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Variants of GPR54/KISS1R gene in the controlled ovarian hyperstimulation response in infertile women underwent assisted reproduction treatment

Grant number: 14/09505-0
Support Opportunities:Scholarships in Brazil - Scientific Initiation
Effective date (Start): August 01, 2014
Effective date (End): July 31, 2015
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal Investigator:Bianca Alves Vieira Bianco
Grantee:Marina Cristina Peres
Host Institution: Faculdade de Medicina do ABC (FMABC). Organização Social de Saúde. Fundação do ABC. Santo André , SP, Brazil


Infertility affects about 20 % of couples of childbearing age. The study of polymorphisms of genes that regulate female reproductive function may help to clarify the mechanisms responsible for gonadal function and fertility in humans. In assisted human reproduction, response to controlled ovarian hyperstimulation is variable and difficult to predict. In young ovulatory women undergoing in vitro fertilization (IVF) protocol standard stimulation can result in both satisfactory answer, as for inadequate response which requires dose adjustment of FSH or ovarian hyperstimulation syndrome, a serious and potentially fatal complication IVF. Identifying patients with potential to develop hyper - response or inadequate response to standard treatment would be of great clinical aid.Currently, basal FSH on the third day of the cycle seems to have the best predictive ability. Moreover, it has been suggested that mutations and polymorphisms in candidate genes can cause arrest of follicular growth leading to decreased ovarian reserve. Since these genes are expressed during oogenesis, its mutations can cause varying degrees of blockage in the formation and / or maturation of germ cells. Small variations in these genes might determine the variability of follicle pool and thus account for the variability of response to ovarian stimulation and outcome of assisted reproduction. The kisspeptin, which is the product of the gene KISS1 located in 1q32 and that stimulates gonadotropin-releasing hormone (GnRH), binds to a G coupled receptor ( GPR54 ) protein encoded by the GPR54 gene located in 19p13.3, which stimulates the release of GnRH by hypothalamic neurons, leading to the secretion of pituitary gonadotropins LH and FSH and sex steroids which in turn will act on the gonads to produce gametes. In humans and rodents, mutations in KISS1 gene and its receptor GPR54, induce infertility due to hypogonadotropic hypogonadism. Transgenic mice that do not express Kiss1 and GPR54 showed no sexual maturation, with underdevelopment of the gonads, hypogonadism and infertility. The earliest evidence relating kisspeptin - KISS1R with playback control studies come from two separate studies reported that mutations causing loss of function of KISS1R were associated with the occurrence of hypogonadotropic hypogonadism in humans, characterized by a deficiency in the secretion of LH and FSH, delayed maturation of reproductive function and infertility. Thus, it has envisaged that the signaling kisspeptin - KISS1R be essential for the increased secretion of gonadotropins during puberty and establishment of reproductive function in mammals. It was also shown that kisspeptin plays an important stimulatory role in the genesis of the preovulatory LH surge, responsible for triggering ovulation in female rodents. These findings confirm the important role of kisspeptin in the physiological regulation of the hypothalamic -pituitary - gonadal axis in mammals. Given the above, the objective of this study is to study GPR54/KISS1R gene polymorphisms in infertile women undergoing assisted reproduction treatment and correlation with serum FSH and estradiol and the results of controlled ovarian hyperstimulation. (AU)

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