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Search for mutations and/or polymorphisms in candidate genes by new generation sequencing in infertile women with and without endometriosis and its correlation with results of controlled ovarian hiperstimulation in human assisted reproduction treatments

Grant number: 17/07769-9
Support Opportunities:Scholarships in Brazil - Post-Doctoral
Effective date (Start): November 01, 2017
Effective date (End): October 31, 2019
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal Investigator:Bianca Alves Vieira Bianco
Grantee:Carla Peluso de Paiva
Host Institution: Centro Universitário Saúde ABC. Fundação do ABC. Santo André , SP, Brazil


Among the main causes of infertility is endometriosis, a chronic inflammation that represents one of the most common benign gynecological diseases. It is estimated that 25%-50% of women with endometriosis are infertile and that 25%-30% of infertile women have endometrial lesions as the only identifiable cause for infertility. The association between endometriosis and infertility is well established, but the mechanisms responsible for these effects are unknown.A 2008 study by Lemos et al that evaluated the ovarian reserve and follicular cohort in infertile women with minimal and mild endometriosis in relation to women with tubal obstruction through serum FSH, AMH and transvaginal ultrasonographic evaluation showed that the value mean of FSH was not different between groups. However, infertile women with endometriosis had significantly lower serum AMH values than the control group. Analysis of the follicular cohort showed that follicle numbers were similar between groups, but the diameter was lower in infertile patients with minimal and mild endometriosis. A study of our group [Andre et al. (Unpublished data]), with 340 infertile women, 126 with male infertility (control group) and 214 with endometriosis (37.9% with minimal/mild endometriosis and 62.1% with moderate/severe) showed that the median baseline serum FSH in the control group was 6.0 IU (5.09 to 7.28 IU) while in the case group it was 6.9 IU (5.4 To 8.75 IU), with a statistically significant difference (p = 0.0016), also suggesting a decrease in ovarian reserve in women with endometriosis.Management of infertility in endometriosis, especially in moderate/severe cases, is still controversial. A multidisciplinary approach is essential to consider the various treatment options and provide individualized care to patients according to different parameters, such as age, degree of injury and location of lesions, presence or absence of ovarian failure, male infertility factors in the couple, etc).In assisted human reproduction, the response to controlled ovarian hyperstimulation with exogenous FSH is variable and difficult to predict, it may result in both satisfactory response or inadequate response requiring adjustment of FSH dose or in ovarian hyperstimulation syndrome. The identification of patients with potential to develop hyperresponsiveness or inadequate response to standard treatment would be of great clinical assistance, allowing dose adjustment and treatment savings.There are two groups of genes that are candidates to affect fertility and, consequently, the response to ovarian stimulation and assisted reproduction results: i) Genes that affect follicular function by exerting a hormonal effect - FSH, FSHR, AMH, AMHR2, ER±, ER², CYP17, CYP19, COMT, MTHFR; KiSS1, GPR54/KISS1R, GnRH and GnRHR and ii) Genes that affect the rate of initial recruitment of the primordial follicular pool to the pool of growing follicles - BMP15, GDF9 and FOXL2. Since these genes are expressed during oogenesis, their mutations can lead to varying degrees of blockage in the formation of germ cells. However, small variations in these genes (polymorphisms) could determine the follicular pool variability and thus respond by the variability of response to controlled ovarian stimulation with recombinant FSH in assisted human reproduction treatments.Thus, the aim of the present study is to improve the understanding of mutations and/or polymorphisms in candidate genes that may be important for the advancement of diagnosis and treatment of infertility in women with and without endometriosis, through new generation sequencing, correlating the findings with FSH, LH, estradiol, AMH and Kisspeptine serum levels and with the results of controlled ovarian hyper stimulation in assisted human reproduction treatments. (AU)

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