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Human chorionic gonadotrophin (HCG) may substitute FSH to complete follicular growth in IVF cycles. This may be useful in the prevention of ovarian hyperstimulation syndrome. Relevant studies were identified on Medline. To evaluate outcomes, a meta-analysis of low-dose HCG-supplemented IVF cycles versus non-supplemented ones was performed with data from 435 patients undergoing IVF who were administered low-dose HCG in various agonist and antagonist protocols and from 597 conservatively treated patients who served, as control subjects. Using these published data, a decision analysis evaluated four different management strategies. Effectiveness and economic outcomes were assessed by FSH consumption, clinical pregnancy and incremental cost-effectiveness ratios. Clinical pregnancy and ovarian hyperstimulation were the main outcome measures. Nine trials published in 2002–2007 were included. From the prospective studies, in the gonadotrophin-releasing hormone antagonist group, a trend for significance in clinical pregnancy rate was evident (odds ratio [OR], 1.54; 95% confidence interval [CI], 0.98–2.42). Ovarian hyperstimulation was less significant in the antagonist low-dose HCG protocol compared with the non-supplemented agonist protocol (OR 0.30; 95% CI 0.09–0.96). Less FSH was consumed in the low-dose HCG group but this difference was not statistically significant. Low-dose HCG supplementation may improve pregnancy rates in antagonist protocols. Overall, low-dose HCG-supplemented protocols are a cost-effective strategy.
Ovarian stimulation with recombinant follicle-stimulating hormone (rFSH) or human menopausal gonodatrophin is a major part of IVF. FSH acts in an anti-apoptotic way (
Lower apoptosis rate in human cumulus cells after administration of recombinant luteinizing hormone to women undergoing ovarian stimulation for in-vitro fertilization procedures.
Molecular evidence that growth of dominant follicles involves a reduction in follicle-stimulating hormone dependence and an increase in luteinizing hormone dependence in cattle.
). Since then, other prospective and retrospective studies have been performed with similar pregnancy rates. From these studies, rFSH replacement by low-dose HCG has emerged as a potential strategy to prevent OHSS because it reduces small, developing ovarian follicles (
Ovarian stimulation with daily late follicular phase administration of low-dose human chorionic gonadotropin for in-vitro fertilization: a prospective, randomized trial.
Clinical effects of ovulation induction with recombinant follicle-stimulating hormone supplemented with recombinant luteinizing hormone or low-dose recombinant human chorionic gonadotropin in the midfollicular phase in microdose cycles in poor responders.
). The main outcomes of the studies are hormonal response after stimulation, embryological characteristics, pregnancy outcome, endometrial thickness and incidence of OHSS (
Clinical effects of ovulation induction with recombinant follicle-stimulating hormone supplemented with recombinant luteinizing hormone or low-dose recombinant human chorionic gonadotropin in the midfollicular phase in microdose cycles in poor responders.
). All studies report similar results between the two groups while in parallel show reduced FSH needs. This decrease is more significant in the studies with a major replacement of FSH (
This study was undertaken to summarize evidence for clinical pregnancy rates, incidence of OHSS, FSH reduction and endocrinological features when administering low-dose HCG during down-regulation. Different down-regulation protocols were examined and the clinical effect after different levels of FSH substitution were evaluated. A meta-analysis, a decision analysis and a cost-effectiveness analysis of alternative ovarian stimulation strategies for IVF, including the low-dose HCG protocols, were performed to define the extent of cost savings by FSH decrease and to suggest a cost-effective choice.
Materials and methods
Identification of eligible relevant studies and data extraction
Medline searches (until September 2007) with various combinations of terms (low-dose HCG administration, GnRH agonist and antagonists, IVF, gonadotrophin administration) and pregnancy rates were used. The search was completed after examination of the references of recovered papers and review articles. Studies that evaluated the comparison of FSH replacement by low-dose HCG with no supplementation in GnRH agonist and antagonist protocols were included.
Although unpublished studies cannot be adequately evaluated for their design and quality, the analysis included meeting proceedings to increase the sample size (
A prospective comparison of in-vitro fertilization (IVF) outcome following controlled ovarian hyperstimulation (COH) regimens using follitropin alpha exclusively or with the addition of low-dose human chorionic gonadotropin (hCG).
). All studies were included, regardless of the size but whenever possible only prospective controlled studies were synthesized. No language limit was set.
For each study, information was obtained on authors, journal and year of publication, country and years of study enrollment, study design and eligibility (inclusion/exclusion) criteria and number of participating centres. Furthermore, withdrawals, power analysis and reports of funding were also mentioned. Finally, the mean age of the subjects, the number of cases and controls, as well as the number of pregnancies per group, were mentioned.
Subgroup analysis was performed for the GnRH down-regulation scheme, low-dose HCG substitution and incidence of OHSS. In addition, analysis that included the retrospective trials was performed. Data extraction was performed independently by two investigators and conflicts were solved after discussion.
Main outcomes
The primary outcome for low-dose HCG replacement was clinical pregnancy rate. As secondary outcomes, incidence of OHSS and the observed endocrinology were considered whenever mentioned. Cost analysis was based on the mean values of FSH consumption for each protocol.
Meta-analysis
The odds ratios with 95% confidence intervals between the low-dose HCG replacement group and the control group for each study were calculated and the results were combined using the fixed (for prospective studies) and the random effects model. Heterogeneity was assessed with I2 statistics. The main analysis includes all studies. Subgroup analyses were also performed based on the GnRH down-regulation protocol and FSH replacement by low-dose HCG. Analyses were performed by RevMan Analyses ((2003); The Cochrane Information Management System) and using the Statistics Package for Social Sciences (SPSS 15.0; SPSS, Chicago, USA).
Decision analysis and cost-effectiveness analysis
Using country-specific data, the analysis compared the clinical pregnancy rates, incidence of OHSS and the costs associated with the current stimulation practices. The comparative performance of alternate strategies was described using the incremental cost-effectiveness ratio (ICER), which is defined as the additional cost of a specific strategy divided by its additional clinical benefit compared with the next least expensive strategy. Incidence of OHSS is not associated with pregnancy outcome and is related only to the protocol, thus the OHSS cost was calculated per protocol. Decision analysis and cost analysis were performed with TreeAge Pro 7 software (TreeAge Software, Williamstown, USA).
Cost effectiveness was calculated by taking the cost in Euros and dividing it by the effectiveness. Effectiveness is considered as 1 if clinical pregnancy is reported and as 0.5 when stimulation is completed but no clinical pregnancy is reported. Efficiency was measured by the ICER, which is defined as the ratio of the change in costs of a therapeutic intervention (compared with the alternative, using the best available alternative treatment) to the change in effects of the intervention: ICER = IC/IE, where incremental efficiency is health benefit per unit of cost (IE) and incremental cost (IC) is the cost per cycle in alternating arm minus cost per patient against a standard arm.
Another more complicated definition of the ICER is [(C1 − C0)/(E1 – E0)], where 1 denotes the intervention under study and 0 the alternative with which it is compared, C1 and C0 are the net present values of costs accrued when the intervention and its alternative are used, and E1 and E0 are their respective health outcomes. Thus, C1 – C0 is the incremental cost and E1 – E0 is the incremental effectiveness of the intervention over the alternative.
Results
Eligible studies
A total of 28 abstracts were retrieved and screened. From these, thirteen articles that attempted to compare low-dose HCG administration in various protocols with FSH IVF cycles were retrieved for full review. One abstract was excluded because it did not mention the sample size included in the trial (
Ovarian stimulation with daily late follicular phase administration of low-dose human chorionic gonadotropin for in-vitro fertilization: a prospective, randomized trial.
Ovarian stimulation with daily late follicular phase administration of low-dose human chorionic gonadotropin for in-vitro fertilization: a prospective, randomized trial.
Clinical effects of ovulation induction with recombinant follicle-stimulating hormone supplemented with recombinant luteinizing hormone or low-dose recombinant human chorionic gonadotropin in the midfollicular phase in microdose cycles in poor responders.
Recombinant follicle-stimulating hormone (rFSH) supplemented with low-dose human chorionic gonadotropin compared with rFSH alone for ovarian stimulation for in-vitro fertilization.
), three recruited women in Brazil, three recruited in USA and one each recruited in Italy, Japan and Turkey. The only multicentre study covered Brazilian centres. The mean age of participating women ranged between 30 and 40 years of age. None of the studies mentioned ethnic origin of recruited patients. The women participating in the studies were enrolled from 2002 until 2006.
Ovarian stimulation with daily late follicular phase administration of low-dose human chorionic gonadotropin for in-vitro fertilization: a prospective, randomized trial.
A prospective comparison of in-vitro fertilization (IVF) outcome following controlled ovarian hyperstimulation (COH) regimens using follitropin alpha exclusively or with the addition of low-dose human chorionic gonadotropin (hCG).
Clinical effects of ovulation induction with recombinant follicle-stimulating hormone supplemented with recombinant luteinizing hormone or low-dose recombinant human chorionic gonadotropin in the midfollicular phase in microdose cycles in poor responders.
Recombinant follicle-stimulating hormone (rFSH) supplemented with low-dose human chorionic gonadotropin compared with rFSH alone for ovarian stimulation for in-vitro fertilization.
Four out of nine studies mentioned inclusion and exclusion criteria. Recruitment patterns and eligibility for participants varied, but typically, women with unexplained infertility, women from couples with mild and severe male infertility and women with tubal factor were eligible. Endogenous FSH concentrations during early follicular phase were varied. Five studies described cancellations and withdrawals. Only three studies mentioned power calculations. More than three outcomes were recorded in all studies. In all of them, interventions were equally experimental. None of the studies reported funding.
Meta-analysis
Eleven comparisons out of nine studies were performed for clinical pregnancy rates (odds ratio [OR] 1.14; 95% confidence interval [CI] 0.87–1.49; random effects model). When only the prospective studies were included, there was no difference in pregnancy rates (OR 1.14; 95% CI 0.80–1.63; random effects model). When controlling for OHSS, no difference was observed between the two groups (OR 0.48; 95% CI 0.21–1.09; random effects model).
Subgroup analyses based on administration protocol
Ovarian stimulation with daily late follicular phase administration of low-dose human chorionic gonadotropin for in-vitro fertilization: a prospective, randomized trial.
) using long agonist protocols included 204 patients. Three of the studies were prospective. There was no significant difference in clinical pregnancy rates when all studies were included (OR 1.15; 95% CI 0.64–2.07) or for only the prospective studies (OR 1.43; 95% CI 0.61–3.31; random effects model). Three studies (
Ovarian stimulation with daily late follicular phase administration of low-dose human chorionic gonadotropin for in-vitro fertilization: a prospective, randomized trial.
) reported OHSS. When comparing low-dose HCG replacement with no replacement in long protocols there was no difference in the incidence of OHSS (OR 0.70; 95% CI 0.04–12.76; random effects model).
Clinical effects of ovulation induction with recombinant follicle-stimulating hormone supplemented with recombinant luteinizing hormone or low-dose recombinant human chorionic gonadotropin in the midfollicular phase in microdose cycles in poor responders.
) reported on supplemented and non-supplemented cycles with the short protocol. There was no significant difference in pregnancy rates between the comparison (OR 0.70; 95% CI 0.24–2.02). This study did not report on OHSS.
Ovarian stimulation with daily late follicular phase administration of low-dose human chorionic gonadotropin for in-vitro fertilization: a prospective, randomized trial.
Recombinant follicle-stimulating hormone (rFSH) supplemented with low-dose human chorionic gonadotropin compared with rFSH alone for ovarian stimulation for in-vitro fertilization.
) including 504 patients were performed in antagonist protocols. Two of them, were prospective. When comparing the prospective ones, there was a trend for a significant difference in clinical pregnancy rates favouring the low-dose HCG-supplemented antagonist protocol (OR 1.54; 95% CI 0.98–2.42; fixed effects model; Figure 2). These two studies also reported on OHSS. There was no significant difference in the incidence of OHSS between a supplemented and non-supplemented antagonist protocol (OR 0.69; 95% CI 0.18–2.64; random effects model).
Figure 2Comparison of low-dose human chorionic gonadotrophin (HCG) supplemented antagonist cycles versus non-supplemented cycles and the odds for clinical pregnancy. CI = confidence interval; OR = odds ratio.
Ovarian stimulation with daily late follicular phase administration of low-dose human chorionic gonadotropin for in-vitro fertilization: a prospective, randomized trial.
) exist for the supplemented antagonist protocol with non-supplemented long agonist protocol. There was no significant difference in clinical pregnancy rates (OR 0.87; 95% CI 0.28–2.67; random effects model), but when comparing for incidence of OHSS there was a significant difference favouring the low-dose HCG-antagonist protocol (OR 0.30; 95% CI 0.09–0.96; fixed effects model; Figure 3). From this comparison, similar pregnancy rates were achieved while ovarian hyperstimulation was minimized favouring the supplemented antagonist protocol.
Figure 3Comparison of low-dose human chorionic gonadotrophin (HCG) supplemented antagonist cycles versus non-supplemented long agonist cycles and the odds for the incidence ovarian hyperstimulation syndrome. CI = confidence interval; OR = odds ratio.
Ovarian stimulation with daily late follicular phase administration of low-dose human chorionic gonadotropin for in-vitro fertilization: a prospective, randomized trial.
) in which FSH was replaced to a major extent by low-dose HCG. (OR 1.51; 95% CI 1.02–2.25; fixed effects model; Figure 4). By excluding the study that added bromocriptine with the low-dose HCG protocol (
), no change was found in the direction of the dichotomous variables (OR 1.59; 95% CI 1.054–2.29).
Figure 4Comparison of studies with major replacement of low-dose human chorionic gonadotrophin (HCG) supplemented cycles versus non-supplemented cycles and the odds for clinical pregnancy.
A prospective comparison of in-vitro fertilization (IVF) outcome following controlled ovarian hyperstimulation (COH) regimens using follitropin alpha exclusively or with the addition of low-dose human chorionic gonadotropin (hCG).
Clinical effects of ovulation induction with recombinant follicle-stimulating hormone supplemented with recombinant luteinizing hormone or low-dose recombinant human chorionic gonadotropin in the midfollicular phase in microdose cycles in poor responders.
Ovarian stimulation with daily late follicular phase administration of low-dose human chorionic gonadotropin for in-vitro fertilization: a prospective, randomized trial.
Clinical effects of ovulation induction with recombinant follicle-stimulating hormone supplemented with recombinant luteinizing hormone or low-dose recombinant human chorionic gonadotropin in the midfollicular phase in microdose cycles in poor responders.
Recombinant follicle-stimulating hormone (rFSH) supplemented with low-dose human chorionic gonadotropin compared with rFSH alone for ovarian stimulation for in-vitro fertilization.
) mentioned comparisons of oestradiol concentrations on the day of HCG administration between different protocols (Table 2). These concentrations were higher in the low-dose HCG group in all protocols. There was no significant difference in these concentrations either between groups or between the different supplemented protocols and between the different non-supplemented protocols (within groups), (one-way analysis of variance (ANOVA)). The short protocol group was excluded from the analysis because only one study (
Clinical effects of ovulation induction with recombinant follicle-stimulating hormone supplemented with recombinant luteinizing hormone or low-dose recombinant human chorionic gonadotropin in the midfollicular phase in microdose cycles in poor responders.
Table 2Oestradiol concentrations on the day of human chorionic gonadotrophin (HCG) administration according to the protocol used.
Long agonist (n=3)
Antagonist (n=3)
Antagonist versus long agonist (n=2)
Low-dose HCG
No supplement
Low-dose HCG
No supplement
Low-dose HCG
No supplement
3550.66 ± 544.15
2607.66 ± 709.26
3201.9 ± 901.77
2138 ± 269.56
3391.35 ± 1187.86
2558.4 ± 290.76
Values are mean ± SD. One-way analysis of variance comparisons were performed. No statistically significant differences were observed between the different supplemented protocols or between the different non-supplemented protocols.
Ovarian stimulation with daily late follicular phase administration of low-dose human chorionic gonadotropin for in-vitro fertilization: a prospective, randomized trial.
) mentioned progesterone concentrations on the day of HCG administration. The mean values varied from 1.1 to 2.6 ng/ml for the low-dose HCG group. One study (
), reported that 14 out of 17 patients in the low-dose HCG group, reached progesterone concentrations over 1.5 ng/ml while the mean value of these concentrations was 2.6 ng/ml. No significant difference was observed, for progesterone concentrations, either between groups or within groups.
Cost analysis based on FSH consumption
The short protocol study was excluded from the comparison between protocols because only one study (
Clinical effects of ovulation induction with recombinant follicle-stimulating hormone supplemented with recombinant luteinizing hormone or low-dose recombinant human chorionic gonadotropin in the midfollicular phase in microdose cycles in poor responders.
) existed. Higher consumption of FSH was noted compared with the other protocols (4902.4 units of FSH; P = 0.044; one-way ANOVA).
Less total FSH (IU) was needed to achieve folliculogenesis in the long protocol (Table 3) while, in parallel, similar pregnancy rates were achieved. Also, less total FSH (IU) was consumed in the antagonist comparison (supplemented versus non-supplemented) and the low-dose HCG antagonist–long agonist protocol comparison. Approximately 400 fewer units were consumed, although the difference did not reach statistical significance (one-way ANOVA). In addition, no significant difference was observed in the FSH needed for the low-dose HCG protocols [Tukey Honestly Significant Difference (HSD) test-homogenous subset procedure]. Specifically, in the comparison between supplemented long agonist and antagonist protocols, the mean difference was 297 units (Tukey HSD test-one-way ANOVA post-hoc test); favouring the long agonist protocol. Such a value is the key driver for cost comparisons and treatment choice between supplemented agonist and antagonist interventions.
Table 3Total FSH (IU) consumed in different protocols.
Long agonist (n=3)
Antagonist (n=3)
Antagonist versus long agonist (n=2)
Low-dose HCG
No supplement
Low-dose HCG
No supplement
Low-dose HCG antagonist
No supplement agonist
1495.33 ± 402.86
2209.33 ± 493.36
1792.4 ± 106.76
2415.36 ± 373
1747.1 ± 102.38
2257.8 ± 142
Values are mean ± SD. HCG = human chorionic gonadotrophin. No statistically significant differences were observed.
When comparing the incidence of OHSS between the low-dose HCG antagonist protocol and the non-supplemented agonist protocol, it was significantly lower in the HCG-antagonist group (odds ratio, 0.30; 95% confidence interval, 0.09–0.96; fixed effect model). This is another parameter that contributes to cost minimization.
Eighty clinical pregnancies were reported in the supplemented antagonist protocol and 20 in the supplemented agonist protocol.
Cost-effectiveness, sensitivity analysis and threshold analysis for supplemented protocol choice according to FSH requirements
The cost assumptions used in the model are summarized in Appendix A. Based on the FSH consumption and incidence of OHSS, the expected cost per clinical pregnancy is €957 in the low-dose HCG agonist protocol, €1188 in the low-dose HCG antagonist and €1939 and €1622 for non-supplemented agonist and antagonist protocols respectively (Figure 5). Incremental cost is presented in Table 4. From the cost-effectiveness graph, it is obvious that both supplemented strategies present are possible optimal choices with the low-dose HCG agonist protocol offering the lowest cost option (Figure 6).
With regard to incremental net monetary benefits of low-dose HCG agonist FSH while using the low-dose HCG antagonist FSH for comparison, it is evident that at a value of 1766.7 units, the incremental net monetary benefit is 0 (Figure 7).
Figure 7One-way sensitivity analysis of net monetary benefits (NMB).
As an extension of one-way sensitivity analysis, threshold analysis was performed by varying the value of FSH requirements for the low-dose HCG agonist protocol. It was found that, between 1244 and 1766.7 units, the option with the highest net benefit was the ‘low-dose HCG agonist strategy’, but between 1766.7 and 1960 units, the option with the highest net benefit was the ‘low-dose HCG antagonist strategy’.
Two-way sensitivity and threshold analysis
Simultaneous changes in the values of two independent variables (FSH requirements in the supplemented protocols) were assessed by two-way sensitivity analysis. The resulting graph (Figure 8) identifies which strategy is optimal in regions of values of FSH; thresholds are the border between two regions.
Figure 8Two-way sensitivity analysis of net monetary benefits (NMB).
Based on the OR derived from the meta-analysis, the number of patients needed to be treated to prevent one incidence of OHSS in the HCG-supplemented antagonist cycles as compared with the non-supplemented agonist cycles is 19.
Discussion
It is obvious from the meta-analysis, that low-dose HCG replacement does not compromise clinical pregnancy rates while in parallel maintains low OHSS rates. Evidence exists that clinical pregnancy rates may be increased in the low-dose HCG-antagonist protocol but this remains to be elucidated in the future. There is no significant difference in the incidence of OHSS between the supplemented long agonist and antagonist protocols. Such substitution achieves the major clinical benefit when there is a major replacement of recombinant FSH.
The benefit of HCG supplementation is lower consumption of recombinant FSH in these protocols, thus contributing to a lower cost. It is important to understand that increased effectiveness can be seen when there is major substitution of rFSH with low-dose HCG.
When comparing the low-dose HCG-supplemented antagonist protocols with non-supplemented agonist protocols, no difference in pregnancy rates was found. In this way, a supplemented antagonist protocol is equally effective as an agonist protocol. Most importantly, there is significant reduction in OHSS (OR 0.30; 95% CI 0.09–0. 96; Figure 3), thus favouring the low-dose HCG antagonist protocol.
Although, there is no difference in pregnancy rates in the study using the short agonist protocol (
Clinical effects of ovulation induction with recombinant follicle-stimulating hormone supplemented with recombinant luteinizing hormone or low-dose recombinant human chorionic gonadotropin in the midfollicular phase in microdose cycles in poor responders.
), no recommendation can be given definitely at this point, because of a lack of other studies. Minor replacement of rFSH was performed in this study, while a study with major replacement is needed. If such a study were to be successful, then FSH consumption could be significantly lowered and could be intensified in the first stages of ovarian stimulation.
The limit of this meta-analysis is the small number of prospective studies that were included. Another limitation is the inclusion of meeting proceedings that cannot be adequately evaluated. This inclusion was necessary to increase the sample size and achieve results that are more accurate. In this analysis, 435 patients were included in the low-dose HCG group and 595 in the control group. A sample size of 524 patients is needed (
) to prove a significant difference between three groups (rFSH only, rFSH + low-dose HCG, or rFSH + HMG). This meta-analysis approaches these numbers. On the other hand, more prospective studies are needed to confirm these results.
The current cost-effectiveness model is based on the results obtained from the meta-analysis. Cancellation rate and miscarriage rate were mentioned separately, in two studies. A detailed Markov chain model needs to be calculated including all pregnancy parameters for more than one treatment cycle (
), the cost-benefit and improved safety of this regimen was discussed. Interestingly, clinical pregnancy rates are improved in the supplemented antagonist protocol and, in comparison to the long agonist protocol, a significant difference in the incidence of OHSS was noted. This finding is important and needs to be further evaluated. It is the first randomized evidence between antagonist–agonist protocols that combines similar efficacy, increased safety and more patient-friendly IVF.
In this meta-analysis, data are pooled for all infertility groups and no results can be drawn specifically for each group. Recombinant FSH was administered in seven trials (
A prospective comparison of in-vitro fertilization (IVF) outcome following controlled ovarian hyperstimulation (COH) regimens using follitropin alpha exclusively or with the addition of low-dose human chorionic gonadotropin (hCG).
Ovarian stimulation with daily late follicular phase administration of low-dose human chorionic gonadotropin for in-vitro fertilization: a prospective, randomized trial.
Clinical effects of ovulation induction with recombinant follicle-stimulating hormone supplemented with recombinant luteinizing hormone or low-dose recombinant human chorionic gonadotropin in the midfollicular phase in microdose cycles in poor responders.
Recombinant follicle-stimulating hormone (rFSH) supplemented with low-dose human chorionic gonadotropin compared with rFSH alone for ovarian stimulation for in-vitro fertilization.
Clinical effects of ovulation induction with recombinant follicle-stimulating hormone supplemented with recombinant luteinizing hormone or low-dose recombinant human chorionic gonadotropin in the midfollicular phase in microdose cycles in poor responders.
Recombinant follicle-stimulating hormone (rFSH) supplemented with low-dose human chorionic gonadotropin compared with rFSH alone for ovarian stimulation for in-vitro fertilization.
) mentioned criteria for HCG administration. In these studies, mean follicle diameter during HCG administration ranged from 17 mm to 18 mm. The HCG was administered mainly in the urinary form (5000–10,000 IU) and one study (
The underlying mechanism responsible for improved pregnancy rates in GnRH antagonist protocols has yet to be clarified. Possible explanations include the LH effect from the addition of low-dose HCG, the increased oestradiol concentrations on the day of HCG administration and the endometrial effect of low-dose HCG. Controversy still exists when examining current evidence for each mechanism.
The effect of added LH in GnRH antagonist cycles is not clear yet. Although some studies present evidence after LH supplementation (
Initiation of gonadotropin-releasing hormone antagonist on day 1 as compared to day 6 of stimulation: effect on hormonal levels and follicular development in in-vitro fertilization cycles.
The Journal of Clinical Endocrinology and Metabolism.2003; 12: 5632-5637
Are endogenous LH levels during ovarian stimulation for IVF using GnRH analogues associated with the probability of ongoing pregnancy? A systematic review.
Are endogenous LH levels during ovarian stimulation for IVF using GnRH analogues associated with the probability of ongoing pregnancy? A systematic review.
) found higher serum oestradiol concentrations on the day of HCG administration and a higher number of mature oocytes but no difference in pregnancy rates. The other study (
) showed that LH add-back strategy (375 IU/day) rescued adverse effects on implantation from high doses of GnRH antagonist. In the current analysis, a trend towards significantly higher clinical pregnancy rates in the low-dose HCG-supplemented versus non-supplemented antagonist protocol was observed, indicating that the LH effect might not be the only responsible factor and that low-dose HCG might also exert an endometrial effect. From luteal phase studies, it is evident (
Prevention of endometrial apoptosis: randomized prospective comparison of human chorionic gonadotropin versus progesterone treatment in the luteal phase.
The Journal of Clinical Endocrinology and Metabolism.2005; 4: 2351-2356
) that HCG prevents apoptosis by exerting a direct effect on endometrial stromal cells.
Another HCG effect in the endometrium can be mimicked by LH. HCG and LH can up-regulate cyclooxygenase-2 gene expression and increase the morphological as well as functional differentiation of human endometrial stromal cells into deciduas (
Up-regulation of cyclooxygenase-2 gene expression by chorionic gonadotropin during the differentiation of human endometrial stromal cells into decidua.
Altered endocrinology has also been observed. Low-dose HCG increased oestradiol concentrations, on the day of HCG administration when compared with non-supplemented protocols. The association between oestradiol concentrations on the day of HCG administration and pregnancy rates is controversial (
Where mentioned, a trend towards higher progesterone concentrations on the day of HCG administration was noted although pregnancy rates did not show a significant difference. In one study in which patients were down-regulated using a long agonist protocol (
), most patients who received low-dose HCG supplementation (14 out of 17) reached over 1.5 ng/ml with a mean concentration of 2.6 ± 0.3 ng/ml. HCG alone stimulates the production of progesterone, oestradiol and testosterone by human luteinized granulosa cells in vitro (
) with reference to progesterone concentrations 0.9 ng/ml and their effect on pregnancy rates. On the other hand, low-dose HCG might exert a complex role in the endometrium (
) thus overcoming the adverse effect from premature luteinization.
Evidently, low-dose HCG can be used as a replacement for completing follicular development either with GnRH agonist or antagonist protocol. Benefits include lower FSH consumption and lower OHSS rates. Low-dose HCG-supplemented protocols are a less costly but equally effective method to complete ovarian stimulation and hold the promise of improved clinical pregnancy rates in antagonist cycles. Answering the question of which supplemented protocol to select, both strategies are presented as equally cost-effective options. Supplemented agonist and antagonist protocols show small differences in FSH consumption. The choice of the less costly supplemented protocol, eventually, will depend on FSH consumption before low-dose HCG initiation. This is a specific target for future research. Another important point is that low-dose HCG antagonist protocols show less standard deviation on FSH consumption (Table 5) than similar long agonist protocols (Table 3), thus indicating a less risky choice.
Table 5Total FSH (IU) consumed in the antagonist protocol.
Low-dose HCG supplemented antagonist
No-supplement antagonist
Prospective studies only
1747.1 ± 102.38
2278.4 ± 113.8
All studies
1792.4 ± 106.76
2415.36 ± 373
Values are mean ± SD. One-way analysis of variance comparisons were performed. HCG = human chorionic gonadotrophin.
In a different study, low-dose HCG (2500 IU) used as the ovulation trigger prevented the development of OHSS in high-risk women without compromising success rates (
). This is probably achieved, by reducing the overproduction of vascular endothelial growth factor that in excess increases vascular permeability leading to OHSS.
More randomized clinical trials need to be performed to confirm these results. Comparisons must include non-supplemented long agonist protocols to compare the clinical efficacy of a patient-friendly and inexpensive protocol with the so-called ‘golden standard protocol’. Adequate reporting of these trials is required.
Appendix A. Cost assumptions in the model
Therapy was defined as participation to the current cycle.
Main outcome of the study was clinical pregnancy rate (intrauterine pregnancy at 6 weeks of gestation confirmed by ultrasound, as derived from the meta-analysis).
Spontaneous pregnancies taking place independently from treatment, whenever mentioned, were excluded from the meta-analysis.
Ovarian hyperstimulation syndrome hospitalization and work absence: €1200.
FSH price was considered the same (for either recombinant FSH or human menopausal gonadotrophin) with a cost of €0.63 per unit.
Overall agonist price = Overall antagonist price.
Direct cost: analysis was performed on the costs of IVF treatment itself, including current IVF cycle. Multiple pregnancy costs, antenatal, perinatal and post-partum care costs in women who became pregnant were not considered.
Ultrasound cost considered equal given the fact that patients returned to the clinic every 2 days for ultrasound and blood sampling.
No discount rate for costs was applied. Costs were considered at the present value.
References
Al-Inany H.G.
Abou-Setta A.M.
Aboulghar M.A.
et al.
HMG versus rFSH for ovulation induction in developing countries: a cost-effectiveness analysis based on the results of a recent meta-analysis.
Clinical effects of ovulation induction with recombinant follicle-stimulating hormone supplemented with recombinant luteinizing hormone or low-dose recombinant human chorionic gonadotropin in the midfollicular phase in microdose cycles in poor responders.
A prospective comparison of in-vitro fertilization (IVF) outcome following controlled ovarian hyperstimulation (COH) regimens using follitropin alpha exclusively or with the addition of low-dose human chorionic gonadotropin (hCG).
Up-regulation of cyclooxygenase-2 gene expression by chorionic gonadotropin during the differentiation of human endometrial stromal cells into decidua.
Are endogenous LH levels during ovarian stimulation for IVF using GnRH analogues associated with the probability of ongoing pregnancy? A systematic review.
Initiation of gonadotropin-releasing hormone antagonist on day 1 as compared to day 6 of stimulation: effect on hormonal levels and follicular development in in-vitro fertilization cycles.
The Journal of Clinical Endocrinology and Metabolism.2003; 12: 5632-5637
Prevention of endometrial apoptosis: randomized prospective comparison of human chorionic gonadotropin versus progesterone treatment in the luteal phase.
The Journal of Clinical Endocrinology and Metabolism.2005; 4: 2351-2356
Molecular evidence that growth of dominant follicles involves a reduction in follicle-stimulating hormone dependence and an increase in luteinizing hormone dependence in cattle.
Lower apoptosis rate in human cumulus cells after administration of recombinant luteinizing hormone to women undergoing ovarian stimulation for in-vitro fertilization procedures.
Ovarian stimulation with daily late follicular phase administration of low-dose human chorionic gonadotropin for in-vitro fertilization: a prospective, randomized trial.
Recombinant follicle-stimulating hormone (rFSH) supplemented with low-dose human chorionic gonadotropin compared with rFSH alone for ovarian stimulation for in-vitro fertilization.
Declaration: The authors report no financial or commercial conflicts of interest.
Footnotes
Ioannis Kosmas MD, MSc, PhD, completed his specialty degree in 2002 at the University of Ioannina, Medical School, Greece. After that he spent some time at the Center of Minimal Invasive Surgery at Royal Free Hospital, London (2003) and at the Center of Reproductive Medicine at the Dutch-speaking Free University of Brussels (2004–2007) where he obtained his subspecialty in Reproductive Medicine. His special interest includes meta-analysis and decision sciences, pharmaco-economics and molecular imaging in embryo implantation. Dr Ioannis Kosmas
Ioannis Kosmas MD, MSc, PhD, completed his specialty degree in 2002 at the University of Ioannina, Medical School, Greece. After that he spent some time at the Center of Minimal Invasive Surgery at Royal Free Hospital, London (2003) and at the Center of Reproductive Medicine at the Dutch-speaking Free University of Brussels (2004–2007) where he obtained his subspecialty in Reproductive Medicine. His special interest includes meta-analysis and decision sciences, pharmaco-economics and molecular imaging in embryo implantation. Dr Ioannis Kosmas
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