J Mandelbaum

Assistance Publique – Hôpitaux de Paris, Lutetia Parisorum, Île-de-France, France

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Publications (152)351.22 Total impact

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    ABSTRACT: Objective: To identify the male molecular causes of failures of IVF (with a deficient binding of spermatozoa to the zona pellucida, without any obvious oocyte anomaly), which are undetected by classical sperm analysis. Design: Case-control prospective study. Setting: University hospital. Patient(s): Proteomic profiles of spermatozoa in patients with a complete failure of fertilization and no spermatozoa bound to the zona pellucida were compared with those of controls (men with normal fertilization and cleavage rates after classical IVF for tubal indication). Intervention(s): All samples were analyzed by two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) after being divided into three fractions according to their isoelectric point. Main Outcome Measure(s): Differentially expressed proteins between infertile men and controls were identified by mass spectrometry. Result(s): Seventeen proteins differentially expressed between cases and controls were found. Twelve of these proteins were identified by mass spectrometry, and two may influence gametes interaction: laminin receptor LR67 and L-xylulose reductase (P34H). Conclusion(s): This study shows that 2D-DIGE might be useful in finding potential targets for diagnosis and prognosis of idiopathic infertility in IVF. ((C)2014 by American Society for Reproductive Medicine.)
    No preview · Article · May 2014 · Fertility and Sterility
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    ABSTRACT: Angiotensin converting enzyme (ACE) is a metalloprotease with two isoforms. The somatic isoform is a key component of the renin-angiotensin system; its main function is to hydrolyse angiotensin I into angiotensin II. The germinal or testicular isoform (tACE) located at the plasma membrane of the spermatozoa, plays a crucial role in the spermatozoa-oocyte interaction during in vivo fertilization, in rodents. Disruption of the tACE in mice has revealed that homozygous male tACE-/- sire few pups despite mating normally. Few spermatozoa from these tACE-/- mice are bound to the zona pellucida (ZP) despite normal semen parameters. Based on these findings in mice models, we hypothesized that some infertile men that have the same phenotype as the tACE-/- mice, ie normal semen parameters and a lack of sperm bind to the ZP in vitro, may have a tACE defect. Twenty four men participated to this study. The case subjects (n = 10) had normal semen parameters according to the WHO guidelines (WHO 1999) but a total in vitro fertilization failure with absence of sperm fixation to the ZP. The control subjects (n = 14) also had normal semen parameters and a normal fertilization rate ≥65%. We investigated the tACE expression in spermatozoa by Western-Blot and performed a DNA sequencing of the tACE gene. Three case-subjects and one control-subject had no tACE expression. There were no statistic differences between the two groups. No mutation was detected in the tACE DNA sequence. Our results didn't show any involvement of tACE in human fertilization especially in ZP binding.
    Full-text · Article · Aug 2013
  • Jacqueline Mandelbaum

    No preview · Article · Dec 2012 · Sciences sociales et santé
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    ABSTRACT: Some patients in IVF programmes repeatedly display an abnormal embryonic development characterized as soon as day 2 post fertilization by a high rate (>60%) of highly fragmented embryos (>= 40% of cytoplasmic fragments) leading to recurrent IVF failures. This study postulated that, for various maternal reasons, some embryos were unable to withstand the in-vitro environment and an early pronucleate-stage transfer was proposed to these couples. Fifty-three patients with recurrent IVF failures (a mean of 2.8 +/- 1.0 previous attempts) characterized by low embryonic quality (a mean of 62.7% of the embryos with extended fragmentation) were included this transfer protocol. As in previous cycles, the mean number of oocytes retrieved and the fertilization rate were normal. The mean number of zygotes per transfer was 2.24. Fourteen clinical pregnancies were obtained, representing a pregnancy rate and a delivery rate per oocyte retrieval of 26.4% and 18.9%, respectively. Recurrent heavy and early embryo fragmentation in vitro characterizes around 3% of IVF couples and leads to lack of transfer or implantation failure. These data on fresh zygote transfers are encouraging and may provide a valid alternative solution for some of these patients.
    No preview · Article · Jan 2012 · Reproductive biomedicine online
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    ABSTRACT: Hypogonadotrophic hypogonadism (HH) is characterized by deficient gonadotrophin secretion, resulting from pituitary or hypothalamic defects. In order to induce spermatogenesis, HH patients are treated with commercially available gonadotrophins. As far as is known, quality and genetic integrity of induced sperm cells have never been investigated, although they represent an important issue, since the ultimate goal of this treatment is to have competent spermatozoa in order to achieve paternity. In order to evaluate the nuclear integrity of induced sperm cells, sperm samples from treated HH patients were compared with sperm samples from normospermic control donors. Sperm cells were analysed by fluorescence in-situ hybridization, using probes specific for chromosomes 13, 21, 18, X and Y, and by TdT (terminal deoxynucleotidyl transferase)-mediated dUDP nick-end labelling assay. Results showed that the rate of aneuploid and diploid sperm cells in patients was not statistically different from controls and that the rate of sperm cells with fragmented DNA was within the normal values. Spermatozoa obtained by gonadotrophin treatment in HH patients are likely to have a balanced chromosomal content and a normal DNA integrity but this conclusion needs to be confirmed by further studies dealing with a greater number of patients.
    No preview · Article · Mar 2011 · Reproductive biomedicine online
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    ABSTRACT: DAX1/NR0B1 mutations are responsible for X-linked congenital adrenal hypoplasia (AHC) associated with hypogonadotropic hypogonadism (HH). Few data are available concerning testicular function and fertility in men with DAX1 mutations. Azoospermia as well as failure of gonadotrophin treatment have been reported. We induced spermatogenesis in a patient who has a DAX1 mutation (c.1210C>T), leading to a stop codon in position 404 (p.Gln404X). His endocrine testing revealed a low testosterone level at 1.2 nmol/l (N: 12–40) with low FSH and LH levels at 2.1 IU/l (N: 1–5 IU/l) and 0.1 IU/l (N: 1–4 IU/l), respectively. Baseline semen analysis revealed azoospermia. Menotropin (Menopur®:150 IU, three times weekly) and human chorionic gonadotrophin (1500 IU, twice weekly) were used. After 20 months of treatment, as azoospermia persisted, bilateral multiple site testicular biopsies were performed. Histology revealed severe hypospermatogenesis. Rare spermatozoa were extracted from the right posterior fragment and ICSI was performed. Four embryos were obtained and, after a frozen–thawed single-embryo transfer, the patient's wife became pregnant and gave birth to a healthy boy. We report the first case of paternity after TESE–ICSI in a patient with DAX1 mutation, giving potential hope to these patients to father non-affected children. Furthermore, this case illustrates the fact that patients with X-linked AHC have a primary testicular defect in addition to HH.
    Full-text · Article · Mar 2011 · Human Reproduction
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    Full-text · Article · Nov 2010 · The American Journal of Human Genetics
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    ABSTRACT: One in seven couples worldwide are infertile, and male factor infertility accounts for approximately 30%-50% of these cases. Although many genes are known to be essential for gametogenesis, there are surprisingly few monogenic mutations that have been conclusively demonstrated to cause human spermatogenic failure. A nuclear receptor, NR5A1 (also called steroidogenic factor 1), is a key transcriptional regulator of genes involved in the hypothalamic-pituitary-steroidogenic axis, and it is expressed in the steroidogenic tissue of the developing and adult human gonad. Mutations of NR5A1 have been reported in 46,XY disorders of sex development and in 46,XX primary ovarian insufficiency. To test the hypothesis that mutations in NR5A1 cause male infertility, we sequenced NR5A1 in 315 men with idiopathic spermatogenic failure. We identified seven men with severe spermatogenic failure who carried missense mutations in NR5A1. Functional studies indicated that these mutations impaired NR5A1 transactivational activity. We did not observe these mutations in more than 4000 control alleles, including the entire coding sequence of 359 normospermic men and 370 fertile male controls. NR5A1 mutations are found in approximately 4% of men with otherwise unexplained severe spermatogenic failure.
    Full-text · Article · Sep 2010 · The American Journal of Human Genetics
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    ABSTRACT: This is a report of a 6-year follow-up of a male patient's semen parameters during heavy chronic alcohol intoxication and after withdrawal. A slowly progressive negative impact of alcohol could be observed: isolated moderate teratozoospermia was firstly noted followed by oligoasthenoteratospermia. Then a severe worsening resulted in cryptozoospermia and ultimately in azoospermia. At this moment, the histological analysis of a testicular biopsy revealed a maturation arrest of the germinal cells at the pachytene stage with no mature sperm cells. Alcohol withdrawal was then obtained, allowing a very fast and drastic improvement of semen characteristics; strictly normal semen parameters were observed after no more than 3 months. Taking into consideration these data, patients should be questioned about their alcohol intake before assisted reproductive technology and should be informed about this adverse effect. Moreover, this case report emphasizes how quickly benefits can be obtained after withdrawal, even in the case of heavy chronic alcohol intake.
    No preview · Article · Mar 2010 · Reproductive biomedicine online
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    ABSTRACT: To raise the possibility that pregnancy can be obtained by assisted reproductive techniques in patients with human seminal plasma allergy. Case report. University hospital. A woman consulted for a 3-year primary infertility. She reported lack of intercourse because of a seminal plasma allergy. One intrauterine insemination associated with antihistamine treatment was performed with carefully washed spermatozoa. Immediately after the insemination, the patient had an allergic reaction treated by steroids. Fortunately, this single attempt led to a successful pregnancy, and the patient gave birth to a healthy girl. Pregnancies can be obtained in patients with seminal plasma hypersensitivity by means of intrauterine insemination. However, serious complications may occur after performing intrauterine insemination, which is not a totally reliable method to prevent an allergic reaction. Thus a multidisciplinary team should follow such patients carefully and watch for the potential risks and side effects. In vitro fertilization may represent the more cautious option.
    No preview · Article · Feb 2010 · Fertility and sterility
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    ABSTRACT: Conflicting results have been published about the determinants of pregnancy after oocyte donation (OD). We used the OD model to determine predictive factors of pregnancy in the recipient after frozen-thawed embryo transfer (FTET) in a specific series where all the embryos were cryopreserved without any prior selection for fresh transfer. We report a retrospective study in a university tertiary care center. Multivariate analysis and logistic regression were used to identify predictive factors of pregnancy in a series of 450 OD FTET cycles in 198 infertile women between January 1992 and December 2006. The mean (+/-SD) recipient age was 35.7 (+/-4.5). Impaired ovarian function was the main indication for OD. The mean +/- SD (range) number of embryos transferred was 1.65 +/- 0.5 (1-3). Overall clinical pregnancy, implantation and delivery rates were 30, 18 and 23%, respectively. After univariate analysis, pregnancy rates were significantly higher in recipients under 35 years, in women with a body mass index (BMI) <30 kg/m(2), in women with an endometrial thickness of > or =8 mm, in amenorrheic women and in women not receiving pituitary down-regulation before endometrial preparation. Using multivariate analysis, the BMI, endometrial thickness and the use of pituitary down-regulation were independent predictors of pregnancy, regardless of age. This study supports that endometrial thickness of <8 mm, obesity and the use of GnRH analogue pituitary down-regulation before endometrial priming negatively impact pregnancy rates, independently of the recipient's age.
    No preview · Article · Sep 2009 · Human Reproduction
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    ABSTRACT: Performance and security questions in human oocyte cryopreservation have been taking researchers for about two decades. Oocytes are usually frozen at metaphase II. Immature oocytes cryopreservation is still a research alternative. Two techniques are currently available for oocyte cryopreservation: slow freezing and vitrification. Experimental data suggest that vitrification has less impact on oocyte physiology than classical slow freezing. After slow freezing of mature oocytes, survival and fertilization rates reach 70 to 80% whereas cleavage rates are around 90%, leading to five implantations and 1.2 births per 100 thawed oocytes. After vitrification of mature oocytes, survival and cleavage rates reach 90% leading to 11 implantations and 1.8 births per 100 thawed oocytes. The obstetrical and neonatal prognosis of these pregnancies is reassuring. No increased risk of congenital anomalies has been observed. However, further evaluation is needed to guarantee the safety of cryopreservation procedures. Immature oocyte cryopreservation is not currently perfected but some indications appear of great interest.
    No preview · Article · Sep 2009 · Gynécologie Obstétrique & Fertilité
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    ABSTRACT: Despite normal sperm parameters, 5% of in vitro fertilization (IVF) attempts result in an unpredictable failure of fertilization. In 56% of the cases, there is no obvious oocyte anomaly, but lack of sperm binding to the zona pellucida. This study aims to contribute to clarify the male molecular causes of failures in IVF, which are undetected by classical sperm analysis. The spermatic proteomic profiles of patients, with a complete failure of fertilization and no spermatozoa bound to the zona pellucida, is compared to controls (patients with normal fertilization and cleavage rates after a classical IVF for tubal indication). All samples are analysed by 2 Dimensional Electrophoresis-Differential In Gel Electrophoresis (2DE-DIGE) after being divided into three fractions according to their isoelectric point (acid, intermediate and basic). Fourteen proteins differentially expressed between all the cases and all the controls were highlighted. Twelve of these proteins were identified by mass spectrometry (six from the acid fraction and six from the basic fraction). Two of these proteins may have an interest in gametic interaction: the laminin receptor LR67 and the L-xylulose reductase. More investigation is needed to understand the involvement of the identified proteins in the IVF fertilization failure of the infertile patients in this study.
    No preview · Article · Sep 2009 · Gynécologie Obstétrique & Fertilité
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    ABSTRACT: The metabolic pathway of folate is thought to influence DNA stability either by inducing single/double stranded breaks or by producing low levels of S-adenosyl-methionine leading to abnormal gene expression and chromosome segregation. Polymorphisms in the genes encoding enzymes in the folate metabolism pathway show distinct geographic and/or ethnic variations and in some cases have been linked to disease. Notably, the gene Methylenetetrahydrofolate reductase (MTHFR) in which the homozygous (TT) state of the polymorphism c.665C>T (p.A222V) is associated with reduced specific activity and increased thermolability of the enzyme causing mild hyperhomocysteinemia. Recently several studies have suggested that men carrying this polymorphism may be at increased risk to develop infertility. We have tested this hypothesis in a case/control study of ethnic French individuals. We examined the incidence of polymorphisms in the genes MTHFR (R68Q, A222V and E429A), Methionine synthase reductase MTRR; (I22M and S175L) and Cystathionine beta-synthase (CBS; G307S). The case population consisted of DNA samples from men with unexplained azoospermia (n = 70) or oligozoospermia (n = 182) and the control population consisted of normospermic and fertile men (n = 114). We found no evidence of an association between the incidence of any of these variants and reduced sperm counts. In addition haplotype analysis did not reveal differences between the case and control populations. We could find no evidence for an association between reduced sperm counts and polymorphisms in enzymes involved in folate metabolism in the French population.
    Full-text · Article · Aug 2009 · PLoS ONE
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    ABSTRACT: We used the cumulative summation test for learning curve (LC-CUSUM), a specifically designed statistical tool, to evaluate the first 50 procedures performed by a trainee in vitrification and to provide a usable model for monitoring the learning process of this technique. Given the lack of models to evaluate IVF technologies, the CUSUM methodology could prove useful for quality control in laboratories.
    No preview · Article · Apr 2009 · Fertility and sterility
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    ABSTRACT: The aim of this study is to determine if Müllerian agenesis has a genetic basis linked to the WNT genes. Genomic DNA analyses for mutations in the coding sequences of four members of this family in a series of 11 women with Mayer-Rokitansky-Kuster-Hauser syndrome found four variants in the coding sequence of these genes, but causal mutations were not observed. This supports the hypothesis that mutations in the coding sequence of WNT4, WNT5A, WNT7A, and WNT9B are not responsible for the Mayer-Rokitansky-Kuster-Hauser syndrome.
    No preview · Article · Feb 2009 · Fertility and sterility
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    ABSTRACT: To determine if there is a relationship between various forms of partial AZFc deletions and spermatogenic failure. Case-control study. Infertility clinic (Tenon Hospital, Paris). 557 men, comprising 364 infertile men from mixed ethnic backgrounds, and 193 men with known fertility (n = 84) and/or normospermic (n = 109). Characterization of 32 partial AZFc deletions. DAZ gene cluster divided into two families (DAZ1/2 and DAZ3/4), CDY1 gene, and Y-chromosome haplogroups. We observed 18 partial AZFc deletions in 364 (4.95%) infertile men compared with 14 out of 193 (7.25%) in the control normospermic/fertile group. The analysis of informative Y-chromosome single nucleotide variants combined with Y-chromosome haplogroup definition enabled us to infer seven deletion classes that occur on a minimum of six Y-chromosome parental architectures. We found no relationship between either the presence or the absence of DAZ1/2, DAZ3/4, CDY1a, or CDY1b with spermatogenic failure at least on one Y-chromosome lineage. The DAZ dosage and Southern blot analyses indicated that the majority of individuals tested carried two copies of the DAZ gene, indicating a partial AZFc deletion. Our data are consistent with the hypothesis that, at least in our study populations, partial AZFc deletions may have a limited impact on fertility.
    No preview · Article · Dec 2008 · Fertility and sterility
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    I. Berthaut · R. Girot · J. Mandelbaum

    Preview · Article · Sep 2008 · Haematologica
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    ABSTRACT: Recent progress in the treatment of sickle cell disease, in particular the use of hydroxyurea, has considerably modified the prognosis of this disease. Many more patients now reach reproductive age. The objective of this study was to assess the potential impact of hydroxyurea on the semen of patients. In this retrospective multicenter study, we evaluated the sperm parameters and fertility of 44 patients and analyzed the potential impact of hydroxyurea. We report data from the largest series so far of semen analyses in patients with sickle cell disease: 108 samples were analyzed, of which 76 were collected before treatment. We found that at least one sperm parameter was abnormal in 91% of the patients before treatment, in agreement with published literature. All sperm parameters seemed to be affected in semen samples collected during hydroxyurea treatment, and this impairment occurred in less than 6 months, later reaching a plateau. Furthermore, after hydroxyurea cessation, while global results in 30 patients were not statistically different before and after hydroxyurea treatment, in four individuals follow-up sperm parameters did not seem to recover quickly and the total number of spermatozoa per ejaculate fell below the normal range in about half the cases. The observed alterations of semen parameters due to sickle cell disease seem to be exacerbated by hydroxyurea treatment. Until prospective studies reveal reassuring findings, we suggest that a pre-treatment sperm analysis be performed and sperm cryopreservation be offered to patients before hydroxyurea treatment.
    Full-text · Article · Aug 2008 · Haematologica
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    ABSTRACT: Oncologic progresses significantly increase the survival rate in some cancer patients groups. In view to save their childbearing potential, it is important to know if these treatments may affect the offspring. With advances in reproductive medicine, including ICSI, it is now possible to use husband's sperm instead of sperm donation, which was the only possibility up to the nineties in case of major sperm alterations. We describe in this paper the effects of cancer and its treatment on spermatogenesis, the indications and methods to preserve fertility, as well as the assisted reproductive technologies that can be offered to these patients today.
    No preview · Article · Jul 2008

Publication Stats

3k Citations
351.22 Total Impact Points

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Institutions

  • 2009-2014
    • Assistance Publique – Hôpitaux de Paris
      Lutetia Parisorum, Île-de-France, France
  • 2009-2011
    • UPMC
      Pittsburgh, Pennsylvania, United States
  • 2006-2011
    • Pierre and Marie Curie University - Paris 6
      Lutetia Parisorum, Île-de-France, France
  • 2008
    • Polytech Paris-UPMC
      Lutetia Parisorum, Île-de-France, France
  • 1986-1996
    • Hôpital Universitaire Necker
      Lutetia Parisorum, Île-de-France, France
  • 1987-1992
    • Unité Inserm U1077
      Caen, Lower Normandy, France
  • 1987-1988
    • French National Centre for Scientific Research
      Lutetia Parisorum, Île-de-France, France
  • 1984-1986
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France