Microdose GnRH Agonist Research Articles

Ovarian stimulation protocols for poor ovarian responders: a network meta-analysis of randomized controlled trials.

To evaluate the efficacy of manifold ovarian stimulation protocols for patients with poor ovarian response. PubMed, Embase, Cochrane Library and Web of Science were systematically searched until February 14, 2021. Primary outcomes included clinical pregnancy rate per initiating cycle and low risk of cycle cancellation. Secondary outcomes included number of oocytes retrieved, number of metaphase II (MII) oocytes, number of embryos obtained, number of transferred embryos, endometrial thickness on triggering day and estradiol (E2) level on triggering day. The network plot, league table, rank probabilities and forest plot of each outcome measure were drawn. Therapeutic effects were displayed as risk ratios (RRs) or mean differences (MDs) with 95% confidence intervals (CIs). This network meta-analysis included 15 trials on 2173 participants with poor ovarian response. Delayed start GnRH antagonist was the best regimen in terms of clinical pregnancy rate per initiating cycle (74.04% probability of being the optimal), low risk of cycle cancellation (75.30%), number of oocytes retrieved (68.67%), number of metaphase II (MII) oocytes (97.98%) and endometrial thickness on triggering day (81.97%), while for E2 level on triggering day, microdose GnRH agonist (99.25%) was the most preferred. Regarding number of embryos obtained and number of transferred embryos, no statistical significances were found between different ovarian stimulation protocols. Delayed start GnRH antagonist and microdose GnRH agonist were the two superior regimens in the treatment of poor ovarian response, providing favorable clinical outcomes. Future investigation is needed to confirm and enrich our findings.

450 IU versus 600 IU gonadotropin for controlled ovarian stimulation in poor responders: a randomized controlled trial

To compare the outcomes of controlled ovarian stimulation/in vitro fertilization cycles using 450 IU and 600 IU gonadotropin per day in women at risk of poor ovarian response. Prospective randomized controlled nonblinded study. University-affiliated private IVF center. Women considered to be at risk of poor ovarian response: aged <41 years with basal FSH >10 IU/L, antimüllerian hormone <1 ng/mL, antral follicle count ≤ 8, or a previous IVF cycle with ≥ 300 IU/d gonadotropin that resulted in a cancellation, <8 follicles, or <5 oocytes. A total of 356 patients underwent a microdose GnRH agonist flare-up IVF/intracytoplasmic sperm injection protocol with a fixed daily dose of either 450 IU FSH (n = 176) or 600 IU FSH (n = 180) equally divided between Menopur and Bravelle. Number of mature oocytes retrieved. The two groups were similar in terms of age, ovarian reserve, cause of infertility, duration of stimulation, and cycle cancellation rate. There were no significant differences in the number of metaphase II oocytes retrieved (4 [range 0-6] vs. 4 [range 2-7]), fertilization rate (62.4% vs. 57.0%), biochemical pregnancy rate (20.5% vs. 22.9%), clinical pregnancy rate (16.4% vs. 18.3%), and implantation rate (29.8% vs. 30.4%) between the 450 IU and 600 IU groups, respectively. Gonadotropin of 600 IU/d does not improve outcome of IVF cycles compared with 450 IU/d in women at risk of poor ovarian response. NCT00971152.

Growth Hormone Supplementation in the Luteal Phase Before Microdose GnRH Agonist Flare Protocol for In Vitro Fertilization

Growth hormone (GH) acts in both early and late follicular development to stimulate the proliferation and differentiation of granulosa cells and to increase the production of estradiol in animal and human ovaries. Investigators have therefore explored GH supplementation to improve outcomes in women undergoing in vitro fertilization, with the greatest interest in women with diminished ovarian reserve. Recent meta-analyses indicate that GH supplementation can be beneficial for poor responders undergoing IVF. In most studies, GH has been given concomitantly with gonadotropins during the follicular phase; this may not be optimal, since follicular recruitment begins during the preceding luteal phase. We therefore wished to examine the effect of GH supplementation in the luteal phase before controlled ovarian stimulation (COH) with a microdose GnRH agonist flare (MDF) protocol in women undergoing in vitro fertilization. We performed a retrospective matched case-control study of patients undergoing treatment at a private IVF facility between June 2012 and July 2013. Patients identified as poor responders to COH were offered adjuvant GH treatment as part of their ovarian stimulation regimen. The patients in the experimental group chose to take GH, 3.33 mg daily by subcutaneous injection for 14 days, before starting COH. All patients had an MDF stimulation protocol using 450 IU of follicle stimulating hormone (FSH) daily. A total of 42 women were included in the study. There were 14 women in the experimental group (GH) and 28 controls (C) matched for age, BMI, and day 3 FSH level. There was no difference between the groups in clinical pregnancy rate (GH = 29%, C = 32%, P = 0.99), number of mature oocytes retrieved (GH = 2.5, C = 5.0, P = 0.13), cycle cancellation rate (GH = 21%, C = 14%, P = 0.88), duration of COH (GH = 10.1, C = 10.1, P = 0.93), or mean peak estradiol level (GH = 4174 pmol/L, C = 5105 pmol/L, P = 0.44). The administration of growth hormone during the luteal phase before a microdose GnRH agonist flare protocol for in vitro fertilization did not improve outcomes in "poor responder" patients.

Changing ovarian stimulation parameters in a subsequent cycle does not increase the number of euploid embryos

To compare the euploidy outcome in patients that underwent 2 ovarian stimulation cycles with trophectoderm biopsy. Retrospective repeated-measures cohort study. University-based fertility center. A total of 116 patients, from 2011 through 2013, that underwent 2 ovarian stimulation cycles followed by trophectoderm biopsy with array comparative genomic hybridization. Days of stimulation, average diameter of the 2 lead follicles on day of trigger, dose of gonadotropins, type of cycle (gonadotropin-releasing hormone [GnRH] antagonist, GnRH-antagonist plus clomiphene citrate [CC], microdose GnRH agonist). Number of euploid embryos. Patients were analyzed based on whether they had ≥1 euploid embryos in their first cycle vs. none. There was no increase in the number of euploid embryos with more days of stimulation or increases in the dose of gonadotropins in either group. Significantly more euploid embryos were seen in patients who had no euploid embryo(s) in the first cycle (Group 0) that had CC added to a GnRH-antagonist cycle (1.11 more euploid embryos) or were triggered when follicle sizes were 2 mm larger (0.40 euploid embryos), but these increases were not significant compared with a control group. Patients with euploid embryo(s) in the first cycle (Group 1) had significantly more euploid embryos when daily dose was increased by 75-149 international units, but this relationship was not significant compared with a control group with no increase in daily dose. No specific intervention increased the number of euploid embryos within the same patient any more than simply repeating a similar stimulation cycle. An attempt was made to control for interpatient variability, but individual patients have considerable intercycle variability.

Comparison between Micro-Dose GnRH Agonist and GnRH Antagonist Protocol in Poor Responders Undergoing Intracytoplasmic Sperm Injection with Embryo Transfer

Objective: To compare the effect of the multiple-dose GnRH antagonist protocol with the microdose GnRH agonist flare-up (MF) protocol in poor ovarian responders for ICSI. Design: Retrospective, Clinical study. Setting:IVF center. Patient(s): Two hundred eighty-six poor responder patients undergoing ICSI-embryo transfer cycle. Intervention(s): one hundred Forty four patients (144 cycles) included in group 1 (microdose GnRH-a flare-up protocol) and one hundred fourty two patients (42 cycles) included in group 2 (multiple dose GnRH antagonist protocol). Main Outcome Measure(s): Serum E2 levels, number of growing follicles and mature oocytes, embryo quality, dose of gonadotropin used, cancellation, fertilization, implantation rate, pregnancy rate (PR) and live birth rate (LR). Results: Total gonadotropin dose used was significantly lower (2730235,45 vs 3189317,81; P<0.05), duration of stimulation was significantly longer and E2 level was significantly higher in group 1. The mean number of oocytes retrived, mature oocytes retrived, embryos transferred and the rate of at least one top-quality embryo transferred was similar in the two groups. The implantation rate was significantly higher in the microdose flare-up group than in the multiple-dose antagonist group (18.79% vs 8.28%; P<.001). Clinical pregnancy and live birth rates were similar in the two groups. Conclusion(s): We achieved comparable pregnancy and live birth rates in poor responders with the use of either GnRH antagonist or flare protocol. However, a significantly higher gonadotropin dose used and lower implantation rate in the antagonist group tips the balance in favor of the flare-up protocol.

Comparison of estradiol and progesterone priming/antagonist/letrozole and microdose flare-up protocols for poor responders undergoing intracytoplasmic sperm injection

Background: To compare the effect of the GnRH antagonist/letrozole/gonadotropin protocol with the microdose GnRH agonist flare-up protocol in poor ovarian responders for intracytoplasmic sperm injection.Materials and methods: One hundred twenty-one consecutive patients suspected of having or with a history of poor ovarian response between January 2009 and June 2010, who were undergoing ICSI were enrolled. The microdose flareup (MF) protocol was used in 79 patients and the estradiol + progesterone/letrozole + gonadotropin and GnRH antagonist (EP/ALG) protocol was used in 42 patients.Results: Age of the patients, duration of infertility, basal FSH, the total gonadotropin consumption, duration of stimulation, E2 level on the day of hCG administration, the number of embryo transferred, the fertilization rate, implantation rate, clinical pregnancy rate and the live birth rate were not statistically different (p > 0.05). Only the number of oocytes retrieved was significantly higher in the EP/LGA group (1.7 ± 0.7 versus 2.6 ± 0.6).Conclusion: The EP/LGA protocol has no significant improvement against the microdose flare-up protocol in poor responder patients.

Growth Hormone Supplementation in the Luteal Phase Prior to Microdose GnRH Agonist Flare Protocol for In Vitro Fertilization

Growth hormone (GH) acts in both early and late follicular development to stimulate the proliferation and differentiation of granulosa cells and increase the production of estradiol in animal and human ovaries1-3. Fertility specialists have therefore explored the potential for GH supplementation to improve outcomes in women undergoing in vitro fertilization (IVF), with the greatest interest in women with diminished ovarian reserve, for whom successful fertilization remains a therapeutic challenge4.

Microdose GnRH agonist flare-up versus flexible GnRH antagonist protocol in poor responders undergoing in-vitro-fertilization (IVF) cycles: a randomized controlled trial

Optimal stimulation protocol for poor responders remains undefined. The aim of this study was to compare the efficacy of microdose flare-up GnRH agonist (GnRH-a) and multiple dose flexible GnRHantagonist protocols in poor responders.

Comparison of microdose GnRH agonist protocol with GnRH antagonist / letrazole protocol in patients with poor ovarian response

Objective: To compare microdose GnRH agonist (MDL) protocol with GnRH antagonist/letrazole (AL) protocol in patients with poor ovarian response. Design: Randomised clinical trial. Setting: Kocaeli University Assisted Reproductive Centre Patients: Fifty-five patients with the diagnosis of poor ovarian response (POR) were randomized and performed either MDL or AL protocol. Interventions: POR was diagnosed according to ESHRE Bologna criteria in case of presence of 2 out of 3 criteria. In the MDL group (n=27), 40µg/0.2 cc subcutaneous leuprolid acetate was given two times a day starting on the first day of menstrual cycle. On the second day of the cycle, gonadotrophin stimulation was started at 450-600 IU and/or 150 IU human menopausal gonadotrophin (hMG) along with leuprolid. In the AL group (n=28), 5 mg letrazole was given for 5 days starting on the second day of the spontaneous cycle and after the 5th day of the cycle, 450-600 IU and/or 150 IU hMG was given. Main Outcome Measures: To compare the outcomes of MDL protocol with AL protocol in patients with poor ovarian response. Results: Stimulation days, total gonadotrophin dose (IU), peak E2 (pg/ml) levels, and endometrial thickness were found to be statistically significantly lower in the AL group. While no cases of cycle cancellation was detected in the MDL group, statistically significantly higher rates of cycle cancellation (%42.8, p<0.001) was detected in the AL group. No statistically significant differences were detected in total oocyte numbers (3.7±2.9 vs 2.7±2.2), number of transferred embryos (1.4±0.5 vs 1.4±1.9) and pregnancy rates (3 vs 2) in between the groups. Comment: Although AL protocol is not superior to MDL protocol in poor ovarian response patients, it may be used as an alternative protocol.

Minimal stimulation protocol using letrozole versus microdose flare up GnRH agonist protocol in women with poor ovarian response undergoing ICSI

Background: To compare the IVF outcomes of letrozole/antagonist and microdose GnRH agonist flare up protocols in poor ovarian responders undergoing intracytoplasmic sperm injection. Materials and methods: A randomized controlled trial was performed in patients with one or more previous failed IVF cycles in which four or less oocytes were retrieved when the gonadotrophin starting dose was at least 300 IU/day. Sixty patients were randomized by computer-generated list to receive either letrozole/antagonist (mild stimulation) n = 30 or GnRH-a protocol (microdose flare) n = 30. Results: Both groups were similar with respect to background and hormonal characteristics (age, duration of infertility, BMI, FSH, LH and E2). The clinical pregnancy rate per cycle was similar in both groups (13.3 vs. 16.6%; OR = 0.769; 95% CI = 0.185, 3.198). The doses of used gonadotropins and the number of stimulation days were significantly lower in the letrozole/antagonist protocol. The peak E2 level on the day of hCG, the endometrial thickness, the retrieved oocytes, the number of fertilized oocytes, the number of transferred embryos and the cancellation rate were statistically similar in both groups. Conclusions: The letrozole/antagonist protocol is a cost-effective and patient-friendly protocol that may be used in poor ovarian responders for IVF/ICSI.

Microdose GnRH agonist flare protocol results in lower incidence of chromosome aneuploid blastocysts

The aim of this study was to evaluate two ovarian stimulation protocols utilized for compromised responders, the luteal phase estradiol priming GnRH antagonist regime and the microdose GnRH agonist flare regime, in relation to the chromosome constitution of the resulting blastocysts.

Comparison of mild and microdose GnRH agonist flare protocols on IVF outcome in poor responders

To compare the IVF outcome of clomiphene citrate/gonadotropin/antagonist (mild protocol) and microdose GnRH agonist flare protocols for poor responders undergoing in vitro fertilization. 159 poor responder patients were randomized and ovarian stimulation was performed with clomiphene citrate, gonadotropin and antagonist (group I) or microdose GnRH agonist flare (group II) protocols. Main outcome was clinical pregnancy rate and secondary outcomes were doses of gonadotropin administration and duration of stimulation. There were no significant differences in age, causes of infertility, basal FSH, BMI, duration of infertility, E(2) level on the day of hCG injection in both groups. Although the cancellation, fertilization, and clinical pregnancy rates were similar in both groups, the endometrial thickness, number of retrieved oocytes, mature oocytes and implantation rate were significantly higher in mild protocol. The doses of gonadotropin administration and duration of stimulation were significantly lower in mild protocol. We recommend mild protocol in assisted reproductive technology cycles for poor responders based on our results regarding less doses of used gonadotropin and a shorter duration of stimulation.

Microdose gonadotropin-releasing hormone agonist in the absence of exogenous gonadotropins is not sufficient to induce multiple follicle development

Because the effectiveness of the "microdose flare" stimulation protocol often is attributed to the dramatic endogenous gonadotropin release induced by the GnRH agonist, the aim of this study was to determine whether use of microdose GnRH agonist alone could induce multiple ovarian follicle development in normal responders. Based on these data, the duration of gonadotropin rise is approximately 24 to 48 hours and is too brief to sustain continued multiple follicle growth.

Comparison of luteal estradiol patch and gonadotropin-releasing hormone antagonist suppression protocol before gonadotropin stimulation versus microdose gonadotropin-releasing hormone agonist protocol for patients with a history of poor in vitro fertilization outcomes

To compare IVF outcomes in poor-responder patients undergoing stimulation after luteal phase E(2) patch/GnRH antagonist (LPG) protocol versus microdose GnRH agonist protocol. Retrospective analysis. University-based IVF center. Forty-five women undergoing ovarian stimulation for IVF using the LPG protocol were compared with 76 women stimulated with the microdose GnRH agonist protocol from May 2005 to April 2006. Cancellation rate, number of oocytes retrieved, and clinical pregnancy rates. The mean number of oocytes (9.1 +/- 4.1 vs. 8.9 +/- 4.3) and mature oocytes (6.7 +/- 3.5 vs. 6.8 +/- 3.1) retrieved were similar, as were the fertilization rates (70.0% +/- 24.2% vs. 69.9% +/- 21.5%) and the number of embryos transferred (2.5 +/- 1.1 vs. 2.7 +/- 1.3). The cancellation rate was not significantly different between the groups (13/45, 28.9% vs. 23/76, 30.3%). Likewise, there were no significant differences among the implantation rate (15.0% vs. 12.5%), clinical pregnancy rate (43.3% vs. 45.1%), and ongoing pregnancy rate per transfer (33.3% vs. 26.0%) between both groups. This study demonstrates that the use of an E(2) patch and a GnRH antagonist during the preceding luteal phase in patients with a history of failed cycles can provide similar IVF outcomes when compared with the microdose GnRH agonist protocol.

Antagonist/letrozole protocol in poor ovarian responders for intracytoplasmic sperm injection: a comparative study with the microdose flare-up protocol

To compare the effect of the GnRH antagonist/letrozole protocol (AL) with the microdose GnRH agonist flare-up (MF) protocol in poor ovarian responders for intracytoplasmic sperm injection (ICSI). Retrospective, case-control study. Anatolia Women and IVF Center. Eight hundred eighty-five consecutive patients (1383 cycles) predicted to have or with a history of poor ovarian response who were undergoing ICSI were enrolled. The MF protocol was used in 673 patients (1026 cycles), and the AL protocol was used in the remaining 212 patients (357 cycles). Controlled ovarian hyperstimulation and ICSI. Cycle cancellation rate, number of oocytes retrieved, fertilization rate, embryo quality, clinical pregnancy, and implantation rates. The total gonadotropin consumption, duration of stimulation, E(2) level on the day of hCG administration, and number of oocytes retrieved were significantly lower with the AL protocol compared with the MF protocol. However, the fertilization rate and the rate of at least one top-quality embryo transferred were higher with the AL compared with the MF protocol. The clinical pregnancy rates were comparable between the two groups. The implantation rates with the MF and AL protocols were 9.8% and 14.5%, respectively. The GnRH AL protocol is an effective protocol that may be used in poor ovarian responders for ICSI.

Microdose gonadotropin-releasing hormone agonist flare-up protocol versus multiple dose gonadotropin-releasing hormone antagonist protocol in poor responders undergoing intracytoplasmic sperm injection–embryo transfer cycle

To compare the efficacy of microdose GnRH agonist (GnRH-a) flare-up and multiple dose GnRH antagonist protocols in patients who have a poor response to a long luteal GnRH-a protocol. Prospective, randomized, clinical study. University hospital. Forty-two poor responder patients undergoing intracytoplasmic sperm injection (ICSI)-embryo transfer cycle. Twenty-one patients received microdose leuprolide acetate (LA) (50 microg twice daily) starting on the second day of withdrawal bleeding. The other 21 patients received 0.25 mg of cetrorelix daily when the leading follicle reached 14 mm in diameter. Serum E(2) levels, number of growing follicles and mature oocytes, embryo quality, dose of gonadotropin used, cancellation, fertilization, implantation rate and pregnancy rate (PR). The mean serum E(2) concentration on the day of hCG administration was significantly higher in the microdose GnRH-a group than in the GnRH antagonist group (1,904 vs. 1,362 pg/mL). The clinical PRs per started cycle of microdose GnRH-a and GnRH antagonist groups were 14.2% and 9.5%, respectively. There were no statistically significant differences in the other ovulation induction characteristics, fertilization and implantation rates. Microdose GnRH-a flare-up protocol and multiple dose GnRH antagonist protocol seem to have similar efficacy in improving treatment outcomes of poor responder patients.

Is Microdose GNRH Agonist in the Absence of Exogenous Gonadotropins Sufficient to Achieve Multiple Ovarian Follicle Development?

Background: The “microdose flare” protocol, commonly used in poor responders, is considered to be one of the most aggressive regimens for controlled ovarian hyperstimulation. Although exogenous gonadotropins are typically added on the third day of treatment, effective ovarian stimulation has largely been attributed to endogenous gonadotropin release induced by the GnRH agonist. Animal studies have demonstrated that low doses of GnRH agonist alone achieve FSH levels which surpass the threshold required for multiple follicle growth.

The effect of luteal phase vaginal estradiol supplementation on the success of in vitro fertilization treatment: a prospective randomized study

To determine whether the use of luteal phase vaginal E(2) supplementation improves clinical pregnancy rates in patients undergoing IVF treatment. Prospective randomized controlled trial. University-based tertiary fertility center. One hundred sixty-six patients undergoing their first cycle of IVF treatment. Patients underwent three different protocols for controlled ovarian hyperstimulation for IVF treatment with long GnRH agonist suppression, use of GnRH antagonist, or a microdose GnRH agonist protocol. Luteal phase support was in the form of IM P. Patients randomized into the study group (n = 84) received E(2) supplementation in the form of vaginal estrace 2 mg twice a day starting on the day of ET. Patients randomized to the control group (n = 82) received no E(2) supplementation. Clinical pregnancy rates. There were no significant differences in the implantation (56/210 [26.7%] vs. 64/203 [31.5%]), clinical pregnancy (42/84 [50%] vs. 52/82 [63.4%]), and ongoing pregnancy rates (40/84 [47.6%] vs. 46/82 [56.1%]) between the study and control groups, respectively. In the subgroup of patients who used the long GnRH agonist suppression protocol, there was a lower clinical pregnancy rate in the study group compared with the control group (27/55 [49.1%] vs. 42/59 [71.2%]). There were, however, no differences in clinical pregnancy rates between the two groups in patients who used either the GnRH antagonist or microdose GnRH agonist protocols. The addition of vaginal E(2) supplementation to routine P supplementation for luteal support does not improve the probability of conception after IVF treatment.

Management of poor responders: can outcomes be improved with a novel gonadotropin-releasing hormone antagonist/letrozole protocol?

To compare the efficacy of a microdose GnRH agonist flare (ML) with a GnRH antagonist/letrozole (AL) protocol before IVF-ET in poor responders. Prospective controlled trial. Private assisted reproductive technology center. Five hundred thirty-four infertile women classified as past or potential poor responders based on clinic-specific criteria. Poor responders were prospectively assigned to an ML or AL protocol in a 2:1 ratio, respectively. Results of controlled ovarian hyperstimulation and implantation and ongoing pregnancy rates. Patient characteristics were similar between the two protocol groups. There were no significant differences in mean age, number of oocytes, fertilization rates, number of embryos transferred, or embryo score. Peak E(2) levels were significantly lower in the AL group. Ongoing pregnancy rates were significantly higher in the ML group (52% vs. 37%). Trends toward increased implantation and lower cancellation rates were also noted, but these did not reach statistical significance. Quantitative results of stimulation between the ML and AL protocols were equivalent with the exception of peak E(2) levels. However, the higher ongoing pregnancy rates and trend toward superior implantation rates would suggest that ML represents a preferred approach for the poor responder. An increased sample size would be necessary to verify these findings.

“Ovarian age-based” stimulation of young women with diminished ovarian reserve results in excellent pregnancy rates with in vitro fertilization

To determine whether pregnancy outcome can be positively affected if the ovarian stimulation in women with diminished ovarian reserve (DOR) is changed. Case control study. Medical school-affiliated private infertility center. Sixty-two women, aged 26-35 years, with the diagnosis of DOR (study group) and 62 age-matched controls with apparently normal ovarian function (control group). Study group patients received a modified (ovarian age-based) stimulation with microdose GnRH agonist (GnRH-a) and 450-600 IU of gonadotropin daily. Women in the control group received a standard "chronological age-based" stimulation with long luteal phase GnRH-a and up to 300 IU of gonadotropins (two patients in this group received an antagonist in place of an agonist). The IVF cycle outcome parameters, including pregnancy rates (PR). Women with DOR and controls did not differ significantly in patient profiles or underlying infertility conditions and received identical embryo numbers at transfer. The DOR patients demonstrated a strong trend toward lower gravidity. Peak E(2) levels were similar between groups but controls produced significantly more oocytes, a strong trend toward more embryos and significantly more cycles of cryopreservation. Both groups achieved a 47% rate of first positive pregnancy test (hCG), with controls demonstrating a 39% and DOR patients a 32% ongoing PR. Women with DOR, if treated with an ovarian age-based rather than chronological age-based ovarian stimulation protocols, will demonstrate surprisingly good PR with IVF in comparison to women with normal ovarian function.