GnRH Agonist Cycles Research Articles

The effects of GnRH antagonist vs. GnRH agonist down regulation on the outcome of IUI cycles

ObjectiveIt has been shown that up to 24% of non-down-regulated COH/IUI cycles may suffer premature luteinization. The use of down-regulation in controlled ovarian hyperstimulation (COH)/IUI cycles has improved pregnancy rates as compared to non-down-regulated cycles. The aim of this study is to compare the efficacy of GnRH antagonist to GnRH agonist down-regulation in COH/IUI cycles.DesignHistorical cohort study.Materials and methodsTable 1Comparison of GnRH agonist cycles to GnRH antagonist cycles outcomeGnRH agonist (n − 1258)GnRH antagonist (n − 626)Total (n = 1884)PPregnancy353 (28.1%)199 (31.9%)552 (29.3%)NSDelivery276 (21.9%)163 (26.0%)439 (23.3%)NSMiscarried63 (17.8%)26 (13.1%)89 (16.1%)NSEctopic14 (4.05)10 (5.0%)24 (4.3%)NS Open table in a new tab ResultsThe mean age for all the women was 32 ± 4.5 years. There was no significant difference in the mean age between the two groups. However, the mean duration of infertility was significantly longer (P=0.01) and the proportion of primary infertility was significantly greater (P=0.02) in the GnRH antagonist group. The mean number of follicles ≥16 mm (4.9 ± 3.0 compared to 4.2 ± 2.6) and the mean peak estradiol (E2) (1480 ± 850 pg/ml compared to 1210 ± 810 pg/ml)were significantly greater in the GnRH agonist group compared to the GnRH antagonist group (P=0.001 and P=0.01 respectively). After multiple logistic regression analyses, the type of infertility and the number of 16 mm follicles remained significant factors. The pregnancy rates in the 2 groups were similar (31.9% and 28.1% for group 1 and group 2 respectively). The delivery, miscarriage and ectopic pregnancy rates were similar in the 2 groups (Table 1).ConclusionsBoth GnRH Antagonist and GnRH agonist appear to have similar effectiveness during COH/IUI cycles. ObjectiveIt has been shown that up to 24% of non-down-regulated COH/IUI cycles may suffer premature luteinization. The use of down-regulation in controlled ovarian hyperstimulation (COH)/IUI cycles has improved pregnancy rates as compared to non-down-regulated cycles. The aim of this study is to compare the efficacy of GnRH antagonist to GnRH agonist down-regulation in COH/IUI cycles. It has been shown that up to 24% of non-down-regulated COH/IUI cycles may suffer premature luteinization. The use of down-regulation in controlled ovarian hyperstimulation (COH)/IUI cycles has improved pregnancy rates as compared to non-down-regulated cycles. The aim of this study is to compare the efficacy of GnRH antagonist to GnRH agonist down-regulation in COH/IUI cycles. DesignHistorical cohort study. Historical cohort study. Materials and methodsTable 1Comparison of GnRH agonist cycles to GnRH antagonist cycles outcomeGnRH agonist (n − 1258)GnRH antagonist (n − 626)Total (n = 1884)PPregnancy353 (28.1%)199 (31.9%)552 (29.3%)NSDelivery276 (21.9%)163 (26.0%)439 (23.3%)NSMiscarried63 (17.8%)26 (13.1%)89 (16.1%)NSEctopic14 (4.05)10 (5.0%)24 (4.3%)NS Open table in a new tab ResultsThe mean age for all the women was 32 ± 4.5 years. There was no significant difference in the mean age between the two groups. However, the mean duration of infertility was significantly longer (P=0.01) and the proportion of primary infertility was significantly greater (P=0.02) in the GnRH antagonist group. The mean number of follicles ≥16 mm (4.9 ± 3.0 compared to 4.2 ± 2.6) and the mean peak estradiol (E2) (1480 ± 850 pg/ml compared to 1210 ± 810 pg/ml)were significantly greater in the GnRH agonist group compared to the GnRH antagonist group (P=0.001 and P=0.01 respectively). After multiple logistic regression analyses, the type of infertility and the number of 16 mm follicles remained significant factors. The pregnancy rates in the 2 groups were similar (31.9% and 28.1% for group 1 and group 2 respectively). The delivery, miscarriage and ectopic pregnancy rates were similar in the 2 groups (Table 1). The mean age for all the women was 32 ± 4.5 years. There was no significant difference in the mean age between the two groups. However, the mean duration of infertility was significantly longer (P=0.01) and the proportion of primary infertility was significantly greater (P=0.02) in the GnRH antagonist group. The mean number of follicles ≥16 mm (4.9 ± 3.0 compared to 4.2 ± 2.6) and the mean peak estradiol (E2) (1480 ± 850 pg/ml compared to 1210 ± 810 pg/ml)were significantly greater in the GnRH agonist group compared to the GnRH antagonist group (P=0.001 and P=0.01 respectively). After multiple logistic regression analyses, the type of infertility and the number of 16 mm follicles remained significant factors. The pregnancy rates in the 2 groups were similar (31.9% and 28.1% for group 1 and group 2 respectively). The delivery, miscarriage and ectopic pregnancy rates were similar in the 2 groups (Table 1). ConclusionsBoth GnRH Antagonist and GnRH agonist appear to have similar effectiveness during COH/IUI cycles. Both GnRH Antagonist and GnRH agonist appear to have similar effectiveness during COH/IUI cycles.

P-63: Differences in clinical application of serum estradiol levels on hCG day between GnRH antagonist and GnRH agonist cycles

P-63: Differences in clinical application of serum estradiol levels on hCG day between GnRH antagonist and GnRH agonist cycles

P-774: High basal LH level may affect pregnancy outcome on GnRH antagonist cycles

In the early follicular phase of GnRH antagonist cycle, unsuppressed endogenous LH concentrations are present as compared with GnRH agonist cycle, while no data were available as to their effect on pregnancy outcomes.To evaluate whether basal LH level have an effect on pregnancy outcomes for GnRH antagonist cycle

O-290: FSH to LH ratio on day 3 is predictive of IVF outcome in down-regulated IVF stimulation cycles

Maternal age and ovarian response are the best predictors of IVF outcome. There are many suggested options of stimulation for the patient but most often a down-regulated protocol is utilized. Studies have clearly demonstrated that the FSH:LH ratio on day two in no GnRH-agonist (GnRH-a) cycles (non-down-regulated) is highly predictive of outcome. Some studies have suggested that even in down-regulated stimulation cycles, the FSH:LH ratio on day three of a withdrawal bleed is predictive of outcome.

Addition of estradiol to progesterone for luteal supplementation in patients stimulated with GnRH antagonist/rFSH for IVF: a randomized controlled trial

The role of progesterone for luteal support in stimulated cycles for IVF is well established. However, controversy still surrounds the benefit of additional supplementation with estradiol (E2) in GnRH agonist (GnRHa) cycles, while no such data are available for GnRH antagonists. The aim of this randomized controlled trial (RCT) was to compare ongoing pregnancy rates in patients stimulated with recombinant FSH (rFSH) and GnRH antagonist for IVF, who received micronized progesterone for luteal phase supplementation, with or without the addition of E2. Two hundred and one patients underwent ovarian stimulation with a fixed dose of 200 IU rFSH and GnRH antagonist. Patients were randomized to receive, for luteal phase supplementation, either 600 mg of micronized progesterone vaginally (n=100, progesterone group) or 600 mg of micronized progesterone and 4 mg of E2 valerate orally (n=101, progesterone/E2 group). The main outcome measure was ongoing pregnancy at 12 weeks per patient randomized. Demographics, stimulation parameters and embryological data were comparable for the two groups compared. Twenty-six ongoing pregnancies were achieved in the progesterone (26%) and 30 in the progesterone/E2 group (29.7%). (Difference: 3.7 and 95%, CI: -15.8 to 8.6%). It appears that the addition of E2 to progesterone in the luteal phase after stimulation with rFSH and GnRH antagonist does not enhance the probability of pregnancy.

Outcome of frozen-thawed blastocysts derived from gonadotropin releasing hormone agonist or antagonist cycles

The aim of this retrospective study was to compare the outcome of frozen-thawed blastocysts derived from the cycles using controlled ovarian stimulation with GnRH agonists vs. GnRH antagonists. Survival, pregnancy and cumulative live birth rates in 231 freeze-thaw cycles derived from the GnRH agonist cycles (GnRH agonist group), and in 175 freeze-thaw cycles derived from the GnRH antagonist cycles (GnRH antagonist group) were compared. In the GnRH agonist group significantly higher proportion of blastocysts survived the thawing procedure than in the GnRH antagonist group (86.1% versus 78.5%; p < 0.01). The differences in cumulative live birth rates did not differ significantly between the groups: in the GnRH agonist group the cumulative live birth rate was 16.5%, and in the GnRH antagonist group it was 14.2%. Frozen-thawed blastocysts derived from the GnRH agonist cycles have better survival rates and similar cumulative live birth rates than those derived from the GnRH antagonist cycles.

Effect of coasting on cycle outcome during in vitro fertilization/intracytoplasmic sperm injection cycles in hyper-responders

To investigate the effect of coasting on IVF outcome in GnRH agonist cycles. Retrospective analysis. Private IVF center. Infertile couples undergoing IVF/intracytoplasmic sperm injection (ICSI) treatment (normal responders [control], hyper-responders [coasting] groups). Coasting to reduce the risk of ovarian hyperstimulation syndrome (OHSS) among hyper-responders. Stimulation, embryology parameters, and pregnancy rate (PR). The average length of coasting was 2.2 days. Age and baseline FSH were comparable to control cycles. There were more follicles and oocytes in the coasting group, but the number of fertilized oocytes and embryos transferred were similar. Implantation rate (22.4% vs. 13.9%) was higher in the control group but the PRs were comparable (45.1% vs. 38.5%). Within the coasting group, baseline, stimulation, and embryology parameters were comparable between successful and unsuccessful cycles. Pregnancy rates were comparable after 1, 2, and 3 or more days of coasting (36.3% vs. 38.4% vs. 40%). Pregnancy rates were also comparable (28.5% vs. 35.7% vs. 44.4%) when groups were compared based on change in E2 (<25%, 25%-50%, >50%). Coasting for 3 days can be used successfully in the management of the hyper-responding patients during IVF.

A Short Ovarian Stimulation Does Not Negatively Impact IVF Pregnancy Rates When Utilizing a GnRH Antagonist Protocol

ObjectiveExisting randomized controlled trials and metanalyses suggest that IVF cycle outcomes of GnRH antagonist and agonist cycles may be comparable. Potential benefits of GnRH antagonist cycles compared to GnRH agonist cycles include reductions in total medication administered, length of cycle, and adverse effects including hot flashes and ovarian hyperstimulation syndrome. Specifically, the role of cycle length in GnRH antagonist cycles is not known. We aimed to examine the relationship between length of gonadotropin stimulation and outcomes in GnRH antagonist IVF cycles.DesignRetrospective data analysis.Materials and methodsWe utilized our program’s database to review all IVF cycles in which a GnRH antagonist (cetrorelix) was used. Cycles were divided into two groups: length of stimulation < 8 days and ≥ 8 days. Differences between the groups were evaluated with the Student’s t-test for continuous variables and the chi-square test for categorical or dichotomous variables. A subgroup analysis of ICSI cycles was conducted.ResultsTabled 1ConclusionsOur retrospective analysis of 2,033 GnRH antagonist IVF cycles demonstrated that length of stimulation is not associated with a significant difference in pregnancy rates. In particular, except for having a reduced chance of being able to freeze excess embryos, a short stimulation cycle is not detrimental to the ultimate outcome of that treatment cycle. ObjectiveExisting randomized controlled trials and metanalyses suggest that IVF cycle outcomes of GnRH antagonist and agonist cycles may be comparable. Potential benefits of GnRH antagonist cycles compared to GnRH agonist cycles include reductions in total medication administered, length of cycle, and adverse effects including hot flashes and ovarian hyperstimulation syndrome. Specifically, the role of cycle length in GnRH antagonist cycles is not known. We aimed to examine the relationship between length of gonadotropin stimulation and outcomes in GnRH antagonist IVF cycles. Existing randomized controlled trials and metanalyses suggest that IVF cycle outcomes of GnRH antagonist and agonist cycles may be comparable. Potential benefits of GnRH antagonist cycles compared to GnRH agonist cycles include reductions in total medication administered, length of cycle, and adverse effects including hot flashes and ovarian hyperstimulation syndrome. Specifically, the role of cycle length in GnRH antagonist cycles is not known. We aimed to examine the relationship between length of gonadotropin stimulation and outcomes in GnRH antagonist IVF cycles. DesignRetrospective data analysis. Retrospective data analysis. Materials and methodsWe utilized our program’s database to review all IVF cycles in which a GnRH antagonist (cetrorelix) was used. Cycles were divided into two groups: length of stimulation < 8 days and ≥ 8 days. Differences between the groups were evaluated with the Student’s t-test for continuous variables and the chi-square test for categorical or dichotomous variables. A subgroup analysis of ICSI cycles was conducted. We utilized our program’s database to review all IVF cycles in which a GnRH antagonist (cetrorelix) was used. Cycles were divided into two groups: length of stimulation < 8 days and ≥ 8 days. Differences between the groups were evaluated with the Student’s t-test for continuous variables and the chi-square test for categorical or dichotomous variables. A subgroup analysis of ICSI cycles was conducted. ResultsTabled 1 ConclusionsOur retrospective analysis of 2,033 GnRH antagonist IVF cycles demonstrated that length of stimulation is not associated with a significant difference in pregnancy rates. In particular, except for having a reduced chance of being able to freeze excess embryos, a short stimulation cycle is not detrimental to the ultimate outcome of that treatment cycle. Our retrospective analysis of 2,033 GnRH antagonist IVF cycles demonstrated that length of stimulation is not associated with a significant difference in pregnancy rates. In particular, except for having a reduced chance of being able to freeze excess embryos, a short stimulation cycle is not detrimental to the ultimate outcome of that treatment cycle.

GnRH Antagonist Use in IVF and ICSI Cycles Decreases Implantation and Clinical Pregnancy Rates Without Affecting Embryo Quality and Blastulation

We aimed to compare the outcome of ovarian stimulation protocols using GnRH antagonist to those incorporating GnRH agonist in IVF or ICSI, non-donor fresh blastocyst transfer cycles. Retrospective comparison of GnRH antagonist IVF or ICSI cycles to GnRH agonist cycles from a university-affiliated private ART program. Cycles were included only if they resulted in blastocyst transfer. A total of 750 IVF and 1288 ICSI, fresh non-donor blastocyst transfer cycles were included. Patients on GnRH agonists received daily leuprolide acetate injections using either long luteal phase or flare protocols. Patients on GnRH antagonist received cetrorelix acetate 3 mg administered 4 days before the start of FSH stimulation for synchronization of the antral follicle cohort and a repeat dose was given when a lead follicular diameter of 13-14 mm was reached. Embryo Progression Index (EPI) was calculated from the area under the curve of numerical conversion of the available embryo progression data by trapezoidal integration. Gardner/Schoolcraft blastocyst grades were converted into numerical Blastocyst Quality Scores (BQS). Mean EPI for day 3 and day 5/6 for all blastocysts and mean BQS of developed and transferred embryos were used as separate variables to serve as measures of embryo progression and blastulation. IVF and ICSI cycles were analyzed separately. The comparisons were made by independent t- and chi-square tests where appropriate. The significant predictors of clinical pregnancy were analyzed by logistic regression. Cycle outcomes were summarized in the following table (Table 1.). Cycles with GnRH antagonists had reduced implantation and clinical pregnancy rates although the embryo progression and blastulation parameters were comparable in IVF cycles and were superior in ICSI cycles which employed GnRH antagonists. Evaluation of first treatment cycles did not change these findings. Logistic regression models further supported the negative impact of GnRH antagonist on clinical pregnancy in both IVF and ICSI cycles. Tabled 1 Non-donor IVF or ICSI cycles with fresh blastocyst transfer using GnRH antagonist result in lower implantation and clinical pregnancy rates as compared with GnRH agonist cycles, although the embryo progression and blastulation scores are comparable or superior in GnRH antagonist cycles. These findings suggest potential adverse effects of GnRH antagonist on endometrial receptivity which justifies further investigation.

GnRH antagonists in ovarian stimulation: a treatment regimen of clinicians’ second choice? Data from the German national IVF registry

The place of GnRH antagonists in ovarian stimulation is controversial. Meta-analyses on studies comparing GnRH agonist and GnRH antagonist treatment regimens have suggested a comparatively lower efficacy of GnRH antagonists, which is likely to have influenced clinicians' attitudes. This report describes GnRH antagonist utilization for ovarian stimulation in Germany from 2000-2003. Data from the national IVF registry were analysed. The majority of ovarian stimulation cycles are still performed in long GnRH agonist protocols, although a significant increase in GnRH antagonist usage has been noted (P < 0.0001). Two observations support the notion that GnRH antagonists are often utilized as a treatment option in cycles with an unfavourable a priori prognosis: (i) the proportion of GnRH antagonist cycles increases with cycle rank (P < 0.0001, chi(2) for linear trend); and (ii) GnRH antagonist cycles are more often conducted in older patients as compared to GnRH agonist cycles (P < 0.0001). This has important implications for interpreting clinical performance of GnRH antagonists outside a research context.

Comparison of GnRH agonists and antagonists in assisted reproduction cycles of patients at high risk of ovarian hyperstimulation syndrome

During IVF or ICSI cycles, ovarian hyperstimulation syndrome (OHSS) is a major problem. The aim of this prospective, multicentre, comparative study (using historical controls) was to assess the efficacy of a GnRH antagonist protocol in preventing OHSS in selected patients who had experienced OHSS or had been at risk of OHSS in their previous IVF/ICSI attempt. Patients underwent a new cycle where the same gonadotrophin protocol was used [same dose of recombinant FSH (rFSH)] but a different protocol was used for pituitary desensitization: cetrorelix 0.25 mg multiple-dose antagonist instead of GnRH agonist long protocol. Cetrorelix 0.25 mg was administered daily, starting when the leading follicle reached a diameter of 14 mm. In other words, rFSH was administered in the new cycle according to the dosage and the step-up or step-down modalities used during the previous cycle, independently of ultrasound findings and serum estradiol (E(2)) levels. Eighty-seven patients entered the study. Out of the 87 cycles involving GnRH agonists, 49 (56.3%) were cancelled and out of the 87 involving GnRH antagonists 28 (32.2%) were cancelled [McNemar's test; 95% confidence interval (CI) -35.8% to -11.2%; P < 0.001]. After GnRH agonist cycles, we recorded 24 cases of OHSS (18 moderate and six severe; 27.6%), whereas after the GnRH antagonist cycles there were 10 cases of OHSS (nine moderate and one severe; 11.5%) (95% CI-26.4% to -5.7%; P = 0.006). There was a statistically significant reduction in the total number of follicles with a diameter >10 mm (Wilcoxon's test; Z = 6.1; P < 0.001) and of E(2) levels on the day of HCG administration (2538 versus 4322.4 pg/ml; P < 0.001) in the GnRH antagonist cycles versus GnRH agonist cycles. Twenty-nine patients had an embryo transfer in the first cycle (76.3% of oocyte retrievals) and 57 in the cycle using GnRH antagonist (96.6%). This 20.3% difference was also significant (Z-test; 95% CI 6.8-36.0%; P = 0.003). After the antagonist cycles, 18 pregnancies (20.7 per initiated cycle; 31.6% per embryo transfer) were obtained. Although this study presents some limitations owing to the use of historical controls, our data show a favourable effect of GnRH antagonists in reducing the incidence of OHSS and the number of assisted fertilization cycles cancelled because of the risk of OHSS in high responder patients. As a consequence, GnRH antagonist plus gonadotrophin administration could also increase the percentage of oocyte retrievals and embryo transfers in this high risk group of patients.

Genomic and proteomic analyses of the endometrium during the window of implantation following laser capture microdissection: Comparison of natural and controlled ovarian hyperstimulation (COH) cycles

The process of embryo implantation is a condition of equilibrium in the up- and down-regulation of diverse endometrial genes/proteins under control of steroid hormones and other local factors. The objective of this study was to compare endometrial gene and protein expression during the window of implantation of natural and COH cycles following tissue compartmentalization using laser capture microdissection (LCM). Prospective, randomized and blinded research study. Endometrial biopsies were obtained during the putative window of implantation (day 21) from (a) COH cycles of oocyte donors (n = 10); and (b) natural cycle controls (n = 5). Oocyte donors were stimulated either with a GnRH agonist (long protocol) and recombinant FSH (rFSH) or with rFSH and a GnRH antagonist. For global gene expression profiling, cRNA was generated and hybridized to Affymetrix Hu95A microarrays. Prior to proteomic analysis, LCM was used to isolate specific endometrial cell types, i.e. epithelial and stromal cells. Proteomics was performed to the compartmentalized endometrium using surface enhanced laser desorption/ionization (SELDI)-time of flight spectrometry (TOF) technology. Protein lysates were loaded robotically on an IMAC 3 chip pretreated with CuSO4. Each resulting protein peak was determined and its intensity normalized for total ion current. Statistical analysis of the genomic data was performed using pair wise multiple group comparison (SAM software), while statistical analysis of the proteomic data was based on the Student’s t test and CART analysis using Ciphergen’s Biomarker Patterns Software. SAM analysis reveled that the endometrium of COH cycles differed in 18 genes in comparison to the timely matched natural cycles. Optineurin and procollagen type 3 endopeptidase were genes up regulated in the COH group, which were validated by real time RT-PCR. SELDI spectra revealed similar protein fingerprinting in the dissected endometrial epithelium in natural versus COH cycles stimulated with a GnRH antagonist. On the other hand, microdissected epithelium from GnRH agonist cycles depicted a different fingerprinting compared to natural and GnRH antagonist cycles. Furthermore, microdissected stromal compartments differed in the protein fingerprinting in the three studied groups. Several proteins, with masses ranging from 2.5 to 17 kD were differentially expressed among the three groups. Importantly, two unique 11 kD and 15 kD protein peaks were observed in the GnRH agonist cycles. Minimal differences in gene expression were found when comparing COH versus natural cycles. SELDI fingerprinting revealed a similar protein expression pattern in the epithelium of natural and GnRH antagonist cycles. However, differences were observed in GnRH agonist cycles. The stromal compartment demonstrated divergent protein fingerprinting amongst groups. These results provide a basic background on global gene and protein expression analysis of the endometrium during the window of implantation under natural and stimulated conditions.

Premature luteinization defined as progesterone estradiol ratio >1 on hCG administration day seems to adversely affect clinical outcome in long gonadotropin-releasing hormone agonist cycles.

To examine the effect of premature luteinization on the outcomes in long gonadotropin-releasing hormone agonist cycles. Two-hundred and forty-eight patients who had undergone assisted reproductive technology for infertility treatment between 2001 and 2002 were enrolled into the study. The patients were separated into two groups according to P/E2 ratios on human chorionic gonadotropin administration day. Group A consisted of the patients whose P/E2 ratio was 1 (n = 116) and Group B consisted of the patients with premature luteinization of which P/E2 ratio was > 1 (n = 132). The P/E2 ratio calculation was performed as follows: P (in ng/mL) x dagger 1,000/E2 (in pg/mL). The primary outcome measures included oocyte quality, fertilization rates and clinical pregnancy rates. The mean number of mature oocytes retrieved in the groups were 9.5 +/- 4.8 and 6.4 +/- 3.6, respectively, and the difference was statistically significant (P < 0.05). Although the difference between the fertilization rates in Group A and Group B was not statistically significant (P > 0.05), the clinical pregnancy rates seemed to be affected adversely in the Group B patients with premature luteinization (41.4%versus 28%, respectively; P < 0.05). Premature luteinization, defined as P/E2 > 1 on human chorionic gonadotropin administration day, in long gonadotropin-releasing hormone agonist cycles seems to adversely affect clinical outcome.

Gonadotropin-releasing hormone antagonists for assisted reproductive techniques: are there clinical differences between agents?

Gonadotropin-releasing hormone (GnRH) antagonists have been tested extensively in ovarian stimulation protocols for assisted reproductive techniques (ART). GnRH antagonists immediately and rapidly inhibit gonadotropin release by the anterior pituitary gland by competitive blockage of the GnRH receptor, preventing and interrupting luteinising hormone surges in controlled ovarian hyperstimulation for infertility treatment. A review of the available literature on GnRH antagonists for ART is presented, focusing on the pharmacological and clinical properties of the two compounds available on the market, cetrorelix and ganirelix. Both cetrorelix and ganirelix are well tolerated and effective drugs for controlled ovarian hyperstimulation and are of comparable value for infertility treatment. Cetrorelix is available as a 0.25mg preparation for daily injections and as a 3mg intermediate depot preparation. Ganirelix is available as a 0.25mg preparation for daily injections.Currently, two treatment protocols are used in clinical practice: the GnRH antagonist multiple-dose protocol and the GnRH antagonist single-dose protocol. Both protocols are effective and well tolerated. Cetrorelix and ganirelix have not yet been directly compared in a clinical trial; nor have the single-dose and the multiple-dose approaches been compared in a randomised, controlled trial. Data to compare these compounds in clinical terms can be extrapolated only from results of phase II dose-finding studies and phase III studies comparing GnRH agonist cycles with GnRH antagonists in single- and multiple-dose protocols. Therefore, all conclusions on clinical differences between cetrorelix and ganirelix should remain tentative, as they are based on a limited amount of available data.Randomised, controlled trials comparing cetrorelix and ganirelix are warranted to further evaluate benefits and drawbacks of individual GnRH antagonists. Furthermore, more data are needed to determine the efficacy and safety of cetrorelix and ganirelix in established treatment protocols in patients other than those included in clinical trials investigating new drugs, such as "poor responders", patients with polycystic ovaries, patients with a history of allergy or overweight patients.

Effect of human chorionic gonadotropin on luteal luteinizing hormone concentrations in natural cycles

Effect of human chorionic gonadotropin on luteal luteinizing hormone concentrations in natural cycles

The use of GnRH antagonists in ovarian stimulation.

GnRH antagonists induce a rapid decrease in LH and FSH, preventing and interrupting LH surges. Their properties do not require a desensitization period, and this allows their use in the late follicular phase. GnRH antagonists could replace GnRH agonists in controlled ovarian stimulation without their side-effects and their long desensitization period. Two protocols for assisted reproduction technology (ART) cycles were designed: the single-dose protocol allies simplicity and efficacy, while the multiple-dose protocol is efficient and could reduce monitoring of the cycle, though compliance is mandatory. A review of the available literature on GnRH antagonists in ART cycles is presented, focusing on phase III controlled trials and ART results. Both protocols using GnRH antagonists were associated with the need for a smaller dose of gonadotrophin, a shorter stimulation period and a lower incidence of ovarian hyperstimulation syndrome (OHSS), albeit with statistically comparable pregnancy rates. A trend is observed in all studies showing a lower pregnancy rates in GnRH antagonist cycles as compared with GnRH agonist cycles. The role of the lower number of embryos, and the potential adverse effects of GnRH antagonists on endometrium or follicle must be studied. More cycles using GnRH antagonists are necessary to confirm their equivalent pregnancy rates. There is room for improvement in both protocols with regard to scheduling, antagonist dose level and the timing of its administration. Until further studies have been conducted, luteal support seems to remain mandatory. Perinatal outcome appears similar to that with other stimulation regimens. Triggering of ovulation can be obtained with GnRH agonist for patients at risk of OHSS. With regard to GnRH antagonists, questions remain regarding pregnancy rates, the indications of their use in patients with polycystic ovary syndrome or poor responders, and in ovarian stimulation outside IVF.

Ovulation induction disrupts luteal phase function.

Abnormalities in the luteal phase have been detected in virtually all the stimulation protocols used in in vitro fertilization, on both the hormonal and endometrial levels. Supraphysiological follicular or luteal sex steroid serum concentrations, altered estradiol: progesterone (E2/P) ratio, and disturbed luteinizing hormone pituitary secretion leading to corpus luteum insufficiency or a direct drug effect have been postulated as the main etiologic factors. Luteinizing hormone supports corpus luteum function, and low LH levels have been described after human menopausal gonadotropin treatment, after gonadotropin-releasing hormone (GnRH)-agonist treatment, or after GnRH-antagonist treatment. These low luteal LH levels may lead to an insufficient corpus luteum function and consequently to a shortened luteal phase or to the low luteal progesterone concentrations frequently described after ovulation induction. A direct effect of the GnRH agonist or GnRH antagonist on human corpus luteum or on human endometrium and thus on endometrial receptivity cannot be excluded, as GnRH receptors have been described in both compartments. Endometrial histology has revealed a wide range of abnormalities during the various stimulation protocols. In GnRH-agonist cycles, mid-luteal biopsies have revealed increased glandulo-stromal dyssynchrony and delay in endometrial development, strong positivity of endometrial glands for progesterone receptors, decreased alphavbeta3-integrin subunit expression, and earlier appearance of surface epithelium pinopodes. These factors suggest a shift forwards of the implantation window. Progesterone supplementation improves endometrial histology, and its necessity has been well established, at least in cycles using GnRH agonists.

Increased progesterone/estradiol ratio in the late follicular phase could be related to low ovarian reserve in in vitro fertilization–embryo transfer cycles with a long gonadotropin-releasing hormone agonist

Objective: To gain insight into the physiologic as well as the clinical significance of premature luteinization in the long gonadotropin-releasing hormone agonist (GnRH-a) cycles and to evaluate whether it may be a manifestation of low ovarian reserve.Design: Prospective evaluation.Setting: A university-affiliated reproductive medicine unit.Patient(s): Seventy-six consecutive infertile women.Intervention(s): The long GnRH-a protocol was used for IVF-ET treatment.Main Outcome Measure(s): Women in the study were prospectively evaluated in their first cycle of treatment and were divided into those with (study group) or without premature luteinization (control group). Premature luteinization was defined as P/E2 ratio of more than 1 on the day of hCG administration.Result(s): Thirty-one (41%) of the women in the study demonstrated premature luteinization. Patients’ characteristics were comparable between the two groups. Late follicular P/E2 ratio was significantly and considerably higher in the study as compared to the control group, 2.4 ± 1.7 and 0.7 ± 0.2, respectively. Ovarian reserve parameters including day 3 FSH, E2 level on hCG day, total amount of hMG, number of follicles, oocytes, and embryos were significantly inferior in the study as compared to the control group. P levels on hCG day were significantly higher in the study as compared to the control group, 1.9 ± 0.7 ng/mL and 1.2 ± 0.6 ng/mL, respectively. However, LH levels on hCG day did not differ between the groups, 1.4 ± 0.7 mIU/mL and 1.2 ± 0.7 mIU/mL, respectively. The clinical pregnancy rate was significantly lower in the premature luteinization group as opposed to controls, 13% and 42%, respectively.Conclusion(s): Premature luteinization, defined as late follicular P/E2 >1, in long GnRH-a cycles seems to adversely affect clinical outcome. Our findings in this setting support the notion that premature luteinization could be related to low ovarian reserve and that this manifestation is not necessarily an LH-dependent event.

Ovarian stimulation in in vitro fertilization with or without the “long” gonadotropin-releasing hormone agonist protocol: effect on cycle duration and outcome

Objective: To study the correlation between stimulation duration of IVF cycles, with and without GnRH agonist (GnRH-a), and cycle outcome. Design: Retrospective analysis of data. Setting: University-affiliated IVF clinic. Patient(s): 998 IVF cycles in which long GnRH-a protocol was used, and 155 cycles with hMG only. Intervention(s): IVF cycles. Main Outcome Measure(s): Cycle outcome in number of oocytes and embryos, and pregnancy rate. Result(s): The mean stimulation duration (±SD) was 9.6 ± 1.7 and 6.7 ± 1.0 for the GnRH-a and the hMG-only cycles, respectively ( P<0.01). In the GnRH-a group, no statistically significant correlation between cycle duration and pregnancy rate was found. Interestingly, the patients treated for 9 days had the highest number of oocytes retrieved and the highest pregnancy rate. Stimulation duration was not affected by age in either protocol. GnRH-a cycles yielded a significantly higher number of oocytes and embryos compared to cycles without GnRH-a. The pregnancy rate was similar in both groups. Conclusion(s): Stimulation duration in the long GnRH-a protocol group was significantly longer than in the hMG-only group. Stimulation duration was not affected by age. No statistically significant correlation was found between stimulation duration and cycle outcome in the long protocol group.

Improved controlled ovarian hyperstimulation in poor responder in vitro fertilization patients with a microdose follicle-stimulating hormone flare, growth hormone protocol

To assess the efficacy of a novel protocol-microdose GnRH agonist (GnRH-a), FSH, and GH, for the stimulation of IVF patients who were canceled previously on a standard luteal GnRH-a, FSH, GH protocol. Prospective evaluation using the patient's previous IVF stimulation attempt as historic controls. Private practice assisted reproductive technology center. Thirty-two patients who had prior ovulation induction cycles canceled using luteal phase GnRH-a suppression followed by exogenous gonadotropins and GH. Precycle treatment with oral contraceptives followed by follicular phase administration of 40 micrograms leuprolide acetate every 12 hours beginning on cycle day 3 and FSH supplemented with GH beginning on cycle day 5. Paired analysis of E2 day 5, number of follicles, ampules of FSH required, and cancellation rate. The number of oocytes, embryos, embryo quality, implantation rate, and pregnancy rate (PR) were determined for completed cycles on the microdose GnRH-a, FSH, GH protocol. Controlled ovarian hyperstimulation was superior during microdose GnRH-a, FSH, GH stimulation when compared with the prior luteal GnRH-a cycle. Specifically, there was a higher E2 response, more oocytes, fewer cycle cancellations, and no premature LH surge or luteinization. The microdose GnRH-a, FSH, GH protocol produced an average of 10 oocytes and a 50% ongoing PR. The microdose GnRH-a, FSH, GH protocol is superior to standard protocols for the treatment of patients with decreased ovarian reserve undergoing controlled ovarian hyperstimulation for IVF.