GnRH agonist versus GnRH antagonist in ovarian stimulation: the role of elevated peak serum progesterone levels

Abstract

Aim: We sought to evaluate the influence of subtle serum progesterone elevation on in vitro fertilization (IVF) cycle outcome and to assess the impact of the type of gonadotropin-releasing hormone (GnRH)-analogue used during controlled ovarian hyperstimulation (COH) on the probability of clinical pregnancy.

Patients and methods: We reviewed the files of all consecutive patients undergoing COH with either GnRH-agonist or antagonist in our IVF unit during a 10-year period and who had their peak serum progesterone levels determined on the day of human chorionic gonadotropin (hCG) administration.

Results: Of the 2244 IVF cycles evaluated, 2103 had peak progesterone level of <1.5?ng/mL (normal-P group) and 141 of >1.5?ng/mL (high-P group) (6.28% of all the study population). Clinical pregnancy rate was significantly higher in the normal-P group (25.4% versus 16.6%; p?<?0.006). Moreover, among the high-P group patients, the use of the long GnRH-agonist suppressive protocol (GnRH-ag) was more prevalent in patients who conceived as compared to those who did not (60.9% versus 39%, respectively; p?<?0.05), with a tendency toward an increase pregnancy rate in those using GnRH-ag compared with GnRH-antagonist protocol (GnRH-antag; p?<?0.059) COH protocols.

Conclusion: While subtle progesterone elevation in patients undergoing COH using GnRH-antag COH protocols, should dictate embryo cryopreservation and cancelation of the fresh transfer, in those undergoing the GnRH-ag COH protocol, a fresh embryo transfer should be recommended.     

A randomised study of GnRH antagonist (cetrorelix) versus agonist (busereline) for controlled ovarian stimulation: effect on safety and efficacy

OBJECTIVE: To assess safety and efficacy of cetrorelix utilisation in controlled ovarian stimulation (COS). STUDY DESIGN: Phase III, randomized, single center study of 131 patients undergoing COS and IVF with or without ICSI, in a University affiliated Hospital. Sixty-six patients were allocated to the protocol with antagonist and 65 to the agonist protocol arm. The Student's t-test, the Mann-Whitney test and the chi-square test were applied as required, using SPSS for Windows with a two-sided 5% significance level. RESULTS: The mean (+/-S.D.) duration of stimulation was 9.5+/-1.7 days in the antagonist group and 10.6+/-2.1 days in the agonist group (P=0.02). The mean (+/-S.D.) duration of suppression was 4.6+/-1.3 days in the antagonist group and 27.3+/-5.2 days in the agonist group (P<0.0001). No significant differences were noted in other outcome measures: amount of rFSH required, estradiol level on hCG day, number of follicles>or=15 mm and endometrial thickness on oocyte retrieval day, number of oocytes retrieved, fertilization rate and number of OHS cases. Clinical pregnancy rates per-attempt and per-transfer were 15.1% and 17.0% in the antagonist group and 16.9% and 20.0% in the agonist group (P=0.79 and 0.71, respectively). CONCLUSIONS: GnRH antagonists are an effective, safe and well tolerated alternative to agonists for COS.     

Ovarian stimulation in women with high and normal body mass index: GnRH agonist versus GnRH antagonist

In modern society, obesity has become a major health problem and has been associated with impaired fertility. The aim of this study is to assess the role of obesity in women undergoing controlled ovarian hyperstimulation (COH) stimulated either with GnRH agonists or with GnRH antagonists. Records of 463 women undergoing in vitro fertilization (IVF) treatment were reviewed. The influence of body mass index (BMI) on treatment outcome was examined, after accounting for differences in stimulation protocols. In the agonist group (286 patients), the total amount of gonadotropins used was significantly higher in patients with a BMI ≥ 25?kg/m², when compared to those with a normal BMI. The same result was found in the antagonist group (177 patients). No significant differences were found in length of stimulation, number of oocytes retrieved or number of embryos transferred. In both the antagonist and the agonist group, the number of clinical pregnancies was found to be higher in patients with normal BMI, suggesting that obesity could impair the ovarian response to exogenous gonadotropins. Considering the results obtained and the many theoretical advantages of GnRH antagonists, ovarian stimulation with GnRH antagonists is an efficient treatment for both women with normal and high BMI.     

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.     

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.     

Severe ovarian hyperstimulation syndrome associated with long-acting GnRH agonist in oncofertility patients

PurposeTo report three cases of severe ovarian hyperstimulation syndrome (OHSS) among oncofertility patients receiving a long-acting GnRH agonist for ovarian suppression after controlled ovarian hyperstimulation (COH) with a GnRH antagonist protocolMethodsChart abstraction was completed for three patients at a single academic medical center. Patients included were undergoing fertility preservation prior to gonadotoxic chemotherapy. All patients underwent COH with GnRH antagonist protocol and embryo cryopreservation immediately followed by ovarian suppression with long-acting GnRH agonist. Main outcome measure was development of OHSS.ResultsDespite using GnRH agonist trigger and freezing all embryos, patients developed ascites, intermittent hyponatremia and hemoconcentration consistent with severe early-onset OHSS after receiving long-acting GnRH agonist immediately following oocyte retrieval for ovarian preservation.ConclusionsRisk of severe OHSS may be increased when a long-acting GnRH agonist is used for ovarian suppression immediately following oocyte retrieval. A delay in initiating long-acting GnRH agonist after oocyte retrieval in patients at high risk for developing OHSS should be considered.     

Serum luteinizing hormone level on the third day after ovarian stimulation in GnRH agonist short protocol is predictive of outcome in poor responders but not in normal responders

Objectives: To identify whether prognostic value of LH measurement in normal responders (NR) is different from poor responders (POR).

Methods: A retrospective, single-center study was conducted among patients who underwent ovarian stimulation with short protocol, with 300 NR and 101 POR, according to Bologna Consensus criteria. LH was measured on 3rd and 5th day after stimulation and HCG administration day.

Results: There was significant difference in the clinical pregnancy rate per cycle initiated among those with LH level on the third day after stimulation (a) below the 25 centile (b) between the 25 and 75 centile and (c) above the 75 centile in women with POR (7.7%, 15.1% vs. 36.4%, p?=?0.02) but not in NR. There was significant correlation between LH ranks and clinical pregnancy rate in POR (p?=?0.02) but not in NR. Factors associated with clinical pregnancy rate in POR were age and LH on the third of stimulation, while factors in NR were age, AFC and FSH.

Conclusion: LH level on the 3rd day of stimulation was predictive of clinical pregnancy in POR but not in NR.     

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.     

改良GnRH-a长方案在控制性促排卵中的应用

目的探讨改良GnRH—a/FSH/hMG联合长方案在控制性促排卵中的应用以及国产阿拉瑞林在此方案中的使用。方法以回顾性分析的方法对174例改良GnRH-a长方案和48例超短方案控制性促排卵的资料进行回顾性分析。结果 改良GnRH—a/FSH/hMG联合长方案在FSH/hMG用药天数、用药量、取卵数、移植数、冻存胚胎数、hCG丑内膜厚度、临床妊娠率、种植率、流产率、OHSS发生率等方面与短方案组相比差异均无显著性(P>0.05),其中流产率明显低于超短方案组。结论改良国产阿拉瑞林/FSH/hMG联合长方案是一种简单、经济、有效的控制性促排卵方案,值得在IVF—ET周期中推广。     

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.     

Ovarian hyperstimulation syndrome following GnRH agonist trigger for final follicular maturation in a patient undergoing random start ovarian stimulation for egg-donation cycle with an inadvertent concomitant early pregnancy

Abstract

We report the first case of OHSS following GnRH agonist trigger for final follicular maturation in random start ovarian stimulation for egg-donation cycles during inadvertent concomitant early pregnancy. As an additional note, the sustained activity exerted by the increasing endogenous hCG production seemed to be responsible for the suboptimal performance in terms of oocyte yield in the current case. OHSS can occur in random-start stimulations protocols even after the use of a GnRH agonist for triggering in case of concomitant unnoticed early pregnancy especially if stimulation is commenced in the periovulatory/luteal phase. The present case report introduces a note of extreme caution when proceeding with this protocol in an otherwise fertile population (egg-donors, elective or oncologic oocyte cryopreservation).     

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).     

Follicular fluid concentrations of IGF-I, IGF-II, IGFBP-3, VEGF, AMH, and inhibin-B in women undergoing controlled ovarian hyperstimulation using GnRH agonist or GnRH antagonist

Objective

To compare follicular fluid concentrations of IGF-I, IGF-II, IGFBP-3, inhibin-B, VEGF, and AMH in women undergoing controlled ovarian hyperstimulation with a long-luteal GnRH agonist protocol or multiple-dose GnRH antagonist protocol.

Study design

A total of 80 cycles were included; long-luteal GnRH agonist group (n = 40) and multiple dose GnRH antagonist group (n = 40). All follicular fluid samples were obtained from mature follicles during oocyte retrieval. IGF-I and IGFBP-3 concentrations were measured by immunoradiometric assay. IGF-II, VEGF, AMH, and inhibin-B concentrations were measured by enzyme-linked immunosorbent assay.

Results

There were no significant differences in the concentrations of the studied follicular fluid markers, cycle parameters, and treatment outcomes between GnRH agonist and GnRH antagonist protocols.

Conclusions

The long-luteal GnRH agonist protocol and multiple-dose GnRH antagonist protocol seem to have similar effects on the follicular microenvironment in women undergoing controlled ovarian hyperstimulation.     

Fine tuning cycle day 3 hormonal assessment of ovarian reserve improves in vitro fertilization outcome in gonadotropin-releasing hormone antagonist cycles

OBJECTIVE: To identify the cut-off values of the baseline (cycle day 3) levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol (E(2)) for improving the outcome prediction of GnRH antagonist in vitro fertilization (IVF) cycles and to determine whether the predictive accuracy of these values is affected by the patient's clinical prognosis. DESIGN: Retrospective analysis. SETTING: An IVF clinic in a tertiary medical center.Women undergoing 230 consecutive IVF cycles using a GnRH antagonist protocol. INTERVENTION: None. MAIN OUTCOME MEASURE(S): Outcome of IVF, measured by ovarian response and pregnancy rates. RESULT(S): Lower baseline levels of FSH and E(2), but not LH, correlated with improved ovarian response and pregnancy rates in IVF cycles using a GnRH antagonist. Compared with our currently used criteria, the cut-off values of FSH <10 IU/L and E(2) <56 pg/mL would have significantly improved the IVF outcome in a population of patients with normal prognosis. However, a stricter baseline FSH cut-off value of 8 IU/L would have been required to improve the IVF outcome in a population of patients with a poor prognosis. CONCLUSION(S): The outcome of IVF may be improved by modifying the hormonal starting criteria to take into account individual patient characteristics such as clinical prognosis.