Luteal phase support with GnRH agonist does not eliminate the risk for ovarian hyperstimulation syndrome

Abstract

This study aims to report a case of early, severe ovarian hyperstimulation syndrome (OHSS) following GnRH agonist trigger for final oocyte maturation despite luteal support with a GnRH agonist. Contrary to the claim that luteal support using a GnRH agonist eliminates the risk for OHSS in high-risk patients, this report alerts practitioners to the risk of severe OHSS development despite GnRH agonist luteal support in patients receiving GnRH antagonist protocol with GnRH agonist triggering and cautions the practitioners to consider other measures of OHSS prevention.     

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

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

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

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

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

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.     

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.     

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.     

Triggering with HCG or GnRH agonist in GnRH antagonist treated oocyte donation cycles: a randomised clinical trial

Aim.?To compare donor and recipient outcome after inducing the final oocyte maturation with hCG or GnRH agonist in GnRH-antagonist treated oocyte donation (OD) cycles.

Methods.?Two-hundred fifty-seven oocyte donors were enrolled to participate in a clinical trial in a private fertility centre. After stimulation with 225 IU rFSH and Cetrorelix 0.25 mg/day, 212 oocyte donors were randomised with sealed envelopes for triggering with recombinant hCG (Ovitrelle 250 μgr, n = 106) or a GnRH agonist (triptorelin 0.2 mg, n = 106).

Results.?The number of retrieved COCs (12 ± 6.3 vs 11.4 ± 6.4), mature oocytes (8 ± 4.6 vs 7.5 ± 4.1), the proportion of mature oocytes (67.2 ± 20.4% vs 67.1 ± 20.9%) and fertilisation rates (67.8 ± 23.5% vs 71.1 ± 22.1%) were comparable. Clinical, ongoing pregnancy and live birth rates were not statistically different in the corresponding recipient groups. Nine cases of mild and one case of severe OHSS occurred in hCG group, whereas no cases were detected in GnRH agonist group.

Conclusions.?The findings of our RCT suggest that donor and recipient outcome are comparable in OD cycles triggered with hCG or a GnRH agonist. Furthermore, the risk of OHSS seems to be reduced considerably, therefore the combination of a GnRH antagonist protocol with GnRH agonist triggering constitutes a safe treatment option for egg-donors.     

Luteal phase support with estradiol and progesterone versus progesterone alone in GnRH antagonist ICSI cycles: a randomized controlled study

In vitro fertilization (IVF) cycles are associated with a defective luteal phase. Although progesterone supplementation to treat this problem is standard practice, estrogen addition is debatable. Our aim was to compare pregnancy outcomes in 220 patients undergoing antagonist intracytoplasmic sperm injection (ICSI) cycles protocol. The patients were randomly assigned into two equal groups to receive either vaginal progesterone alone (90?mg once daily) starting on the day of oocyte retrieval for up to 12 weeks if pregnancy occurred or estradiol addition (2?mg twice daily) starting on the same day and continuing up to seven weeks (foetal viability scan). Primary outcomes were pregnancy and ongoing pregnancy rates per embryo transfer. Secondary outcomes were implantation and early pregnancy loss rates. Pregnancy rates showed no significant difference between group 1 (39.09%) and 2 (43.63%) (p value?=?0.3). Similarly, both groups were comparable regarding ongoing pregnancy rate (32.7% group 1 and 36.3% group 2, p value?=?0.1). Implantation rates showed no difference between group 1 (19.25%) and group 2 (23.44%) (p value?=?0.2). Early pregnancy loss rates were comparable, with 6.3% and 7.2% in groups 1 and 2, respectively, (p value?=?0.4). In conclusion, the addition of 4?mg estrogen daily to progesterone for luteal support in antagonist ICSI cycles is not beneficial for pregnancy outcome.     

Ovulation triggering with GnRH agonist vs. hCG in the same egg donor population undergoing donor oocyte cycles with GnRH antagonist: a prospective randomized cross-over trial

Objective  To compare fertilization, implantation and pregnancy rates in donor oocyte cycles triggered for final oocyte maturation with either human chorionic gonadotropin (hCG) or gonadotropin releasing hormone (GnRH) agonist in the same donor population in two sequential stimulation cycles. Design  Prospective randomized cross-over trial. Setting  Private infertility clinic. Patient(s)  Eighty-eight stimulation cycles in 44 egg donors. Interventions  Controlled ovarian hyperstimulation (COH) with GnRH antagonist protocol triggered with hCG or GnRH agonist (leuprolide acetate 0.15 mg) in the same egg donors in two consecutive cycles. Main outcome measure(s)  The primary outcome measure was the proportion of mature and fertilized oocytes per donor cycle. Secondary outcome measures were implantation and pregnancy rates in the recipients and incidence of ovarian hyperstimulation syndrome (OHSS) in oocyte donors. Result(s)  The proportion of mature oocytes, fertilized oocytes and mean embryo scores were comparable between the two triggering agents. While implantation (36.53% vs, 32.93%), pregnancy (69.08% vs. 68.81%) and clinical pregnancy (41.3% vs. 40.2%) rates were comparable for the groups, the incidence of OHSS was significantly lower in GnRH than in hCG triggered cycles. Conclusion(s)  Fertilization, implantation and pregnancy rates from donor oocytes stimulated with GnRH antagonist protocol were identical for donor cycles triggered with hCG and GnRH agonist. GnRH antagonist triggering in egg donors was associated with lower rates of OHSS. This is the first prospective randomized cross-over study supporting the hypothesis that GnRH agonist is an effective alternative to hCG for the final oocyte maturation in oocyte donor cycles and should be the method of choice, especially for donors with evident risk factors for OHSS.     

GnRH agonist versus GnRH antagonist in IVF/ICSI cycles with recombinant LH supplementation: DNA fragmentation and apoptosis in granulosa cells

Objective

To compare the level of apoptosis and DNA fragmentation in the human granulosa cell (GC) layer exposed to an agonist or antagonist of GnRH in intracytoplasmic sperm injection (ICSI) cycles supplemented with recombinant LH (rLH).

Study design

Patients without ovulatory dysfunction, aged ≤37 years and in their first ICSI cycle were prospectively randomised to receive either a long GnRH agonist protocol or a multi-dose antagonist protocol. In both groups, recombinant FSH supplemented with rLH was used for ovarian stimulation, and the GCs were collected during oocyte denudation. The GCs were then analysed for DNA fragmentation by TUNEL assay and for apoptosis using the annexin-V assay. The outcomes were given as the percentage of GCs with DNA fragmentation and apoptosis out of the total number of GCs analysed. Comparison of the agonist versus the antagonist group was performed using the Mann–Whitney test.

Results

DNA fragmentation: 32 patients were included in either the GnRH agonist group (n = 16) or the antagonist group (n = 16). The percentage of GCs with positive DNA fragmentation did not differ significantly (P = 0.76) between the agonist group (15.5 ± 9.4%) and the antagonist group (18.8 ± 13.3%). Apoptosis: 28 patients were included in either the GnRH agonist group (n = 14) or the antagonist group (n = 14). The percentage of GCs positive for apoptosis did not differ significantly (P = 0.78) between the agonist group (34.6 ± 14.7%) and the antagonist group (36.5 ± 22%).

Conclusions

The results suggest that therapy with either an agonist or antagonist of GnRH is associated with comparable levels of DNA fragmentation and apoptosis in granulosa cells in ICSI cycles supplemented with rLH.     

Comparison of ovarian stimulation regimens for in vitro fertilization (IVF) with and without a gonadotropin-releasing hormone (GnRH) agonist: Results of a randomized study

In order to diminish the cancellation rate due to a premature endogeneous LH surge and/or to a poor ovarian response and thus increasing the pregnancy rate, a GnRH agonist (Buserelin) was applied in patients starting their first ovarian stimulation with gonadotropins for IVF. All patients suffered from tubal infertility and were not older than 40 years. Each woman was allocated randomly to one of three groups: the conventional treatment with hMG alone (group I), patients from group II started the hMG treatment shortly after the LH rise caused by the GnRH agonist and patients in group III commenced the hMG treatment when an hypogonadotropic state was achieved after a long treatment of Buserelin. All male partners had a normal spermiogram. A reduction of poor responders to the superovulation is seen in the short-term group (6%), compared with the other two groups (14%). In some cases from group III ovarian cyst formation led to the cancellation of the treatment. The long-term group differs significantly from the other two in the duration of the gonadotropin stimulation and the number of ampoules hMG used. A severe ovarian overstimulation syndrome was not observed. There is no difference in the number of retrieved oocytes and the fertilization rate among the three groups. The pregnancy rate per cycle or per patients in the group with a short-term GnRH-agonist regimen is significantly higher compared to that of the group using the conventional hMG treatment.     

Triggering with GnRH agonist in oocyte-donation cycles: oestradiol monitoring is not necessary during ovarian stimulation

This prospective observational study evaluated the efficacy and safety of oocyte-donation cycles triggered with a gonadotrophin-releasing hormone (GnRH) agonist without monitoring oestradiol concentrations during ovarian stimulation. A total of 97 oocyte donors received recombinant FSH (150-225/day) and GnRH antagonists (0.25mg/day). Oocyte maturation was triggered with 0.2mg triptorelin s.c. Donors aged 25.4 ± 4.1 years were stimulated for 8.8 ± 0.9 days and underwent 2.9 ± 0.5 (2-4) ultrasound assessments. Total FSH dose was 1703.4 ± 304.7IU, antagonists were administered for 4.3 ± 1.0 days, 14.7 ± 8.8 oocytes were retrieved and there were no cases of ovarian hyperstimulation syndrome. Recipients (n=123) aged 40.3 ± 3.4 years received 10.9 ± 4.3 oocytes, 88.7% of which were metaphase II. Intracytoplasmic sperm injection fertilization rate was 79% and 2.18 ± 0.6 (1-3) embryos were transferred. The pregnancy, clinical pregnancy and twin pregnancy rates were 64.2%, 57.7% and 19.7%, respectively. In conclusion, given the high efficacy and safety of the GnRH-antagonist protocol triggered with a GnRH agonist, the monitoring of oestradiol concentrations is not necessary. Ultrasound monitoring is enough for an adequate follow up of the stimulation cycle in oocyte donors.     

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.     

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.