RBMOnline - Vol 7. No 3. 301–308 Reproductive BioMedicine Online; www.rbmonline.com/Article/903 on web 16 July 2003
Article Comparable effectiveness using flexible singledose GnRH antagonist (cetrorelix) and singledose long GnRH agonist (goserelin) protocol for IVF cycles – a prospective, randomized study
Dr Veljko Vlaisavljevic
Veljko Vlaisavljevic attended the Medical School in Ljubljana, Slovenia. After completing his residency in Obstetrics and Gynecology, he began his career at the Department of Obstetrics and Gynecology in Maribor, Slovenia. He then studied for his PhD in Andrology at the University of Zagreb, Croatia and completed his education in reproduction at RWH in Melbourne, Australia. Now he is a Professor in the Department of Reproductive Medicine at the Maribor Teaching Hospital. At present, he is President of the Slovene Society for Ultrasound in Medicine, Vice-President of the Slovene Society of Reproductive Medicine and member of the Advisory Committee of ESHRE. His clinical practice focuses on infertility, assisted reproductive technology and research. His research interest is focused on ultrasound monitoring of follicle growth and perifollicular vascularization in natural cycles related to oocyte maturation, oocyte quality and IVF outcome.
Veljko Vlaisavljevic1, Milan Reljic, Vida Gavric Lovrec, Borut Kovacic Department of Reproductive Medicine and Gynaecologic Endocrinology, Maribor Teaching Hospital, Ljubljanska 5, SI-2000 Maribor, Slovenia 1Correspondence: e-mail:
[email protected]
Abstract This prospective randomized study compared the effectiveness of a flexible single-dose gonadotrophin-releasing hormone (GnRH) antagonist (cetrorelix) and a single-dose long GnRH agonist (goserelin) protocol for ovarian stimulation in IVF/intracytoplasmic sperm injection (ICSI) cycles. All patients from the waiting list were successively included in the study, pre-programmed with an oral contraceptive, and randomized into goserelin and cetrorelix groups. Depending on the date on which their menstrual period started, patients took oral contraceptives for one or two cycles. Ultimately, 236 patients in the first group received a single dose of depot preparation of goserelin and 224 patients received a single 3 mg dose of cetrorelix in the late follicular phase, when the mean follicle diameter exceeded 12 mm. The mean number of ampoules of FSH and the duration of stimulation was statistically significantly lower in the cetrorelix group than in the goserelin group (25.9 versus 34.5, and 9.6 versus 12.2 days, P < 0.01). The mean number of oocytes retrieved was similar (6.7 ± 4.5 versus 7.2 ± 4.6, NS). Similar results were observed in fertilization rates, blastulation rates and blastocyst transfer rates in both groups. Clinical pregnancy and delivery rates per cycle were higher in the goserelin group (34.3 and 30.1%) than in the cetrorelix group (31.9 and 28.3%), but the differences were not statistically significant. The flexible single-dose GnRH antagonist protocol is an advantageous alternative to the long GnRH agonist protocol, with similar efficacy, shorter duration, a significant reduction in the number of FSH ampoules used and without the menopause-like effects of the GnRH antagonist. Keywords: cetrorelix, flexible protocol, GnRH antagonist, IVF–embryo transfer, single dose
Introduction Gonadotrophin-releasing hormone (GnRH) agonists were introduced to assisted reproductive technologies (ART) about 20 years ago (Ludwig et al., 2001). Today, the so-called ‘long GnRH protocols’ for ovarian stimulation (OS) have proved to be the most successful and are the most frequently used (Olivennes et al., 2000). GnRH antagonists, which have recently been introduced into protocols for OS, offer certain advantages over GnRH agonists
(Devroey, 2000). GnRH antagonists such as cetrorelix (Cetrotide; Serono International S.A., Switzerland) block the pituitary GnRH receptors competitively and their administration during the follicular phase of the cycle can prevent or interrupt the LH rise (Nikolettos et al., 2001). The major cause of interest in GnRH antagonists is the absence of the ‘flare-up’ effect in gonadotrophin secretion as well as the almost immediate effect of the desensitization period following antagonist administration (Olivennes et al., 2000). This mode of action, being different from that of agonists, offers some advantages. The application of an antagonist is
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Articles - Flexible single-dose cetrorelix protocol in IVF cycles - V Vlaisavljevic et al.
scheduled from the middle of the follicular phase of the OS cycle. The length of stimulation, the amount of gonadotrophins used for ovarian stimulation and the incidence of ovarian hyperstimulation syndrome (OHSS) are reduced (Albano et al., 2000; Ludwig et al., 2001; Nikolettos et al., 2001). Other advantages include the possibility of triggering ovulation with native GnRH or GnRH agonists and the possibility of using antagonists in minimal-stimulation or natural cycles (Bouchard and Fauser, 2000). There are also no side effects related to hormonal depletion, such as hot flushes, bleeding and vaginal dryness (Olivennes et al., 2000). On the other hand, there is an ongoing discussion as to whether there is a significant reduction in pregnancy rates when GnRH antagonists are used, since it has been reported in several studies that pregnancy rates are lower in antagonist than in long GnRH agonist protocols (Ludwig et al., 2001; Al-Inany and Aboulghar, 2002). In almost all of these studies, the singleor multiple-dose antagonists were used in a so-called ‘fixed’ protocol. This means that an antagonist was injected on a certain day of the OS cycle, not taking into account individual cycle characteristics. According to some authors, the clinical outcome of GnRH antagonist cycles may be further improved by developing a more flexible regimen (Kol, 2000; Ludwig et al., 2001; Al-Inany and Aboulghar, 2002). The aim of this prospective randomized study was to compare the efficacy of the GnRH antagonist cetrorelix in a flexible single-dose regimen with that of the depot preparation GnRH agonist goserelin (Zoladex 3.6 mg; Astra-Zeneca Pharmaceuticals, Cheshire, UK) in a standard long protocol for OS in IVF/intracytoplasmic sperm injection (ICSI) cycles. A comparison of the pregnancy rate and delivery rate per cycle between the depot GnRH agonist goserelin and subcutaneous daily application of GnRH agonist did not show any difference (Vlaisavljevic et al., 2000)
Material and methods This study was prospective and included 462 consecutive patients undergoing IVF or ICSI in ovarian stimulation cycles between August 1999 and December 2000. The inclusion criteria were as follows: 18- to 45-year-old patients requiring infertility treatment by OS and IVF–embryo transfer with or without ICSI and with normal menstrual cycles, FSH concentrations 40 (%) IVF/ICSI rate rFSH/uFSH-HP rate No. of patients undergoing oocyte retrieval (%) No. of cycles with oocytes (%) No. of FSH ampoulesa Stimulation length (days)a Administration of GnRH antagonist/GnRH agonistb (min–max) No. of oocytes (mean ± SD) No. of severe OHSS (%) aValues are means ± SD. bRelated to the first day of stimulation. NS = not statistically significant.
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Cetrorelix group
Goserelin group
P-value
226 32.9 ± 4.9 (22–44) 14 (6.2) 0.5 0.92 224 (99.1)
236 32.9 ± 4.7 (23–43) 14 (5.9) 0.5 0.95 225 (95.3)
NS NS NS NS NS
223 (98.7)
223 (94.5)
NS
25.9 ± 9.1 9.6 ± 1.8 7.7 ± 1.7, day 5–day 13
34.5 ± 8.7 12.2 ± 4.4 13.8 ± 0.2, day 14
