Evaluation of FSHr, Amh and AMHR2 gene polymorphisms in infertile women and its correlation with human reproduction outcomes

Abstract

Infertility affects about 20% of couples in reproductive age. The study of polymorphisms of genes that regulate female reproductive function may help clarify the mechanisms responsible for gonadal function and fertility in humans. In human assisted reproduction, response to controlled ovarian hyperstimulation is variable and is difficult to predict. In young ovulatory women undergoing in vitro fertilization (IVF), the standard stimulation protocol may result in both satisfactory answer, and in an inadequate response that requires adjusting the dose 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 clinically helpful. Several parameters have been postulated as predictors of ovarian response. The level of basal FSH on the third day of the cycle seems to have the best predictive ability, but significant within-person variability from cycle to cycle has been observed. The FSH receptor (FSHR) also plays an important role in the regulation of gametogenesis and a mutational screening of the FSHR revealed the presence of two common polymorphisms in exon 10 (Ala307Thr and Asn680Ser). Studies have shown that these polymorphisms influence the conformation of the protein and appear to affect the sensitivity of the ovaries to FSH in women undergoing ovulation induction for assisted reproduction treatment. Thus it has been suggested that polymorphisms in FSHR gene may be predictive markers to measure the ovarian response in women undergoing assisted reproduction treatments, but with conflicting results.Anti-Müleriano hormone (AMH) is also involved in the regulation of follicular growth. Studies in knockout mice showed that AMH gene, in the absence of AMH, follicles are recruited at a faster pace and are more sensitive to FSH, suggesting that this hormone may inhibit early growth of primordial follicle growth induced by FSH. In addition, studies in normo-ovulatory women showed association of AMH polymorphisms and its receptor AMHR2 with estradiol levels during the early follicular phase of the menstrual cycle suggesting a role in regulating sensitivity to FSH. Other authors also demonstrated that basal levels of AMH is correlated with the total dose of gonadotropin used, estradiol level, the number of mature follicles on the day of hCG, the number of oocytes retrieved and pregnancy rates in women undergoing IVF. It was also suggested that serum levels of AMH could predict poor ovarian response (poor response) and ovarian hyperstimulation syndrome. Moreover, unlike FSH, although during the menstrual cycle AMH blood have slight fluctuations; it does not interfere in the interpretation of the ovarian reserve. Thus, AMH has been currently regarded as a promising biomarker of ovarian status, and predict outcomes of IVF, however, genetic variations in AMH and AMHR2 genes may influence hormone function. Likewise, FSH is also considered a biomarker of ovarian reserve and has been suggested that polymorphisms in the gene of its receptor - FSHR may be predictive markers of ovarian response in women undergoing assisted reproduction treatments, but with conflicting results. Since the same polymorphism may have different patterns of association in different populations, is of great interest to characterize the real relationship between the polymorphisms of the FSHR gene, AMHR2 and AMH serum levels of FSH, AMH and estradiol, results of ovarian stimulation and results of assisted reproduction in Brazilian women undergoing assisted reproduction treatments. (AU)