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Objective To assess the effect of altering the timing of hCG administration on ongoing pregnancy rates in patients stimulated with recombinant FSH (rec-FSH) and GnRH antagonists for IVF. Design Prospective, randomized, controlled trial. Setting Tertiary referral center. Patient(s) Four hundred thirteen patients undergoing IVF. Intervention(s) Rec-FSH stimulation starting on day 2 of the cycle combined with daily GnRH antagonist starting on day 6 of stimulation. Patients were randomized to receive 10,000 IU of hCG either as soon as at least three follicles were ≥17 mm on ultrasound (early-hCG group, 208 patients) or 2 days later after this criterion was met (late-hCG group, 205 patients). Main outcome measure(s) Ongoing pregnancy rate. Result(s) Fertilization rates and number and quality of embryos transferred did not differ between the two groups. However, a significantly lower ongoing pregnancy rate was present in the late-hCG as compared with the early-hCG group (25.0% vs. 35.6%, respectively). Conclusion(s) Prolongation of the follicular phase in patients stimulated with rec-FSH and GnRH antagonists for IVF does not affect oocyte or embryo quality but is associated with a significantly lower ongoing pregnancy rate.

Objective To compare ongoing implantation rates under two different GnRH antagonist protocols. Design Randomized controlled trial. Setting Tertiary referral center. Patient(s) One hundred eleven women undergoing ovarian stimulation for in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI). Intervention(s) Ovarian stimulation with 150 IU recombinant-FSH (rec-FSH) starting on day 2 of the cycle and GnRH antagonist starting either on day 6 of stimulation (fixed group) or when a follicle of ≥15 mm was present after at least 5 days of stimulation (flexible group). In the flexible group, the rec-FSH dose was increased to 250 IU when the antagonist was initiated. Main outcome measure(s) Ongoing implantation and pregnancy rate. Result(s) In patients with no follicle of ≥15 mm present on day 6 of stimulation, a significantly lower ongoing implantation rate was observed if the flexible scheme was applied as compared with the fixed scheme of administration (8.8% vs. 23.9%, respectively). Exposure of the genital tract to LH or E 2 from initiation of stimulation to antagonist administration was able to distinguish between pregnant and nonpregnant patients in the population studied. Conclusion(s) High exposure of the genital tract to LH and E 2 in the early follicular phase is associated with a reduced chance of pregnancy in cycles stimulated with recombinant FSH and GnRH antagonist for IVF/ICSI.

Objective: To assess the effect of ovarian stimulation with recombinant FSH, GnRH antagonists, and hCG on endometrial maturation on the day of oocyte pick-up. Design: Prospective study. Setting: Tertiary referral center. Patient(s): Fifty-five women undergoing controlled ovarian hyperstimulation for IVF/intracytoplasmic sperm injection (ICSI). Intervention(s): [1] Ovarian stimulation with recombinant FSH, starting on day 2 of the cycle and GnRH antagonist, starting after a median of 6 days of recombinant FSH stimulation (range, 5–12 days); [2] hCG administration for ovulation induction; and [3] aspirational biopsy of endometrium at oocyte pick-up. Main Outcome Measure(s): Endometrial histology at oocyte pick-up by Noyes criteria. Result(s): Advancement of endometrial maturation (2.5 ± 0.1 days) as compared to the expected chronological date was observed in all antagonist cycles at oocyte retrieval. Endometrial advancement at oocyte pick-up increased in line with values of LH at initiation of stimulation and the duration of recombinant FSH treatment before the antagonist was started. Conclusion(s): The higher the values of LH at initiation of stimulation and the longer the duration of recombinant FSH treatment before the antagonist is started, the more advanced the endometrial maturation at oocyte pick-up.

Objective: To summarize data from completed phase II and III clinical trials on children born after controlled ovarian stimulation using the luteinizing hormone–releasing hormone antagonist cetrorelix. Design: All children born after ovarian stimulation in patients treated for infertility who were in prospective studies until March 23, 1999. Setting: Academic research center. Patient(s): Children born after IVF or IVF plus ICSI. Intervention(s): Controlled ovarian stimulation with cetrorelix in a multiple-dose or single/dual-dose protocol. Main Outcome Measure(s): Outcome of pregnancy and, in deliveries, the date of birth, number and sex of children born, birth weight, body length, and abnormalities were recorded. At approximately 1 year of age and 2 years of age, body weight and length and abnormalities in physical and mental development were recorded. Result(s): Two hundred nine and 18 children were born after fresh and frozen embryo transfers, respectively. Of the pregnancies, 76.2% (179 of 234) resulted in live birth and ectopic pregnancy occurred in 3.4% (8 of 231); one heterotopic pregnancy and four induced abortions were recorded. The malformation rate among all live births, stillbirths, and aborted fetuses was 3.1%. Conclusion(s): Use of cetrorelix in controlled ovarian stimulation does not harm the subsequently born children.

Objective: To evaluate the effect of supernumerary preovulatory follicular reduction as an approach to avoid multiple pregnancies in ovulation induction or superovulation cycles. Design: Retrospective study. Setting: Tertiary referral center. Patient(s): In 26 cycles, 24 patients underwent ovulation induction or superovulation with either clomiphene citrate or hMG. Intervention(s): Selective follicle aspiration was performed before hCG administration. Main Outcome Measure(s): Clinical pregnancy rate and numbers of multiple pregnancies. Result(s): A mean number of 4.5 follicles with a diameter ≥15 mm and a mean number of 4.5 follicles with a diameter ≤14 mm were observed before hCG administration. A mean number of 2.3 follicles with a diameter ≥15 mm and a mean number of 1.8 follicles with a diameter ≤14 mm were aspirated before the hCG administration. Seven singleton pregnancies (26.9% per cycle) ensued from the treatment. Conclusion(s): Aspiration of supernumerary follicles after ovulation induction or superovulation seems to be a valid approach to avoid multiple pregnancies without affecting pregnancy rate.

Objective: To compare ICSI with IVF using two insemination concentrations in moderate male infertility and to compare these data with other randomized controlled trials (RCTs). Design: Prospective, randomized, controlled trial and meta-analysis. Setting: University-based tertiary referral center. Patient(s): Seventy-three couples undergoing ART. Intervention(s): In one IVF group a standard insemination concentration of 0.2 × 10 6 /mL was used, whereas in the other group a high insemination concentration (HIC) of 0.8 × 10 6 /mL was used. Each protocol was compared with ICSI on sibling oocytes. Main Outcome Measure(s): Fertilization, fertilization failure, and embryonic development. Result(s): The overall fertilization rate was significantly lower after standard IVF than after ICSI: 37.4% vs. 64.3%. Where HIC IVF was used, the overall fertilization rate was not significantly different from that after ICSI: 59.6% vs. 67.6%. Eight randomized controlled trials were selected and reviewed together with the present randomized controlled trial by meta-analysis. The risk ratio for an oocyte to become fertilized was 1.9 (95% confidence interval of 1.4 to 2.5) in favor of ICSI, and 3.1 ICSI cycles may be needed to avoid one complete fertilization failure after conventional IVF (95% CI of 1.7 to 12.4). Conclusion(s): The data from this study and the meta-analysis show that ICSI is a more efficient technique in terms of fertilization, but not in comparison with HIC IVF.

Objective: To analyze the luteal phase of six patients undergoing controlled ovarian hyperstimulation (COH) with hMG and a new GnRH antagonist, Cetrorelix, without receiving luteal phase supplementation. Design: Phase II study involving the first six patients who did not receive luteal phase support. Setting: Tertiary referral center. Patient(s): Six healthy women undergoing COH for assisted reproductive techniques. Intervention(s): Oocyte retrieval was performed 36 hours after hCG administration, followed by embryo transfer 2 days later. No luteal phase supplementation was given. Main Outcome Measure(s): Serum E 2 , progesterone, LH, and FSH concentrations were measured. Result(s): The length of the luteal phase was ≤12 days in three of the six patients. One of the patients in whom the luteal phase was >12 days had a low serum progesterone concentration (2.9 ng/mL) on day 10. Serum LH concentrations decreased after the preovulatory hCG injection in all patients. However, a progressive increase in LH was observed after day 7, reaching normal values. Conclusion(s): Corpus luteum function seems to be impaired in cycles that are stimulated with hMG and the GnRH antagonist Cetrorelix.

Objective: To assess the minimal effective dose of a GnRH antagonist (Cetrorelix; Asta Medical, Frankfurt, Germany) to prevent premature LH surge in patients undergoing controlled ovarian hyperstimulation (COH) for assisted reproductive technologies. Design: In 69 patients COH was carried out with the association of hMG, starting on day 2 of the menstrual cycle, and a GnRH antagonist (Cetrorelix) was administered from day 6 of the hMG treatment (day 7 of the menstrual cycle) every day up to and including the last day of the hMG injection. In 32 and 30 patients, 0.5 mg and 0.25 mg of Cetrorelix were administered, respectively. Seven patients received 0.1 mg of Cetrorelix. Setting: Tertiary referral center. Result(s): No premature endogenous LH surge occurred in patients treated with 0.5 and 0.25 mg of Cetrorelix, and serum LH concentrations were maintained constantly low during the entire follicular phase in both groups. Follicle-stimulating hormone, LH, E 2 , and P expressed as area under the curve were similar in both groups. A premature LH surge (18 mIU/mL; conversion factor to SI unit, 1.00) with a concomitant P rise (1.7 μg/L; conversion factor to SI unit, 3.180) occurred in one of the seven patients treated with 0.1 mg Cetrorelix; therefore, treatment with this dose was discontinued. Conclusion(s): The minimal effective dose of Cetrorelix able to prevent premature LH surge in COH cycles is 0.25 mg administered daily.