GnRH Agonist Trigger Research Articles

Gnrh agonist with low-dose hCG co-trigger is associated with higher risk of severe OHSS than GnRH agonist alone

Use of a gonadotropin-releasing hormone (GnRH) antagonist protocol with GnRH agonist (GnRHa) trigger for final oocyte maturation is the most effective strategy to reduce the rate of ovarian hyperstimulation syndrome (OHSS) during IVF. However, concerns persist regarding GnRHa trigger and ART outcomes. Use of a combination GnRHa and low-dose human chorionic gonadotropin (hCG) co-trigger has been reported to reduce OHSS and preserve IVF outcomes. The objective of this study was to examine the impact of final oocyte maturation method (GnRHa v co-trigger) on OHSS, oocyte yield and maturity.

Hcg verus agonist trigger in donor oocyte cycles: does hCG have a place in current practice?

The use of GnRH agonist trigger has been shown to reduce OHSS. However in autologous ART, previous meta-analysis suggested GnRH agonist trigger might lower clinical outcomes when compared to hCG trigger. Reducing the risk of OHSS without compromising pregnancy outcomes is of paramount importance in donor oocyte ART. Thus we compared clinical outcomes between donors receiving hCG or GnRH agonist triggers.

The reproducibility of luteinizing hormone surges following agonist trigger: analysis of 1792 agonist triggers

GnRH agonist trigger is frequently used to reduce OHSS risk in high responders on antagonist protocols. It has been reported that oocyte quality is related to the pituitary response of luteinizing hormone (LH) “surge”. We examine the reproducibility of LH surges in repeated cycles in the same subjects.

Dual trigger with GnRH agonist (GnRHa) and varying doses of hCG increases the blastulation rate amongst high responders

GnRHa trigger reduces ovarian hyperstimulation syndrome (OHSS) risk while maintaining acceptable clinical outcomes. The importance of sufficient LH stimulation is evidenced by improved oocyte yield and outcomes when adding hCG. However, there are little data addressing the issue as to whether the addition of an agonist induced FSH surge increases yield, or whether the presence of the endogenous surge allows a reduction in hCG without diminishing outcomes. This study evaluates the outcomes in GnRH-a trigger cycles with varying dose of hCG augmentation, comparing them to cycles triggered with hCG alone to determine if a dual trigger benefits high responders.

Factors predicting oocyte maturation in high responders undergoing controlled ovarian hyperstimulation

Oocyte donors and women electing fertility preservation are at increased risk of developing ovarian hyperstimulation syndrome (OHSS). Different strategies are used to lower the risk, such as decreasing the hCG dose or using gonadotropin releasing hormone agonist (GnRHa) as an alternative to hCG. However, trigger failures can occur when using GnRHa alone. Alternatively, adding low dose hCG to GnRHa may allow a decreased incidence of OHSS while avoiding trigger failures. Retrospective chart review of oocyte donation and fertility preservation cycles using GnRHa and long luteal protocols between 01/01/10 and 02/02/14. 364 total IVF/ICSI cycles were analyzed. Oocyte maturity was induced by either GnRHa, hCG, or GnRHa plus 1500IU hCG. Correlation of post trigger LH and hCG levels to maturation parameters were assessed in 199 cycles. Spearman’s correlation assessed correlation between post-GnRHa trigger LH with proportion of total and mature oocytes retrieved as well as fertilization. 1-way ANOVA was used to compare oocyte maturation between each different trigger. All 3 failed triggers were with GnRHa only. No OHSS developed after GnRHa plus 1500IU hCG. No difference was noted in proportion of metaphase II (MII) oocytes to mature size follicles measured on day trigger, MII oocytes to total oocytes retrieved, or the number of 2 pronuclei (2PN) to total oocytes retrieved between those that were triggered with either hCG, GnRHa, or GnRHa plus 1500IU hCG. No difference was appreciated in the same proportions when comparing hCG trigger dose of 10000, 5000, and 3300 IU. There was a significant negative correlation of the LH level post-GnRHa plus hCG trigger to the proportion of 2PN and oocytes retrieved (p = 0.046) but not with GnRHa alone. No other significant correlations were found between parameters of oocyte maturity and post trigger LH.Tabled 1Characteristics based on triggerVariableshCG onlyGnRHa onlyGnRHa + hCGP valueAge24.9±2.826.7±4.226.3±4.10.079AFC24.6±9.928.9±9.829.1±9.50.004Follicles >13mm18.7±5.726.1±7.924.2±6.4<0.001# MII19.9±8.825.8±12.024.8±12.50.063Maturity(MII/ follicles >13mm)1.07±0.391.03±0.351.02±0.370.831Fertilization (2PN/total oocytes retrieved)0.67±0.160.63±0.160.65±0.190.453Mean ± STD Open table in a new tab Mean ± STD Adding low dose hCG to a GnRHa trigger may allow a decrease in OHSS incidence, and appears to not compromise oocyte maturity while avoiding failed oocyte maturation. Using this alternative form of trigger appears to be most optimal for donor and fertility preservation cycles that are at very high risk of developing OHSS.

Optimal usage of dual trigger to prevent OHSS in a long-protocol IVF cycle

When a patient undergoing an long protocol IVF cycle has high risk of severe OHSS, rescuing the cycle by withdrawing the agonist, replacing (adding) it with an antagonist and triggering with a GnRH agonist has been considered. However, we underwent lower the number of oocytes retrieval in GnRH agonist trigger group. Therefore we aimed to compare outcomes between trigger with GnRH agonist and dual trigger (GnRH agonist and low dose hCG). In addition, optimal hCG dosage is investigated in dual trigger with combination of gonadotropin-releasing hormone agonist and human chorionic gonadotropin. A prospective clinical study. We evaluated total 26 high responder patients with a long protocol during 2009∼2013. We monitored by measuring the follicle number and serum E2 level on day 7 of the cycle. On the first day of monitoring, we observed that serum E2 was 500∼1500pg/mL and 10∼20 follicles were >10mm in each ovary. For these patients, we applied that agonist was interrupted and the antagonist (0.25mg/day) administrated 1-3 times (depending on a patients) until the day of hCG trigger. When at least two follicles had reached 18mm diameter, final follicular maturation was induced with GnRH agonist (Group I, n=7), dose of 1000 IU hCG and GnRH agonist (Group II, n=8) or 2000 IU hCG and GnRH agonist (Group III, n=10). The number of retrieved oocytes in Group I was significantly lower than those in Group II and Group III (4.7±1.5 vs. 10.0±3.7 vs. 20.2±6.8, p<0.01). The oocyte retrieval rate was the highest the Group III (p<0.01). However, no significant difference was observed in fertilization rate (66.7% vs. 67.5% vs. 61.4%) and cleavage rate (86.4% vs. 90.7% vs. 93.5%). Clinical pregnancy rate was significantly higher in group II (75.0%) and III (70.0%) than that in group I (14.3%, P<0.05) However, group II and III didn’t find significant differences. And there was 1 case of mild OHSS in the group III but none in the group II. For higher responders of a long protocol IVF cycle, dual trigger with a combination of GnRH agonist and low dose hCG (1000 IU) is induced the prevention of OHSS, successful high oocyte retrieval rate and ultimately increased pregnancy outcome.

The cycle outcomes of GnRH agonist triggering with different leuprolide acetate doses in high responder patients

in the oocyte’s nuclear and cytoplasmic maturation. Though poor oocyte quality is routinely observed in older women, the impact of reproductive aging on GC function has so far not been fully elucidated and, therefore, was subject of this investigation. DESIGN: Prospective case control study. MATERIALS AND METHODS: We examined effects of aging on cell proliferation and gene expression in in vitro cultured human GCs in 4 young oocyte donors (ages 21-30 years), 4 younger (22-37 years) and 4 older (42-47 years) infertility patients. GC proliferation was examined by counting cell number with a hematocytometer, apoptosis by DAPI staining and gene expression by real-time PCR, following in vitro culture in presence or absence of 10IU/ml follicle stimulating hormone (FSH). RESULTS: We observed statistically significantly lower proliferation and higher apoptosis with advancing female age during in vitro culture of GCs. FSH supplementation in culture stimulated GC growth and prevented luteinization, evaluated by FSH receptor and aromatasemRNA expression; but this effect completely dissipated with advancing female age. CONCLUSION: These data demonstrate age-related functional declines in human GCs, characterized by changes in GC luteinization, proliferation, apoptosis and ability to respond to FSH during in vitro culture. Poor oocyte quality in older infertile women may, therefore, at least in part, be related to the loss of normal ovarian GC function. Supported by: Foundation for Reproductive Medicine, Center for Human Reproduction.

Comparison of starting ovarian stimulation on day 2 versus day 15 of the menstrual cycle in the same oocyte donor and pregnancy rates among the corresponding recipients of vitrified oocytes

To assess the clinical pregnancy rate per transfer in recipients of embryos from donor oocytes obtained after ovarian stimulation initiated on day 2 (D2) or day 15 (D15) of the menstrual cycle with a secondary end point of comparing the response to stimulation. Prospective observational comparative study. Private in vitro fertilization (IVF) program. Oocyte donors (OD) and recipients. Donors stimulated within 3 months, starting on day 2 or day 15 after bleeding, with recombinant follicle-stimulating hormone (FSH), gonadotropin-releasing hormone (GnRH) antagonist, and GnRH agonist trigger, and oocytes vitrified and later assigned to recipients, followed by routine IVF procedures one to two embryos transferred. Primary outcome pregnancy rate, and secondary outcome number of mature oocytes retrieved. Nine D2 and nine D15 cycles were performed in nine donors. There were no differences between D2 and D15 in the number of mature oocytes obtained (14.0±6.96 vs. 16.89±7.52). To date, 20 recipients have received vitrified oocytes (8 recipients received D2 oocytes and 12 recipients received D15 oocytes). There were no differences between the groups of recipients in fertilization rate (77.3% vs. 76.5%) or number of embryos transferred (1.50±0.53 vs. 1.67±0.65). Twelve clinical pregnancies were obtained. No differences were noted in pregnancy rates (62.5% vs. 58.3%) or implantation rates (41.67% vs. 45%) between recipients of D2 oocytes and recipients of D15 oocytes. Donor oocytes obtained after ovarian stimulation initiated on day 15 of the cycle achieve good pregnancy rates. This information is useful for patients with cancer undergoing fertility preservation. NCT 01645241.

Gonadotrophin-releasing hormone agonist trigger and freeze-all strategy does not prevent severe ovarian hyperstimulation syndrome: a report of three cases

Ovarian hyperstimulation syndrome (OHSS) is the most serious iatrogenic complication of IVF cycles. Although the development of effective treatment strategies for this syndrome is important, preventing OHSS is more crucial. Triggering ovulation with a gonadotrophin-releasing hormone (GnRH) agonist is one method used to avoid OHSS. In this paper, three patients who developed severe OHSS after undergoing GnRH agonist triggering and freezing of all embryos in a GnRH antagonist protocol are described. A review of the literature is also provided. This report highlights the ongoing risk of severe OHSS even after GnRH agonist triggering combined with freezing all embryos in GnRH antagonist cycles. Other prevention strategies might be considered for extreme hyper-responders.

Empty follicle syndrome prevalence and management in oocyte donors

Is the drug used for final oocyte maturation a factor in determining the prevalence of empty follicle syndrome (EFS)? The drug used for final oocyte maturation is not a factor in determining the prevalence of EFS among women unaffected by infertility. Despite satisfactory follicular stimulation and adequate follicular development, cases of EFS, i.e. failure to recover any cumulus oocyte complex, have been reported both with hCG and GnRH agonist triggering. No standard management protocol has been proposed so far. Retrospective analysis of oocyte donation cycles performed between August 2006 and April 2013 in a large private fertility centre. The analysis included 12 483 oocyte donation cycles of which 74 were EFS cycles. All cycles were triggered with either hCG or GnRH agonists. There were no differences in the gonadotropic stimulation, pituitary suppression and triggering drug between cycles where oocytes were recovered successfully and EFS cycles. The total prevalence of EFS was 0.59%. Given the rarity of the syndrome, caution is advised when interpreting the analysis. The main limitation of this study is its retrospective nature. Although this is the largest analysis of EFS in donors reported so far, its statistical power is limited because the syndrome has a low incidence. In some cycles of EFS from 2006 to 2007 there is a lack of hormone data. Our findings may be generalized to oocyte donors and IVF patients younger than 35 years old, with cycles undergoing final maturation triggering with either hCG or GnRH agonists. The generalization cannot be extended to patients with an ovarian factor as the cause of their reproductive pathology. The theoretical aetiology of a temporary hypothalamic-pituitary hyposensitivity can explain the cycles where a rescue protocol with hCG has been successful. This work was supported in part by funding from Fundaciò EUGIN. The authors have no conflicts to declare. NA.

The risk of ectopic pregnancy following GnRH agonist triggering compared with hCG triggering in GnRH antagonist IVF cycles.

The aim of this study was to compare the incidence of ectopic pregnancy in GnRH agonist triggered IVF cycles with intensive luteal support versus hCG triggered IVF cycles. This study was conducted as a retrospective cohort analysis of women who underwent IVF treatment employing GnRH agonist or recombinant hCG (rhCG) triggers during 2-year period. The medical charts of women who achieved pregnancies were reviewed and their demographic characteristics, infertility reasons and IVF data were recorded. A multiple logistic regression analysis was performed to estimate the association between the triggering medication used to stimulate final oocyte maturation (GnRHa or rhCG) and EP, with adjustment for important confounders: the day of embryo transfer (ETD), the etiology of infertility and estrogen level at the time of triggering. The number of metaphase II oocytes, fertilized oocytes and good quality embryos were significantly higher in the GnRH agonist triggered group compared with the hCG triggered group (p < 0.001 for all). The clinical pregnancy and implantation rates in the hCG triggered cycles were 38.6 and 31.1 %, respectively and 24.7 and 22 %, respectively in the triptorelin triggered cycles. The ectopic pregnancy rates were 5.3 % in the triptorelin triggered group and 1.4 % in the hCG triggered group. The trigger medication and the day of embryo transfer were found to have a significant effect on the probability of developing ectopic pregnancy (p = 0.028, p = 0.046 respectively). However, the estrogen level was not found to have a significant effect on the probability of developing ectopic pregnancy (p = 0.447). The reasons for higher ectopic pregnancy rates in GnRH agonist triggered cycles relative to hCG triggered cycles may be the decreased receptivity of the endometrium due to insufficient luteal support and higher implantation potential of embryos in correlation with a higher number of good quality embryos obtained in these cycles.

Maternal and neonatal outcomes after gonadotropin-releasing hormone agonist trigger for final oocyte maturation in patients undergoing in vitro fertilization

To compare the rate of congenital anomalies, obstetrical complications, and neonatal complications in antagonist cycles where either GnRH agonist (GnRHa) or hCG was used for final oocyte maturation. Retrospective cohort study. University-based tertiary fertility center. Three hundred ninety-two women under 40years of age who underwent controlled ovarian stimulation using a GnRH antagonist protocol and who had final oocyte maturation triggered with either a GnRHa or hCG that resulted in pregnancy and delivery after 16weeks' gestation. GnRHa versus hCG trigger of final oocyte maturation. Congenital anomaly rates, obstetrical complications, and neonatal complications. There were no significant differences in the rate of congenital anomalies between GnRHa and hCG trigger (6.6 vs. 9.2%). There were also no differences in the maternal complications (27.6 vs. 20.8%) or neonatal complications (19.7 vs. 20.0%) between the GnRHa trigger and hCG trigger groups. GnRHa trigger does not affect the rate of congenital anomalies or obstetrical or neonatal complications and remains a viable option in the prevention of ovarian hyperstimulation syndrome.

GnRH agonist trigger and ovarian hyperstimulation syndrome: relook at ‘freeze-all strategy’

A case is reported of early onset ovarian hyperstimulation syndrome (OHSS) after gonadotrophin-releasing hormone agonist (GnRHa) trigger for final oocyte maturation in a GnRH antagonist protocol. The use of GnRHa in place of HCG as a trigger for final oocyte maturation in an antagonist IVF cycle has been proposed as a method for preventing OHSS in predicted high-responders. This approach, however, did not prevent the occurrence of OHSS in our case despite a freeze-all strategy. To the best of our knowledge, this is a possible index case of severe OHSS with GnRHa trigger for oocyte maturation without any luteal HCG rescue for a high responder, despite IVF cycle segmentation.

GnRH agonist triggers and their use in assisted reproductive technology: the past, the present and the future.

Gonadotropin releasing hormone agonist triggers are very effective in eliminating early-onset ovarian hyperstimulation syndrome (OHSS). However, in most studies they result in inferior pregnancy rates compared to hCG triggers in fresh autologous transfers. This is not due to an effect on embryo quality but rather due to inadequate corpus luteum formation and a defective luteal phase causing poor implantation. Intensive and adjusted steroid support or low-dose hCG may correct this. Late-onset OHSS is eliminated by using a freeze-all strategy. Pregnancy rates after transfer of thawed vitrified embryos are consistently high. A strategy combining a gonadotropin releasing hormone agonist trigger with vitrification of all embryos has been proposed as a means of achieving a truly OHSS-free clinic.

PP-015 - GnRH-agonist triggering and “freeze-all” policy: a safe alternative strategy in high-risk OHSS patients

PP-015 - GnRH-agonist triggering and “freeze-all” policy: a safe alternative strategy in high-risk OHSS patients

HCG (1500IU) administration on day 3 after oocytes retrieval, following GnRH-agonist trigger for final follicular maturation, results in high sufficient mid luteal progesterone levels - a proof of concept

BackgroundControlled ovarian hyperstimulation (COH) which combining GnRH antagonist co-treatment and GnRH agonist trigger with an additional 1500 IU hCG luteal rescue on day of oocytes retrieval, has become a common tool aiming to reduce severe ovarian hyperstimulation syndrome (OHSS). In the present, proof of concept study, we evaluate whether by deferring the hCG rescue bolus for 3 days, we are still able to rescue the luteal phase.MethodsPatients undergoing the GnRH-antagonist protocol, who were considered at high risk for developing severe OHSS and received GnRH-agonist for final oocyte maturation, were included. For luteal phase support, all patients received an “intense” luteal support. Those who had no signs of early moderate OHSS on day 3 after oocytes retrieval were instructed to inject 1500 IU of HCG bolus (hCG group). Ovarian stimulation characteristics and mid luteal progesterone levels were compared between those who received the HCG bolus and those who did not.ResultsEleven IVF cycles were evaluated, 5 in the hCG group and 6 in the intense luteal support only group. While no in-between group differences were observed in ovarian stimulation characteristics, significantly higher mid luteal progesterone levels (>127 nmol/L vs 42.1 ± 14.5 nmol/L, respectively) and a non-significant increase in pregnancy rate (40% vs 16.6%, respectively), were observed in those who receive the hCG bolus compared to those who did not.ConclusionshCG luteal rescue should be offered 3 days after oocytes retrieval only to those patients with no signs of early moderate OHSS. Further studies are required to elucidate the appropriate regimen of luteal HCG administration in patients undergoing final follicular maturation with GnRH-agonist.

Severe ovarian hyperstimulation syndrome after gonadotropin-releasing hormone (GnRH) agonist trigger and “freeze-all” approach in GnRH antagonist protocol

To report two cases with GnRH agonist triggering and a freeze-all approach in a GnRH antagonist protocol resulting in the development of severe ovarian hyperstimulation syndrome (OHSS), requiring hospitalization and peritoneal drainage. Two case reports. A tertiary referral center and an obstetrics and gynecology department of a hospital. Case 1 and case 2: severe OHSS with abdominal distension, ascites development, and hemoconcentration. Case 1 and case 2: diagnosed by clinical, hematologic, and ultrasound findings. Hospitalization, IV infusion, and peritoneal drainage. Symptomatic treatment and prevention of further complication. Complete recovery. Two cases of severe OHSS after GnRH agonist trigger in a GnRH antagonist protocol without the administration of any hCG for luteal-phase support. Clinicians have to be aware that even the sequential approach to ovarian stimulation with a freeze-all attitude does not completely eliminate OHSS in all patients.

Risk Factors for Failure to Respond to GnRH Agonist Trigger in Fresh In Vitro Fertilization Cycles

Gonadotropin-releasing hormone (GnRH) agonists are often used to trigger ovulation during IVF in order to decrease the risk of ovarian hyperstimulation syndrome in high responders. Administration of a GnRH agonist trigger in antagonist cycles causes an endogenous LH surge that promotes follicular maturation prior to oocyte retrieval. Rare instances of failure to mount an appropriate LH surge in response to an agonist trigger have been reported, an event associated with decreased oocyte maturity, low oocyte yield, and compromised cycle outcomes.

Prevention of ovarian hyperstimulation syndrome

Ovarian hyperstimulation syndrome (OHSS) is a potentially serious complication of ovarian stimulation for fertility treatment. Risk factors include polycystic ovaries, high ovarian reserve, and excessive ovarian response to stimulation. It is important to be aware of the risk of OHSS, even in so called low-risk situations. An understanding of the pathophysiology of OHSS may help clinicians to target preventative measures in women who are at risk. Ovarian stimulation regimes based on an individualized reserve assessment may help reduce the incidence of OHSS. Gonadotropin-releasing hormone (GnRH) antagonist regimes are associated with a lower risk than GnRH agonist regimes and the risk may be further reduced if a GnRH agonist trigger is used in place of human chorionic gonadotropin (hCG). Other methods of reducing hCG exposure include avoiding hCG luteal support, cryopreservation of all embryos, and avoidance of multiple pregnancy. However, the only method that guarantees avoidance of OHSS in high-response cycles is cycle cancellation. Clinicians should be aware of the potential value of coasting and dopamine agonists, as measures to reduce risk in the presence of an excessive ovarian response.

A Brief History of GnRH Agonist Trigger and Directions for Future Research

A Brief History of GnRH Agonist Trigger and Directions for Future Research