OBJECTIVE: Does luteal estradiol (E2) pretreatment give a similar number of retrieved oocytes compared to no-pretreatment in advanced-aged women stimulated with corifollitropin alfa in an antagonist protocol?
CONCLUSIONS: Programming antagonist cycles with luteal E2 gave similar number of retrieved oocytes compared to no-pretreatment in women aged 38-42 years.
BACKGROUND: Programming antagonist cycles with luteal E2 pretreatment is a valuable tool to organize the IVF procedure better and is safe without any known impact on cycle outcome. However, variable effects were observed on the number of retrieved oocytes depending on the treated population. In advanced-age women, recruitable follicles tend to decrease in number and to be more heterogeneous in size but it remains unclear if estradiol pretreatment could change the oocyte yield through its negative feed-back effect on FSH intercycle rise.
METHODS: This non-blinded randomized controlled non-inferiority trial was conducted between 2016 and 2022 with centrally computerized randomization and concealed allocation. Participants were 324 women aged 38-42 years undergoing IVF treatment. The primary endpoint was the total number of retrieved oocytes. Statistical analysis was performed with one-sided alpha risk of 2.5% and 95% confidence interval (CI) with the non-inferiority of E2 pretreatment proved by a P value <0.025 and a lower delta margin of the CI within two oocytes compared to no pretreatment. Secondary endpoints were duration and total dosage of recombinant FSH, cancellation rate, percentage of oocyte pick-up (OPU) on working days, total number of metaphase II oocytes and obtained embryos, fresh transfer live birth rate, and cumulative live birth rate.
METHODS: This multicentric study enrolled women with regular cycles, weight >50 kg and body mass index <32, IVF cycle 1-2. According to randomization, micronized estradiol 2 mg twice a day was started on days 20-24 and continued until Wednesday beyond the onset of menses followed by administration of corifollitropin alfa on Friday, i.e. stimulation (S)1 or from D1-3 of a natural cycle in unpretreated patients. GnRH antagonist was started at S6 and additional FSH at S8.
RESULTS: Basal characteristics were similar in patients randomized in E2 pretreated (n = 164) and non-pretreated (n = 160) groups (intended to treat (ITT) population). A total of 291 patients started treatment (per protocol (PP) population), 147 in E2 pretreated group with a mean number [SD] of pre-treatment days 9.8 [2.6] and 144 in the non-pretreated group. Despite advanced age, oocyte yields ranged from 0 to 29 in both groups with a median number of 6 retrieved oocytes in accordance with a mean anti-Müllerian hormone (AMH) level above 1.2 ng/ml. We demonstrated the non-inferiority of E2 pretreatment with a mean difference of -0.1 oocyte 95% CI [-1.5; 1.3] P = 0.004 in the PP population and a mean difference of -0.44 oocyte [-1.84; 0.97] P = 0.014 in the ITT population. Oocyte retrieval was more often on working days in E2 pretreated patients (91.9 versus 74.2%, P < 0.001). In patients reaching OPU, the duration of stimulation was statistically significantly longer (11.7 [1.7] versus 10.8 [1.8] days, P < 0.001) and the extra FSH dosage in addition to corifollitropin alfa was statistically significantly higher (1040 [548] versus 778 [504] IU, P < 0.001) in E2 pretreated than non-pretreated patients. We did not observe any significant differences in the number of retrieved oocytes (8.4 [6.1] versus 9.1 [6.0]), in the number of Metaphase 2 oocytes (7 [5.5] versus 7.3 [5.2]) nor in the number of obtained embryos (5 [4.6] versus 5.2 [4.2]) in E2 pretreated patients compared to non-pretreated patients. The live birth rate after fresh transfer (16.2% versus 18.5%, respectively), and the cumulative live birth rate per patient (17.7% versus 22.9%, respectively) were similar in both groups. Among the PP population, 31.6% of patients fulfilled the criteria for group 4 of Poseïdon classification (AMH <1.2 ng/ml and/or antral follicle count <5). In this sub-group of patients, we observed in contrast a statistically higher number of retrieved oocytes in E2 pretreated patients compared to non-pretreated (5.1 [3.8] versus 3.4 [2.7], respectively, the mean difference of +1.7 oocyte [0.2; 3.2] P = 0.022) but without significant difference in the cumulative live birth rate per patient (15.7% versus 7.3%, respectively).
CONCLUSIONS: Our stimulated women older than 38 years obtained a wide range of collected oocytes suggesting very different stages of ovarian aging in both groups. E2 pretreatment is more likely to increase oocyte yield at the stage of ovarian aging characterized by asynchrony of a reduced follicular cohort. Another limitation is the sample size in sub-group analysis of patients with AMH <1.2 ng/ml. Finally, the absence of placebo for pretreatment could also introduce possible bias.
CONCLUSIONS: Programming antagonist cycles with luteal E2 pretreatment seems a useful tool in advanced age women to better schedule oocyte retrievals on working days. However, the potential benefit of the number of collected oocytes remains to be demonstrated in a larger population displaying the characteristics of decreased ovarian reserve encountered in Poseïdon classification.
BACKGROUND: Research grant from (MSD) Organon, France. I.C., S.D., B.B., X.M., S.G., and C.J. have no conflict of interest with this study. I.C.D. declares fees as speaker from Merck KGaA, Gedeon Richter, MSD (Organon, France), Ferring, Theramex, and IBSA and participation on advisory board from Merck KGaA. I.C.D. also declares consulting fees, and travel and meeting support from Merck KGaA. N.M. declares grants paid to their institution from MSD (Organon, France); consulting fees from MSD (Organon, France), Ferring, and Merck KGaA; honoraria from Merck KGaA, General Electrics, Genevrier (IBSA Pharma), and Theramex; support for travel and meetings from Theramex, Merck KGaG, and Gedeon Richter; and equipment paid to their institution from Goodlife Pharma. N.C. declares grants from IBSA Pharma, Merck KGaA, Ferring, and Gedeon Richter; support for travel and meetings from IBSA Pharma, Merck KGaG, MSD (Organon, France), Gedeon Richter, and Theramex; and participation on advisory board from Merck KGaA. A.G.L. declares fees as speaker from Merck KGaA, Gedeon Richter, MSD (Organon, France), Ferring, Theramex, and IBSA.
BACKGROUND: ClinicalTrials.gov NCT02884245.
UNASSIGNED: 29 August 2016.
UNASSIGNED: 4 November 2016.

UNASSIGNED: Our objective was to investigate the efficacy of letrozole co-treatment in an antagonist protocol for infertile women with polycystic ovary syndrome (PCOS).
UNASSIGNED: This retrospective cohort study included infertile women with PCOS undergoing IVF/ICSI with and without letrozole co-treatment in an antagonist protocol from 2007-2021 at Shanghai Ninth People\'s Hospital (Shanghai, China). A total of 1559 participants were enrolled, with 1227 women in the antagonist group and 332 women in the letrozole co-treatment group. Propensity score-based patient-matching model was conducted to balance covariates between the groups. The primary outcome was the number of retrieved oocytes, with secondary outcomes including endocrine parameters, ovarian stimulation outcomes, pregnancy outcomes, and obstetrical and neonatal complications.
UNASSIGNED: Letrozole co-treatment induced significant changes in hormonal regulation, increased the percentage of large follicles, and resulted in fewer retrieved oocytes (P < 0.05). However, there was no negative impact on the number of usable embryos or good-quality embryos (P > 0.05). The live birth rates following fresh embryo transfer were comparable between the letrozole and control groups (single embryo transfer: 28.9% vs 29.7%, P > 0.05; double embryo transfer: 37.3% vs 45.6%, P > 0.05). Additionally, there were no significant differences between the two groups in the live birth rate per patient after frozen embryo transfer and the cumulative live birth rate (P > 0.05). No significant differences in obstetrical and neonatal complications were observed between the groups (P > 0.05).
UNASSIGNED: The addition of letrozole to the antagonist protocol for women with PCOS undergoing IVF induces a higher percentage of large follicles during oocyte retrieval, while reducing the overall number of retrieved oocytes. Moreover, the use of letrozole demonstrates comparable clinical outcomes following embryo transfers. These findings highlight the potential application of letrozole in an antagonist protocol for women with PCOS.

OBJECTIVE: To study hemodynamic changes along controlled ovarian stimulation in women undergoing in vitro fertilization.
METHODS: Prospective observational cohort study conducted at Mother and Child Department of University Hospital Federico II, in Naples, Italy, between April 2021 and July 2022. Sixty-eight infertile patients undergoing controlled ovarian stimulation with gonadotropin, antagonist protocol and a fresh embryo transfer were included. Haemodynamic assessment was carried out using UltraSonic Cardiac Output Monitor at baseline (T1), estradiol peak (T2), fresh embryo-transfer day (T3). To evaluate relationships between quantitative variables and groups a Student T test for independent data was assessed. One-way analysis of variance (ANOVA) was used to determine the differences between the means of three time points (T1, T2 and T3) for quantitative variables. A mixed-model analysis of variance (ANOVA) was used to determine the differences between groups, among time points (T1, T2 and T3).
RESULTS: Sixty-eight patients were included. Significant differences over the three time points have been observed for CO (f = 3.78 l/min; p = 0.025), SVI (f = 3.56 ml/m2;p = 0.013), and RSVI (f = 4.84 dscm-5 m2; p = 0.009). No significant differences in trends have been found between beta hCG positive and beta hCG negative groups. There were no significant differences in maternal hemodynamic parameters at time-point T3 between patients treated with hCG 10,000 UI and with Triptorelin. Patients considered at increased risk of hyperstimulation reported a significant increase in SVI at baseline (26.9 ± 9.0 mL/m2 vs 21.9 ± 7.0 mL/m2; p = 0.010).
CONCLUSIONS: According to the results of our study, during controlled ovarian stimulation with antagonist protocol, patients undergo significant changes in maternal cardiovascular parameters over a very short period.

UNASSIGNED: To determine whether the late-follicular-phase progesterone to retrieved oocytes (P/O) ratio during in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) impacts pregnancy outcomes.
UNASSIGNED: 12,874 cycles were retrospectively categorized into four groups according to the P/O ratio percentile, with divisions at the 25th, 50th and 75th percentiles.
UNASSIGNED: The clinical pregnancy and live birth rates of fresh cycle embryos in Group D were significantly lower than those in the other three groups (45.1% and 39.0%, 43.2% and 37.2%, 39.6% and 33.5%, 33.4% and 28.2% in Group A, B, C, D, respectively; both P < 0.008). Multivariate logistic regression analysis revealed a significant negative correlation between the P/O ratio and live birth, particularly when the P/O ratio was ≥0.22 (OR = 0.862, 95% CI [0.774-0.959], P = 0.006).
UNASSIGNED: The P/O ratio has certain predictive value for IVF/ICSI pregnancy outcomes and can be used for decision-making decision regarding fresh embryo transfer.

UNASSIGNED: To examine body weight change in women undergoing in vitro fertilization and embryo transfer (IVF-ET) using antagonist protocol after up to three treatment cycles.
UNASSIGNED: A prospective cohort study among IVF patients treated between 2018 and 2019. Each patient underwent weight measurement three times during the treatment cycle: before treatment, at the beginning of the hormonal stimulation, and at the completion of the cycle, on the day of the pregnancy test. Data were also analyzed according to the body mass index (BMI) groups for normal weight, overweight, and obese patients. Finally, weight changes were recorded following altogether 519 treatment cycles, 240, 131, and 148 cycles, for normal weight, overweight, and obese patients, respectively.
UNASSIGNED: The change in the patient\'s weight was clinically non-significant either during the waiting period or during gonadotropin administration, and overall, during the first, second, or third treatment cycles. The recorded mean total weight change of 0.26 ± 1.85, 0.4 ± 1.81, and 0.17 ± 1.7, after the first, second, or third treatment cycles, represent a change of 0.36%, 0.56%, and 0.23% of their initial weights, respectively. This change of less than 1% of the body weight falls short of the clinically significant weight gain of 5%-7%. Analyzing the data for the various BMI groups, the changes observed in body weight were under 1%, hence with no clinical significance.
UNASSIGNED: The findings of the study reject the myth that hormone therapy involves clinically significant weight gain, and this can lower the concerns of many patients who are candidates for treatment of assisted reproductive technology.

UNASSIGNED: Recently POSEIDON (Patient-Oriented Strategies Encompassing Individualized Oocyte Number) classification was proposed to categorize patients with expected poor response to conventional stimulation. Searching for the ideal management of poor responders in IVF is still an active research area.
UNASSIGNED: This study compares GnRH-antagonist and GnRH-agonist short protocols in ICSI cycles for the POSEIDON-4 group.
UNASSIGNED: This retrospective study was conducted in a tertiary infertility unit between January 2016 and December 2020.
UNASSIGNED: Infertile women who met the criteria for POSEIDON 4 group and underwent fresh ICSI-ET in using GnRH-antagonist and GnRH-agonist short protocols was performed. POSEIDON-4 includes patients ≥ 35 years with poor ovarian reserve markers; AFC < 5 and AMH < 1.2 ng/ml.
UNASSIGNED: Numerical variables were compared between both groups by student\'s t test and Mann Whitney test when appropriate. Chi-square test used to compare categorical variables. Multivariate logistic regression models were utilized to adjust for the effect of the different study confounders on live birth rate.
UNASSIGNED: One hundred ninety fresh ICSI cycles were analyzed. Of the total cohort, 41.6 % (79) patients pursued antagonist protocol compared to 58.4% (111) underwent short agonist protocol. Fresh embryo transfer was accomplished in 55.7 % (44/79) vs. 61.3 % (68/111), P = 0.44 in antagonist vs. short protocol respectively. Cycle cancellation due to poor ovarian response was encountered in (32.9%vs. 27.9%, P = 0.50) in the antagonist and short groups, whereas no good-quality embryos were developed after ovum pickup in 11.4% vs. 10.8%, P>0.05. Comparable total gonadotropins dose, number of retrieved and mature oocytes, and good-quality embryos were found in both groups. Likewise, clinical pregnancy rate was not different for the antagonist and short groups [11/79 (13.9%) vs. 20/111 (18%), P = 0.45]. The live birth rate was comparable between both groups (8.9% vs. 10.8%, P = 0.659) for antagonist and short groups respectively. No significant impact for the protocol type on live birth rate was revealed after adjusting to cycle confounders in multivariate analysis (OR: 0.439, 95%CI 0.134-1.434, P = 0.173).
UNASSIGNED: This study shows comparable pregnancy outcomes for antagonist and short-agonist protocols in IVF/ICSI cycles for POSEIDON-4 category.

The present study aimed to compare the effectiveness of two different doses of letrozole (2.5 mg and 5 mg daily) in an antagonist protocol for infertile women with normal ovarian reserve.
This retrospective cohort study included infertile women who underwent in vitro fertilization treatment with letrozole co-treatment at doses of 2.5 mg and 5 mg from 2007 - 2021 at Shanghai Ninth People\'s Hospital (Shanghai, China). The control group comprised infertile women who received gonadotropin-releasing hormone antagonist alone. The primary outcome was the cumulative live birth rate, while secondary outcomes included follicular phase endocrine parameters, ovarian stimulation outcomes, pregnancy outcomes, and the incidences of maternal and neonatal complications. Baseline and follow-up data were compared between the groups using ANOVA for normally distributed variables, the Kruskal-Wallis test for non-normally distributed variables, and the Chi-square test for categorical variables.
A total of 422 participants were enrolled in the study, with 211 women in the antagonist group, 109 women in the 2.5 mg letrozole co-treatment group, and 102 women in the 5 mg letrozole co-treatment group. Letrozole co-treatment significantly suppressed oestradiol and follicle-stimulating hormone concentrations from stimulation day 5 and onwards, while increasing luteinizing hormone levels on stimulation day 5 and trigger day. The effect was more pronounced with a 5 mg dose of letrozole compared to a 2.5 mg dose (P < 0.05). Administration of 5 mg letrozole reduced the gonadotropin dose (P < 0.05) without negatively affecting the number of oocytes retrieved and subsequent embryo parameters (P > 0.05). The analysis of cumulative live birth rates showed rates of 29.4% in the letrozole 5 mg group, 27.5% in the letrozole 2.5 mg group, and 33.6% in the control group, with no statistically significant difference (P > 0.05). There were no reported pregnancy complications in the two letrozole groups. Additionally, there were no significant differences among the three groups in terms of gestational age and birth weight for both singleton and twin births.
This study indicates that the administration of letrozole in an antagonist protocol, at both 2.5 mg and 5 mg dosages, results in comparable clinical outcomes.

OBJECTIVE: To evaluate the origin and ultrastructure of the coarse granules in the perivitelline space (PVS) of oocytes of a group of couples attending assisted reproduction treatment.
METHODS: The ultrastructure of five oocytes with coarse granulues in the PVS obtained from three patients were evaluated by transmission electron microscopy (TEM). The influence of the ovulation induction regimen on the formation of granules in the PVS of the oocytes of 214 couples and the developmental capacity of these oocytes presenting granules in the PVS was analyzed retrospectively.
RESULTS: In TEM analysis, the microvilli structure was irregular, short, and loosely scattered through the oolemma in the oocytes presenting coarse granules in the PVS. Furthermore, dense lipid droplets were identified within the PVS and the surrounding cumulus cells. In retrospective analysis, the number of oocytes with coarse granules in the PVS was positively correlated with the duration of antagonist administration (r=0.23, p=0.013). Regardless of the type of granule, the presence of coarse or moderately coarse granules in the PVS was positively correlated with low-quality embryos on D3 (r=0.29, p=0.005) and the total number of arrested embryos up to D3 (r=0.33, p<0.001). Furthermore, the presence of coarse granules in the PVS severely exacerbated miscarriage rates.
CONCLUSIONS: Our findings suggest that the presence of especially coarse granules in the PVS is correlated with the reduction of further embryonic developmental capacity in post-implantation stages of embryonic development, indicating a negative impact from aggressive ovulation induction protocols on developing oocytes.

Based on dynamic changes of indicators during controlled ovarian hyperstimulation and of clinical outcomes of suboptimal ovarian response with different protocols, this study aimed to summarize the clinical characteristics of SOR and provide clinical recommendations.
Data of 125 patients with SOR and 125 controls who had undergone appropriate protocols for in vitro fertilization-embryo transfer were collected from a single medical center from January 2017 to January 2019. Basic clinical indexes, including age, BMI, antral-follicle count, infertility time, basic follicle-stimulating hormone, luteinizing hormone, LH/FSH ratio, estradiol, progesterone, testosterone, androstenedione, prolactin, anti-Mullerian hormone, and thyroid stimulating hormone levels, were analyzed using T-test. Dynamic indexes during COH, including amount and days of gonadotropin, sex hormone levels, and number of large/medium/small follicles at specified time periods, were analyzed using T-test and joint diagnosis analysis with ROC curves. Indexes of laboratory and clinical indicators were analyzed using the chi-square test.
For the SOR group, BMI, duration time, and dosage of gonadotropin used for SOR were significantly higher. In the ultra-long/long group, ROC curve analysis showed that the LH/FSH ratio and BMI yielded cutoff values of 0.61 and 21.35 kg/m2, respectively. A combined diagnosis of the two indexes showed higher sensitivity (90%) and specificity (59%). In the GnRH-ant group, ROC curve analysis showed an LH level, an LH/FSH ratio on COH day 2, and BMI yielded cutoff values of 2.47 IU/L, 0.57, and 23.95 kg/m2, respectively. Combining the two indexes with BMI, both showed increased sensitivity (77%) and specificity (72% and 74%). The estradiol level and progesterone level during the late follicular stage in SOR patients were significantly lower than those in control patients for both protocol groups. At each monitoring time, delayed follicular development was observed. The live-birth rate in fresh cycles of the ultra-long/long group and the live-birth rate in cumulative cycles of the antagonist group in the SOR group were lower than those in the control group.
SOR had adverse effects on clinical outcome. We provide some threshold values of basic LH/FSH ratio, BMI, COH day 2 LH, counts of follicles, and levels of estradiol/progesterone to be taken as reference to assist the early recognition of SOR.

To evaluate the impact of adding a GnRH agonist (GnRH-a) in luteal phase support (LPS) on live birth rates in IVF/ICSI in antagonist protocols.
In total, 341 IVF/ICSI attempts are analyzed in this retrospective study. Patients were divided into two groups: A f: LPS with progesterone alone (179 attempts) between March 2019 and May 2020; B: LPS with progesterone and an injection of triptorelin (GnRH-a) 0.1mg 6 days after oocyte retrieval (162 attempts) between June 2020 and June 2021. The primary outcome was live birth rate. The secondary outcomes were miscarriage rate, pregnancy rate and ovarian hyperstimulation syndrome rate.
The baseline characteristic are identical between the two groups except the infertility duration (longer in the group B). There was no significant difference between the two groups in live birth rate (24.1% versus 21.2%), pregnancy rate (33.3% versus 28.1%), miscarriage rate (4.9% versus 3.4%) and no increase the SHSO rate. The multivariate regression analysis after adjustment for age, ovarian reserve and infertility duration did not reveal a significant difference in live birth rate between the two groups.
In this study, the results showed no statistically significant association with the single injection of a GnRH-a in addition to progesterone on live birth rate in luteal phase support.