1 Department of Obstetrics and Gynecology, Rambam Medical Center, Haifa, Israel, 2 Fertilitets Centrum, Carlanderska Sjukhuset, Göteborg, Sweden, 3 Academic Hospital, Free University Brussels, Brussels, Belgium, 4 Dijkzigt Academic Hospital, Rotterdam, The Netherlands, 5 Infertility IVF Centre `Geniki Cliniki', Thessaloniki, Greece and 6 NV Organon, Clinical Development Department, Oss, The Netherlands
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Key words: ganirelix/GnRH antagonist/ovarian stimulation/pregnancy/recombinant human FSH
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Clinical experience with GnRH antagonists in IVF treatment thus far has been encouraging and demonstrates a high efficacy in preventing the LH surge. In most cases, treatment is limited to only a few days, sometimes only once in 4872 h (Olivennes et al., 1994, 1995
; Nelson et al., 1995
; Albano et al., 1996
). A recent, multi-centre dose-finding study using six dosages (range 0.06252.0 mg) of the GnRH antagonist ganirelix in 333 patients indicated that 0.25 mg of ganirelix is the minimal effective daily dose. This dose was not only effective in preventing a premature LH rise (
10 IU/l), but also yielded a high implantation rate of 22% and ongoing pregnancy rate of 33% per attempt. Importantly, the six dose groups were similar in terms of the number of oocytes retrieved, as well as in the number of embryos obtained and their quality. However, very low implantation rates of respectively 8.8 and 1.5% were obtained in the two highest dose groups (1 and 2 mg), which resulted in an ongoing pregnancy rate of only 14.1% in the 1 mg group and no ongoing pregnancies in the 2 mg group (Ganirelix Dose-Finding Study Group, 1998
).
The current follow-up study reports on the outcome of freezethaw cycles using embryos cryopreserved in stimulation cycles using recombinant FSH and ganirelix during the above-mentioned dose-finding study. These data may shed new light on the cause(s) for the less favourable results achieved in the fresh cycles with high GnRH antagonist doses.
![]() |
Materials and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Stimulation cycles
Ovarian stimulation was initiated on day 2 of the menstrual cycle, with 150 IU recombinant FSH (rFSH, Puregon®, NV Organon) for 5 days. Ganirelix was administered from day 6 of rFSH onwards, until and including the day of human chorionic gonadotrophin (HCG) when at least three follicles 17 mm diameter were observed by sonography. During ganirelix treatment, the rFSH dose was adjusted depending on the individual ovarian response. To induce ovulation, 10 000 IU of HCG (Pregnyl®, NV Organon) was given. Oocytes were retrieved transvaginally 36 h later, fertilized [either by conventional IVF or by means of intracytoplasmic sperm injection (ICSI)] and up to three embryos were transferred on day 25 post-retrieval. Excess embryos were cryopreserved.
Thaw cycles
Embryos were frozen in eight out of the 13 IVF centres that took part in the dose-finding study. In three IVF centres no embryos were stored and in two German centres only two pronuclear (2PN) oocytes were frozen which were not included in this analysis. Data were collected from 65 subjects who did not become pregnant after replacement of fresh embryos, and for whom spare embryos were cryopreserved. By June 1998, 46 patients had had at least one embryo transfer using thawed embryos. For the first replacement of thawed embryos, 72% of the patients underwent a natural cycle and 28% underwent a `stimulated' cycle during which thawed embryos were replaced. These programmed cycles were performed according to the individual site's clinical routine. Ten out of these 46 patients had two frozen embryo cycles and one patient had four frozen embryo cycles. For three patients the quality of thawed embryos was insufficient for embryo transfer.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The number of subjects who had embryo transfer in each dose group ranged between 5 (0.0625 mg) and 11 (1.0 mg) (see Table I). The mean (±SD) number of transferred embryos was 2.6 ± 1.0 (range 2.22.9). The first frozen embryo cycle resulted in 11 ongoing pregnancies (23.9%) 1216 weeks after embryo transfer and included nine singleton and two twin pregnancies. In total, 11 and eight transfers were performed in subjects who had been treated with 1 mg and 2 mg ganirelix respectively. These transfers resulted in four ongoing pregnancies (36.4%) in the 1 mg group and in two ongoing pregnancies (25.0%) in the 2 mg group. In addition, one subject (0.25 mg) had a miscarriage without proof of a vital fetus and one subject (0.5 mg) had a miscarriage after proof of a vital fetus. In total, 10 subjects who first had a frozen embryo cycle continued with a second frozen embryo cycle, but none of them became pregnant. One patient had four frozen embryo cycles and a singleton ongoing pregnancy was established after her last transfer.
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Theoretically, the lower success rates of fresh embryo transfers from stimulation cycles with higher doses of ganirelix may be due to a direct adverse effect of the GnRH antagonist on the oocyte/embryo quality. The morphological quality of oocytes and embryos obtained after exposure to relatively high or low doses of ganirelix was comparable. However, assessment of embryo quality based on morphological features cannot be used to reflect the true potential of an embryo to develop or to implant. Therefore, additional data should support this finding, particularly because implantation rates varied considerably between the dose groups. Our current data strongly support the possibility that there is no negative effect of a high ganirelix dose on embryo developmental potential, since the overall ongoing pregnancy rate of freezethaw cycles was relatively high (23.9%) and six of the 11 established ongoing pregnancies were obtained from embryos exposed to 1.0 or 2.0 mg of ganirelix in the cycles during which they were created.
A closer look at the dose finding study indicates that both LH and oestradiol serum concentrations on the day of HCG administration were inversely correlated with the ganirelix dose used (Ganirelix Dose Finding Group, 1998). Therefore, one might consider that the low pregnancy rate in the high dose groups may have been caused by an aberrant hormonal milieu during the late follicular phase. However, data analysis did not reveal a direct relationship between serum LH or oestradiol concentrations and clinical outcome. A direct effect on the endometrium by relatively high doses of GnRH antagonist cannot be excluded, since human endometrial GnRH receptors have been identified very recently (Dong et al., 1998; Raga et al., 1998
), but so far, their physiological relevance as well as their possible interaction with GnRH antagonists is unknown.
In summary, we report for the first time the pregnancy outcome of thaw cycles of embryos obtained after ovarian stimulation with rFSH using a GnRH antagonist to prevent premature LH surges. The ongoing pregnancy rate appeared to be good and not related to the dose of GnRH antagonist, suggesting that there is no direct negative effect of the GnRH antagonist on the quality of oocytes and embryos.
![]() |
Notes |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Dong, K.W., Marcelin, K., Hsu, M. et al. (1998) Expression of gonadotropin-releasing hormone (GnRH) gene in human uterine endometrial tissue. Mol. Hum. Reprod., 9, 893898.
Ganirelix Dose-Finding Study Group (1998) A double-blind, randomized, dose-finding study to assess the efficacy of the GnRH-antagonist ganirelix (Org 37462) to prevent premature luteinizing hormone surges in women undergoing controlled ovarian hyperstimulation with recombinant follicle stimulating hormone. Hum. Reprod., 13, 30233031.[Abstract]
Itskovitz-Eldor, J., Kol, S., Mannaerts, B. and Coelingh Bennink, H. (1998) Case report: first established pregnancy after controlled ovarian hyperstimulation with recombinant follicle stimulating hormone and gonadotrophin-releasing hormone antagonist ganirelix (Org 37462). Hum. Reprod., 13, 294295.[Medline]
Jones, H.W. Jr, Out, H.J., Hoomans, E.H.M. et al. (1997) Cryopreservation: the practicalities of evaluation. Hum. Reprod., 12, 15221524.[Abstract]
Nelson, L.R., Fujimoto, V.Y., Jaffe, R.B. and Monroe, S.E. (1995) Suppression of follicular phase pituitary gonadal function by a potent new gonadotropin-releasing hormone antagonist with reduced histamine-releasing properties (ganirelix). Fertil. Steril., 63, 963969.[ISI][Medline]
Olivennes, F., Fachin, R., Bouchard, P. et al. (1994) The single or dual administration of the gonadotrophin-releasing hormone antagonist Cetrorelix in an in vitro fertilization-embryo transfer program. Fertil. Steril., 62, 468476.[ISI][Medline]
Olivennes, F., Fachin, R., Bouchard, P. et al. (1995) Scheduled administration of a gonadotrophin-releasing hormone antagonist (Cetrorelix) on day 8 of in-vitro fertilization cycles: a pilot study. Hum. Reprod., 10, 13821386.[Abstract]
Out, H.J., Mannaerts, B.M., Driessen, S.G.A.J. and Coelingh Bennink, H.J. (1995) A prospective, randomized, assessor-blind multicentre study comparing recombinant and urinary follicle-stimulating hormone (Puregon versus Metrodin) in in-vitro fertilization. Hum. Reprod., 10, 25342340.[Abstract]
Raga, F., Casan, E.M., Kruessel, J.S. et al. (1998) Quantitative gonadotropin-releasing hormone gene expression and immunohistochemical localization in human endometrium throughout the menstrual cycle. Biol. Reprod., 59, 661669.
Smitz, J., Ron-El, R. and Tarlatzis, B.C. (1992) The use of gonadotrophin releasing hormone agonists for in vitro fertilization and other assisted procreation techniques: experience from three centers. Hum. Reprod., 7, 4966.[Abstract]
Submitted on February 24, 1999; accepted on May 27, 1999.