A prospective, randomized comparison of two starting doses of recombinant FSH in combination with cetrorelix in women undergoing ovarian stimulation for IVF/ICSI

BACKGROUND: A prospective randomized study was carried out in two centres to compare the number of oocytes retrieved after two different starting doses of recombinant human FSH (rhFSH) (Gonal-F) in women undergoing ovarian stimulation for IVF/intracytoplasmic sperm injection (ICSI) cycles using the multiple dose regimen of the gonadotrophin-releasing hormone (GnRH) antagonist cetrorelix (Cetrotide) to prevent induction of the premature LH surge. METHODS: Sixty women were randomized to receive rhFSH 150 IU ('low'), and 60 women to receive rhFSH 225 IU ('high') as the starting dose for the first 5 days of stimulation. From stimulation day 6 and onwards, including the day of human chorionic gonadotrophin (HCG) administration, the women received 0.25 mg of cetrorelix as a daily dose. The primary endpoint was the number of oocytes retrieved. RESULTS: The mean number (+/- SD) of oocytes was 9.1 +/- 4.4 and 11.0 +/- 4.6 in the 'low' and 'high' groups respectively (P = 0.024). The mean number of 75 IU ampoules of rhFSH was significantly lower in the 'low' group (23.0 +/- 6.3 versus 30.5 +/- 5.6, P < 0.0001). The ongoing pregnancy rate per started cycle and per embryo transfer were 25.9 and 28.8% versus 25.4 and 26.8% respectively in the 'low' and 'high' rhFSH groups (P = NS). CONCLUSIONS: When using a starting dose of 225 IU rhFSH combined with the multiple dose of 0.25 mg cetrorelix from stimulation day 6, significantly more oocytes were obtained than with a starting dose of 150 IU rhFSH.     

A prospective, randomized, double-blind clinical trial to study the efficacy and efficiency of a fixed dose of recombinant follicle stimulating hormone (Puregon) in women undergoing ovarian stimulation

A prospective, randomized, double-blind, multicentre (n = 5) study was conducted to compare the influence of either a 100 or 200 IU daily fixed-dose regimen of recombinant follicle stimulating hormone (FSH) on the number of oocytes retrieved and the total dose used in down-regulated women undergoing ovarian stimulation. Fertilization was done by intracytoplasmic sperm injection or conventional in-vitro fertilization. A total of 199 women were treated with FSH, 101 subjects with 100 IU and 98 subjects with 200 IU. In subjects of the 200 IU treatment group, significantly more oocytes were retrieved compared to the 100 IU group (10.6 versus 6.2 oocytes, P < 0.001). The total dose needed to develop at least three follicles with a diameter of > or = 17 mm was significantly lower in the 100 IU treatment group (1114 IU versus 1931 IU, P < 0.001). In the low-dose group, significantly lower serum concentrations of oestradiol, progesterone and FSH were observed at the day of human chorionic gonadotrophin administration. Although more cycle cancellations due to low response were seen in the 100 IU group (n = 24 versus n = 3), the clinical pregnancy rate per started cycle was similar (24.7% in the 100 IU group versus 23.3% in the 200 IU group). In the high-dose group, more side-effects, in particular more cases of ovarian hyperstimulation syndrome, were noted. It is concluded that compared to 200 IU, the use of a 100 IU fixed dose is less efficacious in terms of the number of oocytes retrieved, but more efficient as indicated by a lower total dose.     

Treatment with the gonadotrophin-releasing hormone antagonist ganirelix in women undergoing ovarian stimulation with recombinant follicle stimulating hormone is effective, safe and convenient: results of a controlled, randomized, multicentre trial. The European Orgalutran Study Group

A multicentre, open-label, randomized study of the gonadotrophin-releasing hormone (GnRH) antagonist ganirelix (Orgalutran((R))/Antagon((TM))) was performed in women undergoing ovarian stimulation with recombinant FSH (rFSH: Puregon((R))). The study was designed as a non-inferiority study using a long protocol of buserelin (intranasal) and rFSH as a reference treatment. A total of 730 subjects was randomized in a treatment ratio of 2:1 (ganirelix:buserelin) using an interactive voice response system which stratified for age, type of infertility and planned fertilization procedure [IVF or intracytoplasmic sperm injection (ICSI)]. The median duration of GnRH analogue treatment was 5 days in the ganirelix group and 26 days in the buserelin group, whereas the median total rFSH dose was 1500 IU and 1800 IU respectively. In addition, in the ganirelix group the mean duration of stimulation was 1 day shorter. During ganirelix treatment the incidence of LH rises (LH >/=10 IU/l) was 2.8% versus 1.3% during rFSH stimulation in the buserelin group. On the day of triggering ovulation by human chorionic gonadotrophin (HCG), the mean number of follicles >/=11 mm diameter was 10.7 and 11.8, and the median serum oestradiol concentrations were 1190 pg/ml and 1700 pg/ml in the ganirelix and buserelin groups respectively. The mean number of oocytes per retrieval was 9.1 and 10.4 respectively, whereas the mean number of good quality embryos was 3.3 and 3.5 respectively. The fertilization rate was equal in both groups (62.1%), and the same mean number of embryos (2.2) was replaced. The mean implantation rates were 15.7% and 21.8%, and the ongoing pregnancy rates per attempt were 20.3% and 25.7% in the ganirelix and buserelin groups respectively. Evaluation of all safety data indicated that the ganirelix regimen was safe and well tolerated. The overall incidence of ovarian hyperstimulation syndrome was 2.4% in the ganirelix group and 5.9% in the reference group. The results of this study support a safe, short and convenient treatment regimen of ganirelix, resulting in a good clinical outcome for patients undergoing ovarian stimulation for IVF or ICSI.     

Effect of reduced dose of triptorelin at the start of ovarian stimulation on the outcome of IVF: a randomized study.

BACKGROUND: Partial pituitary desensitization using gonadotrophin-releasing hormone (GnRH) agonists may be sufficient in women undergoing controlled ovarian hyperstimulation for assisted reproduction. However, the minimal effective agonist dose remains to be determined. The aim of the study was to investigate the effect of a reduced daily dose of triptorelin, administered at the start of ovarian stimulation, on the results of IVF and intracytoplasmic sperm injection. METHODS: A total of 132 patients was randomized in two groups. Pituitary desensitization was obtained in group 1 (66 patients) with a single 3.75 mg injection (i.m.) of triptorelin. In group 2, 66 patients received 100 microg triptorelin daily, which was then reduced to 50 microg at the start of follicle-stimulating hormone (FSH) stimulation. RESULTS: No significant differences were found in terms of pregnancy rate per transfer (38% in group 1 versus 34.9% in group 2), implantation rate (20.2 versus 18%) and abortion rate (8.3 versus 9.1%). The number of FSH ampoules used, as well as the number of days stimulation required, was significantly reduced in group 2 (41 +/- 26 versus 46.6 +/- 25.3, P < 0.03 and 11 +/- 1.3 versus 11.8 +/- 1.5, P < 0.002 respectively). No significant differences were seen in oestradiol concentrations and in follicle number, in the quantity of oocytes collected and fertilized, or in the number of embryos obtained or transferred. CONCLUSION: A reduced dose of triptorelin is enough for pituitary suppression during ovarian stimulation but provides no significant improvement in IVF cycle outcome when compared with depot formulation. The possibility of a shorter treatment protocol requiring lower amounts of gonadotrophins should be considered in view of its economic advantage.     

Recombinant human LH supplementation during GnRH antagonist administration in IVF/ICSI cycles: a prospective randomized study

BACKGROUND: When administered in the late follicular phase to prevent an LH surge, GnRH antagonists induce a sharp decrease in serum LH levels that may be detrimental for assisted reproductive technology cycle outcome. Therefore, a prospective study was designed to assess the effects of recombinant human (r)LH supplementation during GnRH antagonist (cetrorelix) administration. METHODS: The protocol consisted of cycle programming with oral contraceptive pill, ovarian stimulation with rFSH and flexible administration of a single dose of cetrorelix (3 mg). A total of 218 patients from three IVF centres were randomized (by sealed envelopes or according to woman's birth date) to receive (n = 114) or not (n = 104) a daily injection of rLH 75 IU from GnRH antagonist initiation to hCG injection. RESULTS: The only significant difference was a higher serum peak E2 level in patients treated with rLH (1476 +/- 787 versus 1012 +/- 659 pg/ml, P < 0.001) whereas the numbers of oocytes and embryos as well as the delivery rate (25.2 versus 24%) and the implantation rate per embryo (19.1 versus 17.4%) were similar in both groups. CONCLUSIONS: These results show that in an unselected group of patients, there is no evident benefit to supplement GnRH antagonist-treated cycles with rLH.     

Comparable clinical outcome using the GnRH antagonist ganirelix or a long protocol of the GnRH agonist triptorelin for the prevention of premature LH surges in women undergoing ovarian stimulation

This multicentre, randomized study was performed to assess theefficacy and safety of 0.25 mg ganirelix (Orgalutran^®, Antagon^TM)treatment, using triptorelin (Decapeptyl^®) in a long protocolas a reference treatment. In total, 236 subjects were randomizedto treatment with ganirelix (0.25 mg, s.c.) and 119 to triptorelin(0.1 mg, s.c.) treatment (treatment ratio 2:1). Treatment withganirelix started on day 6 of stimulation, whereas treatmentwith triptorelin started on menstrual cycle day 21 to 24 ofthe previous cycle (i.e. the midluteal phase). The ganirelixregimen was on average 17 days shorter (9 versus 26 days) comparedto the triptorelin regimen. The median total dose of recombinantFSH (Puregon^®) used was 450 IU less (1350 versus 1800 IU)in the ganirelix protocol. The initial follicular growth wasfaster and, consequently, oestradiol concentrations were higherin the ganirelix group. On the day of human chorionic gonadotrophin(HCG), the mean number of follicles 11 mm was 10.1 and 10.7and the median serum oestradiol concentration was 1090 and 1370pg/ml in the ganirelix and triptorelin groups respectively.Per attempt, 7.9 and 9.6 oocytes (mean) were retrieved in theganirelix and triptorelin groups respectively. The fertilizationrates (64.0% ganirelix and 64.9% triptorelin) and the mean numberof good quality embryos (2.7 and 2.9) were comparable in bothtreatment groups. The implantation rate was identical (22.9%).The ongoing pregnancy rate per attempt was 31.0 and 33.9% inthe ganirelix and triptorelin groups respectively. The ganirelixregimen showed an improved local tolerance in that the percentageof subjects with at least one local skin reaction was 2-foldlower than in the triptorelin group (11.9 versus 24.1%). Takingall data together, it may be concluded that ganirelix offersa new treatment regimen in ovarian stimulation that is short,safe and well-tolerated, optimizing convenience for the patient.     

Metformin treatment before IVF/ICSI in women with polycystic ovary syndrome; a prospective, randomized, double blind study

BACKGROUND: Our aim was to investigate the effect of pre-treatment with metformin in women with polycystic ovary syndrome (PCOS) scheduled for IVF stimulation. METHODS: Seventy-three oligo/amenorrhoeic women with polycystic ovaries and at least one of the following criteria: hyperandrogenaemia, elevated LH/FSH ratio, hyperinsulinism, decreased SHBG levels or hirsutism, were studied. Normal weight and overweight patients were randomized separately in a prospective, randomized, double blind study. All patients were treated for at least 16 weeks with metformin (1000 mg bid) or placebo ending on the day of HCG injection. RESULTS: No differences were found in the primary end-points: duration of FSH stimulation 14.4 (13.1-15.7) versus 14.2 (12.6-15.7) days or estradiol on the day of HCG injection 6.8 (5.3-8.2) versus 7.6 (5.6-9.6) nmol/l in the metformin and placebo groups, respectively. The secondary end-points number of oocytes, fertilization rates, embryo quality, pregnancy rates and clinical pregnancy rates were equal. However, in the normal weight subgroup (BMI <28 kg/m(2), n = 27), pregnancy rates following IVF were 0.71 (0.63-0.79) versus 0.23 (0.15-0.31) in the metformin and placebo groups, respectively (P = 0.04). Overall clinical pregnancy rates were equal: 0.51 (0.34-0.68) versus 0.44 (0.27-0.62) in the metformin and placebo groups, respectively. However, in the normal weight subgroup, clinical pregnancy rates were 0.67 (0.43-0.91) and 0.33 (0.06-0.60), respectively (P = 0.06). CONCLUSIONS: Pre-treatment with metformin prior to conventional IVF/ICSI in women with PCOS does not improve stimulation or clinical outcome. However, among normal weight PCOS women, pre-treatment with metformin tends to improve pregnancy rates. Further studies in subgroups of PCOS women are required.     

Tailoring the GnRH antagonist cetrorelix acetate to individual patients' needs in ovarian stimulation for IVF: results of a prospective,randomized study

INTRODUCTION: This study was performed to evaluate whether a tailored approach to the administration of the GnRH antagonist cetrorelix acetate according to follicular size leads to a reduction in the amount of Cetrotide vials used and/or an increased number of monitoring visits. METHODS: Sixty patients were prospectively randomized (using sealed envelopes) to receive either the fixed multiple dose antagonist protocol starting on day 6 of stimulation (group 1), or an individualized protocol with the time of antagonist start according to follicle size (14 mm, group 2), or an individualized single dose protocol (group 3). Recombinant human (rh)FSH was used. The primary endpoints were the number of Cetrotide vials and number of monitoring visits. Statistical power for the parameter Cetrotide vials was 80%. RESULTS: Patients in group 1 needed significantly more Cetrotide vials (6.81 +/- 1.61) than patients of group 2 (4.59 +/- 1.65; P < 0.01). The number of monitoring visits was similar between the three groups. Surprisingly, the number of retrieved oocytes was significantly higher in the individualized groups as compared with group 1. Despite a significantly lower total amount of rhFSH used, estradiol levels were significantly higher in group 2 as compared with group 1. CONCLUSION: Tailoring of GnRH antagonist protocols leads to an optimization of ovarian stimulation with more oocytes retrieved despite less rhFSH used, and the same number of monitoring visits.     

Clinical outcome with half-dose depot triptorelin is the same as reduced-dose daily buserelin in a long protocol of controlled ovarian stimulation for ICSI/embryo transfer: a randomized double-blind clinical trial (NCT00461916)

BACKGROUND: Traditional doses of depot GnRH agonist may be excessive for ovarian stimulation. We compared half-dose depot triptorelin (Group I) with reduced-dose daily buserelin (Group II) in a long protocol ICSI/embryo transfer through a double-blind randomized clinical trial. METHODS: Controlled ovarian stimulation (COS) was started by a pretreatment with oral contraceptives for 21 days. Then, 182 patients were randomized into two groups of 91. Group I received 1.87 mg triptorelin depot i.m. followed by daily s.c. injections of saline. Group II (reduced-dose protocol) received a bolus injection of i.m. saline followed by daily s.c. injections of 0.5 mg buserelin, which was then reduced to 0.25 mg at the start of human menopausal gonadotrophin stimulation. When transvaginal ultrasound showed at least two follicles of 16-20 mm diameter, HCG was given and ICSI was performed 40-42 h later. RESULTS: No significant differences were seen in the mean (SD) number of follicles at HCG administration, as our primary outcome [10.3 (4.4) in Group I versus 11.1 (4.2) in Group II, P = 0.180, mean difference = 0.86, 95% confidence interval 0.39-2.11]. The other early results of COS, clinical and ongoing pregnancy rates, or early pregnancy loss were also not significantly different between the groups. Group I endured longer stimulation period [11.2 (1.8) days versus 10.6 (1.9), P = 0.030]. CONCLUSIONS: Clinical outcomes were not significantly different between Group I and Group II.     

A prospective, randomized clinical trial comparing 150 IU recombinant follicle stimulating hormone (Puregon((R))) and 225 IU highly purified urinary follicle stimulating hormone (Metrodin-HP((R))) in a fixed-dose regimen in women undergoing ovarian stimulation.

A prospective, randomized, open, multicentre (n = 3) study was conducted to compare the efficacy and efficiency of a fixed daily dose of 150 IU (3x50 IU) recombinant follicle stimulating hormone (recFSH, Puregon((R))) and 225 IU (3x75 IU) highly purified urinary FSH (uFSH-HP, Metrodin-HP((R))) in women undergoing ovarian stimulation prior to in-vitro fertilization treatment. A total of 165 women were treated with FSH, 83 subjects with recFSH and 82 subjects with uFSH-HP. In the recFSH group a mean number of 8.8 oocytes were retrieved, compared with 9.8 in the uFSH-HP group (not statistically significant). In the recFSH group, a significantly lower total dose was required compared to the uFSH-HP group, 1479 versus 2139 IU, respectively (P < 0.0001; 95% confidence interval -747 to -572). Treatment with recFSH resulted in a significantly higher embryo development rate (69.6 versus 56.2%; P = 0.003) and more embryos accessible for the embryo freezing programme (3.3 versus 2.0; P = 0.02) compared to uFSH-HP. The vital pregnancy rate per cycle started was 30.2 versus 28.3% in the recombinant and urinary FSH group, respectively. It is concluded that treatment outcome of a fixed daily dose of 150 IU recFSH is comparable to a fixed daily dose of 225 IU uFSH-HP. However, a significantly lower total dose was needed in the recFSH group (nearly 700 IU less).