1 Department of Obstetrics and Gynecology, Rambam Medical Center, 2 Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel and 3 NV Organon, Oss, The Netherlands
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Abstract |
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Key words: GnRH agonist/GnRH antagonist/ovarian hyperstimulation syndrome/recombinant FSH/triggering ovulation
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Introduction |
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An alternative to HCG-induced ovulation triggering, is the use of gonadotrophin releasing hormone (GnRH) agonists. These compounds induce a sustained (>24 h) release of LH (and FSH) from the pituitary, that effectively induces oocyte maturation and ovulation. Importantly, they also provide a means by which OHSS is effectively prevented (Itskovitz et al., 1988, 1991
; Gonen et al., 1990
; Emperaire et al., 1991; Imoedemhe et al., 1991
; Segal et al., 1992; Lanzone et al., 1994
; Lewit et al., 1995
, 1996
).
The major limitation of the use of GnRH agonist to trigger ovulation is that GnRH agonists are ineffective in women with a low gonadotrophin reserve or after pituitary down-regulation with a GnRH agonist. In these situations, the pituitary is unresponsive for inducing an endogenous LH surge. Since GnRH agonist-based protocols are routinely used in most IVF programmes, the application of GnRH agonist for induction of ovulation has been limited.
The recent introduction of GnRH antagonist protocols (Albano et al., 1997; Ganirelix Dose Finding Group, 1998; Itskovitz-Eldor et al.; 1998) has offered new opportunities of using GnRH agonist to trigger ovulation and preventing OHSS due to the mechanism of action of GnRH antagonists, i.e. competitive inhibition and relatively short duration of action. Studies in monkeys (Chillik et al., 1987
) have clearly demonstrated that although tonic gonadotrophins remain suppressed under GnRH antagonist treatment, acute LH release can be elicited in a GnRH challenge test. In small scale studies in humans, it was demonstrated (Felberbaum et al., 1995
) that under GnRH antagonist treatment the pituitary retains its responsiveness to GnRH, while others (Olivennes et al., 1996
) showed in stimulation cycles for intrauterine insemination that ovulation can be triggered by GnRH agonist after GnRH antagonist treatment. From these preliminary reports, it can be deduced that the pituitary response to GnRH or GnRH agonist is preserved during stimulation protocols including GnRH antagonists. The extent of pituitary suppression in this type of protocol is GnRH antagonist dose dependent. Under the reported minimal effective dose of GnRH antagonists (0.25 mg, daily; Ganirelix Dose Finding Group, 1998), it is most probable that ovulation can be safely and effectively triggered with a GnRH agonist.
In this communication, data are presented on the safety and efficacy of triggering final oocyte maturation with 0.2 mg triptorelin in patients with increased risk of developing OHSS after ovarian stimulation with rFSH for intracytoplasmic sperm injection (ICSI) and treatment with the GnRH antagonist ganirelix for the prevention of premature LH surges.
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Materials and methods |
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HCG was withheld in eight women considered at risk of developing OHSS, since more then 20 follicles of >11 mm and/or oestradiol concentrations >3000 pg/ml were observed on the last stimulation day. In these patients, final oocyte maturation was triggered with a single injection of triptorelin 0.2 mg s.c. (Decapeptyl®; Ferring, Malmo, Sweden) at ~30 h after the last injection of ganirelix, and 35 h before oocyte retrieval. Repeated blood samples were taken to document the hormonal changes (oestradiol, progesterone, LH, FSH) 0, 0.5, 1, 2, 4, 12 h following triptorelin. Luteal support was initiated on the day of embryo transfer with daily injections of 50 mg progesterone in oil (Gestone®; Paines and Byrne, UK) and 2 mg oestradiol orally (Estrofem®; Novo Nordisk, Denmark).
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Results |
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Table I presents the stimulation characteristics of each patient including the total amount of rFSH administered, the number of follicles, serum oestradiol levels and the number and maturity of recovered oocytes. On the day of triggering ovulation the mean number of follicles
11 mm was 25.1 ± 4.5 and the median serum oestradiol concentration was 3675 (range 29807670) pg/ml. The mean (±SD) number of oocyte retrieved was 23.4 (±15.4), of which 83% were metaphase II oocytes. In one patient (108, see Table I
) one oocyte was recovered, whereas 22 follicles
11 mm were observed by ultrasound. This patient had repeated unsuccessful treatment with a long protocol of GnRH agonist and HCG for triggering ovulation and was diagnosed as suffering from an empty follicle syndrome. In the other seven patients the total mean (±SD) number of embryos obtained was 15.4 ± 6.6 per patient. There were 88 good quality embryos and seven fresh embryo transfers and for six patients, surplus embryos were frozen (in total 83).
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Fresh transfers resulted in one positive HCG test. Seventeen frozenthawed cycles with embryos obtained during these cycles resulted in four clinical pregnancies (fetal heart activity assessed by ultrasound) so far. Of these four clinical pregnancies, three ended in early abortions and one in normal vaginal delivery of a healthy newborn.
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Discussion |
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The fact that 83% of the oocytes retrieved were mature clearly documents the adequacy of the gonadotrophin surges in initiating the final oocyte maturation process.
The limited clinical experience presented here supports a major advantage of GnRH antagonist protocols in allowing the use of GnRH agonist to trigger and prevent OHSS (Itskovitz et al., 1988, 1991
; Lewit et al., 1995
, 1996
). The rapid fall of oestrogen concentrations after embryo transfer, the lack of mid-luteal oestradiol peak, as well as the absence of free pelvic fluid suggest that triggering of final oocyte maturation with GnRH agonist may lead to a more physiological luteal phase oestradiol and progesterone concentrations. This moderate response is in sharp contrast with the exaggerated luteotrophic effect often seen after ovulation triggering with HCG (Itskovitz-Eldor et al., 1993
). The introduction of the GnRH agonist induced triggering of ovulation in GnRH antagonist protocols would offer additional benefits to all patients, i.e. both high and normal responders, though the efficacy and safety of such new treatment regimen needs to be established in comparative, randomized studies. The relatively low pregnancy rate in our limited series should be assessed in larger scale clinical studies.
In summary, we have demonstrated the ability of a single bolus of 0.2 mg triptorelin to trigger an adequate LH surge in stimulation cycles using a GnRH antagonist protocol. Our results suggest that this regimen may prove highly effective in terms of OHSS prevention, though further studies are needed to establish this potential advantage.
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Notes |
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References |
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Submitted on February 15, 2000; accepted on June 13, 2000.