Characterization of normal and pathological oocyte-cohort after ovarian stimulation : example of endometriosis

L'endométriose est une pathologie gynécologique bénigne fréquente, définie par la présence de tissu endométrial en dehors de la cavité utérine. Ce tissu ectopique hormonodépendant est responsable de saignements lors du cycle menstruel utérin. L'évolution de la maladie est chronique avec une atteinte inflammatoire et sa physiopathologie reste mal élucidée. Différents phénotypes de la maladie ont été décrits selon la localisation des lésions incluant l'endométriose superficielle, profonde et l'endométriome (atteinte ovarienne). L'endométriose affecterait environ 10% des femmes en âge de procréer. Parmi les différentes théories concernant sa pathogenèse, l'hypothèse la plus largement reconnue est fondée sur la théorie de la régurgitation menstruelle. Lorsqu'elle est symptomatique, l'endométriose peut se manifester par des douleurs pelviennes importantes telles que la dysménorrhée ou la dyspareunie, avec un retentissement majeur sur la qualité de vie dans ses différentes composantes. L'endométriose peut également s'associer à une infertilité affectant environ 40% des femmes endométriosiques et dont les causes restent encore mal expliquées. Un des mécanismes responsables serait l'atteinte de la qualité ovocytaire. Cette hypothèse reste largement débattue en raison des moyens d'évaluation limités dont nous disposons actuellement. Afin de mieux comprendre l'impact de l'endométriose sur la compétence de l'ovocyte, nous avons fait le choix d'une méthode d'évaluation novatrice et fonctionnelle à savoir la métabolomique. Nous avons d'abord étudié le profil métabolique dans le sérum de patientes endométriosiques. Nous avons mis en évidence une modification de la balance énergétique avec l'activation de voies alternatives associée à une consommation accrue de certains acides aminés impliqués dans la synthèse de protéines de la phase aiguë de l'inflammation. Enfin, le phénotype de la maladie était associé à un profil métabolique sérique spécifique chez les patientes ayant un endométriome. Nous avons ensuite étudié la composition du liquide folliculaire, milieu dans lequel l'ovocyte réalise sa croissance et sa maturation lors de la folliculogenèse. Nous avons confirmé l'existence d'une différence de sa composition chez les patientes endométriosiques lorsqu'elles étaient comparées aux patientes contrôles mais également entre-elles, avec la description d'une signature métabolique spécifique en cas de présence d'un endométriome. Comme dans le sérum, une modification de la balance énergétique au profit de la lipolyse a été objectivée et confirmée en cas de présence d'endométriome ainsi que l'existence d'une dysfonction mitochondriale qui pourrait potentiellement affecter la fertilité des patientes endométriosiques. Tous ces résultats nous ont amené à confronter les données obtenues en métabolomique à celles portant sur le développement embryonnaire et celles concernant les issues cliniques après transfert d'embryon in utero en termes de grossesse et de naissance. Nous avons ainsi observé une activation accrue des voies énergétiques, principalement celle de la glycolyse anaérobie, associée à une activation de la voie mTOR dans les liquides folliculaires à l'origine d'une bonne qualité embryonnaire et de l'obtention d'une naissance. Ainsi, les besoins énergétiques augmentés, révélés par la composition spécifique du liquide follicullaire, étaient corrélés aux issues positives en assistance médicale à la procréation, en termes de développement embryonnaire et d'issues cliniques après transfert embryonnaire in utero chez les patientes endométriosiques.Endometriosis is a frequent gynecological disease characterized by the presence of endometrial cells outside the uterine cavity. This hormonal-dependent ectopic tissue is responsible for bleeding during menstrual cycles leading to a chronic inflammation and its pathophysiology is poorly understood. Different phenotypes of this disease have been described, including superficial endometriosis, deep infiltrating endometriosis, and ovarian endometrioma. Endometriosis affects 10% of women of reproductive age. Among the various theories regarding its pathogenesis, the most widely recognized hypothesis is based on the retrograde menstruation theory. Endometriosis can cause severe pelvic pain such as dysmenorrhea or dyspareunia, with a major impact on the quality of life in its various components. Endometriosis can also be associated with infertility, affecting approximately 40% of endometriotic women. Its mechanisms are still poorly understood. One could be the oocyte quality impairment in presence of the disease. This hypothesis is still under debate due to the limited available tools for its evaluation. In order to better understand the impact of endometriosis on oocyte competence, we have used the metabolomic approach for the evaluation which is innovative and more functional. We first studied the metabolic profile in the serum of endometriotic patients. We have demonstrated that a modification of the energy balance with the activation of alternative pathways was associated to an increased consumption of certain amino acids involved in the synthesis of proteins in the acute phase of inflammation. Moreover, we have shown the existence of a specific serum metabolic signature according to the phenotype especially in patients with endometrioma.Then we studied the follicular fluid composition because it is the environment in which the oocyte grows during folliculogenesis. We confirmed the existence of a difference in its composition in endometriosis patients when compared to control but also between them, with also the presence of a specific metabolic signature according to the phenotype especially in presence of endometrioma. Our findings confirmed those obtained from serum analysis with a modified energetic balance in favor of lipolysis especially in the presence of endometrioma. We have also described the existence of a mitochondrial dysfunction which could potentially affect the fertility of endometriosis patients. All these results have led us to compare the data obtained in metabolomics with those relating to embryonic development and those concerning clinical outcomes after embryo transfer in terms of pregnancy and livebirth. Thus, we have observed an increased activation of the anaerobic glycolysis, associated to an activation of mTOR signaling pathway in follicular fluids leading to good embryo quality and livebirth occurrence. So, the increased energy needs in endometriotic patients, revealed by the specific composition of their follicular fluid, were correlated to positive outcomes in assisted reproductive technology in terms of embryo development and clinical outcomes after embryo transfer

Intérêt de l'insémination courte des gamètes en FIV classique (étude prospective randomisée)

LIMOGES-BU Médecine pharmacie (870852108) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Fresh or frozen day 6 blastocyst transfer: is there still a question?

International audienceAbstract Background The Live Birth Rate (LBR) after day 5 (D5) blastocyst transfer is significantly higher than that with D6 embryos in both fresh and frozen-vitrified embryo transfer cycles, according to the most recently published meta-analyses. Therefore, for women obtaining only D6 blastocysts, the chances of pregnancy may be lower but nonetheless sufficient to warrant transferring such embryos. The best strategy for transfer (i.e., in fresh versus frozen cycles) remains unclear and there is a paucity of data on this subject. Methods A total of 896 couples with D6 single blastocyst transfers were retrospectively analyzed: patients receiving a fresh D6 embryo transfer (Fresh D6 transfer group, n = 109) versus those receiving a frozen-thawed D6 embryo transfer (Frozen D6 transfer group, n = 787). A subgroup comprising a freeze-all cycle without any previous fresh or frozen D5 embryo transfers (Elective frozen D6, n = 77) was considered and also compared with the Fresh D6 transfer group. We compared LBR between these two groups. Correlation between D6 blastocyst morphology according to Gardner’s classification and live birth occurrence was also evaluated. Statistical analysis was carried out using univariate and multivariate logistic regression models. Results The LBR was significantly lower after a fresh D6 blastocyst transfer compared to the LBR with a frozen-thawed D6 blastocyst transfer [5.5% (6/109) vs. 12.5% (98/787), p = 0.034]. Comparison between LBR after Elective frozen D6 group to the Fresh D6 blastocyst transfers confirmed the superiority of frozen D6 blastocyst transfers. Statistical analysis of the blastocyst morphology parameters showed that both trophectoderm (TE) and inner cell mass (ICM) grades were significantly associated with the LBR after D6 embryo transfer ( p < 0.001, p = 0.037). Multiple logistic regression revealed that frozen D6 thawed transfer was independently associated with a higher LBR compared with fresh D6 transfer (OR = 2.54; 95% CI: [1.05–6.17]; p = 0.038). Our results also show that transferring a good or top-quality D6 blastocyst increased the chances of a live birth by more than threefold. Conclusions Our results indicate that transferring D6 blastocysts in frozen cycles improves the LBR, making it the best embryo transfer strategy for these slow-growing embryos. Clinical trial number Not applicable

The interval between oocyte retrieval and frozen-thawed blastocyst transfer does not affect the live birth rate and obstetrical outcomes.

BACKGROUND:The 'Freeze all' strategy, which consists of cryopreservation of all embryos after the ovarian stimulation has undergone extensive development in the past decade. The time required for the endometrium to revert to a prestimulation state after ovarian stimulation and thus the optimal time to perform a deferred embryo transfer after the stimulation has not been determined yet. OBJECTIVE:To investigate the impact of the time from oocyte retrieval to frozen-thawed blastocyst transfer (FBT) on live birth rate (LBR), obstetrical and neonatal outcomes, in 'Freeze-all' cycle. MATERIALS AND METHODS:We conducted a large observational cohort study in a tertiary care university hospital including four hundred and seventy-four first autologous FBT performed after ovarian stimulation in 'freeze all' cycles. Reproductive outcomes were compared between FBT performed within the first menstrual cycle after the oocyte retrieval ('cycle 1' group) or delayed FBT ('cycle ≥ 2' group). The main Outcome Measure was the Live birth rate. RESULT(S):A total of 188 FBT were included in the analysis in the 'cycle 1' group and 286 in the 'cycle ≥ 2' group. No significant differences were found between FBT performed within the first menstrual cycle after oocyte retrieval (the 'cycle 1' group) and delayed FBT (the 'cycle ≥ 2' group) in terms of the live birth rate [59/188 (31.38%) vs. 85/286 (29.72%); p = 0.696] and the miscarriage rate [20/82 (24.39%) vs. 37/125 (29.60%), respectively; p = 0.413]. The obstetrical and neonatal outcomes were also not significantly different between the two groups. CONCLUSION:Our study did not detect statistically significant differences in the LBR for FBT performed within the first menstrual cycle after oocyte retrieval versus FBT following subsequent cycles. Embryo-endometrium interaction after a FBT does not appear to be impaired by potential adverse effects of COS whatever the number of cycle between oocyte retrieval and embryo transfer

The deferred embryo transfer strategy improves cumulative pregnancy rates in endometriosis-related infertility: A retrospective matched cohort study

<div><p>Background</p><p>Controlled ovarian stimulation in assisted reproduction technology (ART) may alters endometrial receptivity by an advancement of endometrial development. Recently, technical improvements in vitrification make deferred frozen-thawed embryo transfer (Def-ET) a feasible alternative to fresh embryo transfer (ET). In endometriosis-related infertility the eutopic endometrium is abnormal and its functional alterations are seen as likely to alter the quality of endometrial receptivity. One question in the endometriosis ART-management is to know whether Def-ET could restore optimal receptivity in endometriosis-affected women leading to increase in pregnancy rates.</p><p>Objective</p><p>To compare cumulative ART-outcomes between fresh versus Def-ET in endometriosis-infertile women.</p><p>Materials and methods</p><p>This matched cohort study compared def-ET strategy to fresh ET strategy between 01/10/2012 and 31/12/2014. One hundred and thirty-five endometriosis-affected women with a scheduled def-ET cycle and 424 endometriosis-affected women with a scheduled fresh ET cycle were eligible for matching. Matching criteria were: age, number of prior ART cycles, and endometriosis phenotype. Statistical analyses were conducted using univariable and multivariable logistic regression models.</p><p>Results</p><p>135 in the fresh ET group and 135 in the def-ET group were included in the analysis. The cumulative clinical pregnancy rate was significantly increased in the def-ET group compared to the fresh ET group [58 (43%) vs. 40 (29.6%), p = 0.047]. The cumulative ongoing pregnancy rate was 34.8% (n = 47) and 17.8% (n = 24) respectively in the Def-ET and the fresh-ET groups (p = 0.005). After multivariable conditional logistic regression analysis, Def-ET was associated with a significant increase in the cumulative ongoing pregnancy rate as compared to fresh ET (OR = 1.76, CI95% 1.06–2.92, p = 0.028).</p><p>Conclusion</p><p>Def-ET in endometriosis-affected women was associated with significantly higher cumulative ongoing pregnancy rates. Our preliminary results suggest that Def-ET for endometriosis-affected women is an attractive option that could increase their ART success rates. Future studies, with a randomized design, should be conducted to further confirm those results.</p></div

Endometriosis and ART: A prior history of surgery for OMA is associated with a poor ovarian response to hyperstimulation.

BACKGROUND:Many women whose fertility may have been impaired by endometriosis require assisted reproductive technology (ART) in order to become pregnant. However, the influence of ovarian endometriosis (OMA) on ovarian responsiveness to hyperstimulation has not been clearly established. OBJECTIVE:To evaluate the risk of a poor ovarian response (POR) to stimulation and ART outcomes in women with OMA. MATERIALS AND METHODS:We conducted a large observational controlled matched cohort study in a tertiary care university hospital between 01/10/2012 and 31/12/2015. After matching by age and anti-Müllerian hormone (AMH) levels, 201 infertile women afflicted with OMA (the OMA group) and 402 disease-free women (the control group) undergoing an ART procedure were included in the study. The main outcomes that we measured were a POR to hyperstimulation (i.e., ≤ 3 oocytes retrieved, or cancelled cycles), the clinical pregnancy rate, and the live birth rate. All of the women with endometriosis underwent a pre-ART work-up, in order to obtain an accurate diagnosis and staging of their disease. An OMA diagnosis was based on published imaging criteria (obtained by transvaginal sonography or magnetic resonance imaging) or on histological analysis for patients with a prior history of endometriosis surgery. The statistical analyses were conducted using univariate and multivariate logistic regression models. RESULTS:The incidence of a POR to hyperstimulation was significantly higher for the OMA group than for the control group [62/201 (30.8%) versus 90/402 (22.3%), respectively; p = 0.02]. However, no significant differences were found between the OMA and the control group in terms of the clinical pregnancy rate [53/151 (35%) versus 134/324 (41.3%), respectively; p = 0.23] and the live birth rate [39/151 (25.8%) versus 99/324 (30.5%), respectively; p = 0.33]. By multivariate analysis, a prior history of surgery for OMA was found to be an independent factor associated with a POR to stimulation [OR = 2.1; 95% CI: 1.1-4.0], unlike OMA without a prior history of surgery [OR: 1.5; 95% CI: 0.9-2.2]. CONCLUSION:The presence of OMA during ART treatment increased the risk of a POR to hyperstimulation, although the live birth rate was not affected. Furthermore, having OMA and having previously undergone surgery for OMA was identified as an independent risk factor for a POR

Patient inclusion flowchart.

<p>IVF/ICSI, in vitro fertilization / intra cytoplasmic sperm injection; Def-ET: Deferred frozen-thawed embryo transfer—*Cancelled cycles: Poor response—Personal or medical (e.g. non-gynecological) reasons.</p

Assisted reproductive technology outcomes in women with a chronic viral disease

International audienceObjective: The aim of this study was to evaluate the cumulative live birth rate in women undergoing in-vitro fertilization/intracytoplasmic-sperm-injection (IVF/ICSI) according to the type of chronic viral infection [HIV, hepatitis-B virus (HBV) and hepatitis-C virus (HCV)].Design: A cohort study.Setting: A tertiary-care university hospital.Participants: Women with a chronic viral illness HIV, HBV or HCV- were followed until four IVF/ICSI cycles had been completed, until delivery or until discontinuation of the treatment before the completion of four cycles.Main outcome measures: The primary outcome was the cumulative live birth rate after up to four IVF/ICSI cycles.Results: A total of 235 women were allocated to the HIV-infected group (n = 101), the HBV-infected group (n = 114) and the HCV-infected group (n = 20). The cumulative live birth rate after four cycles was significantly lower in the HIV-infected women than in those with HBV [39.1%, 95% confidence interval (95% CI): 17.7-60.9 versus 52.8%, 95% CI: 41.6-65.5, respectively; P = 0.004]. Regarding the obstetrical outcomes, the mean birth weight was lower in the HIV-infected women than in those with HBV or HCV. Multivariate analysis indicated that the age, the anti-Müllerian hormone and the number of cycles performed were significantly associated with the chances of a live birth.Conclusion: HIV-infected women had lower cumulative live birth rate than women with chronic hepatitis, and this was due to less favourable ovarian reserve parameters. These findings underscore the need to better inform practitioners and patients regarding fertility issues and the importance of early fertility assessment. However, larger studies are necessary to gain more in-depth knowledge of the direct impact of HIV on live birth rates

Baseline characteristics in matched fresh and deferred frozen-thawed embryo transfer groups.

<p>Baseline characteristics in matched fresh and deferred frozen-thawed embryo transfer groups.</p