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

BACKGROUND. This is the first published report of a prospective, randomized, controlled trial comparing a fixed, multi-dose GnRH antagonist protocol with a long GnRH agonist protocol in poor responders undergoing IVF. METHODS. Sixty-six poor responders were randomized into two groups: the study group received 0.25 mg of cetrorelix daily starting on day 6 of stimulation; the control group received 600 microg of buserelin acetate daily starting in the mid-luteal phase of the preceding cycle. Both groups were given a fixed dose of recombinant FSH (300 IU daily) for stimulation. RESULTS. There were no significant differences in the cycle cancellation rates, duration of stimulation, consumption of gonadotrophins, and mean numbers of mature follicles, oocytes and embryos obtained. The implantation rates were similar, but the number of embryos transferred was significantly higher for the antagonist group (2.32 +/- 0.58 versus 1.50 +/- 0.83; P = 0.01). The pregnancy rates were also higher in the antagonist group, but the difference was not statistically significant. CONCLUSION. A fixed multi-dose GnRH antagonist protocol is feasible for patients who are poor responders on a long agonist protocol; however, our study failed to demonstrate an overall improvement in ovarian responsiveness. Clinical outcomes may be improved by developing more flexible antagonist regimens, an approach that requires further evaluation.     

GnRH agonist versus GnRH antagonist in oocyte donation cycles: a prospective randomized study

BACKGROUND: The specific role of LH in folliculogenesis and oocyte maturation is unclear. GnRH antagonists, when administered in the late follicular phase, induce a sharp decrease in serum LH which may be detrimental for IVF outcome. This study was performed to evaluate whether the replacement of GnRH agonist (triptorelin) by a GnRH antagonist (ganirelix; NV Organon) in oocyte donation cycles has any impact on pregnancy and implantation rates. METHODS: A total of 148 donor IVF cycles was randomly assigned to use either a GnRH antagonist daily administered from the 8th day of stimulation (group I) or a GnRH agonist long protocol (group II) for the ovarian stimulation of their donors. The primary endpoints were the pregnancy and the implantation rates. RESULTS: The clinical pregnancy rate per transfer (39.72%, 29/73 versus 41.33%, 31/75) based on transvaginal scan findings at 7 weeks of gestation, the implantation rate (23.9 versus 25.4%) and the first trimester abortion rate (10.34 versus 12.90%) were similar in the two groups. CONCLUSION: In oocyte donation cycles the replacement of GnRH agonist by a GnRH antagonist appears to have no impact on the pregnancy and implantation rates when its administration starts on day 8 of stimulation.     

The significance of antral follicle size prior to stimulation in predicting ovarian response in a multiple dose GnRH antagonist protocol

Prediction of ovarian responses prior to stimulation is not only useful for patient counseling, but also important in tailoring the optimal dosage of gonadotrophin for individual patients. By prospectively study of 214 women undergoing in vitro fertilization and embryo transfer (IVF-ET) treatment, we obtained data supporting that antral follicle size could be an additional valuable predictive marker other than the antral follicle count (AFC) in predicting ovarian response. Our studies revealed that AFC achieved the best predictive value in relation to the number of oocyte obtained, followed by antral follicle size, basal follicle stimulating hormone (FSH) and body mass index (BMI). Unlike AFC, antral follicle size was noted to be negatively correlated with the dosage (R = -0.493) and duration (R = -0.465) of rFSH stimulation. Antral follicle size was also found with higher negative regression coefficient (B = -0.661) as compared with that of basal FSH concentration (B = -0.326) and BMI (b = -0.281). More importantly, women with antral follicle size 6-7mm showed significantly higher AFC, oocytes retrieved, fertilized oocytes and grade I/II embryos along with much lower transfer cycle cancellation rate (7.5% vs. 16-17%). Together, our data suggest that basal antral follicle size could be a valued predictive marker in women with IVF-ET treatment, in which women with antral follicle size 6-7mm are likely predisposed to better IVF-ET outcomes.     

Comparison between a GnRH antagonist and a GnRH agonist flare-up protocol in oocyte donors: a randomized clinical trial

BACKGROUND: Little information is available on the outcome of controlled ovarian hyperstimulation (COH) using GnRH antagonist in oocyte donation cycles especially in comparison with the short GnRH agonist protocol. This study was aimed at comparing the two stimulation protocols in oocyte donation (OD) cycles. METHODS: A total of 113 donors randomly received COH using either GnRH antagonist or GnRH agonist. The primary endpoint was the mean number of mature oocytes retrieved per started donor cycle. Secondary endpoints were the mean number of cumulus-oocyte-complexes (COCs) retrieved, the mean proportion of mature oocytes, pregnancy and implantation rates in recipients. RESULTS: Oocytes were distributed to 166 recipients. The mean number (+/- SD) of COC (11.6 +/- 5.8 versus 12.1 +/- 6.7), mature oocytes (8.4 +/- 4.4 versus 8.9 +/- 5.3) and the proportion of mature oocytes (70.8 versus 75.7%) retrieved per started donor cycle were similar in the antagonist and agonist groups, respectively. The implantation rate (26.1 versus 30.1%), clinical (40.2 versus 45.6%) and ongoing pregnancy rate per recipient cycle (32.2 versus 37.9%) were comparable in antagonist and agonist protocols, respectively. CONCLUSIONS: Similar mean number of mature oocytes and comparable pregnancy rates are achieved after OD in which donors received COH using GnRH antagonist or short GnRH agonist protocols.     

Revival of the natural cycles in in-vitro fertilization with the use of a new gonadotrophin-releasing hormone antagonist (Cetrorelix): a pilot study with minimal stimulation

Natural cycles were abandoned in in-vitro fertilization (IVF) embryo transfer, due to premature luteinizing hormone (LH) surges--and subsequent high cancellation rates. In this study, we investigated the administration of a new gonadotrophin-releasing hormone antagonist (Cetrorelix) in the late follicular phase of natural cycles in patients undergoing IVF and intracytoplasmic sperm injection (ICSI). A total of 44 cycles from 33 healthy women [mean age 34.1 +/- 1.4 (range 26-36) years] were monitored, starting on day 8 by daily ultrasound and measurement of serum concentrations of oestradiol, LH, follicle stimulating hormone (FSH) and progesterone. When plasma oestradiol concentrations reached 100-150 pg/ml, with a lead follicle between 12-14 mm diameter, a single injection (s.c.) of 0.5 mg (19 cycles) or 1 mg (25 cycles) Cetrorelix was administered. Human menopausal gonadotrophin (HMG; 150 IU) was administered daily at the time of the first injection of Cetrorelix, and repeated thereafter until human chorionic gonadotrophin (HCG) administration. Four out of 44 cycles were cancelled (9.0%). No decline in follicular growth or oestradiol secretion was observed after Cetrorelix administration. A total of 40 oocyte retrievals leading to 22 transfers (55%) was performed. In 10 cycles (25%), no oocyte was obtained. Fertilization failure despite ICSI occurred in six cycles (15%). In two patients the embryo was arrested at the 2 pronuclear (PN) stage. The stimulation was minimal (4.7 +/- 1.4 HMG ampoules). A total of seven clinical pregnancies was obtained (32.0% per transfer, 17.5% per retrieval), of which five are ongoing. Thus, a spontaneous cycle and the GnRH antagonist Cetrorelix in single dose administration could represent a first-choice IVF treatment with none of the complications and risks of current controlled ovarian hyperstimulation protocols, and an acceptable success rate.     

Comparison of follicular fluid IGF-I, IGF-II, IGFBP-3, IGFBP-4 and PAPP-A concentrations and their ratios between GnRH agonist and GnRH antagonist protocols for controlled ovarian stimulation in IVF-embryo transfer patients

BACKGROUND: Insulin-like growth factors (IGF) and their binding proteins (IGFBP) play a major role in the autocrine and paracrine regulation of folliculogenesis. This is the first study that has compared follicular fluid (FF) IGF-I, IGF-II, IGFBP-3, IGFBP-4 and pregnancy-associated plasma protein (PAPP)-A concentrations, and their ratios, to investigate whether there was any difference in the intrafollicular microenvironment between the GnRH agonist (GnRHa) and antagonist (GnRHant) protocols for controlled ovarian stimulation (COS). METHODS: A total of 68 IVF cycles were included in this study; two groups were studied: GnRHa long protocol group (n = 36) and the flexible GnRHant multiple-dose protocol group (n = 32). FF was obtained from dominant follicles during oocyte retrieval and stored at -70 degrees C until assayed. IGF-I, IGF-II and IGFBP-3 concentrations were measured by radioimmunoassay and IGFBP-4 and PAPP-A by enzyme-linked immunosorbent assay. RESULTS: The duration of COS was significantly longer, and total dose of gonadotrophins used, serum estradiol (E(2)) levels on hCG day and the number of oocytes retrieved were significantly higher in the GnRHa long protocol group. The concentrations of FF IGF-II and IGFBP-4 were significantly higher, and the ratio of IGF-I/IGFBP-4 was significantly lower in the GnRHa long protocol group. Serum E(2) levels per mature follicle were not different between the two groups. CONCLUSIONS: Our data may indicate a difference of intrafollicular microenvironment between cycles using GnRHa long protocols and those using GnRHant protocols. However, the difference in microenvironment does not appear to result in a difference in clinical outcome.     

GnRH agonist (buserelin) or hCG for ovulation induction in GnRH antagonist IVF/ICSI cycles: a prospective randomized study

BACKGROUND: We aimed to determine the efficacy of ovarian hyperstimulation protocols employing a GnRH antagonist to prevent a premature LH rise allowing final oocyte maturation and ovulation to be induced by a single bolus of either a GnRH agonist or hCG. METHODS: A total of 122 normogonadotrophic patients following a flexible antagonist protocol was stimulated with recombinant human FSH and prospectively randomized (sealed envelopes) to ovulation induction with a single bolus of either 0.5 mg buserelin s.c. (n = 55) or 10,000 IU of hCG (n = 67). A maximum of two embryos was transferred. Luteal support consisted of micronized progesterone vaginally, 90 mg a day, and estradiol, 4 mg a day per os. RESULTS: Ovulation was induced with GnRH agonist in 55 patients and hCG in 67 patients. Significantly more metaphase II (MII) oocytes were retrieved in the GnRH agonist group (P < 0.02). Significantly higher levels of LH and FSH (P < 0.001) and significantly lower levels of progesterone and estradiol (P < 0.001) were seen in the GnRH agonist group during the luteal phase. The implantation rate, 33/97 versus 3/89 (P < 0.001), clinical pregnancy rate, 36 versus 6% (P = 0.002), and rate of early pregnancy loss, 4% versus 79% (P = 0.005), were significantly in favour of hCG. CONCLUSIONS: Ovulation induction with a GnRH agonist resulted in significantly more MII oocytes. However, a significantly lower implantation rate and clinical pregnancy rate in addition to a significantly higher rate of early pregnancy loss was seen in the GnRH agonist group, most probably due to a luteal phase deficiency.     

GnRH agonist for triggering final oocyte maturation in the GnRH antagonist ovarian hyperstimulation protocol: a systematic review and meta-analysis

Triggering final oocyte maturation with GnRH agonist during ovarian stimulation is feasible when inhibition of premature LH surge is performed with GnRH antagonists, and we aimed to systematically collate evidence on the clinical efficacy of GnRH agonist triggering in patients undergoing assisted reproduction in GnRH antagonist protocols. Twenty-three publications were identified by a comprehensive literature search that included PubMed, Embase and the Cochrane Library. Three publications out of 23 fulfilled the inclusion criteria for meta-analysis, which were (i) prospective, randomized controlled study design; (ii) stimulation with gonadotropins for induction of multifollicular development; (iii) suppression of endogenous LH by a GnRH antagonist; (iv) triggering of final oocyte maturation with GnRH agonist; (v) control group randomized to receive HCG for final oocyte maturation and (vi) any means of luteal phase support other than HCG. The participants were normoovulatory women undergoing IVF. The outcomes assessed were clinical pregnancy per randomized patient; number of oocytes retrieved; proportion of metaphase II oocytes; fertilization rate; embryo quality score; first trimester abortion rate; ovarian hyperstimulation syndrome (OHSS) incidence. Results are presented as combined standardized differences of the mean and combined odds ratios, as appropriate, with 95% confidence intervals. No significant difference was found for the number of oocytes retrieved (-0.94, -0.33-0.14), proportion of metaphase II oocytes (-0.03, -0.58-0.52), fertilization rate (0.15, -0.09-0.38) or embryo quality score (0.05, -0.18-0.29). No OHSS occurred in two of the studies, whereas in one study OHSS incidence was not reported. Thus from the available data, no conclusion can be drawn as regards OHSS incidence after GnRH agonist triggering. In comparison to HCG, GnRH agonist administration is associated with a significantly reduced likelihood of achieving a clinical pregnancy (0.21, 0.05-0.84; P = 0.03). The odds of first trimester pregnancy loss is increased after GnRH agonist triggering; however, the confidence interval crosses unity (11.51, 0.95-138.98; P = 0.05). In conclusion, the use of GnRH agonist to trigger final oocyte maturation in IVF, where inhibition of premature LH surge is achieved with GnRH antagonists, yields a number of oocytes capable to undergo fertilization and subsequent embryonic cleavage, which is comparable to that achieved with HCG. However, the likelihood of an ongoing clinical pregnancy after GnRH agonist triggering is significantly lower as compared to standard HCG treatment.     

The effect of an individualized GnRH antagonist protocol on folliculogenesis in IVF/ICSI

BACKGROUND: The aim of this study was to assess the effect of an individualized GnRH antagonist regimen on folliculogenesis. METHODS: In a multicentre, randomized, clinical trial, IVF/ICSI patients were allocated to a standard regimen, in which they received daily 0.25 mg GnRH antagonist ganirelix (Orgalutran) from the 6th day of stimulation onward (fixed regimen n = 102) or to an individualized regimen, in which IVF/ICSI patients received daily 0.25 mg GnRH antagonist starting on the day that the dominant follicle had reached a diameter of > or = 15 mm (flexible regimen n = 103). The primary endpoint was to assess the difference in the total number of oocytes. RESULTS: The mean (SD) number of retrieved oocytes was not statistically significantly different: 9.4 (5.8) in the flexible group versus 9.7 (6.5) in the fixed group. The clinical and ongoing pregnancy rates were 22.7 and 21.8% respectively in the flexible group versus 33 and 31.1% in the fixed group [relative rate ratio 0.69 (95% confidence interval 0.44-1.08) and 0.7 (0.44-1.12) respectively]. CONCLUSION: The individualized flexible regimen did not result in an increase in the total number of oocytes obtained.     

Human ovarian steroid secretion in vivo: effects of GnRH agonist versus antagonist (cetrorelix).

BACKGROUND: In order to investigate whether gonadotrophin-releasing hormone (GnRH) antagonists exert a significant effect on steroid secretion in vivo compared with GnRH agonists, concentrations of sex steroid hormones (oestradiol, progesterone and testosterone) were studied in follicular fluid from women undergoing ovarian stimulation and treated with either GnRH agonist or antagonist. In addition, the correlation between follicular fluid steroid hormone concentrations and variables of follicular and oocyte development was evaluated. METHODS: Microparticle enzyme immunoassay and radioimmunoassays were used. RESULTS: The mean (SEM) follicular fluid oestradiol concentration was significantly lower in patients treated with GnRH antagonist than in those treated with GnRH agonist (542.0 +/- 76.9 versus 873.0 +/- 105.1 pg/ml, P = 0.02), which correlates with the mean serum oestradiol concentrations found in these two groups. No significant differences were found between groups in follicular fluid progesterone concentrations. Women undergoing GnRH antagonist treatment showed similar concentrations of follicular fluid testosterone compared with GnRH agonist-treated women (14.8 +/- 1.1 versus 13.3 +/- 2.7 ng/ml). The oestradiol:testosterone ratio was markedly reduced in women treated with GnRH antagonist (49.1 +/- 2.3 versus 60.1 +/- 4.4, P = 0.04). In contrast, no differences were found either in the progesterone:testosterone ratio, or in the oestradiol:progesterone ratio. CONCLUSIONS: GnRH antagonist therapy in women undergoing ovarian stimulation had a significant effect on ovarian follicular steroidogenesis.     

GnRH拮抗剂与GnRH激动剂短方案IVF-ET结局的比较

目的比较GnRH antagonist与GnR Hagonist短方案的IVF-ET结局。方法2006年8月至2007年8月GnR Hantagonist治疗组54人和GnR Hagonist短方案对照组132人,记录促性腺激素的用量及其用药天数、hCG日子宫内膜厚度和激素水平、获卵数、受精率、卵裂率、优胚率、妊娠率和OHSS发生率等指标。结果两组促性腺激素的用量及其用药天数、获卵数、受精率、卵裂率、着床率和妊娠率相比较均无显著差异（P〉0.05）。GnR Hantagonist组在hCG日激素水平低,与对照组比较其差异有统计学意义。结论行GnR Hantagonist方案IVF-ET助孕治疗与传统的GnR Hagonist短方案比较,其hCG日雌激素水平下降可能是OHSS发生率显著下降的主要因素;但卵泡的发育、卵母细胞的受精率、卵裂率及妊娠率和着床率均不受影响。GnR Hantagonist的使用为IVF-ET助孕药物提供了一种新的选择。     

Ovarian stimulation for assisted reproduction with HMG and concomitant midcycle administration of the GnRH antagonist cetrorelix according to the multiple dose protocol: a prospective uncontrolled phase III study

A total of 346 women with normal ovulatory function was stimulated with human menopausal gonadotrophins (HMG) to attain ovarian stimulation for IVF or intracytoplasmic sperm injection (ICSI). Stimulation with HMG started on cycle day 2 or 3. After 6 days of stimulation, Cetrorelix in its minimum effective multiple dose of 0. 25 mg/day, was administered daily until induction of ovulation. In total, 333 patients (96.2%) reached the day of HCG administration, and 324 (93.6%) underwent oocyte retrieval. A mean of 25.2 ampoules of HMG was applied for a mean of 10.4 days. Cetrorelix was administered for a mean time lapse of 5.7 days. The mean normal fertilization rate was 60% in the IVF group and 59% in the ICSI group. Seventy pregnancies were attained, reflecting an ongoing clinical pregnancy rate of 24% per transfer. The ongoing clinical implantation rate was 11.4%. Only three cases of raised luteinizing hormone (LH) (>/=10 IU/l) with increased progesterone secretion (>/=1 ng/ml) were observed after initiation of Cetrorelix administration, reflecting an incidence of premature luteinization of 0.9%. The abortion rate was 17%. The incidence of severe ovarian hyperstimulation syndrome (World Health Organization grade III) was as low as 0.6%.     

In a flexible antagonist protocol, earlier, criteria-based initiation of GnRH antagonist is associated with increased pregnancy rates in IVF

BACKGROUND: The purpose of the study was to assess ongoing pregnancy rates across groups of patients treated by IVF, which were defined according to criteria aimed at the prevention of premature LH surge and used for initiating GnRH antagonist. METHODS: This is a prospective observational cohort study. During the last 3 years, in IVF-ICSI patients undergoing controlled ovarian stimulation (COS) with the antagonist protocol, the antagonist administration was initiated according to at least one of the following patient-specific criteria: (i) at least one follicle measuring >14 mm; (ii) estradiol levels >600 pg/ml; and (iii) LH levels >10 IU/l. Based upon these criteria, 208 cases of normal responders were analysed and categorized into three groups according to the starting day of the regimen: group D4 (n = 40) for day 4, group D5 (n = 98) for day 5 and group D6 (n = 70) for day 6. The main outcome measure was the ongoing pregnancy rate per started cycle. RESULTS: The total number of patients in the D4 and D5 groups (138 out of 208), who received the antagonist earlier, was considerably larger compared with that of D6 (70 out of 208). Ongoing pregnancy rates were 37.5, 34.7 and 18.6% for groups D4, D5 and D6, respectively. Patients who initiated the GnRH antagonist on days 4 and 5 had statistically significant higher pregnancy rates compared with day 6. Rapid response, causing earlier antagonist administration initiation, according to the proposed criteria for the prevention of premature LH surges, and the absence of premature luteinization, as evidenced by normal progesterone levels on HCG day, were found to be independent positive predictive factors for favourable IVF outcome. CONCLUSIONS: The employment of an algorithm of criteria, aimed at the prevention of premature LH surges in a flexible antagonist protocol, resulted in antagonist initiation earlier than on stimulation day 6 in a significant proportion of patients. In those patients, a higher pregnancy rate was observed.     

GnRH agonist protocol administration in the luteal phase in ICSI-ET cycles stimulated with the long GnRH agonist protocol: a randomized, controlled double blind study

BACKGROUND: GnRH agonist administration in the luteal phase was reported to beneficially affect the clinical outcome of intracytoplasmic sperm injection (ICSI) and embryo transfer (ET) cycles. This double blind, randomized, placebo controlled trial evaluates whether a single dose GnRH agonist administered 6 days after ICSI increases ongoing pregnancy rates following ET in cycles stimulated with the long GnRH agonist protocol. METHODS: Five hundred and seventy women undergoing ET following controlled ovarian stimulation with a long GnRH agonist protocol were included. In addition to routine luteal phase support with progesterone, women were randomized to receive a single 0.1 mg dose of triptorelin or placebo 6 days after ICSI. Randomization was done on the day of ET according to a computer generated randomization table. Ongoing pregnancy rate beyond 20th week of gestation was the primary outcome measure. The trial was powered to detect a 12% absolute increase from an assumed 38% ongoing pregnancy rate in the placebo group, with an alpha error level of 0.05 and a beta error level of 0.2. RESULTS: There were 89 (31.2%) ongoing pregnancies in the GnRH agonist group, and 84 (29.5%) in the control group (absolute difference +1.7%, 95% confidence interval -5.8% to +9.2%). Implantation, clinical pregnancy and multiple pregnancy rates were likewise similar in the GnRH agonist and placebo groups. CONCLUSIONS: Single 0.1 mg triptorelin administration 6 days after ICSI following ovarian stimulation with the long GnRH agonist protocol does not seem to result in an increase >or=12% in ongoing pregnancy rates.     

Reply: GnRH agonist (buserelin) or hCG for ovulation induction in gnRH antagonist IVF/ICSI cycles: a prospective randomized study

Sir, Thank you for giving me the opportunity to respond to DoctorsEngmann and Benadiva. First of all, the question concerningthe length of the luteal support with progesterone and estradiolafter triggering of final oocyte maturation in IVF/ICSI     

The detection of gene mutation in transgenic mice (MutaTMMouse) following a single oral dose of 2-acetylaminofluorene

Transgenic mouse assays, such as Muta^TMMouse, provide a methodto predict the potential target organ carcinogenicity of chemicalcompounds. As part of a validation study, 2-acetylaminofluorenewas administered as a single oral dose of either 50 or 100 mg/kg.The mice were killed 3, 7, 14, 28, 56 or 112 days after thissingle treatment. Mutation frequencies were determined in liverDNA. The results showed that a mutagenic response was observedin the mice treated at the highest dose (100 mg/kg) and thisincrease was expressed from 28 up to 112 days after the singleexposure.