Highly purified hmg versus recombinant FSH in ovarian hyperstimulation with GnRH antagonists a randomized study

Human Reproduction Vol.23, No.10 pp. 2346 2351, 2008 Advance Access publication on June 25, 2008 doi:10.1093/humrep/den220 Highly purified hmg versus recombinant FSH in ovarian hyperstimulation with GnRH antagonists a randomized study E. Bosch 1, C. Vidal, E. Labarta, C. Simon, J. Remohi and A. Pellicer Instituto Valenciano de Infertilidad, E-46015 Valencia, Valencia 46015, Spain 1 Correspondence address: E-mail: ebosch@ivi.es BACKGROUND: Highly purified hmg (hp-hmg) has recently shown better cycle outcome than the recombinant FSH (rfsh) when compared in GnRH agonist long protocol cycles. However, they have not yet been compared in GnRH antagonist cycles. METHODS: A RCT comparing the ongoing pregnancy rate (primary end-point) in 280 patients undergoing IVF/ICSI after stimulation with hp-hmg or rfsh controlled with a GnRH antagonist. RESULTS: No significant differences were observed between hp-hmg and rfsh in terms of the ongoing pregnancy rate per started cycle (35.0 versus 32.1%, respectively; P 5 0.61); relative risk: 1.09 (95% confidence interval: 0.78 1.51; risk difference: 2.9%). No differences were observed for implantation, clinical pregnancy and pregnancy loss rates. More oocytes were obtained from patients receiving rfsh then hmg (14.4 + 8.1 versus 11.3 + 6.0, respectively; P 5 0.001). Estradiol was higher at the end of stimulation in the hp-hmg group (P 5 0.02), whereas progesterone was higher in patients stimulated with rfsh (P<0.001). CONCLUSIONS: A similar outcome was observed for hp-hmg and rfsh when used for stimulation in GnRH antagonist cycles. However, some differences were found in ovarian response in terms of oocyte yield and hormonal profile. Clinical Trials.gov Trial registration number: NCT00669786. Keywords: GnRH antagonists; ovarian stimulation; FSH; hmg; RCT Introduction Highly purified hmg (hp-hmg) and recombinant FSH (rfsh) have been widely and successfully used for ovarian stimulation in infertile women undergoing treatment for IVF/ICSI and embryo transfer. Comparing the effectiveness of both compounds has been the object of large debate since the development of embryo transfer (Van Wely et al., 2003). Several studies comparing the outcome of rfsh and hmg have been reported, most of which were performed in women undergoing pituitary down-regulation with a GnRH agonist long protocol (Ng et al., 2001; Westergaard et al., 2001; The European and Israeli Study Group on highly purified hmg versus rfsh, 2002; Balasch et al., 2003; Goldfarb and Desai, 2003; Kilani et al., 2003; Rashidi et al., 2005; Andersen et al., 2006; Hompes et al., 2007). Recently, two meta-analyses showed a better outcome in terms of the live birth rate when hp-hmg was used for ovarian stimulation compared with rfsh in the GnRH agonist long protocol (Al-Inany et al., 2008; Coomarasamy et al., 2008). However, few data of the outcome observed when comparing rfsh versus hp-hmg are available in patients undergoing ovarian stimulation with the GnRH antagonist protocol. Some studies have addressed the issue of the need or convenience of adding LH activity to FSH in ovarian stimulation IVF/ICSI-ET. Regarding GnRH antagonist cycles, neither the studies that related serum LH determinations throughout the follicular phase with cycle outcome (Kolibianakis et al., 2004; Merviel et al., 2004; Bosch et al., 2005), nor those that compared success rates when LH was administered or not (Cédrin-Durnerin et al., 2004; Griesinger et al., 2005) have been able to address the role, if any, that LH administration plays during the follicular phase of a stimulated cycle for IVF-ET under pituitary suppression with this kind of compound. Given this background, it seems appropriate to investigate whether providing multiple follicular development with hp-hmg in GnRH antagonist cycles causes a clinically relevant improvement in cycle outcome in terms of ongoing pregnancy rates when compared with the well-known protocol with rfsh and a GnRH antagonist in the daily dose regimen. Materials and Methods Study population Two hundred and eighty patients undergoing their first IVF/ICSI treatment in our center were randomized to follow ovarian stimulation with hp-hmg (n ¼ 140) or rfsh (n ¼ 140). An Institutional Review Board approval was obtained and the study was conducted from 2346 # The Author 2008. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Pregnancy outcome for hmg versus FSH with GnRH antagonists January 2003 to December 2006, and was continued by a follow-up period to collect pregnancy outcome data. Patients were selected if they met all the following inclusion criteria: women with good physical and mental health, aged 18 37 years; regular menstrual cycles ranging from 25 to 35 days; BMI,30 kg/m 2 ; normal basal serum FSH (10 IU/l) and estradiol (E 2 )(75 pg/ml) levels determined on Day 3 of the cycle previous to controlled ovarian stimulation (COS); no uterine (fibroids, adenomyosis, Mullerian malformations), ovarian (endometrioma, polycystic ovaries) or adnexa (hydrosalpinx) abnormalities assessed by vaginal ultrasound. The exclusion criteria were: patients with a history of recurrent pregnancy loss; any significant systemic disease, endocrine or metabolic disorder; having concomitant medication interfering with the purposes of the study; patients who have received any ovulation induction drug within one month before their inclusion in the study. Study design This was a randomized, open-label, single-center controlled study to compare hp-hmg (Menopurw, Ferring Pharmaceuticals, Copenhagen, Denmark) and rfsh (Gonal F w ; Serono, Geneva, Switzerland) in patients undergoing ovarian stimulation for IVF/ICSI-ET controlled with a GnRH antagonist. Patients were randomized 1:1 to receive hp-hmg or rfsh according to a computer-generated list. This list was arranged into four blocks of 70 patients. Patients were allocated to one group of two when they were scheduled to start ovarian stimulation. The randomization list was centralized at the institution s call center, and the center was contacted to allocate each randomized patient into a group. The primary end-point was the ongoing pregnancy rate per randomized patient (intention-to-treat analysis, ITT). The ongoing pregnancy rate was defined as the presence of at least one viable fetus beyond week 20 of pregnancy on ultrasound. A started cycle was considered when patients had their first injection of gonadotropins. Delivery rate was also recorded. Secondary outcome end-points were a clinical pregnancy rate defined as the presence of a gestational sac with a positive heartbeat 4 5 weeks after embryo transfer, pregnancy loss (including biochemical pregnancies, miscarriages, and ectopic pregnancies), implantation rate and ovarian hyperstimulation syndrome (OHSS) rate. Secondary clinical end-points were the number of cumulus oocyte complexes (COCs) retrieved, the number of metaphase II oocytes obtained (ICSI cycles), fertilization rate, and serum E 2 and progesterone levels on the day of hcg administration. Protocol All included patients received an oral contraceptive pill with 0.030 mg of ethinyl-estradiol and 3.0 mg of drospirenone (Yasminw, Schering España S.A., Madrid, Spain) in the cycle prior to ovarian stimulation. Patients started one tablet daily from cycle Day 3 for 21 days, after determining the hormonal basal profile (FSH and E 2 ). On the second day of the following menstruation, vaginal ultrasound was performed to rule out the presence of any cyst or residual corpus lutea, and ovarian stimulation was started. The starting dose for hmg and rfsh was 225 IU/day s.c. for the first two days of stimulation. Then, a serum E 2 determination was performed for individual adjustments as follows: if E 2 was,100 pg/ml, the dose was increased to 300 IU/day; if E 2 was between 100 and 200 pg/ml, then the dose was maintained at 225 IU/day; if E 2 was.200 pg/ml, the dose was lowered to 150 IU/day. These adjustments were performed equally for both groups of patients for the following 3 days. On stimulation Day 6, 0.25 mg of the GnRH antagonist Cetrorelix (Cetrotidew, Serono) was started daily, and continued until the end of stimulation. Recombinant human chorionic gonadotropin (rhcg) a, 250 mg, s.c. (Ovitrellew, Serono) was administered when at least three follicles reached 18 mm in diameter, and oocyte retrieval was scheduled 36 h later. Standard IVF or ICSI procedures were applied, as previously described (Gil-Salom et al., 1995). A maximum of three embryos were transferred on Day 3 of the cleavage state. Ultrasound guidance was used for all embryo transfers. The luteal phase was supplemented with 400 mg/day of vaginal micronized progesterone (Progeffikw, Effik, Madrid, Spain). A pregnancy test (serum b-hcg determination) was done 13 days after embryo transfer. Statistical analysis The sample size was calculated using a one-sided significance level of 0.05 and a power of 80% to detect a major clinically relevant difference of 1.5 relative risk (RR) in the ongoing pregnancy rate between groups (30 45%), favoring hp-hmg administration. According to these parameters, 128 patients were required for each treatment group. As 10% losses after starting the stimulation per group were predicted, a total of 280 patients (140 in each group) were randomized. This sample size provides a statistical power of 70% in a two-sided hypothesis. Data are expressed as the mean + SD for continuous variables, and as the mean and 95% confidence interval (95% CI) for categorical variables. Normality of distribution of continuous variables was assessed with the Kolmogorov Smirnov test. Differences between groups of normally distributed variables were assessed with the Student s t-test, while not normally distributed variables were compared with the Mann Whitney U test. Non continuous variables were compared with the x 2 test with Yates correction when appropriate. Results Demographic and baseline characteristics of the study participants are shown in Table I. No relevant between-group differences were observed for any of the compared parameters. Distribution of infertility causes was similar between groups, as was the basal hormonal profile. Two hundred and ninety three patients were initially recruited for the study. Of these, 13 were excluded by randomization for various different reasons, which represents a participation rate of 95.6% (Fig. 1). Of the 280 patients initially included, 32 did not reach the oocyte retrieval procedure [14 patients receiving rfsh (10.0%) and 18 having hp-hmg (12.9%); (P ¼ 0.45)]. Nine patients (6.4%) were cancelled because of the low response in both groups. In the rfsh Table I. Demographic and baseline hormonal profile characteristics of the study participants. Baseline parameters r-fsh (n ¼ 140) hp-hmg (n ¼ 140) Age (years) 33.4 + 3.3 33.2 + 2.8 Body mass index (m/kg 2 ) 24.2 + 1.5 23.9 + 1.7 Primary cause of infertility Male factor 119 (85.0%) 115 (82.1%) Tubal infertility 14 (10.0%) 20 (14.3%) Unexplained infertility 7 (5.0%) 5 (3.6%) Basal FSH (IU/l) 6.4 + 2.1 6.5 + 1.6 Basal E 2 (pg/ml) 56.1 + 35.3 45.5 + 22.3 Values are expressed by mean + SD for continuous variables and number (%) for categorical variables. r-fsh, recombinant FSH; hp-hmg, highly purified hmg; E 2, estradiol. 2347

Bosch et al. (three in the hp-hmg group and four in the rfsh group) did not present embryo transfer because of the low quality of their embryos (Fig. 1). Therefore, embryo transfer was performed in 117 patients receiving hp-hmg and 120 patients receiving rfsh. The cycle outcome is detailed in Table III. In short, no significant differences were observed between study groups in terms of implantation, pregnancy, ongoing pregnancy and delivery rates per randomized patient. One patient of each group had a pregnancy loss beyond week 20. Figure 2 shows the RR and 95% CI of each outcome end-point for hp-hmg cycles in relation to the rfsh group. Figure 1: CONSORT statement flow diagram. group, 5 (3.6%) patients were cancelled for being at risk of OHSS, whereas cancellations for this reason in the hp-hmg were 9 (6.4%); (P ¼ 0.27) (Fig. 1). Table II shows the ovarian stimulation parameters outcome. Patients of both groups received a similar total dose of gonadotropins. Serum E 2 levels on the day of rhcg administration were higher in the hp-hmg group, whereas progesterone was higher in patients who received rfsh. Ovarian response was significantly higher in the rfsh group in terms of the number of COCs collected and metaphase II oocytes obtained (ICSI cycles). The fertilization rate, the number of transferred embryos and the embryos available for cryopreservation were comparable between both groups. Eleven patients did not have embryo transfer: 5 patients (4.1%) in the hp-hmg group and 6 (4.8%) in the rfsh group. All the embryos of two patients of each group were cryopreserved because of clinical OHSS. Seven patients Discussion In this study, hp-hmg and rfsh have been compared for the first time when used in ovarian stimulation with a GnRH antagonist for IVF/ICSI-ET. The ongoing pregnancy and delivery rates per randomized patient (ITT analysis) were similar between both groups, with an RR of 1.09 (95% CI: 0.78 1.51) which reflects a non-significant difference between both groups. When other cycle outcome parameters were compared, e.g. implantation and clinical pregnancy rates, similar results were observed. Because of a low response or low risk of OHSS, cancellation rates were comparable between both groups, as were the number of cycles without embryo transfer and the pregnancy loss rate. The comparison of hmg and rfsh effectiveness in ovarian stimulation for IVF/ICSI-ET has been the object of a number of studies. They have been compared in non down-regulated cycles (Jansen et al., 1998), in down-regulated cycles with a GnRH agonist short protocol (Strehler et al., 2001), but mainly in down-regulated cycles through a GnRH agonist long protocol (Ng et al., 2001; Westergaard et al., 2001; Diedrich et al., 2002; The European and Israeli Study Group on highly purified hmg versus rfsh, 2002; Balasch et al., 2003; Goldfarb and Desai, 2003; Kilani et al., 2003; Rashidi et al., 2005; Andersen et al., 2006; Hompes et al., 2007). Nevertheless, very few data have been reported when both compounds were compared in GnRH antagonist cycles (Al-Inany et al., 2008). The different hormonal profile observed in the follicular phase when hmg and rfsh are used, especially as far as the serum LH levels are concerned (Huirne et al., 2007), makes the comparison of hp-hmg and rfsh more interesting. Table II. Ovarian stimulation outcome. Hp-HMG (n ¼ 122) r-fsh (n ¼126) P-value Total Gn dose (IU) 2481 + 994 2624 + 801 0.22 Serum E 2 on day of hcg g/ml) 2066 + 1011 1750 + 973 0.02 Serum progesterone on day of hcg (ng/ml) 0.73 + 0.42 0.99 + 0.48,0.001 Number of COCs collected 11.3 + 6.0 14.4 + 8.1 0.001 Number of Metaphase II (ICSI) 7.8 + 4.0 9.7 + 6.0 0.004 Fertilization rate 69.8 + 26.4 68.9 + 22.3 0.765 Number of transferred embryos 1.7 + 0.8 1.7 + 0.8 0.745 Number of cryopreserved embryos 1.0 + 2.1 1.1 + 1.9 0.858 Values are expressed by mean + SD. Gn, gonadotrophin; COC, cumulus oocyte complexes. 2348

Pregnancy outcome for hmg versus FSH with GnRH antagonists Table III. Cycle outcome per randomized patient. Hp-HMG r-fsh P-value Implantation 37.6 (30.0 45.2) 30.80 (24.1 37.6) 0.19 Clinical pregnancy/randomized patient 59/140 55/140 0.63 42.1 (33.8 50.2) 39.3 (31.1 47.9) Pregnancy loss 11/59 11/55 0.86 18.6 (9.7 30.9) 20.0 (10.4 33.0) Ongoing pregnancy/randomized patient 49/140 45/140 0.61 35.0 (27.1 43.5) 32.1 (24.5 40.6) Delivery/randomized patient 48/140 44/140 0.61 34.3 (26.5 42.8) 31.4 (23.9 39.8) Data are expressed as number of cases, rate and 95% confidence interval. Figure 2: Comparative outcome showing relative risk and 95% confidence interval of hp-hmg with respect to rfsh. The largest body of evidence available on the comparison of these two compounds is derived from two recent meta-analyses (Al-Inany et al., 2008; Coomarasamy et al., 2008) which include 2179 and 2937 cycles, respectively. Both studies observed a significantly better live birth rate when hp-hmg was used for ovarian stimulation, with a relative increase of 18 (Coomarasamy et al., 2008) to 20% (Al-Inany et al., 2008). In the present study, in which a GnRH antagonist was used for the down-regulation, there was a smaller difference in live birth rate, with a relative increase of 9%. Nevertheless, the 95% CI observed (0.78 1.51) is consistent with those observed in two recent single multicenter studies (Andersen et al., 2006; Hompes et al., 2007). In this study, IVF and ICSI cycles were included indiscriminately. Some authors have suggested that differences between hp-hmg and rfsh are mainly observed in the IVF cycles (Westergaard et al., 2001; Platteau et al., 2004). In the present study, the majority of cycles were ICSI as the male factor was the most frequent indication. A separated analysis was not performed because of the low number of pure IVF cycles. The data related to ovarian stimulation outcome obtained in this study are comparable to those reported in the GnRH agonist long protocol trials. Albeit the dose of gonadotropins employed was similar between both groups, the number of COCs retrieved was significantly lower in the hp-hmg group, showing a mean difference of 23.1 oocytes. This finding coincides with the Merit study (Andersen et al., 2006) in which 1.8 oocytes less were obtained in the hp-hmg group, and with that by Hompes et al. (2007) with a mean difference of 2.8 oocytes, thus favoring rfsh. The lower number of COCs obtained when hp-hmg is employed for COS could reflect a LH effect during the follicular phase which induces an atresia of a number of follicles. This has also been observed when hmg and rfsh have been compared in ovulation induction in World Health Organization Group II anovulatory infertility patients (Platteau et al., 2006), where a lower number of intermediate follicles were present in patients receiving hp-hmg. Moreover, it has been demonstrated that the number of oocytes retrieved in GnRH antagonist cycles tends to diminish as serum LH levels increase throughout the follicular phase (Bosch et al., 2005). In close relationship with this finding, the serum E 2 levels were significantly higher at the end of the follicular phase in the hp-hmg group, despite the lower number of COCs finally retrieved, which reflects that E 2 production per mature follicle significantly increased when hp-hmg was administered. This was also observed in the Merit study (Smitz et al., 2007), and was clearly related to LH activity. In GnRH antagonist cycles (Bosch et al., 2005), the patients who showed higher serum LH levels throughout the follicular phase also presented significantly higher serum E 2 concentrations on the day of hcg administration. The administration of hp-hmg has also led to a higher follicular production of E 2 if compared with rfsh (Smitz et al., 2007). This could explain the higher proportion of top-quality embryos per obtained oocyte observed in patients treated with hp-hmg compared with those who received rfsh (Ziebe et al., 2007). In fact in the present study, the number of embryos available for transfer (embryos transferred plus embryos cryopreserved) was equal between groups despite the lower number of COCs obtained in the hp-hmg group. On the other hand, serum progesterone concentrations were significantly higher in the rfsh group. Increased progesterone levels have been already related to FSH administration, in either GnRH antagonist cycles (Bosch et al., 2005) or GnRH agonist long protocol cycles (Andersen et al., 2006). This increase is explained by FSH activity, as demonstrated by several authors (Adonakis et al., 1998; Filicori et al., 2002; 2349

Bosch et al. Smitz et al., 2007), and which may stimulate granulosa cell activity, while LH may induce progesterone catabolism to androgens at the level of theca cells. In this study, the mean progesterone concentration on the day of rhcg administration was 0.99 + 0.48 ng/ml in the rfsh group, versus 0.73 + 0.42 ng/ml in the hp-hmg patients (P, 0.001). However, this difference was not of clinical relevance as progesterone was shown to be detrimental in GnRH antagonist cycles at concentrations.1.2 ng/ml (Bosch et al., 2003). In conclusion, hp-hmg and rfsh displayed a similar outcome when used in ovarian stimulation with a GnRH antagonist for IVF/ICSI-ET in terms of the ongoing pregnancy and delivery rate per started cycle. No differences were observed for implantation, clinical pregnancy and pregnancy loss rates. Although this is the first study comparing both gonadotropins in the GnRH antagonist protocol, these findings are limited because of the small number of patients included. Moreover, the statistical power of the present study in a two-sided test is 70%, as sample size calculation was initially performed for a one-sided hypothesis, expecting a better outcome when hp-hmg was used. According to the results hereby presented, only the absence of a large difference between hp-hmg and rfsh groups in cycle outcome can be concluded, and two-sided tests are recommended if further studies are developed. The significant detection of a relative difference of 10% requires the analysis of more than 3000 patients per group. Therefore, large multicenter analyses or meta-analyses including several single studies are necessary to determine differences of this magnitude. References Adonakis G, Deshpande N, Yates RW, Fleming R. Luteinizing hormone increases estradiol secretion but has no effect on progesterone concentrations in the late follicular phase of in vitro fertilization cycles in women treated with gonadotropin-releasing hormone agonist and follicle-stimulating hormone. Fertil Steril 1998;69:450 453. Al-Inany HG, Abou-Setta AM, Aboulghar MA, Mansour RT, Serour GI. Efficacy and safety of human menopausal gonadotrophins versus recombinant FSH: a meta-analysis. Reprod Biomed Online 2008;16:81 88. Andersen AN, Devroey P, Arce JC. Clinical outcome following stimulation with highly purified hmg or recombinant FSH in patients undergoing IVF: a randomized assessor-blind controlled trial. Hum Reprod 2006;21: 3217 3227. Balasch J, Peñarrubia J, Fábregues F, Vidal E, Casamitjana R, Manau D, Carmona F, Creus M, Vanrell JA. Ovarian responses to recombinant FSH or HMG in normogonadotrophic women following pituitary desensitization by a depot GnRH agonist for assisted reproduction. Reprod Biomed Online 2003;7:35 42. Bosch E, Valencia I, Escudero E, Crespo J, Simón C, Remohí J, Pellicer A. Premature luteinization during gonadotropin-releasing hormone antagonist cycles and its relationship with in vitro fertilization outcome. Fertil Steril 2003;80:1444 1449. Bosch E, Escudero E, Crespo J, Simón C, RemohíJ, Pellicer A. Serum luteinizing hormone in patients undergoing ovarian stimulation with gonadotropinreleasing hormone antagonists and recombinant follicle-stimulating hormone and its relationship with cycle outcome. Fertil Steril 2005;84:1529 1532. Cédrin-Durnerin I, Grange-Dujardin D, Laffy A, Parneix I, Massin N, Galey J, Théron L, Wolf JP, Conord C, Clément P et al. Recombinant human LH supplementation during GnRH antagonist administration in IVF/ICSI cycles: a prospective randomized study. Hum Reprod 2004;19:1979 1984. Coomarasamy A, Afnan M, Cheema D, van der Veen F, Bossuyt PM, van Wely M. Urinary hmg versus recombinant FSH for controlled ovarian hyperstimulation following an agonist long down-regulation protocol in 2350 IVF or ICSI treatment: a systematic review and meta-analysis. Hum Reprod 2008;23:310 315. Diedrich et al. European Israeli study group on highly purified menotropin versus recombinnant follicle-stimulating hormone. Efficacy and safety of highly purified menotropin versus recombinant follicle-stimulating hormone in in vitro fertilization/intracytoplasmic sperm injection cycles: a randomized, comparative trials. Fertil Steril 2002;78:520 528. Filicori M, Cognigni GE, Pocognoli P, Tabarelli C, Spettoli D, Taraborrelli S, Ciampaglia W. Modulation of folliculogenesis and steroidogenesis in women by graded menotropin administration. Hum Reprod 2002;17: 2009 2015. Gil-Salom M, Mínguez Y, Rubio C, De los Santos MJ, Remohí J, Pellicer A. Efficacy of intracytoplasmic sperm injection using testicular spermatozoa. Hum Reprod. 1995 1995;10:3166 3170. Goldfarb JM, Desai N. Follitropin-alpha versus human menopausal gonadotropin in an in vitro fertilization program. Fertil Steril 2003;80:1094 1099. Griesinger G, Schultze-Mosgau A, Dafopoulos K, Schroeder A, Schroer A, von Otte S, Hornung D, Diedrich K, Felberbaum R. Recombinant luteinizing hormone supplementation to recombinant follicle-stimulating hormone induced ovarian hyperstimulation in the GnRH-antagonist multiple-dose protocol. Hum Reprod 2005;20:1200 1206. Huirne JA, Homburg R, Lambalk CB. Are GnRH antagonists comparable to agonists for use in IVF? Hum Reprod 2007;22:2805 2813. Hompes PG, Broekmans FJ, Hoozemans DA, Schats R for the FIRM group. Effectiveness of highly purified human menopausal gonadotropin vs. recombinant follicle-stimulating hormone in first-cycle in vitro fertilizationintracytoplasmic sperm injection patients. Fertil Steril 2007. (4 August, Epub ahead of print). Jansen CA, van Os HC, Out HJ, Coelingh Bennink HJ. A prospective randomized clinical trial comparing recombinant follicle stimulating hormone (Puregon) and human menopausal gonadotrophins (Humegon) in non-down-regulated in-vitro fertilization patients. Hum Reprod 1998; 13:2995 2999. Kilani Z, Dakkak A, Ghunaim S, Cognigni GE, Tabarelli C, Parmegiani L, Filicori M. A prospective, randomized, controlled trial comparing highly purified hmg with recombinant FSH in women undergoing ICSI: ovarian response and clinical outcomes. Hum Reprod 2003;18:1194 1199. Kolibianakis EM, Zikopoulos K, Schiettecatte J, Smitz J, Tournaye H, Camus M, Van Steirteghem AC, Devroey P. Profound LH suppression after GnRH antagonist administration is associated with a significantly higher ongoing pregnancy rate in IVF. Hum Reprod 2004;19:2490 2496. Merviel P, Antoine JM, Mathieu E, Millot F, Mandelbaum J, Uzan S. Luteinizing hormone concentrations after gonadotropin-releasing hormone antagonist administration do not influence pregnancy rates in in vitro fertilization-embryo transfer. Fertil Steril 2004;82:119 125. Ng EH, Lau EY, Yeung WS, Ho PC. HMG is as good as recombinant human FSH in terms of oocyte and embryo quality: a prospective randomized trial. Hum Reprod 2001;16:319 325. Platteau P, Smitz J, Albano C, Sørensen P, Arce J-C, Devroey P. Exogenous luteinizing hormone activity may influence the treatment outcome in in vitro fertilization but not in intracytoplasmic sperm injection cycles. Fertil Steril 2004;81:1401 1404. Platteau P, Nyboe Andersen A, Balen A, Devroey P, Sørensen P, Helmgaard L, Arce J-C. Similar ovulation rates, but different follicular development with highly purified menotrophin compared with recombinant FSH in WHO group II anovulatory infertility: a randomized controlled study. Hum Reprod 2006;21:1798 1804. Rashidi BH, Sarvi F, Tehrani ES, Zayeri F, Movahedin M, Khanafshar N. The effect of HMG and recombinant human FSH on oocyte quality: a randomized single-blind clinical trial. Eur J Obstet Gynecol Reprod Biol 2005;120:190 194. Smitz J, Andersen AN, Devroey P, Arce JC. Endocrine profile in serum and follicular fluid differs after ovarian stimulation with HP-hMG or recombinant FSH in IVF patients. Hum Reprod 2007;22:676 687. Strehler E, Abt M, El-Danasouri I, De Santo M, Sterzik K. Impact of recombinant follicle-stimulating hormone and human menopausal gonadotropins on in vitro fertilization outcome. Fertil Steril 2001;75:332 336. The European and Israeli Study Group on Highly Purified Menotropin versus Recombinant Follicle-Stimulating Hormone. Efficacy and safety of highly purified menotropin versus recombinant follicle-stimulating hormone in in vitro fertilization/intracytoplasmic sperm injection cycles: a randomized, comparative trial. Fertil Steril 2002;78:520 528. van Wely M, Westergaard LG, Bossuyt PM, van der Veen F. Effectiveness of human menopausal gonadotropin versus recombinant follicle-stimulating hormone for controlled ovarian hyperstimulation in assisted reproductive cycles: a meta-analysis. Fertil Steril 2003;80:1086 1093.

Pregnancy outcome for hmg versus FSH with GnRH antagonists Westergaard LG, Erb K, Laursen SB, Rex S, Rasmussen PE. Human menopausal gonadotropin versus recombinant follicle-stimulating hormone in normogonadotropic women down-regulated with a gonadotropinreleasing hormone agonist who were undergoing in vitro fertilization and intracytoplasmic sperm injection: a prospective randomized study. Fertil Steril 2001;76:543 549. Ziebe S, Lundin K, Janssens R, Helmgaard L, Arce JC. Influence of ovarian stimulation with HP-hMG or recombinant FSH on embryo quality parameters in patients undergoing IVF. Hum Reprod 2007;22:2404 2413. Submitted on December 16, 2007; resubmitted on April 30, 2008; accepted on May 7, 2008 2351