* Puregon (recombinant FSH, Org 32489), NV Organon, Oss,

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1 FERTILITY AND STERILITY Copyright 1997 American Society for Reproductive Medicine Published by Elsevier Science Inc. Vol. 68, No.1, July 1997 Printed on acid-free paper in U. S. A. Recombinant follicle-stimulating hormone (follitropin beta, Puregon*) yields higher pregnancy rates in in vitro fertilization than urinary gonadotropinst Henk J. Out, M.D., Ph.D:j: Stefan G. A. J. Driessen, Ph.D:j: Bernadette M. J. L. Mannaerts, M.Sc.:j: Herjan J. T. Coelingh Bennink, M.D., Ph.D:j:1I NV Organon, Oss, The Netherlands Objective: To assess ongoing pregnancy rates (PRs) in IVF after treatment with recombinant FSH (follitropin beta, Puregon; NV Organon, Oss, The Netherlands) as compared with urinary gonadotropins. Design: A combined analysis of three prospective, multicenter, randomized, comparative trials. Setting: Twenty-five IVF centers in 13 countries. Patient(s): Six hundred ninety-seven infertile women receiving recombinant FSH and 463 women receiving hmg or urinary FSH and undergoing one cycle of controlled ovarian hyperstirnulation and IVF-ET. Intervention(s): A center-based and study-based analysis weighing the treatment differences in individual centers and studies, respectively. Main Outcome Measure(s): Pregnancy rate at least 12 weeks after ET per started cycle. Result(s): In the center-based analysis, the ongoing PR was 22.9% for recombinant FSH and 17.9% for urinary gonadotropins. The 5.0% treatment difference (95% confidence interval [Cn, 0.2% to 9.7%) was significant. When the results of the cryoprogram were included, the treatment difference increased to 6.4% (95% CI, 1.4% to 11.3%). Also in the study-based analysis, significantly higher PRs were seen after follitropin beta treatment. Conclusion(s): Follitropin beta (Puregon) used for controlled ovarian hyperstimulation in IVF yields significantly higher PRs compared with urinary gonadotropins. (Fertil Sterilv 1997;68: by American Society for Reproductive Medicine.) Key Words: Pregnancy, FSH, follitropin beta, meta-analysis, IVF Follicle-stimulating hormone is a gonadotropin preparation indicated for the use in controlled ovarian hyperstimulation before assisted reproduction programs or in clomiphene citrate-resistant anovulatory disorders (1). Recently, 99% pure FSH preparations produced by recombinant DNA technology Received December 16, 1996; revised and accepted March 21, * Puregon (recombinant FSH, Org 32489), NV Organon, Oss, The Netherlands. t Supported by NV Organon, Oss, The Netherlands. t Medical Research and Development Unit. Reprint requests: Henk J. Out, M.D., Ph.D., NV Organon, P.O. Box 20, 5340 BH Oss, The Netherlands (FAX: ). II The following investigators participated in this study: Tom Abyholm, M.D., Kvinneklinikken, Rikshospitalet, Oslo, Norway; Pedro Barri, M.D., Servicio de Reproducci6n Humana, Instituto Dexeus, Barcelona, Spain; Bruno Camier, M.D., Centre de Procre- 138 ation Medicalement Assistee, Amiens, France; Jean Cohen, M.D., Centre Hospitalier Intercommunal Jean Rostand, Sevres, France; Paul Devroey, M.D., Center for Reproductive Medicine, Academic Hospital Free University of Brussels, Brussels, Belgium; Klaus Diedrich, M.D., Universitats-Frauenklinik, Bonn, Germany; Robert Forman, M.D., Department of Obstetrics and Gynaecology, Guy's Hospital, London, United Kingdom; Lars Hamberger, M. D., Kvinnoklinikken, Sahlgrenska Sjukhuset, Goteborg, Sweden; Robert Harrison, M.D., Academic Department of Obstetrics and Gynecology, Rotunda Hospital, Dublin, Ireland; Bernard Hedon, M.D., Centre Hospitalier et Universitaire de Montpellier, Montpellier, France; Peter Hornnes, M.D., Department of Gynecology, Fertility Clinic, Rikshospitalet, Copenhagen, Denmark; /97/$17.00 PH S (97)

2 have become available. Compared with urinary gonadotropins, the recombinant technology used to manufacture FSH ensures high batch-to-batch consistency, the absence of any LH activity, and the lack of contaminating urinary proteins of undetermined origin (2). For one of the available recombinant FSH preparations (follitropin beta, Puregon; NY Organon, Oss, The Netherlands), it has been shown that, compared with urinary FSH, significantly more oocytes were retrieved, more embryos were obtained, and more ongoing pregnancies were achieved, when the results of the cryoprogram were included (3). In total, three comparative studies on follitropin beta and urinary gonadotropins have been performed in IVF (3, 4, and one study reviewed [5]). The purpose of the current evaluation was to examine the effects of a combined analysis of these studies on the ongoing pregnancy rates (PRs) directly following the fresh ET. Studies MATERIALS AND METHODS In this study, all but one ofthe randomized clinical trials comparing recombinant FSH (follitropin beta, Puregon) and urinary gonadotropins in IVF have been included (3-5). In total, 25 centers participated in the three studies. One small trial comparing the SC and 1M administration of follitropin beta with hmg (6) was not included in this study because of the different nature of the protocol and the small number of patients (n = 6 in the 1M recombinant FSH group versus n = 7 in the hmg group). Also, Jean-Noel Hugues, M.D., H6pital Jean Verdier, Bondy, France; Jarl Kahn, M. D., Kvinneklinikken, Regionsykehuset i Trondheim, Trondheim, Norway; Cees Jansen, M.D., Department of Obstetrics and Gynaecology, Diaconessenhuis, Voorburg, The Netherlands; Brian Lieberman, M.D., Regional IVF Unit, St. Mary's Hospital, Manchester, United Kingdom; Pedro Lopes, M.D., Hotel Dieu, Nantes, France; R. Shaw, M.D., Department of Obstetrics and Gynaecology, University of Wales College of Medicine, Cardiff, United Kingdom; Zev Shoham, M.D., Department of Obstetrics and Gynecology, Kaplan Hospital, Rehovot, Israel; Niels Sjoberg, M.D., Department of Obstetrics and Gynaecology, University of Lund, Malmo, Sweden; Basil Tarlatzis, M.D., Infertility and IVF Center "Geniki Cliniki," Thessaloniki, Greece; Aila Tiitinen, M.D., Department of Obstetrics and Gynaecology, Helsinki University Central Hospital, Helsinki, Finland; Christine West, M.D., The Assisted Conception Unit, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom; Ludwig Wildt, M.D., Universitats-Frauenklinik, Erlangen, Germany; Robert Winston, M.D., Hammersmith Royal Postgraduate Medical School, Institute of Obstetrics and Gynaecology, London, and IVF Clinic, Royal Masonic Hospital, London, United Kingdom; Jean-Rene Zorn, M.D., Clinique Universitaire Baudelocque, Paris, France. clinical trials using another recombinant FSH preparation (follitropin alpha, Gonal-F; Ares-Sereno, Geneva, Switzerland) have not been included. This has been done because variations in the genetic origin ofthe FSH-producing cell, culture conditions during cell growth, purification procedures to obtain pure FSH, and pharmaceutical formulations in the ampule might result in clinically relevant differences between follitropin alpha and beta (7). The three studies encompassed healthy infertile women between 18 and 39 years of age with normal regulatory cycles. There was no male infertility, nor were there any endocrine abnormalities, such as hyperprolactinemia, polycystic ovary syndrome, or absence of ovarian function. Eligible subjects were randomized by receiving a subject number from a computer-generated randomization list using random numbers corresponding with patient boxes in which the medication was kept. In two studies, a GnRH agonist (GnRH-a) was used in a long protocol, both comparing recombinant and urinary FSH (urofollitrophin, Metrodin, Ares Serono, Switzerland). In the third study, follitropin beta was compared with hmg (menotropin, Humegon; NV Organon) without the use of any GnRH-a in both groups. The protocol included the 1M administration of FSH of 150 or 225 IV for the first 4 days, after which the treatment was individualized according to ovarian response. When at least three follicles of 15 mm (5) or 17 mm (3, 4) were present, ovulation was triggered by a single 1M injection of hcg (Pregnyl; NV Organon). Oocyte pick-up, IVF routines, and luteal support all were done according to the local standards. A maximum of three embryos were replaced. In most centers, the surplus of embryos was cryopreserved. In Table 1 the major properties of the various studies are summarized. Follitropin beta was given to 697 patients, and 463 women received urinary FSH or hmg. The number of subjects treated per center ranged from 3 to 146 (mean, 46.4). The mean ages of the patients treated in the recombinant and urinary gonadotropin groups were 32.2 and 32.3 (3), 32.3 and 31.2 (4), and 32.0 and 31.1 years. (5) The main cause of infertility was of tubal origin (64.4% and 64.1% [3], 61.4% and 66.7% [4], and 57.4% and 48.6% [5]. There were no major differences in the number of embryos transferred between recombinant FSH and the comparative drug. Statistical Analysis Two combined analyses were performed on the ongoing PR per started cycle, defined as a vital pregnancy at least 12 weeks after ET. A center-based Vol. 68, No.1, July 1997 Out et al, Combined analysis ofpuregon studies 139

3 Table 1 Characteristics of Three Comparative Studies Included in a Center-Based and Study-Based Analysis of PRs No. of patients treated Study reference Comparative No. of Recombinant Urinary no. drug centers GnRH-a FSH FSH 3 Urinary FSH 18 Buserelin Urinary FSH 6 Triptorelin hmg 1 None 55t Mean no. of fresh embryos transferred Recombinant Urinary hmg FSH FSH hmg * Including one recombinant FSH-treated woman originally randomized to receive hmg. analysis combined the treatment difference estimates at the level of the individual centers that participated in the trials by means of the Mantel-Haenszel statistics, adjusted for center. Thus, the overall treatment difference is a weighted average of the individual center treatment differences in which the weights are derived from the numbers of subjects treated per center. The 95% confidence interval (Cl) was calculated using the normal distribution as approximate distribution for the treatment difference. The test for interaction (heterogeneity in treatment differences across centers) also was based on this assumption and consisted of the sum of squares of deviations ofindividual center treatment differences from the overall treatment difference compared with a X 2 distribution with 24 df (25 centers). A study-based analysis combined the treatment difference estimates ofthe three studies. The overall treatment difference estimate is a weighted average of the individual study treatment differences, in which the weights now are based on corresponding estimated variances of the treatment differences. This approach has been advocated as a general method for the meta-analysis of randomized clinical trials (8). The corresponding 95% CIs and the test for interaction (heterogeneity) follow the same methodology as described for the center-based analysis except now using the individual study results. Because the individual study results already were based on analyses adjusting for center, no relevant differences between the center-based and studybased analysis were expected. The study-based analysis was performed to stay in line with "usual" metaanalyses, the center-based analysis to indicate the possibility of analyzing three studies as one large multicenter trial. RESULTS Pregnancy Rates Mter the Fresh Transfer The ongoing PRs of the individual studies and all studies taken together are given in Table 2 and Figure 1. The ongoing PRs per study all were higher for 140 Out et at Combined analysis ofpuregan studies recombinant FSH: 22.2% versus 18.2% (3), 30.2% versus 17.4% (4), and 23.6% versus 14.7% (5). In the recombinant FSH versus hmg study (5), one pregnancy in a woman randomized to receive hmg but who erroneously was treated with recombinant FSH was included in the recombinant FSH group. None of the differences per study were statistically significant. The PR per center ranged from 0% to 50.0% for follitropin beta and from 0% to 70.7% for urinary gonadotropins. In the center-based analysis, the overall ongoing PR was 22.9% for follitropin beta and 17.9% for urinarygonadotropins, which was statistically significant (treatment difference, 5.0%; 95% CI of treatment difference, 0.2% to 9.7%; P = 0.039). The test for center treatment interaction was not significant (P = 0.85). In the study-based analysis, the treatment difference in ongoing PRs was 4.9% (95% CI, 0.1% to 9.6%) in favor of follitropin beta (P = 0.044). The test for heterogeneity was negative (P = 0.61). Pregnancy Rates Including the Replacement of Frozen-Thawed Embryos When the ongoing pregnancies as results of the cryoprogram were included, the center-based analysis showed an ongoing PR per started cycle of 26.3% in the follitropin beta group versus 19.9% in the urinary gonadotropin group (treatment difference, 6.4%, 2:: 2.5% (SE); 95% CI of treatment difference, 1.4% to 11.3%; P = 0.011). Also, the study-based analysis showed a significantly higher PR after follitropin beta as compared with urinary gonadotropin treatment (95% CI of treatment difference, 1.4% to 11.3%, P = 0.011). Both the test for interaction in the center-based analysis and the test for heterogeneity in the study-based analysis were not significant (P = 0.98 and 0.91, respectively). DISCUSSION In this study it was demonstrated that significantly more pregnancies could be obtained after Fertility and Sterilityv

4 Table 2 Ongoing PRs in Three Randomized Clinical Trials Comparing Recombinant FSH and Urinary Gonadotropins* Ongoing PR 95% CI of Study reference no. Recombinant Urinary Treatment treatment and analysis FSH FSH hmg differencet difference P % % % % % ± to ± to :1: ± to Center-based analysis ± to Study-based analysis ± to * Follicle-stimulating hormone (Puregon) was obtained from NV Organon, Oss, The Netherlands. t Values are means ± SE. :I: Including one recombinant FSH pregnancy of a woman originally randomized to receive hmg. treatment with follitropin beta (Puregon) than after urinary gonadotropin treatment. This was apparent both directly after the fresh transfer and, cumulatively, after inclusion of the frozen-thawed embryo replacements. The 95% CI of the treatment difference in ongoing PRs averaged approximately 5% but ranged up to clinically relevant differences of approximately 10%. These results were obtained after both a center-based analysis, in which all the treatment differences from the individual centers were averaged using the number of subjects treated per center for weighting, and a study-based analysis, which consisted of a weighted average of the treatment differences of the three studies in which the corresponding estimated variances were used for weighting. This latter approach is common in metaanalyses. Meta-analyses are used increasingly in reproductive medicine to synthesize research (9, 10). These analyses are especially indicated when results from several studies lack statistical significance yet appear to have effects in the same direction (11), One of the major obstacles in assessing the value ofmeta- % 50 _ o._----- t 11 I ~:~::'" MG I.- l~ j - -C-f-'~ lrulill ~ Subjtreated: Center Figure 1 Ongoing pregnancy rates (%) after controlled ovarian hyperstimulation, NF, and fresh ET with recombinant FSH (recfsh) and urinary FSH (ufsh) or hmg as assessed in 25 centers involved in three comparative, randomized clinical trials. I I analyses is publication bias, i.e., overestimating the true difference because negative results are likely not to have been published. In the current study, all randomized trials ever done comparing follitropin beta and urinary gonadotropins in IVF have been included, and therefore this bias could not have occurred. A potential confounding factor in this analysis might be the inclusion of one IVF study in which a GnRH agonist was not used (5). However, although the use of an agonist might lead to better overall results, it is unlikely that the recombinant FSH stimulation would benefit more from the down-regulation than the comparative urinary gonadotropin treatment. In addition, the use ofhmg in this study and urinary FSH in the other two studies (3, 4) does not influence the topic and conclusion ofthe analysis that recombinant FSH (fouitropin beta) gives higher PRs than urinary gonadotropins. A number of reasons can be hypothesized as causes for the increased PR after fouitropin beta treatment. First, the higher PRs directly following the fresh transfer suggest a higher embryo quality after follitropin beta treatment. This may be related to an increased number of available embryos as found in the large IVF study (3), enabling the embryologist to replace the morphologically best embryos. It is believed that embryo morphology correlates well withthe chance for implantation and therefore pregnancy (12). However, one cannot exclude the possibility that oocyte quality and therefore embryo quality are influenced by the type of gonadotropin preparation used. It has been shown in in vitro experiments with mammalian oocytes that meiotic progression, polarbody emission, cumulus-oocyte interactions, and oocyte cytoskeletal organization are influenced by the presence or absence of gonadotropins in the culture medium (13). One can speculate that the different nature offollitropin beta compared with traditional urinary preparations as manifested in the absence of impurities and a more basic isohor- Vol. 68, No.1, July 1997 Out et al. Combined analysis of Puregon studies 141

5 mone profile (14) may influence the ability of the embryo to implant. Further research is needed to elucidate these issues. Second, a quantitative advantage in the number of oocytes retrieved and embryos obtained after follitropin beta treatment leading to a surplus of embryos stored in the freezer will ultimately lead to more pregnancies because of the higher availability of embryos that can be replaced in natural cycles. This will increase the chance for a pregnancy per stimulation cycleand decrease the gonadotropin consumption per cumulative IVF treatment. Therefore, the treatment difference in ongoing PRs was even more in favor of recombinant FSH when the results of the cryoprogram were included (P = 0.011). It seems unlikely that differences in endometrial development at the time of the fresh ET account for the higher PRs obtained with follitropin beta, because these rates also were higher after frozenembryo replacements in natural cycles (5). In conclusion, it has been demonstrated that controlled ovarian hyperstimulation with recombinant FSH (follitropin beta, Puregon) leads to statistically and clinically significantly higher ongoing PRs compared with urinary FSH and hmg. Acknowledgments. Recombinant FSH, hmg, urinary FSH, and hcg study medication were provided by NY Organon. We thank Wilco Hoff, M.Sc., for his contribution to this article. REFERENCES 1. Healy DL, Trounson AO, Andersen AN. Female infertility: causes and treatment. Lancet 1994;343: Olijve W, De Boer W, MuldersJWM, Van WezenbeekPMGF. Molecular biology and biochemistry of human recombinant follicle stimulating hormone (Pu r egon ), Mol Hum Reprod 1996;2: Out HJ, Mannaerts BMJL, Driessen SGAJ, Coelingh Bennink HJT. A prospective, randomized, assessor-blind, multicenter study comparing recombinant and urinary follicle-stimulating hormone (Puregon us Metrodin) in in-vitro fertilization. Hum Reprod 1995; 10: Hedon B, Out HJ, Hugues IN, Camier B, Cohen J, Lopes P, et al. Efficacy and safety of recombinant FSH (Puregon) in infertile women pituitary-suppressed with triptorelin undergoing in-vitro fertilisation: a prospective, randomised, assessor-blind, multicentre trial. Hum Reprod 1995;10: Out HJ, Mannaerts BMJL, Driessen SGAJ, Coelingh Bennink HJT. Recombinant follicle stimulating hormone (rfsh; Puregon) in assisted reproduction: more oocytes, more pregnancies. Results from five comparative studies. Hum Reprod Update 1996;2: Duijkers IJM. Gonadotrophins, some basic and clinical aspects [dissertation]. University of Nijmegen (The Netherlands), Out HJ, Olijve W, Coelingh Bennink HJT. The coming of wonders [letter]. Fertil Steril 1997;67: Whitehead A, Whitehead J. A general parametric approach to the meta-analysis of randomised clinical trials. Stat Med 1991;10: Hughes EG, Sagle MA, Fedorkow DM, Koppel P van de, Daya S, Collins JA. The routine use of gonadotropin-releasing hormone agonists prior to in vitro fertilization and gamete intrafallopian transfer: a meta-analysis of randomized controlled trials. Fertil Steril 1992;58: Daya S, Gunby J, Hughes EG, Collins JA, Sagle, MA. Folliclestimulating hormone versus human menopausal gonadotropin for in vitro fertilization cycles: a meta-analysis. Fertil Steril 1995;64: D'Agostinho RE, Weintraub M. Meta-analysis: a method for synthesizing research. Clin Pharmacol Ther 1995;58: Shulman A, Ben-Nun I, Ghetler Y, Kaneti H, Shilon M, Beyth Y. Relationship between embryo morphology and implantation rate after in vitro fertilization treatment in conception cycles. Fertil Steril 1993;60: Plancha CE, Albertini DF. Hormonal regulation of meiotic maturation in the hamster oocyte involves a cytoskeletonmediated process. Biol Reprod 1994;51: Matikainen T, de Leeuw R, Mannaerts B, Huhtaniemi I. Circulating bioactive and immunoreactive recombinant follicle stimulating hormone (Org 32489) after administration to gonadotropin-deficient subjects. Fertil Steril 1994;61: Out et al, Combined analysis ofpuregon studies Fertility and Sterilityt'

A Case of Pregnancy Using Recombinant Follicle Stimulating Hormone and Gonadotropin Releasing Hormone Antagonist

1 *, ** * * * ** A Case of Pregnancy Using Recombinant Follicle Stimulating Hormone and Gonadotropin Releasing Hormone Antagonist Yoon Sung Nam, Nam Keun Kim*, Eun Kyung Kim**, Hyung Min Chung** and Kwang