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Triggering ovulation for IVF
RBMOnline - Vol 10. No 1. 2005 142 Reproductive BioMedicine Online; www.rbmonline.com/Article/1625 on web 23 November 2004
Letter Triggering ovulation for IVF To the Editor
We read with interest the article by Emperaire and Edwards (2004) in the November issue of Reproductive Biomedicine Online and the appeal for more attention to the use of luteinizing hormone (LH) for induction of ovulation. There are two methods to use LH for triggering ovulation for IVF, the first is the use of recombinant human LH (r-hLH) instead of human chorionic gonadotrophin (HCG), and the second is the injection of one bolus of GnRHa in non-GnRHa down-regulated cycles. Concerning the use of r-hLH for triggering ovulation, in a large multicentre double-blind randomized European study, it was shown that a single dose of r-hLH was effective in inducing final follicular maturation and early luteinization in IVF patients and a dose between 15,000 and 30,000 IU was equivalent to 5000 IU of HCG (European Recombinant LH study Group, 2001). There were no statistically significant differences between urinary HCG (u-HCG) and r-hLH administration in the number of oocytes retrieved per follicle with a diameter >10 mm, oocyte nuclear maturity, oocyte potential for fertilization, the number of embryos, the number of total, biochemical, and clinical pregnancies, and the embryo implantation rate. In terms of safety, r-hLH was well tolerated at a dose of up to 30,000 IU. Moderate ovarian hyperstimulation syndrome (OHSS) was reported in 12.4% of patients who received u-HCG and 12.0% of patients who received two injections of r-hLH. No moderate or severe OHSS was reported in patients who received a single dose of r-hLH up to 30,000 IU. A single dose of r-hLH resulted in a highly significant reduction in OHSS. Later a double-blind large multicentre randomized study (Trial 21447) compared the implantation and pregnancy rates following triggering ovulation by r-hLH versus HCG. In total, 437 patients were randomly allocated in a 2:1 ratio to either the r-hLH treatment group (291 patients) or the u-HCG treatment group (146 patients). The treatment groups were well balanced in terms of age, height, weight, body mass index (BMI), race and smoking habits at baseline across the treatment groups. Overall, the mean values were similar in both groups; mean age was 31.1 ± 4.5 and 30.5 ± 4.5 years; mean height was 164 ± 7 and 165 ± 7 cm; mean body weight was 65.3 ± 11.4 kg and 66.0 ± 11.8 kg; and the mean BMI was 24.4 ± 4.2 and 24.4 ± 4.1 kg/m2 in the r-hLH and u-HCG groups respectively. The majority of patients in the study population were Caucasian (95.9% and 97.9% in the r-hLH and u-HCG groups respectively), and the majority in both treatments groups did not smoke (78.0% and
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82.2% in the r-hLH and u-HCG groups respectively; unpublished data from Serono provided to the authors personally). The results of Trial 21447 showed that the incidence of clinically significant OHSS (all cases and severe cases of OHSS) was significantly lower in the r-hLH group compared with the u-HCG group (P < 0.001). However, pregnancy rates and clinical pregnancy rates were significantly lower in the r-hLH group than in the u-HCG group (P = 0.018 and P = 0.023 respectively). In order for r-hLH to be as efficacious as u-HCG, the dose would have to be increased to a point where the cost/benefit ratio may become adverse. The study was not published and the manufacturer of r-hLH decided not to register or manufacture the high dose of r-hLH used for triggering ovulation. Unfortunately, the clear advantage of r-hLH in reducing the incidence of OHSS, which was demonstrated by the European Recombinant LH study (2001), cannot be utilized in clinical practice because of the lower pregnancy rate after triggering ovulation with r-hLH. For the time being, therefore, we have to continue using HCG for triggering ovulation in the GnRH protocol cycles. Mohamed Aboulghar, Hesham Al-Inany The Egyptian IVF-ET Center, Maadi, Cairo, Egypt
References Emperaire JC, Edwards RG 2004 Time to revolutionize the triggering of ovulation. Reproductive BioMedicine Online 9, 480–483. European Recombinant LH Study Group 2001 Human recombinant luteinizing hormone is as effective as, but safer than, urinary human chorionic gonadotrophin in inducing final follicular maturation and ovulation in in vitro fertilization procedures: results of a multicentre double-blind study. The Journal of Clinical Endocrinology and Metabolism 8, 2607–2618.
Letter Triggering ovulation for IVF To the Editor
We read with interest the article by Emperaire and Edwards (2004) in the November issue of Reproductive Biomedicine Online and the appeal for more attention to the use of luteinizing hormone (LH) for induction of ovulation. There are two methods to use LH for triggering ovulation for IVF, the first is the use of recombinant human LH (r-hLH) instead of human chorionic gonadotrophin (HCG), and the second is the injection of one bolus of GnRHa in non-GnRHa down-regulated cycles. Concerning the use of r-hLH for triggering ovulation, in a large multicentre double-blind randomized European study, it was shown that a single dose of r-hLH was effective in inducing final follicular maturation and early luteinization in IVF patients and a dose between 15,000 and 30,000 IU was equivalent to 5000 IU of HCG (European Recombinant LH study Group, 2001). There were no statistically significant differences between urinary HCG (u-HCG) and r-hLH administration in the number of oocytes retrieved per follicle with a diameter >10 mm, oocyte nuclear maturity, oocyte potential for fertilization, the number of embryos, the number of total, biochemical, and clinical pregnancies, and the embryo implantation rate. In terms of safety, r-hLH was well tolerated at a dose of up to 30,000 IU. Moderate ovarian hyperstimulation syndrome (OHSS) was reported in 12.4% of patients who received u-HCG and 12.0% of patients who received two injections of r-hLH. No moderate or severe OHSS was reported in patients who received a single dose of r-hLH up to 30,000 IU. A single dose of r-hLH resulted in a highly significant reduction in OHSS. Later a double-blind large multicentre randomized study (Trial 21447) compared the implantation and pregnancy rates following triggering ovulation by r-hLH versus HCG. In total, 437 patients were randomly allocated in a 2:1 ratio to either the r-hLH treatment group (291 patients) or the u-HCG treatment group (146 patients). The treatment groups were well balanced in terms of age, height, weight, body mass index (BMI), race and smoking habits at baseline across the treatment groups. Overall, the mean values were similar in both groups; mean age was 31.1 ± 4.5 and 30.5 ± 4.5 years; mean height was 164 ± 7 and 165 ± 7 cm; mean body weight was 65.3 ± 11.4 kg and 66.0 ± 11.8 kg; and the mean BMI was 24.4 ± 4.2 and 24.4 ± 4.1 kg/m2 in the r-hLH and u-HCG groups respectively. The majority of patients in the study population were Caucasian (95.9% and 97.9% in the r-hLH and u-HCG groups respectively), and the majority in both treatments groups did not smoke (78.0% and
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82.2% in the r-hLH and u-HCG groups respectively; unpublished data from Serono provided to the authors personally). The results of Trial 21447 showed that the incidence of clinically significant OHSS (all cases and severe cases of OHSS) was significantly lower in the r-hLH group compared with the u-HCG group (P < 0.001). However, pregnancy rates and clinical pregnancy rates were significantly lower in the r-hLH group than in the u-HCG group (P = 0.018 and P = 0.023 respectively). In order for r-hLH to be as efficacious as u-HCG, the dose would have to be increased to a point where the cost/benefit ratio may become adverse. The study was not published and the manufacturer of r-hLH decided not to register or manufacture the high dose of r-hLH used for triggering ovulation. Unfortunately, the clear advantage of r-hLH in reducing the incidence of OHSS, which was demonstrated by the European Recombinant LH study (2001), cannot be utilized in clinical practice because of the lower pregnancy rate after triggering ovulation with r-hLH. For the time being, therefore, we have to continue using HCG for triggering ovulation in the GnRH protocol cycles. Mohamed Aboulghar, Hesham Al-Inany The Egyptian IVF-ET Center, Maadi, Cairo, Egypt
References Emperaire JC, Edwards RG 2004 Time to revolutionize the triggering of ovulation. Reproductive BioMedicine Online 9, 480–483. European Recombinant LH Study Group 2001 Human recombinant luteinizing hormone is as effective as, but safer than, urinary human chorionic gonadotrophin in inducing final follicular maturation and ovulation in in vitro fertilization procedures: results of a multicentre double-blind study. The Journal of Clinical Endocrinology and Metabolism 8, 2607–2618.