Impact of polymorphisms of gonadotropins and their receptors on controlled ovarian stimulation: a prospective observational study

Study question: Which effect do polymorphisms of gonadotropins and their re- ceptors have on stimulation outcomes in IVF patients co-treated with a GnRHa long down-regulation protocol? Summary answer: Allele C of FSHR-29, LHCGR-291 and FSHR-680 all resulted in a significantly increased cumulative r-FSH dose: total number of oocytes or mature oocytes ratio. What is known already: Specific polymorphisms might influence controlled ovarian stimulation in women undergoing IVF/ICSI. Data regarding the pos- sible interactions of these polymorphisms are still scanty, especially as regards LHCG-R polymorphisms. Study design, size, duration: Prospective observational study in 100 normogo- nadotropic IVF/ICSI patients came from three public IVF Units. Participants/materials, setting, methods: Normogonadotropic Caucasian women fulfilling the following inclusion criteria were enrolled: age 20–34 years; BMI 20–27 kg/m2; basal FSH ≤ 10 IU/l; functional ovaries. Exclusion crite- ria were: uterine anomalies; endocrine, genetic or immunological disorders; PCOS; history of impaired ovarian response (≤ 4 oocytes retrieved) in at least one IVF/ICSI cycle. Patients underwent a GnRH long down-regulation protocol with a starting dose of 150 IU of recombinant FSH daily. Six polymorphisms were genotyped. Main results and the role of chance: The following polymorphisms were analyzed: FSHR-680 (rs6166); FSHR-min29 (rs1394205); LHCGR intronic (rs4073366); LHCGR-291 (rs 12470652); LHCGR-312 (rs2293275); FSHβ- 2623 (rs6169). Basal FSH levels were significantly lower in homozygotic carriers of FSHR-630 (T/T) than in heterozygotic C/T (p = 0.023). Lower basal estradiol levels were seen in homozygotic carriers of FSHR-29 promoter C/C compared to heterozygotic C/T (p = 0.045). Basal estradiol levels and number of fertil- ized and mature oocytes were lower in homozygotic carriers of LHCGR-291 (T/T) compared to heterozygotic C/T (p = 0.035 and p = 0.05 respectively). The presence of allele C on both FSHR-min29 and LHCGR-291 caused an in- creased ratio between the cumulative r-FSH consumption and the total number of oocytes as well as mature oocytes (RR: 5.47, CI 95%: 3.13–7.81, p < 0.001). This observation was also confirmed when polymorphisms of FSHR-680 were included in the analysis. Specifically, the presence of allele C on these three genes was related to an increased ratio between the cumulative FSH consump- tion and the total number of oocytes or mature oocytes (RR: 5.44, CI 95%: 3.18–7.71, p < 0.001). Limitations, reasons for caution: Although limited by the small size of the population, these findings confirm a possible interaction between multiple poly- morphisms in assisted reproductive technology. Wider implications of the findings: These data support the concept that the ovarian response to exogenous FSH seems to be determined by the in- teraction of specific genetic traits. Moreover, this study shows an involve- ment of the LHCGR-291 polymorphism in ovarian response to exogenous gonadotropins. Trial registration number: Not applicable.