FSH receptor N680S genotype-guided choice of gonadotropin increases cumulative pregnancy and live birth rate after in vitro fertilization

Ida Hjelmér^1*Mathilda Nilsson¹Emir Henic^1,2Piotr Jędrzejczak³Hannah Nenonen¹Katarzyna Ozegowska³Aleksander Giwercman^1,2Margareta Laczna Kitlinski²Yvonne Lundberg Giwercman¹

• ¹Lund University, Lund, Sweden
• ²Scanian University Hospital Malmö, Malmo, Sweden
• ³Poznan University of Medical Sciences, Poznań, Greater Poland, Poland

Objective: To compare cumulative (fresh and frozen embryo transfers from one ovarian stimulation [OS] cycle) pregnancy and live birth rates in women in whom the choice between recombinant FSH (rFSH) and urinary FSH (uFSH) for OS was linked to FSH receptor (FSHR) N680S genotype and compared to non-genotyped controls. Methods: To define optimal combination of FSH type and FSHR genotype, 475 women were allocated to either rFSH or to uFSH for OS. The number of aspirated oocytes, cumulative pregnancy rates, and live birth rates in the first OS cycle, were determined. Subsequently, their FSHR N680S (rs6166) variant was analyzed. Clinical data were backed up by in vitro experiments, in which COS-1 cells were transfected with homozygous FSHR variants and stimulated with either uFSH or rFSH. cAMP was measured to evaluate receptor activity. Thereafter, a sub cohort of 221 who received optimal FSH treatment in relation to their FSHR genotype was selected among the total cohort of 475 women. Cumulative pregnancy and live birth rates were compared between 991 non-genotyped controls and those 221 women. Binary logistic regression was used to explore the odds ratio (OR) and 95% confidence intervals (CI) for cumulative pregnancy and live birth rate in the first OS cycle among genotyped and optimally treated women with the non-genotyped cohort set as reference. Adjustment for age and body mass index as well as method of fertilization was done. The combined clinical and in vitro data indicated that uFSH was the optimal choice for FSHR N680S S-allele carriers whereas rFSH was the hormone of choice for NN subjects. The sub cohort consisting of uFSH-treated S-carriers together with rFSH-treated NN-carriers had significantly higher chance of pregnancy (51% vs. 40%; OR: 1.40, 95% CI 1.12-1.75, p=0.003) and live birth (40% vs. 29%; OR: 1.55, 95% CI 1.23-1.96, p<0.001) compared to non-genotyped women, in whom the choice of hormone was based on standard clinical evaluation. A significantly increased chance of pregnancy and live birth can be achieved by a genotype-guided approach. While administration of uFSH should be the choice to S-carriers, rFSH would be beneficial to NN-carrying women.