2013 Sep.; 24(3):

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1 Journal of Reproduction & Contraception doi: /j.issn Sep.; 24(3): Comparison of the Effects and Safety of Mild Ovarian Stimulation and Conventional Ovarian Stimulation with A Long GnRH Agonist Protocol on IVF Outcomes Rong-rong TAN, Dan-hua PU, Jia-yin LIU, Jie WU State Key Laboratory of Reproductive Medicine, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Nanjing Medical University, Nanjing , China Objective To conduct a Meta-analysis of studies that compared the efficacies of mild ovarian stimulation and conventional long GnRH agonist protocol in patients undergoing IVF or intracytoplasmic sperm injection (ICSI). Methods Meta-analysis was performed. All studies were published by July 2012 with data related to outcomes following mild ovarian stimulation compared with the conventional protocol. Odds ratios (ORs) and weighted / standardized mean difference (WMD/SMD) from individual study were pooled in fixed and random effect models. Main outcome measure was the efficacy of mild ovarian stimulation. Results Six articles were included in this Meta-analysis. The number of oocytes retrieved was lower, the cycle cancellation rate was higher and the incidence of ovarian hyperstimulation syndrome (OHSS) was lower in the mild stimulation group than in conventional ovarian stimulation group. Clinical pregnancy rates were similar in both mild and conventional stimulation groups. Conclusions The level of evidence supporting the use of mild stimulation protocols in IVF is low, considering the fewer oocytes retrieved and the higher rates of cycle cancellation. Key words: mild ovarian stimulation; long GnRH agonist ovarian stimulation; in vitro fertilization (IVF) This work was supported by grants from the Medical Research Council (No. XK ) and the Priority Academic Program Development of Jiangsu Higher Education Institutions Corresponding author: Jie WU; jie.wuyale@gmail.com 159

2 In vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) are widely accepted as effective treatments for most causes of infertility. Successful IVF requires adequate follicular recruitment and maturation. Conventional ovarian stimulation protocols aim to stimulate the growth of many follicles so that multiple oocytes can be obtained for IVF/ICSI, thus yielding multiple embryos from which suitable embryos can be selected for transfer [1,2]. Since Fleming et al. [3] first used GnRH agonists to suppress endogenous LH levels during ovulation induction, the success rates of IVF have increased. However, the resultant initial flare in gonadotropin levels necessitates prolonged pretreatment in order to achieve pituitary desensitization. With the introduction of GnRH antagonists, ovarian stimulation protocols in IVF have become considerably shorter, especially, in poor ovarian responders [4]. In 1996, Edwards et al. [5] first used mild ovarian stimulation protocols in IVF, and since then, several studies have proposed that mild stimulation is a safer, more patient-friendly protocol, with minimal treatment risks [6,7]. Recently, there has been a trend to use mild stimulation protocols in order to prevent ovarian hyperstimulation [8-10]. A mild IVF cycle is defined as either 1) a stimulation regimen in which gonadotropins are administered at a lower-than-usual dose and/or for a shorter duration throughout a cycle in which a GnRH antagonist is concurrently; or 2) a stimulation in which oral compounds (e.g., anti-estrogens) are used either alone or in combination with gonadotropins and GnRH antagonists. Luteal support and hcg injections are also administered [11]. The aim of mild ovarian stimulation is to extend the FSH window by administering lowdose exogenous FSH from the mid to late follicular phase, so that the treatment cycle is shorter and more patient-friendly. However, fewer oocytes are obtained after mild ovarian stimulation, and it is unclear whether it impairs IVF outcomes [8]. Importantly, implementing these regimens in the current commercially competitive environment in which IVF is practiced is challenging. Therefore, to address these issues, we reviewed all articles published to date that compared mild ovarian stimulation and conventional (standard) stimulation with long GnRH agonist protocols in women undergoing IVF/ICSI. We also carried out a meta-analysis of all relevant randomized controlled trials (RCTs) in order to estimate effect size and determine the extent of heterogeneity in the strength of associations between the studies. Materials & Methods Search strategy, inclusion and exclusion criteria We searched the MEDLINE ( ), EMBASE ( ), Cochrane Central Register of Controlled Trials (CENTRAL) on the Cochrane Library, China Biology Medicine disc ( ), China National Knowledge Infrastructure ( ) and VIP (

3 2012) databases for all RCTs published up to the end of July 2012 that compared mild ovarian stimulation and conventional stimulation with a long GnRH agonist protocol in women undergoing IVF/ICSI. The search terms used the following keywords: mild ovarian stimulation, minimal ovarian stimulation, soft ovarian stimulation and in vitro fertilization or intracytoplasmic sperm injection. The reference lists of all publications identified were searched for additional studies, and the MEDLINE option Related articles was selected in search for potentially relevant articles. Reviews and references of other relevant studies identified were hand-searched to find additional eligible studies. Articles published in Chinese and English languages were selected when they met the following criteria: 1) the study was an RCT; 2) the study reported the clinical outcomes after mild and conventional protocols for ovarian stimulation. The exclusion criteria were as follows: 1) studies not including mild or conventional stimulation protocols; 2) IVF/ICSI outcomes data were reported only as mean and median values, and sufficient information to calculate them could not be retrieved, despite writing to the corresponding author; 3) IVF/ICSI outcomes were evaluated in special women, such as poor ovarian responders or polycystic ovary syndrome (PCOS) or endometriosis (EMs). Institutional Review Board approval was obtained. Data extraction and outcome measures The following data were extracted from the eligible studies: first author s name, region/ country where the study was conducted, year of publication, study design, patient inclusion criteria, sample size, controls and ovarian stimulation protocols. In addition, the following IVF outcome data for each treatment cycle were collected from the studies: peak serum estradiol level and endometrial thickness on the day of hcg administration, total number of the oocytes retrieved, incidence of ovarian hyperstimulation syndrome (OHSS), cycle cancellation rate (CCR), clinical pregnancy rate (CPR) and live birth rate (LBR). Clinical pregnancy was defined as the detection of a gestational sac and/or fetal heartbeat on transvaginal ultrasonography. All data were independently extracted in duplicate by two authors. Any disagreement between the authors was resolved by discussion. Data not provided in the retrieved articles were obtained via contacting the corresponding authors if possible. Statistical analysis Summary statistics were estimated using the Review Manager 5.1 software (RevMan 5.1, The Nordic Cochrane Center, Rigshospitalet). Continuous variables were denoted as weighted mean difference (WMD) or standardized mean difference (SMD) with its 95% confidence interval (CI). Dichotomous data for each unit of analysis were expressed as an odds ratio (OR) with its 95%CI. The authors considered whether the clinical and methodological characteristics of the included studies were sufficiently similar for Meta-analysis to provide 161

4 a meaningful summary. The heterogeneity between studies was tested by the Q statistic [12]. Statistical heterogeneity was assessed using the I 2 index. An I 2 above 50% was indicated as substantial heterogeneity (The Cochrane Collaboration, 2011). If substantial heterogeneity was detected, a random effect model was used instead of a fixed effect model. Stata software (version 11.0; StataCorp LP, College Station, TX, USA) was used to analyze publication bias, which was investigated with the funnel plot. Funnel plot asymmetry was further assessed by the method of Egger s linear regression test. The significance of the intercept was determined by the t-test, and a P value less than 0.05 was considered statistically significant. Results Our search strategy identified 48 published articles that possibly compared the effects of mild ovarian stimulation versus conventional ovarian stimulation with long GnRH agonist protocols on IVF/ICSI outcomes. After reading the full papers, however, only 6 studies were found to meet our inclusion criteria (Figure 1); these studies included 961 cycles with mild ovarian stimulation and 803 cycles with conventional ovarian stimulation. The detailed characteristics of each study are described in Table 1. Two of the 6 studies were performed Total number of citations retrieved from electronic searches and from examination of reference lists of primary and review articles: n=48 Citation excluded after screening titles and/or abstracts: n=33 RCTs retrieved for detailed evaluation: n=15 Papers excluded if data insufficient: n=5 Potential RCTs appropriate for this Meta-analysis: n=10 RCTs excluded if participants were inappropriate: n=4 (2 for poor ovarian responders; 1 for polycystic ovarian syndrome and 1 for endometriosis) 162 RCTs with usable information included in Meta-analysis: n=6 Figure 1 PRISMA statement flow diagram

5 Table 1 Characteristics of included studies Region Inclusion Interventions Study Main /country criteria Mild protocols Conventional protocols outcomes Dhont et al. [14] (1995) Weigert et al. [9] (2002) Belgium Austria No previous assisted reproduction treatments First IVF cycles, tubal, male factor or unexplained infertility, age years old, normal ovulatory cycles CC 100 mg for 5 d and subsequent hmg 2 amp./d for 3 5 d (n=151 CC 100 mg for 5 d in combination with 225 IU of rfsh and 75 IU of rlh on alternate days (n=154 Long GnRH-a (goserelin) protocol, and flexible hmg doses after 2 3 weeks (n=152 Long GnRH-a (buserelin) protocol, and fixed rfsh doses (150 IU/d) (n=140 Cancellation rate/cycle, pregnancy rate/cycle, live birth rate/ cycle Cancellation rate/cycle, pregnancy rate/cycle OHSS rate/ cycle Hohmann Netherlands No more than 3 previous Fixed rfsh doses Long GnRH-a Cancellation et al. [15] (2003) Heijnen et al. [11] (2007) Baart et al. [13] (2007) Netherlands Netherlands IVF cycles and no previous IVF cycle with poor response or OHSS, younger than 39 years old, regular menstrual cycles (25 35 d), BMI kg/m 2, no relevant systemic diseases First IVF cycle or a healthy born child after a previous IVF treatment, younger than 38 years old with regular menstrual cycle (25 35 d) and BMI kg/m 2 First cycles, younger than 38 years old, regular menstrual cycles (25 35 d), BMI kg/m 2, no relevant systemic diseases, sperm count > /ml 150 IU/d from CD2 (n=48 or CD5 (n=49, GnRH-ant (cetrorelix) from leading follicle 14 mm Fixed rfsh doses 150 IU/d from CD5, GnRH-ant (ganirelix) from leading follicle 14 mm. Combined with single embryo transfer (n=444 Fixed rfsh doses 150 IU/d from CD5, GnRH-ant (orgalutran) from leading follilce 14 mm (n=63 (Decapeptyl) protocol, and fixed rfsh doses (150 IU/d) after 2 weeks (n=45 Long GnRH-a (leuproline or triptorelin) protocol, fixed rfsh doses after 2 weeks 150 IU/d (n=325 Long GnRH-a (triptorelin) protocol, fixed rfsh doses after 2 weeks 225 IU/d (n=41 rate/cycle, pregnancy rate/cycle Pregnancy and term livebirth within 1 year; total costs per couple and child up to 6 weeks after expected delivery; and patients discomfort Number of oocytes obtained 163

6 Table 1 Characteristics of included studies (continued) Study Region Interventions Main Inclusion criteria /country Mild protocols Conventional protocols outcomes Karimzadeh et al. [16] (2010) Iran First IVF cycle, unexplained infertility, male, tubal, early stage endometriosis and cervical factor, age years, regular ovulatory menstruation cycle (26 35 d), BMI kg/m 2, basal FSH<10 IU/L CC 100 mg from CD3 for 5 d and continuous rfsh 75 IU/d from CD5 (n=100 Long GnRH-a (buserelin) protocol, flexible rfsh doses after 2 weeks IU/d (n=100 Cancellation rate/cycle, pregnancy rate/cycle in multiple centers [10,13], while the other 4 were single-center trials [9,14-16]. Randomisation sequence was computer generated double-blind in all included studies. The mild stimulation protocols in the six eligible studies were divided into two types according to the International Society for Mild Approaches in Assisted Reproduction (ISMAAR) definitions [11]. In three studies, gonadotropins were administered at a lower doses and/or for a shorter duration in GnRH antagonist co-treated cycles [10,13,15], and an oral antiestrogen, e.g., clomiphene citrate (CC), was used either alone or in combination with gonadotropins and a GnRH antagonist in the other three studies [9,14,16]. As shown in Figures 2 and 3, the number of oocytes retrieved was smaller (P= , WMD: 3.54, 95%CI: 5.41, 1.68) and the CCR was higher (P=0.02, OR=3.57, 95%CI: 1.25, 10.22) in the mild stimulation group than in the conventional stimulation group. Subgroup analysis showed that in both types of mild stimulation protocols, the number of oocytes retrieved was significantly smaller than that in the conventional stimulation group (low-dose gonadotropin/gnrh-antagonist protocols: P=0.02, WMD: 2.45, 95%CI: 4.55, 0.35; CC protocols: P=0.007, WMD: 4.18, 95%CI: 7.23, 1.14; Figure 2), but the CCRs were similar between the subgroup in which mild stimulation protocols involved CC and the conventional stimulation group (P=0.15, OR=3.87, 95%CI: 0.62, 24.28; Figure 3). The difference in CPR between the mild and conventional stimulation groups was not statistically significant (P=0.40; OR=0.83, 95%CI: 0.53, 1.28; Figure 4). However, a subgroup analysis showed that the CPR was significantly lower (P= , OR=0.56, 95%CI: 0.41, 0.78; Figure 4) in the mild stimulation subgroup involving low-dose gonadotropin protocols than in the conventional stimulation group. The LBR was reported in only two studies (P= , OR=0.59, 95%CI: 0.45, 0.79; Table 2). The occurrence rate of OHSS was significantly lower in the mild stimulation group than in the conventional stimulation group (P< , OR=0.23, 95%CI: 0.12, 0.46; Figure 5), and subgroup analysis of OHSS occurrence rates revealed the same outcome. 164

7 First subgroup: gonadotropins are administered at a lower-than-usual dose and/or for a shorter duration in GnRH-ant co-treated cycles in four studies. Second subgroup: oral anti-estrogen treatment (e.g., CC) is used either alone or in combination with gonadotropins. So are the Figures 3 5 Figure 2 Meta-analysis of mild versus long GnRH agonist ovarian stimulation protocols for the number of oocytes retrieved Figure 3 Meta-analysis of mild versus long GnRH agonist ovarian stimulation protocol for the cycle cancellation rate 165

8 Figure 4 Meta-analysis of mild versus long GnRH agonist ovarian stimulation protocol for clinical pregnancy rates Figure 5 Meta-analysis of mild versus long GnRH agonist ovarian stimulation protocol for OHSS occurrence rates 166

9 Table 2 Results of mild versus long GnRH agonist ovarian stimulation protocol (x s) Item No. of Pooled WMD Pooled SMD Pooled OR P comparisons (95%CI) (95%CI) (95%CI) value Days of stimulation ( 3.86, 0.19) a 0.08 Total ampoule of Gn ( 37.91, 3.27) a 0.02 Endometrial thickness ( 0.18, 0.19) b 0.97 E2 level on hcg injection day ( 1.31, 0.71) a < Live birth rate (0.45, 0.79) b a: random effect model; b: fixed effect model Only the studies with CC protocols reported differences in the peak serum estradiol level and endometrial thickness on the day of hcg administration. The peak serum estradiol level was significantly lower in the mild stimulation group than in the conventional stimulation group (P< , SMD: 1.01, 95%CI: 1.31, 0.71; Table 2), but endometrial thickness did not significantly differ between the two groups (P=0.97, SMD: 0.00, 95%CI: 0.18, 0.19; Table 2). Begg s funnel plot and Egger s test were performed to evaluate the publication bias of literatures. As shown in Figures 6 9, the shape of the funnel plots was symmetrical in the comparisons of IVF outcomes (number of oocytes retrieved, CCR, CPR and OHSS rate). Then, the Egger s test was adopted to provide statistical evidence of funnel plot symmetry. The results still indicated that there was no obvious publication bias in our analysis (P=0.248, 0.213, and 0.052, respectively). Figure 6 Begg s funnel plot of mild versus long GnRH agonist ovarian stimulation protocol for number of oocytes retrieved 167

10 Figure 7 Begg s funnel plot of mild versus long GnRH agonist ovarian stimulation protocol for cycle cancellation rates Figure 8 Begg s funnel plot of mild versus long GnRH agonist ovarian stimulation protocol for clinical pregnancy rates Figure 9 Begg s funnel plot of mild versus long GnRH agonist ovarian stimulation protocol for OHSS occurrence rates 168

11 Discussion In general, the modest number of oocytes retrieved following mild ovarian stimulation provides an optimal chance of achieving a pregnancy [13,15,17]. The observed relationship between smaller oocyte numbers and higher chances of achieving an ongoing pregnancy following mild stimulation suggests that when fewer oocytes are obtained, they are likely to represent a homogenous group of good-quality oocytes [15,17]. This could be the result of the subtle interference with the natural selection of good-quality oocytes or the minimized exposure of growing follicles to the potentially negative effects of ovarian stimulation. Our current findings showed that although fewer oocytes were obtained in the mild stimulation group than in the conventional stimulation group, the CPR did not significantly differ between the two groups; these results are very similar to those of the previous studies [9,15,16]. Interestingly, Baart et al. [13] reported that IVF with mild ovarian stimulation resulted in a significantly higher proportion of euploid embryos than that obtained through conventional stimulation (51% vs 35%; P=0.04), suggesting that the surplus of oocytes and embryos obtained through maximal stimulation are of lower quality. In our study, a subgroup analysis demonstrated that the CPR was significantly lower in the mild stimulation subgroup with low-dose gonadotropin / GnRH-antagonist protocols than in the conventional stimulation subgroup; this result was inconsistent with that of our aggregate analysis, which showed that the CPR was similar in the mild and conventional stimulation groups. However, only two studies reported CPRs for the two groups, and the weight of the study by Heijnen et al. [10], which favored the mild stimulation protocol, was higher; hence, the comparison was insufficient for drawing conclusions. The CCR was significantly higher in the mild stimulation group than in the conventional stimulation group, but a subgroup analysis showed no statistical significance in CCRs between the mild stimulation subgroup with CC protocols and the conventional stimulation group. A higher CCR was observed in the lower dose gonadotropin / GnRH-antagonist protocols, which was probably a result of its lower responsibility. Such a phenomenon could be explained by the biases due to sample selection prior to IVF and sample size of each study. Moreover, a low response leading to a higher CCR may be related with women s increased age and their exposure to higher FSH concentrations at early follicular phase [15] [median age, 35 years old (range, years old) vs 33 years old (range, years old); P<0.001; median FSH, 8.0 IU/L (range, IU/L) vs 5.8 IU/L (range, IU/L); P<0.02; for low and normal response patients, respectively]. In addition, cancellation criteria in mild stimulation protocols may need to be revised due to the number of observed pregnancies in women with a low oocyte yield. Further multi-center RCTs with larger sample sizes are required to confirm 169

12 this hypothesis. The LBR was significantly lower in the mild stimulation group; however, only two of the studies in this Meta-analysis reported LBR data, and they used different mild stimulation protocols, which limited their usefulness. More studies reporting LBR data are needed. OHSS is a serious and potentially life-threatening complication of IVF; it has a mean incidence of 1% 3% in programs involving conventional ovarian stimulation protocols [8]. The significantly lower rate of OHSS was due to the smaller cohort of recruited follicles and the lower circulating estradiol levels during mild ovarian stimulation. Weigert et al. [9] reported an OHSS incidence of 3% and 10% in patients undergoing mild stimulation and conventional stimulation, respectively (P=0.02). In another study, Karimzadeh et al. [16] observed a zero incidence of OHSS in the group treated with mild stimulation vs 6% in the group treated with conventional stimulation, which was consistent with our results (P< ). Several studies suggested that supra-physiological circulating estradiol levels have an adverse impact on the quality of the endometrium and embryo [13,18], but mild stimulation has a lower impact [19]. The mild stimulation regimen is associated with significantly lower peak estradiol levels, and may possibly lead to a more gentle impact on the endometrium than classical regimens. However, the current analysis (by two studies) showed that although the peak serum estradiol level was significantly lower in the mild stimulation group, endometrial thickness did not significantly differ between the two groups. Several studies, including ours, have found that mild stimulation protocols decrease the amount of medications consumed, lower the cost of IVF treatment and minimize risks of complications like OHSS [10,20,21]. The lower cost of these protocols is in part due to a reduction in multiple pregnancies and preterm births following IVF treatment [10,22]. Moreover, mild stimulation enables a shorter, more patient-friendly treatment cycle with fewer complications and might therefore decrease IVF treatment-related stress [23]. A relative shortcoming of the present Meta-analysis is the heterogeneity in the mild ovarian stimulation protocols, even though both regimens were approved by the ISMAAR. The Meta-analysis should have been stratified into two or more subgroups by the type of regimen. However, the studies published did not yield sufficient data for such a subgroup analysis. Hence, more RCTs are needed for the optimization and evaluation of different types of mild ovarian stimulation protocols in IVF. In conclusion, mild ovarian stimulation protocols were found to be associated with a lower number of retrieved oocytes and a higher cycle cancellation rate than conventional stimulation protocols. Nevertheless, the CPR obtained in the mild stimulation group was similar to that in the conventional stimulation group. In addition, incidence of OHSS was lower in the mild stimulation group. Although our results favor the use of mild stimulation 170

13 protocols in IVF, the level of evidence supporting this conclusion is unfavorable. Further prospective randomized controlled studies on mild ovarian stimulation protocols, with larger sample sizes, may offer definitive evidence. Mild ovarian stimulation is likely to be widely used in IVF and possibly even replaces the current conventional stimulation protocols. References 1. Macklon NS, Stouffer RL, Giudice LC, et al. The science behind 25 years of ovarian stimulation for IVF. Endocr Rev, 2006, 27(2): Templeton A, Morris JK. Reducing the risk of multiple births by transfer of two embryos after in vitro fertilization. N Engl J Med, 1998, 339(9): Fleming R, Adam AH, Barlow DH, et al. A new systematic treatment for infertile women with abnormal hormone profiles. Br J Obstet Gynaecol, 1982, 89(1): Pu D, Wu J, Liu J. Comparisons of GnRH antagonist versus GnRH agonist protocol in poor ovarian responders undergoing IVF. Hum Reprod, 2011, 26(10): Edwards RG, Lobo R, Bouchard P. Time to revolutionize ovarian stimulation. Hum Reprod, 1996, 11(5): Nargund G, Frydman R. Towards a more physiological approach to IVF. Reprod Biomed Online, 2007, 14 (5): Ubaldi F, Rienzi L, Baroni E, et al. Hopes and facts about mild ovarian stimulation. Reprod Biomed Online, 2007, 14(6): Fauser BC, Devroey P, Yen SS, et al. Minimal ovarian stimulation for IVF: appraisal of potential benefits and drawbacks. Hum Reprod, 1999, 14(11): Weigert M, Krischker U, Pohl M, et al. Comparison of stimulation with clomiphene citrate in combination with recombinant follicle-stimulating hormone and recombinant luteinizing hormone to stimulation with a gonadotropin-releasing hormone agonist protocol: a prospective, randomized study. Fertil Steril, 2002, 78(1): Heijnen EM, Eijkemans MJ, De Klerk C, et al. A mild treatment strategy for in-vitro fertilization: a randomized non-inferiority trial randomized trial. Lancet, 2007, 369(5963): Nargund G, Fauser BC, Macklon NS, et al. Rotterdam ISMAAR consensus group on terminology for ovarian Stimulation for IVF. The ISMAAR proposal on terminology for ovarian stimulation for IVF. Hum Reprod, 2007, 22(11): Zamora J, Abraira V, Muriel A, et al. Meta-DiSc: a software for meta-analysis of test accuracy data. BMC Med Res Methodol, 2006, 6: Baart EB, Martini E, Eijkemans MJ, et al. Milder ovarian stimulation for in-vitro fertilization reduces aneuploidy in the human preimplantation embryo: a randomized controlled trial. Hum Reprod, 2007, 22(4): Dhont M, Onghena A, Coetsier T, et al. Prospective randomized study of clomiphene citrate and gonadotrophins versus goserelin and gonadotrophins for follicular stimulation in assisted reproduction. Hum Reprod, 1995, 10(4): Hohmann FP, Macklon NS, Fauser BC. A randomized comparison of two ovarian stimulation protocols with gonadotropin-releasing hormone (GnRH) antagonist cotreatment for in vitro fertilization commencing recombinant follicle-stimulating hormone on cycle day 2 or 5 with the standard long GnRH agonist protocol. 171

14 J Clin Endocrinol Metab, 2003, 88(1): Karimzadeh MA, Mashayekhy M, Mohammadian F, et al. Comparison of mild and microdose GnRH agonist flare protocols on IVF outcome in poor responders. Arch Gynecol Obstet, 2011, 283(5): Verberg MF, Eijkemans MJ, Macklon NS, et al. The clinical significance of the retrieval of a low number of oocytes following mild ovarian stimulation for IVF: a meta-analysis. Hum Reprod Update, 2009, 15(1): Devroey P, Bourgain C, Macklon NS, et al. Reproductive biology and IVF: ovarian stimulation and endometrial receptivity. Trends Endocrinol Metab, 2004, 15(2): Check JH, Choe JK, Nazari A, et al. Ovarian hyperstimulation can reduce uterine receptivity. A case report. Clin Exp Obstet Gynecol, 2000, 27(2): Borm G, Mannaerts B. Treatment with the gonadotrophin-releasing hormone antagonist ganirelix in women undergoing ovarian stimulation with recombinant follicle stimulating hormone is effective, safe and convenient: results of a controlled, randomized, multicentre trial. The European Orgalutran Study Group. Hum Reprod, 2000, 15(7): Eijkemans MJ, Heijnen EM, de Klerk C, et al. Comparison of different treatment strategies in IVF with cumulative live birth over a given period of time as the primary end-point: methodological considerations on a randomized controlled non-inferiority trial. Hum Reprod, 2006, 21(2): Polinder S, Heijnen EM, Macklon NS, et al. Cost-effectiveness of a mild compared with a standard strategy for IVF: a randomized comparison using cumulative term live birth as the primary endpoint. Hum Reprod, 2008, 23(2): HØjgaard A, Ingerslev HJ, Dinesen J. Friendly IVF: patient opinions. Hum Reprod, 2001, 16(7): (Received on March 29, 2013) 172