Gonadotropin-releasing Hormone Antagonist Cycles Research Articles

Effects of letrozole co-treatment on outcomes of gonadotropin-releasing hormone antagonist cycles in POSEIDON groups 3 and 4 expected poor responders.

To evaluate the effects of adjuvant letrozole administration on outcomes of gonadotropin-releasing hormone (GnRH) antagonist cycles with intra-cytoplasmic sperm injection in POSEIDON groups 3 and 4 expected poor responder women. This study was conducted by retrospective analysis of patients with expected poor ovarian response (POSEIDON groups 3 and 4) that underwent GnRH antagonist cycles with intra-cytoplasmic sperm injection between 2010 and 2020. A total of 488 patients with letrozole co-administration and 2564 patients without any adjuvant treatment that underwent GnRH antagonist cycles within the selected period of time were included in the study. Implantation rates, clinical pregnancy rates and live birth delivery rates were significantly higher in letrozole administered patients in comparison to controls among POSEIDON group 3 women (0.39 ± 0.46 vs 0.27 ± 0.40, p = 0.01; 46.1% vs 33%, p = 0.014; 42.7% vs 31.5%, p = 0.034, respectively). Mean total doses of gonadotropins required per cycle were significantly lower in letrozole administered patients among both POSEIDON groups 3 and 4 women (2864.65 ± 878.47IU vs 3757.27 ± 1088.89IU, p < 0.001; 3286.06 ± 770.16IU vs 3666.48 ± 959.66IU, p < 0.001, respectively). Adjuvant letrozole co-administration in intra-cytoplasmic sperm injection cycles following GnRH antagonist protocol appears to improve implantation, clinical pregnancy and live birth delivery rates in women with POSEIDON group 3 expected poor ovarian response.

P-569 Reduction of gonadotropin-dosage towards the end of ovarian stimulation for IVF/ICSI improves ART-outcome in a subgroup of patients

Abstract Study question To identify in an unselected patient population those patients, who would benefit from a gonadotropin stepdown towards the end of ovarian stimulation in IVF/ICSI-treatment Summary answer Reduction of gonadotropin-dosage during ovarian stimulation for IVF/ICSI is beneficial in FSH-stimulated patients, aged 26-30 years, and in HMG-stimulated patients, aged 36-40 years of age What is known already Ovarian stimulation with gonadotropins for multi-follicular growth is a crucial part of IVF/ICSI-treatment. Intensive administration of gonadotropins might lead to progesterone elevation (PE) in the late follicular phase, impacting negatively the endometrial receptivity and possibly the embryo quality. During follicular growth, the number of FSH- and LH-receptors shift from predominantly FSH-receptors in the early to predominantly LH-receptors in the late follicular phase, reducing susceptibility of the follicle towards systemic FSH-levels. In a good prognosis population, it was shown that lower systemic FSH-levels on the trigger-day lead to significantly lower progesterone levels without reducing the number of retrieved/mature oocytes. Study design, size, duration Retrospective analysis of 1276 ovarian stimulation cycles, performed as GnRH (Gonadotropin-Releasing-Hormone)-antagonist protocol in an unselected patient population, between January 2018 and December 2020 at ART Fertility Clinic, Abu Dhabi, UAE. Ovarian stimulation cycles were split according to the stimulation medication used (either only recombinant FSH (rFSH) or only human menopausal gonadotropin (HP-HMG)) and whether stimulation-dosage was reduced (reduction group, RG) during the stimulation course or not (non-RG). Furthermore, patients were stratified into age-groups. Participants/materials, setting, methods Couples with primary / secondary infertility and an indication for ovarian stimulation for IVF/ICSI were included, independent of their age or ovarian reserve parameters. Only GnRH antagonist cycles, with either rFSH or HP-HMG as sole medication for ovarian stimulation and available data on Antral Follicle Count (AFC), gonadotropin-dosage at stimulation-start and -end, oocyte yield (number of retrieved / mature) and hormonal parameters of estradiol, progesterone and FSH were included. Main results and the role of chance A total of 1276 ovarian stimulation cycles were included, 495 (38.79%) with rFSH and 781 (61.21%) with HP-HMG as stimulation medication. In the FSH-group, 295 patients reduced (reduction-group=RG) and 200 did not reduce (=non-RG) FSH-dosage during stimulation. In all age-categories (&amp;lt;25; 26-≤30; 31-≤35; 36-≤40; 41-45years), FSH-end-dosage was significantly lower in the RGs compared to the non-RGs (p &amp;lt; 0.001, respectively). Despite not significantly different patient characteristics (AFC, BMI (Body Mass Index), mean age, FSH-starting dosage), in patients aged 26-≤30years, a significantly higher number of oocytes (retrieved/mature) were obtained in the RG (16.0±7.1 vs 20.4±8.3;p&amp;lt;0.001 / 12.6±6.5 vs 15.8±7.0;p=0.004, respectively) without an increase in progesterone-levels (1.0±1.3 vs 0.9±0.6ng/ml;p=0.95). The HP-HMG group was composed of 437 patients in the RG and 344 patients in the non-RG-group. In all age-categories (&amp;lt;25; 26-≤30; 31-≤35; 36-≤40; 41-52years), HP-HMG-end-dosage was significantly lower in the RGs (p &amp;lt; 0.001, respectively). The age-group 36-≤40 showed no significant differences in AFC, BMI, age and HP-HMG-starting-dosage, and still, a significantly higher number of oocytes (retrieved/mature) were obtained in the RG-group (7.2±5.61 vs 9.8±6.13;p&amp;lt;0.001 / 5.7±4.7 vs 7.8±5.0;p&amp;lt;0.001, respectively). The progesterone-levels on trigger day in the nRG-group was 0.5±0.3ng/ml and 0.6±0.4ng/ml in the RG group, which is significantly different (p &amp;lt; 0.001), however, clinically insignificant. Limitations, reasons for caution The retrospective design is a limitation to this study as well as the exclusion of ovarian stimulation cycles, which were cancelled and no oocyte pick-up procedure was performed. Furthermore, in some age-categories, patients in RG and non-RG were different regarding their basic characteristics. Wider implications of the findings This analysis demonstrates, that in specific patient populations, gonadotropin-dosage can be reduced without impacting the oocyte yield and preventing progesterone-elevation despite higher oocyte yield. Furthermore, reduction of gonadotropins towards the end of the follicular phase results in a more physiologic course of the gonadotropin-levels during ovarian stimulation. Trial registration number not applicable

P-657 Administration of an extra Gonadotropin dose on trigger day in patients undergoing elective egg freezing

Abstract Study question Does an extra Gonadotropin (GT) dose on trigger day during a gonadotropin-releasing hormone (GnRH) antagonist cycle for oocyte cryopreservation result in improved cycle outcomes? Summary answer An extra GT dose on trigger day in patients undergoing elective egg freezing is not associated with increased oocyte yield. What is known already The most common controlled ovarian hyperstimulation (COHS) protocol used in elective oocyte cryopreservation cycles is a GnRH antagonist protocol with a GnRH agonist trigger. There is no consensus about the timing of the final gonadotropin dose administration. Some physicians add an extra GT dose during the ovulation trigger day and others advise to receive the last GT dose the day before. The yield of this extra GT dose was not previously evaluated. Study design, size, duration A retrospective cohort study, consisting of cycles of elective oocyte cryopreservation at Hadassah Medical Center from 1.2017 through 5.2021. Patients were divided into 2 groups- women who received their last GT dose a day before the GnRH agonist trigger, and women who received the last GT on the trigger day. Background and gynecologic characteristics, as well as COHS cycle parameters, were compared. The primary outcome was the average number of mature oocytes in each group. Participants/materials, setting, methods Women 30-41 years who were admitted for elective oocyte cryopreservation. Women who were referred due to medical reasons or cycles with a protocol other than GnRH antagonist were excluded. Ovarian stimulation with GT began on the 3rd day of the cycle, and five days later, a GnRH antagonist was added. When more than two mature follicles were demonstrated, a GnRH agonist trigger was administrated and approximately 36 hours later, the oocyte aspiration procedure was performed Main results and the role of chance During the study period, 448 elective egg freezing cycles were performed, 151 cycles with an extra dose on the trigger day and 297 cycles without an extra GT dose. The groups did not differ in their background characteristics, age, BMI, GT used, and the number of induction days. However, the extra GT group had significantly higher day 3 follicular stimulating hormone (FSH), lower anti-Mullerian hormone (AMH), and lower maximal Estradiol (E2) levels. The extra GT dose group had a significantly lower mean number of mature oocytes (11.1±7.1 vs. 6.4±4.5, p &amp;lt; 0.001). To adjust for the maximal E2 parameter, that differed between the groups, an additional analysis was performed, dividing the two groups into subgroups of cycles with maximal E2 above and below 10,000 pmol\l. Interestingly, even in cycles with maximal E2 above 10,000 pmol\l, the extra dose group had poorer results (10.3±4.3 vs. 12.7±7.2, p &amp;lt; 0.001). This difference was also noted in cycles with E2 below 10,000 pmol\l (5.4±4.0 vs 8.7±6.1 mature oocytes, p = 0.011). Additionally, a multiple regression model for the prediction of several oocytes retrieved showed that the extra GT dose parameter was not associated with increased oocytes number. Limitations, reasons for caution The retrospective design of this study and the differences in cycle characteristics between patients that did or did not receive an extra GT dose on trigger day make it prone to selection bias. Wider implications of the findings Our study shows that administration of an extra GT dose on trigger day in oocyte cryopreservation cycles does not yields more mature oocytes. However, wider prospective studies are needed to thoroughly investigate the implications of this treatment’s effect on cycle outcomes. Trial registration number Not applicable

Effects of growth hormone co-treatment on in vitro fertilization outcomes in women with expected normal ovarian response

Objective:This study aimed to evaluate the effects of adjuvant growth hormone (GH) therapy on in vitro fertilization outcomes in women with infertility with expected normal ovarian response who underwent gonadotropin-releasing hormone (GnRH) antagonist protocol with dual triggering.Materials and Methods:Records of women who underwent GnRH antagonist cycles with dual triggering in a single tertiary center between 2017 and 2020 were retrospectively analyzed. A total of 1054 women with expected normal ovarian response were evaluated, of which 131 were found to receive GH co-treatment (study group). Moreover, 950 women did not receive any adjuvant therapy (control group). Their cycle outcomes were compared.Results:The number of retrieved oocytes, oocyte maturation rates, quality of embryos, miscarriage rates, and multiple pregnancy rates were comparable among women who underwent GnRH antagonist cycles with and without GH co-treatment. The number of obtained 2PN embryos (5.68±2.46 vs 5.06±2.5; p=0.003), fertilization rates (0.84±0.16 vs 0.76±0.18; p<0.001), implantation rates (0.34 vs 0.25; p=0.006), clinical pregnancy rates (50.4% vs 38%; p=0.008), and live birth delivery rates (41.8% vs 32.2%; p=0.007) were significantly higher in women who received GH co-treatment.Conclusion:GH co-treatment significantly increased the clinical pregnancy rates and live birth delivery rates in women with infertility and expected normal ovarian response who underwent GnRH antagonist protocol with dual triggering for oocyte maturation, which was possibly due to the increasing endometrial receptivity or improving oocyte quality.

Adding Low Dose hCG to rFSH in GnRH Antagonist ICSI Cycles: A Randomized Controlled Trial

Inhibition of luteinizing hormone (LH) by gonadotropin releasing hormone (GnRH) antagonist may lead to suboptimal response during ovarian stimulation. In addition, several studies suggest that low level of LH is associated with lowered fertilization and implantation rate and increased early pregnancy loss rate. The aim of this study is to study the effect of adding low dose human chorionic gonadotropin (hCG - 200 IU), as an LH supplement, to recombinant follicle stimulating hormone (rFSH) in a GnRH antagonist cycles in women undergoing in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) treatment. Sixty-three infertile women undergoing IVF were randomly divided into two groups. One group was stimulated with the conventional stimulation protocol (rFSH alone), while the second group received 200 IU hCG in addition to rFSH in the late follicular phase (hCG + rFSH). Both groups' results including pregnancy rate, total dose of rFSH required, duration of stimulation, endometrial thickness, oocytes and embryos characteristic, serum hormone levels (Testosterone, Estradiol, Progesterone, and LH) and level of epidermal growth factor (EGF) were compared. The results show that pregnancy rate among the group of women who received the low dose hCG was higher than those who did not receive hCG. However, this difference did not reach statistical significance. Furthermore, other cycle outcomes and hormonal values were comparable between the two stimulation protocols.

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.

PurposeTo 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.MethodsA 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.ResultsThe 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.ConclusionsOur 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.

Supplementation with human menopausal gonadotropin in the gonadotropin-releasing hormone antagonist cycles of women with high AMH: Pregnancy outcomes and serial hormone levels

ObjectiveTo evaluate the value of using both HMG and recombinant FSH (r-FSH) in the GnRH antagonist protocol for women with high AMH. Materials and methodsThis retrospective, single-center cohort study was conducted from January 2013 to December 2018. Of 277 GnRH antagonist IVF/ICSI cycles in women with anti-Mullerian hormone (AMH) ≥5 μg/L, 170 cycles receiving the combination of r-FSH and HMG (77 with HMG added at the beginning of the GnRH antagonist cycle and 93 with HMG added after GnRH antagonist administration) and 107 cycles receiving r-FSH alone were analyzed. The dynamic hormone profiles and embryonic and clinical outcomes of the patients were evaluated. ResultsWe observed significantly lower serum LH levels in the r-FSH + HMG groups during ovarian stimulation. The serum estradiol and progesterone levels were lower in the r-FSH + HMG groups on the trigger day. Nevertheless, there were no significant differences with respect to the number of oocytes retrieved, maturation, fertilization, blastocyst formation rate or ovarian hyperstimulation syndrome (OHSS). The implantation and live birth rates were increased in the r-FSH + HMG groups compared with the r-FSH alone group, with no statistical significance. ConclusionsHMG for LH supplementation in the GnRH antagonist protocol for patients with high AMH is not significantly superior to r-FSH alone in terms of ovarian response and pregnancy outcome. Nevertheless, HMG supplementation might be appropriate for women with an initially inadequate response to r-FSH or intracycle LH deficiency.

Comparison of clinical outcomes between the depot gonadotrophin-releasing hormone agonist protocol and gonadotrophin-releasing hormone antagonist protocol in normal ovarian responders

BackgroundThe gonadotrophin-releasing hormone (GnRH) antagonist protocol has some advantages, such as a simple method, short medication duration, and low incidence of ovarian hyperstimulation syndrome, but whether the GnRH antagonist protocol is suitable for normal ovarian responders has been controversial. We compared the clinical outcomes of fresh and frozen-thawed transfer cycles between the depot GnRH agonist protocol and GnRH antagonist protocol in normal ovarian responders.MethodsData of normal ovarian responders who underwent in vitro fertilization-embryo transfer (IVF-ET) or intracytoplasmic sperm injection-embryo transfer (ICSI-ET) between January 2017 and December 2018 in our hospital were retrospectively analysed. In this study, there were 1119 fresh transfer cycles, including 502 GnRH antagonist cycles (GnRH antagonist group) and 617 depot GnRH agonist cycles (depot GnRH agonist group), as well as 468 frozen-thawed transfer cycles, includng 191 GnRH antagonist cycles (GnRH antagonist group) and 277 depot GnRH agonist cycles (depot GnRH agonist group). The clinical outcomes were compared between the GnRH antagonist group and the depot GnRH agonist group.ResultsWith the fresh transfer cycles, there were no statistically significant differences in the anti-Mullerian hormone level, number of transferred embryos or high-quality embryo rate between the two groups. The total dosage of gonadotropin (Gn), duration of Gn stimulation, number of oocytes retrieved, clinical pregnancy rate and incidences of moderate and severe ovarian hyperstimulation syndrome (OHSS) were significantly lower but the abortion rate was significantly higher in the GnRH antagonist group than in the depot GnRH agonist group (all P < 0.05). With the frozen-thawed transfer cycles, there were no statistically significant differences in the number of transferred embryos, clinical pregnancy rate or abortion rate between the two groups (all P > 0.05).ConclusionsWith the fresh transfer cycles, the GnRH antagonist protocol had a lower clinical pregnancy rate and lower incidences of moderate and severe OHSS than the depot GnRH agonist protocol, but with the frozen-thawed transfer cycles, both protocols had similar clinical pregnancy rates. These results remain to be further confirmed through large-sample, prospective, randomized and controlled studies.

Dual Trigger with Gonadotropin-releasing Hormone Agonist and Human Chorionic Gonadotropin Improves Live Birth Rate for Women with Expected Normal Ovarian Response in Gonadotropin Releasing Hormone Antagonist Cycles: Retrospective Study

Objective: To evaluate and compare cycle outcomes following triggering final oocyte maturation with dual trigger of concomitant gonadotropin-releasing hormone (GnRH) agonist and human chorionic gonadotropin (hCG) administration versus hCG alone for women with expected normal ovarian response that underwent antagonist cycles with intracytoplasmic sperm injection (ICSI). Material and Methods: Women with expected normal ovarian response that underwent GnRH antagonist cycles with ICSI between January 2010 and April 2020 were evaluated in this retrospective cohort study. A total of 2,443 patients were included. Dual trigger was used for oocyte maturation in 637 cycles whereas hCG alone was used for triggering in 1,806 women. Cycles with dual trigger were assigned to study group and cycles with hCG alone are taken as controls. Results: Number of retrieved oocytes (14.08±3.58 vs. 13.15±3.61), number of metaphase 2 oocytes (9.77±3.08 vs. 8.06±3.14), fertilization rate (0.75±0.19 vs. 0.69±0.19), implantation rate (0.43±0.48 vs. 0.35±0.50) and clinical pregnancy rate (49.9% vs. 40.6%) were significantly higher in dual trigger group in comparison to hCG alone group. Higher number of good quality embryos were obtained in dual trigger group (85.7% vs. 76.3%). Live birth rate was significantly increased in dual trigger group in comparison to hCG only trigger group (45.1% vs. 36.7%). Multivariate logistic regression analysis showed dual trigger is a significant factor in predicting live birth deliveries (odds ratio 1.426, 95% confidence interval 1.185-1.716). Conclusion: Dual-triggering appears to improve embryo quality, increase implantation rates, clinical pregnancy rates and live birth rates in women with expected normal ovarian response that underwent GnRH antagonist cycles.

Randomized, assessor-blind, antimüllerian hormone–stratified, dose-response trial in Japanese in vitro fertilization/intracytoplasmic sperm injection patients undergoing controlled ovarian stimulation with follitropin delta

To establish the relationship between follitropin delta doses (recombinant follicle-stimulating hormone produced from the human cell line PER.C6) and ovarian response in Japanese women undergoing invitro fertilization/intracytoplasmic sperm injection treatment and to evaluate the influence of initial antimüllerian hormone (AMH) levels. Randomized, controlled, assessor-blind, AMH-stratified (low 5.0-14.9 pmol/L; high 15.0-44.9 pmol/L) dose-response trial. Reproductive medicine clinics. A total of 158 Japanese women (20-39 years of age). Controlled ovarian stimulation with 6, 9, or 12 μg/d of follitropin delta or 150 IU/d follitropin beta as a reference arm in a gonadotropin-releasing hormone antagonist cycle. Number of oocytes retrieved. Among all women who started stimulation, the mean number (± standard deviation) of oocytes retrieved in the 6 μg/d, 9 μg/d, and 12 μg/d follitropin delta groups was 7.0 ± 4.1, 9.1 ± 5.6, and 11.6 ± 5.6, respectively, and a significant dose-relation was established, which also remained significant within each AMH strata. Significant dose-responses also were observed for serum estradiol, inhibin A, and progesterone at end-of-stimulation with follitropin delta. The vital pregnancy rate per started cycle with follitropin delta was 19% for 6 μg/d, 20% for 9 μg/d, and 25% for 12 μg/d. The rate of early moderate/severe ovarian hyperstimulation syndrome with follitropin delta was 8% for 6 μg/d, 8% for 9 μg/d, and 13% for 12 μg/d, with 82% of the cases in the high AMH stratum. This trial establishes the dose-response relationship between follitropin delta and ovarian response in Japanese women. NCT02309671.

GnRH agonist in association with hCG versus hCG alone for final oocyte maturation triggering in GnRH antagonist cycles

Objective:To analyze gonadotropin-releasing hormone (GnRH) agonist in association with human chorionic gonadotropin (hCG) (dual triggering) versus hCG alone (conventional triggering) for final oocyte maturation triggering in GnRH antagonist cycles in an unselected population of Brazilian women.Methods:This prospective case-control study involved 114 patients referred to autologous in vitro fertilization treatment between February 2018 and August 2019, recruited regardless of age, infertility factor or number of cycles. The patients were randomly allocated into two groups according to oocyte maturation triggering approach: group A (n = 48) - hCG only; and group B (n = 66) - hCG plus GnRH agonist. The main outcomes measured were the number of total and metaphase II (MII) oocytes retrieved.Results:The groups were homogenous in terms of age. There were no moderate or severe ovarian hyperstimulation syndrome events. There were no statistical differences concerning total or MII oocytes retrieved between the groups (p > 0.05). The MII/total oocyte rate was 70.9% in group A, and 74.5% in group B (p = 0.679). There was no oocyte retrieved in 2/48 patients (4.16%) in group A, 1/66 (1.5%) in group B. There were no MII oocytes in 4/48 patients (8.3%) in group A, and 2/66 (3%) in group B. Age was directly correlated to the number of total and MII oocytes retrieved (p < 0.05).Conclusions:Dual triggering was equivalent to conventional hCH triggering in terms of the number of total and MII oocytes retrieved in the general population. Further studies are necessary to ascertain dual triggering indication in selected groups of women.

Endometrial preparation for women undergoing embryo transfer with frozen embryos or embryos derived from donor oocytes.

Endometrial preparation for women undergoing embryo transfer with frozen embryos or embryos derived from donor oocytes.

Effectiveness and safety of follitropin alfa (Ovaleap\xae) for ovarian stimulation using a GnRH antagonist protocol in real-world clinical practice: a multicenter, prospective, open, non-interventional assisted reproductive technology study

BackgroundThe use of recombinant human follicle-stimulating hormone (r-hFSH) in ovarian stimulation protocols for infertility treatment in assisted reproductive technology (ART) clinical practice is well established. More recent advancements include the availability of biosimilar r-hFSH products, which expand the choices available to healthcare practitioners and patients. Better understanding of how such a product contributes to routine clinical practice is valuable to help prescribers make informed treatment choices. The objective of this study was to examine the effectiveness and safety of ovarian stimulation (OS) with follitropin alfa (Ovaleap®) for routine IVF or intracytoplasmic sperm injection treatment in gonadotropin-releasing hormone (GnRH) antagonist cycles in real-world ART clinical practice.MethodsThis non-interventional, multicenter, prospective study was initiated in 34 specialized reproductive medicine centers in Germany. Eligible women were 18–40 years old with a body mass index < 30 kg/m2, menstrual cycle 24–35 days and anti-Müllerian hormone ≥1 ng/mL, who were undergoing a first OS cycle exclusively with Ovaleap® during routine ART using a GnRH antagonist protocol. Primary effectiveness outcomes were number of retrieved oocytes after OS and clinical pregnancy rate (CPR). Secondary outcomes included fertilization rate, number of transferred embryos, live birth delivery rate, safety, and user satisfaction with the Ovaleap® pen.Result(s)Of 507 women screened, 463 received at least 1 dose of Ovaleap® and 439 had Visit 2 data (per protocol population; PPP). The mean(±SD) number of retrieved oocytes was 11.8 ± 7.2 (PPP). The CPR among women with documented embryo transfer was 41.3% (158/383), resulting in a live birth delivery rate of 31.6% (138/437) among PPP patients with available follow-up information. Overall, 8.6% (40/463) of women reported ≥1 adverse drug reaction. Ovarian hyperstimulation syndrome occurred in 23 (5.0%) patients, rated mild in 14 (3.0%), moderate in 8 (1.7%), and severe in 1 (0.2%). Patients reported high user satisfaction and high convenience with use of the Ovaleap® pen.ConclusionThe effectiveness and safety of OS with Ovaleap® in a GnRH antagonist protocol were extended to real-world ART clinical practice for the first time.Trial registrationRegistered on 22 June 2016 (retrospectively registered) at ClinicalTrials.gov (NCT02809989).

Dual trigger using recombinant HCG and gonadotropin-releasing hormone agonist improve oocyte maturity and embryo grading for normal responders in GnRH antagonist cycles: Randomized controlled trial

ObjectivesTo evaluate the effectiveness of dual trigger using gonadotropin-releasing hormone (GnRH) agonist and recombinant human chorionic gonadotropin (rHCG) versus rHCG alone for normal responders in GnRH antagonist intracytoplasmic sperm injection (ICSI) cycles. Patients and methodsThe current study was a registered open-labeled randomized controlled trial (clinical trial.gov: NCT02916173) conducted in the ART Unit of a tertiary University hospital between October 2016 and October 2018. The study participants were randomized to either group I (HCG group) or group II (dual trigger group). The primary outcome was the number of mature (MII) oocytes in both groups. ResultsBoth groups were similar regarding the baseline demographic and clinical characteristics. Women in the dual trigger group had a statistically significant higher number of retrieved oocytes (p = 0.001), MII oocytes (p = 0.01) and the number of grade one embryos (p = 0.04). Both groups were similar regarding the fertilization, implantation, clinical pregnancy and live birth rates in a fresh cycle. Dual trigger group was significantly higher in the clinical pregnancy rate and live birth rate after frozen embryo transfer (p = 0.04, 0.03, respectively). ConclusionDual trigger by GnRH agonist and rHCG improve the oocyte maturity and embryo grading for normal responders in GnRH antagonist ICSI cycles.

Diminished ovarian reserve predisposes to premature luteinizing hormone surges in gonadotropin-releasing hormone antagonist cycles in In vitro fertilization

Context/Background:A premature luteinizing hormone (LH) surge, in in vitro fertilization (IVF) cycles with gonadotropin-releasing hormone (GnRH)-antagonist downregulation, leads to cycle cancellation. Currently, risk factors for the development of premature LH surge remain unknown.Objective:The aim of the study was to determine the incidence and identify the contributing factors for premature LH surge in IVF cycles with GnRH antagonist suppression.Design:This was a retrospective cohort study.Setting:IVF-embryo transfer program at a fertility and research center.Materials and Methods:The study included all patients undergoing IVF from December 1, 2014, to November 30, 2018, in whom GnRH-antagonist (cetrorelix 0.25 mg/d) flexible protocol was used. The primary outcome measure was the identification of premature LH surges (documented by a 2.5-fold increase in LH from the baseline above a threshold of 17 mIU/mL) with or without a decrease in E2 and appearance of free fluid on ultrasound.Results:Premature LH surges occurred in 15 (2.16%) of 692 patients undergoing IVF with GnRH-antagonist suppression. Patients with premature surges had significantly lower ovarian reserve as compared to the controls (as seen from their higher age group, higher day 2 follicle-stimulating hormone (FSH), lower antral follicle counts, and lower anti-Müllerian hormone).Conclusions:Premature LH surge in a GnRH-antagonist cycle can lead to cycle cancellation and disappointment. Although this is a rare event, the incidence is higher in patients with diminished ovarian reserve. Further studies are needed to determine if giving the human chorionic gonadotropin trigger a day earlier or giving higher doses of GnRH-antagonist can benefit such cases.

Effects of cetrorelix versus ganirelix in gonadotropin-releasing hormone antagonist cycles for preventing premature luteinizing hormone surges and on clinical outcomes of IVF-ET cycles

To compare the effects of cetrorelix and ganirelix in gonadotropin-releasing hormone antagonist (GnRH-ant) cycles for preventing premature luteinizing hormone (LH) surges and on clinical outcomes of IVF-ET cycles. We retrospectively analyzed 2572 GnRH-ant cycles of in vitro fertilization and embryo transfer from January, 2013 to December, 2016, including 1368 cycles with cetrorelix treatment and 1204 cycles with ganirelix treatment. The baseline characteristics of the patients and the clinical outcomes of the two groups were compared. Compared with those receiving ganirelix treatment, the patients with cetrorelix treatment had a significantly younger age (33.10 vs 33.89 years, P < 0.001) and a lower body mass index (21.57 vs 21.84 kg/m2, P=0.024). After adjustment for age and body mass index of the patients, no significant differences were found between the two groups in the levels of follicle-stimulating hormone (FSH), LH, estradiol (E2), progesterone (P) levels either at the baseline or on the day of hCG triggering, or in the number of oocytes retrieved (P > 0.05). The two groups also had comparable percentages of patients with LH > 10 U/L on the day of hCG triggering (3.7% vs 3.2%) and similar spontaneous ovulation rate (0.6% vs 0.5%), clinical pregnancy rate (47.7% vs 45.9%) and live birth rate (37.5% vs 33.6%) following fresh embryo transfer (P > 0.05). The incidence of moderate to severe ovarian hyperstimulation syndrome, however, was significantly higher in ganirelix group than in cetrorelix group (0.7% vs 0.1%, P=0.006). Cetrorelix and ganirelix can achieve comparable effects for preventing premature LH surges and can achieve similar clinical outcomes of GnRH-ant cycles, but ganirelix is associated with a significantly higher incidence of moderate to severe ovarian hyperstimulation syndrome.

Comparison of a novel flexible progestin primed ovarian stimulation protocol and the flexible gonadotropin-releasing hormone antagonist protocol for assisted reproductive technology

To determine whether a flexible progestin primed ovarian stimulation (fPPOS) protocol is effective for preventing premature ovulation. Retrospective cohort study. Private assisted reproduction center. Eighty-seven oocyte donors and 191 recipients of fresh oocytes. Each donor was stimulated with a flexible gonadotropin-releasing hormone (GnRH) antagonist protocol in one cycle and with the new fPPOS protocol in the other, within a period of 6months. FSH was started on cycle day 2-3, and 0.25mg/day GnRH antagonist or 10mg/day medroxyprogesterone acetate (MPA) was started on stimulation day 7 or when the leading follicle reached 14mm, whichever came first. Duration of stimulation, gonadotropin consumption, duration of GnRH antagonist or MPA administration, number of metaphase II oocytes, and pregnancy rates in fresh oocyte recipients. Duration of stimulation was 11 (10-11) days in both groups. Total gonadotropin consumption was similar. Pituitary suppression was started on day 7 and lasted for 5days in each group. There were no premature ovulations in any group. The fPPOS yielded a significantly higher number of cumulus oocyte complexes than GnRH antagonist cycles (33 [21-39] vs. 26 [18-36], respectively). Likewise, the fPPOS generated significantly more metaphase II oocytes than GnRH antagonist cycles (24 [17-34] vs. 21 [15-28], respectively). Recipients of fresh oocytes from fPPOS and GnRH antagonist cycles had similar cleavage, blastulation, implantation, and live birth/ongoing pregnancy rates (50% vs. 48.6%). FPPOS with MPA seems to be an effective choice for preventing premature ovulation in women undergoing ovarian stimulation without compromising oocyte quality.

Comparison of recombinant and urinary follicle-stimulating hormones over 2000 gonadotropin-releasing hormone antagonist cycles: a retrospective study

The objective of this paper was to compare the effect of recombinant follicle-stimulating hormone (rFSH) and urinary follicle-stimulating hormone (uFSH) on pregnancy rates and live birth rates with the gonadotropin-releasing hormone (GnRH) antagonist protocol in China. This retrospective study was conducted from January 2014 through August 2017. Patients treated with uFSH had significantly higher levels of luteinizing hormone (3.79 mIU/ml vs. 3.09 mIU/ml) and progesterone (0.93 ng/ml vs. 1.16 ng/ml) on the day of human chorionic gonadotropin (HCG) administration, and they also had higher pregnancy rates (24.19% vs. 22.86%). There was no significant difference in the rate of live births. In the logistic regression results of the rFSH group, the pregnancy rate was positively correlated with the level of luteinizing hormone, with an odds ratio (OR) of 1.09 (95% confidence interval [CI]: 1.00–1.18; P = 0.048). In the uFSH group, the pregnancy rate was negatively correlated with the progesterone level on the day of HCG administration, with an OR of 0.47 (95% CI: 0.27–0.77; P = 0.004). Our research concluded that uFSH performed better than rFSH in terms of pregnancy rates when it was associated with the GnRH antagonist protocol. Meanwhile, no significant differences in the rate of live births were observed between the two groups.

Effect of progesterone/estradiol ratio on pregnancy outcome of patients with high trigger-day progesterone levels undergoing gonadotropin-releasing hormone antagonist intracytoplasmic sperm injection cycles: a retrospective cohort study

This study investigates the predictive power of serum progesterone/estradiol (P/E2) level for estimating the live birth rate in patients who had a serum progesterone (P) rate ≥ 1.5 ng/mL on the human chorionic gonadotropin (hCG) administration day and who received the gonadotropin-releasing hormone (GnRH) antagonist protocol and intracytoplasmic sperm injection (ICSI). This retrospective cohort study included 176 cycles. The P/E2 ratio was lower in patients with a live birth (0.73 ± 0.54) than those without a live birth (1.05 ± 1.38), but the difference was not statistically significant (p = .158). According to the receiver operating characteristic curve analysis of the hCG day P/E2 ratio, the area under the curve was 0.579 (95% confidence interval: 0.478 – 0.680, p = .158) for predicting live birth. In conclusion, this study suggests that a P/E2 ratio is not a significant predictor of a live birth rate in the patients with an hCG-day serum progesterone level of ≥1.5 ng/mL undergoing GnRH antagonist ICSI cycles with a fresh embryo transfer.Impact statementWhat is already known on this subject? As the progesterone (P) levels in the late follicular phase correlate with the estradiol (E2) levels and the increase in mature follicles, earlier studies have proposed the trigger-day progesterone/estradiol (P/E2) ratio as a potential new marker for a premature luteinisation and live birth success. Most of these studies were conducted on long agonist cycles, and found that arbitrarily defined P/E2 ratio of >1 to be associated with poor pregnancy outcomes.What do the results of this study add? This study retrospectively examines the gonadotropin-releasing hormone (GnRH) antagonist cycles with a trigger-day serum P value of ≥1.5 ng/mL undergoing the intracytoplasmic sperm injection (ICSI) treatment. The receiver operating characteristic (ROC) curve analysis did not identify a statistically significant threshold value for the trigger-day P/E2 ratio that was beneficial in predicting a live birth. The P/E2 ratio was also lower in the cycles with a live birth than those without a live birth, although the difference was not statistically significant.What are the implications of these findings for clinical practice and/or further research? The trigger-day P/E2 ratio does not seem to be an efficient prognostic factor for a live birth in the GnRH antagonist ICSI cycles with a trigger-day serum progesterone level of ≥1.5 ng/mL. Further studies are needed to clarify the association of the trigger-day P/E2 ratio and the pregnancy outcomes in GnRH antagonist ICSI cycles.

Added value today of hormonal measurements in ovarian stimulation in gonadotropin-releasing hormone antagonist treatment cycle.

Traditional approach of ovarian stimulation monitoring for in-vitro fertilization involves transvaginal sonography and serum estradiol measurements. Accumulating evidence has shown that hormonal evaluations during ovarian stimulation allow individual cycle optimization, moving away from only predicting the risk of ovarian hyperstimulation syndrome, but in addition assessing the impact of ovarian stimulation on endometrial receptivity, quality of oocytes, and subsequently embryos. The purpose of this review is to discuss the relevance and added value of hormonal monitoring during ovarian stimulation in gonadotropin-releasing hormone antagonist cycles where most of the advances have occurred. Basal hormonal status, particularly estradiol, progesterone, and luteinizing hormone are instrumental in prediction of the patients with poor prognosis. Estradiol levels on the day of trigger are less sensitive in predicting ovarian hyperstimulation syndrome then the number of follicles more than 11 mm in diameter. Progesterone elevation on the day of trigger is associated with lower pregnancy rates. The gold standard treatment for progesterone elevation is to adopt a freeze-all strategy when the threshold of 1.50 ng/ml is exceeded. The effect of progesterone elevation on embryo quality remains to be confirmed by more trials. Endocrine monitoring during ovarian stimulation allows fine-tuning of the physiology of the stimulated cycle and thereby increases the chances of successful treatment outcome.