Kitazato method (Cryotop, Kitazato, Biopharma). Embryo classification was assessed previous vitri... more Kitazato method (Cryotop, Kitazato, Biopharma). Embryo classification was assessed previous vitrification according to IVIRMA criteria. Statistical analyses were conducted using univariate and multivariate regression model Main results and the role of chance: The mean maternal oocyte recipient age was 42.27 § 3.89 years old and body mass index 23 § 3.74 kg/m2). In a multivariate logistic regression analysis, a statistically significant association between embryo survival rate and the day of vitrification and grade of expansion was found. Chance of survival was significantly reduced for blastocyst vitrified on day 6 (n ¼ 737) compared to day 5 (n ¼ 3459) (93,2 % versus 96,0% [OR ¼ 0.976 (0.960-0.993); p¼0.05]). Regarding grade of expansion, cavitated blastocyst (n ¼ 840) survival rate was 97,7% [OR ¼ 1;p<0.001], expanded blastocyst (n ¼ 1866) was 96,2% [OR ¼ 0.095 (0.978-1.013)], hatching blastocysts (n ¼ 1465) was 94% [OR ¼ 0.978 (0.960-0.997); p¼0.02) and fully hatched blastocysts (n ¼ 25) was 60% [OR ¼ 0.704 (0.648-0.765);p<0.001)]. However, no association was found neither between lower inner cell mass quality [OR ¼ 0.964 (0.842-1.104); p¼0.596) nor trophoectoderm [OR ¼ 1.004 (0.981-1.028); p¼0.746)] and survival rate. Analysing the combination of these three variables will give us the possibility to choose the best embryo to warm. The impact of day of vitrification, grade of expansion and blastocyst quality on implantation, clinical pregnancy, miscarriage, and live birth rates will be included in further studies Limitations, reasons for caution: A weakness of this study is that it is retrospective in nature. The single-group design employed in retrospective studies limits the researchers' ability to determine cause and effect. Further studies are needed to determine the impact of these variables on the survival rate Wider implications of the findings: Based on our findings, blastocyst survival rate is influenced mostly by the day of vitrification and degree of expansion. To be able to select the best blastocyst to warm, a comparison between different day of vitrification when we have a similar morphology and embryo quality cohort is needed Trial registration number: Not applicable Abstract citation ID: dead093.194 O-161 Performance of IDAScore prediction models on clinical, obstetric and neonatal outcomes of single vitrified-thawed blastocyst transfer
Introduction Nicotinamide nucleotide transhydrogenase (NNT) gene deficiency has recently been sho... more Introduction Nicotinamide nucleotide transhydrogenase (NNT) gene deficiency has recently been shown to be involved in Primary Adrenal Insufficiency (PAI). NNT encodes an inner mitochondrial membrane protein that produces large amounts of NADPH. NADPH is used in several biosynthesis pathways and the oxidoreduction of free radicals by the glutathione and thioredoxin systems in mitochondria. Patients with PAI due to NNT deficiency may also exhibit extra-adrenal manifestations, usually including gonadal impairment. Case report We present the case of a 35-year-old patient referred to our center for primary infertility with nonobstructive azoospermia, in a context of PAI and obesity. PAI genetic exploration carried out at the age of thirty revealed NNT deficiency due to the presence of two deleterious mutations (one on each allele) in the NNT gene. Scrotal ultrasound revealed a right Testicular Adrenal Rest Tumor (TART). Intensification of glucocorticoid therapy over the course of 8 months failed to reduce the TART volume or improve sperm production and endocrine function. No spermatozoa were found after surgical exploration of both testes, and subsequent histopathological analysis revealed bilateral Sertoli cell-only syndrome. A retrospective review of the hypothalamic-pituitary-gonadic axis hormonal assessment over 20 years showed progressive impairment of testicular function, accelerated during adulthood, leading to hypergonadotropic hypogonadism and non-obstructive azoospermia when the patient reached his thirties, while the PAI remained controlled over the same period. Conclusion This case report provides, for the first time, direct evidence of complete germ line loss in an azoospermic man with NNT deficiency. Additional data further support the hypothesis of a determinant role of oxidative cellular damage due to reactive oxygen species (ROS) imbalance in the severe gonadal impairment observed in this † Lucile Ferreux and Yasmine Boumerdassi should be regarded as joint first authors.
On estime actuellement que 2 à 3% des enfants nés en France ont été conçus par assistance médical... more On estime actuellement que 2 à 3% des enfants nés en France ont été conçus par assistance médicale à la procréation (AMP). Le suivi de ces enfants, à court et moyen terme, suscite donc un questionnement, du fait des caractéristiques même des patients pris en charge (âge, infertilité) et des moyens médicaux et techniques utilisés. L'interprétation des résultats est délicate, dans la mesure où il est difficile d'étudier un facteur isolément et que de nombreux éléments confondants peuvent fausser les conclusions. L'analyse des données de la littérature existante sur le sujet fait l'objet de cet article. D'après celles-ci, il semble acquis que l'AMP est associée à un risque modéré de prématurité (OR de 1,93 à 2,04), d'hypotrophie (OR de 1,40 à 1,77) et de mortalité néonatale (OR de 1,68 à 2,40) par rapport à des enfants conçus naturellement, sans que l'origine de ce risque soit identifiée (infertilité ? procédures cliniques et biologiques ?). Il existe aussi une augmentation significative du taux de malformations congénitales (OR de 1,35 chez les singletons), touchant principalement le système cardiovasculaire, urogénital ou musculosquelettique, et des maladies épigénétiques chez les enfants conçus par AMP par rapport à la population générale. Mais, même si ces taux sont plus élevés que chez les enfants conçus naturellement, les risques absolus restent modérés et rassurants. Les données à plus long terme sont satisfaisantes, avec un développement staturo-pondéral et psychomoteur similaire à celui des enfants conçus naturellement. Il est nécessaire de poursuivre le suivi de ces enfants pour avoir une idée précise de leur développement à l'âge adulte, et notamment de leur fertilité. Health of children conceived by assisted reproductive technologies in France Around 2% to 3% of children born in France are conceived by assisted reproductive technologies (ART). The short or medium term follow-up of these children raises several questions, due to the characteristics of the patients (age, infertility), and to the clinical or biological procedures used. The results should be interpreted with caution, as it is difficult to study each factor alone, and as many other events can bias the conclusions. According to the data from the existing literature, ART is likely to be associated with a moderate risk of prematurity (OR: 1.93-2.04), foetal hypotrophy (OR: 1.40-1.77) and neonatal complications (OR: 1.68-2.40), compared to naturally conceived children without the identification of this risk (infertility? clinical and biological procedures?). There is also increasing evidence that ART-conceived children present more epigenetic diseases and congenital mal formations (OR: 1.35 in singletons), mainly concerning cardiovascular, urogenital and musculoskeletal systems, than naturally conceived children. Nevertheless, even if these rates are higher than in naturally conceived children, absolute risks remain moderate and reassuring. Follow up at longer term is encouraging, with correct growth and psychomotor development of these children, but the follow up must be continued in order to have precise data on their development in adulthood and namely on their fertility.
Are ICSI outcomes impaired in cases of severe asthenozoospermia with multiple morphological abnor... more Are ICSI outcomes impaired in cases of severe asthenozoospermia with multiple morphological abnormalities of the flagellum (MMAF phenotype)? SUMMARY ANSWER: Despite occasional technical difficulties, ICSI outcomes for couples with MMAF do not differ from those of other couples requiring ICSI, irrespective of the genetic defect. WHAT IS KNOWN ALREADY: Severe asthenozoospermia, especially when associated with the MMAF phenotype, results in male infertility. Recent findings have confirmed that a genetic aetiology is frequently responsible for this phenotype. In such situations, pregnancies can be achieved using ICSI. However, few studies to date have provided detailed analyses regarding the flagellar ultrastructural defects underlying this phenotype, its genetic aetiologies, and the results of ICSI in such cases of male infertility. STUDY DESIGN, SIZE, DURATION: We performed a retrospective study of 25 infertile men exhibiting severe asthenozoospermia associated with the MMAF phenotype identified through standard semen analysis. They were recruited at an academic centre for assisted reproduction in Paris (France) between 2009 and 2017. Transmission electron microscopy (TEM) and whole exome sequencing (WES) were performed in order to determine the sperm ultrastructural phenotype and the causal mutations, respectively. Finally 20 couples with MMAF were treated by assisted reproductive technologies based on ICSI. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients with MMAF were recruited based on reduced sperm progressive motility and increased frequencies of absent, short, coiled or irregular flagella compared with those in sperm from fertile control men. A quantitative analysis of the several ultrastructural defects was performed for the MMAF patients and for fertile men. The ICSI results obtained for 20 couples with MMAF were compared to those of 378 men with oligoasthenoteratozoospermia but no MMAF as an ICSI control group. MAIN RESULTS AND THE ROLE OF CHANCE: TEM analysis and categorisation of the flagellar anomalies found in these patients provided important information regarding the structural defects underlying asthenozoospermia and sperm tail abnormalities. In particular, the absence of the central pair of axonemal microtubules was the predominant anomaly observed more frequently than in control sperm (P < 0.01). Exome sequencing, performed for 24 of the 25 patients, identified homozygous or compound heterozygous pathogenic † The authors consider that the last two authors should be regarded as joint last authors.
Objective: To investigate if there are any obvious clinical factors associated with delayed blast... more Objective: To investigate if there are any obvious clinical factors associated with delayed blastulation at day 6 (D6) compared with day 5 (D5). Design: Monocentric observational cohort study from November 2012 to December 2018. Setting: Tertiary-care academic medical center. Patient(s): A total of 941 women with an entire cohort of exclusively D5 blastocysts compared with 162 patients with a cohort of exclusively D6 blastocysts. Intervention(s): None. Main Outcome Measure(s): Clinical characteristics and data related to the ovarian stimulation protocols. Result(s): After univariate analysis, a significantly higher proportion of women who were active smokers was found in the D6 group compared with the D5 group (n ¼ 22/162 [13.6%] vs. n ¼ 82/941 [8.7%]). In addition, the women in the D6 group had a higher rank number of assisted reproductive technology (ART; total no. of ART cycles performed: 2.1 AE 1.4 vs. 1.6 AE 1.1) and a lower antral follicle count (AFC; 18.7 AE 11.3 vs. 22.2 AE 12.8). Moreover, fertilization with the use of intracytoplasmic sperm injection was used more frequently in the D6 group compared with the D5 group. Logistic regression analysis adjusted for confounders highlighted several independent predictors for reaching blastocyst stage at D6 rather than D5: being an active smoker, previous ART cycles, and a lower AFC. Conclusion(s): Obtaining an exclusively D6 blastocyst cohort is independently associated with women who are active smokers, previous ART cycles, and a lower AFC. These findings provide evidence, to be confirmed by further studies, that women who are active smokers could greatly benefit from smoking cessation before undergoing ART.
Introduction Nicotinamide nucleotide transhydrogenase (NNT) gene deficiency has recently been sho... more Introduction Nicotinamide nucleotide transhydrogenase (NNT) gene deficiency has recently been shown to be involved in Primary Adrenal Insufficiency (PAI). NNT encodes an inner mitochondrial membrane protein that produces large amounts of NADPH. NADPH is used in several biosynthesis pathways and the oxidoreduction of free radicals by the glutathione and thioredoxin systems in mitochondria. Patients with PAI due to NNT deficiency may also exhibit extra-adrenal manifestations, usually including gonadal impairment. Case report We present the case of a 35-year-old patient referred to our center for primary infertility with non-obstructive azoospermia, in a context of PAI and obesity. PAI genetic exploration carried out at the age of thirty revealed NNT deficiency due to the presence of two deleterious mutations (one on each allele) in the NNT gene. Scrotal ultrasound revealed a right Testicular Adrenal Rest Tumor (TART). Intensification of glucocorticoid therapy over the course of 8 mont...
Study question What are the feasibility and outcome of ICSI in case of presumably genetic severe ... more Study question What are the feasibility and outcome of ICSI in case of presumably genetic severe asthenozoospermia with Multiple Morphological Abnormalities of the Flagellum (MMAF phenotype)? Summary answer ICSI outcome for couples with MMAF phenotype does not differ from that of other couples requiring ICSI, regardless to the genetic etiology What is known already Severe asthenozoospermia, especially when associated with multiple morphological abnormalities of the sperm flagellum (MMAF phenotype), results in male infertility. Recent findings confirm that a genetic etiology is frequently responsible for this phenotype. In such situations, pregnancies can be obtained using ICSI. However, few studies have provided detailed analyses of the flagellar ultrastructural defects underlying this phenotype, of its genetic etiologies and of the results of ICSI in such cases of male infertility. Study design, size, duration We performed a retrospective study including 25 infertile men showing se...
Que les modèles de culture prolongée postimplantatoire nous apprennent-ils sur le développement d... more Que les modèles de culture prolongée postimplantatoire nous apprennent-ils sur le développement de l'embryon humain ? What do post-implantation extended culture models tell us about the development of the human embryo?
HAL is a multidisciplinary open access archive for the deposit and dissemination of scientific re... more HAL is a multidisciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.
In the original article published, the family name of the second author is incorrect. The correct... more In the original article published, the family name of the second author is incorrect. The correct name is Zine-Eddine Kherraf. The original article has been corrected. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
STUDY QUESTION Are ICSI outcomes impaired in cases of severe asthenozoospermia with multiple morp... more STUDY QUESTION Are ICSI outcomes impaired in cases of severe asthenozoospermia with multiple morphological abnormalities of the flagellum (MMAF phenotype)? SUMMARY ANSWER Despite occasional technical difficulties, ICSI outcomes for couples with MMAF do not differ from those of other couples requiring ICSI, irrespective of the genetic defect. WHAT IS KNOWN ALREADY Severe asthenozoospermia, especially when associated with the MMAF phenotype, results in male infertility. Recent findings have confirmed that a genetic aetiology is frequently responsible for this phenotype. In such situations, pregnancies can be achieved using ICSI. However, few studies to date have provided detailed analyses regarding the flagellar ultrastructural defects underlying this phenotype, its genetic aetiologies, and the results of ICSI in such cases of male infertility. STUDY DESIGN, SIZE, DURATION We performed a retrospective study of 25 infertile men exhibiting severe asthenozoospermia associated with the MM...
Objective: To investigate if there are any obvious clinical factors associated with delayed blast... more Objective: To investigate if there are any obvious clinical factors associated with delayed blastulation at day 6 (D6) compared with day 5 (D5). Design: Monocentric observational cohort study from November 2012 to December 2018. Setting: Tertiary-care academic medical center. Patient(s): A total of 941 women with an entire cohort of exclusively D5 blastocysts compared with 162 patients with a cohort of exclusively D6 blastocysts. Intervention(s): None. Main Outcome Measure(s): Clinical characteristics and data related to the ovarian stimulation protocols. Result(s): After univariate analysis, a significantly higher proportion of women who were active smokers was found in the D6 group compared with the D5 group (n ¼ 22/162 [13.6%] vs. n ¼ 82/941 [8.7%]). In addition, the women in the D6 group had a higher rank number of assisted reproductive technology (ART; total no. of ART cycles performed: 2.1 AE 1.4 vs. 1.6 AE 1.1) and a lower antral follicle count (AFC; 18.7 AE 11.3 vs. 22.2 AE 12.8). Moreover, fertilization with the use of intracytoplasmic sperm injection was used more frequently in the D6 group compared with the D5 group. Logistic regression analysis adjusted for confounders highlighted several independent predictors for reaching blastocyst stage at D6 rather than D5: being an active smoker, previous ART cycles, and a lower AFC. Conclusion(s): Obtaining an exclusively D6 blastocyst cohort is independently associated with women who are active smokers, previous ART cycles, and a lower AFC. These findings provide evidence, to be confirmed by further studies, that women who are active smokers could greatly benefit from smoking cessation before undergoing ART.
In humans, structural or functional defects of the sperm flagellum induce asthenozoospermia, whic... more In humans, structural or functional defects of the sperm flagellum induce asthenozoospermia, which accounts for the main sperm defect encountered in infertile men. Herein we focused on Morphological Abnormalities of the sperm Flagellum (MMAF), a phenotype also termed "short tails", which constitutes one of the most severe sperm morphological defects resulting in asthenozoospermia. In previous work based on whole exome sequencing of a cohort of 167 MMAF individuals, we identified bi-allelic loss of function mutations in over 30% of the tested subjects. In this study, we further analyzed this cohort and identified five individuals with homozygous truncating variants in TTC29, a gene preferentially and highly expressed in the testis, and encoding a Tetratricopeptide Repeat containing protein related to the intra flagellar transport (IFT). One individual carried a frameshift variant, another one carried a homozygous stop-gain variant and three carried the same splicing variant affecting a consensus donor site. The deleterious effect of this last variant was confirmed on the corresponding transcript and protein product. In addition, we produced and analyzed TTC29 loss of function models in the flagellated protist T. brucei and in M. musculus. Both models confirmed the importance of TTC29 for flagellar beating. We showed that in T. brucei the TPR structural motifs, highly conserved between the studied orthologs, are critical for TTC29 axonemal localization and flagellar beating. Overall our work demonstrates that TTC29 is a conserved axonemal protein required for flagellar structure and beating and that TTC29 mutations are a cause of male sterility due to MMAF.
Journal of Assisted Reproduction and Genetics, 2018
Purpose This study was designed to evaluate patient management and quality of information given b... more Purpose This study was designed to evaluate patient management and quality of information given by French oncologists to cancer women concerning fertility issues and possibilities of fertility preservation. Methods An online survey was sent to 1161 physicians in all major cancer centers throughout France between May 2012 and January 2013. Results A total of 102 responses were received and analyzed. Only 46% of all physicians surveyed reported discussing infertility risks with patients of reproductive age and 22% referred them to a fertility center before beginning treatments. Only 14% of practitioners considered themselves knowledgeable in FP techniques and ovarian transposition was the most frequently mentioned technique in consultation. Conclusion This study is at the best of our knowledge the first nationwide survey to assess the state of the art in oncofertility management. It highlights inadequate management of fertility preservation for female patients in France. Physicians reported lacking knowledge and tools that would allow them to provide patients with appropriate information. A better collaboration between cancer and fertility centers needs to be organized in France as already organized in other countries. Keywords Fertility preservation. Cancer. Women. French physician practices Amira Sallem and Joanna Shore consider that the first two authors should be regarded as joint First Authors.
Kitazato method (Cryotop, Kitazato, Biopharma). Embryo classification was assessed previous vitri... more Kitazato method (Cryotop, Kitazato, Biopharma). Embryo classification was assessed previous vitrification according to IVIRMA criteria. Statistical analyses were conducted using univariate and multivariate regression model Main results and the role of chance: The mean maternal oocyte recipient age was 42.27 § 3.89 years old and body mass index 23 § 3.74 kg/m2). In a multivariate logistic regression analysis, a statistically significant association between embryo survival rate and the day of vitrification and grade of expansion was found. Chance of survival was significantly reduced for blastocyst vitrified on day 6 (n ¼ 737) compared to day 5 (n ¼ 3459) (93,2 % versus 96,0% [OR ¼ 0.976 (0.960-0.993); p¼0.05]). Regarding grade of expansion, cavitated blastocyst (n ¼ 840) survival rate was 97,7% [OR ¼ 1;p<0.001], expanded blastocyst (n ¼ 1866) was 96,2% [OR ¼ 0.095 (0.978-1.013)], hatching blastocysts (n ¼ 1465) was 94% [OR ¼ 0.978 (0.960-0.997); p¼0.02) and fully hatched blastocysts (n ¼ 25) was 60% [OR ¼ 0.704 (0.648-0.765);p<0.001)]. However, no association was found neither between lower inner cell mass quality [OR ¼ 0.964 (0.842-1.104); p¼0.596) nor trophoectoderm [OR ¼ 1.004 (0.981-1.028); p¼0.746)] and survival rate. Analysing the combination of these three variables will give us the possibility to choose the best embryo to warm. The impact of day of vitrification, grade of expansion and blastocyst quality on implantation, clinical pregnancy, miscarriage, and live birth rates will be included in further studies Limitations, reasons for caution: A weakness of this study is that it is retrospective in nature. The single-group design employed in retrospective studies limits the researchers' ability to determine cause and effect. Further studies are needed to determine the impact of these variables on the survival rate Wider implications of the findings: Based on our findings, blastocyst survival rate is influenced mostly by the day of vitrification and degree of expansion. To be able to select the best blastocyst to warm, a comparison between different day of vitrification when we have a similar morphology and embryo quality cohort is needed Trial registration number: Not applicable Abstract citation ID: dead093.194 O-161 Performance of IDAScore prediction models on clinical, obstetric and neonatal outcomes of single vitrified-thawed blastocyst transfer
Introduction Nicotinamide nucleotide transhydrogenase (NNT) gene deficiency has recently been sho... more Introduction Nicotinamide nucleotide transhydrogenase (NNT) gene deficiency has recently been shown to be involved in Primary Adrenal Insufficiency (PAI). NNT encodes an inner mitochondrial membrane protein that produces large amounts of NADPH. NADPH is used in several biosynthesis pathways and the oxidoreduction of free radicals by the glutathione and thioredoxin systems in mitochondria. Patients with PAI due to NNT deficiency may also exhibit extra-adrenal manifestations, usually including gonadal impairment. Case report We present the case of a 35-year-old patient referred to our center for primary infertility with nonobstructive azoospermia, in a context of PAI and obesity. PAI genetic exploration carried out at the age of thirty revealed NNT deficiency due to the presence of two deleterious mutations (one on each allele) in the NNT gene. Scrotal ultrasound revealed a right Testicular Adrenal Rest Tumor (TART). Intensification of glucocorticoid therapy over the course of 8 months failed to reduce the TART volume or improve sperm production and endocrine function. No spermatozoa were found after surgical exploration of both testes, and subsequent histopathological analysis revealed bilateral Sertoli cell-only syndrome. A retrospective review of the hypothalamic-pituitary-gonadic axis hormonal assessment over 20 years showed progressive impairment of testicular function, accelerated during adulthood, leading to hypergonadotropic hypogonadism and non-obstructive azoospermia when the patient reached his thirties, while the PAI remained controlled over the same period. Conclusion This case report provides, for the first time, direct evidence of complete germ line loss in an azoospermic man with NNT deficiency. Additional data further support the hypothesis of a determinant role of oxidative cellular damage due to reactive oxygen species (ROS) imbalance in the severe gonadal impairment observed in this † Lucile Ferreux and Yasmine Boumerdassi should be regarded as joint first authors.
On estime actuellement que 2 à 3% des enfants nés en France ont été conçus par assistance médical... more On estime actuellement que 2 à 3% des enfants nés en France ont été conçus par assistance médicale à la procréation (AMP). Le suivi de ces enfants, à court et moyen terme, suscite donc un questionnement, du fait des caractéristiques même des patients pris en charge (âge, infertilité) et des moyens médicaux et techniques utilisés. L'interprétation des résultats est délicate, dans la mesure où il est difficile d'étudier un facteur isolément et que de nombreux éléments confondants peuvent fausser les conclusions. L'analyse des données de la littérature existante sur le sujet fait l'objet de cet article. D'après celles-ci, il semble acquis que l'AMP est associée à un risque modéré de prématurité (OR de 1,93 à 2,04), d'hypotrophie (OR de 1,40 à 1,77) et de mortalité néonatale (OR de 1,68 à 2,40) par rapport à des enfants conçus naturellement, sans que l'origine de ce risque soit identifiée (infertilité ? procédures cliniques et biologiques ?). Il existe aussi une augmentation significative du taux de malformations congénitales (OR de 1,35 chez les singletons), touchant principalement le système cardiovasculaire, urogénital ou musculosquelettique, et des maladies épigénétiques chez les enfants conçus par AMP par rapport à la population générale. Mais, même si ces taux sont plus élevés que chez les enfants conçus naturellement, les risques absolus restent modérés et rassurants. Les données à plus long terme sont satisfaisantes, avec un développement staturo-pondéral et psychomoteur similaire à celui des enfants conçus naturellement. Il est nécessaire de poursuivre le suivi de ces enfants pour avoir une idée précise de leur développement à l'âge adulte, et notamment de leur fertilité. Health of children conceived by assisted reproductive technologies in France Around 2% to 3% of children born in France are conceived by assisted reproductive technologies (ART). The short or medium term follow-up of these children raises several questions, due to the characteristics of the patients (age, infertility), and to the clinical or biological procedures used. The results should be interpreted with caution, as it is difficult to study each factor alone, and as many other events can bias the conclusions. According to the data from the existing literature, ART is likely to be associated with a moderate risk of prematurity (OR: 1.93-2.04), foetal hypotrophy (OR: 1.40-1.77) and neonatal complications (OR: 1.68-2.40), compared to naturally conceived children without the identification of this risk (infertility? clinical and biological procedures?). There is also increasing evidence that ART-conceived children present more epigenetic diseases and congenital mal formations (OR: 1.35 in singletons), mainly concerning cardiovascular, urogenital and musculoskeletal systems, than naturally conceived children. Nevertheless, even if these rates are higher than in naturally conceived children, absolute risks remain moderate and reassuring. Follow up at longer term is encouraging, with correct growth and psychomotor development of these children, but the follow up must be continued in order to have precise data on their development in adulthood and namely on their fertility.
Are ICSI outcomes impaired in cases of severe asthenozoospermia with multiple morphological abnor... more Are ICSI outcomes impaired in cases of severe asthenozoospermia with multiple morphological abnormalities of the flagellum (MMAF phenotype)? SUMMARY ANSWER: Despite occasional technical difficulties, ICSI outcomes for couples with MMAF do not differ from those of other couples requiring ICSI, irrespective of the genetic defect. WHAT IS KNOWN ALREADY: Severe asthenozoospermia, especially when associated with the MMAF phenotype, results in male infertility. Recent findings have confirmed that a genetic aetiology is frequently responsible for this phenotype. In such situations, pregnancies can be achieved using ICSI. However, few studies to date have provided detailed analyses regarding the flagellar ultrastructural defects underlying this phenotype, its genetic aetiologies, and the results of ICSI in such cases of male infertility. STUDY DESIGN, SIZE, DURATION: We performed a retrospective study of 25 infertile men exhibiting severe asthenozoospermia associated with the MMAF phenotype identified through standard semen analysis. They were recruited at an academic centre for assisted reproduction in Paris (France) between 2009 and 2017. Transmission electron microscopy (TEM) and whole exome sequencing (WES) were performed in order to determine the sperm ultrastructural phenotype and the causal mutations, respectively. Finally 20 couples with MMAF were treated by assisted reproductive technologies based on ICSI. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients with MMAF were recruited based on reduced sperm progressive motility and increased frequencies of absent, short, coiled or irregular flagella compared with those in sperm from fertile control men. A quantitative analysis of the several ultrastructural defects was performed for the MMAF patients and for fertile men. The ICSI results obtained for 20 couples with MMAF were compared to those of 378 men with oligoasthenoteratozoospermia but no MMAF as an ICSI control group. MAIN RESULTS AND THE ROLE OF CHANCE: TEM analysis and categorisation of the flagellar anomalies found in these patients provided important information regarding the structural defects underlying asthenozoospermia and sperm tail abnormalities. In particular, the absence of the central pair of axonemal microtubules was the predominant anomaly observed more frequently than in control sperm (P < 0.01). Exome sequencing, performed for 24 of the 25 patients, identified homozygous or compound heterozygous pathogenic † The authors consider that the last two authors should be regarded as joint last authors.
Objective: To investigate if there are any obvious clinical factors associated with delayed blast... more Objective: To investigate if there are any obvious clinical factors associated with delayed blastulation at day 6 (D6) compared with day 5 (D5). Design: Monocentric observational cohort study from November 2012 to December 2018. Setting: Tertiary-care academic medical center. Patient(s): A total of 941 women with an entire cohort of exclusively D5 blastocysts compared with 162 patients with a cohort of exclusively D6 blastocysts. Intervention(s): None. Main Outcome Measure(s): Clinical characteristics and data related to the ovarian stimulation protocols. Result(s): After univariate analysis, a significantly higher proportion of women who were active smokers was found in the D6 group compared with the D5 group (n ¼ 22/162 [13.6%] vs. n ¼ 82/941 [8.7%]). In addition, the women in the D6 group had a higher rank number of assisted reproductive technology (ART; total no. of ART cycles performed: 2.1 AE 1.4 vs. 1.6 AE 1.1) and a lower antral follicle count (AFC; 18.7 AE 11.3 vs. 22.2 AE 12.8). Moreover, fertilization with the use of intracytoplasmic sperm injection was used more frequently in the D6 group compared with the D5 group. Logistic regression analysis adjusted for confounders highlighted several independent predictors for reaching blastocyst stage at D6 rather than D5: being an active smoker, previous ART cycles, and a lower AFC. Conclusion(s): Obtaining an exclusively D6 blastocyst cohort is independently associated with women who are active smokers, previous ART cycles, and a lower AFC. These findings provide evidence, to be confirmed by further studies, that women who are active smokers could greatly benefit from smoking cessation before undergoing ART.
Introduction Nicotinamide nucleotide transhydrogenase (NNT) gene deficiency has recently been sho... more Introduction Nicotinamide nucleotide transhydrogenase (NNT) gene deficiency has recently been shown to be involved in Primary Adrenal Insufficiency (PAI). NNT encodes an inner mitochondrial membrane protein that produces large amounts of NADPH. NADPH is used in several biosynthesis pathways and the oxidoreduction of free radicals by the glutathione and thioredoxin systems in mitochondria. Patients with PAI due to NNT deficiency may also exhibit extra-adrenal manifestations, usually including gonadal impairment. Case report We present the case of a 35-year-old patient referred to our center for primary infertility with non-obstructive azoospermia, in a context of PAI and obesity. PAI genetic exploration carried out at the age of thirty revealed NNT deficiency due to the presence of two deleterious mutations (one on each allele) in the NNT gene. Scrotal ultrasound revealed a right Testicular Adrenal Rest Tumor (TART). Intensification of glucocorticoid therapy over the course of 8 mont...
Study question What are the feasibility and outcome of ICSI in case of presumably genetic severe ... more Study question What are the feasibility and outcome of ICSI in case of presumably genetic severe asthenozoospermia with Multiple Morphological Abnormalities of the Flagellum (MMAF phenotype)? Summary answer ICSI outcome for couples with MMAF phenotype does not differ from that of other couples requiring ICSI, regardless to the genetic etiology What is known already Severe asthenozoospermia, especially when associated with multiple morphological abnormalities of the sperm flagellum (MMAF phenotype), results in male infertility. Recent findings confirm that a genetic etiology is frequently responsible for this phenotype. In such situations, pregnancies can be obtained using ICSI. However, few studies have provided detailed analyses of the flagellar ultrastructural defects underlying this phenotype, of its genetic etiologies and of the results of ICSI in such cases of male infertility. Study design, size, duration We performed a retrospective study including 25 infertile men showing se...
Que les modèles de culture prolongée postimplantatoire nous apprennent-ils sur le développement d... more Que les modèles de culture prolongée postimplantatoire nous apprennent-ils sur le développement de l'embryon humain ? What do post-implantation extended culture models tell us about the development of the human embryo?
HAL is a multidisciplinary open access archive for the deposit and dissemination of scientific re... more HAL is a multidisciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.
In the original article published, the family name of the second author is incorrect. The correct... more In the original article published, the family name of the second author is incorrect. The correct name is Zine-Eddine Kherraf. The original article has been corrected. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
STUDY QUESTION Are ICSI outcomes impaired in cases of severe asthenozoospermia with multiple morp... more STUDY QUESTION Are ICSI outcomes impaired in cases of severe asthenozoospermia with multiple morphological abnormalities of the flagellum (MMAF phenotype)? SUMMARY ANSWER Despite occasional technical difficulties, ICSI outcomes for couples with MMAF do not differ from those of other couples requiring ICSI, irrespective of the genetic defect. WHAT IS KNOWN ALREADY Severe asthenozoospermia, especially when associated with the MMAF phenotype, results in male infertility. Recent findings have confirmed that a genetic aetiology is frequently responsible for this phenotype. In such situations, pregnancies can be achieved using ICSI. However, few studies to date have provided detailed analyses regarding the flagellar ultrastructural defects underlying this phenotype, its genetic aetiologies, and the results of ICSI in such cases of male infertility. STUDY DESIGN, SIZE, DURATION We performed a retrospective study of 25 infertile men exhibiting severe asthenozoospermia associated with the MM...
Objective: To investigate if there are any obvious clinical factors associated with delayed blast... more Objective: To investigate if there are any obvious clinical factors associated with delayed blastulation at day 6 (D6) compared with day 5 (D5). Design: Monocentric observational cohort study from November 2012 to December 2018. Setting: Tertiary-care academic medical center. Patient(s): A total of 941 women with an entire cohort of exclusively D5 blastocysts compared with 162 patients with a cohort of exclusively D6 blastocysts. Intervention(s): None. Main Outcome Measure(s): Clinical characteristics and data related to the ovarian stimulation protocols. Result(s): After univariate analysis, a significantly higher proportion of women who were active smokers was found in the D6 group compared with the D5 group (n ¼ 22/162 [13.6%] vs. n ¼ 82/941 [8.7%]). In addition, the women in the D6 group had a higher rank number of assisted reproductive technology (ART; total no. of ART cycles performed: 2.1 AE 1.4 vs. 1.6 AE 1.1) and a lower antral follicle count (AFC; 18.7 AE 11.3 vs. 22.2 AE 12.8). Moreover, fertilization with the use of intracytoplasmic sperm injection was used more frequently in the D6 group compared with the D5 group. Logistic regression analysis adjusted for confounders highlighted several independent predictors for reaching blastocyst stage at D6 rather than D5: being an active smoker, previous ART cycles, and a lower AFC. Conclusion(s): Obtaining an exclusively D6 blastocyst cohort is independently associated with women who are active smokers, previous ART cycles, and a lower AFC. These findings provide evidence, to be confirmed by further studies, that women who are active smokers could greatly benefit from smoking cessation before undergoing ART.
In humans, structural or functional defects of the sperm flagellum induce asthenozoospermia, whic... more In humans, structural or functional defects of the sperm flagellum induce asthenozoospermia, which accounts for the main sperm defect encountered in infertile men. Herein we focused on Morphological Abnormalities of the sperm Flagellum (MMAF), a phenotype also termed "short tails", which constitutes one of the most severe sperm morphological defects resulting in asthenozoospermia. In previous work based on whole exome sequencing of a cohort of 167 MMAF individuals, we identified bi-allelic loss of function mutations in over 30% of the tested subjects. In this study, we further analyzed this cohort and identified five individuals with homozygous truncating variants in TTC29, a gene preferentially and highly expressed in the testis, and encoding a Tetratricopeptide Repeat containing protein related to the intra flagellar transport (IFT). One individual carried a frameshift variant, another one carried a homozygous stop-gain variant and three carried the same splicing variant affecting a consensus donor site. The deleterious effect of this last variant was confirmed on the corresponding transcript and protein product. In addition, we produced and analyzed TTC29 loss of function models in the flagellated protist T. brucei and in M. musculus. Both models confirmed the importance of TTC29 for flagellar beating. We showed that in T. brucei the TPR structural motifs, highly conserved between the studied orthologs, are critical for TTC29 axonemal localization and flagellar beating. Overall our work demonstrates that TTC29 is a conserved axonemal protein required for flagellar structure and beating and that TTC29 mutations are a cause of male sterility due to MMAF.
Journal of Assisted Reproduction and Genetics, 2018
Purpose This study was designed to evaluate patient management and quality of information given b... more Purpose This study was designed to evaluate patient management and quality of information given by French oncologists to cancer women concerning fertility issues and possibilities of fertility preservation. Methods An online survey was sent to 1161 physicians in all major cancer centers throughout France between May 2012 and January 2013. Results A total of 102 responses were received and analyzed. Only 46% of all physicians surveyed reported discussing infertility risks with patients of reproductive age and 22% referred them to a fertility center before beginning treatments. Only 14% of practitioners considered themselves knowledgeable in FP techniques and ovarian transposition was the most frequently mentioned technique in consultation. Conclusion This study is at the best of our knowledge the first nationwide survey to assess the state of the art in oncofertility management. It highlights inadequate management of fertility preservation for female patients in France. Physicians reported lacking knowledge and tools that would allow them to provide patients with appropriate information. A better collaboration between cancer and fertility centers needs to be organized in France as already organized in other countries. Keywords Fertility preservation. Cancer. Women. French physician practices Amira Sallem and Joanna Shore consider that the first two authors should be regarded as joint First Authors.
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Papers by Lucile Ferreux