Human Reproduction Update Advance Access originally published online on August 25, 2005
Human Reproduction Update 2006 12(1):3-12; doi:10.1093/humupd/dmi030
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Are endogenous LH levels during ovarian stimulation for IVF using GnRH analogues associated with the probability of ongoing pregnancy? A systematic review
1 Department of Obstetrics and Gynaecology, Unit for Human Reproduction, Aristotle University of Thessaloniki, Thessaloniki, Greece, 2 McMaster University, Hamilton, Ontario, 3 Dalhousie University, Halifax, Nova Scotia, Canada and 4 Centre for Reproductive Medicine, Dutch-Speaking Brussels Free University, Brussels, Belgium
5 To whom correspondence should be addressed at: Unit for Human Reproduction, Papageorgiou General Hospital, Nea Efkarpia Peripheral Road, Thessaloniki 54603, Greece. E-mail: stratis.kolibianakis{at}otenet.gr
Submitted on June 6, 2005; revised on July 5, 2005; accepted on July 18, 2005.
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Abstract |
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The aim of this systematic review was to evaluate, among women with normal ovulation or World Health Organization (WHO) II oligoanovulation who undergo ovarian stimulation for IVF using GnRH analogues, whether endogenous LH levels predict the likelihood of ongoing pregnancy beyond 12 weeks. A literature search identified six studies that answered the research question, among which two were prospective studies (one in GnRH agonist and one in GnRH antagonist cycles). None of the retrospective studies suggest that low endogenous LH levels are associated with a significantly decreased probability of ongoing pregnancy beyond 12 weeks in such patients. In the two prospective studies high endogenous LH levels during down-regulation were associated with a decreased probability of ongoing pregnancy beyond 12 weeks. Until further prospective studies modify the existing evidence summarized here, an adverse effect of low endogenous LH levels on the probability of ongoing pregnancy beyond 12 weeks is not a sensible rationale for LH supplementation during ovarian stimulation for IVF using GnRH analogues.
Key words: GnRH agonists / GnRH antagonists / luteinizing hormone / ongoing pregnancy rate
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Introduction |
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The role of endogenous LH during ovarian stimulation for IVF has been controversial since the pre-GnRH analogue era (Stanger and Yovich, 1985
; Howles et al., 1987; Thomas et al., 1989). Following the introduction of analogues, interest focused mainly on whether low LH levels were associated with impaired IVF outcome.
LH levels may be deeply suppressed after pituitary down-regulation for IVF, simulating the endocrine environment encountered in World Health Organization (WHO) I patients. The rationale for LH supplementation in WHO I patients is clear (The European Recombinant Human LH Study Group, 1998); however, it cannot serve as a basis for LH supplementation in normo-ovulatory or WHO II patients. In theory, if low endogenous LH levels are associated with a decreased probability of ongoing pregnancy, then LH supplementation might be indicated and its value should be assessed in randomized-controlled trials. On the other hand, if there is no association between LH and the probability of ongoing pregnancy or if low endogenous LH levels are associated with increased ongoing pregnancy rates, then there is no justification for considering LH supplementation in normo-ovulatory or WHO II patients.
Studies that address the association between LH levels and IVF outcome have measured LH levels on various days during ovarian stimulation and made use of different outcome measures. The outcomes include dose of FSH (Humaidan et al., 2002), estradiol levels on the day of HCG (Fleming et al., 1998), the number of fertilized oocytes (Humaidan et al., 2002), fertilization rates (Esposito et al., 2001), the number of cryopreserved embryos (Fleming et al., 1998) and the developmental potential of cryopreserved embryos (Rekha et al., 1998). To assess whether LH is truly an effector or predictor of IVF outcome in normo-ovulatory or WHO II patients, however, the outcome measure should be live birth, or it’s near-equivalent, ongoing pregnancy. The surrogate outcome measures listed above are not securely associated with live birth.
The purpose of this systematic review is to assess, among normo-ovulatory or WHO II patients undergoing ovarian stimulation in GnRH analogue IVF cycles, whether endogenous LH levels predict ongoing pregnancy beyond 12 weeks.
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Materials and methods |
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Identification of studies
A literature search was performed using MEDLINE and the Cochrane Library. Additionally, references of retrieved articles were hand-searched. The search strategy was based on the following clinical question: among normo-ovulatory or WHO II patients undergoing ovarian stimulation for IVF using GnRH analogues, do endogenous LH levels predict the likelihood of ongoing pregnancy? Ongoing pregnancy was defined as a pregnancy proceeding beyond 12 weeks of gestation. This was considered the most relevant outcome measure, especially in view of existing evidence suggesting an association between endogenous LH levels and early pregnancy loss (Westergaard et al., 2000). The search terms used in both databases were LH and pregnancy/IVF/assisted reproductive technologies (ART)/ovarian stimulation/oocytes/reproduction/embryos.
Meeting proceedings were not considered, because 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 RCT, there is no concomitant publication bias (Evers, 2000).
All published studies addressing the research question were initially considered for this review regardless of the direction of study (retrospective or prospective), the sample size or the day endogenous LH levels were assessed during ovarian stimulation. The next step selected only studies in which ovarian stimulation was performed for IVF using gonadotrophins containing no LH, regardless of the analogue used. Studies were excluded if no down-regulation was used for ovarian stimulation for IVF or if LH levels were assessed only before the initiation of stimulation. If the reported outcome measure (pregnancy rate) was not ongoing pregnancy rate beyond 12 weeks, the study was labelled as ‘pregnancy not as defined’, and these studies are described separately in this report. For those studies identified in which the outcome measure was not clearly defined, the corresponding authors were contacted and the information was retrieved where this was possible.
The first study describing the use of agonists in IVF appeared in the literature in 1984, by Porter et al. Literature search, after 1984, and hand search of the retrieved articles resulted in 416 studies that were potentially able to answer the research question. Of these articles, 78 papers were identified for further evaluation based on their titles and abstracts. Finally, 34 manuscripts were selected for full text review of which 24 manuscripts were excluded from the current review because they did not address the research question (n = 9), were review articles (11) or letters to editors (1), because down-regulation was not used for ovarian stimulation (n = 2) or because the gonadotrophin used for stimulation contained LH (n = 1). Of the 10 articles which did evaluate the association between LH levels during ovarian stimulation for IVF using GnRH analogues and pregnancy achievement in normo-ovulatory or WHO II patients, six studies used as the outcome measure achievement of ongoing pregnancy beyond 12 weeks, and four did not define pregnancy as specified in the research question for the current review.
The following data were recorded from each of the 10 studies: type of study, citation data, country, period of enrolment, number of patients included, number of cycles performed, baseline characteristics of the patients included, type and protocol of ovarian stimulation, type of gonadotrophin administered, criteria for HCG administration, day of embryo transfer, type of luteal support administered and method of LH assessment.
Study features and results were assembled in tabular form and a formal meta-analysis was not done.
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Results |
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Six studies, incorporating 1103 patients, that answered the research question were identified (Westergaard et al., 2000
; Balasch et al., 2001; Esposito et al., 2001; Humaidan et al., 2002; Kolibianakis et al., 2004; Merviel et al., 2004). Two were prospective (Humaidan et al., 2002, Kolibianakis et al., 2004), four involved GnRH agonist cycles (717 patients) and two GnRH antagonist cycles (386 patients) (Tables I, II and III). The median number of patients included in the above studies was 183 (range 116–270). Five of the studies were done in Europe, one in the United States of America and all were published within the last 5 years. Table IV summarizes baseline characteristics of the patients included in the studies that answered the research question in the current review.
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All six studies described inclusion criteria and analysed one cycle per patient. Three of the studies evaluated the association between endogenous LH levels and probability of ongoing pregnancy on day 8 (Westergaard et al., 2000; Humaidan et al., 2002; Kolibianakis et al., 2004), one study on day 7 of stimulation (Balasch et al., 2001) and one study on the day of HCG administration (Merviel et al, 2004). One study reported on the mean periovulatory endogenous LH levels based on 4–5 measurements performed after stimulation day 5 (Esposito et al., 2001) (Table V).
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The LH threshold used to characterize patients as having low endogenous LH levels was defined by percentile analysis of LH values on day 8 of stimulation (Kolibianakis et al., 2004), was an arbitrary choice (Westergaard et al., 2000; Esposito et al., 2001; Humaidan et al., 2002; Merviel et al., 2004), or was based on previously reported arbitrarily defined LH thresholds (Balasch et al., 2001).
Multivariate analysis was performed in two studies to further elucidate the association of endogenous LH levels and ongoing pregnancy achievement (Esposito et al., 2001; Kolibianakis et al., 2004). The studies by Balasch et al. (2001) and Esposito et al. (2001) incorporated estradiol (E2) in the criteria used for HCG administration. In the remaining studies, criteria used for triggering final oocyte maturation were independent of E2 levels. With one exception, however (Kolibianakis et al., 2004), the criteria were loosely defined (e.g. two or more follicles of 16 or more mm diameter). This means that HCG might not be administered as soon as the follicular threshold used in that study was reached but could be postponed.
As Table V summarizes, none of the six studies reporting on LH levels before HCG administration found that low endogenous LH levels were associated with a significantly decreased probability of ongoing pregnancy in normo-ovulatory or WHO II patients undergoing IVF using GnRH analogues for inhibition of premature LH surge. In the prospective GnRH agonist study (Humaidan et al., 2002), the chance of ongoing pregnancy was significantly lower if endogenous LH levels were 
1.5 IU/l on day 8 of stimulation, compared to <1.5 IU/l [24.3% (9/37) versus 42.9% (73/170), respectively; P = 0.04]. In the prospective GnRH antagonist study a significant trend towards decreasing ongoing pregnancy rates with increasing endogenous LH levels on day 8 of stimulation was observed in a recombinant FSH (rFSH) and day 6 start GnRH antagonist protocol (Kolibianakis et al., 2004). In that study not only were the low endogenous LH levels on day 8 of stimulation of no concern for achievement of ongoing pregnancy but they were associated with a higher probability of an ongoing pregnancy.
Tables VI, VII and VIII list the studies in which pregnancy was not defined as specified in the research question for the current review (Fleming et al., 2000; Coppola et al., 2003; Ferrari et al., 2004) or no information could be obtained from the authors regarding definition of pregnancy rate (Loumaye et al., 1997). As Table IX summarizes, only one of four studies found an association between endogenous LH levels and the probability of pregnancy in normo-ovulatory or WHO II patients undergoing IVF using GnRH analogues. In that study, pregnancy rates were higher with LH >0.5 mIU/ml (Ferrari et al., 2004).
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Discussion |
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Six studies evaluated the association between endogenous LH levels during ovarian stimulation and the likelihood of ongoing pregnancy beyond 12 weeks in normo-ovulatory or WHO II patients treated for IVF with GnRH analogues. Several conclusions can be drawn from their results. Although the six studies used different LH assay methods and LH standards may vary among laboratories, the trends in all eligible studies involved no risk of lower on-going pregnancy rates with low LH values and possible risk with higher values. Because the association has been assessed in only two prospective studies, one in GnRH agonists and one in GnRH antagonist cycles there is a need to perform additional prospective studies to strengthen or modify the conclusions drawn from the present review.
Based on the currently available evidence, it can be concluded that low endogenous LH levels during ovarian stimulation for IVF using GnRH analogues are not a rationale for LH supplementation to improve the probability of ongoing pregnancy beyond 12 weeks. On the contrary, it appears that the higher the level of mid-follicular endogenous LH during down-regulation in IVF cycles, the lower the probability of ongoing pregnancy. This was the finding in prospective studies involving either GnRH agonists (Humaidan et al., 2002) or GnRH antagonists (Kolibianakis et al., 2004).
The scope of this systematic review was broad enough to find studies, if they existed, showing that low endogenous LH levels predicted a decreased likelihood of ongoing pregnancy. Such a finding would have served as a rationale for clinical trials to evaluate LH supplementation. LH supplementation could be achieved by adding an extra medication such as recombinant LH. This added step, however, would not simplify ovarian stimulation and would involve increased cost. LH supplementation also could be achieved by using low cost urinary-derived gonadotrophins, although their use has been criticized because of the lack of purity and batch to batch consistency (van de Weijer et al., 2003). If low endogenous LH levels during ovarian stimulation were associated with a decreased probability of ongoing pregnancy, then the above mentioned shortcomings would have to be weighed against increased probability of ongoing pregnancy because of LH supplementation. This study, however, suggests that no such compromise is necessary because there is no evidence of a need for LH supplementation.
It is not the purpose of this systematic review to suggest that studies comparing gonadotrophins with and without LH content should not be done. This has been the aim of many studies and has to date generated several meta-analyses (Daya et al., 1995; Agrawal et al., 2000; Al-Inany et al., 2003; van Wely et al., 2003). New developments in gonadotrophin preparations for IVF were motivated by factors other than the concept of LH supplementation. What this review suggests is that supplementation either by recombinant LH or by use of urinary gonadotrophins containing both FSH and LH cannot currently be justified on the basis of decreased probability of ongoing pregnancy beyond 12 weeks in the patients with low LH levels.
The evidence of the meta-analyses comparing the use of gonadotrophins that contain or not LH is not conclusive (Daya et al., 1995; Agrawal et al., 2000; Al-Inany et al., 2003; van Wely et al., 2003), although there is a small trend towards higher pregnancy rates with urinary gonadotrophins containing LH (relative risk for ongoing pregnancy/delivery per woman is 1.20, 95% CI = 0.99–1.45; van Wely et al., 2003). However, if urinary gonadotrophin use is finally shown to cause higher live birth rates, this systematic review suggests that research should be carried out to identify whether the benefit relates to the LH supplementation or some alternative factor.
Two RCTs evaluating LH supplementation in GnRH antagonist cycles have already been published (Cedrin-Durnerin et al., 2004; Griesinger et al., 2005). These studies did not provide evidence that LH addition to recombinant FSH at antagonist initiation (Cedrin-Durnerin et al., 2004) or from initiation of stimulation (Griesinger et al., 2005) increase the probability of pregnancy. Their rationales were based in part on a presumed adverse role of low LH levels, which is not supported by the current review. Another rationale was the observation that very low endogenous LH levels caused by high antagonist doses were associated with decreased probability of pregnancy in a dose finding GnRH antagonist study (The Ganirelix Dose-Finding Study Group, 1998). This single observation has been used repeatedly as strong evidence of the detrimental role of low endogenous LH to IVF outcome, at least in GnRH antagonist cycles. However, it does not appear to arise from a GnRH antagonist effect on embryo/oocyte quality (Kol et al., 1999) or endometrium quality (Simon et al., 2004). Moreover, it should not be overlooked that the decreased probability of pregnancy occurred in the presence of detectable antagonist levels on the day of transfer, a factor known to adversely affect the implantation potential of developing embryos (Casan et al., 1999; Raga et al., 1999). More recent data in GnRH antagonist cycles clearly show that low LH levels are not associated with low ongoing pregnancy rates (Kolibianakis et al., 2004)
In conclusion, the available evidence suggests that, among women with normal ovulation or WHO II oligo-anovulation, low endogenous LH levels during ovarian stimulation for IVF using GnRH analogues are not associated with a decreased probability of ongoing pregnancy beyond 12 weeks. On the contrary, there is evidence to suggest that the opposite may be true. Unless further prospective studies modify the direction of the current evidence, LH supplementation in ovarian stimulation for IVF using GnRH analogues cannot be based on the rationale that low endogenous LH levels have an adverse effect on the probability of ongoing pregnancy beyond 12 weeks of gestation.
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