In all the studies presented, the multiple-dose protocol uses 0.25mg/day of Cetrorelix or Ganirelix. To compare the antagonist multiple dose protocol (0.25mg/day) to the GnRH-a in IVF cycles, the European Cetrorelix Study Group (21) published the results of an open randomized trial. They studied 188 patients treated with Cetrorelix and 85 patients treated with the long (Buserilin) agonist protocol; both groups received hMG. The authors transferred embryos in 83.5% of Cetrorelix group versus 79% of Buserelin group. The clinical pregnancy rate was 22.3% and 25.9% per started cycle in the Cetrorelix and Buserilin groups, respectively; these differences were not statistically significant. The duration of treatment with gonadotropins and the estradiol serum levels on the day of hCG were lower in the antagonist group. The incidence of ovarian hyperstimulation syndrome (OHSS II and III) was higher in patients using agonist treatment.
The European Ganirelix Study Group (22) also performed a controlled, multicentric, randomized trial to compare two treatment regimens for ovarian stimulation (multiple-dose antagonist vs. long-agonist) in women receiving recombinant FSH. A total of 672 patients were investigated and randomized. The total dose of FSH administered was higher in the Buserilin group (1500 and 1800IU). In addition, patients receiving antagonist had a shorter stimulation duration than the agonist group. The estradiol serum levels on the day of hCG administration were higher in patients using Buserelin than Ganirelix and the incidence of OHSS was higher (5.9 vs. 2.4%) in the Buserelin group. Otherwise, the number of good quality embryos, fertilization rate (62.1% in both groups), and replaced embryos were similar between the two treatments schemes. The implantation rate was lower in the Ganirelix group (15.7%) than in Buserelin group (21.8%), however the clinical pregnancy rates per attempt were not statistically significant.
The North American Ganirelix Study Group (23) was organized to evaluate the efficacy and safety of Ganirelix (multiple-dose protocol) versus leuprolide (long-protocol) in IVF patients. This multicenter (United States and Canada) trial demonstrated that the mean number of retrieved oocytes was similar between the groups (11.6 in antagonist group and 14.1 in agonist group). Moreover, the fertilization rates (62.4% and 61.9%) and implantation rates (21.6% and 26.1%) were also similar in both groups. The ongoing pregnancy rates per attempt were 30.8% in ganirelix group and 36.4% in leuprolide group; however, the antagonist group showed fewer local site reactions after injection administration (12.5%) than the leuprolide group (25.5%). The authors proved the effectiveness and safety of multiple antagonist drug protocol with a shorter stimulation period and fewer side effects when compared with the long agonist (leuprolide) protocol.
Another multicentric European (The European and Middle East) Orgalutran Study Group (24) trial, comparing two treatment schemes (Ganirelix and Triptorelin) in 337 women, demonstrated that the median dose of FSH recombinant was lower in the antagonist protocol. The authors showed also that the estradiol serum levels were lower in Ganirelix group on the day of hCG. The fertilization rates (64% Ganirelix and 64.9% Triptor-elin), the mean number of good quality embryos (2.7 and 2.9, respectively), the implantation rates (22.9% both treatments), and finally the ongoing pregnancy rate per attempt were similar between the two treatments (31% and 33.9%, Ganirelix and Triptorelin, respectively).
The multiple-dose protocol, compared with the long-agonist regimen, offers a simple, safe, and efficient option, with comparable IVF results. The OHSS risk is decreased (25), the total dose of gonadotrophin needed to stimulate the ovulation is lower, and the stimulation period is also shorter than in the long protocol. Patients receiving antagonist treatment had lower estradiol serum levels at the time of hCG administration, probably because of the lower number of follicles. The impact of this finding in implantation rates is disputed and unknown.
In the multiple-dose protocol, there is a small incidence of LH surge (between 1% and 2.5%). These surges were often associated with a lack of compliance by the patients, forgetting one antagonist administration. This point is important to stress to the patients. More recently, some centers have observed a higher incidence of LH surge in poor responders using the multiple-dose protocol (unpublished data). These reports should be confirmed and documented. The dose of 0.25 mg might not be always sufficient. This dose might also have to be adapted to the weight of the patients.
The follicular development was also studied in a controlled randomized multicentric study, in patients using Ganirelix with different doses (0.0625-2.0 mg/day). Patients received recombinant FSH after day 2 of menstrual cycle and Ganirelix were administrated daily after day 6 of ovarian stimulation protocol (26). Overall, 311 patients were studied and compared in terms of number of follicles, total follicular surface area, serum gonadotropin, and steroid hormones levels. Increasing GnRH-nt doses demonstrated an additional suppressive action on estradiol and androstene-dione serum levels, probably by an important inhibition of LH secretion, which may have exerted a harmful effect. The follicular growing pattern was not affected by the dose of GnRH-nt. The decreased secretion of androstenedione and estradiol was not totally explained by the LH inhibition. Other mechanisms could be involved in GnRH-nt action and influence the cycles stimulated with this regimen protocol.
Wikland et al. (27), in a prospective randomized trial, evaluate two starting doses (150 vs. 225IU) of recombinant FSH with the multiple-dose Cetrorelix protocol. The purpose was to increase the number of follicles, oocytes, and embryos to increase the pregnancy rates. Despite a higher number of recovered oocytes in the group of patients receiving 225 IU of recombinant FSH, pregnancy and implantation rates were similar.
The effect of GnRH-nt on oocyte and embryo quality could also be measured by studying the implantation and pregnancy rates after cryopreservation of pronuclear oocytes or embryos. The first study to evaluate this aspect was conducted with 62 patients divided into two groups (28). One group received the multiple GnRH-nt dose protocol (group I) and the other group the conventional GnRH long protocol (group II). The implantation and pregnancy rates, after frozen-thawed procedure in pronucleous oocyte stage, were similar between the groups (3.26% and 8.33% for group I; 3.73% and 10.25% for the group II).
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