|Year : 2019 | Volume
| Issue : 2 | Page : 89-96
Effects of Luteinizing Hormone Supplementation on Ovarian Response and Assisted Reproductive Technology Outcomes in Antagonist In vitro Fertilization/Intracytoplasmic Sperm Injection Cycles: A Meta-analysis
Lei Chen1, Cai-Rong Chen1, Xue-Jian Kong2, Cheng-Ran Qiu3
1 Center for Reproductive Medicine, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan 511518, China
2 Department of Neurology, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan 511518, China
3 Department of Gynecology, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan 511518, China
|Date of Submission||22-Jan-2019|
|Date of Web Publication||9-Jul-2019|
Dr. Lei Chen
Center for Reproductive Medicine, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, No. 21, Yinquan South Road, Qingyuan 511518
Source of Support: None, Conflict of Interest: None
Objective: The study objective was to investigate the effects of luteinizing hormone (LH) supplementation on ovarian response and assisted reproductive technology (ART) outcomes in in vitro fertilization/intracytoplasmic sperm injection cycles with a gonadotropin (Gn)-releasing hormone antagonist protocol.
Methods: This is a meta-analysis, and nine published randomized controlled trials (1,685 patients) were included. Continuous data were extracted in the form of mean ± standard deviation and population size, whereas dichotomous data were extracted in the form of odds ratio.
Results: The total amount of follicle-stimulating hormone (FSH) used, the duration of stimulation (DOS), the number of eggs in MII stage, the total number of formed embryos, the clinical pregnancy rate, and live birth rates were similar between groups, but the estrogen level on the day of human chorionic Gn (hCG) administration was slightly higher in the LH supplementation group. On subgroup analysis, it was reported that the addition of LH could significantly increase estrogen levels on the day of hCG administration in patients older than 35 years, and LH supplementation starting on the day of FSH administration may slightly extend the DOS. Moreover, regardless of the timing of LH supplementation, an increase in estrogen levels was found on the day of hCG administration.
Conclusions: LH supplementation of an antagonist protocol increases estrogen levels on the day of hCG administration, but does not increase the number of mature oocytes retrieved, and also fails to improve ART outcomes.
Keywords: Assisted Reproductive Technology; Gonadotropin-Releasing Hormone Antagonist Protocol; Luteinizing Hormone Supplementation; Meta-Analysis
|How to cite this article:|
Chen L, Chen CR, Kong XJ, Qiu CR. Effects of Luteinizing Hormone Supplementation on Ovarian Response and Assisted Reproductive Technology Outcomes in Antagonist In vitro Fertilization/Intracytoplasmic Sperm Injection Cycles: A Meta-analysis. Reprod Dev Med 2019;3:89-96
|How to cite this URL:|
Chen L, Chen CR, Kong XJ, Qiu CR. Effects of Luteinizing Hormone Supplementation on Ovarian Response and Assisted Reproductive Technology Outcomes in Antagonist In vitro Fertilization/Intracytoplasmic Sperm Injection Cycles: A Meta-analysis. Reprod Dev Med [serial online] 2019 [cited 2020 May 29];3:89-96. Available from: http://www.repdevmed.org/text.asp?2019/3/2/89/262386
| Introduction|| |
Gonadotropin-releasing hormone (GnRH) antagonists are widely used in the treatment of assisted reproductive technology (ART). Although these can inhibit premature luteinizing hormone (LH) surges, they do not affect the role of follicle-stimulating hormone (FSH), and can also shorten cycle duration, compared with that using GnRH agonists.
The need for LH supplementation and its effectiveness in patients undergoing ovarian stimulation remains unclear. In a GnRH agonist protocol, the addition of LH is often considered effective due to relatively complete downregulation of the pituitary, which can promote follicular growth and may increase the live birth rate (LBR). Unlike GnRH agonists, the principal mechanism of action of GnRH antagonists is through competitive binding to GnRH receptors. The suppression of LH during controlled ovarian stimulation (COS) by GnRH antagonists becomes a point of concern, and many studies have investigated the effects of supplementation of LH to the antagonist protocol., Some reports suggested that LH supplementation can increase the implantation rate in the antagonist cycle. Polyzos et al. believed that LH supplementation could improve the pregnancy rate in patients younger than 40 years with poor ovarian response. However, other authors believed that supplementation of LH is not beneficial in an antagonist protocol., A recent multicentric observational study reported that supplementation of LH was associated with improvement in the outcome of autologous antagonist cycles. Another study reported that low endogenous LH concentration induced by GnRH antagonists may negatively affect treatment outcomes due to poor oocyte quality.
We performed this meta-analysis, in consonance with the PRISMA report guideline, to clarify the above issues. The aim of this study is to investigate the effects of LH supplementation on ovarian response and the outcomes of ART inin vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) with a GnRH antagonist protocol, and then we are looking forward to getting some guidance on clinical practice.
A literature search was performed for articles published between January 2004 and December 2018, using the PubMed, Embase, Cochrane Library, and Web of Science databases. The following search terms and their combinations were used: antagonist, LH/rLH/exogenous LH/luteinizing hormone/hMG, IVF/in vitro fertilization, and ICSI/intracytoplasmic sperm injection. The language of the publications was restricted to English.
The following were included: (1) randomized controlled trials (RCTs) that compared the outcomes of patients with or without LH supplementation during IVF/ICSI antagonist cycles; and (2) studies that assessed the ovarian responses to COS and at least one of the ART outcomes mentioned in the next section.
Abstracts, letters, review articles, case reports, and animal research were excluded. Patients with polycystic ovarian syndrome and other ovarian diseases or surgeries were also excluded.
Data extraction and outcome measures
Two investigators (Lei Chen and Cai-Rong Chen) independently extracted the data to ensure homogeneity of the data collection, and any disagreement was resolved through consultation with a third reviewer (Xue-Jian Kong). The following outcome measures were extracted from all the included studies: total amount of gonadotropin (Gn) used for FSH (TOG), the duration of stimulation (DOS), the estrogen (E2) level on the day of human chorionic Gn (hCG, in pg/mL) administration (E2L), the number of eggs in MII stage (MII), the total number of formed embryos (TFE), and the clinical pregnancy rate (CPR) and LBR. The primary outcome measures were CPR and LBR. The secondary outcome measures were also investigated. Continuous data were reported as mean ± standard deviation (SD) and population size, whereas dichotomous data were reported as odds ratio (OR). Clinical pregnancy was defined by the presence of an intrauterine gestational sac at 3–4 weeks after embryo transfer. Live birth means giving birth to a living baby.
Quality assessment of all the included RCTs was based on the Cochrane Collaboration tool for assessing risk of bias.
All meta-analyses were performed using Review Manager 5.3 (Cochrane Collaboration, Oxford, UK), and all data retrieved as continuous variables were analyzed using the weighted mean difference or OR with 95% confidence interval (CI). If no SD was provided by a study, the value was calculated using methods described by Hozo et al. Heterogeneity was evaluated graphically using forest plots and quantified using the I2 statistic. An I2 >50% represented significant heterogeneity between studies. A random-effects model was used for analyzing significant heterogeneity between studies; otherwise, a fixed-effects model was used. We screened for potential publication bias using funnel plots.
| Results|| |
The literature search identified 2,488 studies from five databases [Figure 1]. Of these, 2,468 were excluded based on the title and abstract or duplication of research, and 11 were excluded after a detailed review. Therefore, nine studies fulfilled the predefined criteria and were finally included in this meta-analysis [Figure 1].,,,,,,,,
The characteristics of the studies are shown in [Table 1]. Of the nine included studies, six were conducted in Europe, two in Asia, and one in the USA. A total of 814 experimental (FSH + LH) groups and 871 control groups (FSH alone) were included. The daily dose of FSH used was 150–300 IU. The publication date ranged from 2004 to 2016. All retrieved studies were designed as RCTs. The results of quality assessment of the RCTs are shown in [Figure 2]. All studies were age matched, and all patients had regular menstrual cycles. It should be noted that “Bosch et al., 2011” and “Kim et al., 2010” each provided two cohorts for this meta-analysis.
|Figure 2: Risk-of-bias summary: Reviewer judgments for each risk-of-bias item in each included study.|
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We evaluated publication bias by Egger's test (STATA version 12, StataCorp, College Station, TX, USA). [Figure 3] shows a funnel plot of the studies included in this meta-analysis. All studies were within the 95% CI, with an even distribution around the vertical, indicating no obvious publication bias.
Results of meta-analysis
Clinical pregnancy rate
In a comparison of CPR between groups, nine of nine cohorts from eight studies,,,,,,, showed no statistically significant differences. The pooled data for 1,180 patients did not show a statistically significant difference between groups [Table 2]. The I2 value was 0% (P = 0.99), indicating no evidence of heterogeneity between studies [Figure 4]a.
|Figure 4: Forest plots of the original analysis between groups. (a) Clinical pregnancy rate; (b) Live birth rate; (c) Total amount of gonadotropin used for follicle-stimulating hormone; (d) Duration of stimulation; (e) The estrogen level on the day of human chorionic gonadotropin administration; (f) The number of eggs in MII stage; (g) The total number of formed embryos. IV: Inverse variance; CI: Confidence interval; M–H: Mantel–Haenszel.|
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Live birth rate
In a comparison of LBR between groups, two of two cohorts from two studies, showed no statistically significant differences. The pooled data for 443 patients did not show a statistically significant difference between groups [Table 2]. The I2 value was 0% (P = 0.79), indicating no evidence of heterogeneity between studies [Figure 4]b.
In a comparison of TOG between groups, only one of eight cohorts from six studies,,,,, favored LH supplementation, while the rest showed no statistically significant differences. The pooled data for 1,351 patients did not show a statistically significant difference between groups [Table 2]. These eight cohorts showed statistically significant variation, as indicated by an I2 value of 83% (P < 0.00001) [Figure 4]c.
Duration of stimulation
In a comparison of DOS between groups, only one of nine cohorts from seven studies,,,,,, favored FSH alone, while the rest showed no statistically significant differences. The pooled data for 1,525 patients did not show a statistically significant difference between groups [Table 2]. The I2 value was 39% (P = 0.11), indicating relatively little variation between studies [Figure 4]d.
In a comparison of E2L between groups, four of nine cohorts from seven studies,,,,,, favored LH supplementation, while the rest showed no statistically significant differences. The pooled data for 1,525 patients showed a statistically significant difference between groups [Table 2], indicating that addition of LH can increase E2L. The I2 value was 41% (P = 0.09), indicating relatively little variation between studies [Figure 4]e.
In a comparison of MII between groups, three of three cohorts from two studies, showed no statistically significant differences. The pooled data for 687 patients did not show a statistically significant difference between groups [Table 2]. The I2 value was 0% (P = 0.41), indicating no evidence of heterogeneity between studies [Figure 4]f.
Total number of formed embryos
In a comparison of TFE between groups, three of three cohorts from three studies,, showed no statistically significant differences. The pooled data for 518 patients did not show a statistically significant difference between groups [Table 2]. The I2 value was 50% (P = 0.13), indicating relatively little variation between studies [Figure 4]g.
According to age (≤35 years or >35 years)
[Table 3] shows that there were no significant differences in this subgroup analysis compared with the original analysis (P = 0.43) [Supplementary Figure 1]a.
|Table 3: Main results of subgroup analysis comparing FSH + LH with FSH alone, according to the age and timing of LH supplementation|
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Duration of stimulation
[Table 3] shows that there were no significant differences in this subgroup analysis compared with the original analysis (P = 0.79) [Supplementary Figure 1]b.
[Table 3] shows that age had no effect on E2L in the subgroup aged ≤35 years; however, in the subgroup aged >35 years, LH supplementation increased E2L (P = 0.001) [Supplementary Figure 1]c.
According to the timing of luteinizing hormonesupplementation (commencing with follicle-stimulating hormone stimulation or cetrorelix injection)
Clinical pregnancy rate
[Table 3] shows that there were no significant differences in this subgroup analysis compared with the original analysis (P = 0.64) [Supplementary Figure 2]a.
[Table 3] shows that there were no significant differences in this subgroup analysis compared with the original analysis [Supplementary Figure 2]b.
Duration of stimulation
[Table 3] shows that the timing of LH supplementation had no effect on DOS in the cetrorelix injection subgroup; however, in the FSH stimulation subgroup, LH supplementation can extend the DOS (P = 0.006). The overall results of subgroup analysis were consistent with those of the meta-analysis (P = 0.08) [Supplementary Figure 2]c.
[Table 3] shows that the timing of LH supplementation increased E2L in both the FSH stimulation subgroup (inverse variance [IV]: 0.19; 95% CI: [0.05, 0.34], P = 0.009) and cetrorelix injection subgroup (IV: 0.26; 95% CI: [0.11, 0.40], P = 0.0004). The overall results of subgroup analysis showed an increase in E2L in the experimental group (P < 0.0001) [Supplementary Figure 2]d.
| Discussion|| |
This study showed that adding LH to FSH-driven stimulation in GnRH antagonist cycles is associated with a significant increase in serum E2 levels on the day of hCG administration. Estrogen levels were lower in the control group, possibly because follicles were under the influence of relative LH depletion caused by mid-follicular phase antagonist administration without exogenous LH supplementation. Without exogenous supplementation, the LH levels will be relatively decreased, and the levels of androgens produced by follicular theca cells stimulated by LH will also be decreased. Therefore, the levels of androgens, which are precursors of estrogen synthesis, will be relatively low, resulting in lower estrogen levels. The main finding of this study is that E2 levels were substantially higher after treatment with LH, compared with those using FSH alone; however, this failed to increase the number of oocytes in MII stage and did not improve ART outcomes. This finding has been reported in GnRH antagonist cycles, and is attributed to the continuous exposure to LH activity, which induces higher levels of aromatizable androgens, leading to higher E2 concentrations in the middle of the follicular phase. The higher estrogen levels when LH is employed for COS could reflect improved granulocyte function during the follicular phase, which is critical in follicular maturation. The essential role of LH for physiological ovarian folliculogenesis and steroidogenesis has been well demonstrated in natural cycles.
In close association with this finding, the serum E2 levels were significantly higher at the end of the follicular phase in the LH supplementation group; however, the final ART outcomes were similar between groups, indicating that E2 production per mature follicle significantly increased when LH was administered. This also indicated that low doses of endogenous LH could affect E2 biosynthesis to some extent in maturing follicles. In an environment with low endogenous LH, particularly among women with LH concentrations <1.2 mIU/mL, FSH alone for ovulation induction has been found to result in poor pregnancy outcomes, while insufficient LH has been found to result in inadequate steroidogenesis. Should this prompt us to add LH when the concentration is <1.2 mIU/mL? A conclusive recommendation is made difficult by the pulsatile mode of endogenous LH secretion, which may make measurement difficult, especially following GnRH antagonist treatment. It is worth noting that some studies reported that endogenous LH concentrations are not correlated with pregnancy in GnRH antagonist cycles., Moreover, it has been suggested that only 1% of follicular LH receptors must be occupied to allow normal steroidogenesis. This also highlights the fact that addition of 75–150 IU of exogenous LH is sufficient. It is known that a premature LH surge will lead to follicular atresia and degradation, which can also lead to adverse pregnancy outcomes. The above evidence reinforces the concept of an “LH ceiling,” meaning that each follicle has a corresponding low and a high LH value necessary for growth; however, the specific threshold of the LH ceiling remains unknown. O'Dea et al. proposed that the LH ceiling is between 1.2 and 5.0 mIU/mL, indicating the need to avoid excess LH supplementation during COS.
A study found that ovarian responses in COS are affected more by the timing of administration than by the total dose of LH. The results coincide with our subgroup results [Supplementary Figure 2], showing that LH supplementation in both early- and mid-to-late-follicular phases can increase E2L. This suggests that early LH supplementation is unnecessary, based on the following considerations: first, the cost is increased; and second, in the early follicular phase, endogenous LH is sufficient to occupy the receptors on the granulosa cells, and the LH receptors on the granulocytes become active in the mid- and late-follicular phases. Another study showed that LH receptors are detectable on the granulosa component in the mid-follicular phase. Therefore, in the middle phase of follicular development, the addition of antagonists without supplementation of exogenous LH may lead to a relative deficiency of LH, which then affects estrogen synthesis by granulocytes. Our subgroup analysis supported this finding by showing [Supplementary Figure 2] that, no matter which time point you start adding LH, from the 1st day or the 5th–7th day of stimulation, the outcomes of ART are similar.
At present, urinary hMG and recombinant LH (rLH) are commonly used. The use of urinary hMG has a risk of allergic reactions and the supply is limited. Accordingly, rLH (Luveris®, Merck-Serono, Geneva, Switzerland) is now widely used. Pharmacodynamic studies of rLH have shown it to have volume of distribution, half-life, and bioactivity similar to those of hMG. This was also observed in a study in which recombinant FSH (rFSH) stimulation plus rLH or hMG yielded similar COS results. However, a recent RCT found that hMG plus rFSH used for controlled ovarian hyperstimulation had better effect than rLH on fertility outcomes in IVF patients. A weakness of the current meta-analysis is that most included studies used rLH; thus, we were unable to further examine differences between the effects of hMG and rLH on ART outcomes. Our study did not find that supplementation of LH could reduce the total amount of Gn used, making it necessary to consider cost-effectiveness. As hMG is more economical than rLH, hMG should be preferred when choosing to add LH.
One included study found that rLH had added benefits for patients aged >35 years in GnRH antagonist cycles through higher implantation rates, but failed to benefit patients aged <35 years. However, another included study did not find differences in implantation rates between groups. Therefore, we found that LH supplementation could increase estrogen levels more significantly in patients aged >35 years [Supplementary Figure 1], but were also unable to increase the number of mature oocytes obtained, and did not improve the pregnancy outcomes. It is possible that patients aged >35 years are more susceptible to profound LH suppression in GnRH antagonist cycles, and are therefore more likely to benefit from exogenous LH. Similarly, Younis et al. found that rLH supplementation of the GnRH antagonist protocol at an advanced reproductive age could improve endocrine dynamics, but this difference does not really improve the ART outcome.
Another interesting point to consider is a finding in a study that examined both agonist and antagonist cycles, in which patients who appeared to have an unexpectedly poor response to rFSH monotherapy in a prior cycle benefited from the addition of 150 IU of rLH, without the need to increase the rFSH starting dose in subsequent treatment cycles, thus resulting in the improvement of IVF outcomes. Whether this suggests that LH rescue in antagonist cycles is better than FSH step-up to improve IVF outcomes in unexpectedly poor responders is unclear, and requires further research.
Our study has several strengths. This meta-analysis included nine RCTs with 1,685 patients, which made the pooled results more reliable. Our inclusion criteria were very strict, and we conducted subgroup analysis both according to the age and timing of LH supplementation to evaluate their effect on our results and to make our analysis more accurate and comprehensive.
Our study also had some limitations. First, as most of our included studies used rLH, we were unable to further investigate differences between the effects of hMG and rLH on ART outcomes. A second limitation could be related to the selection criteria for inclusion. The choice of language and databases may have prevented retrieval of all possibly relevant studies.
In conclusion, LH supplementation of an antagonist protocol can increase estrogen levels on the day of hCG administration, but does not increase the number of mature oocytes retrieved, and also fails to improve ART outcomes. Despite some shortcomings, our findings enrich the existing data and provide a relatively reliable conclusion on this topic. Further well-designed studies are needed to obtain robust data and more detailed outcomes.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3]