Follicular Fluid Profile After Stimulation With Highly Purified Menotropin and Recombinant FSH in IVF Cycles

Abstract

To investigate the hormonal milieu in the follicles of women stimulated with highly purified menotropin or recombinant FSH while undergoing IVF treatment. Analysis of a large, randomized, open-label, assessor-blind, multicenter, multinational trial (MERIT) comparing two gonadotropin preparations in IVF cycles with the long GnRH agonist protocol. 731 ovulatory women with tubal factor, mild male factor, endometriosis stage I/II or unexplained infertility were downregulated with triptorelin 0.1 mg SC daily from the mid-luteal phase and randomised to either HP-hMG (MENOPUR, Ferring Pharmaceuticals) (n=363) or recombinant FSH (GONAL-F, Serono) (n=368). The starting dose was 225 IU SC for the first five days and thereafter dose adjustments of 75 IU were allowed not more frequently than every four days. Recombinant hCG 250 μg SC was administered when 3 or more follicles of 17 mm or greater were observed. Follicular fluid from at least one follicle of 17 mm or more was collected for 676 women (HP-hMG: 335, recombinant FSH: 341) and analysed centrally for FSH, LH, hCG, estradiol, progesterone, androstenedione, total testosterone, SHBG, insulin, inhibin A, inhibin B, VEGF and IGF-1. For each parameter, the treatment difference with 95% confidence interval and p-value was estimated based on a linear model of the ln-transformed data including treatment and age strata as the explanatory variables. The levels of FSH, LH, hCG and estradiol detected in the follicular fluid were significantly (p<0.0001) higher among women stimulated with HP-hMG compared to those exposed to recombinant FSH. Follicular levels of progesterone were significantly (p<0.0001) higher in the recombinant FSH group than in the HP-hMG group. Androstenedione and total testosterone were significantly (p<0.0001) higher with HP-hMG compared to recombinant FSH, while SHBG did not differ significantly, leading to significantly (p<0.0001) higher FAI levels in the HP-hMG group. The ratios of androstenedione / estradiol, total testosterone / estradiol and progesterone / estradiol were all significantly (p<0.0001) higher in the follicular fluid from women in the recombinant FSH group compared to the HP-hMG group. The follicular levels of insulin were not significantly different between the two groups. Concerning the inhibins, inhibin A was significantly (p<0.01) higher in the recombinant FSH group while inhibin B was significantly (p<0.001) higher in the HP-hMG group. The inhibin A / inhibin B ratio was significantly (p<0.0001) higher in the recombinant FSH group. The follicular level of VEGF was significantly (p<0.001) higher among women stimulated with recombinant FSH. The IGF-1 levels detected in the follicular fluid were not significantly different between treatment groups. Major differences in the follicular fluid endocrine profile exist between women stimulated with HP-hMG and those stimulated with recombinant FSH. The follicular micro-environment associated with gonadotropins containing LH-activity is more estrogenic than androgenic or progestogenic compared to that associated with preparations without LH activity. These distinct profiles may be of relevance for interpreting differences on embryo quality parameters.