Human Reproduction, Vol. 14, No. 9, 2207-2215,
September 1999
© 1999 European Society of Human Reproduction and Embryology
Recombinant versus urinary follicle stimulating hormone for ovarian stimulation in assisted reproduction
1 Departments of Obstetrics and Gynaecology and 2 Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada
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Abstract |
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The recent availability of recombinant follicle stimulating hormone (rFSH), with its high level of purity and batch-to-batch consistency has made it an attractive alternative to urinary FSH (uFSH) for ovarian stimulation. Several trials have compared the two preparations, but none had sufficient power to detect a clinically meaningful difference in pregnancy rates. The purpose of this study was to determine the clinical pregnancy rates per started cycle by pooling data from randomized trials which compared the use of rFSH and uFSH in treatment cycles using in-vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI). A thorough search of the literature identified 12 trials which met the inclusion criteria. In four trials, both IVF and ICSI were performed, in seven trials only IVF was performed and in one trial only ICSI was performed. Data were extracted and pooled using the principles of meta-analysis. There was no significant heterogeneity of treatment effect across the trials. The common odds ratio and the risk difference (and their 95% confidence intervals), obtained by pooling the data using a fixed effects model, were 1.20 (1.02–1.42) and 3.7% (0.5–6.9%) respectively, in favour of rFSH. The pregnancy rate with the alpha preparation of rFSH was statistically significantly higher than with uFSH in IVF cycles. The overall conclusion from this meta-analysis is that the use of rFSH in assisted reproduction is preferred over uFSH.
Key words: assisted reproductive technology/IVF/metaanalysis/recombinant FSH
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Introduction |
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TopAbstractIntroductionMaterials and methodsResultsFertilization procedureFollitrophin type and...Logistic regression analysisDiscussionReferences |
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The strategy of stimulating the ovaries with exogenous gonadotrophins to induce multifollicular development in women undergoing therapy with assisted reproduction techniques such as in-vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) is now well established. The role of follicle stimulating hormone (FSH) in this process is essential, whereas luteinizing hormone (LH) plays a relatively minor role. In fact, too much LH during the period of follicular development and in the periovulatory phase may have detrimental effects on reproductive outcome (Stanger and Yovich, 1985
; Howles et al., 1987; Homburg et al., 1988; Regan et al., 1990).
Human FSH is a glycoprotein hormone consisting of two non-co-valently linked, non-identical protein chains (
and ß subunits) to each of which are attached two complex carbohydrate structures. Endogenously secreted FSH consists of a family of isoforms with identical primary structures, but with variable composition of the carbohydrate side-chains and sialic acid residues (Chappel, 1995). This heterogeneity is responsible for differences in plasma half-life and consequent biological activity of the isoforms (Chappel, 1995).
Until recently, the main source of exogenous FSH was urine of postmenopausal women. Menotrophin [human menopausal gonadotrophin (HMG)], which consists of a mixture of FSH, LH and urinary proteins, was the first such preparation. Two decades later, a further refinement in the extraction process permitted the removal of LH by absorbing it onto an antibody column. The resulting urofollitrophin, although essentially devoid of LH activity, still contained urinary protein contaminants. Over the last decade, further advances in purification techniques, using monoclonal antibodies, enabled the extraction of FSH from urine to produce highly purified (HP) urofollitrophin from which all of the contaminant proteins and LH had been removed leaving only FSH activity. Recently, biotechnology has made available a recombinant preparation of FSH (rFSH), produced by inserting the genes encoding for and ß subunits of FSH into expression vectors that are transfected into a Chinese hamster ovary cell line (Howles, 1996). The use of mammalian cells for this purpose is necessary because glycosylation is required to ensure full biological activity of the protein (Howles, 1996). There are two rFSH preparations currently available for clinical use: follitrophin alpha, marketed as Gonal-F® by Ares-Serono, Geneva, Switzerland, and follitrophin beta, marketed as Puregon® or Follistim® by NV Organon, Oss, The Netherlands. Although both preparations have been developed using the same technique, the post-translation glycosylation process and purification procedures are not identical (Olijve et al., 1996). The purification procedure used for follitrophin alpha includes the use of immunochromatographic methods, whereas purification of follitrophin beta does not involve immunological methods (Olijve et al., 1996).
The purity and batch-to-batch consistency of rFSH makes it an attractive alternative to urinary FSH (uFSH). In a combined analysis of three randomized trials, rFSH was observed to be associated with a significantly higher pregnancy rate in IVF treatment cycles compared to urinary gonadotrophins (Out et al., 1997). However, in this study, the trials selected were limited to those in which follitrophin beta was used. Furthermore, in one of the trials, rFSH use was compared with HMG (Jansen and Van Os, 1996; Out et al., 1996). The observation that HMG is not as efficacious as FSH (Daya et al., 1995a,b; Daya, 1998) suggests that the inclusion of this trial is likely to have biased the overall conclusion of the combined analysis. Therefore, the purpose of this study was to review the evidence from all randomized trials comparing rFSH (both follitrophin alpha and follitrophin beta) with uFSH to evaluate the relative efficacy with respect to clinical pregnancy rates in treatment cycles with IVF or ICSI.
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Materials and methods |
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Identification of trials
Trials were identified using several search strategies. The Medline data base of the National Library of Medicine covering the period from 1990 to 1999 was searched on-line using medical subject (MeSH) headings `pregnancy', `gonadotrophin', and `fertilization in vitro', and publication type `randomized controlled trial'. The search was performed on titles, abstracts and key words of the listed articles.
The Excerpta Medica CD: Fertility data base, which contains publications in human reproduction and all publications in the Excerpta Medica Data base (Embase) related to obstetrics and gynaecology, was searched, covering the period 1985 to October 1998. The search was performed on titles and abstracts using `recombinant FSH', `IVF' and `randomized' as keywords.
The bibliographies of relevant publications and review articles were scanned, and abstracts of major scientific meetings from 1992 to 1999 were hand-searched. The Cochrane Menstrual Disorders and Subfertility Specialized Register was also searched. When necessary, authors of relevant abstracts were contacted for detailed data on their studies. Peer consultation was sought for any remaining articles. Finally, the pharmaceutical companies that manufacture the gonadotropin preparations were consulted for additional information.
Reports of clinical trials were selected only if they met the inclusion criteria and if the outcome information was provided in sufficient detail to enable the data to be pooled.
Study inclusion
This systematic review was limited to trials reporting random allocation to rFSH (either follitrophin alpha or follitrophin beta) or uFSH (either urofollitrophin or urofollitrophin HP) for ovarian stimulation in infertile women undergoing treatment with IVF or ICSI. Trials were included whether or not the stimulation protocol included pituitary down-regulation with gonadotrophin releasing hormone agonists (GnRHa). The primary outcome of interest was the clinical pregnancy rate (usually defined as a gestational sac seen by ultrasonography), which was calculated per treatment cycle commenced.
Validity assessment and data extraction
For many of the trials, additional information concerning the methods of the trial and the outcome data was obtained from the authors. The methodological quality of each trial was assessed using a predetermined scoring system consisting of eight criteria as shown in Table I. Each trial was assessed independently by two reviewers and ranked for its methodological rigor and its potential to introduce bias. The evaluation included how the randomization procedure was undertaken and whether it was concealed, the use of blinding, the presence of cointervention, the completeness of follow-up of trial subjects, whether a sample size calculation had been performed, whether a crossover design was used, in which case only data from the first period (i.e. before crossover) were admissible, and whether the unit of comparison was patient or treatment cycle. Any disagreement between the two reviewers was resolved by consensus whenever possible. In the event of persistent disagreement, a third reviewer was consulted. Data were extracted and checked for accuracy in a second review.
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Statistical analysis
The data on the outcome for each trial selected for inclusion in the analysis were extracted into two-by-two tables and summarized using the odds ratio (OR) and the risk difference. The OR was chosen because its mathematical properties allow for ease in combining data to provide an overall estimate of the effect size and in testing for statistical significance. The risk difference, which is a measure of the absolute treatment effect, was chosen because it is more easily understood by clinicians and more helpful for decision making when applying the results to clinical practice. It is calculated as a weighted (for sample size) mean difference in pregnancy rates between rFSH and uFSH. Statistical significance was established if, with a two-tailed test, P
0.05.
Effectiveness was evaluated using the Peto modification of the Mantel-Haenszel method (Mantel and Haenszel, 1959; Peto, 1987), which is a test of overall association across all trials. A test of the homogeneity of treatment effect across all trials was performed (Breslow and Day, 1980). A nonsignificant result (i.e. lack of heterogeneity) indicates that no trial has an OR that is statistically significantly worse or better than the overall common OR obtained by pooling the data. Only when homogeneity of treatment effect was confirmed were the data pooled using the fixed effects model, otherwise the random effects model was used.
A funnel plot (in which the effect estimate of each trial was plotted against the precision of the effect, calculated as the inverse of its standard error) was used to detect publication bias. The value of the funnel plot is based on the fact that precision in estimating the underlying treatment effect will increase as the sample size of the trial increases (Egger et al., 1997). Thus, results from small trials will have a wide scatter at the bottom of the scatter plot, the spread decreasing as the trials become larger. A symmetrically inverted funnel shape to the scatter plot indicates that publication bias is unlikely.
Subgroup analyses were performed to identify whether the two types of follitrophin (i.e. alpha or beta), and the two types of fertilization procedure (i.e. ICSI or IVF) had any effect on the overall combined result. The data were recoded according to these variables and subjected to logistic regression analysis to identify the model that best predicted clinical pregnancy per started cycle.
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Results |
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TopAbstractIntroductionMaterials and methodsResultsFertilization procedureFollitrophin type and...Logistic regression analysisDiscussionReferences |
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Trials included
Out of 17 trials identified, 12 met the selection criteria for this systematic review and were included in the analysis (O'Dea et al., 1993
; Alvino et al., 1995; Hedon et al., 1995; Out et al., 1995; RHFSG, 1995; Bergh et al., 1997; Manassiev et al., 1997; Andersen et al., 1998; Frydman et al., 1998; Franco et al., 1999; Lenton et al., unpublished results; Schats et al., unpublished results). The reasons for excluding the other five trials were as follows: no pregnancy outcome data were available in one of the trials (Fisch et al., 1995) despite several requests for the missing information from the authors; in one trial (Mantzavinos et al., 1998) it was determined, after contacting the authors, that the patients were not randomly allocated to treatment, as had been indicated in the abstract; two trials (Sunde et al., 1994; Mitchell et al., 1996) were excluded because they were part of a larger multicentre randomized trial (Out et al., 1995) which had already been selected for the present analysis; and one trial (Out et al., 1997) was a report of a combined analysis of three randomized trials, two of which have been included in this study (Hedon et al., 1995; Out et al., 1995) whereas the third was a comparison of rFSH with hMG. In four of the 12 included trials, additional data were available from the authors so that the outcomes for IVF and ICSI could be considered separately (Bergh et al., 1997; Frydman et al., 1998; Lenton et al., unpublished results; Schats et al., unpublished results). In one of these trials (Schats et al., unpublished results), a few patients underwent both IVF and ICSI treatment in the same cycle, and these were included as ICSI cycles. Thus, data from a total of 16 comparisons from 12 trials were available for analysis.
The validity scores for methodological rigour of the 12 trials included in the analysis are shown in Table II and indicate that most trials are of moderate to high grading based on the predetermined validity criteria used. The methodological details of these trials are listed in Table III. Apart from minor differences, the patient profiles were quite similar and representative of the infertile population requesting treatment, and the interventions used conform to the currently accepted standards of care. All trials used GnRHa in a long protocol as part of the ovarian stimulation regimen.
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Meta-analysis
Overall analysis
The overall meta-analysis included a total of 2875 cases, of which 1556 were allocated to rFSH and 1319 to uFSH. It can be seen from the OR tree of the trials, shown in Figure 1
, that the direction of the estimate of the treatment effect in all except two of the trials was in favour of rFSH. The OR for the 12 trials ranged from 0.83 to 2.27, but no individual estimate of treatment effect was statistically significant. There was no significant heterogeneity of treatment effect across all trials (Breslow–Day statistic = 7.5, P = 0.94). The common OR for clinical pregnancy per started cycle, obtained by pooling the data using a fixed-effects model, was 1.20 [95% confidence interval (CI), 1.02–1.42, P = 0.03] in favour of rFSH. The risk difference represented a 3.7% (95% CI, 0.5–6.9%) increase in clinical pregnancy rate per cycle started with rFSH, compared with uFSH.
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Subgroup analyses
After separating the data based on the type of fertilization procedure performed (i.e. IVF or ICSI) and the type of follitrophin administered (i.e. alpha or beta) several subgroup analyses were undertaken as shown below.
A funnel plot of the ORs for clinical pregnancy per cycle started, shown in Figure 2, demonstrates that the data are distributed along a symmetrical, inverted-funnel shape, indicating that publication bias was unlikely to be present. Although the median sample size of the trials was 160, the range extended from 55 to 981, with the number in all except two trials (Out et al., 1995; Schats et al., unpublished results) below 300. Thus, no trial was designed with adequate power to test the null hypothesis of no difference in pregnancy rates between the two gonadotrophin preparations.
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Follitrophin type
In the subgroup analyses by type of rFSH administered, there were nine trials (comprising 1639 cycles) representing 13 comparative assessments of follitrophin alpha with uFSH (Table IV
). There was no significant heterogeneity of treatment effect among the trials (Breslow–Day statistic 7.3, P = 0.84). The common OR was 1.21 (95% CI 0.97–1.51, P = 0.09) in favour of rFSH (Figure 3). The risk difference was 3.7% (95% CI, –0.5–7.9%).
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There were three trials (with an aggregate sample size of 1236 cycles) in which follitrophin beta was compared with uFSH. No significant heterogeneity of treatment effect was observed (Breslow-Day statistic 0.20, P = 0.91). The common OR was 1.19 (95% CI 0.93–1.53, P = 0.16) in favour of rFSH (Figure 3
and Table IV). The risk difference was 3.7% (95% CI, –1.5–8.8%). |
Fertilization procedure |
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TopAbstractIntroductionMaterials and methodsResultsFertilization procedureFollitrophin type and...Logistic regression analysisDiscussionReferences |
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Data for IVF were available from seven trials in which IVF was the only procedure performed, and from four trials in which the IVF cycles could be separated from the ICSI cycles. The aggregate sample size was 2308 cycles. There was no significant heterogeneity of treatment effect among the trials in which IVF was performed (Breslow–Day statistic 5.0, P = 0.89). The common OR was 1.26 (95% CI 1.05–1.52, P = 0.02) in favour of rFSH (Figure 3
). The risk difference was 4.4% (95% CI, 0.9–8.0%).
Data for ICSI were available from four trials in which the ICSI cycles could be separated from the IVF cycles, and from one trial in which ICSI was the only procedure performed. In the five trials in which ICSI was performed (with an aggregate sample size of 567 cycles), there was no significant heterogeneity of treatment effect (Breslow-Day statistic 1.4, P = 0.84). The common OR was 1.02 (95% CI, 0.72–1.45, P = 0.92) in favour of rFSH (Figure 3). The risk difference was 0.3% (95% CI, –7.4–7.9%).
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Follitrophin type and fertilization procedure |
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TopAbstractIntroductionMaterials and methodsResultsFertilization procedureFollitrophin type and...Logistic regression analysisDiscussionReferences |
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Among the trials in which IVF was performed, follitrophin alpha was used in eight (representing 1072 cycles) and follitrophin beta was used in three (representing 1236 cycles) (Table IV
). There were five trials (representing 567 cycles) in which ICSI was performed and in all of them follitrophin alpha was used (Table IV). Thus, no trials compared follitrophin beta with uFSH in patients undergoing treatment with ICSI. The common OR and the risk differences, together with their respective 95% CI, broken down by follitrophin type and fertilization procedure, are shown in Table V.
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Logistic regression analysis |
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TopAbstractIntroductionMaterials and methodsResultsFertilization procedureFollitrophin type and...Logistic regression analysisDiscussionReferences |
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The independent variables tested to determine which one(s) would enter the final model that predicted clinical pregnancy per cycle started were: fertilization procedure (IVF or ICSI), type of FSH (follitrophin alpha, follitrophin beta, urofollitrophin HP or urofollitrophin), source of FSH (recombinant or urinary) and GnRHa protocol (long follicular, long luteal or long unspecified). There were 2875 cases available for analysis. The variables that entered the model were fertilization procedure (F to enter 6.9, P = 0.009) and source of FSH (F to enter 6.2, P = 0.013). The clinical pregnancy rate was significantly higher when ICSI was performed, compared with IVF (OR 1.3, 95% CI 1.1–1.6). Similarly, rFSH was associated with a significantly higher clinical pregnancy rate, compared with uFSH (OR 1.2, 95% CI 1.1–1.5).
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Discussion |
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TopAbstractIntroductionMaterials and methodsResultsFertilization procedureFollitrophin type and...Logistic regression analysisDiscussionReferences |
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The overall conclusion from this meta-analysis of all the available randomized trials which compared rFSH and uFSH for ovarian stimulation in infertility treatment cycles is that the clinical pregnancy rate per cycle started is statistically significantly higher with rFSH. The total sample size on which this conclusion is based was 2875, which is large enough to demonstrate, with power of
0.8, a difference in clinical pregnancy rate of the size observed in this meta-analysis.
The possibility of publication bias influencing the results is a potential concern with any meta-analysis, and every effort has been made to identify all the trials that have been published and as many of the unpublished trials as is humanly possible. The funnel plot is a useful graphical assessment of the likelihood of publication bias being present (Egger et al., 1997). The scatter plot of the odds ratios from the trials in this review demonstrated a symmetrical, inverse-funnel shape (Figure 2), thereby providing reassurance that selective publication is unlikely to be a source of bias in this meta-analysis.
Although the patient profiles in the trials were relatively similar, and the IVF and ICSI procedures used were standard, there were differences in the type of gonadotrophin preparations administered. Two different types of follitrophin (i.e. alpha and beta) were compared with two different types of uFSH (i.e. urofollitrophin and urofollitrophin HP), thus producing four pair-wise comparisons. Subgroup analyses of each of these comparisons is not reliable because only one trial compared follitrophin beta with urofollitrophin HP (Andersen et al., 1998). Nevertheless, the common OR and risk differences for clinical pregnancy started per cycle for each of the comparisons are as follows: follitrophin alpha versus urofollitrophin (OR = 1.19, risk difference 2.9%), follitrophin alpha versus urofollitrophin HP, IVF cycles only (OR = 1.42, risk difference 6.1%), follitrophin beta versus urofollitrophin (OR = 1.21, risk difference 3.9%) and follitrophin beta versus urofollitrophin HP (OR = 1.10, risk difference 2.1%). Although some of the differences in the magnitude of these estimates of the treatment effect can be explained by the small number of trials in each comparison, an important factor to be considered is the FSH isoform heterogeneity among the various preparations.
Pituitary gonadotrophins secreted into the circulation consist of a mixture of gonadotrophin molecules with a similar peptide structure, but with wide differences in the carbohydrate moieties (Wide, 1997). When synthesized in the cell, the carbohydrate chains contain sites for the addition of negatively charged groups of either terminal sialic acid residues or sulphate. The number of negatively charged sialic acid and sulphate groups produces variability in the overall charge (as revealed by electrophoresis) of the isoforms. The physiological significance of the charge heterogeneity is not well understood, but is believed to influence the biological properties of the isoform, in terms of its metabolic clearance rate and endocrinological effects at the target organ (Wide, 1997). The less negatively charged (i.e. more basic) isoforms have a shorter half-life in the circulation, but have increased biological activity (Ulloa-Aguirre et al., 1988). In contrast, the more negatively charged (i.e. more acidic) forms have a longer half-life but lower bioactivity. These observations suggest that the biological activity of the pharmaceutical preparations of FSH also may be dependent on their charge distribution (Ulloa-Aguirre et al., 1988).
Based on chromatofocusing studies, the charge distribution patterns for follitrophin beta, urofollitrophin and urofollitrophin HP demonstrated that the amount of material with isoelectric point (pI) <4 was <24%, 40% and 74%, respectively (i.e. progressively more acidic) (Robertson, 1997). The two follitrophins had a similar pattern, except that follitrophin alpha contained glycoforms with a narrower pI band (i.e. 4–5) than follitrophin beta (3.5–5.5) (Robertson, 1997). Thus, if terminal charge pattern dictates in-vivo biological activity, the follitrophins should have greater activity than the urofollitrophins. Unfortunately, information on biological endpoints including oocyte quality, and amount of oestradiol production was not available consistently in all the trials in this meta-analysis, making it difficult to test this hypothesis. Instead, clinical pregnancy was used as a surrogate measure of biological activity. Interestingly, differences in outcome have been reported recently in randomized studies comparing the two follitrophins. The morphological quality of embryos (Phillips et al., 1999) and the number of `good embryos' obtained (Von During et al., 1999) were significantly higher with follitrophin alpha compared to follitrophin beta.
The ideal method of evaluating the relative efficacy of the four different gonadotropin preparations is to conduct a four-arm randomized trial with sufficient power and with several biological endpoints, including cycle performance characteristics, oocyte and embryo quality, and incidence of ovarian hyperstimulation syndrome, spontaneous abortion, clinical pregnancy and live birth. Until then, or until more comparative data become available to supplement the data in this meta-analysis, these results indicate that there is a statistically significant difference in clinical pregnancy rates when rFSH is compared with uFSH. This finding, and the knowledge that the recombinant preparations have batch-to-batch consistency, are free from urinary protein contaminants and have the potential of being produced in limitless quantities, indicate that rFSH is more appealing for clinical use than uFSH. A cost-effectiveness analysis is currently being undertaken to determine if there are additional advantages, in terms of cost savings, of using one preparation versus the other.
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Acknowledgments |
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We are grateful to the investigators of the included trials, who provided additional information to address our questions regarding their studies. We are also grateful to Dr Colin Howles, Ares–Serono, Geneva, Switzerland for making available data from trials recently conducted by E.Lenton in the UK and R.Schats in The Netherlands. We understand that these data are currently being prepared for publication.
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Notes |
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3 To whom correspondence should be addressed at: Department of Obstetrics and Gynaecology, McMaster University, 1200 Main Street West, Hamilton, Ontario, Canada L8N 3Z5
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References |
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TopAbstractIntroductionMaterials and methodsResultsFertilization procedureFollitrophin type and...Logistic regression analysisDiscussionReferences |
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Submitted on September 21, 1998; accepted on June 24, 1999.
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