Skip Navigation



Hum. Reprod. Advance Access published online on April 11, 2008
Human Reproduction, doi:10.1093/humrep/den115
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF ) Freely available
Right arrow All Versions of this Article:
23/6/1346    most recent
den115v1
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Kolibianakis, E.M.
Right arrow Articles by Griesinger, G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kolibianakis, E.M.
Right arrow Articles by Griesinger, G.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2008. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Estrogen addition to progesterone for luteal phase support in cycles stimulated with GnRH analogues and gonadotrophins for IVF: a systematic review and meta-analysis

E.M. Kolibianakis1,3, C.A. Venetis1, E.G. Papanikolaou1, K. Diedrich2, B.C. Tarlatzis1 and G. Griesinger2

1 Unit for Human Reproduction, 1st Department of Obstetrics and Gynaecology, Papageorgiou General Hospital, Aristotle University of Thessaloniki, Nea Efkarpia Peripheral Road, Thessaloniki 54603, Greece 2 Department of Obstetrics and Gynaecology, University Clinic of Schleswig-Holstein, Campus Luebeck, Luebeck, Germany

3 Correspondence address. E-mail: stratis.kolibianakis{at}irg.gr


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Acknowledgements
 References
 Excluded studies 
 
BACKGROUND: The purpose of the present systematic review and meta-analysis was to examine whether the probability of pregnancy is increased by adding estrogen to progesterone for luteal phase support in patients treated by in vitro fertilization (IVF).

METHODS: A literature search covering MEDLINE, EMBASE, CENTRAL, meeting proceedings and reference lists of published articles was performed to identify relevant RCTs. Data were extracted for meta-analysis yielding pooled relative risks (RR) and 95% confidence intervals (CI). Sensitivity analyses by including studies with pseudo-randomization or unclear method of randomization were also performed (n=1141 patients in total).

RESULTS: Four RCTs (n=587 patients) were eligible for inclusion. No statistically significant differences were present between patients who received a combination of progesterone and estrogen for luteal support when compared with those who received only progesterone, in terms of positive hCG rate (RR: 1.02, 95% CI: 0.87–1.19), clinical pregnancy rate (RR: 0.94, 95% CI: 0.78–1.13) and live birth rate (RR: 0.96, 95% CI: 0.77–1.21) per woman randomized. These results did not materially differ in the sensitivity analyses performed.

CONCLUSIONS: The currently available evidence suggests that the addition of estrogen to progesterone for luteal phase support does not increase the probability of pregnancy in IVF. However, there is an obvious need for further RCTs that will assess, with more confidence, the effect of estrogen addition to progesterone during the luteal phase on the probability of pregnancy.

Key words: estrogen/GnRH analogue/IVF/luteal support/progesterone


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Acknowledgements
 References
 Excluded studies 
 
Ovarian stimulation for in vitro fertilization (IVF) results in supraphysiological steroid levels and is associated with very low luteinizing hormone (LH) concentrations during the luteal phase (Tavaniotou et al., 2001Go). Approximately 9 days after the triggering of final oocyte maturation with human chorionic gonadotrophin (hCG), the resulting corpora lutea are deprived from hCG, their exogenous trophic stimulus. In this way, production of estradiol (E2) and progesterone is decreased and the probability of pregnancy is diminished (Smitz et al., 1992Go).

The recognition of this problem led to the supplementation of the luteal phase with hCG. HCG administration during the luteal phase aimed at maintaining stimulation of corpora lutea to produce progesterone and E2 in order to allow implantation of the developing blastocysts (Pritts and Atwood, 2002Go). However, although luteal hCG administration proved to be an effective way to overcome luteal phase defects, it was also associated with a high incidence of ovarian hyperstimulation syndrome. This has led eventually to its replacement by progesterone administration, currently the most widely used form of luteal phase supplementation.

Under progesterone supplementation, however, it has been shown that mid-luteal E2 levels decrease in a proportion of patients and that this might be associated with a concomitant decrease in pregnancy rates (Sharara and McClamrock, 1999Go). Not unexpectedly, research for optimizing luteal phase support has been directed towards the addition of estrogen to progesterone supplementation.

Many studies have been performed so far, to evaluate the concept of estrogen addition during the luteal phase (Tables I and II), leading to inconclusive results. However, in order for estrogen addition to be used routinely for luteal phase support, the superiority of this regimen in terms of pregnancy rates must be clearly demonstrated. This is especially true considering that estrogen addition makes luteal phase management more complex and costly.


View this table:
[in this window]
[in a new window]

  		Table I. Studies excluded from the systematic review and reason for exclusion.

 

View this table:
[in this window]
[in a new window]

  		Table II. Characteristics of eligible RCTs.

 
The purpose of the current systematic review and meta-analysis is to summarize the best available evidence regarding the value of estrogen supplementation in IVF by answering the following question: is the probability of pregnancy increased by adding estrogen to progesterone for luteal phase support in IVF cycles performed with the use of gonadotrophins and gonadotrophin releasing hormone (GnRH) analogues?


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Acknowledgements
 References
 Excluded studies 
 
Search strategy
A literature search was performed by two of the reviewers (E.M.K. and C.A.V.) in the following electronic databases: MEDLINE (1966 to July 2007), EMBASE (1980 to July 2007), CENTRAL (The Cochrane Library Issue 3, 2007), the Cochrane Menstrual Disorders and Subfertility Group trial registry (searched in 25th June 2007). For this purpose, the free-text search terms (‘estradiol or oestradiol’ or ‘estrogen or oestrogen’ or ‘E2’) combined with (‘luteal phase’ or ‘luteal support’) and (‘in-vitro fertilization’ or ‘in vitro fertilization’ or ‘in-vitro fertilisation’ or ‘in vitro fertilisation’ or ‘IVF’ or ‘intracytoplasmic sperm injection’ or ‘intra-cytoplasmic sperm injection’ or ‘ICSI’) were used. These results were subsequently combined with the highly sensitive search strategy proposed by the Cochrane Collaboration for the identification of randomized controlled trials RCTs (Higgins and Green, 2006Go). Additionally, the citation lists of all relevant publications and review articles were hand-searched. Meeting proceedings of the European Society of Human Reproduction and Embryology and the American Society for Reproductive Medicine were also hand-searched for the identification of relevant studies. No language limitations were applied.

Selection of studies
Criteria for inclusion/exclusion of studies were established prior to the literature search. Studies had to fulfil the following criteria for eligibility: (a) randomized trial, (b) population of women undergoing IVF after ovarian stimulation with gonadotrophins and GnRH analogues and (c) comparison of pregnancy outcome between groups of patients receiving progesterone only versus progesterone plus estrogen for luteal support. All studies that followed this design were included in the current systematic review and meta-analysis, irrespective of the type and dose of estrogen or progesterone administered, as well as the route of their administration. Studies that offered data to answer the research question but used pseudo-randomization methods (consecutive numbers, date of birth, allocation by week day, etc.) were excluded. This was also the case for studies in which patients had contributed more than one cycle. Selection of the studies was performed independently by two of the reviewers (E.M.K. and C.A.V.). Any disagreement was resolved unanimously by discussion.

Identification of studies
The literature search yielded 523 studies (Fig. 1). The screening of the titles of these studies resulted in 48 publications that could provide information relevant to the question of interest. The evaluation of the abstracts of those studies reduced the potentially eligible trials to 24, the manuscripts of which were retrieved for a more detailed evaluation. Where necessary, an attempt was made to contact the authors in order to retrieve missing information regarding study design. Eventually, 20 studies were excluded for various reasons (Table I). Thus, four studies were considered eligible (Table II) and were included in the present systematic review and meta-analysis (Fatemi et al., 2006Go; Serna et al., 2006Go; Ceyhan et al., 2008Go; Engmann et al., 2007Go).


Figure 1
View larger version (16K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Figure 1: QUOROM statement flow diagram.

 
Data extraction
Data extraction was performed independently by two of the reviewers (E.M.K. and C.A.V.). The following data were recorded from each of the four eligible studies: demographic (citation data, country, study period, number of patients included and selection of cycles), methodological (timing and method of randomization, allocation concealment), procedural (whether financial support was declared, type of GnRH analogue and protocol used for LH surge inhibition, type and starting dose of gonadotrophin administered for ovarian stimulation, criteria, type and dose of medication used for triggering final oocyte maturation, timing of oocyte retrieval, type of fertilization, day of embryo transfer, type, dose, route of administration, as well as timing of initiation and duration of luteal support with progesterone, type, dose, route of administration, as well as timing of initiation and duration of luteal support with estrogen) and outcome data (positive hCG rate, clinical pregnancy rate, live birth rate, as well as, biochemical, clinical and total miscarriage rates). Any disagreement between the two reviewers responsible for data extraction was solved unanimously by discussion.

Outcomes
The main outcome measure chosen for meta-analysis was achievement of pregnancy per patient randomized, expressed as positive hCG, clinical pregnancy (defined as the detection of fetal heart by ultrasound at 6–8 weeks of gestation), and live birth per patient randomized. Secondary outcome measures included biochemical miscarriage per patient with positive hCG (defined as the failure to achieve clinical pregnancy after positive hCG), clinical miscarriage per patient with a clinical pregnancy (defined as the failure to achieve live birth after the confirmation of clinical pregnancy) and total miscarriage per patient with positive hCG (defined as the failure to achieve live birth after positive hCG). In case the studies did not report data regarding one or more of the above outcome measures, the authors were contacted and asked to provide the missing information.

Quantitative data synthesis
The dichotomous data results for each of the eligible for meta-analysis studies were expressed as relative risk (RR) with 95% confidence intervals (CI). These results were combined for meta-analysis using the Mantel/Haenszel model, when using the fixed effects method, and the DerSimonian and Laird model, when using the random effects method.

When the outcome of interest was of a continuous nature, the differences were pooled across the studies which provided information on this outcome, resulting in a weighted mean difference with 95% CI. The inverse variance method and the DerSimonian and Laird method were used when the fixed or random effects method was applied, respectively.

All results were combined for meta-analysis with Revman Software (Version 4.2 for Windows, Copenhagen: the Nordic Cochrane Centre, The Cochrane Collaboration, 2003). Study-to-study variation was assessed by using the {chi}2 statistic (the hypothesis tested was that the studies are all drawn from the same population, i.e. from a population with the same effect size). A fixed effects model was used where no statistically significant heterogeneity was present, whereas in the presence of statistically significant heterogeneity, a random effects model was applied. Harbord–Egger’s test was performed in order to detect the presence of publication bias. Statistical significance was set at a P level of 0.05.

Sensitivity analyses were a priori planned to be performed with the addition of the studies that answered the research question of interest but in which pseudo-randomization or unclear methods of randomization were used for patient allocation.

Moreover, subgroup analyses were a priori planned to be performed based on: (a) the GnRH analogue used for LH surge inhibition, (b) the type and dose of estrogen, (c) the timing of initiation of estrogen administration, (d) the type of patients studied and (e) the type and dose of the signal used to trigger final oocyte maturation.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Acknowledgements
 References
 Excluded studies 
 
Four RCTs fulfilled the inclusion criteria and were included in the analysis with no disagreement noted between the authors responsible for study selection. Characteristics of the included studies are listed in Tables II–IV.


View this table:
[in this window]
[in a new window]

  		Table IV. Estrogen and progesterone supplementation in the eligible studies.

 
None of the analysed studies was multicentric and all were published between 2006 and 2007. Three of the studies are published as full papers, while one study is in the form of a published abstract, which however has been submitted as a full paper. The size of the studies ranged from 60 to 201 patients and the median number of patients included was 163. In two of the studies allocation was concealed, while in the remaining studies concealment of allocation was either not performed or was not reported (Table II).

All eligible studies were double armed and contained no statement about financial support (Table II). None of the studies was powered to detect a clinically important difference in the probability of achieving live birth (2504 patients would be required to detect a difference of ≥5%, in a dichotomous variable, such as positive hCG, clinical pregnancy or live birth, assuming a baseline rate of 25%).

To inhibit premature LH surges, two studies used daily antagonist administration; one study used the long agonist protocol and in the remaining study either agonists or antagonists were used for that purpose (Table III).


View this table:
[in this window]
[in a new window]

  		Table III. Characteristics of treatment protocols used in the eligible RCTs.

 
In all studies, recombinant gonadotrophins were used for ovarian stimulation. Criteria for triggering final oocyte maturation were not reported in two of the studies, whereas in the remaining studies these criteria varied and were based on follicular data. Urinary hCG was used to trigger final oocyte maturation in three studies (10 000 IU in two studies; 3300–10 000 in one study). For the same purpose, 250 µg of recombinant hCG were administered in one study (Table III).

Fertilization methods included both IVF and ICSI in three studies, whereas in one study only ICSI was performed. Embryo transfers were performed 2–5 days after oocyte retrieval (Table III).

Type, dose, route of administration, as well as timing of initiation and duration of luteal support with estrogen and progesterone varied between the eligible studies (Table IV).

Criteria used in the eligible studies for patient selection are shown in Table V.


View this table:
[in this window]
[in a new window]

  		Table V. Study population in the included RCTs.

 
The studies that were excluded due to lack of true randomization (Rashidi et al., 2004Go) or due to unclear method of randomization (Lewin et al., 1994Go; Tay and Lenton, 2003Go; Paredes Chavez et al., 2004; Karlikaya et al., 2006Go; Table I) were included in the sensitivity analyses, with the exception of the study by Paredes et al. (2006), in which no definition of pregnancy was reported or could be retrieved by the authors.

Positive hCG
Three eligible studies offered data for positive hCG rates (527 patients). The probability of positive hCG between patients who received estrogen in addition to progesterone when compared with those who received only progesterone was not statistically different (RR: 1.02, 95% CI: 0.87–1.19; P = 0.84; heterogeneity: P = 0.75; fixed effects model) (Fig. 2). The rate difference (RD) for positive hCG was +1%, favouring estrogen addition (95% CI: –7 to +9; P = 0.84; heterogeneity: P = 0.77, fixed effects model), also not significant. No publication bias could be detected (Harbord–Egger’s test: P = 0.28).


Figure 2
View larger version (30K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Figure 2: RR for positive HCG in randomized trials and in trials with pseudo-randomization or unknown randomization methods, evaluating estrogen addition to progesterone during the luteal phase.

P, progesterone; E, estrogen; CI, confidence interval; Df, degrees of freedom; M–H, Mantel/Haenszel model.

 
A further analysis (in total 981 patients) that included three non-eligible studies (with pseudo- or unknown method of randomization) (454 patients), which offered data on positive hCG, did not materially change the original results (RR: 1.01, 95% CI: 0.89–1.14; P = 0.90; heterogeneity: P = 0.98; RD: 0%, 95% CI: -6 to +6; P = 0.90; heterogeneity: P = 0.99).

Clinical pregnancy
Four eligible studies offered data for clinical pregnancy (587 patients). The probability of clinical pregnancy between patients who received estrogen in addition to progesterone when compared with those who received only progesterone was not statistically different (RR: 0.94, 95% CI: 0.78–1.13; P = 0.52; heterogeneity: P = 0.48; fixed effects model) (Fig. 3). The RD for clinical pregnancy was –3%, favouring progesterone only luteal support (95% CI: –10 to +5; P = 0.51; heterogeneity: P = 0.37, fixed effects model), also not significant. No publication bias could be detected (Harbord–Egger’s test: P = 0.85).


Figure 3
View larger version (31K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Figure 3: RR for clinical pregnancy in randomized trials and in trials with pseudo-randomization or unknown randomization methods, evaluating estrogen addition to progesterone during the luteal phase.

P, progesterone; E, estrogen.

 
A further analysis (in total 1141 patients) that included four non-eligible studies (with pseudo- or unknown method of randomization) (554 patients), which offered data on clinical pregnancy, did not materially change the original results (RR 0.97, 95% CI: 0.84–1.12; P = 0.72; heterogeneity: P = 0.83; RD: –1%, favouring progesterone only luteal support, 95% CI: –7 to +5; P = 0.72; heterogeneity: P = 0.80).

Live birth
Three eligible studies offered data for live birth (527 patients). The probability of live birth between patients who received estrogen in addition to progesterone when compared with those who received only progesterone was not statistically different (RR: 0.96, 95% CI: 0.77–1.21; P = 0.75; heterogeneity: P = 0.55; fixed effects model) (Fig. 4). The RD for live birth was –1%, favouring progesterone only luteal support (95% CI: –9 to +7; P = 0.75; heterogeneity: P = 0.55, fixed effects model), also not significant. No publication bias could be detected (Harbord–Egger’s test: P = 0.23).


Figure 4
View larger version (24K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Figure 4: RR for live birth in randomized trials and in trials with pseudo-randomization or unknown randomization methods, evaluating estrogen addition to progesterone during the luteal phase.

P, progesterone; E, estrogen.

 
A further analysis (in total 940 patients) that included two of the non-eligible studies (with pseudo- or unknown method of randomization) (413 patients), which offered data on live birth, did not materially change the original results (RR: 1.02, 95% CI: 0.86–1.21; P = 0.81; heterogeneity: P = 0.68; RD: +1%, favouring estrogen addition, 95% CI: –5 to +7; P = 0.81; heterogeneity: P = 0.68).

Secondary outcomes
Biochemical miscarriage
Three eligible studies offered data for biochemical miscarriage (222 patients with positive hCG). The probability of biochemical miscarriage between patients with positive hCG who received estrogen in addition to progesterone when compared with those who received only progesterone was not statistically different (RR: 1.49, 95% CI: 0.87–2.53; P = 0.14; heterogeneity: P = 0.21; fixed effects model). The RD for biochemical miscarriage was +8%, favouring progesterone only luteal support (95% CI: –2 to +19; P = 0.13; heterogeneity: P = 0.19, fixed effects model), also not significant.

A further analysis with the addition of three of the non-eligible studies with pseudo- or unknown method of randomization that offered data on biochemical miscarriage (217 patients with positive hCG) did not materially change the original results (RR: 1.15, 95% CI: 0.79–1.69; P = 0.47; heterogeneity: P = 0.29; RD: +3%, favouring progesterone only luteal support, 95% CI: –5 to +10; P = 0.46; heterogeneity: P = 0.25).

Clinical miscarriage
Three eligible studies offered data for clinical miscarriage (217 patients with clinical pregnancy). The probability of clinical miscarriage between patients with clinical pregnancy who received estrogen in addition to progesterone when compared with those who received only progesterone was not statistically different (RR: 0.79, 95% CI: 0.39–1.58; P = 0.50; heterogeneity: P = 0.80; fixed effects model). The RD for clinical miscarriage was –3%, favouring estrogen addition (95% CI: –12 to +6; P = 0.50; heterogeneity: p = 0.89, fixed effects model), also not significant.

A further analysis with the addition of two of the non-eligible studies with pseudo- or unknown method of randomization that offered data on clinical miscarriage (168 patients with clinical pregnancy) did not materially change the original results (RR: 0.77, 95% CI: 0.47–1.27; P = 0.31; heterogeneity: P = 0.96; RD: –4% favouring estrogen addition, 95% CI: –11 to +3; P = 0.31; heterogeneity: P = 0.94).

Total miscarriage
Three eligible studies offered data for total miscarriage (269 patients with positive hCG). The probability of total miscarriage between patients with positive hCG who received estrogen in addition to progesterone when compared with those who received only progesterone was not statistically different (RR: 0.85, 95% CI: 0.57–1.27; P = 0.43; heterogeneity: P = 0.79; fixed effects model). The RD for total miscarriage was –4%, favouring estrogen addition (95% CI: –14 to +6; P = 0.43; heterogeneity: P = 0.88, fixed effects model), also not significant.

A further analysis with the addition of one of the non-eligible studies with pseudo- or unknown method of randomization that offered data on total miscarriage (171 patients with positive hCG) did not materially change the original results (RR: 0.80, 95% CI: 0.59–1.08; P = 0.15; heterogeneity: P = 0.85; RD: –6%, favouring estrogen addition, 95% CI: –14 to +2; P = 0.15; heterogeneity: P = 0.90).


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Acknowledgements
 References
 Excluded studies 
 
The present systematic review and meta-analysis compared the effectiveness of the combination of estrogen and progesterone administration for luteal phase support versus progesterone only administration, in terms of pregnancy achievement, in IVF cycles where GnRH analogues and gonadotrophins were used for ovarian stimulation. It is suggested that the probability of pregnancy (expressed as positive hCG, clinical pregnancy or live birth rate) is not altered significantly by the addition of estrogen to progesterone during the luteal phase.

Moreover, the occurrence of biochemical miscarriage, clinical miscarriage and total miscarriage was not dependent on the type of luteal phase support administered. No statistical heterogeneity was present in the studies analysed for all outcome measures examined and thus a fixed effects model was used to summarize data. The above findings were stable in the sensitivity analyses performed, which included four RCTs in which pseudo-randomization or unclear methods of randomization were used for patient allocation. Thus, currently, the available evidence is not sufficient to recommend routine estrogen addition to progesterone for luteal phase support.

However, it should be stressed that the maximum number of patients analysed in the eligible trials (n = 587) or even the maximum number of patients analysed in the sensitivity analyses performed (n = 1141) is far below the sample size required to exclude a clinically important difference. The confidence interval for the RD between the two methods of luteal phase support in terms of positive hCG rate, clinical pregnancy rate or live birth rate cannot exclude a clinically important difference, arbitrarily defined as a difference ≥5%. Thus, there is an obvious need for further RCTs that will assess, with more confidence, the effect of estrogen addition to progesterone during the luteal phase on the probability of pregnancy.

Moreover, due to the small number of eligible trials, it was not possible to conduct a meaningful subgroup analysis as planned in the study protocol, considering the type of GnRH analogue used for LH surge inhibition, the type and dose of estrogen added, the timing of its administration, the type and dose of the signal used to trigger final oocyte maturation as well as the type of population studied. This task might be feasible with the accumulation of further trials. It should be noted that the above parameters varied in the studies analysed (Tables III and IV) and it cannot be excluded that these clinical variations might be associated with the effectiveness or not of estrogen addition to progesterone for luteal phase support. For example, estrogen addition to progesterone might have a different effect on the probability of pregnancy depending on the type and protocol of GnRH analogue used for LH surge inhibition. In this respect, there is evidence suggesting that estrogen addition to progesterone during the luteal phase is associated with higher pregnancy rates in the long, when compared with the short, GnRH agonist protocol (Farhi et al., 2000). However, this finding remains to be confirmed in future RCTs.

The currently observed differences in pregnancy rates between the two forms of luteal phase support are very small (<5%) and thus, if confirmed by the addition of further trials, probably of limited clinical importance. However, it cannot be excluded that addition of estrogen to progesterone for luteal phase support might not be effective when applied to all patients, regardless of their hormonal status during the luteal phase, as was the case with the eligible studies (Table V). The assumption for estrogen supplementation is that a serum E2 drop occurs in some patients and it is perhaps these patients that must be targeted in future trials. It might be worth establishing a cut-off E2 level in progesterone only supported IVF cycles, on a certain day during the luteal phase, probably around Day 8, when hCG is about to disappear from circulation. It has been shown that subnormal mid-luteal E2 concentrations are associated with endometrial maturation delay and reduced endometrial receptivity (De Hertogh et al., 1989Go; de Ziegler and Bouchard, 1993Go). Such a cut-off level would aim at distinguishing patients who will achieve pregnancy and those who will not. In turn, it might be worth examining the addition of estrogen to progesterone for luteal phase support in those patients with serum E2 below the above established cut-off level. However, before such data are available, routine use of estrogen addition during the luteal phase cannot be recommended.

In conclusion, it is necessary to perform further well-designed RCTs examining the effect on the probability of pregnancy of estrogen addition to progesterone for luteal support. However, on the basis of the currently best available evidence, routine use of estrogen addition during progesterone supported luteal phase in IVF cycles stimulated with GnRH analogues and gonadotrophins is not justified.


   Acknowledgements
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Acknowledgements
References
 Excluded studies 
 
We would like to thank the following persons for their support in this work: F. Causio (Italy), S.T. Ceyhan (Turkey), L. Engmann (UK), J. Farhi (Israel), H. Gorkemli (Turkey), G. Karlikaya (Turkey), E. Lenton (UK), K. Lukaszuk (Poland), J.L. Pouly (France), B. Rashidi (Iran), J. Serna (Spain), V. Unfer (Italy) and A. Weissman (Israel).


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Acknowledgements
 References
Excluded studies 
 
Ceyhan T, Basaran M, Duru NK, Goktolga U, Yilmaz A, Korkmaz C, Baser I. Use of luteal estrogen supplementation in normal responder patients treated with fixed multi dose GnRH antagonist. Hum Reprod (2007) 22:P320.

de Ziegler D, Bouchard P. Understanding endometrial physiology and menstrual disorders in the 1990s. Curr Opin Obstet Gynecol (1993) 5:378–388.[Web of Science][Medline]

De Hertogh R, Vanderheyden I, Glorieux B, Ekka E. Oestrogen and progesterone receptors in endometrium and myometrium at the time of blastocyst implantation in pregnant diabetic rats. Diabetologia (1989) 32:568–572.[Web of Science][Medline]

Engmann L, Diluigi A, Schmidt D, Benadiva C, Maier D, Nulsen J. The effect of luteal phase vaginal estradiol supplementation on the success of in vitro fertilization treatment: a prospective randomized study. Fertil Steril (2008) 89:554–561.[CrossRef][Web of Science][Medline]

Fatemi HM, Kolibianakis EM, Camus M, Tournaye H, Donoso P, Papanikolaou E, Devroey P. Addition of estradiol to progesterone for luteal supplementation in patients stimulated with GnRH antagonist/rFSH for IVF: a randomized controlled trial. Hum Reprod (2006) 21:2628–2632.[Abstract/Free Full Text]

Karlikaya G, Karagozoglu H, Kumbak B, Lacin S, Guney A, Kahraman S. Adding estradiol to progesteron for luteal phase support does not improve the clinical outcome in assisted reproductive technologies (ART) cycles. Fertil Steril (2006) 86:S112.

Lewin A, Benshushan A, Mezker E, Yanai N, Schenker JG, Goshen R. The role of estrogen support during the luteal phase of in vitro fertilization-embryo transplant cycles: a comparative study between progesterone alone and estrogen and progesterone support. Fertil Steril (1994) 62:121–125.[Web of Science][Medline]

Paredes Chavez FC, Barros Delgadillo JC, Ochoa Rueda SS, Barroso Villa G, Villalobos Acosta S, Sanchez Solis V, Osorio Caballero M, Gavino Gavino F. Estrogen role in the luteal phase support in in vitro fertilization with embryo transfer cycles [Spanish]. Ginecol Obstet Mex (2004) 72:645–655.[Medline]

Pritts EA, Atwood AK. Luteal phase support in infertility treatment: a meta-analysis of the randomized trials. Hum Reprod (2002) 17:2287–2299.[Abstract/Free Full Text]

Rashidi BH, Asheghan H, Jafarabadi M, Nejad ET. The role of estrogen supplementation during the luteal phase in in vitro fertilization-embryo transfer cycles: a comparative study between progesterone alone and estrogen plus progesterone support: Research Papers in Fertility and Reproductive Medicine. Proceedings of the 18th World Congress on Fertility and Sterillity (IFFS 2004). International Congress Series (2004) 1271:1203.

Serna J, Cholquevique JL, Villasante A, Oriol B, Requena A, Garcia-Velasco J. Adding estradiol patches to the luteal phase of IVI/ICSI cycles did not improve pregnancy nor miscarriage rates. Fertil Steril (2006) 86:S73.[Medline]

Sharara FI, McClamrock HD. Ratio of oestradiol concentration on the day of human chorionic gonadotrophin administration to mid-luteal oestradiol concentration is predictive of in-vitro fertilization outcome. Hum Reprod (1999) 14:2777–2782.[Abstract/Free Full Text]

Smitz J, Erard P, Camus M, Devroey P, Tournaye H, Wisanto A, Van Steirteghem AC. Pituitary gonadotrophin secretory capacity during the luteal phase in superovulation using GnRH-agonists and HMG in a desensitization or flare-up protocol. Hum Reprod (1992) 7:1225–1229.[Abstract/Free Full Text]

Tavaniotou A, Albano C, Smitz J, Devroey P. Comparison of LH concentrations in the early and mid-luteal phase in IVF cycles after treatment with HMG alone or in association with the GnRH antagonist Cetrorelix. Hum Reprod (2001) 16:663–667.[Abstract/Free Full Text]

Tay PY, Lenton EA. Inhibition of progesterone secretion by oestradiol administered in the luteal phase of assisted conception cycles. Med J Malaysia (2003) 58:187–195.[Medline]


   Excluded studies 
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Acknowledgements
 References
 Excluded studies 
 
Causio F, Leonetti T. Luteal phase support with estrogen and progesterone in in vitro fertilization cycles using GnRH-a and FSH. Giornale Italiano di Ostetricia e Ginecologia (1997) 19:277–282.

Devroey P, Smitz J, Bourgain C, Van Steirteghem A. Only micronized progesterone is needed to substitute the luteal phase in stimulated cycles. Contraception Fertilite Sexualite (1992) 20:1021–1024.[Web of Science]

Engmann L, Diluigi A, Schmidt D, Benadiva C, Maier D, Nulsen J. A prospective randomized trial evaluating the effect of luteal phase estradiol supplementation on the success of IVF treatment. Fertil Steril (2005) 84:S88.

Farhi J, Steinfeld Z, Shorer M, Nahum H, Weissman A, Glezerman M, Levran D. Estrogen supplementation during luteal phase improves pregnancy rate in IVF–ET. Fertil Steril (1999) 72:S161.[CrossRef]

Farhi J, Weissman A, Steinfeld Z, Shorer M, Nahum H, Levran D. Estradiol supplementation during the luteal phase may improve the pregnancy rate in patients undergoing in vitro fertilization–embryo transfer cycles. Fertil Steril (2000) 73:761–766.[CrossRef][Web of Science][Medline]

Fatemi HM, Kolibianakis EM, Camus M, Tournaye H, Van Steirteghem A, Devroey P. Progesterone versus progesterone combined with estradiol as luteal support in cycles stimulated with Gnrh antagonist/Rec-Fsh for Ivf: a randomized clinical trial. Fertil Steril (2005) 84:S322.

Friedrich F, Burger F, Pfeiffer P. Good results with E2 supplementation in luteal phase of controlled ovarian hyperstimulation cycles. Journal fur Fertilitat und Reproduktion (2001) 11:29–33.

Gleicher N, Brown T, Dudkiewicz A, Karande V, Rao R, Balin M, Campbell D, Pratt D. Estradiol/progesterone substitution in the luteal phase improves pregnancy rates in stimulated cycles—but only in younger women. Early Pregnancy [Electronic Resource] (2000) 4:64–73.

Gorkemli H, Ak D, Akyurek C, Aktan M, Duman S. Comparison of pregnancy outcomes of progesterone or progesterone+estradiol for luteal phase support in ICSI–ET cycles. Gynecol Obstet Invest (2004) 58:140–144.[CrossRef][Web of Science][Medline]

Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of Interventions 4.2.6 [updated September 2006]. http://www.cochrane.org/resources/handbook/hbook.htm accessed 25th January 2008.

Kaider AS, Coulam CB. Luteal estrogen supplementation in pregnancies associated with low serum estradiol concentrations. Early Pregnancy [Electronic Resource] (2000) 4:191–199.

Liss J, Lukaszuk K, Lukaszuk M, Maj B, Lukaszuk K. Increase of the pregnancy rate by the estradiol supplementation during the luteal phase in IVF–ET cycles. Hum Reprod (2005) 20:i20.

Lukaszuk K, Liss J, Lukaszuk M, Maj B. Optimization of estradiol supplementation during the luteal phase improves the pregnancy rate in women undergoing in vitro fertilization–embryo transfer cycles [see comment]. Fertil Steril (2005) 83:1372–1376.[CrossRef][Web of Science][Medline]

Pouly JL, Piekrishvili R, Beaume-Brugon F, Schubert B, Janny L. Luteal phase supplementation with oestrogens does not improve the IVF pregnancy rate: a randomized study. Hum Reprod (2005) 20:i72.[CrossRef]

Smitz J, Bourgain C, Van Waesberghe L, Camus M, Devroey P, Van Steirteghem AC. Prospective randomized study on oestradiol valerate supplementation in addition to intravaginal micronized progesterone in buserelin and HMG induced superovulation. Hum Reprod (1993) 8:40–45.[Abstract/Free Full Text]

Unfer V, Casini ML, Gerli S, Costabile L, Mignosa M, Di Renzo GC. Phytoestrogens may improve the pregnancy rate in in vitro fertilization–embryo transfer cycles: a prospective, controlled, randomized trial. Fertil Steril (2004) 82:1509–1513.[CrossRef][Web of Science][Medline]

Submitted on December 6, 2007; resubmitted on January 28, 2008; accepted on February 22, 2008.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?



This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF ) Freely available
Right arrow All Versions of this Article:
23/6/1346    most recent
den115v1
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Kolibianakis, E.M.
Right arrow Articles by Griesinger, G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kolibianakis, E.M.
Right arrow Articles by Griesinger, G.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?