1 Infertility Unit, Department of Obstetrics-Gynaecology, University of Milan, Milan, 2 Reproductive Unit of Brunico, Bolzano and 3 Centro Scienze della Natalità, Istituto Scientifico S. Raffaele, Milan, Italy
4 To whom correspondence should be addressed. Email: g.ragni{at}icp.mi.it
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Abstract |
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Key words: GnRH antagonist/ICSI/IVF/ovarian hyperstimulation syndrome/recombinant FSH
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Introduction |
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Although the incidence of the severe form of OHSS is low (0.55%) (Delvigne and Rozenberg, 2002), the large number of IVF/ICSI cycles performed every year throughout the world means that a considerable number of patients are affected. Factors influencing the incidence of OHSS include age (Enskog et al., 1999
), body mass index (BMI) (Navot et al., 1988
), polycystic ovary syndrome (PCOS) (MacDougall et al., 1992
; Delvigne et al., 1993
), use of exogenous HCG to induce ovulation (Segal and Casper, 1992
; Kulikowski et al., 1995
; Shalev et al., 1995
), luteal phase supplementation with HCG (Penzias, 2002
) and, more importantly, the stimulation regimen. The incidence of OHSS is lower when clomiphene citrate is used for ovarian stimulation and increases when urinary or recombinant gonadotrophins are administered. Moreover, the introduction of GnRH agonists in 1986 led to a large increase (six-fold) in the incidence of OHSS (Forman et al., 1990
; Asch et al., 1991
). More recently, there have been reports that the incidence of OHSS is lower when GnRH antagonists are used (Ludwig et al., 2000
; Olivennes et al., 2000
), although a systematic review of five randomized trials failed to demonstrate a significant reduction in the incidence of OHSS using GnRH antagonists instead of GnRH agonists in gonadotrophin regimens for ovarian stimulation (Al-Inany and Aboulghar, 2002
). However, it should be said that the main focus of these five studies was pregnancy rate, and not OHSS prevention.
In contrast, another meta-analysis from Ludwig et al. (2001), in which more studies were included, showed a reduction in OHSS risk using the GnRH antagonist cetrorelix. Therefore, the available studies are insufficient to draw definitive conclusions on the advantage of using a GnRH antagonist instead of a GnRH agonist for patients at risk for OHSS.
The aim of this prospective, multicentre, comparative study with historical controls was to assess the efficacy of a GnRH antagonist protocol in preventing OHSS, used in selected patients found to have experienced OHSS or to have been at risk of OHSS in their previous IVF/ICSI attempt, using a GnRH agonist mid-luteal long protocol.
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Materials and methods |
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All couples gave written informed consent to ovarian stimulation and IVF/ICSI protocol. After a washout period of 26 months after the previous IVF/ICSI cycle, the patients underwent a new cycle where the same gonadotrophin protocol was used [same dose of recombinant FSH (rFSH); -follitropin: Puregon, Organon, The Netherlands; or
-follitropin: Gonal-F, Serono, Switzerland], but a different protocol was used for pituitary desensitization: cetrorelix 0.25 mg (Cetrotide; Serono) multiple-dose antagonist instead of GnRH agonist long protocol. Cetrorelix 0.25 mg was administered daily, starting when the leading follicle reached a diameter of 14 mm. In other words, rFSH was administered in the new cycle according to the dosage and the step-up or step-down modalities used during the previous cycle, independently of ultrasound findings and serum E2 levels. If a patient required a rFSH dose reduction because of OHSS risk, rFSH dosage was reduced and the cycle continued, but for final evaluation the patient was included among the number of stopped cycles. Urinary HCG (Profasi; Serono) was administered 36 h before oocyte pick-up, when the diameter of the leading follicle was at least 18 mm. The results obtained in each patient with GnRH antagonist were retrospectively compared with those obtained in the previous cycle using GnRH agonist.
The primary aim of this study was to compare the percentage of cycles stopped due to OHSS risk and the incidence of moderate or severe OHSS/initiated cycles. Secondary aims were to evaluate and compare outcomes of IVF/ICSI cycles in terms of E2 levels on the day of HCG administration, number of follicles on the day of HCG administration, implantation rate and pregnancy rate.
Statistical methods
Data were analysed using paired analyses with comparison of proportions (McNemar's test); 95% confidence intervals (CIs) were calculated. Wilcoxon's test for rank comparison was applied for the number of follicles. Stating a 50% reduction in cancelled cycles and OHSS cases as being clinically relevant, and setting type I and type II error of 0.05 and 0.20, respectively, we calculated that the sample size should be 85 patients (Machin et al., 1997).
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Results |
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The mean number of follicles with a diameter >10 mm, >15 mm or >18 mm on the day of HCG day administration after GnRH agonist or antagonist use are detailed in Table II. The only statistically significant difference was a reduction of the total number of follicles with a diameter >10 mm in the GnRH antagonist cycles versus GnRH agonist cycles (Wilcoxon's test; Z=6.1; P < 0.001).
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Oocyte retrieval was obtained in 38 patients in the cycle with the GnRH agonist (43.7% per initiated cycle) and in 59 patients in the cycle with the GnRH antagonist (67.8% per initiated cycle). This 24.1% increase was statistically significant (McNemar's test; 95% CI 12.235.8%; P < 0.001) (Figure 1).
Twenty-nine patients had an embryo transfer in the first cycle (76.3% of retrievals) and 57 in the cycle using GnRH antagonist (96.6% of retrievals). The 20.3% difference was significant (Z-test; 95% CI 6.836.0%; P=0.003) (Figure 1).
After the antagonist cycles, 18 pregnancies (20.7 per initiated cycle; 31.6% per embryo transfer) were obtained: 10 clinical pregnancies (one twin and nine singleton pregnancies), one first trimester miscarriage, two ectopic pregnancies and five biochemical pregnancies. The implantation rate in this cycle was 9.3%.
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Discussion |
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In the late 1990 s, a third generation of GnRH antagonists became available: these compounds suppress gonadotrophin release by competitive receptor binding resulting in an immediate suppression and blockage of gonadotrophin secretion rather than pituitary desensitization. The safety and efficacy of GnRH antagonists and agonists in IVF and ICSI cycles have been reported to be similar (Albano et al., 2000; European Orgalutran Study Group, 2000
; Olivennes et al., 2000
; European-Middle East Orgalutran Study Group, 2001
; Fluker et al., 2001
). GnRH antagonists are now part of the therapeutic options of infertility units worldwide.
In the study by Albano et al. (2000), stimulation with cetrorelix plus HMG was compared with buserelin plus HMG: in the cetrorelix-treated patients a shorter duration of stimulation and a lower number of ampoules of HMG were described. In the antagonist group a significantly lower incidence of OHSS was also observed (1.1% versus 6.5% in the buserelin group; P < 0.03). These data were confirmed when the other GnRH antagonist on the market, ganirelix, was tested in another multicentre study (European Orgalutran Study Group, 2000
). In this latter study a reduced duration of stimulation and a lower amount of rFSH ampoules were needed in the ganirelix-treated patients compared with patients treated with buserelin. The incidence of OHSS was also reduced in the antagonist group (2.4% versus 5.9% in the buserelin group). Therefore, the results seem to be related to the antagonist protocol rather than to a particular antagonist choice (cetrorelix or ganirelix), at least when compared with buserelin. Results seem also to be independent of the use of HMG or rFSH. In other two clinical trials, the incidence of OHSS was reported to be reduced using GnRH antagonists rather than the GnRH agonist long luteal protocol (Ludwig et al., 2000
; Olivennes et al., 2000
), although a systemic review and meta-analysis including five randomized trials failed to confirm this finding (Al-Inany and Aboulghar, 2002
). However, it should be noted that, with the exception of the study by Ludwig et al. (2000)
, none of the above-mentioned studies was specifically designed to determine differences in OHSS incidence between the two treatment protocols. Moreover, the patients studied were usually normo-responders, and in two of these studies, PCOS patients were excluded (Albano et al., 2000
; Olivennes et al., 2000
); therefore, they recorded a low total incidence of OHSS. Another meta-analysis published in 2001 showed a reduction in OHSS risk for the antagonist cetrorelix only (Ludwig et al., 2001
).
Since OHSS incidence seems to be related to the stimulation regimen used, and in particular to the amount of gonadotrophin administered, a comparison between agonist and antagonist use should be carried out, comparing cycles using the same FSH treatment protocol (the same FSH product and the same timing for dose adjustments). This is the reason for our study design, where each patient was compared with her own previous cycle (historical control). In the new cycle, the same amount of rFSH that was used during the first cycle was administered. The only difference between the two cycles was that a GnRH antagonist was used in the new cycle (multiple dose protocol) instead of a GnRH agonist used in the previous cycle (long luteal protocol). We included patients considered at high risk of OHSS because they had experienced OHSS in the first treatment cycle or because their first cycle had been stopped due to high E2 serum levels or a high number of follicles, factors that are both generally considered as risk factors for OHSS (Crooke, 1970; Haning et al., 1983
; Navot et al., 1988
; Asch et al., 1991
; Enskog et al., 1999
; Marthur et al., 2000
).
This study design presents some inconveniences: pregnant patients are excluded from the second treatment cycle and ovarian response could be reduced over time. To minimize the possibility of the latter bias, we performed the second cycle as soon as possible after the first cycle (26 months).
In our study, ovarian stimulation with a GnRH antagonist proved to be more frequently successful, and oocyte retrieval could be performed significantly more frequently and with a reduced risk compared with cycles using GnRH agonists. The incidence of OHSS was significantly reduced in the GnRH antagonist cycles. This result was probably due to the shorter stimulation in the antagonist cycles, to the lower number of follicles and the lower E2 levels on the day of HCG administration found in this group. Data on reduction of the ovarian stimulation duration and of the gonadotrophin amount needed for each patient are consistent with findings reported by other studies comparing mid-luteal GnRH agonist and GnRH antagonist protocols (Albano et al., 2000; Olivennes et al., 2000
; Al-Inany and Aboulghar, 2002
). Patients treated with GnRH antagonist reached oocyte retrieval more promptly, with a reduced amount of gonadotrophin administered.
The data show that ovarian stimulation using a GnRH antagonist could produce a more physiological follicular selection than the long luteal GnRH agonist protocol, recruiting a smaller number of follicles and thus reducing OHSS risk.
Raga et al. (2002) proposed an interesting hypothesis regarding the lower OHSS rates observed in antagonist cycles. In a recent prospective, randomized study, higher vascular endothelial growth factor mRNA and protein levels in IVF patients treated with GnRH agonists were found than in patients treated with GnRH antagonists, providing a hypothetical biological explanation for our findings.
In conclusion, our data show a favourable effect of GnRH antagonists in reducing the incidence of OHSS and the number of assisted fertilization cycles cancelled because of the risk of OHSS in high responder patients. As a consequence, GnRH antagonist plus gonadotrophin administration could also increase the percentage of oocyte retrievals and embryo transfers in this high risk group of patients. Further prospective randomized controlled trials focusing on this issue should be conducted to confirm our findings and support our belief that a GnRH antagonist regimen is more suitable in patients at risk of OHSS.
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References |
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Al-Inany H and Aboulghar M (2002) GnRH antagonist in assisted reproduction: a Cochrane review. Hum Reprod 17, 874885.
Asch RH, Li HP, Balamceda JP, Weckstein LN and Stone SC (1991) Severe ovarian hyperstimulation syndrome in assisted reproductive technology: definition of high risk groups. Hum Reprod 6, 13951399.[Abstract]
Crooke AC (1970) Induction of ovulation with gonadotrophins. Br Med Bull 26, 1721.[ISI][Medline]
Delvigne A and Rozenberg S (2002) Epidemiology and prevention of ovarian hypersstimulation syndrome (OHSS): a review. Hum Reprod Update 8, 559577.
Delvigne A, Demoulin A, Smitz J, Donnez J, Koninckx P, Dhont M, Englert Y, Delbeke L, Darcis L, Gordts S et al. (1993) The ovarian hyperstimulation syndrome in in-vitro fertilization: a Belgian multicentric study. I: Clinical and biological features. Hum Reprod 8, 13531360.[Abstract]
Enskog A, Henriksson M, Unander M, Nilsson L and Brannstrom M (1999) Prospective study of the clinical and laboratory parameters of patients in whom ovarian hyperstimulation syndrome developed during controlled ovarian hyperstimulation for in vitro fertilization. Fertil Steril 71, 808814.[CrossRef][ISI][Medline]
European-Middle East Orgalutran Study Group (2001) Comparable clinical outcome using the GnRH antagonist ganirelix or a long protocol of the GnRH agonist triptorelin for the prevention of premature LH surges in women undergoing ovarian stimulation. Hum Reprod 16, 644651.
European Orgalutran Study Group (2000) Treatment with the gonadotrophin-releasing hormone antagonist ganirelix in women undergoing ovarian stimulation with recombinant follicle stimulating hormone is effective, safe and convenient: results of a controlled, randomized, multicentre trial. Hum Reprod 15, 14901498.
Fluker M, Grifo J, Leader A, Levy M, Meldrum D, Muasher SJ, Rinehart J, Rosenwaks Z, Scott RT Jr, Schoolcraft W et al. (2001) Efficacy and safety of ganirelix acetate versus leuprolide acetate in women undergoing controlled ovarian hyperstimulation. Fertil Steril 75, 3845.[CrossRef][ISI][Medline]
Forman RG, Frydman R, Egan D, Ross C and Barlow DH (1990) Severe ovarian hyperstimulation syndrome using agonist of gonadotropin-releasing hormone for in vitro fertilization: a European series and a proposal for prevention. Fertil Steril 53, 502509.[ISI][Medline]
Haning RV Jr, Austin CW, Carlson IH, Kuzma DL, Shapiro SS and Zweibel WJ (1983) Plasma estradiol is superior to ultrasound and urinary estriol glucuronide as a predictor of ovarian hyperstimulation during induction of ovulation with menotropins. Fertil Steril 40, 3136.[ISI][Medline]
Kulikowski M, Wolczynski S, Kuczynski W, Grochowski D and Szamatowicz M (1995) Use of GnRH analog for induction of the ovulatory surge of gonadotropins in patients at risk of the ovarian hyperstimulation syndrome. Gynecol Endocrinol 9, 97102.[ISI][Medline]
Ludwig M, Felberbaum RE, Devroey P, Albano C, Riethmüller-Winzen H, Schüler A, Engel W and Diedrich K (2000) Significant reduction of the incidence of ovarian hyperstimulation syndrome (OHSS) by using the LHRH antagonists Cetrorelix (Cetrotide®) in controlled ovarian stimulation for assisted reproduction. Arch Gynecol Obstet 264, 2932.[ISI][Medline]
Ludwig M, Katalinic A and Diedrich K (2001) Use of GnRH antagonists in ovarian stimulation for assisted reproductive technologies compared to the long protocol. Meta-analysis. Arch Gynecol Obstet 265, 175182.[CrossRef][Medline]
MacDougall MJ, Tan SL and Jacobs HS (1992) In-vitro fertilization and the ovarian hyperstimulation syndrome. Hum Reprod 7, 597600.[Abstract]
Machin D, Campbell M, Fayers P and Pinol A (1997) Sample Size Tables for Clinical Studies. 2nd. Blackwell Science, Oxford, UK.
Marthur RS, Akande AV, Keay SD, Hunt LP and Jenkins JM (2000) Distinction between early and late ovarian hyperstimulation syndrome. Fertil Steril 73, 901907.[CrossRef][ISI][Medline]
Mordel N and Schenker JG (1993) Gonadotrophin-releasing hormone agonists and ovarian hyperstimulation syndrome in assisted reproduction. Hum Reprod 8, 20092014.[Abstract]
Navot D, Relou A, Birkenfels A, Rabinowitz R, Brzezinski A and Margalioth EJ (1988) Risk factors and prognostic variables in the ovarian hyperstimulation syndrome. Am J Obstet Gynecol 159, 210215.[ISI][Medline]
Olivennes F, Belaisch-Allart J, Emperaire JC, Dechaud H, Alvarez S, Moreau L, Nicollet B, Zorn JR, Bouchard P and Frydman R (2000) Prospective, randomized, controlled study of in vitro fertilization-embryo transfer with a single dose of a luteinizing hormone-releasing hormone (LH-RH) antagonist (cetrorelix) or a depot formula of an LH-RH agonist (triptorelin). Fertil Steril 73, 314320.[CrossRef][ISI][Medline]
Penzias AS (2002) Luteal phase support. Fertil Steril 77, 318323.[CrossRef][ISI][Medline]
Raga F, Casañ EM, Dubon MD, Marti R, Bonilla-musoles F and Polan ML (2002) Modulation of vascular endothelial growth factor by GnRH analogues: potential use in clinical management of ovarian hyperstimulation syndrome. Abstract presented at the 18th Meeting of the European Society of Human Reproduction and Embryology. Hum Reprod 17 (Suppl 1), 14 (abstract O-037).
Rizk B and Smitz J (1992) Ovarian hyperstimulation syndrome after superovulation using GnRH agonists for IVF and related procedures. Hum Reprod 7, 320327.[Abstract]
Segal S and Casper RF (1992) Gonadotropin-releasing hormone agonist versus human chorionic gonadotropin for triggering follicular maturation in in vitro fertilization. Fertil Steril 57, 12541258.[ISI][Medline]
Shalev E, Geslevich Y, Matilsky M and Ben-Ami M (1995) Induction of pre-ovulatory gonadotrophin surge with gonadotrophin-releasing hormone agonist compared to pre-ovulatory injection of human chorionic gonadotrophins for ovulation induction in intrauterine insemination treatment cycles. Hum Reprod 10, 22442247.[Abstract]
Submitted on November 10, 2004; resubmitted on April 8, 2005; accepted on April 12, 2005.
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