In vitro fertilization stimulation protocol for normal responder patients

The aim of this prospective observational study is to determine the different outcomes of IVF/ICSI treatments after using antagonists or agonists of gonadotrophin-releasing hormone (GnRH) for controlled ovarian hyperstimulation (COH) in normal responder patients. Two hundred forty-seven patients undergoing IVF treatment at the Centre of Reproductive Medicine, Rome (CERMER), from January 2005 to December 2008, were included in the study. Patients were stimulated either with a standard long protocol with GnRH agonists (n = 156) or with GnRH antagonists (n = 91). The use of GnRH antagonists resulted in a significant reduction in the duration of the stimulation (Agonist Group 14.10?±?2.25 vs Antagonist Group 11.34?±?2.11; p < 0.001) and in the amount of gonadotrophin (IU of r-FSH) needed (Agonist Group 1878?±?1109 vs Antagonist Group 1331?±?1049; p = 0.0014). Moreover a lower number of cycles were cancelled with the antagonist protocol (4.39 vs 6.41%). The GnRH antagonist protocol, when compared to the GnRH agonist one, is associated with a similar clinical pregnancy rate, similar implantation rate, significantly lower gonadotrophin requirement and shorter duration of stimulation. For this reason, GnRH antagonists might be a good treatment even for normal responder patients undergoing IVF.     

A randomized trial of microdose leuprolide acetate protocol versus luteal phase ganirelix protocol in predicted poor responders

We performed a randomized trial to compare IVF outcomes in 54 poor responder patients undergoing a microdose leuprolide acetate (LA) protocol or a GnRH antagonist protocol incorporating a luteal phase E(2) patch and GnRH antagonist in the preceding menstrual cycle. Cancellation rates, number of oocytes retrieved, clinical pregnancy rates (PR), and ongoing PRs were similar between the two groups.     

GnRH antagonist versus long GnRH agonist protocol in poor IVF responders: a randomized clinical trial

Objective

To compare the efficacy of the long GnRH agonist and the fixed GnRH antagonist protocols in IVF poor responders.

Study design

This was a randomized controlled trial performed in the Iakentro IVF centre, Thessaloniki, from January 2007 to December 2011, concerning women characterised as poor responders after having 0–4 oocytes retrieved at a previous IVF cycle. They were assigned at random, using sealed envelopes, to either a long GnRH agonist protocol (group I) or a GnRH antagonist protocol (group II).

Results

Overall 364 women fulfilled the inclusion criteria and were allocated to the two groups: finally 330 participated in our trial. Of these, 162 were treated with the long GnRH agonist protocol (group I), and 168 with the fixed GnRH antagonist protocol (group II). Numbers of embryos transferred and implantation rates were similar between the two groups (P = NS). The overall cancellation rate was higher in the antagonist group compared to the agonist group, but the difference was not significant (22.15% vs. 15.2%, P = NS). Although clinical pregnancy rates per transfer cycle were not different between the two groups (42.3% vs. 33.1%, P = NS), the clinical pregnancy rate per cycle initiated was significantly higher in the agonist compared to the antagonist group (35.8% vs. 25.6%, P = 0.03).

Conclusions

Although long GnRH agonist and fixed GnRH antagonist protocols seem to have comparable pregnancy rates per transfer in poor responders undergoing IVF, the higher cancellation rate observed in the antagonist group suggests the long GnRH agonist protocol as the first choice for ovarian stimulation in these patients.     

Effect of delayed initiation of gonadotropin in luteal long protocol on in vitro fertilization

Abstract

Objective: To evaluate whether delayed initiation of gonadotropin in luteal long protocol affected the outcome of in vitro fertilization (IVF).

Study design: Prospective randomized study at the reproductive centre of a university-based hospital. Eighty-five subfertile women undergoing IVF embryo transfer after a standardized gonadotropin-releasing hormone agonists (GnRHa) long protocol. The patients were randomized into group A (stimulated 3 weeks after GnRHa administration) and group B (stimulated 2 weeks after GnRHa administration), according to the time of gonadotropin initiation after GnRHa-mediated pituitary suppression. The main outcome measures were clinical pregnancy and live birth rates.

Results: There were no significant differences in baseline characteristics such as age, body mass index and basal follicle-stimulating hormone (bFSH) between the two groups. In group B, the days of gonadotropin stimulation were significantly greater than that in group A (p?<?0.05), while the total dose of gonadotropin in group A was comparable to that in group B. Serum luteinizing hormone was lower and follicle-stimulating hormone higher in group A than in group B (p?<?0.05) on initiation day. There were no significant differences in hormone profile measurements between the two groups. Moreover, the clinical pregnancy rate, implantation rate, live birth rate, miscarriage rate and moderate ovarian hyperstimulation syndrome rate were not significantly different between the groups.

Conclusion: Delay of gonadotropin stimulation in a standard long protocol may increase clinical efficiency, without significantly changing clinical outcome.     

Luteal phase oestradiol administration in ovarian stimulation cycles with GnRH antagonist is comparable to the GnRH agonist (long) protocol

Purpose: The purpose of the study was to compare the effectiveness of GnRH antagonist with luteal phase estradiol administration to GnRH agonist cycles, long protocol. Methods: 55 IVF-ICSI patients received oestradiol in the luteal phase of the cycle, before a cycle with GnRH antagonist. Fifty-five patients submitted to IVF-ICSI with the use of agonist were allocated, age matched, as a control group (historical control). The primary outcome was the number of retrieved oocytes. Results: Patients were similar in terms of clinical characteristics. No differences were found in the number of oocytes retrieved (study group, 8.1 ± 4.7; control group, 7.4 ± 4.5) or in oocyte quality. Conclusions: We clearly demonstrated that the effectiveness of GnRH antagonist when combined with luteal phase estradiol is comparable to GnRH agonist cycles. Capsule Oestradiol associated to GnRH antagonist may increase the rates of oocytes causing reproductive results to be comparable to the results with the use of agonists.     

GnRH antagonist versus follicular-phase single-dose GnRH agonist protocol in patients of normal ovarian responses during controlled ovarian stimulation

Objective: This study aims to explore the differences of the ovarian stimulation (OS) characteristics, laboratory, and clinical outcomes between follicular-phase single-dose gonadotropin-releasing hormone (GnRH) agonist protocol and GnRH antagonist protocol during controlled ovarian hyperstimulation (COH).

Methods: About 1883 consecutive IVF/ICSI fresh cycles of normal ovarian responders were retrospectively analyzed, with 1229 in the single-dose GnRH agonist protocol group and 654 in the GnRH antagonist protocol group at Reproductive Medical Center of Tongji Hospital from 1 January 2014 to 31 December 2017.

Results: The follicular-phase single-dose GnRH agonist group showed significantly more oocytes obtained, higher implantation rate and pregnancy rate, as well as lower luteinizing hormone (LH) level and estradiol (E2)/oocyte ratio on the day of human chorionic gonadotropin (hCG) administration. However, differences were not significant in meiosis II (MII) oocyte rate, two pronuclear zygote (2PN) embryo rate, viable embryo rate or high-quality embryo rate, compared with the GnRH antagonist group. Further comparison of clinical outcomes in the first frozen-thawed cycles did not show significant difference in either implantation or clinical pregnancy rate between the two protocol groups.

Conclusions: Follicular-phase single-dose GnRH agonist protocol may achieve better clinical outcomes in normal ovarian responders, which could be explained more by positive effect on endometrial receptivity rather than embryo quality.     

Gn-RH antagonists in intrauterine insemination: the weekend-free protocol

Objective : To compare the results of intrauterine insemination (IUI) when GnRH antagonist was added—to avoid IUI on weekend—with those obtained with the standard IUI protocol. Study design : In an IUI program under ovarian stimulation with gonadotropins when one or more follicles of 15–16 mm were seen, if it was not possible for logistic reasons (weekend) to perform the insemination 72 h later, GnRH antagonist was administered until human chorionic gonadotropin (hCG) administration. The IUI was performed on Monday. We compared the results of this IUI ``weekend-free' group with our results in standard IUI cycles, where IUI was performed 36–38 h after reaching optimal follicular growth. Results : Both groups were comparable regarding the main demographic parameters, except for higher estradiol levels, due to the prolonging ovarian stimulation. The per cycle pregnancy rate (PR) were very similar in both groups: 15.7% in the weekend-free IUI versus 16.5% in standard IUI. The multiple pregnancy rate and the hyperstimulation rate were also similar. A non-significant trend to higher high-order multiple pregnancy was observed in the weekend-free IUI. Conclusions : In IUI cycles under ovarian suprastimulation with gonadotrophins, the use of GnRH antagonist allows the manipulation of the follicular development in such a way that it is possible to avoid inseminations on the weekends, without apparently reducing the PR.     

The effect of oral contraceptive pill for cycle scheduling prior to GnRH-antagonist protocol on IVF cycle parameters and pregnancy outcome

Objective To evaluate the effect of oral contraceptive pills (OCP) pretreatment on IVF cycle outcome in GnRH-antagonist protocol. Design Retrospective cohort study. Setting Major tertiary university-affiliated center. Patients All patients treated with GnRH antagonist in our IVF unit during the last 3 years were included in the study. Overall 1,799 IVF cycles were performed. Of these, in 604 cycles OCP pretreatment was used prior to GnRH-antagonist for cycle scheduling. Patients were divided into two age groups—young group aged ≤35 years and older group aged ≥36 years. Interventions The young group underwent 927 cycles, 281 cycles with OCP pretreatment and 646 cycles without. The older group underwent 872 cycles, 323 cycles with OCP pretreatment and 549 cycles without. Data was analyzed within each age group. Main outcome measures Treatment duration and total dose of FSH IU used for stimulation, number of oocytes retrieved, implantation and pregnancy rates. Results All OCP-pretreated cycles required significantly longer stimulation than non-pretreated cycles (young: 10.76 vs. 9.21 days; older: 10.48 vs. 8.73 days, respectively) and higher total dose of FSH IU (young: 3,210 IU vs. 2,565 IU; older: 4,973 IU vs. 3,983 IU, respectively). There were no other differences in cycle characteristics between groups. Implantation and pregnancy rates were not affected by OCP pretreatment. Conclusions OCP pretreatment can be offered as a mode for cycle scheduling prior to GnRH-antagonist protocol, though it may be associated with longer stimulation and higher gonadotropin consumption. Capsule OCP prior to GnRH-antagonist protocol enables cycle scheduling without compromising cycle outcome and patient’s age is not a limitation in decision making for the use of this approach.     

Prolonging GnRH-agonist to achieve ovarian suppression does not compromise the results of a long protocol

Objectives

In the long gonadotropin-releasing hormone agonist (GnRHa) protocols, stimulation is delayed until complete pituitary-ovarian suppression has been achieved, which usually takes a minimum of 10 days. In women who do not achieve timely suppression we set out to evaluate if prolonging GnRHa affects the results of the IVF process.

Study design

We analyzed cycle and pregnancy outcome in 506 consecutive women undergoing IVF-ET after a standardized long GnRHa protocol, according to the time required to achieve ovarian suppression (i.e. estradiol < 40 pg/mL and no follicle >6 mm at ultrasound).

Results

Suppression was obtained after 14 GnRHa days in 383 (75.70%) women (Group 1) and 123 (24.30%) women (Group 2) required a mean ± SD (range) of 10 ± 4 (7-28) additional days to achieve complete suppression. Both groups were comparable for baseline clinical and biological characteristics. The rate of cancelled cycles due to poor ovarian response, the number of the oocytes retrieved, fertilization rates, the number and quality of the embryos cultured and transferred were similar in both groups, as well as the pregnancy, implantation and live birth rates. In Group 2, receiver-operator characteristics analysis showed that the probability of pregnancy was not related to the duration of GnRHa treatment.

Conclusions

In a standardized long GnRHa protocol, prolonging desensitization to achieve complete ovarian suppression does not affect the outcome.     

GnRH拮抗剂方案中HCG扳机时机对胚胎的影响

目的:探讨促性腺激素释放激素拮抗剂(GnRH antagonist)方案超促排卵过程中推迟人绒毛膜促性腺激素(HCG)扳机时机对胚胎质量及妊娠率等的影响。方法:回顾性分析2015年1月至12月在我院接受体外受精-胚胎移植(IVF-ET)助孕的不孕症患者183例,均采用GnRH拮抗剂促排方案,于月经周期第2天启用促性腺激素(Gn),当有卵泡平均直径达到14mm,加用GnRH拮抗剂。按照传统HCG扳机时机(有3个≥17mm卵泡)与推迟1天扳机分为2组:早期HCG组(149例)和晚期HCG组(34例),比较两组数据。结果:HCG扳机日,晚期HCG组≥15mm的卵泡数明显多于早期HCG组(P=0.026)。晚期HCG组Gn使用天数及Gn使用总量均明显高于早期HCG组(P=0.000,P=0.012)。妊娠结局方面,晚期HCG组较早期HCG组具有更高的妊娠率(76.00%vs 50.45%,P=0.020)。两组受精率、继续妊娠率、流产率、异位妊娠率均无显著差异(P0.05)。结论:GnRH拮抗剂促排方案中,适当推迟HCG扳机时间不影响胚胎质量和妊娠率,可以推行。     

Recombinant luteinizing hormone supplementation to recombinant follicle-stimulation hormone during induced ovarian stimulation in the GnRH-agonist protocol: A meta-analysis

Purpose: to compare the efficacy of recombinant LH supplementation for controlled ovarian stimulation in recombinant FSH and GnRH-agonist protocol. Methods: Search strategies included on-line surveys of databases. The fixed effects model was used for odds ratio and effect size (weighted mean difference). Four trials fulfilled the inclusion criteria. Results: a fewer days of stimulation (p<0.0001), a fewer total amount of r-FSH administered (p<0.0001) and a higher serum estradiol levels on the day of hCG administration (p<0.0001) were observed for the r-LH supplementation protocol. However, differences were not observed in number of oocyte retrieved, number of mature oocytes, clinical pregnancy per oocyte retrieval, implantation and miscarriage rates. Conclusions: more randomized controlled trials are necessary before evidence-based recommendations regarding exogenous LH supplementation in ovarian stimulation protocols with FSH and GnRH-agonist for assisted reproduction treatment can be provided.     

An oocyte donation protocol using the GnRH antagonist ganirelix acetate,does not compromise embryo quality and is associated with high pregnancy rates

Purpose: To evaluate the effect of the GnRH antagonist, ganirelix acetate, on oocyte quality. Methods: Stimulation characteristics, implantation rates and clinical pregnancy rates were compared between 29 oocyte donors 21–31 years of age who underwent 31 cycles of ovarian stimulation with gonadotropins and ganirelix acetate, and 36 infertile couples of similar age range who underwent 51 cycles of ovarian stimulation using the same protocol. Results: A significantly lower number of embryos were transferred in the donor/recipient group as compared to the infertile group (2.32±0.54 vs. 2.82±0.71, P<0.05). In contrast, implantation and clinical pregnancy rates per transfer, were significantly higher in the donor/recipient group (38.1% vs. 10.4%, P<0.01) and (61.3% vs. 23.1%, P<0.05) respectively, as compared to the infertile group. Conclusions: Incorporation of ganirelix acetate for pituitary suppression in stimulation protocols for oocyte donation is associated with high pregnancy rates suggesting that ganirelix acetate does not exert an adverse effect on oocyte or embryo quality.Capsule: Incorporation of ganirelix acetate in stimulation protocols for oocyte donation is associated with high pregnancy rates suggesting that there is no adverse effect on oocyte quality     

Effectiveness of mild ovarian stimulation versus GnRH agonist protocol in women undergoing assisted reproductive technology: a meta-analysis

Objective: our meta-analysis was conducted to evaluate the effectiveness of the mild ovulation induction protocol using CC/gonadotropin/GnRH antagonist compared to the conventional GnRH agonist protocol in women undergoing ART. Method: Six electronic databases were searched from their date of establishment until August 2016. Outcomes in our analysis were calculated in terms of relative risk (RR) and weighted mean differences (WMD) and standard mean differences (SMD) with 95% confidence intervals (CI) using random effect models or fixed effect models.

Results: Six prospective controlled clinical trials with 1543 women comparing the clinical impacts of the two protocols were included. The synthesized results suggested a significant reduction in the quantity of gonadotropins (SMD: ?1.96, 95% CI: ?2.28 to 1.64, I²?=?78.5%), the incidence of OHSS (RR: 0.16, 95% CI 0.03–0.86, I²?=?0%) and an increase in the cycle cancelation rate (RR: 1.46, 95% CI 1.05–2.03, I²?=?89.4%). While no evidence of statistically signi?cant differences between the groups existed in the other clinical outcomes.

Conclusion: This study suggested that the probable benefits of the mild protocol, including its less costs and safer process without reducing the overall IVF treatment success rates, seemed to make it a better treatment option. Larger sample prospective trials evaluating live birth, clinical pregnancy, OHSS, multiple pregnancy incidence and so on were desired to establish.     

Progestin-primed ovarian stimulation versus GnRH antagonist protocol in poor responders: Risk of premature LH surge and outcome of oocyte retrieval

PurposeFor poor ovarian responders (PORs), gonadotropin-releasing hormone (GnRH) antagonist was commonly used for prevention of premature LH surge during controlled ovarian stimulation (COS) over the past two decades. The application of progestin-primed ovarian stimulation (PPOS) recently increased, but the role of PPOS for PORs was uncertain. We aimed to analyze the incidence of premature luteinizing hormone (LH) surge and the outcome of oocyte retrieval among PPOS and GnRH antagonist protocol for PORs.MethodsThis was a single-center retrospective study, which enrolled the PORs (defined by the Bologna criteria) undergoing COS with PPOS or flexible GnRH antagonist protocol during January 2018 to December 2021. We compared the incidence of premature LH surge (LH > 10 mIU/mL) and the outcome of oocyte retrieval between the PPOS group and the GnRH antagonist group.ResultsA total of 314 women were recruited, with 54 in the PPOS group and 260 in the GnRH antagonist group. The PPOS group had lower incidence of premature LH surges compared with the GnRH antagonist protocol group (5.6% vs 16.9%, P value 0.035). There was no significant difference between the two groups regarding the number of oocytes retrieved (3.4 vs 3.8, P value 0.066) and oocyte retrieval rates (88.9% vs 88.0%, P value 0.711).ConclusionCompared with PPOS, GnRH antagonist protocol had higher risk of premature LH surges for PORs but may not affect pregnancy rates. PPOS is suitable for oocyte or embryo cryopreservation, but should not totally replace GnRH antagonist protocol for patients undergoing in vitro fertilization (IVF).