GnRH Agonist Trigger Research Articles

Impact of clomiphene citrate during ovarian stimulation on the luteal phase after GnRH agonist trigger

The use of a gonadotrophin-releasing hormone (GnRH) agonist to trigger final oocyte maturation in a GnRH antagonist protocol has been associated with poorer clinical outcomes due to an increased luteal-phase defect. It has been shown that LH activity is crucial in a normal luteal phase. Studies assessing the LH concentrations after clomiphene citrate co-treatment have observed increased luteal-phase LH concentrations. The purpose of this prospective cohort study was to analyse the effect of clomiphene citrate on the endocrine profile in the luteal phase when using GnRH agonist trigger. This was evaluated in eight oocyte donors undergoing ovarian stimulation using clomiphene citrate in combination with recombinant FSH compared with a control group of five donors treated with recombinant FSH only. The endocrine profile was comparable in both groups, except for serum LH concentrations on the day after trigger (121.3±53.0IU/l versus 52.9±21.5IU/l, respectively, P=0.022). No significant differences in LH concentrations were found on the day of trigger or 5days after oocyte retrieval. In conclusion, a luteal-phase defect was observed despite treatment with clomiphene citrate during ovarian stimulation.The use of gonadotrophin-releasing hormone (GnRH) agonist to trigger ovulation in IVF has been associated with poorer pregnancy outcomes due to an increased luteal-phase defect. The luteal phase is the last phase of the menstrual cycle and is defined as the period between ovulation and the beginning of pregnancy or menses. It has been shown the activity of LH is crucial in a normal luteal phase. Studies assessing the LH concentrations after clomiphene citrate, an oestrogen receptor inhibitor, co-treatment have observed increased luteal-phase LH concentrations. The purpose of this prospective cohort study was to analyse the effect of clomiphene citrate on menstrual cycle day 2–6 on the hormone profile in the luteal phase when using GnRH agonist trigger. This was evaluated was in eight oocyte donors undergoing ovarian stimulation using recombinant FSH compared with a control cohort of donors treated with recombinant FSH only. The current prospective cohort study reports higher LH concentrations on the day after GnRH agonist trigger, but not 5days after oocyte retrieval (i.e. in the luteal phase). In conclusion, a luteal-phase defect was observed despite the administration of clomiphene citrate during ovarian stimulation. Additional treatment with clomiphene citrate in the follicular phase is therefore not a valid alternative to prevent luteal-phase defect after GnRH agonist trigger.

Impact of final oocyte maturation using gonadotropin-releasing hormone agonist triggering and different luteal support protocols on endometrial gene expression

To use microarray technology to analyze endometrial gene expression after gonadotropin-releasing hormone agonist (GnRH-a) triggering with four different protocols of luteal support in comparison with results obtained after a human chorionic gonadotropin (hCG) trigger. Prospective, randomized, controlled trial. University-affiliated private assisted-reproduction center. 25 healthy oocyte donors undergoing controlled ovarian stimulation. On day of final oocyte maturation, randomization to [1] GnRH-agonist triggering and luteal support with oral estradiol (2 mg/8 hours) and vaginal progesterone (200 mg/12 hours), [2] GnRH-a and a daily dose of 150 IU of recombinant LH from oocyte pickup, [3] GnRH-a and a single bolus of 60 μg of recombinant hCG on oocyte pickup, [4] GnRH-a and three doses of 20 μg of recombinant hCG separated by 48 hours, or [5] 250 μg of recombinant hCG for trigger and standard luteal support; with endometrial biopsy samples collected 7 days after triggering. Gene expression using the Endometrial Receptivity Array (ERA) and pathway and network analysis of study groups 1-4 compared with controls (group 5). The 56 genes in group 1 (25 up-regulated and 31 down-regulated) exhibited altered expression compared with the 36 genes from group 2 (13 up-regulated and 23 down-regulated), 44 from group 3 (28 up-regulated and 16 down-regulated), and 30 (20 up-regulated and 10 down-regulated) from group4. Differences were seen in endometrial gene expression related to the type of ovulation trigger and luteal support. However, gene expression after the GnRH-a trigger and modified luteal support adding LH/hCG activity more closely resembles the pattern seen in the hCG group. EudraCT 2011-003250-34.

HCG dose as low as 500 IU in combination with GnRH agonist trigger can be efficacious for fresh embryo transfer

Cycles using GnRH agonist trigger alone are reportedly associated with poor IVF outcomes following fresh transfer, and some centers have therefore combined low-dose hCG with the agonist trigger. The minimum effective hCG dose for this method has not been established. This study compares IVF outcomes for different ranges of hCG dose used in combination with GnRH agonist in fresh autologous embryo transfer in high responders.

Improved clinical outcomes and lower OHSS risk with GnRH agonist trigger and hCG incorporated luteal support, compared to hCG trigger in GnRH-antagonist protocol for anticipated high responders

To compare the clinical outcomes and incidence of OHSS between GnRH-agonist trigger [incorporating hCG, estrogen and progesterone luteal phase support (LPS)] and hCG trigger in GnRH-antagonist protocol for high responders of IVF/ICSI. Retrospective study of consecutive women at high risk of OHSS who underwent IVF/ICSI (one cycle/ patient) with GnRH-antagonist protocol. Women with AMH levels >25 pmol/l, who had IVF/ICSI using GnRH-antagonist in a tertiary-level fertility clinic between Oct 09 and Oct 12. Final oocyte maturation was done by GnRH-agonist (n=62) or hCG (n=29). The continuous and categorical variables are compared by t-test/ Fisher's and χ2 tests respectively. No difference in the mean age, BMI, AMH, FSH, LH, starting/ total dose of FSH; proportion of PCOS, ICSI; mean number of eggs (17.9vs14.1, p=0.06) embryos (9.8vs7.1, p=0.13); fertilization (54.6%vs55.6%, p=0.77) and implantation (30.8%vs28.9%, p=0.94) rates between GnRH-agonist and hCG group. Blastocysts transfer (54.7%vs35.0%, p=0.04) was more with GnRH-agonist. One clinical miscarriage in each group and 4 ‘biochemical’ with GnRH-agonist. Clinical pregnancy (42.6%vs40%, p=0.85) and ongoing pregnancy rates (40.7%vs35.0%, p=0.74) per embryo-transfer were similar between GnRH-agonist and hCG. Ongoing pregnancy 11.4% higher with GnRH-agonist and similar twin rates (GnRH-agonist: 13.2%vs hCG: 22.2%, p=0.42) when double-embryo transferred. Fewer mild-moderate (16.2%vs 31.0%, p=0.10), no severe OHSS and no hospitalization with GnRH-agonist, while 1 severe OHSS with hCG; less need for freeze-all embryos (9.7%vs27.6%, p=0.04) for risk of secondary-OHSS with GnRH-agonist. Our study reassures that addition of single 1500 iu hCG as LPS following GnRH-agonist trigger results in as good, if not better treatment outcomes and further reduction of OHSS, when compared with hCG trigger. Adequately powered randomised control trial is required to confirm this.

Modified luteal support following GnRH-agonist trigger

To demonstrate the use of modified luteal support following GnRh-agonist trigger in patients undergoing IVF/ICSI and at risk of Ovarian Hyper Stimulation Syndrome [OHSS] in preventing early OHSS without compromising pregnancy rate. This prospective, observational study was carried out on 49 patients undergoing IVF/ICSI and at risk of OHSS at Nova IVI Fertility, Ahmedabad from January 2012 to December 2012. The patients aged between 26 and 34 years [average 31 years], underwent stimulation from second day of period with 100 to 300IU of Gonadotropins[average 200IU] using the flexible antagonist protocol. GnRH agonist,[Triptorelin 0.2mg] was given to induce final oocyte maturation in patients at risk of developing OHSS[>20 follicles of >16 mm on the day of trigger].Average estradiol on the day of trigger was 5353+3983 pg/ml. Transvaginal oocyte retrieval[OR]was performed 35hours after the trigger. Luteal phase support was provided in form of vaginal progesterone tablets(200mg 3times/day) and oral estradiol valerate(2mg twice/day)from day after OR. Patients also received 1500 I.U. of recombinant hCG on day of ET. 2embryos were transferred on day3 after OR. An average 22.7+5.6 oocytes were retrieved,76% of which were at metaphaseII. Fertilization rate was 81% and 14+5 embryos were obtained. 2embryos were transferred on day3 in 42 patients and positive hCG rate was 30.9%[13/42] per ET. There was no early OHSS;one patient developed late onset pregnancy induced severe OHSS. Implantation rate was 19%[16/84], rates of miscarriage, ectopic and twins were 7.6%, 15.3%, 23% & ongoing pregnancy rate at 10 weeks was 23.8% [10/42]. GnRH agonists can be used effectively as an alternative to hCG trigger in patients at high risk of OHSS. This delayed administration of hCG provides luteal support& gives time to assess the number & grade of embryos & decide whether the patient should be given hCG & have an ET or should have elective cryopreservation of all embryos.

Use of GnRH agonist for final oocyte maturation is associated with similar endocrine profiles, mature oocyte yield, and pregnancy outcomes in PCOS patients compared to other high responders

Use of gonadotropin-releasing hormone agonists (GnRHa) for oocyte maturation during IVF cycles decrease the risk of ovarian hyperstimulation syndrome (OHSS). An intact hypothalamic-pituitary-ovarian-axis is needed for the action of GnRHa, however women with PCOS may have abnormalities in GnRH and LH pulsatility. This study compares endocrine profiles and IVF outcomes after GnRHa trigger in women with and without PCOS.

GnRH agonist triggering: is it really the ultimate tool to OHSS prevention?

Ovarian hyperstimulation syndrome(OHSS) remains a significant complication and fear in patients undergoing artificial reproductive therapy(ART). Recent developments have shown that the administration of a GnRH agonist to induce final oocyte maturation after ovarian stimulation can virtually eliminate the risk of OHSS.

Choosing the right ovulation trigger in antagonist cycles for an OHSS free clinic

The use of hCG as ovulation trigger is associated with high incidence of ovarian hyperstimulation syndrome(OHSS).The advent of GnRH agonist trigger in antagonist cycles decreased the incidence of OHSS but also compromised pregnancy rates. The addition of low dose hCG for luteal support in these women was found to be as effective as hCG and safe. We compared these two methods of final ovulation maturation trigger on various outcomes of IVF.

Comparison of reproductive outcomes between trigger with hCG versus GnRH agonist in eggs donors cycle

The aim of this study is to compare the controlled ovarian stimulation (COS) protocols and their reproductive outcomes in donors using trigger with human chorionic gonadotropin (hCG) versus GnRH agonist (GnRHa) for In Vitro Fertilization (IVF) cycles of two private centers. Multicenter, Prospective and Comparative Analysis. A total of 66 consecutive cycles of COS in donors from two centers were reviewed. Two groups were formed: Group 1, donors with a luteal phase agonist protocol triggered with 10,000 IU of hCG, and Group 2 with an antagonist protocol using trigger with 0.8 ml of GnRHa (Lucrin Depot®3.75mg). ANOVA test was used for statistical analysis. Both groups were homogeneous for demographic characteristics and stimulation protocols (P=NS): donor age (22.4 ±2.0 vs. 23.7 ±2.2); receptor age (39.1 ±4.9 vs. 42 ±4.2); BMI (23.7 ±3.06 vs. 22.5±2.18); FSH day3 (5.05 ±1.55 vs. 5.95 ±0.97 mIU/ml); LH day3 (3.02 ±1.22 vs. 2.9 ± 1.13 mIU/ml); antral follicles (14.85 ±3.6 vs. 14.83 ±4.9); total doses of rFSH (1700 ±293.8 vs. 1643 ±393.2 IU). During the period of study was reported a single case of OHSS, and one case of ovarian torsion, in group 1. There were no complications in group 2. Reproductive outcomes are described in table 1.Tabled 1Table1. Ovarian stimulation outcomes by group.Group 1 (n=35)Group 2 (n=31)P valueE2 day 10 α2333 ± 147mIU/ml1810 ± 599 mIU/ml0.068Retrieved oocytes α15120.058Oocyte MII α12.510.80.185Embryo transfer α2.82.70.644Embryo transfer G142%54%0.734Gestational sac α1.61.30.662Implantation rate32%26%0.980Pregnancy rate61%54%0.244Ongoing pregnancy rate54%41%0.392α: Mean; G1: grade 1. Open table in a new tab α: Mean; G1: grade 1. Trigger with hCG remains the best option for final oocyte maturation. However, the use of GnRH agonist trigger after GnRH antagonist protocol is equally effective for oocyte maturation, fertilization and pregnancy in donor cycles. In addition it reduces the risk of OHSS and complications of stimulation in high risk patients (donors).

Consistent high clinical pregnancy rates and low ovarian hyperstimulation syndrome rates in high-risk patients after GnRH agonist triggering and modified luteal support: a retrospective multicentre study

Are clinical pregnancy rates satisfactory and the incidence of OHSS low after GnRH agonist trigger and modified intensive luteal support in patients with a high risk of ovarian hyperstimulation syndrome (OHSS)? GnRH agonist trigger combined with 1500 IU hCG at the time of oocyte retrieval and subsequent estradiol and progesterone replacement in OHSS high-risk patients can facilitate fresh embryo transfer with high clinical pregnancy rates and a low risk of severe OHSS. Conventional luteal support packages are inadequate to facilitate a fresh transfer after a GnRH agonist trigger. A low dose of hCG (1500 IU) after oocyte aspiration can be used to replace the actions of early luteal LH to sustain implantation and the function of the early corpus luteum, although the level of risk of severe OHSS with this strategy is unclear. This international multicentre retrospective case study, including 275 women at high risk of OHSS, was undertaken during the period January 2011-December 2012. Women were identified as at high risk of OHSS, based on IVF response, ovarian reserve characteristics and previous history of having had treatment, in three clinical IVF centres in UK, Belgium and Australia. All three centres used a GnRH agonist trigger followed by one bolus of 1500 IU hCG 1h after oocyte retrieval. Moreover, the luteal phase was supported with daily vaginal progesterone and twice daily estradiol valerate. A total of 275 autologous cycles with fresh transfer were undertaken in a cohort of high-risk women as defined by baseline characteristics [median (interquartile range)]: age 31.6 (29-35) years, antral follicle count median 25 (18-34) and anti-Müllerian hormone median 49.1 pmol/l (35.2-69.3). At the end of stimulation, the peak estradiol median of 12 000 pmol/l (9400-15 914) and the mean oocyte yield of 17.8 ± 8.4 confirmed a high response. The overall clinical pregnancy rate was 41.8% per cycle started, with only two cases of severe OHSS reported (0.72%). No significant differences in clinical pregnancy rates between centres were identified. This is a retrospective study and future randomized controlled trials will be able to compare whether these outcomes can be improved upon by either segmentation of the stimulation cycle and embryo transfer or alternative aggressive luteal support strategies. In women who are undergoing ovarian stimulation and who develop an excessive ovarian response, the use of a GnRH agonist trigger combined with modified luteal support can provide the opportunity to proceed to fresh embryo transfer with adequate clinical pregnancy rates. However, this procedure will not completely eliminate the risk of OHSS and for women with an extreme ovarian response or with significant comorbidity, where the possibility of severe OHSS is unacceptable, we recommend GnRH agonist trigger followed by a freeze-all policy to completely avoid OHSS.

Comparison of gene expression profiles in granulosa and cumulus cells after ovulation induction with either human chorionic gonadotropin or a gonadotropin-releasing hormone agonist trigger

To explore differences in follicle transcriptomes in patients having oocyte maturation with either a bolus of hCG or GnRHa. Cumulus cells (CC) and mural granulosa cells (MGC) were isolated from preovulatory follicles in patients undergoing controlled ovarian stimulation, prospectively randomized to GnRHa or hCG triggering. University-based facilities for clinical services and research. Twenty women with indication for IVF or intracytoplasmic sperm injection treatment were randomly allocated to hCG or GnRH agonist (GnRHa) trigger. MGC and CC were collected from individual follicles in connection with oocyte retrieval. RNA was extracted, labeled, amplified, and hybridized on HumanGene1.0ST GeneChip Affymetrix array. Expression data were robust multichip average normalized and compared using Partek and Ingenuity software. Array data were confirmed with reverse transcription-polymerase chain reaction analysis. Comparing the transcriptomes between the groups, 391 and 252 genes were differentially expressed (fold change >1.5) in CC and MGC, respectively. The enriched bionetworks showed that CC genes highly represented "lipid metabolism and small molecule biochemistry" (network score, 41), while in MGC, the top network was "cardiovascular development and function and cellular movement" (network score, 50). For both CC and MGC, the regulator analysis suggested LH as the upstream regulator for the difference observed. In CC, the LH receptor was more highly expressed after GnRHa trigger, while in MGC, genes involved in angiogenesis such as angiopoietin 1 and semaphorin 3A were down- and up-regulated, respectively, in GnRHa- as compared with hCG-triggered patients. The comparisons between somatic cell transcriptomes from GnRHa- and hCG-triggered follicles showed significant functional differences in both CC (steroidogenesis) and MGC (angiogenesis) compartments.

Risk factors for ovarian hyperstimulation syndrome: relevance of the number of follicles, serum estradiol levels and the number of oocytes collected

13:1901–1906. SeyhanA, Ata B, PolatM, SonWY, Yarali H,DahanMH. Severe early ovarian hyperstimulation syndrome following GnRH agonist trigger with the addition of 1500 IU hCG. Hum Reprod 2013. doi:10.1093/det124. Triwitayakorn A, Suwajanakorn S, Pruksananonda K, Sereepapong W, Ahnonkitpanit V. Correlation between human follicular diameter and oocyte outcomes in an ICSI program. J Assist Reprod Genet 2003; 20:143–147.

COMPARISON OF GNRH AGONIST WITH LOW-DOSE URINARY HCG FOR THE INDUCTION OF FINAL OOCYTE MATURATION IN HIGH-RISK PATIENTS UNDERGOING INTRACYTOPLASMIC SPERM INJECTION-EMBRYO TRANSFER (ICSI-ET)

Faiz Abdulwahid Alwaeely Basra Medical College, Almanar Fertility and Endoscopy Center Abstract The aim of this study is to compare clinical pregnancy rates in ICSI-ET cycles where GnRH agonist or hCG was used to induce final maturation of the oocytes. A total of 97 women who produced more than 14 follicles following ovulation induction with recombinant FSH and GnRH antagonist were selected for randomization. Human chorionic gonadotropin (hCG, 5.000 IU, IM) or GnRH agonist (triptorelin 0.2 mg, SC) was used for the induction of final maturation. Women in GnRH agonist group received higher dose of progesterone (100 mg vs. 50 mg) and estradiol (6 mg orally per day vs. none) compared to women in hCG group in the luteal phase starting on the day of oocyte pick-up. Age, duration of stimulation, dose of gonadotropins, peak estradiol levels were similar in both groups. The mean number of collected oocytes (14.7±2.1 vs. 13.8±4.3) and fertilization rates (70.7 ±18 vs.71.8 ±21) were not significantly different between women allocated to hCG group (n=53) and GnRH agonist group (n=44). Clinical pregnancy rates (37.7 vs. 36.3), miscarriage rates (15% vs. 18.7%) and ongoing pregnancy rates (32% vs. 29.5%) were similar between hCG group and GnRH agonist group, respectively. Two cases of moderate/severe OHSS occurred in the hCG group, and none in the GnRH agonist group. In conclusion, GnRH-agonist triggering together with high dose steroid supplementation in the luteal phase yields similar clinical pregnancy rate to that obtained with lower dose of hCG administration for final maturation. However, lower dose of hCG was associated with a higher incidence of moderate/severe OHSS.

GnRHa trigger and individualized luteal phase hCG support according to ovarian response to stimulation: two prospective randomized controlled multi-centre studies in IVF patients

Does a GnRH agonist (GnRHa) trigger followed by a bolus of 1.500 IU hCG in a group of patients at risk of ovarian hyperstimulation syndrome (OHSS) reduce the OHSS incidence compared with hCG trigger? A GnRHa trigger followed by early luteal hCG support with one bolus of 1.500 IU hCG appears to reduce OHSS in patients at risk of OHSS; however, in a low-risk group a second bolus of 1.500 IU hCG induced two cases of late onset OHSS. A GnRHa trigger is an alternative to hCG in GnRH antagonist co-treated cycles. Two RCTs were performed in four Danish IVF units. A total of 446 patients were assessed for eligibility and 390 patients were enrolled in the study from January 2009 until December 2011. The primary outcome of the study was OHSS incidence in the group at risk of OHSS. Patients received a fixed dose of recombinant human FSH for the first 4 days. On the day of triggering, patients were assessed for their risk of OHSS based on the total number of follicles ≥11 mm diameter, and were classified as being at risk of OHSS when the total number of follicles ≥11 mm was between 15 and 25 and at low risk of OHSS when the total number of follicles ≥11 mm was ≤14. Two separate randomization lists were used for each of the OHSS risk groups. Women at risk of OHSS were allocated (RCT 1) to either: Group A (n = 60), ovulation triggering with a bolus of 0.5 mg buserelin (GnRHa) s.c. followed by a single bolus of 1.500 IU hCG s.c. after the oocyte retrieval-or: Group B (n = 58): 5.000 IU hCG. Similarly, women at low risk of OHSS were allocated (RCT 2) to receive either: Group C (n = 125), a bolus of 0.5 mg buserelin s.c., followed by a bolus of 1.500 IU hCG s.c. after oocyte retrieval and a second bolus of 1.500 IU hCG on the day of oocyte retrieval +5-or: Group D (n = 141), 5.000 IU hCG. Groups C and D were included in order to obtain preliminary data. In women at risk of OHSS (RCT 1) (15-25 follicles) no OHSS case was seen in Group A (GnRHa trigger and one bolus of 1.500 IU hCG), whereas two cases of moderate late-onset OHSS occurred in group B (3.4%), (P = 0.24). In contrast, in women at a low risk of OHSS (RCT 2) (≤14 follicles) two cases of late-onset OHSS occurred in Group C (GnRHa trigger and two boluses of 1.500 IU hCG), whereas no OHSS case was encountered in Group D (P = 0.22). Although the first RCT was powered to include 168 patients at risk of OHSS (15-25 follicles ≥11 mm) randomized to either GnRHa trigger or hCG trigger, the trial was prematurely discontinued when a total of 118 patients at risk of OHSS were randomized. In addition the second RCT in the OHSS low-risk group was designed as a feasibility study to assess the incidence of OHSS after GnRHa trigger and dual hCG administration versus 5.000 IU hCG. No power calculation was performed for this trial. In addition, there was a lack of blinding in the RCTs. Although a non-significant result, one bolus of 1.500 IU hCG after GnRHa trigger tended to reduce the OHSS rate in patients with 15-25 follicles ≥11 mm as well as secure the ongoing pregnancy rate. In contrast, in patients at low risk of OHSS the administration of two boluses of 1.500 IU hCG after GnRHa trigger should be avoided as it may induce OHSS.

Treatment of Luteal Phase Defects in Assisted Reproduction

Abnormal luteal function is a common issue in assisted reproduction techniques associated with ovarian stimulation probably due to low levels of LH in the middle and in the late luteal phase. This defect seems to be associated with supraphysiological steroid levels at the end of follicular phase. The luteal phase insufficiency has not got a diagnostic test which has proven reliable in a clinical setting. Luteal phase after ovarian stimulation becomes shorter and insufficient, resulting in lower pregnancy rates. Luteal phase support with progesterone or hCG improves pregnancy outcomes and no differences are found among different routes of administration. However, hCG increases the risk of ovarian hyperstimulation syndrome. In relation to the length of luteal support, the day of starting it remains controversial and it does not seem necessary to continue once a pregnancy has been established. After GnRHa triggering ovulation, intensive luteal support or hCG bolus can overcome the defect in luteal phase, but more studies are needed to show the LH utility as support.

GnRH-Agonist Triggering to Avoid Ovarian Hyperstimulation Syndrome: A Review of the Evidence

Ovarian hyperstimulation syndrome (OHSS) is the most serious iatrogenic complication associated with ovarian stimulation. It is only in recent years that the understanding of OHSS has advanced sufficiently to develop treatment options aimed at reducing the incidence and effects of OHSS. Currently, there is no good test or method for identifying susceptible patients. Nevertheless, progress has been made in the prevention of OHSS. Physicians have a wide range of treatment options, including coasting, re-initiation of a GnRH antagonist, and application of agonists, like dopamine in the luteal phase or triggering oocyte maturation with a bolus of GnRH agonist. These treatments, together with other procedures, like oocyte/embryo vitrification, have allowed physicians to improve the prediction and prevention of OHSS.

Effect of follicle-stimulating hormone receptor N680S polymorphism on the efficacy of follicle-stimulating hormone stimulation on donor ovarian response

The aim of this study was to investigate whether N680S FSHR polymorphism has a predictive value for the ovarian response to stimulation with gonadotropins and cycle outcome in our egg donor program. The oocyte donor candidates were selected according to the Instituto Bernabeu egg donation program requirements and ASRM and ESHRE guidelines for oocyte donation. The FSHR polymorphism N680S was studied in 145 oocyte donors. All donors underwent controlled ovarian hyperstimulation (COH) (n=355) using urinary follicle-stimulating hormone in a GnRH antagonist protocol and receiving a GnRH agonist triggering. The main outcome measures were oocyte yield, days of stimulation, gonadotropin doses, biochemical pregnancy, ongoing pregnancy, and miscarriage rates. Significant differences were reported in the antral follicle count (16.5 ± 5.0 for NN, 14.5 ± 4.7 for NS, and 14.1 ± 3.8 for SS), number of eggs retrieved (21.5 ± 9.2 for NN, 18.5 ± 8.2 for NS, and 19.8 ± 8.9 for SS), and gonadotropin doses (2098.5 ± 639.4 IU for NN, 2023 ± 490.1 IU for NS, and 2149.5 ± 552.3 IU for SS) between the genotypes. The clinical outcome was not affected by the N680S polymorphism of the FSHR gene in the egg donors. In a population of fertile egg donors, the FSHR gene polymorphism at position 680 is associated with different ovarian responses to COH. The genotype of the FSHR gene is an important factor for determining the prognosis of the COH cycles in normo-ovulatory fertile women.

Severe early ovarian hyperstimulation syndrome following GnRH agonist trigger with the addition of 1500 IU hCG

Is severe early ovarian hyperstimulation syndrome (OHSS) completely prevented with the GnRH agonist trigger and 1500 IU hCG luteal rescue protocol? Severe early OHSS can occur even after the GnRH agonist trigger and 1500 IU hCG luteal rescue protocol. Prior studies including over 200 women who received the GnRH agonist trigger and 1500 hCG luteal rescue protocol have reported complete prevention of severe early OHSS. Only a few late OHSS cases have been reported and it has been suggested that this protocol can be safely applied to any women under risk. This retrospective cohort study included all women who were at high risk of OHSS and were given the GnRH agonist trigger plus hCG luteal rescue protocol between December 2008 and August 2012 in the two participating centers. There were 23 women with a mean estradiol level of 4891 ± 2214 pg/ml and a mean number of >12 mm follicles of 20 ± 6 on the day of ovulation triggering. OHSS was categorized according to the Golan criteria. Overall 6 of the 23 (26%) women developed severe OHSS. Five women had severe early OHSS requiring ascites drainage and hospitalization and three of these women did not undergo embryo transfer. The number of follicles measuring 10-14 mm on the day of triggering was significantly different between women who developed severe early OHSS and those who did not. The small number of women with severe early OHSS may have prevented identification of other significant risk factors. Although the GnRH agonist plus 1500 IU hCG luteal rescue protocol significantly decreases the risk of severe OHSS, this life threatening complication can still occur in high-risk patients. It would be prudent to avoid hCG luteal rescue and freeze all embryos for future transfer in such women particularly when there are ≥18 follicles with 10-14 mm diameters even with few larger follicles.

Low-dose hCG supplementation after GnRH agonist triggering: don't be too quick on the trigger

Induction of final oocyte maturation using a GnRH agonist was first described in the early nineties, though with the advent of the GnRH antagonist era it has gained ever increasing attention some two decades later (Humaidan et al., 2011). The primary motive for substituting the ‘classical’ hCG trigger is the complete elimination of clinically significant ovarian hyperstimulation syndrome (OHSS). When used alone (or with steroid-only luteal support) GnRH agonist triggering is undoubtedly themost efficient and powerfulwayof (secondary)OHSSprevention. So far there is no confirmedOHSS case in the literature that proves the opposite (Kol and Humaidan, 2012). This prevention occurs due to a massive, rapid and irreversible luteolysis leading to a practical, total elimination of clinically significant moderate/severeOHSS (Kol, 2004). Consequently when fresh embryo transfer is not planned this strategy has established itself as the first choice option in oocyte donor/fertility preservation cycles and before total freezing of oocytes or embryos (Bodri et al., 2010; Griesinger et al., 2011). However, if the primary goal is performing fresh embryo transfer then the challenge is to save the severely impaired luteal phase without increasing the risk of early/late-onset OHSS. After the discouraging results of initial trials only a few dedicated research groups have made further efforts to undertake research in this area (Humaidan et al., 2006; Engmann et al., 2008; Castillo et al., 2010; Papanikolaou et al., 2011b). Humaidan et al. developed the concept of a modified luteal support aimed at rescuing the impaired luteal phase by administering small boluses of luteotropic substances. This hypothesis was first tested in pilot studies, both in normal and high responders (Humaidan et al., 2006 Humaidan, 2009) and later in a randomized clinical trial (Humaidan et al., 2010). The first randomized trial (mainly involving normal responders) suggested that the reproductive outcome can be improved to the level of control patients with a single, low-dose (1500 IU) hCG bolus administered at the time of oocyte retrieval, without increasing the risk of OHSS (Humaidan et al., 2010). These encouraging results were also reproduced in a retrospective study by an Australian group (Radesic and Tremellen, 2011). Although Radesic and Tremellen used the aforementioned strategy with a fairly high OHSS risk population (without a pre-established upper limit of ovarian response) they were cautious enough to only perform mandatory single embryo transfer to reduce the risk of any late-onset OHSS. In the current issue of Human Reproduction the case series by Seyhan et al., report the combined experience from two geographically distant centres in Canada and Turkey with IVF patients at high risk of OHSS, who received the low-dose hCG rescue protocol. Despite using co-interventions (such as coasting and cabergoline administration) the authors reported a worryingly high rate (22%) of early onset severe OHSS requiring hospitalization. Although the presented retrospective case series is fairly small, the authors felt that it was important to highlight that early onset OHSS can still occur after applying the low-dose hCG rescue protocol. At first sight their findings are in blunt disagreement with most previously published studies that have also used low-dose hCG luteal support (single or multiple-bolus) following GnRH agonist trigger (Table I). However, at closer look notable differences can be observed. Among the four studies that were conducted in high OHSS risk patients Seyhan et al.’s 23 patients represent the highest ovarian response category with extremes of 49 and 65 oocytes retrieved. Moreover, although in one of the participating centres total freeze was considered in 33% of the cases, in the other fresh transfer was performed only transferring two to three embryos. Taken altogether these factors considerably influence the risk of early and late-onset OHSS. Although it was based on a very limited number of cases (5 versus 18) Seyhan et al. also suggested a threshold (≥18 follicles) based on the number of intermediate-sized (10–14 mm) follicles above which embryo/oocyte freezing is strongly recommended. This threshold (which was the only significant finding in this series) was based on the number of intermediate follicles and might be less practical for everyday clinical use than the total follicular count (Papanikolaou et al., 2006). Interestingly, in the design of a more recent randomized trial by Humaidan et al. on low-dose hCG support, patients with .25 follicles .11 mm were judged to be at too high risk and excluded from participation (www.clinicaltrials.gov: NCT00627406).

Combination of cabergoline and embryo cryopreservation after GnRH agonist triggering prevents OHSS in patients with extremely high estradiol levels—a retrospective study

Embryo cryopreservation after triggering oocyte maturation with GnRH agonist (GnRHa) in GnRH antagonist protocols has been proposed to prevent ovarian hyperstimulation syndrome (OHSS). However, a small percentage of patients still developed severe OHSS. The purpose of the study was to investigate the efficacy of preventing OHSS in patients at very high risk when cabergoline was given in addition to elective cryopreservation after GnRHa triggering. This is a retrospective observational study. The patients were stimulated with GnRH antagonist protocol. When serum E2 concentration was >6,000 pg/ml and there were more than 20 follicles ≥11 mm on the day of final oocyte maturation, GnRHa was used to trigger oocyte maturation. Cabergoline was given to augment the effect of preventing OHSS. The embryos were electively cryopreserved by vitrification and thawed in subsequent cycles. The primary outcome measure was the incidence of severe OHSS. The secondary outcome measure was the clinical pregnancy rate in the first frozen-thawed embryo transfer cycle. One hundred and ten patients underwent 110 stimulated cycles were included for analysis. No patients developed moderate/severe OHSS. Mean E2 concentration on the day of final oocyte maturation was 7,873 pg/ml, and an average of 22.7 oocytes was obtained from each patient. One hundred and ten thawing cycles were performed, resulting in 69 clinical pregnancies (62.7 %). Combining cabergoline and embryo cryopreservation after GnRHa triggering in GnRH antagonist protocol could prevent OHSS in patients at very high risk.