Hum Reprod. 1998 Nov;13(11):3023-31.
A multicentre, double-blind, randomized dose-finding study of Org 37462 (ganirelix) was conducted in 333 women undergoing ovarian stimulation with recombinant follicle stimulating hormone (rFSH; Puregon) to establish the minimal effective dose preventing premature luteinizing hormone (LH) surges during ovarian stimulation. For ovarian stimulation, rFSH was given in a fixed daily dose of 150 IU for 5 days from days 2 to 6 of the menstrual cycle. From cycle day 7 onward, up to and including the day of human chorionic gonadotrophin (HCG), Org 37462 (dosages 0.0625, 0.125, 0.25, 0.5, 1.0 and 2.0 mg/0.5 ml) was administered once daily by s.c. injection, and the rFSH dose was adjusted depending on ovarian response. The lowest (0.0625 mg) and highest (2.0 mg) dose groups were terminated prematurely on the advice of an external independent advisory committee. Serum Org 37462 concentrations increased in a linear dose-proportional manner, whereas serum LH and increases of oestradiol fell with increasing Org 37462 dose. During Org 37462 treatment, serum LH concentrations > or =10 IU/l were observed in the lowest dose groups with incidences of 16% (0.0625 mg), 9% (0.125 mg) and 1.4 % (0.25 mg). On the day of HCG, the number of follicles > or =11, > or =15 and > or =17 mm were similar in the six dose groups, whereas serum oestradiol concentrations were highest in the 0.0625 mg group (1475 pg/ml) and lowest in the 2 mg group (430 pg/ml). The median daily dose of rFSH was between 150 and 183 IU and the overall median duration of Org 37462 treatment was approximately 5 days in the six treatment groups. Overall, Org 37462 treatment appeared to be safe and well tolerated. The mean number of recovered oocytes and good-quality embryos was similar in all dose groups and ranged from 8.6 to 10.0 and 2.5 to 3.8, respectively. The mean number of replaced embryos in the different dose groups ranged from 2.3 to 2.7. The implantation rate was highest in the 0.25 mg group (21.9%) and lowest in the 2 mg group (1.5%). The early miscarriage rates (first 6 weeks after embryo transfer) were 11.9 and 13% in the 1 and 2 mg group respectively, whereas in the other dose groups this incidence was zero (0.0625%) up to a maximum of 3.7% (0.5 mg group). The vital pregnancy rate (with heart activity) at 5-6 weeks after embryo transfer was highest in the 0.25 mg group, i.e. 36.8 % per attempt and 40.3 % per transfer, and resulted in an ongoing pregnancy rate 12-16 weeks after embryo transfer of 33.8% per attempt and 37.1% per transfer. In conclusion, a daily dose of 0.25 mg Org 37462 prevented LH surges during ovarian stimulation and resulted in a good clinical outcome.
一项针对Org 37462（加尼瑞克）的多中心、双盲、随机剂量探索性研究在333名接受重组促卵泡激素（rFSH；果纳芬）进行卵巢刺激的女性中开展，以确定在卵巢刺激期间预防促黄体生成素（LH）过早激增的最小有效剂量。对于卵巢刺激，在月经周期的第2至6天，rFSH以每日150 IU的固定剂量给药5天。从周期第7天起，直至并包括人绒毛膜促性腺激素（HCG）注射日，Org 37462（剂量为0.0625、0.125、0.25、0.5、1.0和2.0 mg/0.5 ml）通过皮下注射每日给药一次，rFSH剂量根据卵巢反应进行调整。根据外部独立咨询委员会的建议，最低剂量（0.0625 mg）组和最高剂量（2.0 mg）组提前终止。血清Org 37462浓度呈线性剂量比例增加，而血清LH和雌二醇的增加量随Org 37462剂量增加而下降。在Org 37462治疗期间，最低剂量组中观察到血清LH浓度≥10 IU/L，发生率分别为16%（0.0625 mg）、9%（0.125 mg）和1.4%（0.25 mg）。在HCG注射日，六个剂量组中直径≥11、≥15和≥17 mm的卵泡数量相似，而血清雌二醇浓度在0.0625 mg组最高（1475 pg/ml），在2 mg组最低（430 pg/ml）。六个治疗组中rFSH的中位日剂量在150至183 IU之间，Org 37462治疗的总体中位持续时间约为5天。总体而言，Org 37462治疗似乎安全且耐受性良好。所有剂量组中回收的卵母细胞和优质胚胎的平均数量相似，分别为8.6至10.0个和2.5至3.8个。不同剂量组中移植胚胎的平均数量在2.3至2.7个之间。植入率在0.25 mg组最高（21.9%），在2 mg组最低（1.5%）。早期流产率（胚胎移植后的前6周）在1 mg组和2 mg组分别为11.9%和13%，而在其他剂量组中，该发生率为零（0.0625%）至最高3.7%（0.5 mg组）。胚胎移植后5至6周的活胎妊娠率（有心脏活动）在0.25 mg组最高，即每次尝试为36.8%，每次移植为40.3%，导致胚胎移植后12至16周的持续妊娠率为每次尝试33.8%，每次移植37.1%。总之，每日0.25 mg的Org 37462剂量可预防卵巢刺激期间的LH激增，并产生良好的临床结果。
