The use of recombinant luteinizing hormone in patients undergoing assisted reproductive techniques with advanced reproductive age: A systematic review and meta-analysis

Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA.
Fertility and sterility (Impact Factor: 4.59). 02/2012; 97(5):1108-14.e1. DOI: 10.1016/j.fertnstert.2012.01.130
Source: PubMed

ABSTRACT To evaluate the effect of recombinant LH in assisted reproduction technology (ART) cycles in patients of advanced reproductive age.
A systematic review and meta-analysis.
Published randomized controlled clinical trials comparing recombinant LH plus recombinant FSH versus recombinant FSH only in patients of advanced reproductive age.
Patients 35 years and older undergoing assisted reproduction.
Recombinant LH plus recombinant FSH controlled ovarian hyperstimulation (COH) versus recombinant FSH stimulation only in assisted reproduction cycles.
Implantation and clinical pregnancy.
Seven trials were identified that met inclusion criteria and comprised 902 assisted reproduction technology cycles. No differences in serum E(2) on the day of hCG administration were reported in any trials. Two trials reported lower oocyte yield and one trial reported lower metaphase II oocyte yield in the recombinant LH-supplemented group. One trial reported higher fertilization rates in the recombinant LH-supplemented group. In a fixed effect model, implantation was higher in the recombinant LH-supplemented group (odds ratio 1.36, 95% confidence interval 1.05-1.78). Similarly, clinical pregnancy was increased in the recombinant LH-supplemented group (odds ratio 1.37, 95% confidence interval 1.03-1.83).
The addition of recombinant LH to ART cycles may improve implantation and clinical pregnancy in patients of advanced reproductive age.

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Available from: Micah J Hill, Jan 29, 2015
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    • "Although these findings should be interpreted with caution (as the primary end-point was not met and the study was not powered to make conclusions about secondary end-points), further investigation in a larger sample using clinical pregnancy, live birth or both, as end-points would be of great interest. The meta-analysis reported by Hill et al. (2012) found LH supplementation to be associated with higher rates of implantation and clinical pregnancy in women aged ≥35 years undergoing ovarian stimulation for assisted reproduction techniques compared with those receiving rhFSH alone; however, that study did not explore the optimal day to initiate LH during ovarian stimulation. Published evidence suggesting that high levels of LH can lead to follicular atresia and spontaneous abortion (Howles et al., 1986; Stanger and Yovich, 1985) has led to the concept of a 'therapeutic window' for LH to stimulate optimal oestradiol production and promote success in assisted reproduction techniques and ovulation induction (Kumar and Sait, 2011; Shoham, 2002). "
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    ABSTRACT: In this open-label study, women aged 36-40 years undergoing ovarian stimulation were randomized to recombinant human FSH (rhFSH) plus recombinant human luteinizing hormone (rhLH) from stimulation day 1 (group A; n = 103), or rhFSH alone (days 1-5) followed by rhFSH plus rhLH from day 6 (group B; n = 99). The primary objective was equivalence in number of oocytes retrieved per patient. The mean (±SD) number of oocytes retrieved was 9.7 (±6.9) in group A and 10.9 (±6.5) in group B; the estimated difference between groups (-1.28 oocytes [95% confidence interval: -3.15 to 0.59]) did not reach the predefined limit of equivalence (±3 oocytes). The study's primary objective was therefore not met. In both groups, a mean (±SD) of 1.9 (±0.6) embryos were transferred per patient. Implantation rates were 24.7% in group A and 13.3% in group B. Clinical pregnancy rates per started cycle and per embryo transfer were 31.6% and 34.4% in Group A, 17.2% and 18.9% in Group B. Ovarian hyperstimulation syndrome was reported in four (group A) and five (group B) patients. The potential benefit of initiating LH supplementation earlier during ovarian stimulation in older women is of interest, warranting further exploration. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.
    Reproductive biomedicine online 06/2015; 31(3). DOI:10.1016/j.rbmo.2015.06.002 · 3.02 Impact Factor
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    • "Some authors suggested the addition of recombinant LH during gonadotropin stimulation in poor responder patients [80]. However, two meta-analyses [81, 82] showed that the addition of recombinant LH does not increase the number of oocyte retrieved, the total dose of FSH, the cancellation rates, and the ongoing pregnancy rates in poor responder patients. "
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    ABSTRACT: Despite the fact that in the last two decades an enormous number of papers on the topic of poor ovarian response have been published in the literature, so far it has been impossible to identify any efficient treatment to improve the ovarian response and the clinical outcome of this group of patients. The incidence of poor ovarian responders among infertile women has been estimated at 9-24% but according to recent reviews, it seems to have slightly increased. The limitation in quantifying the incidence of these patients among the infertile population is due to the difficulty of a clear definition in literature. A recent paper by the Bologna ESHRE working group on poor ovarian response has been the first real attempt to find a common definition. Current literature proposes new risk factors which could be the cause of a reduction in ovarian reserve, which also includes genetic factors. This represents the first necessary step towards finding applicable solutions for these patients. To date, there is a substantial lack of literature that identifies an ideal protocol for these patients. The use of the "Bologna criteria" and the introduction of long acting gonadotropin in clinical practice have given rise to new promising stimulation protocols for this group of patients.
    BioMed Research International 07/2014; 2014:352098. DOI:10.1155/2014/352098 · 3.17 Impact Factor
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    • "Another meta-analysis conducted in women of advanced reproductive age (≥35 years) found that the clinical pregnancy rate was higher in the r-hLH supplementation group than in the r-hFSH alone group (seven studies, n = 902; OR 1.37; 95% CI 1.03–1.83) [35]. In agreement with the findings of our meta-analysis, an additional meta-analysis found a statistically significant higher pregnancy rate in favour of r-hFSH plus r-hLH compared with r-hFSH alone in a subgroup of patients with poor ovarian response (POR) (three studies; n = 310; OR 1.85; 95% CI 1.10–3.11) "
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    ABSTRACT: The potential benefit of adding recombinant human luteinizing hormone (r-hLH) to recombinant human follicle-stimulating hormone (r-hFSH) during ovarian stimulation is a subject of debate, although there is evidence that it may benefit certain subpopulations, e.g. poor responders. A systematic review and a meta-analysis were performed. Three databases (MEDLINE, Embase and CENTRAL) were searched (from 1990 to 2011). Prospective, parallel-, comparative-group randomized controlled trials (RCTs) in women aged 18-45 years undergoing in vitro fertilization, intracytoplasmic sperm injection or both, treated with gonadotrophin-releasing hormone analogues and r-hFSH plus r-hLH or r-hFSH alone were included. The co-primary endpoints were number of oocytes retrieved and clinical pregnancy rate. Analyses were conducted for the overall population and for prospectively identified patient subgroups, including patients with poor ovarian response (POR). In total, 40 RCTs (6443 patients) were included in the analysis. Data on the number of oocytes retrieved were reported in 41 studies and imputed in two studies. Therefore, data were available from 43 studies (r-hFSH plus r-hLH, n = 3113; r-hFSH, n = 3228) in the ITT population (all randomly allocated patients, including imputed data). Overall, no significant difference in the number of oocytes retrieved was found between the r-hFSH plus r-hLH and r-hFSH groups (weighted mean difference -0.03; 95% confidence interval [CI] -0.41 to 0.34). However, in poor responders, significantly more oocytes were retrieved with r-hFSH plus r-hLH versus r-hFSH alone (n = 1077; weighted mean difference +0.75 oocytes; 95% CI 0.14-1.36). Significantly higher clinical pregnancy rates were observed with r-hFSH plus r-hLH versus r-hFSH alone in the overall population analysed in this review (risk ratio [RR] 1.09; 95% CI 1.01-1.18) and in poor responders (n = 1179; RR 1.30; 95% CI 1.01-1.67; intention-to-treat population); the observed difference was more pronounced in poor responders. These data suggest that there is a relative increase in the clinical pregnancy rates of 9% in the overall population and 30% in poor responders. In conclusion, this meta-analysis suggests that the addition of r-hLH to r-hFSH may be beneficial for women with POR.
    Reproductive Biology and Endocrinology 02/2014; 12(1):17. DOI:10.1186/1477-7827-12-17 · 2.23 Impact Factor
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