Open Access

Recombinant human follicle-stimulating hormone (r-hFSH) plus recombinant luteinizing hormone versus r-hFSH alone for ovarian stimulation during assisted reproductive technology: systematic review and meta-analysis

  • Philippe Lehert1, 2Email author,
  • Efstratios M Kolibianakis3,
  • Christos A Venetis3,
  • Joan Schertz4,
  • Helen Saunders5, 6,
  • Pablo Arriagada5, 6,
  • Samuel Copt5, 7 and
  • Basil Tarlatzis3
Reproductive Biology and Endocrinology201412:17

DOI: 10.1186/1477-7827-12-17

Received: 5 November 2013

Accepted: 12 February 2014

Published: 20 February 2014

Abstract

Background

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.

Methods

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).

Results

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 intention-to-treat (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; ITT population); the observed difference was more pronounced in poor responders.

Conclusions

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.

Keywords

In vitro fertilization Poor ovarian response Pregnancy Recombinant human follicle-stimulating hormone Recombinant human luteinizing hormone supplementation

Background

The efficacy of recombinant human follicle-stimulating hormone (r-hFSH) for ovarian stimulation is well established [1]; however, the role of supplementary recombinant human luteinizing hormone (r-hLH) is less clear. LH has a number of roles in follicular development [2] and in the periovulatory phase, LH is involved in the induction of ovulation [2], completion of meiosis I [3], early luteinization and the production of progesterone [4]. Ovarian steroidogenesis can be driven by activation of a low number (around 1%) of LH receptors and, during cycles of assisted reproductive technology (ART), adequate levels of endogenous LH are usually present despite pituitary suppression with gonadotrophin-releasing hormone (GnRH) analogues [5, 6].

r-hLH in association with an FSH preparation is indicated for the stimulation of follicular development in adult women with severe LH and FSH deficiency [7]; in clinical trials these patients were defined by an endogenous serum LH level of <1.2 IU/l [8]. In addition to the utility of r-hLH supplementation in women with hypogonadotropic hypogonadism [9], evidence suggests that r-hLH supplementation may be beneficial for certain subpopulations of women; for example, those with an initial suboptimal (poor) ovarian response to r-hFSH monotherapy [911] and those aged >35 years [9, 11]. Despite these potential benefits, the use of r-hLH supplementation during ovarian stimulation has long been debated and there is conflicting evidence in the literature [2].

The primary objective of the meta-analysis reported here was to compare the effectiveness of treatment with r-hFSH plus r-hLH with r-hFSH alone in infertile women undergoing ovarian stimulation with GnRH analogues. The investigation of the effect of r-hLH supplementation was also conducted in subpopulations of patients: for example, patients with a poor ovarian response (POR).

Methods

The protocol used for this systematic review and meta-analysis (see Additional file 1: Supplementary Material A) adhered to the International Conference on Harmonisation (ICH) E9 Statistical Principles for Clinical Trials [12], the Cochrane Handbook for Systematic Reviews of Interventions [13] and the Committee for Proprietary Medicinal Products guidelines [14]. The project was initiated in November 2010 and completed in September 2011.

Literature searches

Literature searches were conducted to identify studies published between 1 January 1990 and 1 May 2011. Three databases were searched: MEDLINE, Embase and CENTRAL. Google Scholar and relevant journals, symposia and conference proceedings were also used to identify further relevant publications. Non-published research (if available) could also be included as was any Merck Serono randomized controlled trial (RCT) known to be unpublished (prior to 2002). The search was not limited by language. The search strategy used key words/terms and database-specific indexing terminology (the MEDLINE search strategy is shown in Additional file 2: Table S1).

Study selection

The inclusion criteria (established before the search) were: prospective, randomized, parallel-, comparative-group trials conducted in women aged 18–45 years undergoing in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI) or both, treated with GnRH analogues and r-hFSH plus r-hLH or r-hFSH alone for multifollicular development. Studies in patients or subgroups with anovulatory infertility or polycystic ovarian syndrome were excluded.

The titles of retrieved citations were initially reviewed by two authors to remove duplicates. The search results were cross-checked against publications listed in previous meta-analyses [1519] to ensure that all relevant studies were included.

Data collection

The eligibility and relevance of the trials were assessed by reviewing each abstract or the full text if the abstract was inadequate. If additional information was required, the corresponding authors and/or study sponsors were contacted.

To assess the methodological quality of RCTs, a qualitative checklist was completed and independently evaluated by each reviewer [13]. The checklist comprised seven items assessing internal, external and statistical validity (Additional file 1: Supplementary Material B).

The co-primary endpoints used for the meta-analysis were number of retrieved oocytes and clinical pregnancy rate, which was defined according to International Committee Monitoring Assisted Reproductive Technologies and the World Health Organization criteria as ultrasonographic visualization of one or more gestational sacs.

Other endpoints included: number of metaphase II oocytes, embryos and transferred embryos; positive β-human chorionic gonadotrophin test; ongoing pregnancy (defined as ultrasound evidence of at least one gestational sac with foetal cardiac activity); live birth (defined as the number of live births per started cycle); number of good quality embryos; duration of ovarian stimulation; peak oestradiol levels; and total dose of r-hFSH.

Statistical methods

All statistical analyses were performed using R statistical packages (release 2.15.2).

The full analysis set from the studies was used because it is as close as possible to the intention-to-treat [ITT] principle of including all randomized patients. In this analysis, the ITT population consisted of all randomly allocated patients and included imputed data. In addition, the per-protocol (PP) population (patients from all studies in which the endpoint was fully documented) was used in supportive analyses.

The meta-analysis used a random effects model, which was calculated using both the restricted maximum likelihood (REML) and the DerSimonian and Laird approach [20]. Meta-regression on the ITT dataset considered pre-specified relevant covariates.

Four covariates were selected: 1) patient age – all patients (young/normal age, i.e. no selection regarding age) or advanced maternal age (>35 years); 2) ovarian response to treatment – normal or poor (POR); 3) mode of endogenous LH suppression – GnRH agonist or antagonist; and 4) insemination technique – IVF or ICSI. POR was defined according to study authors’ criteria and although the studies were published prior to European Society of Human Reproduction and Embryology (ESHRE) consensus definition for POR [21], in 10 of the 14 studies reporting POR data, the definition of POR employed was aligned with the subsequently reported ESHRE definition. Hierarchical clustering of studies was undertaken based on the first three covariates because most studies (n = 27; 60%) used both IVF and ICSI for the insemination technique.

For binary variables (e.g. clinical pregnancy), the risk ratio (RR) was evaluated as the main calculation of effect size [22]. Continuous variables (e.g. number of oocytes retrieved) were evaluated using the weighted mean difference, or the standardized mean difference (Cohen’s effect size) if the endpoints did not use the same measurement scale.

For missing endpoints, data were imputed using another endpoint related to the missing value as the covariate in a regression model to estimate the missing value. The calculations and coefficients for data imputation are shown in Additional file 3: Table S2. The linear relationship between the two variables was measured using the R2 and its 95% confidence interval (CI).

The internal and external validity of the meta-analysis were optimized by maximizing the sample size and controlling for bias. Sources of external bias were assessed to determine their possible impact on the observed effect size.

The risk of publication bias was assessed using the funnel plot method and analysed statistically using a linear regression test to determine the linear regression coefficient between log odds ratio (OR) and its standard error. Radial Galbraith plots were used to assess the consistency of the observed outcomes with different precisions (e.g. due to sampling variances).

See Additional file 1: Supplementary Material C for additional details of the statistical methods employed.

Results

Of the 2371 publications initially identified, 36 eligible published RCTs were included in the analysis (Figure 1). There were four relevant unpublished RCTs from the Merck Serono S.A. (Merck Serono S.A. – Switzerland, an affiliate of Merck KGaA, Darmstadt, Germany) database (study reference numbers: MS8839, MS9029, MS9032 and MS9640) and so these were also included. In total, data from 6443 patients undergoing ovarian stimulation for IVF/ICSI using r-hFSH plus r-hLH or r-hFSH alone (and a GnRH analogue) were available for analysis. Data for the co-primary endpoints were available for most (95.6%) studies. A summary of the studies (n = 40), including their subgroup categories, is shown in Table 1. Five RCTs included subgroups and these were considered as separate studies; thus, a total of 45 quantitative studies were included in the meta-analysis (Figure 1). In three studies [2325], patients were divided according to young/normal versus advanced maternal age subgroups. In another study [26], the patient population in each group was prospectively stratified by age (young/normal versus advanced maternal age) and in another study [27], there were two subgroups classified according to the LH suppression method used (long GnRH agonist and GnRH antagonist protocol).
https://static-content.springer.com/image/art%3A10.1186%2F1477-7827-12-17/MediaObjects/12958_2013_Article_1194_Fig1_HTML.jpg
Figure 1

The study selection process. a2274 records excluded based on title. bStudies MS8839, MS9029, MS9032 and MS9640. cAge subgroups from Humaidan et al., 2004 [23]; Marrs et al., 2004 [25]; Nyboe Andersen et al., 2008 [28]; Bosch et al., 2011 [26]; gonadotrophin-releasing hormone analogue subgroup from Motta et al., 2005 [27]. MS, Merck Serono S.A. – Switzerland, an affiliate of Merck KGaA, Darmstadt, Germany; r-hFSH, recombinant human follicle-stimulating hormone.

Table 1

Main characteristics of the studies included in the meta-analysis (n = 40)

Study

Total number of patients in study

Patient response categorya

Age category (age restrictions)b

GnRH agonist, GnRH antagonist or both

Insemination technique

Starting dose

Stimulation day (r-hLH initiated)

      

r-hFSH (IU)

r-hLH (IU)

 

Williams 2000 [47]

60

Normal

None

Agonist

IVF/ICSI

300

25

 

MS8839 [48]

76

Normal

None

Agonist

IVF

150

75

1

MS9032 [49]

45

Normal

None

Agonist

ICSI

c

75

1

MS9029 [50]

42

Poor

None

Agonist

ICSI

450

75

1

Balasch 2001 [51]

30

Normal

None

Agonist

IVF/ICSI

450

75

1

MS9640 [52]

141

Normal

None

Agonist

IVF/ICSI

225

75

1

Lisi 2002a [53]

453

Poor

None

Agonist

IVF

225

75

7

Lisi 2002b [54]

22

Normal

None

Agonist

IVF/ICSI

150

75

7

De Moustier 2002 [55]

169

Normal

Advanced

Agonist

IVF

225

c

 

Ludwig 2003 [56]

20

Normal

None

Antagonist

IVF/ICSI

 

75

 

Sauer 2004 [57]

42

Normal

None

Antagonist

ICSI

225

150

7

Cedrin-Durnerin 2004 [58]

203

Normal

None

Antagonist

IVF/ICSI

c

75

 

Ferraretti 2004 [10]

108

Poor

None

Agonist

IVF/ICSI

c

c

 

Humaidan 2004 [23]

231

Normal

Two subgroups

Agonist

IVF/ICSI

c

c

8

Marrs 2004 [25]

431

Normal

Two subgroups

Agonist

ICSI

225

150

6

Motta 2005 [27]

102

Poor

None

Both

IVF/ICSI

 

75

 

Griesinger 2005 [59]

127

Normal

None

Antagonist

IVF/ICSI

150

75

1

Demirol 2005 [60]

106

Poor

None

Antagonist

ICSI

450

150

1

De Placido 2005 [61]

130

Poor

None

Agonist

IVF/ICSI

225

150

8

Tarlatzis 2006 [62]

114

Normal

None

Agonist

IVF/ICSI

150

75

 

Ramirez 2006 [63]

34

Poor

None

Antagonist

IVF/ICSI

c

150

 

Levi-Setti 2006 [64]

40

Normal

None

Antagonist

ICSI

225

75

 

Abdelmassih 2006 [65]

206

Normal

None

Agonist

IVF/ICSI

225

75

7

Aytac 2006 [66]

35

Poor

None

Agonist

ICSI

 

150

 

Fabregues 2006 [67]

120

Normal

Advanced

Agonist

IVF/ICSI

c

150

6

Ruvolo 2007 [68]

42

Poor

None

Agonist

IVF/ICSI

225

c

8

Polidoropoulos 2007 [69]

136

Poor

None

Agonist

ICSI

450

75

 

Berkkanoglu 2007 [70]

97

Normal

None

Agonist

ICSI

600

75

7

Nyboe Andersen 2008 [24]

526

Normal

Two subgroups

Agonist

IVF/ICSI

c

c

7

Barrenetxea 2008 [71]

84

Poor

Advanced

Agonist

ICSI

375

150

6

Pezzuto 2010 [72]

80

Normal

None

Agonist

ICSI

c

75

6

Brunet 2009 [73]

94

Poor

None

Agonist

IVF

 

75

8

Gutman 2009 [74]

20

Normal

None

Agonist

IVF/ICSI

c

75

 

Matorras 2009 [75]

131

Normal

Advanced

Agonist

ICSI

c

150

6

Lahoud 2010 [76]

103

Normal

None

Agonist

IVF/ICSI

 

75

7

Kovacs 2010 [77]

50

Normal

None

Agonist

IVF/ICSI

150

75

1

Wiser 2011 [78]

30

Normal

None

Antagonist

IVF/ICSI

c

75

 

Musters 2012 [79]

244

Poor

Advanced

Agonist

IVF/ICSI

c

c

1

Caserta 2011 [80]

999

Normal

None

Agonist

ICSI

150

75

7

Bosch 2011 [26]

720

Normal

Two subgroups

Antagonist

IVF/ICSI

c

75

6

Total

6443

       

aNormal = normal ovarian response, poor = poor/risk of poor ovarian response.

bAdvanced = advanced maternal age, two subgroups = study had two age-based subgroups.

cStarting dose varied according to numerous factors, such as patient age or body mass index; blank spaces indicate that the data were not reported by the study author.

GnRH, gonadotrophin-releasing hormone; ICSI, intracytoplasmic sperm injection; IVF, in vitro fertilization; r-hFSH, recombinant human follicle-stimulating hormone; r-hLH, recombinant human luteinizing hormone.

Note: the study by Musters et al. was included in the analysis prior to its publication in 2012.

Nineteen studies reported their policy regarding the number of embryos that could be transferred: maximum of two embryos (n = 4); maximum of three embryos (n = 12); maximum of four embryos (n = 2); and in one study, the authors stated that they followed international guidelines although the maximum number of embryos transferred was not given.

No sources of publication bias were found. See Additional file 1: Supplementary Material D, Additional file 4: Figure S1 and Additional file 5: Figure S2 for the results of publication bias assessments and the consistency of the observed outcomes.

Number of oocytes retrieved

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). The PP population (the ‘available data’ subset) consisted of 41 studies (r-hFSH plus r-hLH, n = 3045; r-hFSH, n = 3194).

Overall, no significant difference in the number of oocytes retrieved was found between the r-hFSH plus r-hLH and r-hFSH groups in either the ITT population (mean difference: −0.03; 95% CI −0.41 to 0.34) or the PP population (mean difference: −0.03; 95% CI −0.40 to 0.34). Heterogeneity between studies was high (Q-test: P < 0.0001).

Covariate analyses

The patient’s ovarian response had a possible influence on the effect of r-hFSH plus r-hLH compared with r-hFSH alone for the number of oocytes retrieved, as a significant estimated effect on the number of oocytes retrieved was observed for r-hFSH plus r-hLH in poor (14 studies, n = 1179) versus normal (31 studies, n = 5264) responders: mean difference of 1.17 (P = 0.002; Table 2).
Table 2

Results of meta-regression for the effect of subgroup and covariates analyses for number of oocytes and clinical pregnancy

Moderator (covariate)a

Number of oocytes

Clinical pregnancy

 

Difference

95% CI

Pvalue

RR

95% CI

P value

Analysis of patient response subgroups

      

POR vs. normal responders

1.17

0.42 to 1.92

0.002

1.3

1.05 to 1.62

0.016

Other analyses

      

Advanced maternal age (>35 years) vs. younger age

−0.66

−1.51 to 0.20

0.132

1.1

0.90 to 1.33

0.378

Typology (NPG class vs. othersb)

1.40

0.35 to 2.46

0.009

1.3

0.98 to 1.75

0.067

Missing data: imputed vs existing data

1.52

−3.68 to 6.73

0.566

1.3

0.76 to 2.23

0.332

Publication year

−0.04

−0.16 to 0.09

0.577

1.0

0.97 to 1.03

0.934

Published vs. unpublished (congress abstracts)

0.87

−0.76 to 2.51

0.296

0.7

0.44 to 1.25

0.262

Published vs. unpublished (full papers)

0.27

−1.22 to 1.75

0.724

0.8

0.48 to 1.30

0.346

Methodological quality score (MQS)

−0.96

−2.44 to 0.52

0.204

0.9

0.68 to 1.30

0.693

Sponsored vs. non-sponsored studies

−0.35

−1.15 to 0.45

0.394

0.9

0.78 to 1.09

0.346

Multicentre vs. single centre

0.36

−0.45 to 1.17

0.386

0.9

0.80 to 1.12

0.517

ART technique (ICSI vs. IVF)

0.21

−0.17 to 0.59

0.281

1.1

0.94 to 1.33

0.212

GnRH antagonist vs. GnRH agonist

−0.12

−1.02 to 0.77

0.787

0.9

0.78 to 1.10

0.364

aWith the exception of continuous variables, the categories of the meta-regressors were binary, e.g. POR vs. normal responders.

bOther typology groups: NNG (young/normal age, normal response, GnRH agonist); ANG (advanced maternal age, normal response, GnRH agonist); NNN (young/normal age, normal response, GnRH antagonist); NPN (young/normal age, poor response, GnRH antagonist); APG (advanced maternal age, poor response, GnRH agonist); and ANN (advanced maternal age, normal response, GnRH antagonist).

ART, assisted reproductive technology; CI, confidence interval; GnRH, gonadotrophin-releasing hormone; ICSI, intracytoplasmic sperm injection; IVF, in vitro fertilization; NPG, young/normal age, poor response, GnRH agonist; POR, poor ovarian response; RR, risk ratio.

The results of other covariate analyses for number of oocytes retrieved are shown in Table 2.

Subgroup analyses

The results of the subgroup analysis for normal and poor responders are shown in Figure 2. In the ITT population, a significant benefit on the number of oocytes retrieved was found for r-hFSH plus r-hLH versus r-hFSH alone in poor responders (12 studies, n = 1077 [data for the two studies conducted by Motta et al., 2005 [27] could not be imputed]); mean difference +0.75 oocytes (95% CI 0.14–1.36). The results in the PP population were consistent with those of the ITT population, with a significant benefit of +0.75 oocytes (95% CI 0.13–1.36) for r-hFSH plus r-hLH versus r-hFSH alone in poor responders.
https://static-content.springer.com/image/art%3A10.1186%2F1477-7827-12-17/MediaObjects/12958_2013_Article_1194_Fig2_HTML.jpg
Figure 2

Forest plot of the number of oocytes retrieved in normal versus poor responders (intention- to- treat population). Studies are listed by first author’s last name followed by the year of publication. Some studies were divided by subgroup designations: y, young/normal or o, advanced maternal age. The grey-shaded box designates studies of patients with a poor ovarian response. CI, confidence interval; MS, Merck Serono S.A. – Switzerland, an affiliate of Merck KGaA, Darmstadt, Germany; r-hFSH, recombinant human follicle-stimulating hormone; r-hLH, recombinant human luteinizing hormone.

A non-significant negative effect was observed for r-hFSH plus r-hLH versus r-hFSH alone in normal responders (31 studies, n = 5264): mean difference −0.42 oocytes (95% CI −0.86 to 0.01) in the ITT population and −0.44 oocytes (95% CI −0.87 to 0.00) in the PP population.

Study typology analysis of r-hFSH plus r-hLH versus r-hFSH alone for the number of oocytes retrieved (Additional file 6: Table S3) found a significant benefit for the subgroup of patients who were young/normal age, with a poor response, and received GnRH agonist (mean difference +1.40 oocytes; 95% CI 0.35–2.46; P = 0.01).

Clinical pregnancy rate

Data on clinical pregnancy rate were reported for 39 studies and imputed for four studies; therefore, data were available from 43 studies (r-hFSH plus r-hLH, n = 3139; r-hFSH, n = 3254) in the ITT population and 39 studies (r-hFSH plus r-hLH, n = 3065; r-hFSH, n = 3172) in the PP population.

A significant benefit of r-hFSH plus r-hLH over r-hFSH alone was found for clinical pregnancy rate: RR 1.09 (95% CI 1.01–1.18) in the overall ITT population. The RR for this variable for r-hFSH plus r-hLH versus r-hFSH alone in the PP population was not significant (1.09 [95% CI 1.00–1.19]).

Heterogeneity between studies was low for RR (Q-test: P = 0.437; I2 [percentage of total variability due to heterogeneity] 1.85%).

Covariate analyses

There was a significant increase in clinical pregnancy rate (RR 1.3; 95% CI 1.05–1.62; P = 0.016) with r-hFSH plus r-hLH versus r-hFSH alone in poor responders compared with normal responders (Table 2).

The results of the other covariate analyses for clinical pregnancy rate are given in Table 2.

Subgroup analyses

A significant benefit on the clinical pregnancy rate was found for r-hFSH plus r-hLH versus r-hFSH alone in poor responders (14 studies, n = 1179): RR 1.30 (95% CI 1.01–1.67) in the ITT population (Figure 3). In the PP population, the results were not significant: RR 1.29 (95% CI 0.96–1.73).
https://static-content.springer.com/image/art%3A10.1186%2F1477-7827-12-17/MediaObjects/12958_2013_Article_1194_Fig3_HTML.jpg
Figure 3

Forest plot of the clinical pregnancy rate for normal versus poor responders (intention- to- treat population). Studies are listed by first author’s last name followed by the year of publication. Some studies were divided by subgroup designations: y, young/normal or o, advanced maternal age; g, GnRH agonist or t, GnRH antagonist. The grey-shaded box designates studies of patients with a poor ovarian response. CI, confidence interval; MS, Merck Serono S.A. – Switzerland, an affiliate of Merck KGaA, Darmstadt, Germany; r-hFSH, recombinant human follicle-stimulating hormone; r-hLH, recombinant human luteinizing hormone.

A non-significant difference in clinical pregnancy rates for r-hFSH plus r-hLH versus r-hFSH alone was observed in normal responders (29 studies): RR 1.09 (95% CI 0.95–1.24). Similar results were obtained in the PP population (28 studies): RR 1.09 (95% CI 0.94–1.26).

Study typology analysis found no significant benefits on clinical pregnancy rate for either r-hFSH plus r-hLH or r-hFSH (Additional file 6: Table S3).

Secondary endpoints

Ongoing pregnancy rate

Ongoing pregnancy rate was reported in 14/45 studies and data imputation was performed for 25 other studies; there were 3065 and 3172 patients in the r-hFSH plus r-hLH and r-hFSH groups, respectively (ITT population). The gestational age used for ongoing pregnancy was reported in nine studies and ranged from 10 to 20 weeks. The RR for ongoing pregnancy rate was significant in favour of r-hFSH plus r-hLH (1.14; 95% CI 1.05–1.25; Table 3). In the PP population, the RR for ongoing pregnancy rate was not significant.
Table 3

Outcomes of other efficacy endpoints investigated in the meta-analysis in the overall population and in the normal and poor response subgroups (difference between r-hFSH plus r-hLH and r-hFSH alone groups; ITT population)

 

Mean difference/RR (95% CI) between r-hFSH plus r-hLH and r-hFSH groups

 

Overall ITT population

Poor responders

Normal responders

Number of metaphase II oocytes

0.02 (−0.29 to 0.33)a

0.69 (0.12 to 1.25)a

−0.28 (−0.66 to 0.10)a

Number of embryos

0.09 (−0.11 to 0.30)a

0.34 (−0.05 to 0.73)a

−0.01 (−0.27 to 0.25)a

Number of transferred embryos

0.09 (0.01 to 0.17)a

0.27 (0.07 to 0.47)a

0.05 (−0.05 to 0.15)a

Number of good quality embryos

0.26 (0.16 to 0.36)a

0.43 (0.26 to 0.06)a

0.17 (0.05 to 0.29)a

Peak oestradiol (ng/L)

0.24 (0.06 to 0.42)a

0.21 (−0.12 to 0.54)a

0.26 (0.03 to 0.48)a

Duration of ovarian stimulation (days)

−0.23 (−0.50 to 0.05)a

−0.51 (−1.15 to 0.12)a

−0.15 (−0.49 to 0.18)a

Total r-hFSH dose (IU/1000)

−0.11 (−0.22 to 0.00)a

−0.38 (−0.59 to −0.17)a

−0.06 (−0.16 to 0.04)a

Biochemical pregnancy rate

1.25 (1.13 to 1.38)b

1.38 (1.06 to 1.80)b

1.22 (1.04 to 1.42)b

Ongoing pregnancy rate

1.14 (1.05 to 1.25)b

1.36 (1.04 to 1.79)b

1.13 (1.00 to 1.27)b

Live birth rate

1.11 (1.01 to 1.21)b

1.30 (0.95 to 1.78)b

1.10 (0.94 to 1.29)b

aMean difference (95% CI).

bRR (95% CI).

CI, confidence interval; ITT, intention-to-treat; r-hFSH, recombinant human follicle-stimulating hormone; r-hLH, recombinant human luteinizing hormone; RR, risk ratio.

Note: bold denotes statistical significance for r-hFSH plus r-hLH versus r-hFSH alone.

In poor responders (11 studies; 1043 patients), a statistically significant benefit was observed for r-hFSH plus r-hLH for ongoing pregnancy rate (RR 1.36; 95% CI 1.04–1.79; Table 3). A non-significant benefit for r-hFSH plus r-hLH for ongoing pregnancy rate was observed in normal responders (RR 1.13; 95% CI 1.00–1.27; Table 3).

Live birth rate

Live birth rates were reported for 8/45 studies and data were imputed for 31 studies; n = 3065 and n = 3172 patients in the r-hFSH plus r-hLH and r-hFSH groups, respectively (ITT population). The RR for live birth rate was statistically significant in favour of r-hFSH plus r-hLH (1.11 [95% CI 1.01–1.21]; Table 3). In the PP population, there was a non-significant benefit in favour of r-hFSH plus r-hLH for live birth rate.

A non-significant benefit for r-hFSH plus r-hLH on live birth rate was observed in both poor (RR 1.30; 95% CI 0.95–1.78) and normal (RR 1.10; 95% CI 0.94–1.29) responders (Table 3).

Other efficacy endpoints

The outcomes of other efficacy endpoints in the r-hFSH plus r-hLH and r-hFSH treatment groups in the ITT population are shown in Table 3.

Discussion

To date, this meta-analysis is the most comprehensive compilation of data to assess the outcomes of r-hFSH plus r-hLH or r-hFSH alone for ovarian stimulation during ART. Our findings indicate that there was no significant difference in the number of oocytes retrieved with r-hFSH plus r-hLH versus r-hFSH alone in the overall population studied. However, we also found that significantly more oocytes were retrieved in women treated with r-hFSH plus r-hLH versus r-hFSH alone in the subgroup of poor responders (+0.75; 95% CI 0.14–1.36). In addition, a significant benefit of r-hFSH plus r-hLH versus r-hFSH alone on clinical pregnancy rate was demonstrated in the poor responders subgroup (RR 1.30; 95% CI 1.01–1.67), which suggests a 30% relative increase in clinical pregnancy rate among poor responders who received r-hLH supplementation. In the overall pooled population analysed here, a significant difference in clinical pregnancy rate was also found in favour of r-hFSH plus r-hLH versus r-hFSH alone (RR 1.09; 95% CI 1.01–1.18). This suggests that there was a smaller (estimate of 9%) relative increase in clinical pregnancy rate among all patients who received r-hLH supplementation compared with that seen in poor responders.

Our findings in the subgroup of poor responders are particularly relevant because many patients undergoing ART are poor responders to ovarian stimulation (although prevalence estimates vary because of differences in the definitions of POR used). Ferraretti and colleagues reported that approximately 33% of patients aged <30–39 years undergoing ovarian stimulation were poor responders (patients with <4 oocytes retrieved) [21]. In addition, evidence in the literature to identify interventions that could improve treatment outcomes in women with POR is limited [2830] and the traditional clinical approach of increasing the FSH dose to improve follicular response appears to be ineffective [3133]. Some physicians have attempted to exploit the potential benefit of r-hLH supplementation in women with POR. However, currently, women with POR may undergo multiple unsuccessful ART treatment cycles because of inadequate follicular response, repeated cycle cancellation or a negative pregnancy test.

The use of r-hLH supplementation during ovarian stimulation is a subject of debate in the literature and this lack of clarity has led to the publication of a number of earlier meta-analyses. The first showed a beneficial effect of ‘LH activity’ versus r-hFSH on clinical pregnancy rates (RR 1.18; 95% CI 1.02–1.36) in normogonadotropic women who underwent GnRH agonist downregulation [34]. In contrast to those results and the findings of our meta-analysis, three subsequent meta-analyses reported no clinical benefit of LH supplementation: no statistically significant differences were observed with r-hFSH plus r-hLH versus r-hFSH alone in pregnancy [15], live birth [16] or clinical pregnancy [18] rates. 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) [17]. It should be noted that until the development of the ESHRE consensus POR definition in 2011 [21], heterogeneous definitions of POR were used.

In the current meta-analysis, the chosen co-primary endpoints were number of retrieved oocytes and clinical pregnancy. Of the 45 studies analysed, 41 reported data for number of oocytes, and 39 reported data for clinical pregnancy. Although live birth rate is the outcome measure that patients are most interested in, data for this endpoint were reported sporadically in the RCTs. Oocytes are the direct physiological result of ovarian stimulation by FSH and so reflect the pharmacological effect of FSH, therefore, the number of oocytes retrieved is an appropriate endpoint. Furthermore, the number of oocytes retrieved is not influenced by events occurring after oocyte retrieval, such as fertilization, implantation, or embryo/foetal development, whereas other endpoints of cycle success, such as pregnancy outcomes and live birth rates, may be impacted by these other events.

In addition, number of oocytes retrieved has been widely used as a measure of ovarian response to FSH stimulation and is commonly referenced as a predictor of successful ART outcomes. Increase in pregnancy rates associated with an increased number of oocytes retrieved has been reported by numerous authors through large and smaller retrospective analyses of IVF, ICSI and oocyte donation cycles [3643]. Sunkara and co-workers (using data from 400,135 ART cycles) found a strong association between live birth rate and number of oocytes retrieved, with live birth rate increasing as the number of oocytes retrieved increased (up to 15 oocytes retrieved) [41]. For patients with a low number (three or fewer) of oocytes retrieved, an increase in live birth rate was observed when as few as one additional oocyte was retrieved [41]. Also, for patients aged ≥40 years with a low number of oocytes retrieved, an increase of just one oocyte had a marked increase in the predicted live birth rate. In addition, an evaluation of nearly 8000 ART cycles found the ongoing pregnancy rate to be highly correlated with the number of oocytes retrieved [44]. These findings suggest that in patients who may be expected to have lower numbers of oocytes retrieved, for example patients with POR, an increment of one additional oocyte might have a significant effect on pregnancy outcomes, such as ongoing pregnancy rate and live birth rate. Supporting this, a recent systematic review reported that the likelihood of pregnancy is reduced in women with POR when fewer oocytes are retrieved (pregnancy rate per started cycle of 0–7% with one oocyte, compared with 11.5–18.6% with four oocytes) [45].

The meta-analysis reported here found an increase in clinical pregnancy rate with r-hLH supplementation in the overall study population of women undergoing ovarian stimulation, and this finding has been reported in one previous meta-analysis [34]. However, this was not observed in two other meta-analyses [15, 18] that involved fewer studies and smaller numbers of patients than the analysis reported here.

Our analysis attempted to utilize all available data, by imputing missing secondary endpoints, so that the sample size for each endpoint was the best possible for all endpoints. Data imputation for uncommon endpoints, such as live birth rate, may be viewed with caution by some, however, we felt that this practice was justified to allow a greater sample size to be analysed for live birth rate. In contrast to the statistically significant difference in clinical pregnancy rates between r-hFSH plus r-hLH versus r-hFSH alone in poor responders in the ITT population, the difference between the two treatments was not significant in poor responders in the PP population, although the effect size was similar. Data were imputed for the ITT population but not for the PP population.

It is interesting to note that a non-significant negative bias was identified for trials sponsored by the pharmaceutical industry, with a smaller effect of r-hFSH plus r-hLH versus r-hFSH alone in industry-sponsored trials compared with non-sponsored trials. This contrasts with previous findings of a significant positive outcome bias related to industry sponsorship [46]. In addition, the decision to include unpublished data was made to enable evaluation of as much data as possible in the analysis to provide a complete picture of the use of r-hFSH plus r-hLH compared with r-hFSH alone. Furthermore, we conducted analyses of various covariates, including ones for publication status (unpublished data versus congress abstract and unpublished data versus peer-reviewed paper).

The key strength of this meta-analysis is that it comprised the largest number of studies (to the best of our knowledge, all studies) on this subject. In addition, no a priori selection was admitted and bias control was systematically conducted through meta-regression.

A possible limitation of the current meta-analysis is that the 14 studies of women with POR that were included had been conducted prior to the publication of the ESHRE consensus POR definition in 2011 [21]. Accordingly, heterogeneous definitions of POR were used in these studies. When comparing the study authors’ definitions of POR with the ESHRE consensus criteria [21], each of the studies in the POR analysis were aligned with at least one of the ESHRE criteria and the ESHRE definition of POR was reflected (through alignment with at least two ESHRE criteria) in 10 of these studies.

Conclusions

This systematic review and meta-analysis suggests that r-hLH supplementation of r-hFSH compared with r-hFSH alone may result in benefits in terms of clinical pregnancy rate in the overall pooled population, as well as in poor responders. In addition, a benefit for r-hFSH plus r-hLH versus r-hFSH alone may be seen for the number of oocytes retrieved in poor responders.

Abbreviations

ART: 

Assisted reproductive technology

CI: 

Confidence interval

ESHRE: 

European Society of Human Reproduction and Embryology

FSH: 

Follicle-stimulating hormone

GnRH: 

Gonadotrophin-releasing hormone

ICH: 

International Conference on Harmonisation

ICSI: 

Intracytoplasmic sperm injection

ITT: 

Intention-to-treat

IVF: 

In vitro fertilization

LH: 

Luteinizing hormone

OR: 

Odds ratio

POR: 

Poor ovarian response

PP: 

Per-protocol

RCT: 

Randomized controlled trial

REML: 

Restricted maximum likelihood

r-hLH: 

recombinant human luteinizing hormone

r-hFSH: 

recombinant human follicle-stimulating hormone

RR: 

Risk ratio.

Declarations

Acknowledgements

This systematic review and meta-analysis was supported by Merck Serono S.A. – Switzerland, an affiliate of Merck KGaA, Darmstadt, Germany. The authors thank Jocelyn Woodcock of Caudex Medical, Oxford, UK (supported by Merck Serono S.A. – Switzerland, an affiliate of Merck KGaA, Darmstadt, Germany), for her assistance in the preparation of this manuscript.

Authors’ Affiliations

(1)
Faculty of Economics, Université Catholique de Louvain (UCL Mons)
(2)
Faculty of Medicine, the University of Melbourne
(3)
Unit for Human Reproduction, 1st Department of Obstetrics and Gynaecology, Medical School, Aristotle University of Thessaloniki
(4)
Fertility Global Clinical Development Unit, EMD Serono, Inc, Rockland
(5)
Formerly Merck Serono S.A
(6)
Preglem SA
(7)
Biosensors

References

  1. Hill MJ, Levy G, Levens ED: Does exogenous LH in ovarian stimulation improve assisted reproduction success? An appraisal of the literature. Reprod Biomed Online. 2012, 24: 261-271. 10.1016/j.rbmo.2011.12.005.View ArticlePubMed
  2. Fischer R: Understanding the role of LH: myths and facts. Reprod Biomed Online. 2007, 15: 468-477. 10.1016/S1472-6483(10)60375-6.View ArticlePubMed
  3. Sen A, Caiazza F: Oocyte maturation: a story of arrest and release. Front Biosci (Schol Ed). 2013, 5: 451-477.View Article
  4. Shoham Z, Schacter M, Loumaye E, Weissman A, MacNamee M, Insler V: The luteinizing hormone surge–the final stage in ovulation induction: modern aspects of ovulation triggering. Fertil Steril. 1995, 64: 237-251.PubMed
  5. Sommer L, Zanger K, Dyong T, Dorn C, Luckhaus J, Diedrich K, Klingmuller D: Seven-day administration of the gonadotropin-releasing hormone antagonist Cetrorelix in normal cycling women. Eur J Endocrinol. 1994, 131: 280-285. 10.1530/eje.0.1310280.View ArticlePubMed
  6. Doody K, Devroey P, Gordon K, Witjes H, Mannaerts B: LH concentrations do not correlate with pregnancy in rFSH/GnRH antagonist cycles. Reprod Biomed Online. 2010, 20: 565-567. 10.1016/j.rbmo.2009.12.019.View ArticlePubMed
  7. UK Summary of product characteristics Luveris 75 IU. 2013, [http://​www.​medicines.​org.​uk/​emc/​medicine/​8289/​spc]
  8. European Recombinant Human LH Study Group: Recombinant human luteinizing hormone (LH) to support recombinant human follicle-stimulating hormone (FSH)-induced follicular development in LH- and FSH-deficient anovulatory women: a dose-finding study. J Clin Endocrinol Metab. 1998, 83: 1507-1514.
  9. Howles CM: Luteininzing hormone supplementation in ART. How to Improve Your ART Success Rates. Edited by: Kovacs G. 2011, Cambridge, UK: Cambridge University Press, 99-104.View Article
  10. Ferraretti AP, Gianaroli L, Magli MC, D’Angelo A, Farfalli V, Montanaro N: Exogenous luteinizing hormone in controlled ovarian hyperstimulation for assisted reproduction techniques. Fertil Steril. 2004, 82: 1521-1526. 10.1016/j.fertnstert.2004.06.041.View ArticlePubMed
  11. Alviggi C, Mollo A, Clarizia R, De Placido G: Exploiting LH in ovarian stimulation. Reprod Biomed Online. 2006, 12: 221-233. 10.1016/S1472-6483(10)60865-6.View ArticlePubMed
  12. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use: ICH harmonized tripartite guideline: statistical principles for clinical trials E9. http://​www.​ich.​org/​fileadmin/​Public_​Web_​Site/​ICH_​Products/​Guidelines/​Efficacy/​E9/​Step4/​E9_​Guideline.​pdf
  13. Higgins JPT, Green S: Cochrane handbook for systematic reviews of interventions version 5.1.0. The Cochrane Collaboration. 2011, Electronic source is [http://​www.​cochrane-handbook.​org]
  14. Committee for Proprietary Medicinal Products. Points to consider on application with 1. Meta-analyses 2. One pivotal study. CPMP/EWP/2330/99. [http://​www.​ema.​europa.​eu/​docs/​en_​GB/​document_​library/​Scientific_​guideline/​2009/​09/​WC500003657.​pdf]
  15. Baruffi RL, Mauri AL, Petersen CG, Felipe V, Martins AM, Cornicelli J, Cavagna M, Oliveira JB, Franco JG: Recombinant LH supplementation to recombinant FSH during induced ovarian stimulation in the GnRH-antagonist protocol: a meta-analysis. Reprod Biomed Online. 2007, 14: 14-25. 10.1016/S1472-6483(10)60758-4.View ArticlePubMed
  16. Kolibianakis EM, Kalogeropoulou L, Griesinger G, Papanikolaou EG, Papadimas J, Bontis J, Tarlatzis BC: Among patients treated with FSH and GnRH analogues for in vitro fertilization, is the addition of recombinant LH associated with the probability of live birth? A systematic review and meta-analysis. Hum Reprod Update. 2007, 13: 445-452. 10.1093/humupd/dmm008.View ArticlePubMed
  17. Mochtar MH, van der Veen F, Ziech M, Van Wely M: Recombinant luteinizing hormone (rLH) for controlled ovarian hyperstimulation in assisted reproductive cycles. Cochrane Database Syst Rev. 2007, 2: CD005070-PubMed
  18. Oliveira J, Mauri A, Petersen CG, Martins AMC, Cornicelli J, Cavanha M, Pontes A, Baruffi R, Franco JG: Recombinant luteinizing hormone supplementation to recombinant follicle-stimulation hormone during induced ovarian stimulation in the GnRH-agonist protocol: a meta-analysis. J Assist Reprod Genet. 2007, 24: 67-75. 10.1007/s10815-006-9095-4.PubMed CentralView ArticlePubMed
  19. Westergaard LW, Bossuyt PMM, van der Veen F, van Wely M: Human menopausal gonadotropin versus recombinant follicle stimulation hormone for ovarian stimulation in assisted reproductive cycles. Cochrane Database Syst Rev. 2003, 1: CD003973-PubMed
  20. Raudenbush S: Analyzing effect sizes: Random effects models. The handbook of research synthesis and meta-analysis. Edited by: Cooper H, Hedges LV. 2012, New York: Russell Sage Foundation, 295-315. 2
  21. Ferraretti AP, La Marca A, Fauser BC, Tarlatzis B, Nargund G, Gianaroli L: ESHRE consensus on the definition of ‘poor response’ to ovarian stimulation for in vitro fertilization: the Bologna criteria. Hum Reprod. 2011, 26: 1616-1624. 10.1093/humrep/der092.View ArticlePubMed
  22. Akobeng AK: Communicating the benefits and harms of treatments. Arch Dis Child. 2008, 93: 710-713. 10.1136/adc.2008.137083.View ArticlePubMed
  23. Humaidan P, Bungum M, Bungum L, Yding Andersen C: Effects of recombinant LH supplementation in women undergoing assisted reproduction with GnRH agonist down-regulation and stimulation with recombinant FSH: an opening study. Reprod Biomed Online. 2004, 8: 635-643. 10.1016/S1472-6483(10)61643-4.View ArticlePubMed
  24. Nyboe Andersen A, Humaidan P, Fried G, Hausken J, Antila L, Bangsboll S, Rasmussen PE, Lindenberg S, Bredkjaer HE, Meinertz H: Recombinant LH supplementation to recombinant FSH during the final days of controlled ovarian stimulation for in vitro fertilization. A multicentre, prospective, randomized, controlled trial. Hum Reprod. 2008, 23: 427-434.View Article
  25. Marrs R, Meldrum D, Muasher S, Schoolcraft W, Werlin L, Kelly E: Randomized trial to compare the effect of recombinant human FSH (follitropin alfa) with or without recombinant human LH in women undergoing assisted reproduction treatment. Reprod Biomed Online. 2004, 8: 175-182. 10.1016/S1472-6483(10)60513-5.View ArticlePubMed
  26. Bosch E, Labarta E, Crespo J, Simon C, Remohi J, Pellicer A: Impact of luteinizing hormone administration on gonadotropin-releasing hormone antagonist cycles: an age-adjusted analysis. Fertil Steril. 2011, 95: 1031-1036. 10.1016/j.fertnstert.2010.10.021.View ArticlePubMed
  27. Motta E, Massaguer A, Serafini P, Beltrame A, Yadid I, Coslowsky M: Supplementation with rec-FSH or rec-LH is equally effective to modulate sub-optimal response for IVF cycles. A prospective randomized trial. Hum Reprod. 2005, 20 (Suppl 1): i125-
  28. Kyrou D, Kolibianakis EM, Venetis CA, Papanikolaou EG, Bontis J, Tarlatzis BC: How to improve the probability of pregnancy in poor responders undergoing in vitro fertilization: a systematic review and meta-analysis. Fertil Steril. 2009, 91: 749-766. 10.1016/j.fertnstert.2007.12.077.View ArticlePubMed
  29. Venetis CA, Kolibianakis EM, Tarlatzi TB, Tarlatzis BC: Evidence-based management of poor ovarian response. Ann N Y Acad Sci. 2010, 1205: 199-206. 10.1111/j.1749-6632.2010.05665.x.View ArticlePubMed
  30. Kolibianakis EM, Venetis CA, Diedrich K, Tarlatzis BC, Griesinger G: Addition of growth hormone to gonadotrophins in ovarian stimulation of poor responders treated by in-vitro fertilization: a systematic review and meta-analysis. Hum Reprod Update. 2009, 15: 613-622. 10.1093/humupd/dmp026.View ArticlePubMed
  31. Alviggi C, Clarizia R, Pettersson K, Mollo A, Humaidan P, Strina I, Coppola M, Ranieri A, D’Uva M, De Placido G: Suboptimal response to GnRHa long protocol is associated with a common LH polymorphism. Reprod Biomed Online. 2009, 18: 9-14. 10.1016/S1472-6483(10)60418-X.View ArticlePubMed
  32. Kailasam C, Keay SD, Wilson P, Ford WC, Jenkins JM: Defining poor ovarian response during IVF cycles, in women aged <40 years, and its relationship with treatment outcome. Hum Reprod. 2004, 19: 1544-1547. 10.1093/humrep/deh273.View ArticlePubMed
  33. Keay SD, Liversedge NH, Mathur RS, Jenkins JM: Assisted conception following poor ovarian response to gonadotrophin stimulation. Br J Obstet Gynaecol. 1997, 104: 521-527. 10.1111/j.1471-0528.1997.tb11525.x.View ArticlePubMed
  34. van Wely M, Westergaard LG, Bossuyt PM, van der Veen F: Effectiveness of human menopausal gonadotropin versus recombinant follicle-stimulating hormone for controlled ovarian hyperstimulation in assisted reproductive cycles: a meta-analysis. Fertil Steril. 2003, 80: 1086-1093. 10.1016/S0015-0282(03)02187-3.View ArticlePubMed
  35. Hill MJ, Levens ED, Levy G, Ryan ME, Csokmay JM, DeCherney AH, Whitcomb BW: The use of recombinant luteinizing hormone in patients undergoing assisted reproductive techniques with advanced reproductive age: a systematic review and meta-analysis. Fertil Steril. 2012, 97: 1108-1114. 10.1016/j.fertnstert.2012.01.130.View ArticlePubMed
  36. Meniru GI, Craft IL: Utilization of retrieved oocytes as an index of the efficiency of superovulation strategies for in-vitro fertilization treatment. Hum Reprod. 1997, 12: 2129-2132. 10.1093/humrep/12.10.2129.View ArticlePubMed
  37. Timeva T, Milachich T, Antonova I, Arabaji T, Shterev A, Omar HA: Correlation between number of retrieved oocytes and pregnancy rate after in vitro fertilization/intracytoplasmic sperm infection. ScientificWorldJournal. 2006, 6: 686-690.View ArticlePubMed
  38. Lane DE, Vittinghoff E, Croughan MS, Cedars MI, Fujimoto VY: Gonadotropin stimulation demonstrates a ceiling effect on in vitro fertilization outcomes. Fertil Steril. 2006, 85: 1708-1713. 10.1016/j.fertnstert.2005.11.057.View ArticlePubMed
  39. Yih MC, Spandorfer SD, Rosenwaks Z: Egg production predicts a doubling of in vitro fertilization pregnancy rates even within defined age and ovarian reserve categories. Fertil Steril. 2005, 83: 24-29. 10.1016/j.fertnstert.2004.05.096.View ArticlePubMed
  40. Stern JE, Goldman MB, Hatasaka H, MacKenzie TA, Surrey ES, Racowsky C: Optimizing the number of cleavage stage embryos to transfer on day 3 in women 38 years of age and older: a Society for Assisted Reproductive Technology database study. Fertil Steril. 2009, 91: 767-776. 10.1016/j.fertnstert.2007.12.051.View ArticlePubMed
  41. Sunkara SK, Rittenberg V, Raine-Fenning N, Bhattacharya S, Zamora J, Coomarasamy A: Association between the number of eggs and live birth in IVF treatment: an analysis of 400 135 treatment cycles. Hum Reprod. 2011, 26: 1768-1774. 10.1093/humrep/der106.View ArticlePubMed
  42. Stoop D, Ermini B, Polyzos NP, Haentjens P, De Vos M, Verheyen G, Devroey P: Reproductive potential of a metaphase II oocyte retrieved after ovarian stimulation: an analysis of 23 354 ICSI cycles. Hum Reprod. 2012, 27: 2030-2035. 10.1093/humrep/des131.View ArticlePubMed
  43. Lukaszuk K, Kunicki M, Liss J, Lukaszuk M, Jakiel G: Use of ovarian reserve parameters for predicting live births in women undergoing in vitro fertilization. Eur J Obstet Gynecol Reprod Biol. 2013, 168: 173-177. 10.1016/j.ejogrb.2013.01.013.View ArticlePubMed
  44. Bosch E, Ezcurra D: Individualised controlled ovarian stimulation (iCOS): maximising success rates for assisted reproductive technology patients. Reprod Biol Endocrinol. 2011, 9: 82-10.1186/1477-7827-9-82.PubMed CentralView ArticlePubMed
  45. Oudendijk JF, Yarde F, Eijkemans MJ, Broekmans FJ, Broer SL: The poor responder in IVF: is the prognosis always poor?: a systematic review. Hum Reprod Update. 2012, 18: 1-11. 10.1093/humupd/dmr037.View ArticlePubMed
  46. Lexchin J, Bero LA, Djulbegovic B, Clark O: Pharmaceutical industry sponsorship and research outcome and quality: systematic review. BMJ. 2003, 326: 1167-1170. 10.1136/bmj.326.7400.1167.PubMed CentralView ArticlePubMed
  47. Williams RS: The Serono r-hFSH and r-hLH Study Group: A multi-center study comparing the efficacy of recombinant human follicle stimulating hormone (r-hFSH, Gonal-Ft) versus r-hFSH plus recombinant human luteinizing hormone (r-hLH, Lhadit) in patients undergoing controlled ovarian hyperstimulation (COH) for assisted reproductive technologies (ART). Fertil Steril. 2000, 74 (suppl 1): S228-S229.View Article
  48. Merck Serono: MS8839: A phase IIIb, open, randomized, parallel group, multicentre study to compare the safety and efficacy of recombinant human follicle stimulating hormone (Gonal-F) alone with r-hFSH plus recombinant human luteinizing hormone (Lhadi) for superovulation in women undergoing in vitro fertilization and embryo transfer. 2000, Geneva: Data on file
  49. Merck Serono: MS9032: A comparative clinical trial on treatment with r-hFSH alone or supplemented with r-hLH for induction of superovulation in IVF/ET. 2001, Geneva: Data on file
  50. Merck Serono: MS9029: Multicentric, randomized, controlled clinical trial to assess the efficacy and safety of the supplementation of r-hLH to r-hFSH treatments for controlled ovarian stimulation in patients with poor response in previous IVF/ET cycles. 2001, Geneva: Data on file
  51. Balasch J, Creus M, Fabregues F, Civico S, Carmona F, Puerto B, Casamitjana R, Vanrell JA: The effect of exogenous luteinizing hormone (LH) on oocyte viability: evidence from a comparative study using recombinant human follicle-stimulating hormone (FSH) alone or in combination with recombinant LH for ovarian stimulation in pituitary-suppressed women undergoing assisted reproduction. J Assist Reprod Genet. 2001, 18: 250-256. 10.1023/A:1016662100572.PubMed CentralView ArticlePubMed
  52. Merck Serono: MS9640: A phase III, single centre, parallel, randomised open label comparative study to assess the safety and efficacy of recombinant human luteinising hormone (Luveris) used in conjunction with recombinant human follicle stimulation hormone (GONAL-F) in women undergoing multifollicular development for assisted reproduction. 2001, Geneva: Data on file
  53. Lisi F, Rinaldi L, Fishel S, Lisi R, Pepe GP, Picconeri MG, Campbell A: Better implantation rate overimposing recombinant LH (Luveris) on recombinant FSH (Gonal F) in multiple follicular stimulation for IVF. Hum Reprod. 2002, 17 (suppl 1): 134-
  54. Lisi F, Rinaldi L, Fishel S, Lisi R, Pepe GP, Picconeri MG, Campbell A: Use of recombinant LH in a group of unselected IVF patients. Reprod Biomed Online. 2002, 5: 104-108. 10.1016/S1472-6483(10)61610-0.View ArticlePubMed
  55. De Moustier B, Brinsden P, Bungum L, Fisch B, Pinkstone S, Warne D, Loumaye E: The effects of combined treatment of recombinant (r) FSH and rLH in ratios: 1:1, 2:1, and 3:1 in women aged 38–42 years undergoing IVF-ICSI treatment. Hum Reprod. 2002, 17 (Suppl 1): 55-
  56. Ludwig M, Katalinic A, Schultze-Mosgau A, Griesinger G, Schroeder AK, Diedrich K: LH supplementation in GnRH antagonist protocols: preliminary results of a prospective, randomized study. Hum Reprod. 2003, 18 (suppl 1): ×viii3-
  57. Sauer MV, Thornton MH, Schoolcraft W, Frishman GN: Comparative efficacy and safety of cetrorelix with or without mid-cycle recombinant LH and leuprolide acetate for inhibition of premature LH surges in assisted reproduction. Reprod Biomed Online. 2004, 9: 487-493. 10.1016/S1472-6483(10)61631-8.View ArticlePubMed
  58. Cedrin-Durnerin I, Grange-Dujardin D, Laffy A, Parneix I, Massin N, Galey J, Theron L, Wolf JP, Conord C, Clement P, Jayot S, Hugues JN: Recombinant human LH supplementation during GnRH antagonist administration in IVF/ICSI cycles: a prospective randomized study. Hum Reprod. 2004, 19: 1979-1984. 10.1093/humrep/deh369.View ArticlePubMed
  59. Griesinger G, Schultze-Mosgau A, Dafopoulos K, Schroeder A, Schroer A, von Otte S, Hornung D, Diedrich K, Felberbaum R: Recombinant luteinizing hormone supplementation to recombinant follicle-stimulating hormone induced ovarian hyperstimulation in the GnRH-antagonist multiple-dose protocol. Hum Reprod. 2005, 20: 1200-1206. 10.1093/humrep/deh741.View ArticlePubMed
  60. Demirol A, Gurgan T, Girgin B: Supplementation of rec-LH for poor responder patients in ART. Hum Reprod. 2005, 20 (Suppl 1): i74-
  61. De Placido G, Alviggi C, Perino A, Strina I, Lisi F, Fasolino A, De Palo R, Ranieri A, Colacurci N, Mollo A: Recombinant human LH supplementation versus recombinant human FSH (rFSH) step-up protocol during controlled ovarian stimulation in normogonadotrophic women with initial inadequate ovarian response to rFSH. A multicentre, prospective, randomized controlled trial. Hum Reprod. 2005, 20: 390-396.View ArticlePubMed
  62. Tarlatzis B, Tavmergen E, Szamatowicz M, Barash A, Amit A, Levitas E, Shoham Z: The use of recombinant human LH (lutropin alfa) in the late stimulation phase of assisted reproduction cycles: a double-blind, randomized, prospective study. Hum Reprod. 2006, 21: 90-94.View ArticlePubMed
  63. Ramirez M, Monzo A, Garcia-Gimeno T, Rubio J, Montanana V, Duque C, Herrero G, Romeu A: Role of LH administration during the follicullar phase in women with risk of low response in ovarian stimulation with FSH and cetrorelix for IVF. Rev Iberoamer de Fertil. 2006, 23: 281-290.
  64. Levi-Setti PE, Cavagna M, Bulletti C: Recombinant gonadotrophins associated with GnRH antagonist (cetrorelix) in ovarian stimulation for ICSI: comparison of r-FSH alone and in combination with r-LH. Eur J Obstet Gynecol Reprod Biol. 2006, 126: 212-216. 10.1016/j.ejogrb.2005.11.023.View ArticlePubMed
  65. Abdelmassih V, Salgueiro L, Abdelmassih R, Carizza C: Less miscarriage rate using LH (rLH) in GnRH agonist long protocol. Hum Reprod. 2006, 21 (Suppl 1): i7-
  66. Aytac R, Ozmen B, Satiroglu H, Aydos K, Baltaci V: Addition of r-LH to ovulation scheme of patients with low serum estradiol levels on days 5–6 improves ovulation induction outcomes. Hum Reprod. 2006, 21 (Suppl 1): i27-View Article
  67. Fabregues F, Creus M, Penarrubia J, Manau D, Vanrell JA, Balasch J: Effects of recombinant human luteinizing hormone supplementation on ovarian stimulation and the implantation rate in down-regulated women of advanced reproductive age. Fertil Steril. 2006, 85: 925-931. 10.1016/j.fertnstert.2005.09.049.View ArticlePubMed
  68. Ruvolo G, Bosco L, Pane A, Morici G, Cittadini E, Roccheri MC: Lower apoptosis rate in human cumulus cells after administration of recombinant luteinizing hormone to women undergoing ovarian stimulation for in vitro fertilization procedures. Fertil Steril. 2007, 87: 542-546. 10.1016/j.fertnstert.2006.06.059.View ArticlePubMed
  69. Polidoropoulos N, Papanikopoulos C, Stefanis P, Tavaniotou M, Argyrou M, Doriza S, Sisi V, Karamalegos C, Moschopoulou M, Karagianni T, Christopikou D, Garantzioti A, Davies S, Mastrominas M: Addition of exogenous recombinant LH in poor responders protocols: does it really help?. Hum Reprod. 2007, 22 (Suppl 1): i4-
  70. Berkkanoglu M, Isikoglu M, Aydin D, Ozgur K: 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. Fertil Steril. 2007, 88: 665-669. 10.1016/j.fertnstert.2006.11.150.View ArticlePubMed
  71. Barrenetxea G, Agirregoikoa JA, Jimenez MR, Lopez De Larruzea A, Ganzabal T, Carbonero K: Ovarian response and pregnancy outcome in poor-responder women: a randomized controlled trial on the effect of luteinizing hormone supplementation on in vitro fertilization cycles. Fertil Steril. 2008, 89: 546-553. 10.1016/j.fertnstert.2007.03.088.View ArticlePubMed
  72. Pezzuto A, Ferrari B, Coppola F, Nardelli GB: LH supplementation in down-regulated women undergoing assisted reproduction with baseline low serum LH levels. Gynecol Endocrinol. 2010, 26: 118-124. 10.3109/09513590903215516.View ArticlePubMed
  73. Brunet C, Dechanet C, Reyftmann I, Hamamah S, Hedon B, Dechaud H: Impact of r-LH supplementation on the estradiol level during ovarian stimulation for IVF: a randomized prospective study. Fertil Steril. 2009, 92 (Suppl): S240-View Article
  74. Gutman G, Barak V, Maslovitz S, Amit A, Lessing JB, Geva E: Recombinant luteinizing hormone induces increased production of ovarian follicular adiponectin in vivo: implications for enhanced insulin sensitivity. Fertil Steril. 2009, 91: 1837-1841. 10.1016/j.fertnstert.2008.02.006.View ArticlePubMed
  75. Matorras R, Prieto B, Exposito A, Mendoza R, Crisol L, Herranz P, Burgues S: Mid-follicular LH supplementation in women aged 35–39 years undergoing ICSI cycles: a randomized controlled study. Reprod Biomed Online. 2009, 19: 879-887. 10.1016/j.rbmo.2009.09.016.View ArticlePubMed
  76. Lahoud R, Ryan J, Costello M, Illingworth P: Recombinant LH supplementation in patients with a relative reduction in LH levels during IVF/ICSIi cycles: a prospective randomised controlled trial. Hum Reprod. 2010, 25 (suppl 1): i90-
  77. Kovacs P, Kovats T, Kaali SG: Results with early follicular phase recombinant luteinizing hormone supplementation during stimulation for in vitro fertilization. Fertil Steril. 2010, 93: 475-479. 10.1016/j.fertnstert.2008.12.010.View ArticlePubMed
  78. Wiser A, Hourvitz A, Yinon Y, Levron J, Dor J, Elizur S: Recombinant human luteinizing hormone supplementation may improve embryo quality in in vitro fertilization/intracytoplasmic sperm injection cycles with gonadotrophin-releasing hormone antagonist protocol. Open J Obstet Gynecol. 2011, 1: 31-35. 10.4236/ojog.2011.12007.View Article
  79. Musters AM, Van Wely M, Mastenbroek S, Kaaijk EM, Repping S, van der Veen F, Mochtar MH: The effect of recombinant LH on embryo quality: a randomized controlled trial in women with poor ovarian reserve. Hum Reprod. 2012, 27: 244-250. 10.1093/humrep/der371.View ArticlePubMed
  80. Caserta D, Lisi F, Marci R, Ciardo F, Fazi A, Lisi R, Moscarini M: Does supplementation with recombinant luteinizing hormone prevent ovarian hyperstimulation syndrome in down regulated patients undergoing recombinant follicle stimulating hormone multiple follicular stimulation for IVF/ET and reduces cancellation rate for high risk of hyperstimulation?. Gynecol Endocrinol. 2011, 27: 862-866. 10.3109/09513590.2010.544133.View ArticlePubMed

Copyright

© Lehert et al.; licensee BioMed Central Ltd. 2014

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://​creativecommons.​org/​licenses/​by/​2.​0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://​creativecommons.​org/​publicdomain/​zero/​1.​0/​) applies to the data made available in this article, unless otherwise stated.

Advertisement