Human Reproduction, Vol. 14, No. 11, 2709-2715,
November 1999
© 1999 European Society of Human Reproduction and Embryology
Comparison of two recombinant follicle-stimulating hormone preparations in in-vitro fertilization: a randomized clinical study
1 Infertility Clinic, The Family Federation of Finland, Kalevankatu 16, FIN-00100 Helsinki and 2 Departments I and II of Obstetrics and Gynaecology, University Central Hospital of Helsinki, Helsinki, Finland
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Abstract |
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A randomized comparison of two recombinant human follicle-stimulating hormone (recFSH) preparations (Gonal-F® and Puregon®) in ovarian stimulation for in-vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) was carried out at the Infertility Clinic of the Family Federation of Finland. A total of 348 women (aged 22–43 years) suffering from infertility due to miscellaneous causes was recruited. Of these, 344 underwent stimulation using equal starting doses (150 IU/day: Gonal-F® n = 164, Puregon® n = 158 or 300 IU/day: Gonal-F® n = 8, Puregon® n = 14) after down-regulation with intranasal buserelin from the mid-luteal phase. Similar clinical pregnancy rates were achieved with both preparations; 33.5% per cycle and 37.4% per embryo transfer (24.5% one-embryo and 75.5% two-embryo transfers, n = 147) with Gonal-F® (150 IU/day) and 32.9% per cycle and 36.4% per embryo transfer (30.1% one-embryo and 69.9% two-embryo transfers, n = 145) with Puregon® (150 IU/day). The ongoing cumulative pregnancy rates after frozen–thawed embryo transfer were 35.4% with Gonal-F® and 37.7% with Puregon®. Six cycles were cancelled because of a low response (three in each group). Similar numbers of oocytes were obtained in both groups; 13.0 with 150 IU/day and 6.1 with 300 IU/day Gonal-F®, and 12.4 with 150 IU/day and 7.1 with 300 IU/day Puregon®. The fertilization and cleavage rates and the incidence of moderate or severe ovarian hyperstimulation syndrome (Gonal-F®, 2.0% and Puregon®, 0.7%) were also similar. Gonal-F® and Puregon® were equally and highly effective in stimulation for IVF and ICSI.
Key words: embryo transfer/follicle-stimulating hormone/in-vitro fertilization/intracytoplasmic sperm injection/pregnancy rate
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Introduction |
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Urinary-derived gonadotrophins have successfully been used for induction of follicular growth for over 30 years. Recently, follicle stimulating hormone (FSH) preparations produced by recombinant DNA technology have become available and will eventually replace the existing urinary-derived compounds. By transfecting Chinese hamster cell lines with the human genes for FSH
and ß subunits, a highly pure (>99%) FSH preparation with bioactivity identical to that of native pituitary FSH without luteinizing hormone bioactivity has been developed (Olijve et al., 1996
; Shoham and Insler, 1996).
A number of studies comparing recombinant (rec) FSH and urinary-derived gonadotrophins administered for ovulation induction (Coelingh Bennink et al., 1998; Messinis et al., 1998), or in women undergoing assisted reproduction techniques (Hedon et al., 1995; Out et al., 1995; Recombinant Human FSH Study Group, 1995; Aboulghar et al., 1996; Ubaldi et al., 1996; Bergh et al., 1997; Jansen et al., 1998), have been performed. In most (Hedon et al., 1995; Out et al., 1995; Aboulghar et al., 1996; Ubaldi et al., 1996; Bergh et al., 1997; Jansen et al., 1998) but not in all studies (Recombinant Human FSH Study Group 1995), recFSH appeared to be more effective than urinary FSH. Significantly higher numbers of follicles were recruited, oocytes collected and embryos obtained after a shorter duration of treatment with a lower total dose of recFSH. Clinical pregnancy rates in recFSH cycles have been comparable (Hedon et al., 1995; Out et al., 1995; Aboulghar et al., 1996; Ubaldi et al., 1996; Bergh et al., 1997), or even higher (Out et al., 1997; Jansen et al., 1998) than in cycles with urinary FSH when frozen–thawed embryo replacement cycles were included.
Two recFSH preparations with slightly different carbohydrate compositions are currently on the market, follitropin (Gonal-F®; Ares Serono, Geneva, Switzerland) and follitropin ß (Puregon®; NV Organon, Oss, the Netherlands). It has been proposed that differences in the isoform profiles of the two recFSH preparations could influence their clinical effectiveness (de Leeuw et al., 1996; Olijve et al., 1996; Shoham and Insler, 1996). However, information about the possible superiority of one or the other is still under debate.
Controversy exists as regards the appropriate dose of gonadotrophin to be used to induce multiple follicular development but at the same time to avoid ovarian hyperstimulation syndrome (OHSS). Currently, starting doses of 150 IU/day or 225 IU/day are widely used. However, in the light of the possibly higher bioactivity of recFSH over urinary FSH (Out et al., 1995; Bergh et al., 1997; Coelingh Bennink et al., 1998; Devroey et al., 1998; Jansen et al., 1998), a lower dose may be appropriate, at least in women at a high risk of OHSS.
We designed an assessor-blind, randomized study to compare the efficacy of the two recFSH preparations for stimulating multiple follicular development in women undergoing conventional in-vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI). Furthermore, we evaluated the total ongoing pregnancy rates, including frozen–thawed embryo replacement cycles.
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Materials and methods |
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Between July 1997 and September 1998, 348 women undergoing ovarian stimulation for IVF or ICSI were recruited to the study, with the approval of the local ethics committee. The women were aged between 22 and 43 years, had a body mass index (BMI) <35 kg/m2 and had regular menstrual cycles of 25–35 days. Indications for IVF and ICSI included tubal factors, moderate or severe endometriosis, other female factors (including ovulation disorders), male factors [<1.0x106 motile spermatozoa after preparation and/or fewer than 2% spermatozoa with normal morphology according to World Health Organization (WHO) criteria], combined male and female factors and unexplained factors. Women with a previous history of severe OHSS were excluded from the study.
Pituitary down-regulation with buserelin (Suprecur®, Hoechst Ab, Frankfurt, Germany, 900 µg/day intranasally) was started 1 week before an expected menstrual period. After 2 weeks, down-regulation was confirmed by the absence of ovarian follicles >12 mm in diameter, endometrial thickness <5 mm (both layers) in vaginal ultrasonographic examination and/or serum oestradiol concentration <0.2 nmol/l. If pituitary down-regulation was not achieved within 2 weeks, the dose of buserelin was increased to 1200 µg/day intranasally.
Patients were randomly allocated to ovarian stimulation with either Gonal-F® or Puregon® according to a computer-generated randomization list. The medication was given in a blind fashion for the administering physician. Both drugs were administered by daily subcutaneous injections at a starting dose of 150 IU. In women with a poor response (fewer than five follicles) in the previous treatment cycle, the starting dose was 300 IU/day. Simultaneously with the start of recFSH treatment, the dose of buserelin was reduced (450 µg/day) and gonadotrophin-releasing hormone agonist (GnRHa) was administered until the day of human chorionic gonadotrophin (HCG) injection. After 5 days, the dose of recFSH was adjusted according to serum oestradiol measurements and vaginal ultrasound examinations. HCG (5000 IU; Profasi®, Ares Serono in the Gonal-F® group and Pregnyl® in the Puregon® group) was given when the three largest follicles exceeded 18 mm in diameter.
Ultrasound-guided transvaginal follicle aspiration was performed 36–38 h after HCG injection. The oocytes were cultured in Medi-Cult Universal IVF Medium (Medi-Cult A/S, Copenhagen, Denmark) and fertilized in vitro (Moilanen et al., 1999). The meiotic stage of all oocytes was assessed 17–20 h after insemination.
For ICSI, the cumulus cells were removed and assessment of the meiotic maturation stage was made. Only MII-stage oocytes were injected. The presence of two pronuclei (PN) and polar bodies was confirmed 17–20 h after insemination or after microinjection. The cleavage state of the normally fertilized oocytes was assessed 48 h after retrieval. Embryo morphology was assessed as previously described by Veeck (Veeck, 1991): grade 1: no anucleate fragments, symmetrical blastomeres; grade 2: fragmentation <10% of volume; grade 3: 10–20% fragmentation; grade 4: 20–60% fragmentation (Veeck, 1991). One or two embryos were replaced 2 or 3 days after oocyte retrieval.
Supernumerary embryos were frozen at either the PN or cleavage stage using a slow freezing–thawing protocol with 1.5 mol/l 1,2-propanediol and 0.1 mol/l sucrose as cryoprotectants in a programmable cryomachine (Kryo 10 Series II, Planer Products Ltd, Sunbury-on-Thames, UK) with manual seeding at –8°C.
Luteal support was provided for 3 weeks by giving 600 mg micronized vaginal progesterone daily (Lugesteron®, Leiras, Turku, Finland). Serum HCG was assessed 14 days after embryo transfer. If the pregnancy test result was positive, the viability of the pregnancy was assessed by transvaginal ultrasonographic (TVS) examination 4–5 weeks after embryo transfer. Clinical pregnancies were defined gestations with observable embryonic sacs on TVS.
For frozen embryo transfer, the embryos were thawed either on the previous day of replacement or on the day of replacement by warming and gradual removal of the propanediol and sucrose. The embryos were then replaced either during a natural cycle or during hormone replacement treatment using buserelin combined with exogenous oestradiol and progesterone [Suprecur® 450 (Hoechst, Frankfurt, Germany) intranasally, Progynova®, 4–6 mg/day (Schering, Berlin, Germany), Lugesteron®, 600 mg/day)].
According to power analysis, to confirm better efficacy of either recFSH preparation a difference of more than three in the mean number of oocytes collected per subject had to be demonstrated. Hence, a study population of 282 women was calculated to be necessary to reveal the better efficacy of either recFSH preparation as regards the number of oocytes retrieved, with 95% probability.
Hormone assays
Serum oestradiol concentrations were measured using solid phase fluoroimmunoassay (Delfia, Wallac, Turku, Finland). The intra- and inter-assay coefficients of variation were 3.8–10.0% and 3.6–9.7% respectively.
The results are expressed as mean ± SEM. Data comparisons between the study groups were made by 
2 test and by analysis of variance after logarithmic transformation when appropriate.
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Results |
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In total, 348 women were recruited to the study before the beginning of down-regulation. In one subject the treatment was discontinued because of an endometriotic cyst in the ovary. Three subjects did not become down-regulated and they were excluded from the study. Of the remaining 344 subjects, 172 were randomized to the Gonal-F® (starting dose 150 IU/day n = 164; starting dose 300 IU/day n = 8) and 172 to the Puregon® group (starting dose 150 IU/day n = 158; starting dose 300 IU/day n = 14, Figure 1
). ICSI was performed in 31.4% of treatment cycles with Gonal-F® and in 26.7% with Puregon® (not significant).
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Both study groups were comparable in respect to the age of the female partner, parity, duration and cause of infertility, the number of previous treatment cycles and basal FSH concentrations on day 3–5 of the menstrual cycle taken within 6 months before the treatment cycle (Table I
).
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Of the 344 treatment cycles, six (three in the Gonal-F® 150 IU/day group, two in the Puregon® 150 IU/day group and one in Puregon® 300 IU/day group) were cancelled because there was a monofollicular ovarian response. After 5 days of treatment, the recFSH dose was adjusted according to the ovarian response. In 19 women (11.6%) on Gonal-F® at 150 IU/day and in 13 (8.2%) on Puregon® at 150 IU/day the dose was increased (not significant). The dose was decreased in 10 high responders (6.1%) in the Gonal-F® group and in 12 (7.6%) in the Puregon® group (not significant). In women receiving recFSH at 300 IU/day, no change in the dose of recFSH was required.
No significant differences emerged between the Gonal-F® and Puregon® groups according to the starting dose with respect to serum oestradiol concentrations on days 6 and 9, in endometrial thickness or in the number of recruited follicles of 
12 mm in diameter on day 9 of the recFSH treatment (Table II). The mean duration of stimulation and the total amount of recFSH medication used were comparable. No significant differences were observed in the mean number of oocytes collected in the Gonal-F® or Puregon® groups (starting dose 150 IU/day: 13.0 ± 0.7 versus 12.4 ± 0.7, not significant; starting dose 300 IU/day: 6.1 ± 1.6 versus 7.1 ± 1.1, not significant, Table II).
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Women who needed an increase in dose exhibited lower concentrations of oestradiol throughout the stimulation period, a smaller cohort of follicles of
12 mm in diameter and thinner endometrium on day 9 of recFSH stimulation than those who continued at 150 IU/day throughout the stimulation period. The duration of recFSH stimulation was significantly longer and the total amount of FSH medication used was higher in the poor responders who needed an increased dose compared with normal responders (Table III). This poor response to stimulation resulted in significantly lower numbers of oocytes in women receiving Gonal-F® (6.6 ± 1.0 versus 12.9 ± 0.6, P < 0.001) or Puregon® (5.9 ± 0.8 versus 12.8 ± 0.7, P < 0.001) than in normal responders.
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In high responders, the mean duration of stimulation was comparable to that in normal responders but significantly less recFSH was required for follicular maturation than in subjects using the standard dose of 150 IU/day (Table III
). The large number of recruited follicles of 12 mm in diameter in these women was associated with high serum oestradiol concentrations on treatment days 6 and 9 and high mean numbers of oocytes recovered (Table III).
The proportion of mature oocytes was similar in the Gonal-F® and Puregon® groups, as were the rates of normal fertilization and embryo cleavage (Table IV). No overall differences were observed between IVF and ICSI cycles in the rates of 2PN formation or the number of cleaved embryos (data not shown). The medication used did not affect the grades of embryos or the proportion of fast dividing embryos in IVF or ICSI (data not shown).
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Failure to proceed to embryo transfer in the Gonal-F® group (n = 14, starting dose 150 IU/day) was due to no oocytes obtained in one subject, fertilization failure in eight subjects (six IVF and two ICSI), risk of developing OHSS in four subjects and bacterial contamination of the embryo culture medium in one subject. In the Puregon® group (n = 11, starting dose 150 IU/day), failure to proceed to embryo transfer was due to no HCG administration in one subject, absence of fertilization in four subjects undergoing IVF, risk of developing OHSS in four women and personal reasons in two. In women receiving recFSH at 300 IU/day, embryo transfer was not performed in one woman in both recFSH groups as a result of fertilization failure (Figure 1
).
With the starting dose of 150 IU/day, 89.6% of subjects underwent embryo transfer in the Gonal-F® group and 91.8% in the Puregon® group. With the starting dose of 300 IU/day, the respective percentages were 87.5 and 92.3%. One or two embryos were replaced each time. Elective one-embryo transfers accounted for 24.5% of transfers in the Gonal-F® group (starting dose 150 IU/day) and 30.1% of transfers in the Puregon® group (starting dose 150 IU/day). The implantation rates per embryo replaced were 25.6 and 26.3% respectively (not significant). The clinical pregnancy rates per started cycle in the Gonal-F® and Puregon® groups were 33.5 versus 32.9%, and per embryo transfer, 37.4 versus 36.4% (not significant). Of these pregnancies, eight (14.5%) in the Gonal-F® group (starting dose 150 IU/day) and five (9.6%) in the Puregon® group (starting dose 150 IU/day) ended in miscarriage. Two pregnancies in both groups were ectopic. Seven of the 45 (15.6%) ongoing pregnancies in the Gonal-F® group were twin pregnancies, and there were nine (20.0%) among the 45 ongoing pregnancies in the Puregon® group (Figure 1). None of the women receiving Gonal-F® at 300 IU/day became pregnant, whereas in the Puregon® group two singleton ongoing pregnancies were achieved (Figure 1). Considering the morphology of the best embryo transferred, 90.4 and 91.7% of the pregnancies in the Gonal-F® and Puregon® groups occurred when grade 1–2 embryos were transferred (not significant). Similar good pregnancy results were shown when on day 2 the fastest dividing embryo was in the 4-cell stage (76.9 versus 79.2%, not significant). Of all 79 single embryo transfers performed, 25 (31.6%) resulted in clinical and 19 (24.1%) in ongoing pregnancies.
Supernumerary embryos were frozen in 63.8% of the treatment cycles with Gonal-F® (starting dose 150 IU/day) and in 69.1% of those with Puregon® (starting dose 150 IU/day) (not significant). In women receiving 300 IU/day, embryo freezing was carried out in 28.6% and 50.0% of the cycles with Gonal-F® and Puregon® respectively. So far, 189 frozen embryos have been thawed in connection with 55 women receiving Gonal-F® and 216 embryos in connection with 62 women receiving Puregon®. The survival of embryos after thawing was comparable in both groups (84.0% in the Gonal-F® group and 79.7% in the Puregon® group, not significant). Implantation rates were 15.9% for frozen–thawed embryos after Gonal-F® and 9.1% after Puregon® stimulation (not significant). Of the 19 clinical pregnancies that resulted from frozen–thawed embryo transfer cycles in the Gonal-F® group, 13 (68.4%) are ongoing. Similarly, of the 16 pregnancies in the Puregon® group, 15 (93.8%) have progressed beyond 16 weeks of gestation. Ongoing pregnancy rates per started stimulation, when frozen embryo transfers were included were 35.4% in the Gonal-F® 150 IU/day group, and 37.7% in the Puregon® 150 IU/day group (not significant).
Mild abdominal swelling and discomfort was observed in 13 women (7.9%) in the Gonal-F® group and in 12 (7.5%) in the Puregon® group. These women were followed up as outpatients. Of the 13 women in the Gonal-F® group, 12 underwent embryo transfer and nine became pregnant. Similarly, of the 12 women in the Puregon® group, nine underwent embryo transfer and four became pregnant. Four women (2.0%) in the Gonal-F® group and one in the Puregon® group (0.7%) needed hospital treatment for moderate or severe OHSS. Only one of these women underwent embryo transfer and she did not become pregnant. Of the five women with OHSS, three later became pregnant after frozen–thawed embryo replacement. All cases of moderate OHSS occurred in women whose recFSH dose was decreased.
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Discussion |
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The results of previous studies have confirmed either similar (Hedon et al., 1995
; Out et al., 1995; Aboulghar et al., 1996; Ubaldi et al., 1996; Bergh et al., 1997), or increased (Out et al., 1997; Jansen et al., 1998) efficacy of human recFSH over urinary menopausal gonadotrophins in terms of number of oocytes retrieved, embryos obtained and embryos cryopreserved. Furthermore, pregnancy rates in association with recFSH have been similar to or even higher than those associated with urinary FSH preparations when replacement of frozen–thawed embryos has been included. The reason for this higher effectiveness of recFSH over urinary FSH preparations is not known, but it may involve subtle differences at the level of oligosaccharide moieties and isohormone composition of recFSH over urinary FSH (Olijve et al., 1996; Shoham and Insler, 1996). In this study we were able to confirm that both Gonal-F® and Puregon® were equally effective in inducing multiple follicular growth.
The two recFSH preparations currently in use have undergone slightly different purification procedures and are therefore not identical. Although exact molecular differences between the two recFSH hormones have not been determined, both Gonal-F® and Puregon® show slightly more basic FSH isoform profiles than seen with urinary FSH preparations. This, in turn, may bring about differences in their biological activities and clinical effectiveness (Olijve et al., 1996; Shoham and Insler, 1996). This possibility is supported by the lower oestradiol concentrations and a lower number of follicles >14 mm in diameter on the day of HCG administration in a study comparing Gonal-F® with urinary FSH (Recombinant FSH Study Group, 1995). These findings are clearly in disagreement with those from a larger study comparing Puregon® with urinary FSH (Out et al., 1997; Jansen et al., 1998). Recent studies, however, comparing Gonal-F® with highly purified urinary FSH in a large number of subjects confirmed the higher efficacy of Gonal-F® over urinary preparations (Bergh et al., 1997).
In the present prospective, randomized study we were able to show that Gonal-F® and Puregon® were equally effective in terms of number of oocytes collected, the quality and number of embryos obtained, embryos frozen as well as in ongoing pregnancy rates per cycle (including fresh and frozen–thawed cycles). It therefore appears that subtle changes in carbohydrate structure are not reflected in clinical efficacy. Cumulative pregnancy rates are a good indicator of the efficacy of the treatment given, particularly when only a small number of embryos are replaced during one cycle. It is also clear from our study that the availability of a large number of good quality embryos for cryopreservation will ultimately improve the couple's chances for conception.
Multiple pregnancies accompany IVF and ICSI, as approximately every fifth pregnancy is a twin pregnancy (Wennerholm et al., 1991; Rufat et al., 1994; Söderström-Anttila et al., 1998). The rates of perinatal mortality and fetal and maternal complications are higher in twin pregnancies than in singleton pregnancies and the incidence of adverse outcome rises with an increasing number of multiples (Wennerholm et al., 1991; Rufat et al., 1994; Söderström-Anttila et al., 1998). The current policy of replacing two instead of three embryos in Nordic countries has resulted in a reduction of high order multiple pregnancies but not in twin pregnancies, without affecting the pregnancy rates (Bergh et al., 1997; Moilanen et al., 1999). A radical strategy to reduce the rate of multiple births would be to replace only one embryo. Recent evidence indicates that elective transfer of only one embryo results in acceptable pregnancy rates, particularly in women who have more than one good quality embryo for transfer (Vilska et al., 1999). This is also evident from the results of the present study as approximately one-third of fresh embryo transfers were elective one-embryo transfers, and a third of these transfers resulted in clinical pregnancy. We therefore recommend one-embryo transfer when good quality embryos are available and the couple is undergoing their first or second IVF or ICSI treatment.
OHSS is a potentially life-threatening complication accompanying up to 7%, usually 0.5–2.0%, of all IVF or ICSI cycles (Bergh and Lundqvist, 1992; Bergh et al., 1997; Out et al., 1997; Orvieto and Ben-Rafael, 1998). High oestradiol concentrations on the day of HCG administration and a high number of follicles aspirated have been associated with an increased risk of developing OHSS (Orvieto and Ben-Rafael, 1998). Despite the high number of follicles recruited and the high serum oestradiol concentrations seen in this study the incidence of moderate or severe OHSS requiring hospitalization was comparable to that seen in previous studies using either recFSH or urinary FSH preparations (Bergh et al., 1997; Out et al., 1997; Orvieto and Ben-Rafael, 1998). Cancellation of the cycle before HCG administration, or withholding embryo replacement and elective cryopreservation of all embryos, has been recommended in subjects at great risk of OHSS (Rizk and Aboulghar, 1991). We chose the latter strategy. Our choice did not reduce the incidence of OHSS but it may have lessened its severity, since precipitation of OHSS by HCG produced by the trophoblast was avoided. Furthermore, our results confirmed the experience (Tiitinen et al., 1995) that pregnancy rates after subsequent replacement of frozen–thawed embryos are good. Moderate and severe forms of OHSS in the present study occurred in women who needed a decrease in the dose of recFSH. In this subgroup, the use of a lower dose may have prevented unwanted over-stimulation (Devroey et al., 1998; Out et al., 1999). Nevertheless, careful monitoring is essential in preventing OHSS.
In conclusion, the present results clearly demonstrate that Gonal-F® and Puregon® are equally effective and safe in producing multiple follicular growth and provide good chances of pregnancy in a single treatment cycle.
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Acknowledgments |
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The study was supported by a grant from Helsinki University Central Hospital Research Fund. We thank Ms Ingemo Törnroos for typing the manuscript.
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3 To whom correspondence should be addressed
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References |
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Submitted on March 29, 1999; accepted on August 12, 1999.
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J. Harlin, A. Aanesen, G. Csemiczky, H. Wramsby, and G. Fried Delivery rates following IVF treatment, using two recombinant FSH preparations for ovarian stimulation Hum. Reprod., February 1, 2002; 17(2): 304 - 309. [Abstract] [Full Text] [PDF]
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H. J. Out, S. Daya, and J. Gunby Meta analysis on rFSH versus uFSH Hum. Reprod., March 1, 2001; 16(3): 593 - 595. [Full Text] [PDF]
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