failure of endometriosis to regress in response to treatment with progestins in a significant number of patients is another indication of progesterone resistance. Progesterone action is mediated by its cognate receptors that belong to the nuclear hormone receptor family (7). Recently, two progesterone receptor (PR) isoforms have been identified, namely PR-A and PR-B (8). PR-A is a 94-kDa protein, whereas PR-B is a 114-kDa protein that contains additional 164 amino acids at its amino terminal (9, 10, 11). These isoforms may arise as a result of either initiation of translation from alternative sites in the same messenger RNA (mRNA) (12) or by transcription from alternative promoters (13).
Although the exact functions for each of these isoforms are still unclear, there is increasing evidence that they are functionally different (13, 14). PR-B tends to be a stronger activator of progesterone target genes, whereas PR-A has been shown to act as a dominant repressor of PR-B (15, 16). PR-A also decreases the response to other steroid hormones such as androgen and estrogen (17, 18). PR isoforms have differential target gene specificity and may interact differently with a given promoter. For example, PR-A is able to activate the ovalbumin promoter (14), whereas PR-B activates the mouse mammary tumor virus promoter more efficiently than PR-A (19). Furthermore, several studies have shown that the differences between these isoforms are not only promoter specific but also cell specific (15, 16, 19, 20). Therefore, it is conceivable that the alterations in the ratio of PR-A to PR-B in a certain target tissue may modify the overall progesterone action via differential regulation of specific progesterone response genes.
The aim of this study is to investigate whether there is a differential expression of PR-A and PR-B between eutopic endometrium and its diseased counterpart, endometriotic tissue. The alteration in the ratio of PR-A to PR-B in endometriotic tissue may be an important mechanism that is responsible for progesterone resistance (e.g. failure of endometriotic glandular cells to express 17ß-HSD type 2 in response to progesterone). As mentioned earlier, the lack of this enzyme will lead to impaired inactivation of estradiol, giving rise to elevated levels of this mitogen in endometriotic tissue.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Eighteen patients (age range, 22–36) undergoing laparoscopy for endometriosis associated with chronic pelvic pain, severe dysmenorrhea, dyspareunia, and infertility were included in this study. At the time of laparoscopy, paired samples of eutopic endometrium and extra-ovarian endometriosis were obtained from each of these patients. None of these patients received hormonal treatment for at least 3 months before the surgery. Patients had regular predictable menstrual cycles with intervals varying from 26–31 days. Tissues were washed several times with ice-cold phosphate buffered saline (PBS) to remove blood. A portion each of specimen was stored in formalin for histological examination. The remaining tissues of eutopic endometrium and endometriosis were snap-frozen and transported to the laboratory in liquid nitrogen. Specimens were stored at -70 C before protein and RNA extraction. All specimens were confirmed histologically. Written informed consent was obtained from patients participating in the study, and the protocol was approved by the Institutional Review Board for human research of the University of Texas Southwestern Medical Center.
Protein extraction
Protein extraction and immunoblotting were performed as described previously (21). In the cold room, a cytosol fraction was prepared by homogenizing the tissue in 4 mL lysis buffer per gram wet weight. Lysis buffer was comprised of 10 mM Tris-HC1 (pH 7.4), 1 mM EDTA, 0.4 M NaCl, and 10% glycerol. A mixture of protease inhibitors containing appotinin (77 µg/mL), leupeptin (1 µg/mL), pepstatin A (1 µg/mL), bacitracin (100 µg/mL), benzamidine (1 µg/mL), and phenylmethylsulfonyl fluoride (5 mM) was added to the lysis buffer. The homogenate was kept on ice for 1 h and was centrifuged at 10,000 g for 20 min. The supernatant was centrifuged at 100,000 x g for 30 min at 4 C. Protein concentration was determined using the BCA protein assay Kit (Pierce Chemical Co., Rockford, IL).
Western blotting for PR
Western analysis was performed after immunoprecipitation, as described previously, with some modifications (22). One hundred micrograms of eutopic endometrial and 300 µg endometriotic protein extracts were mixed with 4 µg mouse monoclonal anti-PR antibody (AB-52) (Santa Cruz Biotechnology, Inc., Santa Cruz, CA), which recognizes a common region for both PR-A and PR-B. The mixture was kept on ice for 1 h. Each sample was then mixed with 100 µL protein A-Sepharose (Amersham Pharmacia Biotech, Piscataway, NJ). The antibody, AB-52 readily binds to protein A-Sepharose. Protein A-Sepharose was prepared by mixing an equal volume of packed swollen protein A-Sepharose with buffer A [10 mM Tris, 1.5 mM EDTA and 12 mM monothioglycerol (pH 7.5)]. The mixture was incubated at 4 C on a rocker platform for 1 h, and the immuno-complex was collected by centrifugation at 10,000 x g for 1 min. Each pellet was washed twice with 500 µl buffer A, suspended in SDS loading buffer, and incubated at 100 C for 5 min. The pellet of protein A-Sepharose was then removed by centrifugation at 10,000 x g for 1 min. Ten micrograms of T47D breast cancer cell protein extract were used as a positive control and were subjected to immunoprecipitation, as described above. Disease-free peritoneal biopsies (n = 3) from patients with endometriosis were used as negative controls. As a negative control for the method, cytosols derived from human endometrium were subjected to these steps, except that no antibody (AB-52) was added. The supernatant was then separated on a 6% polyacrylamide gel by electrophoresis at room temperature and transferred to a nitrocellulose membrane overnight at 4 C. The membrane was blocked for 2 h at room temperature in PBS containing 10% low fat milk powder and 0.1% Tween. The membrane was then incubated with AB-52 (10 µg/mL) overnight at 4 C. The blot was then washed with PBS containing 0.1% Tween and incubated with horseradish peroxidase-linked sheep antimouse IgG (Zymed, South San Francisco, CA) at a dilution of 1:10,000 for 1 h. The blot was washed with PBS containing 0.1% Tween, and immunoreactive proteins in blots were detected using the enhanced chemiluminescence (ECL) reagent (Amersham Pharmacia Biotech), or alternatively ECL Plus reagent (Amersham Pharmacia Biotech) as per the manufacturer’s instructions.
Western blotting for estrogen receptor- (ER-)
Protein extracts from paired samples of eutopic endometrium (30
µg) and endometriosis (30 µg) were immunoprecipitated using mouse
monoclonal antibody (Santa Cruz Biotechnology, Inc.) against ER-.
T47D breast cancer cell protein extracts were used as positive
controls, whereas protein extracts of the disease-free peritoneum from
patients with endometriosis were used as negative controls. The
immuoprecipitate was fractionated on a 10% polyacrylamide gel, and
immunoreactive protein was detected using the ECL kit.
RNA isolation and RNase protection assay
As mentioned earlier, PR-B protein and its truncated isoform PR-A may be encoded via the use of alternative translation start sites in the full-length (PR-B) mRNA or from truncated (PR-A) and full-length (PR-B) mRNA species that arise by transcription using alternative promoters (8, 12, 13). To determine the mechanism that is responsible for the lack of PR-B protein in endometriotic tissue, we developed an RNase protection assay (RPA) to detect the specific transcripts of PR-B. Total RNA was isolated from tissues by the guanidium thiocyanate-cesium chloride method, as described previously (23). Then, riboprobes for the RPA were prepared in the following fashion: reverse transcription (RT) was performed using 3 µg total RNA from T47D cells using superscript II and random hexamers to generate a complementary DNA (cDNA) library. Specific oligodeoxynucleotide primers were synthesized according to the published information for PR cDNA (21, 24). A 126-bp cDNA fragment specific for PR-B transcripts was generated by PCR using specific primers and represents the sequence from +627 bp to +752 bp. (The transcription of PR-B mRNA starts at +1 bp.) This 126-bp sequence was designed to detect only PR-B transcripts, because the transcription of PR-A mRNA starts at +751 bp (8). A second 213-bp cDNA fragment was generated by PCR using specific primers from +1251 bp to +1463 bp and represents a common region in both PR-B and PR-A transcripts. These PCR products were sequenced to confirm their identity and ligated into Topo II vector (Invitrogen, Carlsbad, CA). These plasmids were used subsequently to generate two riboprobes, one that recognized a common region in both PR-A and PR-B and a second probe that recognized a PR-B-specific region. [32P]-labeled probes were prepared using the Maxiscript T7/SP6 polymerase kit (Ambion Inc., Austin, TX). The reactions were run on a 5% polyacrylamide gel, and the full-length probes were excised. The probes were then eluted at room temperature for 6 h. An 80-bp riboprobe for 18S RNA was used as an internal control. Because 18S RNA is strikingly more abundant than PR mRNA, a [32P]-labeled 18S RNA probe was prepared at 1000-fold lower specific activity. This ensured that the 18S RNA probe could be used in molar excess to its target and a similar exposure time could be used for all probes. The labeled PR mRNA and 18S RNA probes were added to each RNA sample (10 µg). RPA was performed according to the manufacturer-suggested protocol (Ambion Inc.). Following hybridization and RNase digestion, the protected fragments were separated on a 6% polyacrylamide gel. Total RNA from T47D cells and yeast were used as positive and negative controls, respectively.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Using direct Western blotting, we were able to detect PR-A and
PR-B in T47D cells and some samples of eutopic endometrium, however, we
were not able to detect PR isoforms in any of endometriotic or the
majority of eutopic endometrial tissues. Therefore, we performed
immunoprecipitation to concentrate PRs prior to Western analysis.
Protein extracts from 18 paired samples of extra-ovarian endometriotic
tissue and eutopic endometrium obtained during various stages of the
menstrual cycle were subjected to immunoprecipitation, followed by
Western blotting. This method permitted us demonstrate the presence of
PR-A in all (n = 18) and PR-B in 17 of 18 eutopic endometrial
samples (Fig. 1
). A sample of protein
extract from T47D breast cancer cells was used as a positive control
(lane 11), whereas a nonimmunoprecipitated eutopic endometrial tissue
protein extract was used as a negative control (lane 10). The
determination of both PR-A and PR-B bands were made by the virtue of
molecular weights of the immunoreactive bands. The appearance of double
bands that corresponded to PR-B in this Western blot could be explained
by the phosphorylation of this isoform that was previously described by
Beck et al. (25). We were also able to
demonstrate cyclic changes in the expression of PR isoforms in the
eutopic endometrium. For example, the highest levels of PR-B were
observed in the preovulatory phase (days 10–14) of the menstrual
cycle. Although, changes in PRA levels also followed a similar pattern,
these were not as prominent as in the case of PR-B. Cycle days were
determined according to the date of the patients’ last menstrual
periods and were confirmed by histological dating of eutopic
endometrial samples.
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). PR-B, however, could not be
demonstrated in endometriotic samples despite using measures that
enhanced the detection of PR-A. Fig. 2 illustrates a representative
blot with single bands corresponding to PR-A in nine endometriotic
tissue samples. Patients 1 to 9 correspond to the eutopic endometrial
samples represented in Fig. 1
. In contrast to the eutopic endometrium,
no cyclic variation in PR-A levels was observed in endometriotic
samples. T47D cell protein extract was used as a positive control
showing both PR-A and PR-B (lane 11), whereas no bands were visualized
in the negative tissue control (lane 10), which was a sample of
disease-free peritoneum from a patient with endometriosis.
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in eutopic endometrium and
endometriosis
Lower levels of PR-A and the lack of PR-B in endometriotic protein
samples might have been the consequences of dilution of endometriotic
tissue by the surrounding peritoneum at the time of surgical resection.
To determine whether this was a significant factor, we used ER-
expression as an internal control in eutopic endometrium and
endometriotic tissue. Using equal amounts of protein extracts (30 µg)
from both eutopic endometrial and endometriotic tissues, we
demonstrated the presence of comparable amounts of ER- in both
tissues using either direct Western blotting or Western blotting
following immunoprecipitation. Fig. 3
illustrates a representative immunoprecipitation-Western blot showing
single bands that correspond to ER- in paired samples of eutopic
endometrial and endometriotic tissues. A protein sample from T47D cells
was used as a positive control. The identification of ER- was made
by the virtue of molecular weight of the immunoreactive band and in
comparison to a single band in protein extract from T47D cells. Protein
samples from disease-free peritoneum taken from patients with
endometriosis were used as negative controls. We concluded that the
striking differences in PR-B content in these two tissue types was not
due to the underrepresentation of endometriotic tissue in surgical
samples but could rather be accounted for by the deficient expression
of this PR isoform in endometriotic tissue.
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In eutopic endometrial samples (n = 8), we demonstrated two
PR-related protected bands: the 213-bp band represented a common region
for both PR-A and PR-B, whereas the 126-bp band corresponded to a
specific region in PR-B (Fig. 4). In endometriotic tissue, however,
only a single protected band of 213 bp that represented the common
region in both PR-A and PR-B transcripts was present. The PR-B
mRNA-specific band of 126 bp was not detected in endometriotic tissue
samples (n = 8). It follows then that the single band detected in
endometriotic tissues did not include PR-B mRNA and represented PR-A
mRNA. All tissue samples also contained a third band of 80 bp, which
corresponded to the 18S RNA internal control. A sample of yeast RNA was
used as a negative control, whereas RNA from T47D cells was used as a
positive control, which demonstrated two bands indicating the presence
of both PR-A and PR-B mRNA species. Moreover, levels of PR-B mRNA were
higher in eutopic endometrial samples obtained during the preovulatory
phase (lanes 1, 4, and 5 in the representative experiment shown in Fig. 4). Thus, the preovulatory increase in PR-B protein was observed to be
accompanied by comparable changes in its mRNA levels. We conclude that
the use of alternative promoters giving rise to mRNA species specific
for PR-A and PR-B is responsible for cycle-specific alterations in the
levels of these PR isoforms in endometrium and the lack of PR-B in
endometriotic tissue.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Thus far, two groups of investigators have reported variation in the expression of PR-A and PR-B in the eutopic endometrium during the menstrual cycle (22, 26). Mangal et al. (22) reported that PR-B expression increased significantly during days 14–16, which then become virtually undetectable during the secretory and early proliferative phases. These findings are consistent with our results. In another recent publication, Mote et al. (26) demonstrated by immunohistochemistry that both PR-A and PR-B expression increased during the proliferative phase and reached their highest expression during late proliferative phase. These studies emphasize that hormonally regulated expression of PR isoforms, in a cell-specific manner, may determine the inhibitory or stimulatory nature of progestogenic action.
A recent immunohistochemical study demonstrated a predominance of immunoreactive PR-A in stromal cells of the eutopic endometrium (26). Thus, the lack of PR-B protein in endometriotic tissue may be interpreted to be a consequence of a lower gland to stroma ratio in this tissue compared with the eutopic endometrium. We suggest, however, that this is not the cause for PR-B deficiency in endometriotic tissue for the following reasons. First, we confirmed the presence of epithelial cells in all endometriotic tissue biopsies. Second, we used an extremely sensitive method (i.e. RPA) and confirmed the absence of PR-B expression in endometriotic tissue. Even if our results were due to a lower gland to stroma ratio in endometriosis, we would have detected some PR-B transcripts in this tissue. Third, Mote et al. (26) did demonstrate the presence of immunoreactive PR-B in eutopic endometrial stromal cells.
Several studies were conducted to compare the levels of total PR in eutopic endometrial tissue to those in endometriosis, but the results were inconclusive. Using immunohistochemistry, PR levels were found to be lower in endometriotic tissue compared with eutopic endometrium (27, 28, 29). On the other hand, using the same technique, another group of investigators found that total PR levels were similar in both eutopic endometrium and endometriosis during proliferative phase (30). These differences may be explained in part by tissue heterogenicity (31) and the inability of immunohistochemistry to differentiate between different PR isoforms. One recent report by Misao et al. (32) indicated a higher PR-B to total PR mRNA ratio in ovarian endometriomas compared with the eutopic endometrium. These authors, however, used RT-PCR and did not find any cyclic variation in the levels of PR-B or total PR in the eutopic endometrium (32). The discrepancy between the findings of these authors and ours may be due to: 1) their use of ovarian endometrioma cyst walls vs. our use of extraovarian endometriosis; 2) possible contamination of their endometrioma samples with normal ovarian tissue containing PR; and/or 3) their reliance on RT-PCR as the only method. (We used RPA to detect mRNA and confirmed these findings with comparable levels of protein.)
The ability of either PR-A or PR-B isoforms to activate transcription may play a major role in the biology of endometriosis. Whereas PR-B seemed to activate transcription in many target tissues, PR-A was shown to act as a dominant repressor of PR-B (16). Furthermore, the differences between PR isoforms are both cell and promoter specific. Therefore, alterations in PR-A/PR-B ratio may render tissues responsive or resistant to progesterone. In eutopic endometrial tissue, it seems that PR-A is primarily present in stromal cells, with minimal fluctuation during the menstrual cycle (26). On the other hand, PR-B expression peaked just before ovulation and decreased thereafter (22, 33, 34). This elevation in PR-B in the preovulatory period suggests that PR-B might play an important role in endometrial changes during the secretory phase. Therefore, we speculate that the inability of progesterone to stimulate 17ß-HSD type 2 expression in endometriotic glandular cells is due to the lack of PR-B in this tissue. This, subsequently, may result in elevated concentrations of estradiol in endometriotic implants, which are essential for the growth of this tissue. PR-B deficiency in endometriotic tissue may also be responsible for other consequences of progesterone resistance (e.g. failure to down-regulate ER during the luteal phase).
The findings of strikingly lower levels of total PR and the lack of
PR-B in endometriotic tissue in contrast to eutopic endometrium were
confirmed under very stringent conditions. For example, we used three
times as much protein extract from endometriotic tissues compared with
extract from eutopic endometrial samples, and we also used an
ultra-sensitive detection system in Western blots. Because we were
unable to detect either PR or ER- in disease-free peritoneal
biopsies in agreement with previously published data (35),
we decided to use ER- as an internal control to exclude the
possibility of the dilution of endometriotic protein samples with the
surrounding normal peritoneum. Using equal amounts of endometriotic and
eutopic endometrial protein extracts, we demonstrated comparable
amounts of ER- in both tissues, indicating that endometriotic
specimens were not diluted with the surrounding peritoneum. Moreover,
the preovulatory surge detected in PR-B levels in eutopic endometrium
was in agreement with a previous study (22) and further
validated the methods used in the present study.
One clinically relevant aspect of these findings may be to encourage efforts for the development of selective progesterone response modifiers that can interact with PR-A in endometriotic cells and exhibit an antiproliferative effect. Furthermore, demonstration of physiologically significant molecular differences between eutopic endometrium and endometriosis will lead to the identification of new therapeutic targets and the development of novel strategies for the treatment of endometriosis.
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Acknowledgments |
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Footnotes |
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2 Present address: Department of Obstetrics and Gynecology, Columbia
University, New York, New York 10032.
Received November 15, 1999.
Revised May 17, 2000.
Accepted May 17, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-dihydroprogesterone dehydrogenase activities in human endometrial
glands and stroma: progestin induction of steroid dehydrogenase
activities in vitro is restricted to the glandular
epithelium. Endocrinology. 111:743–749.[Abstract]
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T. Shiozawa, H.-C. Shih, T. Miyamoto, Y.-Z. Feng, J. Uchikawa, K. Itoh, and I. Konishi Cyclic Changes in the Expression of Steroid Receptor Coactivators and Corepressors in the Normal Human Endometrium J. Clin. Endocrinol. Metab., February 1, 2003; 88(2): 871 - 878. [Abstract] [Full Text] [PDF]
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A. Akoum, A. Lemay, and R. Maheux Estradiol and Interleukin-1{beta} Exert a Synergistic Stimulatory Effect on the Expression of the Chemokine Regulated upon Activation, Normal T Cell Expressed, and Secreted in Endometriotic Cells J. Clin. Endocrinol. Metab., December 1, 2002; 87(12): 5785 - 5792. [Abstract] [Full Text] [PDF]
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