Hum. Reprod. Advance Access originally published online on August 18, 2006
Human Reproduction 2007 22(1):129-135; doi:10.1093/humrep/del325
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Progesterone receptor polymorphism +331G/A is associated with a decreased risk of deep infiltrating endometriosis
1 Research Institute GROW, University of Maastricht and 2 Department of Obstetrics and Gynaecology, University Hospital Maastricht, Maastricht, The Netherlands
3 To whom correspondence should be addressed at: Research Institute GROW, University of Maastricht, Maastricht, The Netherlands. E-mail: kvk{at}sgyn.azm.nl
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Abstract |
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BACKGROUND: Alterations in the progesterone receptor (PR) are considered a risk factor for the development of endometriosis. In this study, the frequencies of the PROGINS and +331G/A polymorphisms of the PR gene were determined in deep infiltrating endometriosis and correlated with the expression of the PR protein. METHODS AND RESULTS: The frequencies of the PR polymorphisms were determined in women with deep infiltrating endometriosis (n = 72), women with adenomyosis in the uterine wall (n = 40), gynaecological patients without symptomatic endometriosis (n = 102) and healthy females (n = 93). Detection of +331G/A and PROGINS polymorphisms was performed using PCR-restriction fragment length polymorphism (RFLP) analysis. Expression of PR-A and PR-B protein was assessed with immunohistochemistry. The allelic frequency of the polymorphic allele +331A was lower in women with endometriosis (P < 0.01) and adenomyosis (P < 0.02) compared with healthy females. The frequency of the PROGINS polymorphism did not differ between the groups. The mean staining index (SI) for PR-B in endometriotic epithelium was higher in the presence of the +331A polymorphic allele (n = 2) (P < 0.001) compared with +331G/G individuals (n = 61). The PROGINS polymorphism did not affect the SI for PR-A and PR-B. CONCLUSIONS: The presence of the PR gene polymorphic allele +331A is associated with a reduced risk of deep infiltrating endometriosis and adenomyosis compared with healthy population controls. The PROGINS polymorphism does not seem to modify the risk of deep infiltrating endometriosis.
Key words: +331G/A/endometriosis/progesterone receptor/PROGINS
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Introduction |
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Endometriosis is one of the most commonly encountered benign problems in gynaecology. Women with symptomatic endometriosis suffer from dysmenorrhoea, dyspareunia, chronic pelvic pain and/or subfertility. Past research indicates that a combination of immunologic, genetic, anatomic and hormonal factors contribute to a woman’s susceptibility to the development of endometriosis. Regarding the pathogenesis of this disease, Sampson’s retrograde transplantation theory is the most widely accepted, which implies that there is reflux of viable endometrial fragments through the Fallopian tubes during menstruation, with subsequent adhesion, implantation and growth on and into the peritoneum (Sampson, 1940
). It has been argued that all women with patent tubes develop asymptomatic peritoneal endometriosis to a certain extent during their lifetime (Koninckx, 1994). However, Sampson’s theory does not explain why only in a minority of women retrograde menstruation results in the development of symptomatic endometriosis. Endometriosis has long been recognized as having heritable tendencies and is considered a polygenic disease with a multifactorial aetiology (Bischoff and Simpson, 2000; Simpson and Bischoff, 2002; Simpson and Elias, 2003; Simpson et al., 2003). Genetic association studies have been performed for a number of candidate genes potentially involved in the pathogenesis of endometriosis (Cramer et al., 1996; Georgiou et al., 1999; Hadfield et al., 2001; Nakago et al., 2001; Vigano et al., 2003). However, so far results have been inconsistent.
A gene of specific interest within this context is the progesterone receptor (PR) gene. Progesterone is a potent antagonist of estrogen-induced proliferation in the endometrium and as such may play a pivotal role in the pathogenesis of endometriosis. The actions of progesterone are mediated by two functionally distinct receptor isoforms, PR-A and PR-B, which are expressed from a single gene as a result of transcription from two alternative promoters (Punyadeera et al., 2003). The PR-A and PR-B isoforms are ligand-dependent members of the nuclear receptor family that are structurally identical, except for an additional 164 amino acids at the amino terminal of PR-B (Horwitz and Alexander, 1983; Lessey et al., 1983). This region encodes a transactivation function that is specific to PR-B and is required to specify target genes that can be activated by PR-B but not PR-A (Li and O’Malley, 2003). The ability of either PR-A or PR-B to activate transcription of progesterone target genes may be important in the pathogenesis of endometriosis. PR-B functions as a stronger transcriptional activator of progesterone target genes, whereas PR-A is a transcriptionally inactive dominant repressor of steroid hormone transcription activity that is thought to decrease the response to estrogen (Giangrande et al., 2000). Furthermore, the responses of ligand-activated PR-A and PR-B strongly depend on the cellular context. Hence, the anti-proliferative effects of progesterone depend on a tight regulation of the PR-A and PR-B isoform balance. Therefore, the hypothesis was made that DNA polymorphisms altering the activity of the protein or altering the PR-A-to-PR-B ratio may lead to unopposed estrogen action and therefore to an increased risk of developing endometriosis.
The PROGINS polymorphism of the PR gene has been shown to be associated with endometriosis in previous studies (Wieser et al., 2002; Lattuada et al., 2004). This polymorphism consists of a 320 bp PV/HS-1 Alu insertion in intron G, a silent point mutation in exon 5 (H770H) and a single amino acid change in exon 4 (V660L) (Rowe et al., 1995). The functional consequences of the PROGINS polymorphism are not yet fully understood and are still a subject of investigation.
The +331G/A polymorphism is located in the promoter region of the PR gene and gives rise to an increased synthesis of PR-B by generating an additional TATA box, thereby altering the PR-A-to-PR-B ratio (De Vivo et al., 2002). This polymorphism has not been investigated before with respect to the risk of developing endometriosis.
Deep infiltrating endometriosis, for example in the rectovaginal space, histologically closely resembles adenomyosis in the uterine wall. This might imply that the pathogenesis of these two entities is similar. In order to ascertain if the presence of the PROGINS polymorphism or the +331G/A polymorphism contributes to the risk of developing these subtypes of endometriosis, we investigated the prevalence of these polymorphisms in women with deep infiltrating endometriosis and women with adenomyosis in the uterine wall. The prevalence of these polymorphisms in two groups of women without symptomatic endometriosis served as control. In addition to this, we determined the expression levels of PR-A and PR-B in endometriotic lesions by immunohistochemistry in relation to the presence of either polymorphism.
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Materials and methods |
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Patients and tissue specimens
Patients with a surgical and histological diagnosis of deep infiltrating endometriosis who were operated between 1998 and 2004 in the University Hospital of Maastricht (n = 72) were included in the study. Deep infiltrating endometriosis was defined as the presence of one or more deep infiltrating lesions in the bowel wall, vaginal wall, bladder wall and/or rectovaginal septum. Patients with adenomyosis in the uterine wall (n = 40) were selected from the Dutch National Pathology Database (PALGA). The first control group consisted of gynaecological patients without symptoms of endometriosis who underwent a hysterectomy for benign indications such as prolapse, pelvic pain or menstrual cycle disorders (gynaecological controls, n = 102). Patients with uterine fibroids and post-menopausal women were excluded from this group. A second group of controls was taken from a DNA control panel derived from female subjects who had been referred to the Clinical Genetics department for molecular testing for various disease genes. Only subjects that were tested negative for these diseases were included in the control panel, as they can be regarded as healthy, random controls (population controls, n = 93). Both patients and controls originated from the same geographic region of the Netherlands.
DNA isolation
In patients with deep infiltrating endometriosis, patients with adenomyosis in the uterine wall and the gynaecological control group, the analyses were performed on DNA isolated from paraffin-embedded archival tissue. After reviewing all paraffin-embedded tissue specimens for the presence of endometriotic and/or adenomyotic lesions, five consecutive sections of 20 µm were cut from each tissue sample. Genomic DNA isolation was performed using proteinase K (Qiagen, Hilden, Germany) digestion in combination with the Puregene DNA Isolation Kit (Gentra Systems, Minneapolis, MN, USA), following the recommendations of the manufacturer.
The analyses of the population control group were performed on DNA isolated from blood. Genomic DNA was isolated from 8 ml of whole blood (EDTA tubes) using the Wizard Genomic DNA Purification Kit (Promega, Leiden, the Netherlands), following the manufacturer’s protocol.
PROGINS and +331G/A detection
Detection of both polymorphisms was performed using restriction fragment length polymorphism (RFLP) analysis. From the patients with deep infiltrating endometriosis, patients with adenomyosis and the gynaecological controls, only paraffin-embedded archival tissue was at our disposal, which is known to yield lower amounts of DNA of inferior quality compared with DNA isolated from blood or fresh tissue. Therefore, a nested PCR approach, previously described and validated by Pijnenborg et al. (2005), was used to obtain a higher sensitivity. We were able to successfully genotype 65/72 patients with deep infiltrating endometriosis, 38/40 patients with adenomyosis and 101/102 gynaecological controls for the PROGINS polymorphism. For the +331G/A polymorphism, 65/72 patients with deep infiltrating endometriosis, 39/40 patients with adenomyosis and 91/102 of gynaecological controls were genotyped successfully. In the population control group DNA isolated from blood was used for analyses, and we were able to successfully genotype all 93 individuals in this group for both polymorphisms.
For the detection of the PROGINS polymorphism, samples were analysed for the V660L mutation in exon 4. Upon digestion with BrsI (isoschizomer BrsSI, Promega), the 138 bp PCR fragment was cut in three bands (95, 23 and 20 bp) in case of the V660 allele (indicated as T1 allele), or only two bands (115 and 23 bp) in case of the PROGINS allele (indicated as T2 allele). Electrophoresis was performed with the use of a 3% agarose gel stained with Gelstar (Cambrex, ME, USA) before casting for visualization of the PCR products (Figure 1). A similar approach was used for the detection of the +331G/A polymorphism. The 206 bp fragment amplified by PCR was digested by NlaIV (isoschizomer BspLI, Fermentas) generating two bands (149 and 57 bp) in case of the most common allele (+331G) or one band (206 bp) in case of the polymorphic allele (+331A). The obtained digestion products were loaded on a 2% agarose gel stained with Gelstar (Cambrex) for electrophoresis (Figure 2). All PCRs were performed in a volume of 20 µl containing 100 ng of genomic DNA, 50 nM of each primer, 0.1 mM of each dNTP, 1 U of Taq DNA polymerase (Qiagen) and 1x buffer with 2.5 mM MgCl2.
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In all four groups, only women of reproductive age were included (range: 20–50 years old). All samples were analysed in duplicate for both polymorphisms. In case of a discrepancy between the first and second result, the analysis was repeated. If the result remained inconclusive, the sample was omitted from the analysis.
Immunohistochemistry
The PgR636 mouse monoclonal antibody (DAKO, Copenhagen, Denmark) was used to detect PR-A and PR-B; the B30 mouse monoclonal antibody (Santa Cruz Biotechnology, Santa Cruz, CA, USA) was used for specific detection of PR-B. Paraffin-embedded lesions of patients with deep infiltrating endometriosis or adenomyosis in the uterine wall were sectioned (5 µm) and fixed on Starfrost adhesive slides (Klinipath, Duiven, the Netherlands). Sections were deparaffinized in xylene and rehydrated in alcohol series before blocking endogenous peroxidase activity by incubation with 3% hydrogen peroxide/methanol for 20 min. After rinsing three times with phosphate-buffered saline (PBS, pH 7.2), antigen retrieval was performed (Tris–EDTA, pH 9.0; microwave treatment: 20 min at 650 W). Sections were cooled down to room temperature and washed again three times in PBS followed by incubation with the primary antibody (room temperature, 2 h). After three PBS rinses, sections were exposed to the secondary antibody (Envision rabbit anti-mouse, ChemMateTM detection kit, DAKO) for 30 min at room temperature. Antibody binding was visualized using 3,3'-diaminobenzidine. Sections were counterstained mildly with haematoxylin, dehydrated and mounted in Entellan for light microscopy.
Evaluation of immonostaining in endometriotic tissues
The percentage of stained endometrial stromal and epithelial cells (0, 0–10, 10–50 and >50%) and the intensity of staining (absent, weak, moderate and strong) were determined (0, 1, 2 or 3 for each variable) for the entire lesion. A staining index (SI, ranging from 0 to 9) was calculated for both the epithelial and stromal fraction of endometriotic lesions by multiplying catagorized parameters. Two different observers (P.G.G. and K.v.K.) performed evaluation of immunostaining in a blinded fashion and independently. Both observers scored the sections once. The mean of these two observations was used for analyses.
Statistical analysis
Hardy–Weinberg equilibrium for the two polymorphims was assessed in each group by comparing the Pearson’s goodness of fit with a chi-square distribution with one degree of freedom (Institute of Human Genetics, Munich, Germany: http://www.ihg.gsf.de/). Allele and genotype frequencies were compared between groups using Fisher’s exact test. The odds ratio (OR) was used to measure the strength of the association between the frequencies of allele and genotype and deep infiltrating endometriosis.
The difference in PR-A and PR-B expression between patients with the +331G/A or PROGINS polymorphism and women without either polymorphism was determined by using a two-sample t-test with separate variance estimates. Calculations were done using SPSS software (version 11.5). All P-values were two-tailed and 95% confidence intervals (95% CIs) were calculated. P < 0.05 was considered to be statistically significant.
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PROGINS
Results are summarized in Tables I and II. The allele T1 homozygote (T1/T1) was the dominating genotype in the group of women with deep infiltrating endometriosis (66.2%) (Table I), in the group of women adenomyosis in the uterine wall (71.1%), the gynaecological control group (73.3%) and the population control group (71.0%). The overall frequency of the PROGINS complex of genomic alterations (T1/T2, heterozygote + T2/T2, homozygote) was 33.8% in the group of women with deep infiltrating endometriosis, 28.9% in women with adenomyosis in the uterine wall, 26.7% in the gynaecological control group and 29.0% in the population control group. The T2/T2 homozygous PROGINS genotype was found in 4.2% of women with severe endometriosis, 5.3% of women with adenomyosis, 1% of women in the gynaecological control group and 3.2% of women in the population control group. None of the observed differences were statistically significant.
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+331G/A
Results are summarized in Tables III and IV. The percentage of women carrying the +331A polymorphic allele was lower in patients with deep infiltrating endometriosis (3.0%) and adenomyosis (2.6%) than in the gynaecological control group (8.8%) and the population control group (18.3%). The presence of the polymorphic allele +331A was associated with a significant reduction of the risk of having the disease phenotype in women with deep infiltrating endometriosis (OR 0.22; 95% CI 0.06–0.77, P < 0.01) and adenomyosis (OR 0.12, 95% CI 0.02–0.95, P < 0.02) compared with women from the population control group. Compared with gynaecological controls, statistical significance was not reached. There was no significant difference in the distribution of the +331G/A polymorphism between women with adenomyosis and women with deep infiltrating endometriosis. There was one homozygous +331G/A carrier in the group of women with deep infiltrating endometriosis and one in the population control group. In the other two groups, no homozygous +331G/A carriers could be observed.
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Immunohistochemistry
Immunohistochemical staining could be performed on 61/69 lesions from women without either polymorphism, 31/35 lesions of women with the PROGINS polymorphism and 2/3 lesions from women with the +331A polymorphic allele. Photographs of representative PR-A/B and PR-B staining are shown in Figure 3A–C. The overall level of PR-B expression was low in all three groups. In most endometriotic lesions, no staining was observed. Strong staining with the PgR636 antibody is therefore related to the presence of PR-A.
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PR-A/B
Results are shown in Figure 4A. The presence of the PROGINS polymorphic allele (T2) did not affect the SI for PR-A/B in endometrial epithelium (5.6 ± 2.7 in PROGINS carriers versus 5.5 ± 3.1 in T1/T1 individuals) or stroma (5.4 ± 2.2 in PROGINS carriers versus 5.3 ± 2.5 in T1/T1 individuals). The expression of PR-A/B in the stromal fraction of endometriotic lesions in patients carrying the +331A polymorphic allele (SI = 6.4 ± 3.0) did not differ significantly from that in +331G/G patients (SI = 5.3 ± 2.5). There also was no significant difference in the expression of PR-A/B in the epithelium of endometriotic lesions between patients carrying the +331A allele (SI = 3.8 ± 3.8) and +331G/G patients (SI = 5.5 ± 3.1).
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PR-B
Results are shown in Figure 4B. There was no difference in mean SI for PR-B in endometriotic epithelium (SI = 0.2 ± 0.4 versus 0.2 ± 0.5) or stroma (SI = 0.4 ± 0.6 versus 0.3 ± 0.5) between PROGINS carriers (T1/T2 + T2/T2) and T1/T1 individuals. The mean SI for PR-B in endometriotic epithelium was significantly higher in the presence of the +331A polymorphic allele (SI = 2.0 ± 0 in +331A carriers versus 0.3 ± 0.5 in +331G/G patients, P < 0.001). There was no significant difference in mean SI for PR-B in endometriotic stroma between +331A carriers and +331G/G individuals (SI = 1.5 ± 0.7 versus 0.3 ± 0.5).
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Discussion |
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Endometriosis is an estrogen-dependent disease, and an adequate response to progesterone in the endometrium is required to antagonize estrogen-dependent proliferation. Structurally and functionally intact PRs are essential to mediate the anti-proliferative effects of progesterone on the growth of endometriotic tissue (Fang et al., 2004
). Aberrations in the PR gene, such as DNA polymorphisms, may cause a diminished response to physiological levels of progesterone and may therefore lead to an increased risk of developing endometriosis. However, in this study we show that the PROGINS polymorphism was not associated with an increased risk of deep infiltrating endometriosis or adenomyosis in the uterine wall. Interestingly, the presence of the +331A polymorphic allele was shown to be associated with a statistically significant decrease in the risk of deep infiltrating disease and adenomyosis in the uterine wall, which is suggestive of a protective effect. Furthermore, the frequencies of both polymorphisms in women with adenomyosis in the uterine wall did not differ significantly from the frequencies observed in women with deep infiltrating endometriosis. This may signify that these two entities share a similar predisposing genotype.
To this date, three studies have been carried out on the relationship between the presence of PROGINS and the risk of developing endometriosis. In two studies, a statistically significant association between PROGINS and endometriosis was found (Wieser et al., 2002; Lattuada et al., 2004). However, findings in the third study agreed with our results and failed to provide support for an association between the PROGINS allele and endometriosis (Treloar et al., 2005). Even though we detected a higher frequency of the PROGINS T2 allele in women with deep infiltrating endometriosis compared with gynaecological and population controls, statistical significance was not reached. It is not surprising that conflicting results are published in genetic association studies. Ioannidis et al. (2003) have shown that only 16% of genetic associations identified were subsequently replicated with formal statistical significance. He also showed that in a large number of genetic associations, a differential magnitude of effect was noted in large versus small studies. Moreover, results from first studies frequently differed significantly from the results of subsequent research, to the extent that large studies and subsequent research suggested weak associations or no association at all, compared with strong associations proposed by smaller studies and first research.
The relative expression of PR-A and PR-B is considered to be of great importance for an adequate response to progesterone and, as a result, for normal reproductive tissue functioning. Eutopic endometrium was shown to express both PR-A and PR-B isoforms, whereas in simultaneously biopsied peritoneal endometriotic tissue from the same patient, PR-A, but not PR-B, was detectable (Attia et al., 2000). The absence of PR-B conceivably leads to a perturbation of the PR-A-to-PR-B ratio in endometriotic implants, rendering this tissue less responsive to the anti-proliferative effects of progesterone.
In previous research, the PROGINS polymorphism was shown to increase transcriptional activity of the PR, because of increased stability and increased half-life of both PR-A and PR-B isoforms (Agoulnik et al., 2004). Whether this has any functional consequences for the PR remains unclear. Expression levels of PR-A and PR-B are probably not affected, as we did not see a consistent increase in the expression of PR-A and PR-B in endometriotic tissues from women bearing the PROGINS allele.
Past research has shown that the +331A polymorphic allele creates a unique transcription start site by generating an additional TATA box. As a consequence, transcription of the PR gene is increased, favouring the production of PR-B (De Vivo et al., 2002). We were able to show that the presence of the +331G/A heterozygous genotype is associated with a significant decrease in the risk of developing deep infiltrating endometriosis. Like PROGINS, the +331G/A polymorphism of the PR gene has also been studied with respect to the risk of developing several gynaecological malignancies. In one study, the presence of the +331A polymorphic allele was associated with a reduced risk of endometrioid and clear cell ovarian cancers (Berchuck et al., 2004). There was also preliminary evidence of a protective effect of this polymorphism against endometriosis in controls. However, in contrast to the present study, the diagnosis of endometriosis in the former study was self-reported and was not supported by medical records or surgical and/or histological evidence of the disease.
One could hypothesize that overproduction of PR-B may correct the imbalance between PR-A and PR-B in endometriotic tissue. In this manner, the development and growth of endometriotic implants may be prevented to the extent that they become symptomatic. This point of view is supported by the fact that we find higher expression levels of PR-B in endometriotic epithelium of +331A carriers. However, we need to emphasize the fact that, although this result is statistically significant, the group of +331A carriers in this study that could be analysed immunohistochemically consists of only two patients. It may therefore not be possible to draw any definitive conclusions on the effect of the presence of the +331A polymorphic allele on the expression levels of PR-A and PR-B. Another limitation to our findings is the fact that it was not possible to satisfyingly evaluate the results for deep infiltrating endometriosis and adenomyosis separately, as in both groups only one +331A carrier could be observed. The association we found needs to be confirmed in a larger number of patients. Future research should be aimed at gaining more insight in the mechanism through which the +331G/A polymorphism exerts its protective effect against the development of endometriosis.
Strikingly, the decrease in the risk of developing deep invasive endometriosis as a result of carriership of the +331G/A polymorphism only reached statistical significance when women with deep infiltrating endometriosis were compared with population controls. When compared with gynaecological controls, this was not the case. A possible explanation for this finding is the fact that a control group consisting of gynaecological patients is probably biased with respect to the prevalence of (undiagnosed) endometriosis. Although the women in our gynaecological control group had not reported symptoms of endometriosis, a hysterectomy was performed as a result of gynaecological complaints such as pelvic pain or irregular or heavy menstrual bleeding. Given the fact that endometriosis can cause similar complaints but may not always be recognized as such, it may explain why the prevalence of underreported and undiagnosed endometriosis is higher in this group compared with the general population.
In conclusion, we have shown that the presence of the PR gene polymorphic allele +331A reduces the risk of deep infiltrating endometriosis and adenomyosis in the uterine wall compared with the +331G/G genotype. In contrast, the PROGINS polymorphism does not seem to modify the risk of developing deep infiltrating endometriosis or adenomyosis. Moreover, our findings indicate that a general population-based control group is more suitable for this field of research than a probably biased control group consisting of gynaecological patients.
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Submitted on May 7, 2006; resubmitted on June 28, 2006; accepted on July 17, 2006.
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