Human Reproduction Update Advance Access originally published online on June 23, 2007
Human Reproduction Update 2007 13(5):445-452; doi:10.1093/humupd/dmm008
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Among patients treated with FSH and GnRH analogues for in vitro fertilization, is the addition of recombinant LH associated with the probability of live birth? A systematic review and meta-analysis
1 Unit for Human Reproduction, 1st Department of Obstetrics and Gynaecology, Aristotle University of Thessaloniki, Papageorgiou General Hospital, Nea Efkarpia Peripheral Road, Thessaloniki 54603, Greece 2 Department of Obstetrics and Gynaecology, University Clinic of Schleswig-Holstein, Campus Luebeck, Luebeck, Germany
3 Correspondence address. Tel, Fax: 2310414089; E-mail: stratis.kolibianakis{at}irg.gr
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Abstract |
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The aim of this systematic review and meta-analysis was to assess whether the addition of recombinant luteinizing hormone (LH) increases live birth rate, among patients treated with follicle stimulating hormone (FSH) and gonadotrophin-releasing hormone (GnRH) analogues for in vitro fertilization (IVF). Eligible studies were randomized controlled trials (RCTs) answering the research question that contained sufficient information to allow ascertainment of whether randomization was true and whether equality was present between the groups compared, regarding baseline demographic characteristics, gonadotrophin stimulation protocol, number of embryos transferred and luteal phase support administered. A literature search identified seven RCTs (701 patients) that provided the information of interest, among which five reported agonist and two antagonist cycles. The reported outcome measure, clinical pregnancy, was converted to live birth using published data in one study. No significant difference in the probability of live birth was present with or without rLH addition to FSH (odds ratio [OR]: 0.92, 95% confidence interval (CI): 0.65–1.31; P = 0.65). This finding remained stable in subgroup analyses that ordered the studies by dose of rLH added, the type of analogue used to inhibit premature LH surge, the time rLH was added during the follicular phase, the age of patients analysed, the presence of allocation concealment and by the way the information on live birth was retrieved. In conclusion, the available evidence does not support the hypothesis that the addition of recombinant LH increases the live birth rate in patients treated with FSH and GnRH analogues for IVF.
Key words: luteinizing hormone / GnRH agonists / GnRH antagonists / live birth rate
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Introduction |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionConflict of interestAcknowledgementsReferences |
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The role of endogenous LH levels during ovarian stimulation has attracted a lot of attention since the early in-vitro fertilization (IVF) years (Stanger and Yovich, 1985
; Howles et al., 1987; Thomas et al., 1989). At present, available evidence suggests that among women with normal ovulation or World Health Organization (WHO) II oligo-anovulation, low endogenous LH levels during ovarian stimulation for IVF using gonadotrophin-releasing hormone (GnRH) analogues are not associated with a decreased probability of ongoing pregnancy beyond 12 weeks (Kolibianakis et al., 2006). On the basis of these data, an adverse role of low endogenous LH levels on the probability of pregnancy cannot serve as a rationale for LH supplementation in ovarian stimulation for IVF. However, it cannot be excluded that LH supplementation during the follicular phase might be beneficial for pregnancy achievement, independently of any effect of endogenous LH levels. Several studies have so far evaluated the addition of recombinant LH (rLH) to FSH in ovarian stimulation for IVF (Table 1). Due to sample size restrictions, however, these individual studies are usually not conclusive as regards the effect of LH supplementation on pregnancy likelihood.
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The purpose of the current systematic review and meta-analysis was to summarize the available published evidence regarding the role of rLH addition in ovarian stimulation for IVF by answering the following clinical question: among patients treated with FSH and GnRH analogues for IVF, does the addition of rLH increase live birth rate?
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Materials and Methods |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionConflict of interestAcknowledgementsReferences |
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Identification of studies
In April 2006, a computerized literature search was performed on the bibliographic databases EMBASE, MEDLINE and CENTRAL without time limitations. Additionally, references of retrieved articles were hand-searched. The search strategy aimed at identifying randomized controlled trials (RCTs) on the basis of the following clinical question: among patients treated with FSH and GnRH analogues is the addition of rLH associated with the probability of live birth? Search terms used were ‘luveris’, ‘lutropin alfa’, ‘recombinant LH’ and ‘recombinant luteinizing hormone’. The search was limited to RCTs in humans. Meeting proceedings were not considered, since unpublished studies cannot be adequately evaluated for their design and quality. Moreover, it has been shown that although there is a considerable publication deficit in reproductive medicine for RCTs, there is no concomitant publication bias (Evers, 2000).
Criteria for inclusion/exclusion of studies were established prior to the literature search. Eligible studies were RCTs answering the research question that contained sufficient information to allow ascertainment of whether randomization was true and whether equality was present between the groups compared, regarding baseline demographic characteristics, gonadotrophin stimulation protocol, number of embryos transferred and luteal phase support (LPS) administered. An effort was made to contact all authors or sponsors of studies to retrieve missing or additional information.
Studies were excluded if no down-regulation was used for ovarian stimulation for IVF or if the gonadotrophin used for ovarian stimulation contained LH. Language of publication or number of patients analysed was not amongst the exclusion criteria.
Literature search yielded 74 studies that were potentially able to answer the research question. Further evaluation based on study titles and abstracts and/or assessment of full manuscripts resulted in 15 studies that evaluated the role of LH addition on the probability of live birth. Thirty-seven studies were excluded after screening the titles and a further 22 were excluded after screening the abstracts. The question of interest was answered in seven of these studies (Tables 1 and 2). Eight studies were excluded because a quasi-randomization was used for patient allocation (n = 2), because randomization method was unclear (n = 1), because, besides rLH addition, the dose of FSH was also modified at the same time (n = 3) or because problems occurred during the study period (n = 2) (Table 3).
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Data extraction
The following data were recorded from each of the studies in parallel by two of the authors (L.K., E.M.K.): demographic (type of study, country of origin and period of enrolment), methodological (randomization method, allocation concealment, randomization ratio, whether sample size calculation was performed), procedural (whether financial support was declared, number of patients included, type and protocol of ovarian stimulation, type of gonadotrophin administered, criteria for human chorionic gonadotrophin (hCG) administration and dose of hCG, type of fertilization, day of embryo transfer and type of luteal support administered) and outcome data (live birth rate, duration of stimulation, dose of FSH required, fertilization rate, number of cumulus–oocyte complexes (COCs) retrieved, estradiol (E2) and progesterone level on the day of hCG administration). Where standard deviation (SD) was not reported by the authors, it was calculated from the standard error of the mean (SEM). The values reported as SDs in the study by Fabregues et al. (2006) were considered as SEMs following communication with the authors. Any disagreement between the persons responsible for data extraction was solved by discussion.
Where live birth was not reported in a study that fulfilled the inclusion criteria, an effort was made to contact the corresponding authors to retrieve the missing information. If this was not possible, the reported outcome measure, clinical pregnancy, was converted to live birth using published data (84% probability of live birth after confirmation of clinical pregnancy with a living fetus at the 7th week of gestation) (Arce et al., 2005). This live birth equivalent was calculated in one study: Sauer et al. (2004). In addition, information was sought from the corresponding authors regarding live birth in patients who were randomized but did not start treatment within the study period. Where this information was not available (Griesinger et al., 2005), these patients were considered as not pregnant (n = 1).
The primary outcome variable was live birth rate per randomized patient (described as delivery rate in the study by Sills et al., 1999). Secondary outcome variables were clinical pregnancy rate, gonadotrophin consumption (per cycle); duration of stimulation (per cycle), E2 level on the day of hCG, progesterone level on the day of hCG, number of COCs retrieved (per cycle), fertilization rate (per cycle) and number of 2PN oocytes (per cycle).
Study features and results were assembled in tabular form, and a formal meta-analysis was performed. The dichotomous data results for each study were expressed as an odds ratio (OR) with 95% confidence intervals (CI). These results were combined for meta-analysis with Comprehensive Meta-analysis software (Biostat, 14 North Dean St, Englewood NJ 07631, USA), using the Mantel/Haenszel method. Live birth rate was calculated for each study per patient randomized.
When the outcome of interest was of a continuous nature, the differences were pooled across the studies that provided information on this outcome variable, resulting in a weighted mean difference (WMD) with 95% CI.
Study-to-study variation was assessed by using 
2 statistic (the hypothesis tested was that the studies are all drawn from the same population, i.e. from a population with the same effect size). A fixed effects model was used where no heterogeneity was present, whereas in presence of significant heterogeneity a random effects model was applied.
Subgroup analyses were carried out to check the stability of the main finding. These analyses ordered the studies according to the dose of rLH added (75 IU, 150 IU), the type of analogue used to inhibit premature LH surge (agonist, antagonist), the time rLH was added during the follicular phase (early follicular phase, mid-follicular phase), the age of patients analysed (>35 years of age, all ages), the type of allocation concealment (allocation concealed, concealment unknown) and according to the way the information on live birth was retrieved (reported by authors or calculated).
It was calculated that the optimal information size required to reject the null hypothesis (no difference in live birth rates between the two treatment groups) was 2504 subjects, assuming a clinically important difference of 5%, a baseline live birth rate of 25% and using beta 0.2, alpha 0.05 and a two-tailed hypothesis test.
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Results |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionConflict of interestAcknowledgementsReferences |
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Seven RCTs fulfilled the inclusion criteria and were included in the analysis with no disagreement noted between the authors responsible for study selection. Characteristics of the included studies are listed in Tables 1 and 2. All analysed studies were published between 1999 and 2006. The size of the studies ranged from 29 to 231 patients (median 114), whereas a total of 701 patients were analysed (FSH only: n = 354, FSH + rLH: n = 347). Characteristics of the patients included in these trials are shown in supplementary Table 1. Two studies were multicentre trials and all others were single-centre studies. In five studies, patient allocation was concealed, whereas in the remaining studies concealment of allocation had not been performed or was not reported.
All the studies were double arm with the exception of the study by Sauer et al. (2004). In this three-armed study, data were extracted for analysis from the study arms that provided the information with respect to the study research question.
Financial support by a pharmaceutical company was declared in four out of the seven analysed studies. Two out of the seven studies reported a power analysis aiming to detect differences in the probability of pregnancy achievement (Table 1).
To inhibit premature LH surges, agonists were used in five studies (leuprorelin: n = 2, daily triptorelin: n = 1, buserelin n = 2) and antagonists in two studies (cetrorelix daily: n = 1, single dose cetrorelix: n = 1).
For ovarian stimulation, one study used highly purified gonadotrophins, whereas the remaining studies used recombinant gonadotrophins. Criteria for triggering final oocyte maturation varied across studies and were based on follicular data (n = 4) or on a combination of follicular data and hormonal levels (n = 3). In three studies, recombinant hCG was used for triggering final oocyte maturation, whereas the remaining studies used urinary hCG (10 000 IU in three studies; 5000 IU in one study).
Fertilization methods included both IVF and intracytoplasmic sperm injection (ICSI). Embryo transfers were performed 2–5 days after oocyte retrieval. Luteal support varied between studies. The majority of the studies analysed used micronized progesterone for luteal support.
The OR for live birth was 0.92 (95% CI: 0.65 to 1.31, P = 0.65; heterogeneity: P = 0.39, fixed effects model), suggesting that the probability of live birth was not associated with the addition of rLH to FSH stimulation (Fig. 1). The rate difference was 1.5% in favour of the FSH only group (95% CI: –7.7 to +4.85, P = 0.65; heterogeneity P = 0.32, fixed effects model).
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Subgroup analyses of the likelihood of live birth ordered the studies by dose of rLH added (75 IU, 150 IU), the time rLH was added during the follicular phase (early follicular, mid-cycle), the category of analogue used for inhibition of premature LH surge (agonist, antagonist), the age of the patients analysed (all ages, >35 years of age), the type of allocation concealment (allocation concealed, concealment unknown) and the way the information on live birth was retrieved (reported by authors or calculated). As illustrated in Figures 2–3 and supplementary Figures 1–4 the difference in live birth rate between patients treated with FSH only and those treated with FSH + rLH remained not significant in all subgroup analyses. In none of these analyses was heterogeneity present, and thus a fixed effects model was used.
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In five studies, information was reported both for live birth and for clinical pregnancy. rLH addition was not associated with either the probability of clinical pregnancy (OR: 0.85, 95% CI: 0.57–1.26) or live birth (OR: 0.94, 95% CI: 0.62–1.43) in these studies.
Repeating the analysis with the three excluded quasi-randomized studies (Lisi et al., 2002; Cedrin-Durnerin et al., 2005; Toporcerova et al., 2005) sums 1414 patients and does not materially change the OR for live birth: 1.05 (95% CI: 0.82–1.36, P = 0.69; heterogeneity: P = 0.50, fixed effects model). The rate difference was 0.9% in favour of the FSH + LH group (95% CI: –3.7 to +5.5, P = 0.89; heterogeneity P = 0.39, fixed effects model).
The OR for clinical pregnancy in the included studies was 0.86 (95% CI: 0.61–1.20, P = 0.37; heterogeneity: P = 0.35, fixed effects model), suggesting that the probability of clinical pregnancy was not associated with the addition of rLH to FSH stimulation. The rate difference was 3.0% in favour of the FSH only group (95% CI: –9.5 to +3.5, P = 0.36; heterogeneity P = 0.34, fixed effects model).
FSH requirement
No significant difference was detected regarding the number of units of FSH required for ovarian stimulation in patients treated with FSH + rLH as compared with those treated with FSH only (WMD: +64.44 IU, 95% CI: –51.15 to +180.02; P = 0.27; heterogeneity: P = 0.69, fixed effects model). Six studies offered data for this outcome measure.
Duration of FSH stimulation
The duration of stimulation was not significantly different between patients treated with FSH + rLH as compared with those treated with FSH only (WMD: –0.04 days, 95% CI: –0.31 to +0.23; P = 0.77; heterogeneity: P = 0.19; fixed effects model). Seven studies offered data for this outcome measure.
E2 on the day of hCG administration
Serum E2 was not significantly higher in patients treated with FSH and rLH as compared with those treated with FSH only (WMD: +214.42 pg/ml, 95% CI: –107.93 to +536.78 P = 0.019; heterogeneity: P = 0.04; random effects model). Six studies offered data for this outcome measure.
Progesterone on the day of hCG administration
Only two studies offered data on the level of serum progesterone on the day of hCG, which was not significantly different between patients treated with FSH + rLH as compared with those treated with FSH only (WMD: +0.06 ng/ml, 95% CI: –0.18 to +0.29 P = 0.63; heterogeneity: P = 0.38; fixed effects model).
COCs retrieved
The number of COCs retrieved was not significantly different between patients treated with FSH + rLH as compared with those treated with FSH only (WMD: –0.57 COCs, 95% CI: –1.46 to +0.31 P = 0.21; heterogeneity: P = 0.42; fixed effects model). Seven studies offered data for this outcome measure.
Fertilization rate
Fertilization rate was not significantly different between patients treated with FSH + rLH as compared with those treated with FSH only (WMD: –4.15%, 95% CI: –9.24 to +0.93 P = 0.11; heterogeneity: P = 0.24; fixed effects model). This result is based on the analysis of four studies.
2PN oocytes
The mean number of 2PN oocytes was not significantly different between patients treated with FSH only and those treated with FSH and rLH (WMD: +0.03 2PN oocytes, 95% CI: –0.51 to +0.58; P = 0.90; heterogeneity: P = 0.38, fixed effects model). This result is based on the analysis of five studies.
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Discussion |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionConflict of interestAcknowledgementsReferences |
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The current systematic review suggests that, among patients treated with FSH and GnRH analogues for IVF, the addition of rLH does not increase live birth rate.
It has to be noted that this result should be viewed with caution since the optimal sample size, required to exclude a clinically significant difference, has not yet been reached. Thus the addition of further RCTs to examine the effect of adding rLH to FSH in ovarian stimulation for IVF is necessary. Nevertheless, the main finding of the current meta-analysis is supported by the fact that it remained stable in all subgroup analyses performed, whereas no significant heterogeneity was present between the RCTs analysed.
Interestingly, no trend for a beneficial effect of rLH addition was present depending on the dose of rLH added to FSH stimulation. As yet, an optimal dose of rLH has not been systematically assessed in normogonadotropic women (De Placido et al. 2004). The current evidence suggests that an improvement of the probability of live birth does not depend on the addition of either 75 or 150 IU of rLH.
In addition, the time that rLH addition was initiated during the follicular phase (early or mid-follicular), did not affect the probability of live birth. It should be noted that the three studies in which rLH was started during the early follicular phase did not favour such an intervention (Fig. 2). Finally, the type of down-regulation (agonist or antagonist) did not seem to modify the effect of rLH addition to FSH. The two studies performed using GnRH antagonists for down-regulation did not favour the addition of rLH to FSH.
In the current meta-analysis, one study out of the seven analysed reported only clinical pregnancy rates for the population analysed, whereas information on live birth was not available. In this study, live birth was calculated using published data (Arce et al. 2005). This choice was made in order to include this eligible trial in the current meta-analysis, since otherwise it would have to be ignored. The assumption for this calculation is that, following confirmation of clinical pregnancy, the probability of live birth is not different between patients that received rLH and those that did not receive rLH in addition to FSH. No published data exist to object to this assumption, which is further supported by the fact that no significant effect of rLH addition was detected either for clinical pregnancy or for live birth in the studies that reported both outcomes.
Regarding secondary outcomes no significant differences were observed between patients who received rLH and those who did not, which is in line with the non-significant difference observed in the probability of live birth.
In conclusion, the current review suggests that, among patients treated with FSH and GnRH analogues for IVF, the addition of rLH does not increase live birth rate. Moreover, the available evidence does not indicate a beneficial effect of rLH addition on secondary outcome variables.
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Conflict of interest |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionConflict of interestAcknowledgementsReferences |
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Dr G.G. and Dr B.C.T. are co-authors of two of the randomized controlled studies included in the current meta-analysis (Griesinger et al., 2005
; Tarlatzis et al., 2006).
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Acknowledgements |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionConflict of interestAcknowledgementsReferences |
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We would like to thank the following persons for their support in this work: G.G. (Luebeck, Germany), B.C.T. (Thessaloniki, Greece), J. Balasch (Barcelona, Spain), P. Humaidan (Copenhagen, Denmark), G. De Placido (Napoli, Italy), I. Cedrin-Durnerin (Paris, France), E.S. Sills (New York, USA), A.P. Ferraretti (Bologna, Italy), M. Sauer (New York, USA) P.E. Levi-Setti (Milan, Italy) and F. Fabregues (Barcelona, Spain).
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