Timing of human chorionic gonadotropin (hCG) hormone administration in IVF/ICSI protocols using GnRH agonist or antagonists: a systematic review and meta-analysis

Objective: To evaluate the effect of altering the timing of human chorionic gonadotropin (hCG) administration on the clinical outcome of in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) using gonadotropic hormone releasing hormone (GnRH) agonist or antagonist.

Methods: We systematically searched six databases. Randomized controlled trials (RCTs) of the effects of altering the timing of hCG administration on the clinical outcome of IVF and ICSI using GnRH agonist or antagonist were included. A meta-analysis was conducted following a quality evaluation performed with Cochrane Collaboration’s Review Manager (RevMan) 5.0.2.

Results: Seven RCTs and a total of 1295 participants were included. Significant difference was observed regarding estradiol and progesterone levels on the day of hCG administration and oocyte retrieval between early hCG and late hCG administration group and in favor of the latter. The fertilization rate was not statistically different between early and 24-h late hCG groups, but it is significantly higher in the 48-h late hCG group. The pooled results showed no significant differences in the ongoing pregnancy rate per oocyte pick-up, the miscarriage rate and the live birth rate.

Conclusion: The prolongation of follicular phase by delaying hCG administration could increase estradiol, progesterone levels and oocyte retrieval, which will not influence ongoing pregnancy rate per oocyte pick-up, miscarriage rate and live birth rate. Postponing hCG may enable increased flexibility of cycle scheduling to avoid weekend procedures.     

Progesterone elevation on the day of HCG administration may affect rescue ICSI

To investigate the relationship between serum progesterone concentration on the day of human chorionic gonadotrophin (HCG) administration and rescue intracytoplasmic sperm injection (ICSI), a total of 9858 patients who underwent IVF or rescue ICSI were retrospectively analysed. The results showed a significant difference in serum progesterone concentration on the day of HCG administration between the IVF group and rescue ICSI group (P < 0.01). Multivariate logistic regression showed that progesterone concentration was positively and significantly associated with rescue ICSI (OR 1.297, 95% CI 1.153–1.460, P < 0.001). Moreover, an increased rescue ICSI rate was associated with progressively higher progesterone concentrations in all cycles. In addition, patients with progesterone >1.5 ng/ml demonstrated a significantly higher rescue ICSI rate compared with patients with progesterone concentration ⩽1.5 ng/ml (P < 0.05). In conclusion, elevated progesterone on the day of HCG administration had an adverse effect on oocyte fertilization; thus, greater attention should be paid to these patients in an attempt to avoid fertilization failure, especially when progesterone is >1.50 ng/ml.For the issue of oocytes fertilization, most literatures have found the presence of a negative association between P elevation and fertilization. They suggested that P elevation may only influence the endometrium, leading to impaired endometrial receptivity and had no adverse effect on the fertilization of oocytes. On the contrary, we enrolled 9,858 fresh cycles and found elevated P had an adverse effect on the oocytes fertilization, especially if the P concentration >1.50 ng/mL. It is the first report about the relationship between the rescue ICSI and serum P levels.     

Early pregnancy loss rates were different among singleton gestations conceived by ICSI using GnRH agonist and antagonist

This study compared early pregnancy losses (termination of pregnancy before 12 weeks of gestation, EPL) among conceptions achieved by ICSI according to the type of GnRH analogue for ovarian stimulation. Only singleton gestations (2,184) and fresh embryo transfers were included. GnRH agonist was used in 848 gestations out of 2,184 and GnRH antagonist was used in the remaining 1,336 gestations. EPL was found to be significantly higher in GnRH antagonist gestations compared to GnRH agonist (27.2% vs 18.9%). This significant difference persisted when gestations were segregated according to maternal age, especially among women younger than 35 years old. Therefore our results suggest that gestations conceived by ovarian stimulation including GnRH antagonists may have higher propabilty of having EPL.     

A comparative study on oxidative and antioxidative markers of serum and follicular fluid in GnRH agonist and antagonist cycles

Objective

To determine whether concentrations of oxidative stress markers of follicular fluid and serum are different in GnRH agonist protocol from GnRH antagonist protocol.

Material and method

This was a cross-sectional study. Eighty-four women undergoing controlled ovarian stimulation with either GnRH agonist (n = 39) or GnRH antagonist protocols (n = 45) for IVF/ICSI treatment were assigned by a physician. Blood was obtained at the time of oocyte retrieval, and follicular fluid (FF) from the mature follicles of each ovary was centrifuged and frozen until analysis. Malondialdehyde (MDA), nitric oxide (NO), protein carbonyl (PC), hydroxyl proline (OH-P), sodium oxide dismutase (SOD), reduced glutathione (GSH), glutathione peroxidase (GSH-Px), adenosine deaminase (ADA) and xanthine oxidase (XO) were assessed in the serum and follicular fluid of each participants.

Results

The mean serum concentrations of GSH-Px, GSH and MDA were lower in the GnRH antagonist group compared to GnRH agonist group, but mean serum SOD was higher in the GnRH antagonist group. The mean follicular SOD, ADA and NO were higher in GnRH antagonist group than GnRH agonist group. The IVF/ICSI outcomes were similar in both groups.

Conclusion(s)

GnRH antagonist protocol is associated with increased oxidative stress. The relation of GnRH analogues with oxidative stress and its implication in follicular growth needs to be addressed in further studies.     

Progesterone level significance in agonist versus antagonist protocols

Objective

to evaluate the impact of serum progesterone level on the clinical outcome across agonist & antagonist protocols.

Impact of estradiol and progesterone levels during the late follicular stage on the outcome of GnRH antagonist protocols

Abstract

The study aimed to assess the impacts and the targets of progesterone (P4) and estradiol (E2) levels on IVF outcomes in GnRH antagonist protocols. The study was retrospective and concerned patients for their first fresh embryo transfers, after stimulation by a recombinant FSH (rFSH)-GnRH antagonist protocol, between September 2012 and July 2017 in the Toulouse University Hospital. Multivariable analysis, taking into account female age and the ovarian stimulation index, showed that E2 levels had no impact on IVF outcomes, while high P4 levels (>1.10?ng/mL) were associated to low pregnancy rate. The P4 concentrations were significantly negatively correlated to the percentage of top embryos and to the implantation rate. Therefore, the deleterious effect of high levels P4 could to act mainly by impairing embryo quality, which questions the place of the freeze-all strategy in these cases.     

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.     

Scheduling GnRH antagonist cycles by a short course of oral estradiol administration during early follicular phase: a comparative study with non-scheduled cycles

Abstract

This hypothesis generating study investigated whether GnRH antagonist cycles can be scheduled by a short course of oral estradiol administration during the follicular phase without impairing treatment outcome. Thirty-five women who underwent follicular phase estrogen scheduling (ES) of GnRH antagonist cycles were retrospectively matched for age and number of prior failed cycles with 35 women who underwent unscheduled GnRH antagonist cycles. ES group was given 6?mg/day estradiol orally from cycle day 2 until (including) one day before the scheduled start of stimulation. Gonadotropins were started on cycle days 2–3 in the control group. Flexible GnRH antagonist protocol was employed in both groups. ES group received estradiol for a median of 5 days. Total gonadotropin consumption was similar but one more GnRH antagonist injection was required in the ES group. Endometrial thickness on the day of hCG injection was increased in the ES group (12 versus 10?mm, p?<?0.01). Number of oocytes, metaphase II oocytes and transferred embryos were similar. Embryo implantation rates were 44.8% versus 34.4% (p?=?0.3), and clinical pregnancy rates were 48.6% versus 37.1%, (p?=?0.33) in the ES and control groups, respectively. All women in the ES group had oocyte retrieval and embryo transfer within the desired period.     

Effect of in vivo GnRH agonist and GnRH antagonist on hCG and insulin-stimulated progesterone production by human granulosa-lutein cells in vitro

Purpose : To investigate hCG and insulin-stimulated progesterone (P) production by human granulosa-lutein cells (hGLC) in vitro. Methods : hGLCs were isolated from patients undergoing IVF-ET cycles in which GnRH agonist or GnRH antagonist was used to prevent a midcycle gonadotropin surge. The cells were cultured for 3 days, and then treated with hCG 0.5, 1, and 10 IU/I, and insulin 0.01, 0.1, and 1 M in serum free conditions. In vitro P production was measured by enzyme immunoassay. Results : hCG stimulated P production by hGLCs from cycles in which GnRH antagonist was used, but a blunted response was seen in GnRH-agonist treated cycles. Insulin-stimulated P production was similar in cells from cycles in which GnRH-agonist or GnRH-antagonist treatment was used. Conclusions : Because insulin and hCG may share common pathways beyond the level of receptor activation, we hypothesize that GnRH agonist, but not GnRH antagonist, may affect the expression and/or activation of LH receptors in the hGLCs.     

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.     

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.     

Follicular growth and oocyte maturation in GnRH agonist and antagonist protocols for in vitro fertilisation and embryo transfer

Background.?The aim of this study was to evaluate the response to treatment in a group of patients undergoing IVF and randomised to receive GnRH-antagonist or the GnRH-agonist. The endpoints were the pattern of follicular growth, the maturity of the oocytes collected, the embryo quality and the pregnancy outcome.

Methods.?A total of 136 patients undergoing IVF were included. Sixty-seven patients were allocated to the GnRH antagonist and 69 patients to the GnRH agonist. GnRH antagonist was administered when the leading follicle reached a diameter of 12–14 mm. GnRH agonist was administered in a long luteal protocol.

Results.?The mean numbers of oocytes retrieved and mature oocytes were significantly higher in the agonist than in the antagonist group (p < 0.02 and p < 0.01, respectively). Embryo quality, implantation rate, clinical pregnancy rates, ongoing pregnancy rate and miscarriage rate were similar in both groups.

Conclusions.?Better follicular growth and oocyte maturation are achieved with GnRH agonist treatment. However, both regimens seem to have similar efficacy in terms of implantation and pregnancy rates. Further studies clarifying the effect of the GnRH antagonist on ovarian function are needed, as well as a clear definition of the best period of the follicular phase for the GnRH antagonist administration.     

The use of gonadotropin-releasing hormone antagonist in a flexible protocol: a pilot study

OBJECTIVE: The purpose of this study was to investigate the efficacy of a flexible protocol of starting gonadotropin-releasing hormone antagonist according to the size of the leading follicle. STUDY DESIGN: This was a pilot study that included 123 couples who were undergoing in vitro fertilization/intracytoplasmic sperm injection cycles at the Egyptian IVF-ET Center. Couples were recruited into two groups: group I (n=64), gonadotropin-releasing hormone antagonist was administered when the diameter of the leading follicle reached 16 mm; group II (n=59), gonadotropin-releasing hormone antagonist was administered on day 6 of stimulation. RESULTS: The mean number of antagonist injections was significantly lower in the flexible protocol compared to the fixed protocol (3.4+/-1.1 vs 5.3+/-1.8, P<.05). There was no significant difference between the two protocols regarding the number of embryos, implantation rate, clinical pregnancy rate (odds ratio, 0.85; 95% CI, 0.45-1.59) or multiple pregnancy rate (odds ratio, 1.26; 95% CI, 0.45-3.51). CONCLUSION: Starting the gonadotropin-releasing hormone antagonist according to the size of the leading follicle is as effective as starting on a fixed day and reduces the antagonist administration.     

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.