Follicular Output Rate Research Articles

Expert Opinion on Refined and Extended Key Performance Indicators for Individualized Ovarian Stimulation for ART

ObjectiveTo assess the adequate ovarian follicular development and oocyte recovery between ovarian potential (antral follicle count [AFC]) before the start of ovarian stimulation (OS) and oocyte quantity and quality at oocyte retrieval. A holistic overview of the current key performance indicators (KPIs) was applied to identify the complementary strengths and identify where the current repertoire can be expanded. DesignExpert opinion. SubjectsNot applicable. InterventionNone. Main Outcome MeasuresTo formulate a proposal for a refined and expanded repertoire of KPIs for individualized OS for Assisted Reproductive Technology. ResultsThe performance and outcomes of OS on ovarian follicular development can be evaluated through the application of defined KPIs. Current KPIs for OS are the ovarian sensitivity index (OSI), the follicular output rate (FORT), the oocyte retrieval rate (ORR), and the follicle to oocyte index (FOI). Notably, there are no specific KPIs dedicated to the assessment of follicular development (i.e., recruitment, selection, growth and dominance). In light of this, we recommend expanding the current KPIs for OS to include “Early FORT” (accounting for the number of follicles measuring ≥10–11 mm on Day 5/6 of OS relative to AFC) and “Modified FORT” (the ratio between the number of follicles measuring ≥12 mm at the time of oocyte maturation triggering and AFC); the extension of ORR to include two discrete categories at oocyte retrieval: follicles ≥12 mm and follicles ≥16 mm, to ensure all responsive follicles are accounted for; and FOI to be measured at oocyte maturation triggering and oocyte retrieval ("Advanced FOI”). ConclusionsOnce validated and adopted in clinical practice, we envisage that the proposed expanded KPIs measuring the effect of OS on follicular development (recruitment, selection, growth and dominance) will increase the understanding of the relationship between ovarian reserve measured by AFC and oocyte quantity and quality at oocyte retrieval. This understanding will enable physicians to better evaluate the direct effect of different gonadotropins and doses on ovarian response, leading to a more personalized approach to OS in the context of ART treatment.

P-670 The impact of fixed day-one versus day-six progestin initiation on ovarian response following progestin primed ovarian stimulation

Abstract Study question Does ovarian response differ between a fixed stimulation day (SD) 1 and SD 6 progestin start in a progestin primed ovarian stimulation (PPOS) protocol? Summary answer Fixed SD 1 and SD 6 PPOS protocols showed no significant differences in terms of ovarian response to stimulation. What is known already Ovulation prior to oocyte retrieval is a potential concern during ovarian stimulation (OS). Progestins, when compared to GnRH analogues, also effectively prevent premature ovulation with the added convenience in terms of its oral administration and lower costs. For this purpose, progestins may be started immediately with OS (SD 1) or later in the cycle, usually around SD 6, when the risk for ovulation increases. While the latter approach may be associated with a lower follicle growth suppression, evidence regarding the impact of the two protocols on ovarian response is still lacking. Study design, size, duration We conducted a single center retrospective cohort study in a private fertility clinic, including 923 patients (584 in the SD1 group and 339 in the SD6 group) who underwent 1064 OS cycles (652 in the SD1 group and 412 in the SD6 group) using a PPOS protocol between January 2016 and May 2023. Among these, 394 (37.03%) were oocyte donation cycles, 341 (32.05%) were autologous IVF/ICSI cycles and 329 (30.92%) were autologous vitrification cycles. Participants/materials, setting, methods We included women under the age of 44 who performed an OS cycle following a PPOS protocol. LH peak suppression was performed with daily desogestrel 75µg started either on SD 1 or on SD 6. The number of oocytes retrieved, number of mature (MII) oocytes, follicle-to-oocyte index (FOI) and follicular output rate (FORT) were compared between the groups. Comparisons are presented as adjusted regression coefficients (β) and 95% confidence intervals (95%CI) following multivariable linear regression. Main results and the role of chance The majority of patients in the SD1 group were donors (59.66%), while in the SD6 group most patients were doing assisted reproductive techniques (ART) with autologous oocytes (98,78%). In the SD1 group, patients were older (38.93±3.81 vs. 37.93±4.00, p < 0.001), had a higher antral follicle count (AFC) (20.79±8.66 vs. 14.12±9.96, p < 0.001), underwent OS with a lower gonadotropin dose (2036.25±766.20IU vs. 2715.20±976.40IU, p < 0.001) and triggered mostly with GnRHa (86.44% vs. 57.50%, p < 0.001). Both groups presented a similar body mass index (BMI) (22.80±2.96 vs. 21.71±3.25kg/m2, p = 0.175). Bivariate analysis revealed a higher number of oocytes retrieved (19.40±12.02 vs. 10.10±8.19, p < 0.001), number of MII oocytes (12.05±5.97 vs. 7.42±5.91, p < 0.001), FORT (81.53±20.59% vs. 73.72±23.80%, p < 0.001) and FOI (95.49±48.78% vs. 76.31±47.60%, p < 0.001) in the SD1 group. No difference was found in the cancellation rates among the two groups (1.99% for SD1 vs. 3.16% for SD6, p = 0.322). Following adjustment for age, BMI, AFC, ART treatment, type of trigger and total gonadotropin dose, no difference was found regarding the number of oocytes retrieved (β=-0.62; 95%CI -2.53 to 1.30), number of MII oocytes (β=-1.66; 95%CI -3.43 to 0.10), oocyte maturation rate (β = 2.30; 95%CI -4.60 to 9.20), FOI (β=-3.29; 95%CI -13.15 to 6.57) or FORT (β=-1.78; 95%CI -5.66 to 2.10). Limitations, reasons for caution Despite attempting to mitigate confounding effects through multivariable linear regression analysis, the retrospective nature of the study and limited sample size may still be insufficient to eliminate bias. Moreover, reproductive and perinatal outcomes were not reported. Wider implications of the findings Our study suggests that both the SD1 and SD6 PPOS protocols can be employed based on patients’ and clinicians’ preference, regardless of the type of ART treatment or patient’s ovarian reserve, without impact on ovarian response to stimulation. Trial registration number not applicable

O-010 Luteal estradiol versus follicular GnRH antagonist for ovarian follicular synchronization in POSEIDON poor responders: a multicentric randomized controlled trial

Abstract Study question In order to improve follicular synchronization, is pre-treatment with Luteal Estradiol (LE) more efficacious than Follicular GnRH Antagonist (FA) among poor responders? Summary answer Luteal Estradiol is better than Follicular GnRH Antagonist to improve maturation rates in Poor Ovarian Responders (POR) What is known already In poor responders, follicular asynchrony is a major obstacle in optimizing the pregnancy rates and leads to more cycle cancellations and increases the requirement of additional pool up cycles. It imposes significant financial burden on patients. ESHRE recommendations on FA and LE are conditional and require better quality studies. Several studies have evaluated the individual role of pre-treatment with LE or FA in synchronising the number of mature oocytes retrieved. There have been no studies comparing the efficacy of luteal estradiol versus follicular antagonist Study design, size, duration A randomised controlled trial was conducted at multiple centres of a private fertility clinic over 1year. Block randomization was performed using a Web-based randomization system.Allocation concealment was done using envelopes. 196 POR patients were randomized and 145 successfully completed the study. 80 patients(55.17%) received LE while 65 patients (44.83%) received FA. A per-protocol analysis was conducted. A subgroup analyses was done after excluding endometriosis and male-factor infertility as they could have been significant confounding factors. Participants/materials, setting, methods We randomised POR patients(POSEIDON criteria) into 2 arms, in their previous menstrual cycle. LE arm received oral Estradiol valerate 4 mg/day from 7days before expected menses to Day1 of menses. FA arm received Inj.Cetrorelix 0.25mg S.C from Day1 to Day5 of menses. The primary outcomes analysed were oocytes retrieved ,Follicular Output Rate(FORT), Follicle-to-Oocyte Index(FOI), Ovarian Sensitivity Index(OSI), maturation rate and MII /AFC. Secondary outcomes were cycle cancellation rates, fertilization rate, cleavage rate and blastulation rate. Main results and the role of chance There was a significant improvement in maturation rates with luteal phase pre-treatment using estradiol (LE) compared to follicular GnRH antagonist (FA) (0.72 ± 0.03 vs. 0.63 ± 0.03, p-value = 0.045). However, there were no statistically significant differences observed in the oocytes retrieved, Follicle-to-Oocyte Index (FOI), Follicular Output Rate (FORT), or Ovarian Sensitivity Index (OSI) between the two pre-treatment groups. These non-significant differences remained consistent among both expected (poseidon category 3 and 4) and unexpected (posiedon group 1 and 2) poor responders. Secondary outcomes, including cycle cancellation rates, fertilization rate, cleavage rate, and blastulation rate, did not show significant variations between the luteal estradiol (LE) and follicular GnRH antagonist (FA) pre-treatment groups. Subgroup analyses without endometriosis (N = 136) and severe male factor infertility (N = 122), revealed no significant differences between the two study groups in these specific subpopulations. Limitations, reasons for caution Limited generalizability due to small sample size, potential bias from lack of blinding, restricted insight into long-term outcomes, and patient heterogeneity are notable limitations in this study. Wider implications of the findings Among poor responders, luteal estradiol demonstrated a significant improvement in maturation rates, probably due to better follicle synchronicity at trigger, compared to follicular antagonist. It’s also more cost-effective and patient-friendly. However, further research with larger sample size and long-term clinical endpoints are needed to validate these findings and optimise clinical strategies. Trial registration number CTRI registration no. CTRI/2023/06/053760

P-556 Genetic variation in genes related to folliculogenesis and steroidogenesis in Caucasian and Asian women: Baby steps towards a pharmacogenetic approach in assisted reproductive techniques

Abstract Study question What is the impact of single nucleotide polymorphisms (SNPs) in genes related to the folliculogenesis and steroidogenesis on ovarian response to stimulation? Summary answer SMAD2 rs13381619 and COMT rs4680 variants are associated with the follicular output rate (FORT). What is known already The prediction of ovarian response (OR) is crucial for an optimal and individualized management. Despite the good accuracy of ovarian reserve markers in the prediction of OR, a proportion of patients are unexpected hypo-responders. Therefore, a link between OR and individual genotype has been suggested. However, the available evidence is limited by small sample sizes and heterogeneous study designs, including patients with different profiles and allowing for dose adjustments during treatment. Our aim was to analyze the association between SNPs in genes related to folliculogenesis and steroidogenesis and OR in an ethnic diverse population treated with the same fixed-dose protocol. Study design, size, duration This is a secondary analysis of a multicenter multinational prospective study, including 368 patients from Vietnam, Belgium, and Spain (168 from Europe and 200 from Asia) recruited from 11/2016-06/2019. The study included predicted normal responders <38 years old undergoing their first or second ovarian stimulation (OS) cycle. All patients underwent OS in an antagonist protocol with a fixed daily dose of 150 IU rFSH until triggering. Participants/materials, setting, methods First, an interactome was developed using “FSHR” and “LHCGR” as keyword imputed in the Homo sapiens STRING database for protein network analysis. Genetic information from sixty-eight final SNPs involved in the folliculogenesis and steroidogenesis was obtained and used for clustering analysis. Secondly, genotype-phenotype analysis was performed. The prevalence of hypo-responders (<10 oocytes retrieved), number of oocytes retrieved, FORT and follicle to oocyte index (FOI) were compared between different SNPs genotypes. Main results and the role of chance Clustering analysis revealed four distinct genetic clusters according to the selected SNPs related to folliculogenesis and steroidogenesis. Principal component analysis (PCA) was used to display individuals’ distribution according to the fertility centre, resulting in an obvious distribution according to ethnicity. However, PCA failed to demonstrate a clinically significant association between our interactome and the outcomes of interest. We further refined our SNP panel by categorizing SNPs according to their physiological pathway and analyzed their individual impact on OR. Following multivariable linear regression adjusting for patient’s age, Anti-Mullerian hormone (AMH), duration of stimulation and ethnicity, SMAD2 rs13381619 genotype GC (estimated mean difference (EMD) 11.57, 95% Confidence interval (CI) 2.66-20.49), and COMT rs4680 genotype AA (EMD 18.31, 95% CI 4.91-31.72) were associated with improved FORT. No impact of the studied polymorphisms was found on the prevalence of hypo-response, number of oocytes retrieved nor FOI. Limitations, reasons for caution The study was performed in young women with a normal ovarian reserve to eliminate biases related to age-related fertility decline, precluding the extrapolation of the results to other populations. Moreover, the low prevalence of some genotypes might have limited the analysis of some of the included variants. Wider implications of the findings Our findings confirm the variation of SNPs prevalence according to ethnic diversity, highlighting the importance of the intercontinental design of our study. Moreover, a novel association between SMAD2 and COMT variants and OR was reported, opening new opportunities for further pharmacogenetics studies and paving the way towards personalized medicine. Trial registration number Not applicable

P-619 AMH/AFC ratio as a predictive factor for ovarian responsiveness to gonadotropins during ovarian stimulation

Abstract Study question Does AMH/AFC ratio correlate to the number of follicles on the day of trigger and to the number of oocytes retrieved after ovarian stimulation? Summary answer The AMH/AFC ratio correlates significantly to the number of pre-ovulatory follicles and the number of oocytes collected after ovarian stimulation (OS). What is known already Although AFC is a robust marker of oocyte yield after OS, its combination with Anti-Mullerian hormone (AMH) seems to improve the predictability. Besides, Follicular Output Rate [FORT: (number of pre-ovulatory follicles on day of trigger/AFC at baseline) x 100] and Follicle-to-Oocyte Index [FOI: (number of retrieved oocytes/AFC) × 100] evaluate the ovarian responsiveness to gonadotropins during OS, representing its sensitivity to exogenous FSH. Both parameters take antral follicle count (AFC) only into consideration. AMH and AFC as a ratio might optimize the accuracy of FORT and FOI metrics, helping to predict which patients are at higher risk of suboptimal results. Study design, size, duration This retrospective study analyzed 2,163 ovarian stimulation cycles for IVF/ICSI, performed between May 2015 and October 2023 in a tertiary referral IVF centre. For all the cycles, measurement of AMH using Elecsys (Roche®) no longer than 6 months before starting OS, AFC at baseline, number of pre-ovulatory follicles on the day of trigger, and the treatment outcomes were available. Participants/materials, setting, methods Couples with primary/secondary infertility who underwent OS with antagonist protocol, starting on day 2/3 for IVF/ICSI were included, independent of their age or ovarian reserve parameters. Exclusion criteria were patients with body mass index (BMI) >40 kg/m2, non-vaginal ultrasound measurement for AFC and/or follicles during OS, cycles with previous estradiol priming or oral contraceptives. Ethical approval was obtained from the Research Ethics Committee. Main results and the role of chance 2,163 ovarian stimulation cycles were included in the analysis. The mean age, BMI, AMH, AFC, FOI and FORT of the included women were: 35.6±6.1 years, 27.5±4.7 kg/m2, 2.4±2.1 ng/mL, 12±7 follicles, 1.02±0.66 and 1.38±0.79. The correlation of AMH/AFC ratio (coefficient: 0.62, 95% CI: 0.59 to 0.65, p<0.001) to FOI was stronger than the correlation of AMH (coefficient: 0.31, 95% CI: 0.27 to 0.34, p<0.001) or AFC alone (coefficient: -0.09, 95% CI: -0.14 to -0.05, p<0.001). The correlation of AMH/AFC ratio (coefficient: 0.62, 95% CI: 0.59 to 0.64, p<0.001) to FORT was also stronger than the correlation of AMH (coefficient: 0.21, 95% CI: 0.16 to 0.25, p<0.001) or AFC alone (coefficient: -0.23, 95% CI: -0.27 to -0.19, p<0.001). AMH/AFC ratio was better at predicting stimulation efficiency parameters, FOI and FORT, compared to joint use of AMH and AFC (p>0.001 for both). However, regression analysis showed stand-alone use of the AMH/AFC ratio did not provide a better prediction for collected oocyte count compared to joint use of AMH and AFC. In fact, prediction errors were significantly larger for the AMH/AFC ratio (median: -0.4, range: -11 to 11) compared to the model using AMH and AFC separately (median: -0.2, range: -6 to 7). Limitations, reasons for caution Although clinical assessment was performed in the same centre following the same methodology, inter-observer variability for AFC is a limitation. Additionally, AMH levels used in the study were not obtained in the same cycles, which may adversely affect the performance of the ratio. Wider implications of the findings While AMH/AFC ratio was better at predicting stimulation efficiency compared to FOI and FORT parameters, it was not significantly better at predicting absolute oocyte yield. This may imply AMH/AFC ratio can represent the ovarian sensitivity to exogenous FSH. Trial registration number Not applicable

Value of estrogen pretreatment in patients with diminished ovarian reserve and elevated FSH on a line antagonist regimen: a retrospective controlled study.

The key to enhancing the efficacy of antagonistic regimens in pregnancy is to better synchronize follicular growth during cycles of controlled ovarian stimulation (COS), especially in patients with diminished ovarian reserve (DOR). During in vitro fertilization-embryo transfer (IVF-ET) treatment, luteal phase estrogen pretreatment may enhance follicular development synchronization and yield of mature oocytes. However, the effect of estrogen pretreatment in DOR patients with elevated basal follicle-stimulating hormone (FSH) levels has not been well studied. We retrospectively analyzed the clinical data of patients with elevated basal FSH levels and DOR (401 cycles) who underwent IVF/intracytoplasmic monosperm injection (ICSI)-assisted conception. Both groups were treated with a flexible gonadotropin-releasing hormone (GnRH) antagonist regimen and were further divided into two groups according to whether they received luteal estrogen pretreatment. There were 79 patients in the estrogen pretreatment group and 322 patients in the control group. On the second day of the menstrual cycle, gonadotropin (Gn) stimulation of the ovaries was initiated. The general characteristics, clinical, biological parameters and outcomes of the two groups were compared. The basic profiles of the two groups were similar (P > 0.05). More patients in the pretreatment group showed FSH rebound after gonadotropin (Gn) initiation, resulting in a significantly higher number of Gn days and total Gn than those in the control group (P < 0.05). There was no statistically significant difference in the number of days of antagonist use, follicle output rate (FORT), number of metaphase II(MII)eggs obtained, number of Two pronuclei (2PN) fertilized, number of D3 quality embryos, blastocyst formation rate, fresh embryo clinical pregnancy rate, cumulative pregnancy rate, and non-transferable embryo rate between the two groups (P > 0.05). The use of luteal phase estrogen pretreatment in patients with elevated basal FSH combined with DOR resulted in high FSH levels after the release of negative feedback, which was detrimental to early follicular growth, did not increase the follicular output rate, may have increased the use and duration of controlled ovarian stimulation drugs, and did not increase the number of eggs gained or improve clinical outcomes.

Effect of breast cancer prognostic factors on ovarian reserve and response in fertility preservation

Research questionDo breast cancer prognostic factors influence ovarian reserve and response to ovarian stimulation in the context of fertility preservation? DesignObservational, bicentric retrospective study of 352 women with breast cancer who underwent ovarian stimulation using a random start gonadotrophin releasing hormone antagonist protocol and vitrified oocytes between November 2015 and August 2022. Serum anti-Müllerian hormone (AMH) levels and antral follicle count (AFC) were measured. The number of oocytes recovered, maturation rate and follicular output rate (FORT) were analysed according to patients’ characteristics and breast cancer prognostic factors. ResultsMedian age was 34 years (31.1–37.1). Median AFC and serum AMH level were 17 (12–26) follicles and 2 (1.2–3.4) ng/ml, respectively. After ovarian stimulation, 10.5 (6.0–16.0) oocytes were recovered, with eight (4–13) being mature. Mean oocyte maturation rate was 79% (62–92). Antral follicle count (>12) significantly affected the risk of recovering fewer than eight mature oocytes (P < 0.0001, multivariate analysis). Follicular responsiveness to FSH, assessed by the follicular output rate (FORT index) and number of oocytes recovered, were 31% (21–50) and 10.5% (6.0–16.0), respectively. FORT index and ovarian stimulation outcomes were not influenced by breast cancer prognostic factors. ConclusionBreast cancer prognostic factors do not influence ovarian reserve markers or response to ovarian stimulation in fertility preservation. Therefore, tumour grade, triple-negative status, HER2 overexpression and high Ki67 should not alter the fertility-preservation strategy when considering ovarian stimulation for oocyte vitrification.

Male Infertility – An Overview of Management

Objectives: In search of a qualitative indicator of ovarian function, we sought to determine if antral follicles' reproductive competence is correlated with their Follicular Output Rate (FORT), which indicates how sensitive they are to FSH administration. Patients and Methods: After ethical committee approval and informed consent from the patients, this Prospective Cohort study was performed on 300 IVF-ET candidates, aged between 20 and 35, who had undergone controlled ovarian hyper-stimulation with comparable beginning levels of FSH and had primary infertility without apparent cause from January 2020 to June 2022 at Al-Azhar University Hospital and in a private IVF unit in Cairo, Egypt. Antral follicle (3–8 mm) count (AFC) and pre-ovulatory follicle (18–24 mm) count (PFC) were performed, respectively, at the achievement of pituitary suppression (before FSH treatment) and on the day of hCG administration. The FORT was calculated by PFC × 100/AFC. FORT groups were set according to tercile values: low (4.3%; n = 13), average (30.7%; n = 92) and high (65%; n = 195). Results: The odds ratio for clinical pregnancy increases with increasing endometrial thickness, number of collected oocytes, and follicular output rate, with odds ratios of 1.123, 1.121, and 1.312, respectively. Conclusion: The observed association between IVF-ET result and the proportion of antral follicles attaining pre-ovulatory maturity that successfully react to FSH injection shows that FORT may be a qualitative mirror of ovarian follicular competency. More research with broader inclusion criteria and more tailored techniques is required to verify these findings.

Antral Follicle Responsiveness to Follicle Stimulating Hormone Administration Assessed by the Follicular Output Rate (FORT) May Predict In Vitro Fertilization-Embryo Transfer Outcome

Objectives: In search of a qualitative indicator of ovarian function, we sought to determine if antral follicles' reproductive competence is correlated with their Follicular Output Rate (FORT), which indicates how sensitive they are to FSH administration. Patients and Methods: After ethical committee approval and informed consent from the patients, this Prospective Cohort study was performed on 300 IVF-ET candidates, aged between 20 and 35, who had undergone controlled ovarian hyper-stimulation with comparable beginning levels of FSH and had primary infertility without apparent cause from January 2020 to June 2022 at Al-Azhar University Hospital and in a private IVF unit in Cairo, Egypt. Antral follicle (3–8 mm) count (AFC) and pre-ovulatory follicle (18–24 mm) count (PFC) were performed, respectively, at the achievement of pituitary suppression (before FSH treatment) and on the day of hCG administration. The FORT was calculated by PFC × 100/AFC. FORT groups were set according to tercile values: low (4.3%; n = 13), average (30.7%; n = 92) and high (65%; n = 195). Results: The odds ratio for clinical pregnancy increases with increasing endometrial thickness, number of collected oocytes, and follicular output rate, with odds ratios of 1.123, 1.121, and 1.312, respectively. Conclusion: The observed association between IVF-ET result and the proportion of antral follicles attaining pre-ovulatory maturity that successfully react to FSH injection shows that FORT may be a qualitative mirror of ovarian follicular competency. More research with broader inclusion criteria and more tailored techniques is required to verify these findings.

Understanding the implications of follicular output rate (FORT) and follicle to oocyte index (FOI) on human embryo morphokinetics

Objective To study if there are any effects of follicular output rate (FORT) and follicle to oocyte index (FOI) on embryos morphokinetics. Study design Kinetic data of 8,376 embryos, cultured in a time-lapse imaging incubator, derived from 2,470 patients undergoing ICSI cycles were analysed. Embryos were split into groups according to FOI value: Low FOI (n=247 cycles and 894 embryos) and High FOI (n=2,223 cycles and 7,482 embryos) and according to the FORT value: Low FORT (n= 753 cycle and 2,556 embryos), Medium FORT (n=874 cycles and 2,970 embryos), and High FORT (n=843 cycles and 2,850 embryos). Morphokinetic data were compared among the groups. Results Embryos derived from cycles with a low FOI presented slower development, a significantly lower KID score D5, blastocyst formation, and implantation rates when compared with those from cycles with high FOI. For the FORT, an increased time to complete morphokinetic events, significantly lower rates of blastocyst formation and implantation was observed among embryos derived from cycles with low FORT, followed by those with medium FORT, while embryos derived from cycles with high FORT presented a better development competence. However, no significant differences were noted in clinical pregnancy, miscarriage, or livebirth rates when the low, medium, and high FORT groups were compared. Conclusion FORT and FOI correlate with faster embryo development and may be a valuable approach to predict embryo developmental potential.

The impact of baseline serum luteinizing hormone levels on follicular output rate and follicle-to-oocyte index in ovarian stimulation cycles with gonadotropin-releasing hormone antagonist protocol

The impact of baseline serum luteinizing hormone levels on follicular output rate and follicle-to-oocyte index in ovarian stimulation cycles with gonadotropin-releasing hormone antagonist protocol

Evaluative effectiveness of follicular output rate, ovarian sensitivity index, and ovarian response prediction index for the ovarian reserve and response of low-prognosis patients according to the POSEIDON criteria: a retrospective study.

The aim was to explore the implications of follicular output rate (FORT), ovarian sensitivity index (OSI), ovarian response prediction index (ORPI), and follicle-to-oocyte index (FOI) in low-prognosis patients defined by POSEIDON criteria. In total, 4030 fresh in vitro fertilization (IVF) cycles from January 2013 to October 2021 were included in this retrospective cohort analysis and were categorized into four groups based on the POSEIDON criteria. The FORT between Groups 1 and 2 (0.61 ± 0.34 vs. 0.65 ± 0.35, P = 0.081) and Groups 3 and 4 (1.08 ± 0.82 vs. 1.09 ± 0.94, P = 0.899) were similar. The OSI in the order from the highest to the lowest were 3.01 ± 1.46 in Group 1, 2.28 ± 1.09 in Group 2, 1.54 ± 1.04 in Group 3, and 1.34 ± 0.96 in Group 4 (P < 0.001). The trend in the ORPI values was consistent with that in the OSI. FORT, OSI, ORPI, and FOI complemented each other and offered excellent effectiveness in reflecting ovarian reserve and response, but they were not good predictors of clinical pregnancy rate (CPR) from IVF.

In Vitro Fertilization Outcomes With a Dual Trigger in Normoresponders in Antagonist Cycles.

Objectives To evaluate whether the dual trigger of ovulation with a gonadotropin-releasing hormone (GnRH) agonist and the standard dose of recombinant human chorionic gonadotropin (hCG) (dual trigger) is better than hCG alone in in vitro fertilization (IVF) cycles of patients who responded well to ovarian stimulation. Methods Between January 2013 and December 2021, 5593 antagonist cycles of patients were reviewed. This study included women who had an antral follicle count of 5 or more and exhibited a normoresponse to ovarian stimulation using the GnRH antagonist protocol, as determined by the follicular output rate (FORT).The primary outcome indicators consisted of the quantities of retrieved oocytes and mature oocytes. The secondary outcome markers included live birth rates, clinical pregnancy rates, and continued pregnancy rates. Results A total of 1244 normoresponder women who met the inclusion criteria were identified from the scanned files and subsequently enrolled in the GnRH antagonist protocol. A total of 383 cycles were observed in the group that was given the standard hCG triggerwhile 861 cycles were observed in the group that was given the dual trigger. The number of mature oocytes and top-quality embryos was significantly higher in the dual trigger group. The maturation rate in the hCG group was 74.8%while it was 76.9% in the dual trigger group (p=0.018). The dual trigger group exhibited an ongoing pregnancy rate of 37.6%, whereas the hCG group had a rate of 30.1% (p = 0.02). The dual trigger group exhibited a slightly higher live birth rate (34.3% vs 29.2%, p = 0.11), although this difference did not reach statistical significance. Conclusion Dual trigger of ovulation was superior to hCG alone in terms of the number of mature oocytes yielded, top quality of embryos, maturation rates, andongoing pregnancy in IVF cycles of normoresponders having ovarian stimulation on the GnRH antagonist protocol.

P-694 Desogestrel did not affect Follicular Output Rate (FORT) during controlled ovarian stimulation for oocyte vitrification: prospective cohort study

Abstract Study question Does desogestrel an option for LH suppression during controlled ovarian stimulation for oocyte vitrification? Summary answer This new option for LH suppression did not affect FORT and, consequently, the number of collected oocytes for vitrification. What is known already Traditionally, LH suppression is achieved by using a gonadotropin-releasing hormone (GnRH) analogue. However, improved cryopreservation techniques and freeze-all strategies are introducing new concepts, including the possibility of using progesterone instead of GnRH analogues. Progesterone compounds are currently wide-used during ovarian stimulation for oocyte freezing for LH suppression. The use of oral medroxyprogesterone was previously shown to effectively prevent the LH surge, without impacting embryo development or pregnancy rates after frozen embryo transfer. The use of dydrogesterone with the same purpose was also effective. Desogestrel is a progesterone broadly known and accepted, and has good tolerability and low cost. Study design, size, duration A prospective cohort study was performed during the period of 2019-2021 including 75 patients submitted to oocyte freezing and 173 women matched by age as the controls (patients submitted to IVF for the first time). Participants/materials, setting, methods Patients from the control group used a flexible GnRH antagonist for LH suppression, and patients in the desogestrel group utilized desogestrel 75 mcg oral twice a day (starting from the beginning of gonadotropin to hCG/agonist day). All patients received the same gonadotropin regimen (recombinant FSH). The final oocyte maturation was equal for both groups (recombinant hCG and GnRH analogue agonist). The primary endpoint was the antral follicle responsiveness to follicle-stimulating hormone, measured by FORT. Main results and the role of chance Age [control group= 36 years (median 28-45); desogestrel group= 36 years (median 23-43); p = 0.793; Mann Whitney U test], baseline antral follicle count [control group= 8 (2-23); desogestrel group= 9 (2-21); p = 0.741; Mann Whitney U test] and anti-Mullerian hormone [control group= 1.5 (0.05-7.95); desogestrel group= 1.00 (0.01-16.00); p = 0.540; Mann Whitney U test] were similar between both groups. However, the controlled ovarian stimulation length was shorter in the control group [10.4±1.6 vs. 11.0±1.6; p = 0.044; t-student test,] and those patients utilized less gonadotropin than the desogestrel group [2736 UI ± 745 vs. 2933 UI ± 785; p = 0.047; t-student test,]. Finally, Follicular Output Rate (FORT) [control group= 45%; desogestrel group= 52%; p = 0.217; t-student test], number of collected oocytes [control group= 6 (1-33); desogestrel group= 8 (1-20); p = 0.293; Mann Whitney U test] and MII [control group= 5 (1-27); desogestrel group= 6 (1-19); p = 0.156, Mann Whitney U test] were the same between both groups. Limitations, reasons for caution The small sample size and the absence of randomization are the main limitations of our study. Since the first results were encouraging, a randomized study should be performed. Wider implications of the findings Desogestrel is a cheap and easy option to be used during controlled ovarian stimulation for oocyte vitrification, since the final results are the same. This is the first scientific report showing the use of desogestrel did not affect FORT and, consequently, the number of collected oocytes for vitrification. Trial registration number Not applicable

O-274 Influence of breast cancer prognostic factors on ovarian reserve and response to ovarian stimulation in fertility preservation

Abstract Study question Do breast cancer (BC) prognostic factors influence ovarian reserve and response to controlled ovarian hyperstimulation (COH) in the context of fertility preservation (FP)? Summary answer BC prognostic factors do not influence ovarian reserve and response to COH in the context of FP. What is known already Tumor Grade, triple-negative status, overexpression of HER2, as well as high Ki67 expression are all established prognostic factors for BC, influencing patients’ therapeutic management. Yet, there are still concerns about the potential impact of cancer status on ovarian reserve and response to COH. Previous studies analyzing the results of COH in BC patients have shown conflicting findings. However, there is limited data on the potential impact of BC status and prognostic factors on ovarian reserve and response to ovarian stimulation in women undergoing urgent FP. Study design, size, duration Observational, bicentric retrospective study including all BC patients who had vitrified oocytes after COH using a random start GnRH antagonist protocol after measurement of serum AMH levels and antral follicle count (AFC) between November 2013 and August 2021. Participants/materials, setting, methods Three-hundred-fifty-two BC patients having undergone one cycle of COH were analyzed. Number of oocytes recovered, maturation rate (number of mature oocytes/number of oocytes recovered), and Oocyte Retrieval Rate (number of retrieved oocytes/AFC) were studied according to the patients’ general characteristics, ovarian reserve markers, as well as BC diagnostic and prognostic factors: histological type, uni/multifocal character, TNM or UICC stage, hormonal receptors expression, HER2 status, Ki67, Grade, presence of vascular emboli, lymph node and BRCA1/2 status. Main results and the role of chance Overall, mean patients’ age was 33.6 ± 4 years. Mean AFC and serum AMH level were 20.5 ± 13.0 follicles and 2.7 ± 4.6 ng/mL, respectively. After ovarian stimulation, 12.5 ± 8.5 oocytes were recovered and 9.3 ± 6.9 were mature and further vitrified. Mean oocyte maturation rate was 74 ± 23%. As expected, patient’s age was significantly related to the number of mature oocytes recovered. Indeed, the risk of yielding less than 8 oocytes increased significantly after the age of 35 years. In addition, the oocyte maturation rate was also significantly higher before the age of 30 years, with an OR of 0.64 (0.43-0.96) to obtain a maturation rate &amp;lt;60%. Follicular responsiveness to FSH assessed by the follicular output rate (FORT index) as well as OOR were 30 ± 24% and 61 ± 27%, respectively, and both indexes were not influenced by tumor characteristics. However, maturation rate &amp;lt;60% was significantly related to SBR grade (OR = 0.73 (0.54-0.97), p&amp;lt;0.03) and the presence of a BRCA1/2-mutation (OR = 0.64 (0.42-0.99), p&amp;lt;0.03). Limitations, reasons for caution The main weakness is the retrospective nature of the study. Furthermore, the lack of data on reutilization of oocytes after FP prevents drawing reliable conclusions on the fate of these frozen gametes. Wider implications of the findings Our findings indicate that BC prognostic factors do not influence ovarian reserve markers nor the response to ovarian stimulation in the context of FP. Therefore, tumor grade, triple-negative status, overexpression of HER2, and high Ki67 should not modify the FP strategy when COH for oocyte vitrification is considered. Trial registration number N/A

Factors Influencing Follicular Output Rate and Follicle-to-Oocyte Index in POSEIDON-Defined Low-Prognosis Women in Vietnam: A Cross-Sectional Study.

This study aimed to identify the factors that influence follicular output rate (FORT) and follicle-to-oocyte index (FOI) among infertile Vietnamese women, as described by the Poseidon classification of poor responders. This cross-sectional analysis includes women who received IVF/ICSI treatment at Hue University Hospital, Vietnam, between January 2017 and December 2019. The study population was divided into four groups: Group 1 (age < 35, AFC ≥ 5 and AMH ≥ 1.2 ng/mL, number of oocytes retrieved in the previous cycle ≤ 9), group 2 (age ≥ 35; AFC ≥ 5 and AMH ≥ 1.2 ng/mL, number of oocytes retrieved in the previous cycle ≤ 9), group 3 (age < 35; AFC < 5 and/or AMH < 1.2 ng/mL) and group 4 (age ≥ 35; AFC < 5 and/or AMH < 1.2 ng/mL). All of the patients underwent controlled ovarian stimulation utilizing GnRH antagonist. A total of 243 cases were recruited into groups 1 (n = 44), 2 (n = 33), 3 (n = 54), and 4 (n = 112). There were statistically significant differences between the four groups in terms of age, infertility type, menstrual cycle, body mass index (BMI) and waist-hip ratio (WHR), endocrine tests, and total retrieved oocytes (p 0.05). The average number of oocytes per participant was 7.27, with the highest number occurring in group 1 (10.77) and the lowest occurring in group 4 (5.59). There was a relationship between FORT and BMI (ß: -0.146, p=0.039), FSH starting dose (ß: 0.146, p=0.030), and AMH (ß:0.166, p=0.015). No statistically significant correlation was detected between FOI and other variables. The starting dose of FSH for ovarian stimulation and AMH concentration were positively associated with FORT in individuals with a poor prognosis, whereas BMI was negatively correlated with FORT; No other parameters were found to correlate with FOI.

The follicular output rate in normo-ovulating women undergoing ovarian stimulation is increased after unilateral oophorectomy

Does unilateral oophorectomy modify the antral follicular responsiveness to exogenous FSH, assessed by the Follicular Output RaTe (FORT) in normo-ovulating women? Antral follicle responsiveness to exogenous FSH, as assessed by the FORT index, is significantly higher in women with a single ovary in comparison with the ipsilateral ovary of age-matched controls. Growing evidence indicates that the innovative FORT may be a remarkable tool to evaluate the follicle responsiveness to exogenous FSH, independently of the size of the pretreatment cohort of small antral follicles. It is conceivable that in the unclear compensating mechanisms at play in women having undergone unilateral oophorectomy, an increase in the sensitivity of antral follicles to FSH may be involved. To clarify this issue, we decided to investigate whether the responsiveness of follicles to exogenous FSH, as assessed by the FORT, is altered in unilaterally oophorectomized patients. The study included 344 non-polycystic ovary syndrome, non-endometriotic women, aged 22-43 years old. There were 86 women who had a single ovary as a result of unilateral oophorectomy or adnexectomy (Single Ovary group; average time since surgery: 52 (8-156) months), and each of them was retrospectively matched with three patients having two intact ovaries, according to age (±1 year), year of ovarian stimulation, and FSH starting dose (±50 IU) (Control group, n = 258). Serum anti-Mullerian hormone (AMH) levels and total antral follicle count (AFC) (3-12 mm) were assessed on cycle day 3 in both groups. In all patients, follicles were counted before exogenous FSH administration (baseline) and on the day of oocyte trigger (OT) (dOT; preovulatory follicles; 16-22 mm). Antral follicle responsiveness to FSH was estimated in both groups by the FORT, determined by the ratio of the preovulatory follicle count on dOT × 100 to the small AFC at baseline. FORT in the Single Ovary group was compared to the overall FORT considering both ovaries or the index calculated on the ipsilateral ovary of matched controls. Overall, serum AMH levels and total AFC (1.0 (0.5-2.1) vs 1.8 (1.0-3.3), P < 0.005) and (9.0 (6.0-17.0) vs 13.0 (8.0-21.0), P < 0.001, respectively) were lower in the Single Ovary group compared to the Control group. When considering the FORT calculated on the basis of the overall ovarian response in women with two ovaries, the results were similar when compared to those obtained in patients unilaterally oophorectomized (30.4% (15.6-50.0) vs 32.5% (14.0-50.0), respectively). Interestingly, the comparison of FORT between women with a single ovary and the ipsilateral ovary of age-matched controls, revealed, after adjustment for AMH and AFC, a significantly higher ratio after unilateral oophorectomy (32.5% (14.8-50.0) vs 25.0% (10.0-50.0), P < 0.002, respectively). This study was based on retrospective data in a limited population. In addition, the FORT index has inherent limitations due to its indirect assessment of follicular responsiveness to FSH. The present investigation provides evidence that the responsiveness of antral follicles to exogenous FSH is increased in women having undergone unilateral oophorectomy when compared to the ipsilateral ovary of age-matched controls. This is consistent with the implication of a compensating phenomenon that drives the follicular changes in unilaterally oophorectomized patients. Further studies directly assessing the granulosa cell function and the density of FSH receptors in small antral follicles are required to confirm our findings. The authors have no funding or competing interests to declare. N/A.

Letrozole cotreatment improves the follicular output rate in high-body-mass-index women with polycystic ovary syndrome undergoing IVF treatment.

Women who have polycystic ovary syndrome (PCOS) with high body mass index (BMI) typically have an attenuated ovarian response and decreased follicular size, which are linked to unfavourable clinical outcomes following in vitro fertilization (IVF) therapy. The follicular output rate (FORT), a qualitative indicator of follicular response, seems to be positively linked to the clinical outcomes of IVF. Progestin-primed ovarian stimulation (PPOS) has become an alternative to gonadotropin-releasing hormone (GnRH) analogues to inhibit the premature luteinizing hormone (LH) surge. As letrozole (LE) shows promise in enhancing ovarian response, we compared PPOS with and without LE for PCOS in high BMI women with a focus on the FORT and associated clinical and pregnancy outcomes. For the recruited 1508 women, ten variables including AFC; age; basal sex hormone level; BMI; infertility type; period of infertility and number of previous IVF attempts were chosen in the propensity score matching (PSM) model to match 1374 women who taken the MPA+ hMG protocol with 134 women who received the MPA+ hMG+ LE treatment at a 1:1 ratio. FORT was selected as the primary outcome measure. The number of oocytes retrieved, viable embryos, hMG dosage, duration, oocyte maturity rate, fertilization rate, and implantation rate were established as secondary outcomes. FORT was substantially elevated in the MPA+hMG+LE group compared with the MPA+hMG group (61% [35%, 86%] vs. 40% [25%, 60%], P <.001). Interestingly, the LE cotreatment group had a considerably lower mature oocyte rate despite having a similar number of mature oocytes and embryos recovered. The average hMG dosages and durations in the study group were similar to those in the control group. The implantation rate in the study group was numerically higher but without statistic significant than that in the control groups (43.15% (107/248) vs. 38.59% (115/298), OR 1.008, 95% CI 0.901-1.127; P >.05). The effect of LE combined with PPOS on FORT is better than the effect of the standard PPOS treatment in women with PCOS and a high BMI, but there is no substantially beneficial impact on pregnancy outcomes or the cycle features of COS, including consumption of hMG.

Ovarian sensitivity index can be used as a more sensitive indicator than follicular output rate to predict IVF/ICSI outcomes in patients of normal expected ovarian response stimulated with GnRH antagonist protocol

This retrospective study was performed to investigate the predictive power of the Ovarian Sensitivity Index (OSI) for IVF/ICSI outcomes in infertile patients who were of normal expected ovarian response. A total of 912 infertile patients who underwent GnRH antagonist protocol between January 2017 to August 2019 at the Medical Center for Human Reproduction, Beijing Chao-Yang Hospital were included. All patients completed the full oocyte retrieval cycle and either had a live birth or had no embryos left. OSI was significantly lower in patients with a live birth (196.0 ± 120.4 in the live birth group vs 276.4 ± 235.7 in the non-live birth group, p < 0.001) while follicular output rate (FORT, defined as the ratio of pre-ovulatory follicle count on hCG day x 100/small antral follicle count at baseline) showed no significant difference. Patients were divided into low, average and high OSI groups and analysed in tertiles. From the low to the high OSI group, the cumulative live birth rate (CLBR) decreased dramatically (72.7 vs 67.2 vs 54.8%, p < 0.001). Multivariate regression analysis showed that OSI was an independent factor affecting CLBR (OR: 0.996, 95%CI: 0.995–0.998, p < 0.001) in our study population. In conclusion, OSI can be used as an independent indicator to distinguish fecundity in infertile patients with normal expected ovarian response and is probably more sensitive than FORT.

Effects of follicular output rate on cumulative clinical pregnancy rate and cumulative live birth rate in PCOS patients with different characteristics.

We aim to explore the effects of follicular output rate (FORT) on cumulative clinical pregnancy rate (CCPR) and cumulative live birth rate (CLBR) in polycystic ovary syndrome (PCOS) patients with different characteristics undergoing in vitro fertilization (IVF) treatment. This retrospective study analyzed 454 patients with PCOS undergoing their first IVF cycle at our center from January 2016 to December 2020. FORT was calculated as pre-ovulatory follicle count (PFC) × 100/antral follicle count (AFC). Multivariate regression analyses were conducted to explore the relationships between FORT and CCPR and CLBR. Curve fitting and threshold effect analyses were established to find nonlinear relationships. Effect modification in different subgroups were examined by stratification analyses. Based on the FORT values, individuals were classified into the following three groups: low-FORT group, middle-FORT group and high-FORT group. Multivariate regression analyses revealed that FORT was an independent factor affecting the CCPR and CLBR significantly (OR = 1.015, 95% CI: 1.001, 1.030 and OR = 1.010, 95% CI:1.001, 1.020). Curve fitting and threshold effect analyses showed that the CCPR and CLBR had a positive correlation with FORT when the FORT was less than 70% (OR = 1.039, 95% CI: 1.013, 1.065 and OR = 1.024, 95% CI: 1.004, 1.044). Stratification analyses showed that the CLBR increased by 1.3% with each additional unit of FORT for patients with hyperandrogenic manifestations (OR = 1.013, 95% CI: 1.001, 1.025). Compared with the low-FORT group, in the high-FORT group, CCPR increased 1.251 times for patients with polycystic ovarian morphology, while CCPR and CLBR increased 1.891 times and 0.99 times for those with ovulation disorder, respectively (OR = 2.251, 95% CI: 1.008, 5.028 and OR = 2.891, 95% CI: 1.332, 6.323 and OR = 1.990, 95% CI: 1.133, 3.494). In patients with PCOS, cumulative IVF outcomes have a positive correlation with FORT when the FORT is less than 70%. For PCOS patients with polycystic ovarian morphology, ovulation disorder or hyperandrogenic manifestations, a high FORT could be conductive to achieving better pregnancy outcomes.