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Randomized, comparative pilot study of pituitary suppression with depot leuprorelin versus cetrorelix acetate 3 mg in gonadotropin stimulation protocols for oocyte donors

2010; Elsevier BV; Volume: 94; Issue: 6 Linguagem: Inglês

10.1016/j.fertnstert.2010.02.059

1556-5653

Fracisca Martínez, Elisabeth Clúa, Paula Santmartí, Montserrat Boada, Ignacio Rodríguez, Buenaventura Coroleu,

Ovarian function and disorders

In a pilot study, implantation and pregnancy rates per transfer were favorable in recipients of donated eggs treated with a single dose of cetrorelix acetate 3 mg compared with recipients of donated eggs treated with the long protocol (42.3% vs. 30.5%, and 71.0% vs. 46.7%, respectively; NS). The stimulation protocol based on gonadotropins and a single dose of cetrorelix acetate 3 mg is adequate in terms of safety and comfort of donors and the likelihood of pregnancy among recipients, although these favorable results require confirmation in future studies. In a pilot study, implantation and pregnancy rates per transfer were favorable in recipients of donated eggs treated with a single dose of cetrorelix acetate 3 mg compared with recipients of donated eggs treated with the long protocol (42.3% vs. 30.5%, and 71.0% vs. 46.7%, respectively; NS). The stimulation protocol based on gonadotropins and a single dose of cetrorelix acetate 3 mg is adequate in terms of safety and comfort of donors and the likelihood of pregnancy among recipients, although these favorable results require confirmation in future studies. Since the first pregnancy using egg donation was reported in 1984, the technique has become increasingly widespread. Given the potential risks of the procedure to donors and the altruistic nature of donation itself, it is mandatory to develop treatments that cause minimum discomfort and are as safe as possible. GnRH agonists have been routinely used in egg donation programs (EDPs) to treat donors and facilitate synchronization with recipients (1Sauer M.V. Kavic S.M. Oocyte and embryo donation 2006: reviewing two decades of innovation and controversy.RBM Online. 2006; 12: 153-162Google Scholar). Reported outcomes are excellent, with pregnancy rates of around 60% per transfer in oocyte recipients (2Martínez F. Boada M. Coroleu B. Clua E. Parera N. Rodríguez I. et al.A prospective trial comparing oocyte donor ovarian response and recipient pregnancy rates between suppression with gonadotrophin-releasing hormone agonist (GnRHa) alone and dual suppression with a contraceptive vaginal ring and GnRH.Hum Reprod. 2006; 21: 2121-2125Crossref PubMed Scopus (23) Google Scholar). Recently, there has been an increase in the use of GnRH antagonists in donor stimulation protocols (3Ricciarelli E. Sanchez M. Martínez M. Andrés L. Cuadros J. Hernandez E. Impact of the gonadotropin-releasing hormone antagonist in oocyte donation cycles.Fertil Steril. 2003; 79: 1461-1463Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar) because these drugs reduce treatment times, do not pose a risk of cyst formation or symptoms of estrogen deprivation, can be self-administered, require fewer injections and a lower dose of gonadotropins (4Tarlatzis B.C. Fauser B.C. Kolibianakis E.M. Diedrich K. Rombauts L. Devroey P. GnRH antagonists in ovarian stimulation for IVF.Hum Reprod Update. 2006; 12: 333-340Crossref PubMed Scopus (192) Google Scholar), and are better tolerated and easier to handle (5Prapas N. Prapas Y. Panagiotidis Y. Prapa S. Vandezwalmen P. Schoysman R. et al.GnRH agonist versus GnRH antagonist in oocyte donation cycles: a prospective randomized study.Hum Reprod. 2005; 20: 1516-1520Crossref PubMed Scopus (51) Google Scholar, 6Martínez F. Clua E. Parera N. Rodríguez I. Boada M. Coroleu B. Prospective, randomized, comparative study of leuprorelin + human menopausal gonadotropins versus ganirelix + recombinant follicle-stimulating hormone in oocyte donors and pregnancy rates among the corresponding recipients.Gynecol Endocrinol. 2008; 24: 188-193Crossref PubMed Scopus (15) Google Scholar). Comparative studies of gonadotropin treatment with GnRH agonists or antagonists in EDPs have shown that agonist treatment offers a better pregnancy rate per ET, although the number of cancelled cycles is higher, the treatment is longer, and it causes greater discomfort in donors (6Martínez F. Clua E. Parera N. Rodríguez I. Boada M. Coroleu B. Prospective, randomized, comparative study of leuprorelin + human menopausal gonadotropins versus ganirelix + recombinant follicle-stimulating hormone in oocyte donors and pregnancy rates among the corresponding recipients.Gynecol Endocrinol. 2008; 24: 188-193Crossref PubMed Scopus (15) Google Scholar). However, other authors have reported similar pregnancy and implantation rates for the two treatments (5Prapas N. Prapas Y. Panagiotidis Y. Prapa S. Vandezwalmen P. Schoysman R. et al.GnRH agonist versus GnRH antagonist in oocyte donation cycles: a prospective randomized study.Hum Reprod. 2005; 20: 1516-1520Crossref PubMed Scopus (51) Google Scholar, 7Bodri D. Vernaeve V. Guillén J.J. Vidal R. Figueras F. Coll O. Comparison between a GnRH antagonist and a GnRH agonist flare-up protocol in oocyte donors: a randomized clinical trial.Hum Reprod. 2006; 21: 2246-2251Crossref PubMed Scopus (30) Google Scholar). On the other hand, to trigger LH surge for oocyte maturation, it is possible, in antagonist protocols, to use an agonist bolus, avoiding the risk of ovarian hyperstimulation syndrome (OHSS) without affecting the embryo implantation rate in recipients (8Galindo A. Bodri D. Guillén J.J. Colodrón M. Vernaeve V. Coll O. Triggering with HCG or GnRH agonist in GnRH antagonist treated oocyte donation cycles: a randomised clinical trial.Gynecol Endocrinol. 2009; 25: 60-66Crossref PubMed Scopus (68) Google Scholar, 9Bodri D. Guillén J.J. Trullenque M. Schwenn K. Esteve C. Coll O. Early ovarian hyperstimulation syndrome is completely prevented by gonadotropin releasing hormone agonist triggering in high-risk oocyte donor cycles: a prospective, luteal-phase follow-up study.Fertil Steril. 2010; 97: 2418-2420Abstract Full Text Full Text PDF Scopus (45) Google Scholar). In our EDP the long, gonadotropin stimulation protocol involves the administration of leuprorelin via an IM injection. After suppression, the gonadotropins (recombinant FSH [rFSH] or hMG) are administered SC. The protocols with antagonists are usually based on daily administration of the drug. The availability of an antagonist with prolonged action (cetrorelix 3 mg) would enable donor stimulation with fewer injections and greater safety. One small, retrospective, comparative study of a long protocol (daily dose of agonist) with a flexible protocol (a single 3 mg dose of antagonist) found no differences among donors during stimulation or in the pregnancy rates attained by recipients (10Erb T.M. Wakim A.N. GnRH agonist long protocol vs. a single 3-mg gnRH antagonist: a comparison of 2 protocols for pituitary down-regulation in oocyte donor-controlled ovarian hyperstimulation cycles.J Reprod Med. 2008; 53: 331-337PubMed Google Scholar). We aimed to compare the results obtained when using a GnRH antagonist (cetrorelix acetate 3 mg) versus a GnRH agonist (depot leuprorelin) to identify a treatment that could offer optimum outcomes for egg recipients while ensuring the safety and minimal discomfort of donors. A sample of at least 40 evaluable participants per group was considered to be sufficient for this pilot study. We performed a randomized, comparative pilot study of synchronous egg donation cycles performed consecutively between May and December 2007 in the Institut Universitari Dexeus (Barcelona). The study was approved by the Institutional Review Board of our institution. A total of 84 egg donors initiated treatment, all of whom fulfilled the clinical and legal requirements established under Spanish law (Royal Decree 1301/2006). The donors were aged between 18 and 35 years. Candidates had to have baseline FSH <10 U, a body mass index (BMI) <30, no history of hereditary disease, and normal results on all the tests performed (6Martínez F. Clua E. Parera N. Rodríguez I. Boada M. Coroleu B. Prospective, randomized, comparative study of leuprorelin + human menopausal gonadotropins versus ganirelix + recombinant follicle-stimulating hormone in oocyte donors and pregnancy rates among the corresponding recipients.Gynecol Endocrinol. 2008; 24: 188-193Crossref PubMed Scopus (15) Google Scholar). Donors were randomly assigned to one of two groups: group DI: (n = 44), donors treated with a GnRH antagonist (cetrorelix 3 mg, Cetrotide, Merck-Serono, Madrid); group DII: (n = 40), donors treated with a GnRH agonist (leuprorelin 3.75 mg depot, Ginecrin 3.75, Abbott Laboratories, S.A., Madrid). In group DI, donors were given a contraceptive preparation for 1–2 months. Five days after ceasing the contraceptive, gonadotropin stimulation was initiated with a fixed dose over 5 days. The 3-mg dose of cetrorelix was injected on day 6 of stimulation. Additional daily doses of cetrorelix acetate 0.25 mg were administered up to and including the day of hCG administration, when needed. In group DII, pituitary suppression was achieved by depot leuprorelin, 3.75 mg IM, once on day 20–22 of the previous menstrual cycle. Stimulation was initiated 14–16 days after (6Martínez F. Clua E. Parera N. Rodríguez I. Boada M. Coroleu B. Prospective, randomized, comparative study of leuprorelin + human menopausal gonadotropins versus ganirelix + recombinant follicle-stimulating hormone in oocyte donors and pregnancy rates among the corresponding recipients.Gynecol Endocrinol. 2008; 24: 188-193Crossref PubMed Scopus (15) Google Scholar). In both groups, stimulation was performed with gonadotropins as described elsewhere (6Martínez F. Clua E. Parera N. Rodríguez I. Boada M. Coroleu B. Prospective, randomized, comparative study of leuprorelin + human menopausal gonadotropins versus ganirelix + recombinant follicle-stimulating hormone in oocyte donors and pregnancy rates among the corresponding recipients.Gynecol Endocrinol. 2008; 24: 188-193Crossref PubMed Scopus (15) Google Scholar). When at least three follicles with a diameter of ≥20 mm were observed, we administered 10,000 IU of hCG (hCG Lepori, Madrid). Oocyte pickup was performed 36 hours after the hCG injection. Cycles were cancelled for poor response if after 8 days of stimulation there were not at least six developing follicles. In recipients, endometrial preparation involved the administration of E2 valerate and micronized vaginal P as described elsewhere (2Martínez F. Boada M. Coroleu B. Clua E. Parera N. Rodríguez I. et al.A prospective trial comparing oocyte donor ovarian response and recipient pregnancy rates between suppression with gonadotrophin-releasing hormone agonist (GnRHa) alone and dual suppression with a contraceptive vaginal ring and GnRH.Hum Reprod. 2006; 21: 2121-2125Crossref PubMed Scopus (23) Google Scholar, 6Martínez F. Clua E. Parera N. Rodríguez I. Boada M. Coroleu B. Prospective, randomized, comparative study of leuprorelin + human menopausal gonadotropins versus ganirelix + recombinant follicle-stimulating hormone in oocyte donors and pregnancy rates among the corresponding recipients.Gynecol Endocrinol. 2008; 24: 188-193Crossref PubMed Scopus (15) Google Scholar). In patients with ovarian function, the pituitary was suppressed with GnRH agonists (2Martínez F. Boada M. Coroleu B. Clua E. Parera N. Rodríguez I. et al.A prospective trial comparing oocyte donor ovarian response and recipient pregnancy rates between suppression with gonadotrophin-releasing hormone agonist (GnRHa) alone and dual suppression with a contraceptive vaginal ring and GnRH.Hum Reprod. 2006; 21: 2121-2125Crossref PubMed Scopus (23) Google Scholar). Depending on the protocol that was followed by their respective donor, each recipient was assigned to one of two groups: group RI; (n = 31), recipients of eggs from donors treated with cetrorelix 3 mg; group RII: (n = 30), recipients of eggs from donors treated with leuprorelin. On the day of donation, oocytes were inseminated via conventional IVF or intracytoplasmic sperm injection (ICSI). In all cycles, two embryos were transferred under ultrasound guidance on day 2 after follicular puncture (11Coroleu B. Carreras O. Veiga A. Martell A. Martinez F. Belil I. et al.Embryo transfer under ultrasound guidance improves pregnancy rates after in-vitro fertilization.Hum Reprod. 2000; 15: 616-620Crossref PubMed Scopus (151) Google Scholar). Any surplus embryos were cryopreserved. The diagnosis of pregnancy was confirmed by ultrasound at 6 weeks of gestation. Estro-progesterone treatment was either stopped on the day of a negative beta-hCG result or continued until the tenth week of pregnancy. The biostatistics unit of our center generated a randomization table using SAS software. Women were assigned to one of the two treatment groups according to the random values derived from a uniform distribution [0–1]. If the value was less than 0.5, the woman was assigned to group DI, whereas women with higher values were assigned to group DII. The researcher was blinded to the randomization. Quantitative variables were compared by means of parametric tests, either the Student's t-test or analysis of variance. Categorical variables were compared with either the χ2 or Fisher's exact test. The statistical analyses were performed using SPSS version 15.0. All the tests were bilateral, and the significance level was set at 0.05. The original study sample comprised 88 egg donors from our EDP who were screened and randomized by the study coordinator. At recruitment, egg donors were randomly assigned to either group DI (n = 44) or DII (n = 44). Four women did not continue scheduled visits, for personal reasons. The general characteristics of donors and recipients are shown in Table 1. Of the 84 donors initiating treatment, 21 (25%) had their treatment cycle cancelled owing to a poor response (<6 follicles after 8 days of stimulation). The group distribution for cancelled cycles was 13 in group DI and eight in group DII (29.5% vs. 20.0%), a difference that was not statistically significant (p = 0.44). The two groups had a similar distribution of donors treated with either rFSH or hMG. The remaining 63 donors all underwent follicular puncture and were included in the analysis. There were no significant differences between the groups regarding treatment duration, total dose of gonadotropins, level of E2 on the day of hCG administration, and the number of oocytes retrieved (Table 1).Table 1Characteristics of egg donors and response to stimulation treatment and corresponding recipients and outcomes.Egg donorGroup DI (n = 44)Group DII (n = 40)Age28.4 ± 4.227.9 ± 3.8BMI21.3 ± 2.722.9 ± 2.6Baseline FSH6.2 ± 1.95.1 ± 1.1Antral follicle count13.8 ± 4.514.4 ± 4.3Dose of hpHMG, IU2,021 ± 6712,172 ± 568Dose of rFSH, IU1,726 ± 4301720 ± 501Days of stimulation10.7 ± 1.711.2 ± 1.2E2 level on day of hCG, pg/mL1,986 ± 1,0512,449 ± 1,091No. of oocytes retrieved14.0 ± 5.716.3 ± 6.8Cancellation rate, %29.5 (13/44)20.0 (8/40)RecipientGroup RI(n = 31)Group RII(n = 30)Age40.95 ± 5.2940.83 ± 4.96BMI21.64 ± 2.322.02 ± 2.13E2, pg/mlL171.8 ± 6.52224.0 ± 166P, ng/mL15.43 ± 6.5215.25 ± 10.52Endometrial thickness, mm10.97 ± 2.6411.55 ± 4.04No. of oocytes inseminated9.74 ± 3.2410.70 ± 4.96Fertilization rate, %76.474.9No. of embryos transferred1.97 ± 0.301.97 ± 0.32Score for embryo quality7.32 ± 1.237.04 ± 1.34Pregnancy rate per transfer, %71.0 (22/31)46.7 (14/30)Implantation rate, %42.3 (25/59)30.5 (18/59) Open table in a new tab The retrieved oocytes were assigned to 61 synchronous recipients who underwent a fresh transfer cycle. The eggs from the remaining two donors were assigned to two recipients who had to freeze their embryos (asynchronous donation, not included in the analysis). There were no significant differences between the general characteristics of the two groups of recipients (Table 1). Although the rates of implantation and pregnancy per transfer were higher in group RI than in group RII (42.3% vs. 30.5%, and 71.0% vs. 46.7%, respectively), these differences were not statistically significant (P=.25 and P=.071; Table 1). The present study shows that the treatment of egg donors with gonadotropins and suppression with cetrorelix 3 mg offers recipients an excellent pregnancy rate. This rate is better than that achieved when leuprorelin 3.75 mg is used for suppression, although the difference does not reach statistical significance. In this study, donor stimulation was achieved with either rFSH or hpHMG (Menopur, Ferring, Spain). In IVF/ICSI with the woman's own oocytes and in a long protocol with agonists, previous research found no significant differences in the pregnancy rates achieved with the two gonadotropins (12Van Wely M. Westergaard L.G. Bossuyt P.M. Van der Veen F. Human menopausal gonadotropin versus recombinant follicle stimulation hormone for ovarian stimulation in assisted reproductive cycles.Cochrane Database Syst Rev. 2003; (1):CD003973PubMed Google Scholar), thus suggesting that the type of gonadotropin used does not influence the pregnancy rate. The cancellation rate in the group of donors treated with cetrorelix 3 mg was higher than that among donors treated with depot leuprorelin, although the difference was not significant. One could speculate that this high cancellation rate is related to the intense inhibitory effect of the high dose of antagonist. Erb and Wakim (10Erb T.M. Wakim A.N. GnRH agonist long protocol vs. a single 3-mg gnRH antagonist: a comparison of 2 protocols for pituitary down-regulation in oocyte donor-controlled ovarian hyperstimulation cycles.J Reprod Med. 2008; 53: 331-337PubMed Google Scholar), in a retrospective study using a flexible protocol for antagonist administration, found no differences in either the number of oocytes retrieved or the level of E2 on the day of hCG administration. To avoid the risk of OHSS, the initial doses of gonadotropins administered in our center for the ovarian stimulation of egg donors are deliberately moderate. This could have contributed to the poor response of some donors and, therefore, to the subsequent cancellation of cycles. However, the cancellation rate should have helped in terms of selecting cycles with better quality oocytes. Some authors have reported that the strong suppression of FSH enables the retrieval of eggs with a good implantation potential and prevents the development of follicles with defective or atretic oocytes (1Sauer M.V. Kavic S.M. Oocyte and embryo donation 2006: reviewing two decades of innovation and controversy.RBM Online. 2006; 12: 153-162Google Scholar). As regards E2 levels, a prospective study by Bodri et al. (7Bodri D. Vernaeve V. Guillén J.J. Vidal R. Figueras F. Coll O. Comparison between a GnRH antagonist and a GnRH agonist flare-up protocol in oocyte donors: a randomized clinical trial.Hum Reprod. 2006; 21: 2246-2251Crossref PubMed Scopus (30) Google Scholar) compared donors treated with antagonist versus agonist in a short protocol and found significantly higher levels of E2 in the agonist group. The antagonist-based suppression enables fewer follicles to be recruited, thereby reducing the incidence of OHSS. Our results showed no significant differences between the two donor groups in either E2 levels on the day of hCG administration or the number of oocytes retrieved, nor were there any differences in terms of embryo quality. We also found no differences between the two groups of recipients in the rate of fertilization or the number and quality of embryos, suggesting that the type of analog used does not affect the quality of oocytes or embryos. This finding is consistent with previous reports (5Prapas N. Prapas Y. Panagiotidis Y. Prapa S. Vandezwalmen P. Schoysman R. et al.GnRH agonist versus GnRH antagonist in oocyte donation cycles: a prospective randomized study.Hum Reprod. 2005; 20: 1516-1520Crossref PubMed Scopus (51) Google Scholar, 7Bodri D. Vernaeve V. Guillén J.J. Vidal R. Figueras F. Coll O. Comparison between a GnRH antagonist and a GnRH agonist flare-up protocol in oocyte donors: a randomized clinical trial.Hum Reprod. 2006; 21: 2246-2251Crossref PubMed Scopus (30) Google Scholar, 13Vlaisavljevic V. Reljic M. Lovrec V.G. Kovacic B. Comparable effectiveness using flexible single-dose GnRH antagonist (cetrorelix) and single-dose long GnRH agonist (goserelin) protocol for IVF cycles—a prospective, randomized study.RBM Online. 2003; 7: 301-308Scopus (31) Google Scholar) and in contrast to others (3Ricciarelli E. Sanchez M. Martínez M. Andrés L. Cuadros J. Hernandez E. Impact of the gonadotropin-releasing hormone antagonist in oocyte donation cycles.Fertil Steril. 2003; 79: 1461-1463Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar, 14Lindheim S.R. Morales J. GnRH antagonists followed by a decline in serum estradiol results in adverse outcomes in donor oocyte cycles.Hum Reprod. 2003; 18: 2048-2051Crossref PubMed Scopus (48) Google Scholar). We found no difference in implantation rates, although the discrepancy is probably due to the size of the present sample. Indeed, the main limitation of this study is the sample size. Nevertheless, the promising results, especially the good pregnancy rates achieved after stimulation with gonadotropins and a 3-mg dose of cetrorelix, as opposed to depot leuprorelin, suggest that it is worthwhile studying this protocol in greater depth. We are currently planning a new broader study to confirm our results, and our biostatistician has calculated that, assuming a 60% pregnancy rate for antagonist protocol and 50% for agonist protocol, to detect a difference <10%, with a 5% bilateral significance with 80% power, we should recruit 390 patients per treatment group. This is particularly relevant in terms of improving aspects such as the rate of cancelled cycles and identifying the maximum safe dose of gonadotropins. The initial stimulation dose could be increased with a low risk of OHSS, bearing in mind the possibility of using a dose of agonist to trigger the endogenous LH surge, instead of hCG (9Bodri D. Guillén J.J. Trullenque M. Schwenn K. Esteve C. Coll O. Early ovarian hyperstimulation syndrome is completely prevented by gonadotropin releasing hormone agonist triggering in high-risk oocyte donor cycles: a prospective, luteal-phase follow-up study.Fertil Steril. 2010; 97: 2418-2420Abstract Full Text Full Text PDF Scopus (45) Google Scholar), and being flexible with respect to the day of antagonist administration, the reference criterion being the size of the dominant follicle (10Erb T.M. Wakim A.N. GnRH agonist long protocol vs. a single 3-mg gnRH antagonist: a comparison of 2 protocols for pituitary down-regulation in oocyte donor-controlled ovarian hyperstimulation cycles.J Reprod Med. 2008; 53: 331-337PubMed Google Scholar). During the study period considered here, and owing to the homogeneity of the groups, the indication was to administer 10,000 IU of hCG for preovulatory down-regulation. Nevertheless, there were no cases of OHSS that required hospitalization. In conclusion, the stimulation protocol based on gonadotropins and short suppression with a single dose of cetrorelix acetate 3 mg is adequate not only in terms of the safety and discomfort of donors but also in terms of the likelihood of pregnancy among recipients. Owing to the small size of the present sample, the favorable results require confirmation in future studies with greater numbers of patients. This work was performed under the auspices of the Cátedra de Investigación en Obstetricia y Ginecología del Insitut Universitari Dexeus.