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


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.
    Full-text · Article · Jun 2015 · Reproductive biomedicine online
    • "years of age (Kolibianakis et al., 2007). Conversely, recent systematic reviews of r-LH supplementation in any women undergoing IVF have suggested that r-FSH/ r-LH improves the clinical pregnancy rate compared with r-FSH overall (risk ratio [RR] 1.09; 95% CI 1.01– 1.18) (Lehert et al., 2014), in women aged ≥35 years (OR 1.37, 95% CI 1.03 –1.83) (Hill et al., 2012) and in those with poor ovarian response (OR 1.3, 95% CI 1.05 –1.62) (Lehert et al., 2014). Some individual studies have also reported results that conflict with those of the current study in women aged ≥35 years (Humaidan et al., 2004; Matorras et al., 2009). "
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    ABSTRACT: Does luteinizing hormone (LH) supplementation improve live birth rate after in vitro fertilization (IVF) in patients aged ≥35 years receiving a gonadotrophin-releasing hormone (GnRH) antagonist protocol? There was no difference in live birth rate with use of LH during IVF in patients aged ≥35 years undergoing IVF treatment using a GnRH antagonist protocol. Use of GnRH analogues as part of a controlled ovarian hyperstimulation protocol during IVF treatment cycles decreases the amount of LH available to developing follicles. The role of LH supplementation for improving outcomes in patients undergoing controlled ovarian hyperstimulation as part of assisted reproduction treatments, particularly those involving a GnRH antagonist protocol, is unclear. It has been suggested that higher risk patients (e.g. age ≥35 years, poor ovarian reserve) may benefit from LH supplementation. This single-centre, randomized controlled trial was conducted from 1 October 2012 to 30 June 2014. A total of 240 women aged ≥35 years undergoing IVF received ovarian stimulation using a GnRH antagonist protocol, with recombinant follicle-stimulating hormone (r-FSH; Gonal-F(®)) starting from cycle day 2 or 3. GnRH antagonist (Cetrotide(®)) was administered on Day 5 of r-FSH administration. On Day 6, patients in the LH supplementation group were switched to r-FSH/r-LH (Pergoveris(®)) 150/75 IU/day. Randomization to study treatments was performed in blocks of 4 via a computer-generated random number list. Of the 240 patients randomized to treatment, 120 received r-FSH/r-LH and 120 received r-FSH. Patients were recruited from the IVFAS, An Sinh Hospital, Ho Chi Minh City, Vietnam. Live birth rate did not differ significantly (P > 0.05) between r-FSH/r-LH and r-FSH recipients (16.7 versus 17.5%; between-group difference 0.8, 95% confidence interval [CI] -9.5, 11.2). In addition, there were no significant differences between the r-FSH/r-LH and r-FSH groups with respect to the number of oocytes retrieved, implantation rate, miscarriage rate and clinical pregnancy rate. The open-label design could have introduced bias, and the relatively small sample size may have allowed detection of only the most common adverse events. In addition, the study was likely to be underpowered based on differences between the response rate assumptions used in the sample size calculation and the actual response rate during the study. The results of this study found no additional benefit from adding LH supplementation to ovarian stimulation with a GnRH antagonist protocol in women aged ≥35 years, and add to the body of evidence in this area. However, findings across studies are still inconsistent and additional research is needed before any clear recommendations for clinical practice can be made. This study was supported by the Research Center for Genetics and Reproductive Health, School of Medicine, Vietnam National University HCMC. The authors state that they have no financial or commercial conflicts of interest. The trial was registered with (NCT02244866). © The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email:
    No preview · Article · Mar 2015 · Human Reproduction
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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.
    Full-text · Article · Jul 2014 · BioMed Research International
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