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Abstract Human embryo culture under 2–8% O2 is recommended by ESHRE revised guidelines for good practices in IVF labs. Nevertheless, notably due to the higher costs of embryo culture under hypoxia, some laboratories perform embryo culture under atmospheric O2 tension (around 20%). Furthermore, recent meta-analyses concluded with low evidence to a superiority of hypoxia on IVF/ICSI outcomes. Interestingly, a study on mice embryos suggested that oxidative stress (OS) might only have an adverse impact on embryos at cleavage stage. Hence, we aimed to demonstrate for the first time in human embryos that OS has a negative impact only at cleavage stage and that sequential culture conditions (5% O2 from Day 0 to Day 2/3, then «conventional» conditions at 20% O2 until blastocyst stage) might be a valuable option for human embryo culture. 773 IVF/ICSI cycles were included in this randomized clinical trial from January 2016 to April 2018. At Day 0 (D0), patients were randomized using a 1:2 allocation ratio between group A (20% O2; n = 265) and group B (5% O2; n = 508). Extended culture (EC) was performed when ≥ 5 Day 2-good-quality-embryos were available (n = 88 in group A (20% O2)). In subgroup B, 195 EC cycles were randomized again at Day 2 (using 1:1 ratio) into groups B’ (5% O2 until Day 6 (n = 101)) or C (switch to 20% O2 from Day 2 to Day 6 (n = 94). Fertilization rate, cleavage-stage quality Day 2-top-quality-embryo (D2-TQE), blastocyst quality (Day 5-top-quality-blastocyst (D5-TQB) and implantation rate (IR) were compared between groups A and B (= cleavage-stage analysis), or A(20% O2), B’(5% O2) and C(5%-to-20% O2). Overall, characteristics were similar between groups A and B. Significantly higher rates of early-cleaved embryos, top-quality and good-quality embryos on Day 2 were obtained in group B compared to group A (P

BACKGROUND: Assisted hatching (AH) in fresh embryo transfer (ET) could be associated with increased implantation rates. However, very few prospective randomized studies have specifically addressed the issue of AH during frozen-thawed embryo transfers (FET) cycles, those that have reported controversial results. The aim of this study was to evaluate the benefit of an enzymatic zona pellucida treatment of frozen-thawed embryos before transfer. METHODS: This was a prospective study including 125 non-donor FET cycles from 125 infertile couples. FETs were randomly allocated into AH group (n = 61, embryos pretreated with pronase 5 IU/ml for 1 min at 37°C) or control group (n = 64, untreated embryos). Zona pellucida thickness was measured for each transferred embryo. The main outcome parameters were clinical pregnancy and implantation rates. RESULTS: The two groups were comparable regarding mean women’s age, duration and indications of infertility, IVF outcome after fresh ETs, numbers and quality of fresh and frozen embryos, frozen-thawed embryo survival rates and blastomeres survival indexes. Despite a statistically significant decrease of zona pellucida thickness after pronase treatment [(mean ± SD) 18.5 ± 2.25 versus 14.5 ± 2.75 µm; P < 0.0001], implantation (9.6 versus 9.2%) and clinical pregnancy rates (18.0 versus 17.2%) were not statistically different after FETs, with a similar mean number of embryos transferred between AH and control groups, respectively. CONCLUSION: Within the constraints of our protocol, partial enzymatic digestion of zona pellucida by pronase was not related with any benefit of the FET outcome especially concerning the implantation ability of frozen-thawed embryos. [ABSTRACT FROM AUTHOR]

BACKGROUND: In primates, androgens can play a synergistic role with FSH in promoting the early follicular recruitment, which is critical in assisted reproduction technique programmes. OBJECTIVE: To assess whether poor responders can benefit from androgen application. METHODS: Inclusion criteria were a previous poor ovarian response to controlled ovarian stimulation and a decreased hormonal ovarian reserve. Selected women were randomized to receive either transdermal application of testosterone (n = 24) or placebo (n = 25) gel for 15 days before FSH treatment for a second IVF cycle. Similar GnRH analogue and equivalent FSH daily doses were used in both cycles. The primary outcome was the total number of oocytes retrieved. RESULTS: Testosterone gel application resulted in a significant increase in plasma testosterone levels but did not significantly improve the antral follicle count. Furthermore, after gel application, the main parameters of the ovarian response (numbers of pre-ovulatory follicles, total and mature oocytes and embryos) did not significantly differ between testosterone and placebo-treated patients. CONCLUSION: No significant beneficial effects of androgen administration on the ovarian response to FSH could be demonstrated. However, subsequent clinical trials are needed to determine whether an optimal dose and/or a longer duration of testosterone administration may be helpful. [ABSTRACT FROM AUTHOR]

BACKGROUND: The aim of this study was to determine the pronostic value of a sperm–zona pellucida (ZP) binding assay, combined with World Health Organization (WHO) grade ‘a’ sperm motility on the day of the IVF attempt, to predict sperm fertilizing ability in unexplained and moderate male factor infertilities. METHODS: In total, 84 couples (64 unexplained infertility; 20 male factor) underwent both a sperm–ZP binding assay and an IVF attempt, irrespective of the test’s result. The test was negative when grade ‘a’ motility was #5% and/or the ZP binding index was <0.7. Fertilization and pregnancy rates were related to the test’s results. RESULTS: Thirty-one patients had a negative test (group N) and 53 a positive test (group P). A difference was observed concerning the fertilization rate [median (range): 0 (0–75%) versus 50 (0–100%); P = 0.0001] and the number of cycles with fertilization rate <20% (65 versus 23%; P = 0.0002) between groups N and P respectively. In the group of unexplained and male factor infertilities, the test showed a sensitivity of 83 and 60%, specificity of 50 and 90%, positive predictive value of 76 and 86%, and negative predictive value of 61 and 69% respectively. CONCLUSION: Sperm–ZP binding test, combined with WHO grade ‘a’ motility assessment, is relevant to prevent IVF fertilization failures in unexplained infertility and, most particularly, in moderate male factor infertility. [ABSTRACT FROM AUTHOR]

BACKGROUND: In normo-ovulatory infertile women undergoing mild ovarian stimulation out of IVF, FSH stimulation regimen must be carefully adjusted to control the number of recruited follicles and to prevent multiple pregnancies. The aim of this prospective study was to assess the effect of the timing of FSH administration (fixed dose and duration) on the number of large follicles. METHODS: Women were prospectively randomized by means of sealed envelopes to receive daily 112.5 IU recombinant FSH (rFSH), either from cycle day (CD) 2–6 (Group A) or from CD 7–11 (Group B). Hormonal measurements and follicular ultrasound assessments were performed on CD 2, 7 and 12. RESULTS: On CD 12, the development rate of exactly two follicles ≥14 mm in diameter was significantly lower in Group A than in Group B (4% of women versus 42%, P = 0.002). Although the pattern of serum estradiol (E2) concentrations in Group A displayed a plateau from CD 7, the cancellation rate for overstimulation (more than three follicles ≥14 mm in diameter) was significantly increased (P = 0.009). CONCLUSIONS: Preventing the closure of the FSH window by mid to late follicular phase FSH administration better fulfils the objective of obtaining a limited number of large follicles than surpassing the FSH threshold by an early administration. [ABSTRACT FROM AUTHOR]

Objective: Various gonadotropins are used for ovarian stimulation (OS). This study investigated the cost-effectiveness of different gonadotropins based on real-world data from the French National Health Database (SNDS) over a 7-year follow-up of assisted reproductive technology (ART) treatments., Design: Cost-effectiveness analysis of different gonadotropins based on real-world data from the French National Health Database (SNDS)., Participants: Women from SNDS undergoing OS leading to oocyte pick-up registered between 31 Jan 2013 and 31 Dec 2018 (N=245,534 stimulations) and receiving either r-hFSH alfa originator (110,439), its biosimilars (12,287), or urinaries (mainly HP-hMG[65,654] and marginally u-hFSH-HP[7,821]) were included (follow-up:31 Dec 2019)., Methods: Clinical inputs for this model, including live birth (LB) and cumulative LB (CLB) were calculated from data as published in Grynberg et al. 2022. A decision-tree model was developed comprising pregnancy and live birth rate (LBR) states for a complete ART cycle, including one fresh and ≤4 frozen/thawed embryo transfers and related costs. Cost inputs included those of drugs, ART procedure, pregnancy and delivery, and adverse events. Cost per LB and CLB, and incremental cost-effectiveness ratio (ICER) were assessed. Robustness of results was determined by comprehensive sensitivity analyses., Results: Overall, r-hFSH alfa originator was found to be associated with a lower cost per LB and per CLB (cost per LB: €26,010; CLB: €22,278) versus its biosimilars (cost per LB: €28,037; CLB: €23,807) and versus urinaries (cost per LB: €26,636; CLB: €23,335). Calculated ICERs with r-hFSH alfa for LB were €5,538 and €14,090, whereas for CLB were €1,945 and €13,742 versus biosimilars and urinaries, respectively. Cost-effectiveness acceptability curve showed that in a majority of iterations r-hFSH alfa originator had a probability of being cost-effective at a hypothetical threshold of €20,000/live birth. Sensitivity analyses showed that the most important variable impacting the outcome in fresh transfers was the probability of birth for biosimilars and the probability of pregnancy for urinaries, while for cumulative transfers it was the probability of pregnancy for biosimilars and the probability of birth for urinaries., Limitations: As the clinical data were obtained from a non-interventional study and not a randomised controlled trial, the results may still be susceptible to residual confounding or other biases Conclusions: r-hFSH alfa originator is cost-effective compared to its biosimilars and to urinaries (mainly HP-hMG) and is associated with a lower cost per LB compared to these gonadotropins, where the main driver is the higher live birth efficacy rate achieved with it., (The Author(s). Published by S. Karger AG, Basel.)

Diminished ovarian reserve (DOR) and primary ovarian insufficiency (POI) are major causes of female infertility. We recently found a monogenic etiology in 29.3% of POI, leading to personalized medicine. The genetic landscape of DOR is unknown. A prospective study (2018-2023) of an international cohort of 120 patients with unexplained DOR was performed using a large custom targeted next-generation sequencing panel including all known POI-causing genes. The diagnostic yield, based on the American College of Medical Genetics, was 24, 2%. Genes belong to different pathways: metabolism and mitochondria (29.7%), follicular growth (24.3%), DNA repair/meiosis (18.9%), aging (16.2%), ovarian development (8.1%), and autophagy (2.7%). Five genes were recurrently found: LMNA , ERCC6 , SOX8 , POLG , and BMPR1B . Six genes identified in single families with POI were involved in DOR, GNAS , TGFBR3 , XPNPEP2 , EXO1 , BNC1 , ATG , highlighting their role in maintaining ovarian reserve. In our cohort, 26 pregnancies were recorded, but no pregnancy was observed when meiosis/DNA repair genes were involved, suggesting severely impaired oocyte quality. Additional studies should confirm these preliminary results. This study with a large NGS panel defines the genetic landscape of a large cohort of DOR. It supports routine genetic diagnosis. Genetics could be a biomarker predicting infertility and progression to POI.

Study Question: What are the potential risk factors for poor oocyte recuperation rate (ORR) and oocyte immaturity after GnRH agonist (GnRHa) ovulation triggering?, Summary Answer: Lower ovarian reserve and LH levels after GnRHa triggering are risk factors of poor ORR. Higher BMI and anti-Müllerian hormone (AMH) levels are risk factors of poor oocyte maturation rate (OMR)., What Is Known Already: The use of GnRHa to trigger ovulation is increasing. However, some patients may have a suboptimal response after GnRHa triggering. This suboptimal response can refer to any negative endpoint, such as suboptimal oocyte recovery, oocyte immaturity, or empty follicle syndrome. For some authors, a suboptimal response to GnRHa triggering refers to a suboptimal LH and/or progesterone level following triggering. Several studies have investigated a combination of demographic, clinical, and endocrine characteristics at different stages of the treatment process that may affect the efficacy of the GnRHa trigger and thus be involved in a poor endocrine response or efficiency but no consensus exists., Study Design, Size, Duration: Bicentric retrospective cohort study between 2015 and 2021 (N = 1747)., Participants/materials, Setting, Methods: All patients aged 18-43 years who underwent controlled ovarian hyperstimulation and ovulation triggering by GnRHa alone (triptorelin 0.2 mg) for ICSI or oocyte cryopreservation were included. The ORR was defined as the ratio of the total number of retrieved oocytes to the number of follicles >12 mm on the day of triggering. The OMR was defined as the ratio of the number of mature oocytes to the number of retrieved oocytes. A logistic regression model with a backward selection method was used for the analysis of risk factors. Odds ratios (OR) are displayed with their two-sided 95% confidence interval., Main Results and the Role of Chance: In the multivariate analysis, initial antral follicular count and LH level 12-h post-triggering were negatively associated with poor ORR (i.e. below the 10th percentile) (OR: 0.61 [95% CI: 0.42-0.88]; P = 0.008 and OR: 0.86 [95% CI: 0.76-0.97]; P = 0.02, respectively). A nonlinear relationship was found between LH level 12-h post-triggering and poor ORR, but no LH threshold was found. A total of 25.3% of patients suffered from oocyte immaturity (i.e. OMR < 75%). In the multivariate analysis, BMI and AMH levels were negatively associated with an OMR < 75% (OR: 4.34 [95% CI: 1.96-9.6]; P < 0.001 and OR: 1.22 [95% CI: 1.03-1.12]; P = 0.015, respectively). Antigonadotrophic pretreatment decreased the risk of OMR < 75% compared to no pretreatment (OR: 0.72 [95% CI: 0.57-0.91]; P = 0.02)., Limitations, Reasons for Caution: Our study is limited by its retrospective design and by the exclusion of patients who had hCG retriggers. However, this occurred in only six cycles. We were also not able to collect information on the duration of pretreatment and the duration of wash out period., Wider Implications of the Findings: In clinical practice, to avoid poor ORR, GnRHa trigger alone should not be considered in patients with higher BMI and/or low ovarian reserve, balanced by the risk of ovarian hyperstimulation syndrome. In the case of a low 12-h post-triggering LH level, practicians must be aware of the risk of poor ORR, and hCG retriggering could be considered., Study Funding/competing Interest(s): None., Trial Registration Number: N/A., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

This comparative non-interventional study using data from the French National Health Database (Système National des Données de Santé) investigated real-world (cumulative) live birth outcomes following ovarian stimulation, leading to oocyte pickup with either originator recombinant human follicle-stimulating hormone (r-hFSH) products (alfa or beta), r-hFSH alfa biosimilars, or urinaries including mainly HP-hMG (menotropins), and marginally u-hFSH-HP (urofollitropin). Using data from 245,534 stimulations (153,600 women), biosimilars resulted in a 19% lower live birth (adjusted odds ratio (OR) 0.81, 95% confidence interval (CI) 0.76-0.86) and a 14% lower cumulative live birth (adjusted hazard ratio (HR) 0.86, 95% CI 0.82-0.89); and urinaries resulted in a 7% lower live birth (adjusted OR 0.93, 95% CI 0.90-0.96) and an 11% lower cumulative live birth (adjusted HR 0.89, 95% CI 0.87-0.91) versus originator r-hFSH alfa. Results were consistent across strata (age and ART strategy), sensitivity analysis using propensity score matching, and with r-hFSH alfa and beta as the reference group., Competing Interests: Declaration of competing interest MG has received fees from Merck Healthcare KGaA, Darmstadt, Germany, as a medical expert for this study, and lecture fees from Merck KGaA, Darmstadt, Germany, MSD, Ferring, IBSA, Gedeon Richter, Theramex, General Electric, Novartis, Besins Healthcare. I-CD has received fees from Merck Healthcare KGaA, Darmstadt, Germany, as a medical expert for this study, and lecture fees from Merck KGaA, Darmstadt, Germany, MSD, Ferring, IBSA, Gedeon Richter, and Theramex. FR and EH are employees of HEVA, Lyon, France. LL, FP, SP, and CC-B are employees of Merck Santé, Lyon, France, an affiliate of Merck KGaA, Darmstadt, Germany. PV, JES, and TDH are employees of Merck Healthcare KGaA, Darmstadt Germany. CH is an employee of Merck KGaA, Darmstadt Germany. MB has received fees from Merck Healthcare KGaA, Darmstadt, Germany, as a medical expert for this study, and lecture fees from Merck KGaA, Darmstadt, Germany., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Economic evaluations of the value-for-money of Medically Assisted Reproduction (MAR) interventions are increasingly important due to growing pressure on healthcare budgets. Although such evaluations are commonplace in the published literature, the number/methodological complexity of different evaluations available, and the challenges specific to MAR interventions, can complicate the interpretation of such analyses for fertility treatments. This article aims to serve as an educational resource and provide context on the design/interpretation of economic analyses for MAR interventions. Several areas are relevant for first-line providers and decision makers: scope of analysis, comparator used, perspective/time horizon considered, outcomes used to measure success, and how results from cost-effectiveness studies can be summarised and used in clinical practice. We aim to help clinicians better understand the strengths/weaknesses of economic analyses, to enable the best use of the evidence in practice, so resources available for MAR interventions can provide maximum value to patients and society., Competing Interests: Declaration of competing interest The authors in this manuscript were qualified according to ICMJE criteria and has received no fees for their authorship. ML and TDH are employees of Merck Healthcare KGaA, Darmstadt, Germany. Outside of the submitted manuscript, MPC has received honoraria for a lecture from Merck KGaA, Darmstadt, Germany; AR has received, individually or as part of his institution, grants, honoraria or consultation fees from Merck Healthcare, Darmstadt, Germany, Ferring and MSD. The remaining authors report no disclosures., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Primary Ovarian Insufficiency (POI), a public health problem, affects 1-3.7% of women under 40 yielding infertility and a shorter lifespan. Most causes are unknown. Recently, genetic causes were identified, mostly in single families. We studied an unprecedented large cohort of POI to unravel its molecular pathophysiology., Methods: 375 patients with 70 families were studied using targeted (88 genes) or whole exome sequencing with pathogenic/likely-pathogenic variant selection. Mitomycin-induced chromosome breakages were studied in patients' lymphocytes if necessary., Findings: A high-yield of 29.3% supports a clinical genetic diagnosis of POI. In addition, we found strong evidence of pathogenicity for nine genes not previously related to a Mendelian phenotype or POI: ELAVL2, NLRP11, CENPE, SPATA33, CCDC150, CCDC185, including DNA repair genes: C17orf53(HROB), HELQ, SWI5 yielding high chromosomal fragility. We confirmed the causal role of BRCA2, FANCM, BNC1, ERCC6, MSH4, BMPR1A, BMPR1B, BMPR2, ESR2, CAV1, SPIDR, RCBTB1 and ATG7 previously reported in isolated patients/families. In 8.5% of cases, POI is the only symptom of a multi-organ genetic disease. New pathways were identified: NF-kB, post-translational regulation, and mitophagy (mitochondrial autophagy), providing future therapeutic targets. Three new genes have been shown to affect the age of natural menopause supporting a genetic link., Interpretation: We have developed high-performance genetic diagnostic of POI, dissecting the molecular pathogenesis of POI and enabling personalized medicine to i) prevent/cure comorbidities for tumour/cancer susceptibility genes that could affect life-expectancy (37.4% of cases), or for genetically-revealed syndromic POI (8.5% of cases), ii) predict residual ovarian reserve (60.5% of cases). Genetic diagnosis could help to identify patients who may benefit from the promising in vitro activation-IVA technique in the near future, greatly improving its success in treating infertility., Funding: Université Paris Saclay, Agence Nationale de Biomédecine., Competing Interests: Declaration of interests The authors declare no conflict of interest., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Study Question: Do breast cancer (BC) characteristics influence IVM of oocytes outcomes in patients undergoing fertility preservation (FP)?, Summary Answer: Scarff-Bloom-Richardson (SBR) III grade, triple-negative BC and HER2 overexpression are independent predictors of fewer oocytes or poor IVM outcomes in young women seeking FP., What Is Known Already: SBR grade, triple-negative status and overexpression of HER2, as well as a high Ki67 proliferation index are all established prognostic factors for BC, influencing patients' therapeutic management. Yet there are also concerns about the potential impact of cancer status on ovarian reserve and function. Previous studies analysing the results of ovarian stimulation in BC patients have shown conflicting findings. Nevertheless, there is no data on the potential impact of BC status and prognostic factors on IVM outcome in women undergoing urgent FP., Study Design, Size, Duration: We studied 321 BC patients, 18 to 41 years of age, who were also candidates for oocyte cryopreservation following IVM. The number of oocytes recovered, maturation rate and total number of cryopreserved oocytes were assessed., Participants/materials, Setting, Methods: Ovarian reserve markers (antral follicle count [AFC] and serum anti-Müllerian hormone [AMH] levels) and IVM outcomes were compared according to BC characteristics (Ki67 proliferation index >20%, progesterone and/or oestrogen receptors expression, HER2 status and SBR grade). Logistic regression analysis was then performed to determine the variables that could be independently associated with poor IVM outcomes, such as oocyte retrieval rate <50%, oocyte maturation rate <60% and total number of frozen oocytes <5., Main Results and the Role of Chance: Overall, the mean age of the population was 32.3 ± 4.1 years. Mean AFC and serum AMH levels were 22.8 ± 13.9 follicles and 3.8 ± 3.1 ng/ml, respectively. AMH levels were significantly lower in case of triple-negative BC when compared with ER/PR/HER2 status positive cancer (3.1 ± 2.6 ng/ml vs 4.0 ± 3.3 ng/ml, P = 0.02). The mean number of recovered oocytes was 10.2 ± 9.1. After a mean maturation rate of 58.0 ± 26.1%, 5.8 ± 5.3 mature oocytes were cryopreserved per cycle. The number of retrieved and cryopreserved oocytes after IVM were significantly lower in patients presenting with an SBR III tumour when compared with an SBR I or II tumour (9.6 ± 8.7 vs 11.7 ± 9.8, P = 0.02 and 5.4 ± 5.4 vs 6.6 ± 5.8, P = 0.02, respectively). Multivariate statistical analysis showed that HER2 positive status was associated with a mean maturation rate <60% (odds ratio: 0.54; 95% CI (0.30-0.97)). Ki67 and hormonal status were not correlated with poor IVM outcomes., Limitations, Reasons for Caution: A weakness is the retrospective nature of the study. Moreover, as with many studies focusing on FP in oncology patients, the lack of data after reutilization of IVM oocytes prevents drawing reliable conclusions on the fate of these frozen gametes., Wider Implications of the Findings: BC prognostic factors might influence IVM outcomes. Moreover, HER2 is likely to be involved in the ovarian function and oocyte maturation process. Further investigations are needed to better understand the mechanisms at play and their possible impact on the competence of IVM oocytes., Study Funding/competing Interest(s): No specific funding was used and there are no conflicts of interest., Trial Registration Number: N/A., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: In absence of contraindication, breast cancer patients of reproductive age can undergo fertility preservation with controlled ovarian stimulation for oocyte/embryo cryopreservation before the administration of potentially gonadotoxic treatments. High hormonal levels induced by ovarian stimulation might have an adverse impact on hormone-positive breast cancer. Whether letrozole supplementation during ovarian stimulation (COSTLES) reduces serum progesterone levels after GnRHa trigger remains unknown. We aimed to determine whether COSTLES might be useful for breast cancer patients undergoing fertility preservation to reduce early luteal progesterone levels following GnRH-agonist (GnRHa)trigger., Methods: All women who underwent COS with GnRH antagonist protocol with GnRHa trigger were included. Serum progesterone level measured 12 h after GnRHa trigger was compared between patients undergoing COS with letrozole supplementation (COSTLES group) and patients undergoing COS without letrozole (Control group) for fertility preservation purposes., Results: A total of 246 patients were included, of which 84 patients (34.1%) in the COSTLES group and 162 patients (65.6%) in the Control group. All patients in the COSTLES group were BC patients (n = 84, 100%), while the Control group included 77 BC patients (47.5%). Patients in the two groups were comparable. The mean number of oocytes recovered and vitrified at metaphase 2 stage did not significantly differ between the two groups. Serum progesterone levels on the day after GnRHa trigger were significantly lower in the COSTLES group (8.6 ± 0.7 vs. 10.5 ± 0.5 ng/mL, respectively, p < 0.03), as well as serum E2 levels (650.3 ± 57.7 vs. 2451.4.0 ± 144.0 pg/mL, respectively, p < 0.01). However, the GnRHa-induced LH surge was significantly higher in in the COSTLES group (71.9 ± 4.6 vs. 51.2 ± 2.6 UI/L, respectively, p < 0.01)., Conclusions: Our results show that COSTLES for fertility preservation in breast cancer patients using GnRHa trigger reduces serum progesterone levels compared to ovarian stimulation without letrozole. These findings encourage the use of COSTLES in this context to decrease the potential deleterious effect of elevated hormonal levels on hormone-positive breast cancer., (© 2022. The Author(s).)

Human embryo culture under 2-8% O2 is recommended by ESHRE revised guidelines for good practices in IVF labs. Nevertheless, notably due to the higher costs of embryo culture under hypoxia, some laboratories perform embryo culture under atmospheric O2 tension (around 20%). Furthermore, recent meta-analyses concluded with low evidence to a superiority of hypoxia on IVF/ICSI outcomes. Interestingly, a study on mice embryos suggested that oxidative stress (OS) might only have an adverse impact on embryos at cleavage stage. Hence, we aimed to demonstrate for the first time in human embryos that OS has a negative impact only at cleavage stage and that sequential culture conditions (5% O2 from Day 0 to Day 2/3, then «conventional» conditions at 20% O2 until blastocyst stage) might be a valuable option for human embryo culture. 773 IVF/ICSI cycles were included in this randomized clinical trial from January 2016 to April 2018. At Day 0 (D0), patients were randomized using a 1:2 allocation ratio between group A (20% O2; n = 265) and group B (5% O2; n = 508). Extended culture (EC) was performed when ≥ 5 Day 2-good-quality-embryos were available (n = 88 in group A (20% O2)). In subgroup B, 195 EC cycles were randomized again at Day 2 (using 1:1 ratio) into groups B' (5% O2 until Day 6 (n = 101)) or C (switch to 20% O2 from Day 2 to Day 6 (n = 94). Fertilization rate, cleavage-stage quality Day 2-top-quality-embryo (D2-TQE), blastocyst quality (Day 5-top-quality-blastocyst (D5-TQB) and implantation rate (IR) were compared between groups A and B (= cleavage-stage analysis), or A(20% O2), B'(5% O2) and C(5%-to-20% O2). Overall, characteristics were similar between groups A and B. Significantly higher rates of early-cleaved embryos, top-quality and good-quality embryos on Day 2 were obtained in group B compared to group A (P < 0.05). This association between oxygen tension and embryo quality at D2 was confirmed using an adjusted model (P < 0.05). Regarding blastocyst quality, culture under 20% O 2 from Day 0 to Day 6 (group A) resulted in significantly lower Day 5-TQB number and rates (P < 0.05) compared to both groups B' and C. Furthermore, blastocyst quality was statistically equivalent between groups B' and C (P = 0.45). At Day 6, TQB numbers and rates were also significantly higher in groups B' and C compared to group A (P < 0.05). These results were confirmed analyzing adjusted mean differences for number of Day 5 and Day 6 top quality embryos obtained in group A when compared to those respectively in groups B' and C (P < 0.05). No difference in clinical outcomes following blastocyst transfers was observed. These results would encourage to systematically culture embryos under hypoxia at least during early development stages, since OS might be detrimental exclusively before embryonic genome activation., (© 2021. The Author(s).)

Purpose: The aim is to report the first live-birth following ICSI using spermatozoa previously vitrified in a Stripper Tip., Principal Results: A 34-year-old cryptozoospermic man was enrolled in a sperm vitrification program. After failure of conventional freezing technique, spermatozoa were vitrified using two carriers: a commercially-available, Cell Sleeper, and a "home-made" one, Stripper Tip. This man and his 30-year-old wife underwent an ICSI attempt using vitrified-warmed spermatozoa from these devices. All frozen-warmed spermatozoa were quickly recovered. Among the oocytes retrieved, six were injected with sperm from the Cell Sleeper, and seven with sperm from the Stripper tip, leading to 4 embryos in each case. Two embryos, arising from sperm frozen in the Stripper tip, were transferred, resulting in a healthy live-birth., Conclusions: This is the first successful delivery following the use of spermatozoa frozen in an original device, the Stripper Tip, giving a promising prospect for managing severe male infertilities., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: Is serum progesterone(P) level on day 2 of vaginal P administration in a hormonally substituted mock cycle predictive of live birth in oocyte donation(OD)?, Methods: Retrospective analysis of 110 mock cycles from 2008 to 2016 of OD recipients having at least one subsequent embryo transfer (ET). Endometrial preparation consisted of sequential administration of vaginal estradiol, followed by transdermal estradiol and 600 mg/day vaginal micronized P. In mock cycles, serum P was measured 2 days after vaginal P introduction. OD was performed 1 to 3 years later, without P measurement., Results: In mock cycles, mean serum P level on day 2 was 12.8 ± 4.5 ng/mL (range: 4-28 ng/mL). A total of 32% patients had P < 10 ng/mL. At the time of first OD, age of recipients and donors, number of retrieved and attributed oocytes, and number of transferred embryos were comparable between patients with P < 10 ng/mL in their mock cycles compared with P ≥ 10 ng/mL. Pregnancy and live birth rate after first ET were significantly lower for patients with P < 10ng/mL (9% vs. 35 %; P = 0.002 and 9% vs. 32%; P = 0.008, respectively). Considering both fresh and subsequent frozen-thawed ET, cumulative live birth rate per-patient and per-transfer were significantly lower in patients with P < 10 ng/mL in their mock cycle (14% vs. 35%; P = 0.02 and 11% vs. 27%; P = 0.03)., Conclusion: A low P level in hormonally substituted cycles several years before ET performed with the same endometrial preparation is associated with a significantly lower chance of live birth. This suggests that altered vaginal P absorption is a permanent phenomenon. Monitoring serum P in hormonally substituted cycles appears mandatory to adjust luteal P substitution.

In vitro maturation (IVM) of oocytes retrieved at germinal vesicle stage, followed by vitrification of mature oocytes, has emerged as a fertility preservation (FP) option. This technique was first developed for patients with polycystic ovarian syndrome. In this population, providing LH activity prior to oocyte collection has been associated with better IVM outcomes. However, the benefit of this treatment in normo-ovulatory breast cancer (BC) patients undergoing IVM for FP purpose has never been investigated. To assess if the absence of therapeutic intervention prior to oocyte retrieval for IVM modifies IVM outcomes in BC patients undergoing urgent FP, we performed a non-inferiority, randomized controlled trial. The main outcome was the total number of mature oocytes obtained and cryopreserved after IVM. A total of 172 normo-ovulatory women, suffering from BC, 18 to 39 years of age received no injection or a subcutaneous injection of hCG or GnRH agonist (GnRHa) 36 h before oocytes retrieval according to randomized allocation. The total number of cryopreserved oocytes were 5.1 ± 3.8, 5.4 ± 3.8, and 6.0 ± 4.2 oocytes, respectively in the without, hCG and GnRHa groups. Mean differences were not significant between the three groups (- 0.5; CI 97.5% [- 2.03:1.02] and - 0.22; CI 97.5% [- 1.75:1.32], respectively). Intention to treat analyses failed to show non-inferiority in the "without injection group" in comparison with hCG or GnRHa groups. Our results are not conclusive enough to modify our practices and to stop administering hCG or GnRHa before IVM cycles for FP. The study was retrospectively registered to clinical trial (ID NCT03954197) in May 2019.

Objective: To determine whether post-warming culture duration (1 hour vs. 18 hours) influences implantation rates (IRs) of good-quality blastocysts (GQB) in a good-prognosis population., Design: Prospective interventional randomized study., Setting: University hospital., Patient(s): One hundred sixty-two GQB transfers., Intervention(s): Patients' vitrified blastocysts were randomly allocated to group A, warming on the day before transfer (n = 81), or B, warming on the day of transfer (n = 81)., Main Outcome Measure(s): IR, live birth rate, reexpansion degree, and quality after warming and immediately before transfer., Result(s): Quality of the warmed and transferred blastocysts was similar (respectively, 39.1% and 32.7% top quality [≥B4AA/AB/BA] in group A vs. 41.7 and 42.2% in group B). In group A, 14 of 102 blastocysts (12.2%) appeared to be unsuitable for transfer, versus only 1 of 103 (0.9%) in group B, thus leading to an additional warming. As expected, reexpansion degree just before transfer was higher in group A (0.90 vs. 0.70). Likewise, the proportion of hatched blastocysts before transfer was higher after a longer culture period (38.6% in group A vs. 12.7% in group B). IRs were similar (38.0% in group A vs. 36% in group B), as were live birth rates (35.8% in group A vs. 34.6% in group B)., Conclusion(s): IRs were not different, whatever the duration of post-warming culture of GQB. Both warming strategies could be applied to good-prognosis patients to optimize the laboratory workflow without any detrimental effect., (Copyright © 2018 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

The genetic causes of oocyte meiotic deficiency (OMD), a form of primary infertility characterised by the production of immature oocytes, remain largely unexplored. Using whole exome sequencing, we found that 26% of a cohort of 23 subjects with OMD harboured the same homozygous nonsense pathogenic mutation in PATL2 , a gene encoding a putative RNA-binding protein. Using Patl2 knockout mice, we confirmed that PATL2 deficiency disturbs oocyte maturation, since oocytes and zygotes exhibit morphological and developmental defects, respectively. PATL2's amphibian orthologue is involved in the regulation of oocyte mRNA as a partner of CPEB However, Patl2's expression profile throughout oocyte development in mice, alongside colocalisation experiments with Cpeb1, Msy2 and Ddx6 (three oocyte RNA regulators) suggest an original role for Patl2 in mammals. Accordingly, transcriptomic analysis of oocytes from WT and Patl2 -/- animals demonstrated that in the absence of Patl2, expression levels of a select number of highly relevant genes involved in oocyte maturation and early embryonic development are deregulated. In conclusion, PATL2 is a novel actor of mammalian oocyte maturation whose invalidation causes OMD in humans., (© 2018 The Authors. Published under the terms of the CC BY 4.0 license.)

Objective: To perform a prospective evaluation of postoperative fertility management using the endometriosis fertility index (EFI)., Study: This prospective non-interventional observational study was performed from January 2013 to February 2016 in a tertiary care university hospital and an assisted reproductive technology (ART) centre. In total, 196 patients underwent laparoscopic surgery for endometriosis-related infertility. Indications for surgery included pelvic pain (dysmenorrhoea, and/or deep dyspareunia), abnormal hysterosalpingogram, and failure to conceive after three or more superovulation cycles with or without intra-uterine insemination. Multidisciplinary fertility management followed the surgical diagnosis and treatment of endometriosis. Three postoperative options were proposed to couples based on the EFI score: EFI score ≤4, ART (Option 1); EFI score 5-6, non-ART management for 4-6 months followed by ART (Option 2); or EFI score ≥7, non-ART management for 6-9 months followed by ART (Option 3). The main outcomes were non-ART pregnancy rates and cumulative pregnancy rates according to EFI score. Univariate and multivariate analyses with backward stepwise logistic regression were used to explain the occurrence of non-ART pregnancy after surgery for women with EFI scores ≥5. Adjustment was made for potential confounding variables that were significant (p<0.05) or tending towards significance (p<0.1) on univariate analysis., Results: The cumulative pregnancy rate was 76%. The total number of women and pregnancy rates for Options 1, 2 and 3 were: 26 and 42.3%; 56 and 67.9%; and 114 and 87.7%, respectively. The non-ART pregnancy rates for Options 1, 2 and 3 were 0%, 30.5% and 48.2%, respectively. The ART pregnancy rates for Options 1, 2 and 3 were 50%, 60.6% and 80.3%, respectively. The mean time to conceive for non-ART pregnancies was 4.2 months. The benefit of ART was inversely correlated with the mean EFI score. On multivariate analysis, the EFI score was significantly associated with non-ART pregnancy (odds ratio 1.629, 95% confidence interval 1.235-2.150)., Conclusion: In daily prospective practice, the EFI was useful for subsequent postoperative fertility management in infertile patients with endometriosis., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Clinical outcomes of 291 day-5 blastocyst transfers carried out between January 2012 and March 2016 were retrospectively compared according to their quality at day 2 and 3. Inclusion criteria were female age younger than 37 years; first or second IVF and intracytoplasmic sperm injection cycle; quality of the transferred blastocyst: blastocoele B3 or higher; inner-cell-mass A/B; trophectoderm A/B; and known implantation outcome for each transferred blastocyst. Blastocysts were classified into good-quality and poor-quality embryo groups at day 2 and 3. Implantation (38.7% versus 41.4), clinical pregnancy (40.3% versus 45.9%), miscarriage (22.2% versus 26.7%;) and live birth rates (37.4% versus 38.8%) were comparable in day 2 good and poor-quality embryo groups. No signficiant differences in morphology of transferred blastocysts at day 3 were found. Multivariable analysis highlighted that poor or good embryo quality at day 2 and day 3 were not predictive of the implantation of good-quality blastocysts (at day 2: adjusted odds ratio = 0.82 CI 95% 0.49 to 1.38; at day 3: adjusted odds ratio = 1.39; CI 95% 0.77 to 2.52). Good-quality blastocyst transfer should, therefore, be carried out irrespective of embryo quality at cleavage stage, as it may not compromise success rates in a good-prognosis population., (Copyright © 2017 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Objectives: To study the role of ovarian stimulation procedures on the risk of pregnancy-induced hypertension, gestational diabetes mellitus and neonatal outcomes according to women's characteristics and the causes of infertility., Design: Retrospective, observational, case/control study., Patients: Spontaneous pregnancies (group A, n=8107), pregnancies achieved after mild ovarian ovulation induction without other Assisted Reproductive Technology (ART) procedures (group B, n=44), pregnancies after mild ovarian stimulation and ART procedures (group C, n=53) or pregnancies after multi (>2) follicular stimulation with gonadotrophin therapy and ART procedures (group D, n=133); all of the groups had identical protocols for prenatal care., Main Outcome Measurements: Pregnancy-induced hypertension (PIH), fetal macrosomia (estimated fetal weight >90th percentile), gestational diabetes mellitus, caesarean section, and neonatal outcomes., Results: The incidence rates of PIH (2.7, 11.6, 4.2, and 2.5%) in groups A, B, C and D, respectively, (p=0.004), fetal macrosomia (4.7, 7.0, 20.8, and 7.6%, respectively, p<0.001), caesarean section (21.8, 37.2, 21.7, and 17.6%, respectively, p=0.048), differed among the groups. The high incidence of PIH in pregnancies following ovulation induction was driven by polycystic ovarian syndrome (PCOS) per se., Conclusion: PCOS per se was associated with more PIH, and ART procedures after mild mono/bi follicular ovarian stimulation were associated with more fetal macrosomia., (Copyright © 2017. Published by Elsevier B.V.)