Effect of GnRH agonist alone or combined with different low-dose hCG on cumulative live birth rate for high responders in GnRH antagonist cycles: a retrospective study.

BACKGROUND: There is insufficient evidence regarding the impact of dual trigger on oocyte maturity and reproductive outcomes in high responders. Thus, we aimed to explore the effect of gonadotropin-releasing hormone agonist (GnRHa) trigger alone or combined with different low-dose human chorionic gonadotropin (hCG) regimens on rates of oocyte maturation and cumulative live birth in high responders who underwent a freeze-all strategy in GnRH antagonist cycles. METHODS: A total of 1343 cycles were divided into three groups according to different trigger protocols: group A received GnRHa 0.2 mg (n = 577), group B received GnRHa 0.2 mg and hCG 1000 IU (n = 403), and group C received GnRHa 0.2 mg and hCG 2000 IU (n = 363). RESULTS: There were no significant differences in age, body mass index, and rates of oocyte maturation, fertilization, available embryo, and top-quality embryo among the groups. However, the incidence of moderate to severe ovarian hyperstimulation syndrome (OHSS) was significantly different among the three groups (0% in group A, 1.49% in group B, and 1.38% in group C). For the first frozen embryo transfer (FET) cycle, there were no significant differences in the number of transferred embryos and rates of implantation, clinical pregnancy, live birth, and early miscarriage among the three groups. Additionally, the cumulative ongoing pregnancy rate and cumulative live birth rate were not significantly different among the three groups. Similarly, there were no significant differences in gestational age, birth weight, birth height, and the proportion of low birth weight among subgroups stratified by singleton or twin. CONCLUSIONS: GnRHa trigger combined with low-dose hCG (1000 IU or 2000 IU) did not improve oocyte maturity and embryo quality and was still associated with an increased risk of moderate to severe OHSS. Therefore, for high responders treated with the freeze-all strategy, the single GnRHa trigger is recommended for final oocyte maturation, which can prevent the occurrence of moderate to severe OHSS and obtain satisfactory pregnancy and neonatal outcomes in subsequent FET cycles.

Early Follicular Phase Human Chorionic Gonadotropin Addition May Improve the Outcomes of In Vitro Fertilization/Intracytoplasmic Sperm Injection in Patients With "Unpredictable" Poor Response to Gonadotropin-Releasing Hormone Antagonist Protocol.

Purpose: To compare the effects of early and mid-late follicular phase administration of 150 IU of human chorionic gonadotropin (hCG) on gonadotropin-releasing hormone (GnRH) antagonist protocol in "unpredictable" poor ovarian response (POR) women undergoing in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) treatment. Methods: A retrospective single-center cohort study was conducted on 67 patients with "unpredictable" POR in their first IVF/ICSI cycle receiving GnRH antagonist protocol. Patients were treated with a second IVF/ICSI cycle using the same GnRH antagonist protocol with the same starting dose of recombinant follicle-stimulating hormone (rFSH) as the first cycle; a daily dose of 150 IU of hCG was administrated on either stimulation day 1 (Group A, n = 35) or day 6 (Group B, n = 32). The number of oocytes retrieved, number of usable embryos, serum level of estradiol (E2) on day of hCG trigger, and clinical pregnant outcomes were studied. Results: The addition of 150 IU of hCG on either the first day or sixth day of stimulation increases the serum level of E2, luteinizing hormone (LH), and hCG on the day of hCG trigger. Only the use of 150 IU of hCG on the first stimulation day improved the number of oocytes retrieved, mature of oocytes, and usable embryos, but not the addition of hCG on stimulation day 6. Implantation rate, clinical pregnancy rate, and ongoing pregnancy rate showed an increasing trend in patients receiving 150 IU of hCG in the early phase compared with mid-late phase, even thought there was no statistically significant difference. Conclusions: Our study demonstrated that adding 150 IU of hCG in subsequent GnRH antagonist cycle in "unpredictable" poor responders is associated with the improvement of response to stimulation. Furthermore, early follicular phase addition of 150 IU of hCG significantly increased the number of oocytes retrieved and usable embryos than did the mid-late addition of the same dose.

Luteal phase support after gonadotropin-releasing hormone agonist triggering: does it still matter?

Despite the increasing utilization of freeze-only IVF protocols, there is still a need for adequate management of the luteal phase after GnRH agonist trigger for patients who desire a fresh embryo transfer. Two approaches, intensive luteal support with E2 and P, and the use of adjuvant low-dose hCG either at the time of GnRH agonist trigger (dual trigger) or at the time of oocyte retrieval, have been shown to be effective in maintaining adequate pregnancy outcomes. The addition of low-dose hCG should be used with caution, because it may increase the risk of ovarian hyperstimulation syndrome. For patients with peak E2 of >4,000 pg/mL, we recommend against adding low-dose hCG, because intensive luteal support alone seems to provide adequate results.

The dual trigger study: Rationale and study design of a prospective double-blind randomized clinical trial comparing pregnancy rates after co-administration of low dose hCG at the time of GnRH agonist trigger or 35 h later for the prevention of OHSS.

Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic complication of controlled ovarian stimulation. The use of gonadotropin releasing hormone (GnRH) agonist for the trigger of oocyte maturation is effective in the prevention of OHSS although it may result in a lower pregnancy rate. The use of adjuvant low dose human chorionic gonadotropin (hCG) at the time of trigger or at the time of oocyte retrieval may improve pregnancy rates. The goal of this dual trigger study is to evaluate the safety and efficacy of the use of low dose hCG administered at the time of GnRH agonist trigger or 35 h later as well as the potential impact on pregnancy rates. The population will consist of 82 women undergoing IVF treatment who are at risk of developing OHSS. This study will be a single center prospective randomized double-blind placebo controlled trial. The randomization schedule will be administered by the Investigational Drug Services of the University. After controlled ovarian stimulation, induction of oocyte maturation will be achieved using a GnRH agonist and patients will be randomized to receive either low dose hCG 1000 IU at the time of trigger and placebo at oocyte retrieval (Study group) or placebo at the time of trigger and hCG 1500 IU at the time of oocyte retrieval (Control group). The main outcomes will be live birth rates and incidence of OHSS. Two ancillary studies will include a quality of life survey and serum assessment of independent corpus luteum function.

GnRH agonist with low-dose hCG (dual trigger) is associated with higher risk of severe ovarian hyperstimulation syndrome compared to GnRH agonist alone.

PURPOSE: The purpose of this study was to compare rates of ovarian hyperstimulation syndrome (OHSS) after using gonadotropin-releasing hormone agonists (GnRHa) alone and GnRHa in combination with low-dose human chorionic gonadotropin (hCG, dual trigger) for final oocyte maturation in women undergoing controlled ovarian hyperstimulation (COH). METHODS: A retrospective cohort study was conducted at an academic center. Study population included 108 women who received GnRHa trigger and 66 women who received dual trigger (GnRHa + low-dose [1000 IU] hCG trigger). The main outcome measure was OHSS. Secondary outcomes included total oocyte yield and oocyte maturity. RESULTS: The incidence of early OHSS was significantly higher after dual trigger than GnRHa trigger (8.6 vs 0 %). Moreover, four of the six patients that developed OHSS developed severe OHSS. Logistic modeling revealed that the combination of age, BMI, baseline AFC, and E2 >4000 pg/mL was predictive of OHSS with an area under the receiver operating characteristic curve of 0.84 and was superior to each factor alone. Adjusted analyses revealed that dual trigger was associated with a higher number of total oocytes (adjusted OR 1.27; 95 % confidence interval, 1.18, 1.38) and percentage of mature oocytes (AOR 1.10; 95 % confidence interval, 1.03, 1.17) obtained compared to GnRHa trigger alone. CONCLUSIONS: Dual trigger for final oocyte maturation using GnRHa and low-dose hCG is associated with a significantly increased risk of severe OHSS compared to GnRH alone. However, dual trigger may be associated with a modest increase in oocyte yield, both in terms of number and maturity.

Low-dose human chorionic gonadotropin alone can complete follicle maturity: successful application to modified natural cycle in vitro fertilization.

OBJECTIVE: To investigate the feasibility of utilizing low-dose hCG alone to complete follicle maturity in a natural cycle, without the need for antecedent exogenous FSH stimulation. DESIGN: Case series. SETTING: Academic fertility program. PATIENT(S): Normally ovulatory women with infertility thought to be predominantly due to male factor. INTERVENTION(S): Modified natural IVF cycles were conducted as follows: natural ovulatory cycles were monitored with serial ultrasound examinations and serum E2 determinations. When the lead follicle reached preovulatory status according to cycle day, ultrasound, and E2 levels, 0.25 mg of the GnRH antagonist ganirelix acetate was administered along with 200 IU of hCG. These medications were repeated daily for 2 to 3 days with further serial monitoring. A trigger dose of 10,000 IU of hCG was followed by follicle aspiration, IVF, and ET in a standard manner. MAIN OUTCOME MEASURE(S): Follicle maturity, live births, documentation of the feasibility of this new approach. RESULT(S): In all cases, E2 levels rose and the dominant follicle continued to increase in size in response to low-dose hCG after GnRH antagonist administration. Follicle aspiration yielded one or more mature oocytes. In vitro fertilization and ET resulted in live births. CONCLUSION(S): Low-dose hCG can be used to complete follicle maturity in a natural cycle without the need for antecedent exogenous FSH stimulation. This finding may have strong clinical utility in modified natural cycle IVF.

Daily low-dose hCG stimulation during the luteal phase combined with GnRHa triggered IVF cycles without exogenous progesterone: a proof of concept trial.

STUDY QUESTION: Can the luteal phase support be improved in terms of efficacy, hormonal profiles and convenience as compared with today's standard care? SUMMARY ANSWER: Daily low-dose rhCG supplementation in GnRHa triggered IVF cycles can replace the traditional used luteal phase support with exogenous progesterone. WHAT IS KNOWN ALREADY: A bolus of hCG for final maturation of follicles in connection with COS may induce the risk of OHSS and the luteal phase progesterone levels rise very abruptly in the early luteal phase. STUDY DESIGN, SIZE, DURATION: This is a proof-of-concept study conducted as a three arm RCT with a total of 93 patients. First patient enrolled in January 2012 and the study finished in January 2014. PARTICIPANTS/MATERIALS, SETTING, METHODS: Normal responder women undergoing IVF/ICSI treatment in a university hospital. One arm served as control, where women followed a standard antagonist protocol. Two study arms were included both having 125 IU hCG daily for luteal phase support without exogenous progesterone after using a GnRHa trigger for ovulation induction. In both study arms exogenous FSH was stopped on stimulation day 6 and replaced by exogenous hCG that was initiated on either stimulation day 2 or day 6. Blood samples were obtained on the day of ovulation induction, on the day of oocyte pickup (OPU) and day OPU + 7. MAIN RESULTS AND THE ROLE OF CHANCE: The mean serum levels of hCG did not exceeded the normal physiological range of LH activity in any samples. Mid-luteal progesterone levels were significantly higher in the two study groups receiving daily low-dose hCG for luteal phase support as compared with the control group (control group: 177 ± 27 nmol/l; study group 1: 334 ± 42 nmol/l; study group 2: 277 ± 27 nmol/l; (mean ± SEM). No differences in reproductive outcome were seen between groups. LIMITATIONS, REASONS FOR CAUTION: The number of patients included is limited and conclusions need to be verified in a larger RCT. WIDER IMPLICATIONS OF THE FINDINGS: Endogenous production of progesterone may become more attractive as the luteal phase support with levels of LH-like activity only in the physiological range and may, from the patients' point of view, replace inconvenient exogenous progesterone preparation. Further hCG may reduce the cost of stimulation and may collectively be used for stimulation of the follicular phase, ovulation induction and for luteal phase support. STUDY FUNDING/COMPETING INTERESTS: An unrestricted grant from ARTS Biologics made this study possible. None of the authors has any competing interests to declare. TRIAL REGISTRATION NUMBER: ClinicalTrial.gov number: NCT01504139. TRIAL REGISTRATION DATE: 28 December 2011.

Luteal phase supplementation after gonadotropin-releasing hormone agonist trigger in fresh embryo transfer: the American versus European approaches.

The challenges in attaining an adequate luteal phase after GnRH agonist (GnRHa) trigger to induce final oocyte maturation have resulted in different approaches focused on rescuing the luteal phase insufficiency so that a fresh transfer can be carried out without jeopardizing IVF outcomes. Over the years, two different concepts have emerged: intensive luteal support with aggressive exogenous administration of E2 and P; and low-dose hCG rescue in the form of a small dose of hCG either on the day of oocyte retrieva or on the day of GnRHa trigger (the so called "dual trigger"). Both approaches have been shown to be effective in achieving pregnancy rates similar to those obtained after conventional hCG trigger and resulting in a very low risk of ovarian hyperstimulation syndrome (OHSS). Although the idea of freezing all embryos after GnRHa trigger and transferring them in a subsequent frozen-thawed cycle has been gaining momentum, a fresh transfer leading to the live birth of a healthy child is currently considered to be the goal of IVF treatment.

Retrospective comparison of GnRH agonist trigger with HCG trigger in GnRH antagonist cycles in anticipated high-responders.

All IVF-ICSI cycles carried out between October 2009 and October 2012 using GnRH agonist (GnRHa) ovulation trigger (n = 62) followed by a single dose of HCG plus progesterone and oestradiol in the luteal phase because of anticipated ovarian hypertsimulation were retrospectively compared with historic control cycles using HCG trigger (n = 29) and standard luteal phase support. Women's mean age, body mass index, anti-Müllerian hormone, FSH, LH, starting and total stimulation dose, number of follicles, oocytes, embryos, fertilization, implantation, polycystic ovary syndrome, ICSI, live birth and ongoing pregnancy rates per embryo transfer were similar (GnRHa 40.7% versus HCG 35.0%). For each started cycle, GnRHa resulted in 11.4% higher (statistically non-significant) live birth and ongoing pregnancy rate (OR 1.73, CI 0.64 to 4.69), with a similar difference for double-embryo transfers (OR 1.62, CI 0.44 to 6.38) and less need for freezing all embryos (9.7% versus 27.6%; P = 0.04). Incidence of mild-to-moderate OHSS was 16.2% with GnRHa trigger and 31.0% with HCG trigger) and no severe OHSS in the former. The addition of single low-dose HCG in the luteal phase after GnRHa trigger for suspected high-responders reduced the incidence of OHSS with good clinical outcomes, compared with HCG trigger.

Improving the luteal phase after ovarian stimulation: reviewing new options.

The human chorionic gonadotrophin (HCG) trigger used for final follicular maturation in connection with assisted reproduction treatment combines ovulation induction and early luteal-phase stimulation of the corpora lutea. The use of a gonadotrophin-releasing hormone agonist (GnRHa) for final follicular maturation has, however, for the first time allowed a separation of the ovulatory signal from the early luteal-phase support. This has generated new information that may improve the currently employed luteal-phase support. Thus, combined results from a number of randomized controlled trials using the GnRHa trigger suggest an association between the reproductive outcome after IVF treatment and the mid-luteal-phase serum progesterone concentration. It appears that a minimum mid-luteal progesterone threshold of approximately 80-100 nmol/l exists, which, when surpassed, results in reduced early pregnancy loss and an increased live birth rate. Further, the trade off between the HCG bolus and the subsequent risk of ovarian hyperstimulation syndrome has resulted in a trend to reduce the HCG bolus from 10,000 IU to 6500-5000 IU, which augments the HCG/LH deficiency during the early/mid-luteal phase. The mid-luteal HCG/LH shortage results in an altered progesterone profile, showing the highest concentration during the early luteal phase, contrasting with the mid-luteal peak seen in the natural menstrual cycle.