The Impact of FSHR Gene Polymorphisms Ala307Thr and Asn680Ser in the Endometriosis Development.

Endometriosis is an estrogen-dependent inflammatory disease that affects a large number of women in reproductive age. Follicle-stimulating hormone (FSH) plays a role in steroidogenesis and acts through a transmembrane glycoprotein, FSH receptor (FSHR). Polymorphisms in FSHR gene were previously associated with variability in FSH serum level and reproductive outcomes, but its relation with endometriosis has not been clarified and demonstrated conflicting results, ranging from strong links to no association to endometriosis. Inspired by these findings, we aimed to investigate the influence of FSHR Ala307Thr and Asn680Ser polymorphisms in the risk of endometriosis development and/or progression and the status of fertility in 352 women with endometriosis and 510 fertile controls. Single-marker analysis revealed no significant difference for both Ala307Thr and Asn680Ser polymorphisms between overall endometriosis and control group. However, when the endometriosis group was subdivided according to fertility status and disease stage, a positive association was found between 680Ser/Ser or GG genotype of the Asn680Ser polymorphism and fertile women with endometriosis (p = 0.004). Combined alleles of FSHR polymorphisms revealed that "GG/307Ala680Ser" was more frequently found in fertile women with endometriosis (haplotype frequency of 45.4% in fertile women with endometriosis and 38.3% in controls, p = 0.041). The combined alleles of FSHR polymorphisms disclosed that "GG/307Ala680Ser" was more frequently found in fertile women with endometriosis (haplotype frequency of 45.4% in fertile women with endometriosis and 38.3% in controls, p = 0.049), while "GA/307Ala680Asn" haplotype was less frequently found in endometriosis group (haplotype frequency of 6.5% in cases and 11.9% in controls, p = < 0.001), regardless of fertility status and stage of the disease. The findings suggest that 680Ser-Ser/GG genotype and "GG/307Ala680Ser" haplotype increase the risk of endometriosis in fertile women, while "GA/307Ala680Asn" haplotype decreases the risk of endometriosis development and progression.

Evaluation of the frequency of G-765C polymorphism in the promoter region of the COX-2 gene and its correlation with the expression of this gene in the endometrium of women with endometriosis.

OBJECTIVE: To evaluate the frequency of polymorphism G-765C (rs20417) of the COX-2 gene and the expression of this gene in the endometrium of women with endometriosis. STUDY DESIGN: This is a case-control study of 365 women with endometriosis (251 infertile and 114 fertile) submitted to laparoscopy/laparotomy with histological confirmation of endometriosis. The control group was composed of 522 fertile women without endometriosis. Of these, 37 patients from the endometriosis group and 47 from the control group were submitted to biopsy of the endometrium for analysis of the expression of the COX-2 gene. The genotypes were determined using analysis by High-Resolution Melt. Gene expression was measured by qRT-PCR with TaqMan methodology using the GAPDH gene as normalizer of the reactions. RESULTS: The distribution of the genotypes and alleles in the group of fertile women with moderate/severe endometriosis showed a statistically significant difference, demonstrating association of the ancestral allele, -765G, with increased risk of endometriosis (p = 0.028; OR 0.53; CI 0.32-0.90). The mean expression of the COX-2 gene (mRNA PTGS2) in the group of women with endometriosis was statistically higher compared to the control group (3.85 versus 2.84, p = 0.028). CONCLUSION: The present study identified that in Brazilian women the presence of the ancestral allele, -765G, of the COX-2 gene is associated with an increased risk for development of moderate/severe endometriosis associated with fertility, and that the eutopic endometrium of women with endometriosis showed increased expression of COX-2 when compared to the control group.

Aspiração e alcoolização de endometriomas ovarianos recorrentes prévios ao tratamento de fertilização in vitro - estudo piloto / Aspiration and ethanol sclerotherapy to treat recurrent ovarian endometriomas prior to in vitro fertilization - a pilot study

Objective: To describe the evolution of controlled ovarian hyperstimulation in women with recurrent ovarian endometriomas treated with sclerotherapy. Methods: Twenty-one patients with a laparoscopic diagnosis of stage III or IV endometriosis who had an endometrioma larger than 3 cm before ovarian hyperstimulation for in vitro fertilization were included in the study. After using a GnRH agonist analog for at least 20 days, the cysts were punctured using ultrasound guidance and subsequent ethanol sclerotherapy was performed. Then, the patients were stimulated with 100 or 200 U/day of recombinant follicle stimulating hormone, varying the dose according to the patient's age or history of a previous unilateral oophorectomy. Results: The ovarian cysts had an average diameter of 4.7 ± 1.4 cm and did not recur after aspiration during the ovulation induction. Oocyte extraction occurred after 11 days of hyperstimulation, with 3.95 ± 3.30 oocytes obtained per cycle, on average. Embryo transfer occurred in 71.4% (15/21) of patients, and the pregnancy rate after transfer was 20% (3/15). Conclusion: Aspiration followed by ethanol sclerotherapy prior to in vitro fertilization can be an option for patients who desire a pregnancy and have recurrent endometriomas.

Objetivo: Relatar a evolução da hiperestimulação ovariana controlada em mulheres com endometriomas ovarianos recorrentes tratados com escleroterapia. Métodos: Foram estudadas 21 pacientes acompanhadas no ambulatório de reprodução humana com indicação de fertilização in vitro e diagnóstico laparoscópico de endometriose III ou IV que apresentavam endometrioma recidivado maior que 3 cm após a cirurgia. Foi realizado bloqueio prévio com análogo agonista de GnRH por pelo menos 20 dias, e os cistos foram submetidos à punção guiada por ultrassonografia e alcoolização subsequente. As pacientes foram estimuladas com 100 ou 200U/dia de hormônio folículo estimulante recombinante, com a dose variando de acordo com a idade ou ooforectomia unilateral prévia. Resultados: Os cistos ovarianos aspirados tinham em média 4,7 ± 1,4 cm e em nenhum caso a imagem se refez durante a indução da ovulação. A captação oocitária ocorreu, em média, após 11 dias de indução com 3,95 ± 3,30 oócitos por ciclo. Houve transferência embrionária em 71,4% (15/21) das pacientes, e a taxa de gravidez por transferência foi de 20% (3/15). Conclusão: A aspiração seguida da alcoolização previamente ao tratamento de fertilização in vitro pode ser uma opção para as pacientes com endometriomas recidivados e desejo reprodutivo.

Combination of polymorphisms in luteinizing hormone ß, estrogen receptor ß and progesterone receptor and susceptibility to infertility and endometriosis.

OBJECTIVES: To determine whether the combination of PR (PROGINS), ERß G+1730A and/or LHß G1502A polymorphisms in infertile women with and without endometriosis and in a control group increases the risk of infertility and/or endometriosis. STUDY DESIGN: Case-control study including 201 infertile women with endometriosis, 80 infertile women without endometriosis and 206 fertile women as control group. PROGINS was identified by PCR (polymerase chain reaction) and ERß G+1730A and LHß G1502A were identified by PCR-RFLP (restriction fragment length polymorphism). RESULTS: A statistically significant difference was found for the combination of LHß+ERß polymorphisms among infertile patients with endometriosis and control group (p=0.003, OR=2.468), among infertile patients with endometriosis I/II and control group (p=0.002, OR=3.081), among infertile patients with endometriosis III/IV and control group (p=0.035, OR=2.136) and for the combination of LHß+PROGINS polymorphisms among infertile patients with endometriosis I/II and control group (p=0.014, OR=3.081). However, the odds of developing endometriosis are not enhanced in the presence of the two polymorphisms, being similar to the odds when only LH polymorphism is present. CONCLUSIONS: Individually, the presence of LHß G1502A and ERß G+1730A polymorphisms is associated with infertility and endometriosis associated infertility. However, when two polymorphisms are present in the same individual it does not appear to increase the chance of developing endometriosis or infertility.

COMT polymorphism and the risk of endometriosis-related infertility.

Estrogens are important factors in the development of endometriosis, and can induce cell proliferation and stimulate cell division. COMT constitutes a crucial element in estrogen metabolism and has been suggested to be involved in the development of endometriosis. This study had the objective of to determine whether the presence of COMT val/met polymorphism (rs4680) increases the risk to endometriosis in infertile patients. A case-control study that included 198 infertile women with endometriosis, 71 infertile women without endometriosis, and 168 fertile women as control group of the Faculdade de Medicina do ABC. COMT (val/met) genotypes were identified by real time PCR (genotyping TaqMan assay) and the results were analyzed statistically by χ² test. The data showed no statistical difference in the distribution of COMT genotypes neither between infertile patients with endometriosis and control group (p = 0.567), regardless disease degree, nor between infertile patients without endometriosis and control group (p = 0.460). In conclusion, the COMT val/met polymorphism is not associated to endometriosis-related infertility in the Brazilian population evaluated. However, more studies in larger populations are necessary to confirm these results.

Aspiration and ethanol sclerotherapy to treat recurrent ovarian endometriomas prior to in vitro fertilization - a pilot study.

OBJECTIVE: To describe the evolution of controlled ovarian hyperstimulation in women with recurrent ovarian endometriomas treated with sclerotherapy. METHODS: Twenty-one patients with a laparoscopic diagnosis of stage III or IV endometriosis who had an endometrioma larger than 3 cm before ovarian hyperstimulation for in vitro fertilization were included in the study. After using a GnRH agonist analog for at least 20 days, the cysts were punctured using ultrasound guidance and subsequent ethanol sclerotherapy was performed. Then, the patients were stimulated with 100 or 200 U/day of recombinant follicle stimulating hormone, varying the dose according to the patient's age or history of a previous unilateral oophorectomy. RESULTS: The ovarian cysts had an average diameter of 4.7 ± 1.4 cm and did not recur after aspiration during the ovulation induction. Oocyte extraction occurred after 11 days of hyperstimulation, with 3.95 ± 3.30 oocytes obtained per cycle, on average. Embryo transfer occurred in 71.4% (15/21) of patients, and the pregnancy rate after transfer was 20% (3/15). CONCLUSION: Aspiration followed by ethanol sclerotherapy prior to in vitro fertilization can be an option for patients who desire a pregnancy and have recurrent endometriomas.