Recombinant human follicle-stimulating hormone produces more oocytes with a lower total dose per cycle in assisted reproductive technologies compared with highly purified human menopausal gonadotrophin: a meta-analysis

Abstract

BackgroundHuman menopausal gonadotrophins and recombinant human follicle stimulating hormone are the two main gonadotrophin products utilized for controlled ovarian stimulation in assisted reproductive technologies. In this meta-analysis, the number of oocytes was designated as the most relevant endpoint directly resulting from ovarian stimulation, and therefore where the drug effect may be estimated with the best sensitivity.MethodsAll published randomized controlled trials on ovarian stimulation comparing the two gonadotrophin products were evaluated. Internal validity was determined using Chalmers' validated scale. If trials did not meet the established quality criteria, a sensitivity analysis assessed the stability of the results. The comparison of continuous variables was conducted following the weighted mean difference and the standardized mean difference (Cohen's effect size) with the random model. Given the known relationship of baseline conditions on treatment endpoints, results were adjusted for age, body mass index and type of infertility.ResultsSixteen studies involving 4040 patients were included. Treatment with human menopausal gonadotrophins resulted in fewer oocytes (-1.54; 95% CI: -2.53 to -0.56; P < 0.0001) compared to recombinant human follicle-stimulating hormone. When adjusting for baseline conditions, the mean difference estimate was -2.10 (95% CI: -2.83 to -1.36; P < 0.001). A higher total dose of human menopausal gonadotrophin was necessary (mean difference, 235.46 IU [95% CI: 16.62 to 454.30; P = 0.03]; standardized mean difference, 0.33 [95% CI: 0.08 to 0.58; P = 0.01]). The pregnancy absolute risk difference (RD [hMG-r-hFSH]) for fresh transfers was 3% (P = 0.051), and the relative risk 1.10 (P = 0.06). When adjusted for baseline conditions, the relative risk was 1.04 (P = 0.49) and absolute difference was 0.01 (P = 0.34), respectively.ConclusionsBecause baseline conditions are predictive of outcome, meta-analytic results are more sensitive when these variables are considered. Using an endpoint closely associated with the stimulation period, sufficient sensitivity is achieved to compare gonadotrophin treatments. As the largest meta-analysis published to date on this subject, treatment with human menopausal gonadotrophins is characterized by fewer oocytes and a higher total dose. When considering only fresh transfers, pregnancy rates were similar.

The Use of rLH, HMG and hCG in Controlled Ovarian Stimulation for Assisted Reproductive Technologies

“…The number of patients required to show a benefit in hMG had been calculated at over 2100 (76) (77). Two more recent meta-analyses in 2010 each failed to show a significant improvement in live birth with the use of hMG (74,78). However, the p values for these studies were borderline significant (0.051-0.06) and the odds ratio of pregnancy was similar to the other trials.…”

“…These trials are relatively homogenous, with similar dosing strategies and primarily GnRH agonist pituitary downregulation. These RCT have been systematically evaluated in several meta-analyses shown in Table 1 (74)(75)(76)(77)(78). The number of patients required to show a benefit in hMG had been calculated at over 2100 (76) (77).…”

Efficacy, efficiency and effectiveness of gonadotropin therapy for infertility treatment

“…37 A number of meta-analyses of randomized controlled trials have compared the efficacy of different gonadotropin products, as can be seen in Table 5. [38][39][40][41][42][43][44][45] Despite the heterogeneity of several of these meta-analyses pertaining the different stimulation protocols and choice of fertilization with standard in vitro fertilization (IVF) or intracytoplasmatic sperm injection (ICSI), the overall conclusion is that both urinary gonadotropins, mainly hMG preparations, and recombinant gonadotropins have similar efficacy in terms of achieving a pregnancy or live birth per treatment cycle. While some of these studies were in favour of hMG preparations, 38,39,41 in spite of the fact that the confidence limits were just 1% lower, others reported no differences in pregnancy outcomes between the two treatments.…”

“…While some of these studies were in favour of hMG preparations, 38,39,41 in spite of the fact that the confidence limits were just 1% lower, others reported no differences in pregnancy outcomes between the two treatments. 40,[43][44][45] Furthermore, no significant differences were noted for spontaneous abortion, multiple pregnancy, cycle cancellation and ovarian hyperstimulation syndrome (OHSS) rates. [38][39][40][41][42][43][44][45] Although live birth per started cycle is an important endpoint in assisted reproductive technologies (ART), it is confounded by many variables, apart from the stimulation protocol itself, which are difficult to ascertain.…”

What is the Clinical Relevance of Follicle-Stimulating Hormone Isoforms in Fertility Treatment?

“…Whether administered as u-hFSH alone or in combination with LH activity (as in hMG), higher doses are needed and may result in fewer oocytes than r-hFSH. [44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60]65 This again highlights that the more basic isoform profile of r-hFSH may be more effective in recruiting follicles than u-hFSH or hMG (which contain less potent, more acidic FSH isoforms) and thereby results in the retrieval of higher numbers of oocytes.…”