Evaluation of mutations/polymorphisms in candidate genes in infertile women and its correlation with human reproduction outcomes

• Grant number: 14/06177-2
• Support Opportunities: Regular Research Grants
• Start date: August 01, 2014
• End date: January 31, 2017
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Bianca Alves Vieira Bianco
• Grantee: Bianca Alves Vieira Bianco
• Host Institution: Faculdade de Medicina do ABC (FMABC). Organização Social de Saúde. Fundação do ABC. Santo André , SP, Brazil
• Associated researchers: Caio Parente Barbosa ; Denise Maria Christofolini ; Fernando Luiz Affonso Fonseca

Abstract

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 the FSHR gene may cause the arrest of follicular growth leading to decreased ovarian reserve. Studies have shown that these polymorphisms appear to affect the sensitivity of the ovaries to FSH in women undergoing ovulation induction for assisted reproduction, with conflicting results. However, other polymorphisms appear to influence the ovarian response. There are groups of genes that are candidates for affecting fertility and thus the response to ovarian stimulation and the results of assisted reproduction: i) genes that affect the function of the follicular hormone exert an effect - FSH, FSHR, AMH, AMHR2, ER± , ER², CYP17, CYP19, COMT, MTHFR, GNRH1, KISS1 and KISS1R ii) genes that affect the rate of the initial recruitment of the primordial follicle pool to the pool of growing follicles - BMP15, GDF9 and FOXL2 iii) genes that encode DNA binding proteins and transcription factors such as LHX8 and RNA binding proteins as NANOS3. Since these genes are expressed during oogenesis, its mutations can cause varying degrees of blockage in the formation 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 and KISS1 stimulates gonadotropin-releasing hormone (GnRH), which binds to a receptor coupled to G (GPR54) protein, 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 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, delay 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. Thus, the objective of this study is to improve understanding of the mutations / polymorphisms in candidate genes that may be important to advance the diagnosis and treatment of infertility. (AU)

Scientific publications

(7)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

PELUSO, CARLA; DE OLIVEIRA, RENATO; LAPORTA, GABRIEL ZORELLO; CHRISTOFOLINI, DENISE MARIA; FONSECA, FERNANDO LUIZ AFFONSO; LAGANA, ANTONIO SIMONE; BARBOSA, CAIO PARENTE; BIANCO, BIANCA. Are ovarian reserve tests reliable in predicting ovarian response? Results from a prospective, cross-sectional, single-center analysis. Gynecological Endocrinology, v. 37, n. 4, JUL 2020. (14/06177-2)

TREVISAN, CAMILA MARTINS; NASLAVSKY, MICHEL SATYA; MONFARDINI, FREDERICO; WANG, JAQUELINE; ZATZ, MAYANA; PELUSO, CARLA; PELLEGRINO, RENATA; MAFRA, FERNANDA; HAKONARSON, HAKON; FERREIRA, FREDERICO MORAES; et al. Variants in the Kisspeptin-GnRH Pathway Modulate the Hormonal Profile and Reproductive Outcomes. DNA AND CELL BIOLOGY, v. 39, n. 6, APR 2020. (14/06177-2, 16/25953-9)

PABALAN, NOEL; MONTAGNA, ERIK; SINGIAN, ELOISA; TABANGAY, LANI; JARJANAZI, HANNDI; BARBOSA, CAIO PARENTE; BIANCO, BIANCA. Associations of Polymorphisms in Anti-Mullerian Hormone (AMH Ile49Ser) and its Type II Receptor (AMHRII-482 A > G) on Reproductive Outcomes and Polycystic Ovary Syndrome: a Systematic Review and Meta-Analysis. CELLULAR PHYSIOLOGY AND BIOCHEMISTRY, v. 39, n. 6, p. 2249-2261, 2016. (14/06177-2)

PELUSO, CARLA; FONSECA, FERNANDO L. A.; GASTALDO, GUILHERME G.; CHRISTOFOLINI, DENISE M.; CORDTS, EMERSON BARCHI; BARBOSA, CAIO P.; BIANCO, BIANCA. AMH and AMHR2 Polymorphisms and AMH Serum Level Can Predict Assisted Reproduction Outcomes: A Cross-Sectional Study. CELLULAR PHYSIOLOGY AND BIOCHEMISTRY, v. 35, n. 4, p. 1401-1412, 2015. (13/06989-4, 11/08681-1, 11/15045-4, 14/06177-2)

DE MATTOS, CLARISSA SANTIAGO; TREVISAN, CAMILA MARTINS; PELUSO, CARLA; ADAMI, FERNANDO; CORDTS, EMERSON BARCHI; CHRISTOFOLINI, DENISE MARIA; BARBOSA, CAIO PARENTE; BIANCO, BIANCA. ESR1 and ESR2 gene polymorphisms are associated with human reproduction outcomes in Brazilian women. JOURNAL OF OVARIAN RESEARCH, v. 7, DEC 20 2014. (11/15045-4, 14/06177-2)

PABALAN, NOEL; TREVISAN, CAMILA MARTINS; PELUSO, CARLA; JARJANAZI, HAMDI; CHRISTOFOLINI, DENISE MARIA; BARBOSA, CAIO PARENTE; BIANCO, BIANCA. Evaluating influence of the genotypes in the follicle-stimulating hormone receptor (FSHR) Ser680Asn (rs6166) polymorphism on poor and hyper-responders to ovarian stimulation: a meta-analysis. JOURNAL OF OVARIAN RESEARCH, v. 7, n. 122, DEC 20 2014. (14/06177-2)

PELUSO, CARLA; GOLDMAN, CECILIA; CAVALCANTI, VIVIANE; GASTALDO, GUILHERME; TREVISAN, CAMILA MARTINS; CHRISTOFOLINI, DENISE MARIA; BARBOSA, CAIO PARENTE; BIANCO, BIANCA. Use of Bone Morphogenetic Protein 15 Polymorphisms to Predict Ovarian Stimulation Outcomes in Infertile Brazilian Women. GENETIC TESTING AND MOLECULAR BIOMARKERS, v. 21, n. 5, p. 328-333, MAY 2017. (12/00566-1, 14/06177-2)