Causes of endometriosis and prevalent infertility in patients undergoing laparoscopy without achieving pregnancy.

BACKGROUND: Endometriosis is a disease with an unknown pathogenesis that can lead to infertility. Endometrial polyps, fibroids, and polycystic ovarian syndrome (PCOS) have relatively high frequency and are causes of infertility. We hypothesized a possible relationship between the presence of polyps, fibroids, and PCOS in infertile women with endometriosis who underwent laparoscopy and did not get pregnant, compared to women in the control group. METHODS: This study was a cross-sectional study of 1243 infertile patients (621 with endometriosis and 622 controls). Endometriosis, Body Mass Index (BMI), infertility duration, age, and smoking habits were analyzed in relation to the presence of endometrial polyps, fibroids, and PCOS. RESULTS: Polyps, 1.8 (95% CI 1.3-2.5); fibroids, 2.5 (95% CI 1.5-4.1); and PCOS, 1.0 (95% CI 0.6-1.6 were observed in the endometriosis group. A total of 285 patients (45.9%) were classified presenting endometriosis grades I and II, and 336 patients (54.1%) with grades III and IV. Our findings showed a significant association between the presence of fibroids in 129 women with endometriosis (20.8%), and in 69 (53.9%) with endometriosis grades III and IV (P=0:04). Among the 31 PCOS patients, 24 (77.4%) showed grades I and II (P<0.001). CONCLUSIONS: Endometriosis and infertility are associated with the presence of polyps and fibroids. Furthermore, associations between the presence of fibroids with endometriosis grades III and IV, and presence of PCOS with grades I and II were observed.

Aberrant telomerase expression in the endometrium of infertile women with deep endometriosis.

BACKGROUND AND AIMS: Considering the complex cellular and molecular mechanisms involved in endometriosis formation and progression and the similarities concerning the association of endometriosis with tumorigenesis and metastasis, we hypothesized a possible relationship between telomerase and the development/progression of endometriosis. The present study aimed to evaluate the expression of telomerase in the endometrium and peritoneal endometriotic lesions from women with endometriosis and controls. METHODS: A case-control study was performed comprising 25 infertile women with endometriosis and 44 fertile women without endometriosis as controls. Samples of endometrium and endometriotic peritoneal lesions of the same patient were harvested in the late luteal phase of the cycle. The expression of hTERT and GAPDH genes was measured by mRNA using qRT-PCR based on TaqMan methodology. Student t test was used to compare the values between the groups; p >0.05 was accepted as statistically significant. RESULTS: The mean expression of hTERT in the endometriosis group was significantly high when compared to the control group (1.24 ± 4.67 vs. 0.31 ± 1.10, p = 0.026). When the expression of hTERT was compared in relation to disease stage, the group of moderate/severe endometriosis showed increased expression in relation to control group (2.59 ± 7.35 vs. 0.31 ± 1.10, p = 0.026). Regarding endometriotic peritoneal lesions, only one 1/25 expressed hTERT mRNA. This patient had deep endometriosis. CONCLUSIONS: There was an association between the expression of telomerase (hTERT mRNA) and the genesis and progression of endometriosis.

Genetic association study of polymorphisms FOXP3 and FCRL3 in women with endometriosis.

OBJECTIVE: To consider a possible cumulative effect of two genetic polymorphisms (FOXP3 C-2383T/rs3761549 and FCRL3 C-169T/rs7528684) that were previously shown to be associated with endometriosis. DESIGN: Genetic association study. SETTING: Human reproduction outpatient clinic of Faculdade de Medicina do ABC. PATIENT(S): One hundred eighty-eight infertile women with endometriosis and 169 controls. INTERVENTION(S): Detection of polymorphisms FOXP3 (C-2383T/rs3761549) and FCRL3 (C-169T/rs7528684) by TaqMan real-time polymerase chain reaction. The results were analyzed statistically. MAIN OUTCOME MEASURE(S): Genotype distribution, allele frequency, and combination analysis of the FOXP3 and FCRL3 polymorphisms. RESULT(S): Single-marker analysis revealed a significant association of FOXP3 C-2383T and FCRL3 C-169T, independently, with endometriosis-related infertility, regardless of the stage of the disease. Considering the combined genotypes of FCRL3 and FOXP3 polymorphisms, a positive association was found between genotypes FCRL3TT/FOXP3CT, FCRL3CT/FOXP3CT, and FCRL3CC/FOXP3CT and the risk of endometriosis development. Moreover, a progression of the disease risk was observed according to the presence of one or two copies of risk allele FCRL3 C and only one copy of risk allele FOXP3 T (odds ratio [OR] = 2.14, OR = 3.25, and OR = 6.0, respectively, for genotypes FCRL3TT/FOXP3CT, FCRL3CT/FOXP3CT, and FCRL3CC/FOXP3CT). CONCLUSION(S): Our findings support a possible gene-gene interaction leading to a cumulative effect on endometriosis development.

The possible role of genetic variants in autoimmune-related genes in the development of endometriosis.

Numerous hypotheses have been put forward to explain the presence of ectopic endometrial tissue and stroma. The immune system participates in the homeostasis of the peritoneal cavity, and modifications in its functioning have been advanced to explain endometriosis and its consequences. Recently, the powerful anti-inflammatory effect of progesterone was recognized as a potential causal factor for endometriosis and could contribute to the autoimmune nature of endometriosis, as well as to more specific local and systemic changes. Autoimmune and inflammatory diseases are a diverse group of complex diseases characterized by loss of self-tolerance causing immune-mediated tissue destruction. Just as in autoimmune diseases, in endometriosis similar immunologic alterations occur, such as an increase in the number and cytotoxicity of macrophages, polyclonal increase in the activity of B lymphocytes, abnormalities in the functions and concentrations of B and T lymphocytes, and reduction in number or activity of natural killer cells. Furthermore, the presence of specific antiendometrial and antiovary antibodies was found both in endometriosis and infertility. Genetic factors play a role in the pathogenesis of endometriosis, and autoimmunity genes are therefore reasonable candidate genes for endometriosis and endometriosis-associated infertility. Single nucleotide polymorphisms are common in the human genome and affect the function of crucial components of the T-cell-antigen-receptor signaling pathways; they could have profound effects on the function of the immune system and thus on the development of autoimmune diseases. Here, we conducted a critical medical literature review about the possible role of genetic variants in autoimmune-related genes in the development of endometriosis.

Genetic variants in fibrinolytic system-related genes in infertile women with and without endometriosis.

AIMS: The aim of this study was to evaluate urokinase-type plasminogen activator gene (uPA) and thrombin-activatable fibrinolysis inhibitor gene (TAFI) genotypes in a group of infertile women with and/or without endometriosis and controls. METHODS: A case-control study comprising 180 infertile women with endometriosis, 68 women with idiopathic infertility, and 152 fertile women as controls was carried out. Detection of uPA (C422T/rs2227564) and TAFI (G438A/rs2146881) polymorphisms was performed by TaqMan polymerase chain reaction. The results were statistically analyzed and a p-value of <0.05 was considered significant. RESULTS: We found no association among both uPA or TAFI polymorphisms and endometriosis-related infertility (p=0.920 and p=0.356, respectively) or idiopathic infertility (p=0.502 and p=0.392, respectively) comparing to controls, even considering minimal/mild and moderate/severe endometriosis separately. Both uPA and TAFI polymorphisms were in Hardy-Weinberg equilibrium for all studied groups. The combinatory analysis of both uPA and TAFI polymorphisms to endometriosis-related infertility, idiopathic infertility, and control group showed no statistical difference to any combination. CONCLUSION: The data suggest that, in the Brazilian population, genetic variations in both uPA and TAFI were not relevant to endometriosis and/or infertility.

Association of FCRL3 -169T/C polymorphism with endometriosis and identification of a protective haplotype against the development of the disease in Brazilian population.

An aberrant immunologic mechanism has been suggested to be involved in the pathogenesis of endometriosis. Fc receptor-like 3 gene (FCRL3) has been proposed as a novel autoimmune predisposing factor. The authors have hypothesized a possible relationship between endometriosis, infertility, and FCRL3 polymorphisms. This was a case-control study that included 170 women with endometriosis-related infertility, 91 women with idiopathic infertility, and 166 controls. Detection of FCRL3 polymorphisms (-169C/T, -110G/A, +358C/G and +1381 A/G) was performed using TaqMan PCR. The results were analyzed statistically and a p value <0.05 was considered significant. Results Single-marker analysis revealed that FCRL3 -169C/T was significantly associated with endometriosis (p = 0.004), regardless of the stage of the disease, p = 0.011 and p = 0.035, respectively to minimal/mild and to moderate/severe endometriosis. No association was found considering -110A/G, +358C/G, and +1381 A/G polymorphisms either for the endometriosis-related infertility group or the idiopathic infertility group. Haplotype analysis of four FCRL3 polymorphisms identified a haplotype GGGC associated with endometriosis (p = 0.026). The haplotype AGAT was associated with protection against endometriosis (p = 0.011) and infertility (p = 0.041). The data from this study point to a possible association of the FCRL3 -169C/T polymorphisms with endometriosis, especially minimal/mild endometriosis, and the haplotype AGAT may be protective against the development of the disease, in Brazilian women. However, these findings clearly need to be replicated in an independent sample and in different populations.

Association of FCRL3 C-169T promoter single-nucleotide polymorphism with idiopathic infertility and infertility-related endometriosis.

An aberrant immunological mechanism is thought to be involved in the pathogenesis of endometriosis. The present study aimed to determine whether there is a relationship between endometriosis and/or infertility and the FCRL3 C-169T polymorphism. This case-control study included 167 infertile women with endometriosis, 60 women with idiopathic infertility and 167 fertile women. Detection of the FCRL3 C-169T polymorphism was performed using TaqMan PCR. A significant difference in the genotype and allele frequencies of the FCRL3 C-169T polymorphism between endometriosis-related infertility (p=0.003 and p=0.001) and idiopathic infertility (p=0.027 and p=0.0185) versus controls was demonstrated. In conclusion, the results suggest that the FCRL3 C-169T polymorphism may play an important role in the pathogenesis of endometriosis and/or infertility.

Analysis of FOXP3 polymorphisms in infertile women with and without endometriosis.

OBJECTIVE: To evaluate FOXP3 polymorphisms (rs3761549, rs3761548, rs2232368, rs2232366, and rs2280883) in a group of infertile women with and without endometriosis and controls. DESIGN: Case control study. SETTING: Human Reproduction Outpatient Clinic of Faculdade de Medicina do ABC. PATIENT(S): The study groups were 177 infertile women with endometriosis, 71 women with idiopathic infertility, and 171 fertile women as controls. INTERVENTION(S): The FOXP3 polymorphisms were identified by TaqMan polymerase chain reaction (PCR). The results were analyzed statistically. MAIN OUTCOME MEASURE(S): Genotype distribution, allele frequency, and haplotype analysis of the FOXP3 polymorphisms. RESULT(S): Single-marker analysis revealed that FOXP3 rs3761549 was significantly associated with endometriosis. In the infertile group without endometriosis, single-marker analysis revealed statistical difference for rs2280883 and rs2232368 FOXP3 polymorphisms. No associations were found with rs3761548 and rs2232366 either for endometriosis-related infertility group or idiopathic infertility group. Haplotype analysis of five FOXP3 polymorphisms identified a haplotype CTTGA associated with endometriosis and ACTAG associated with idiopathic infertility. CONCLUSION(S): This is the first study to report an association between FOXP3 polymorphisms and endometriosis and/or infertility. These findings require replication in other populations but suggest that the FOXP3 polymorphisms can be associated with risk of idiopathic infertility (rs2280883 and rs2232368) and endometriosis (rs3761549) in Brazilian women.