Sophie Christin-Maitre

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

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Publications (152)572.58 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: Multiple Endocrine Neoplasia syndrome type 1 (MEN1), which is secondary to mutation of the MEN1 gene, is a rare autosomal-dominant disease that predisposes mutation carriers to endocrine tumors. Most studies demonstrated the absence of direct genotype-phenotype correlations. The existence of a higher risk of death in the GTE-cohort associated with a mutations in the JunD interacting domain, suggests heterogeneity across families in disease expressivity. This study aims to assess the existence of modifying genetic factors by estimating the intra-familial correlations and heritability of the six main tumor types in MEN1. Methods: The study included 797 patients from 265 kindred and studied seven phenotypic criteria: parathyroid and pancreatic neuroendocrine tumors (NETs), pituitary, adrenal, bronchial and thymic tumors (ThNETs) and the presence of metastasis. Intra-familial correlations and heritability estimates were calculated from family tree data using specific validated statistical analysis software. Results: Intra-familial correlations were significant and decreased along parental degrees distance for pituitary, adrenal and th-NETs. The heritability of these three tumor types was consistently strong and significant with 64% (Standard Error [SE]=0.13; p < 0.001) for pituitary tumor, 65% (SE=0,21; p < 0.001) for adrenal tumors, and 97% (SE=0.41; p=0.006) for thNETs. Conclusion: The present study shows the existence of modifying genetic factors for thymus, adrenal and pituitary MEN1 tumor types. The identification of at-risk subgroups of individuals within cohorts is the first step towards personalization of care. Next generation sequencing on this subset of tumors will help identify the molecular basis of MEN1 variable genetic expressivity.
    European Journal of Endocrinology 09/2015; DOI:10.1530/EJE-15-0691 · 4.07 Impact Factor
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    ABSTRACT: Worrying trends regarding human reproductive endpoints (e.g. semen quality, reproductive cancers) have been reported and there is growing circumstantial evidence for a possible causal link between these trends and exposure to endocrine disrupting chemicals (EDCs). However, there is a striking lack of human data to fill the current knowledge gaps. To answer the crucial questions raised on human reproductive health, there is an urgent need for a reproductive surveillance system to be shared across countries. A multidisciplinary network named HUman Reproductive health and Global ENvironment Network (HURGENT) was created aiming at designing a European monitoring system for reproductive health indicators. Collaborative work allowed setting up the available knowledge to design such a system. Furthermore we conducted an overview of 23 potential indicators, based upon a weight of evidence (WoE) approach according to their potential relation with EDC exposure. The framework and purposes of the surveillance system are settled as well as the approach to select suitable reproductive indicators. The indicators found with the highest scores according to the WoE approach are prostate and breast cancer incidence, sex ratio, endometriosis and uterine fibroid incidence, indicators related to the testicular dysgenesis syndrome, precocious puberty incidence and reproductive hormone levels. Not only sentinel health endpoints, but also diseases with high burdens in public health are highlighted as prior indicators in the context of EDC exposure. Our work can serve as a basis to construct, as soon as possible, the first multi-country reproductive monitoring system. © The Author 2015. Published by Oxford University Press on behalf of the European Public Health Association. All rights reserved.
    The European Journal of Public Health 09/2015; DOI:10.1093/eurpub/ckv153 · 2.59 Impact Factor
  • Hervé Lefebvre · Sophie Christin-Maître
    Annales d Endocrinologie 08/2015; 76(4). DOI:10.1016/j.ando.2015.07.924 · 0.87 Impact Factor
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    ABSTRACT: Hirsutism induced by hyperandrogenism can be associated with polycystic ovary syndrome, 21-hydroxylase deficiency or androgen secreting tumors, including ovarian and adrenal tumors. Adrenal androgen-secreting tumors are frequently malignant. Adrenal oncocytomas represent rare causes of hyperandrogenism. The aim of the study was to investigate steroidogenic enzyme expression and steroid secretion in an androgen-secreting adrenal oncocytoma in a young woman presenting with hirsutism. Hyperandrogenism was diagnosed on the basis of elevated plasma ?4-androstenedione and testosterone levels. Pelvic ultrasound was normal, CT scan revealed a right adrenal mass. Androgens were assessed in adrenal and ovarian vein samplings and proved a right adrenal origin. Adrenalectomy normalized androgen levels and the adrenal tumor was diagnosed as an oncocytoma. Real time-PCR, immunohistochemistry and cell culture studies were performed on tumor explants to investigate the steroid secretion profile. Among enzymes required for cortisol synthesis, 17?-hydroxylase (OH) and 3?- hydroxysteroid dehydrogenase (HSD) 2 were highly expressed whereas 21-OH and 11?-OH were weakly produced at mRNA and/or protein levels. Enzymes involved in testosterone production, 17?-HSD5 and 17?-HSD3, were also detected. ACTH receptor was present in the tissue. Cortisol, ?4-androstenedione and testosterone secretions by cultured cells were increased by ACTH. Data provide the first demonstration of abnormal expression profile of steroidogenic enzymes in an adrenocortical oncocytoma. Our results also indicate that ?4-androstenedione hypersecretion resulted from high 17?-OH and 3?-HSD2 expression in combination with low expression of 21-OH and 11?-OH. Testosterone production was ascribed to occurrence of 17?-HSD5 and 17?-HSD3. Finally, our data demonstrate that androgen secretion was stimulated by ACTH.
    Endocrine Connections 06/2015; 4(2). DOI:10.1530/EC-15-0014
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    ABSTRACT: Outcomes of congenital adrenal hyperplasia (CAH) due to classic 21-hydroxylase deficiency (21OHD) have been widely studied in children and women but less in men. To analyze data from a network of metropolitan French teaching hospitals on the clinical outcome of classic 21OHD in a large sample of CAH/21OHD genotyped adult men, and particularly the impact of 21OHD on the gonadotrope axis, testicular function and fertility. From April 2011 to June 2014, tertiary endocrinology departments provided data for 219 men with 21OHD (18-70 y; 73.6% salt wasters (SW) and 26.4% simple virilizers (SV)). Testicular sonography was performed in 164 men and sperm analysis in 71 men. Mean final height was 7.8 cm lower than in a reference population. Obesity was more common and mean blood pressure was lower than in the reference population. None of the patients was diabetic and lipid status was generally normal. Blood electrolyte status was normal in the vast majority of men, despite markedly elevated ACTH and renin levels. Serum progesterone (PROG), 17OHPROG and androstenedione levels were above-normal in the vast majority of cases. Hormonal profiling variously showed a normal gonadotrope-testicular axis, gonadotropin deficiency, or primary testicular insufficiency. Testicular sonography revealed adrenal rest tumors (TARTs) in 34% of 164 men. Serum inhibin B and FSH levels were respectively significantly lower and higher in patients with TARTs. Severe oligospermia or azoospermia was found in 42% of patients, and was significantly more prevalent in men with TARTs (70%) than in men with normal testes (3.6%;p<0.0001). Among men living with female partners, TARTs were significantly more prevalent in those who had not fathered children. We report the spectrum of testicular/gonadotrope axis impairment in the largest cohort of 21OHD men studied to date. Our results suggest that French men with 21OHD managed in specialized centers frequently have impaired exocrine testicular function but that its reproductive implications are often overlooked.
    The Journal of Clinical Endocrinology and Metabolism 03/2015; 100(6):jc20144124. DOI:10.1210/jc.2014-4124 · 6.21 Impact Factor
  • Article: Amenorree
    M. Bretault · S. Christin-Maitre
  • Article: Amenorrea
    M. Bretault · S. Christin-Maitre
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    ABSTRACT: Background: Multiple endocrine neoplasia Type-1 (MEN1) in young patients is only described by case-reports. Objective: Improve knowledge of MEN1 natural history before 21 years old. Methods: Description of first symptoms occurring before 21 years old (clinical symptoms, biological or imaging abnormalities), surgical outcomes related to MEN1 Neuro Endocrine Tumors (NETs) occurring in a group of 160 patients extracted from the "Groupe d'étude des Tumeurs Endocrines" MEN1 cohort. Results: The first symptoms were related to hyperparathyroidism in 122 cases (75%), pituitary adenoma in 55 cases (34%), non-secreting pancreatic tumor (NSPT) in 14 cases (9%), insulinoma in 20 cases (12%), gastrinoma in three cases (2%), malignant adrenal tumors in 2 cases (1%) and malignant thymic-NET in one (1%). Hyperparathyrodism was the first lesion in 90 cases (56%). The first symptoms occurred before 10 years old in 22 cases (14%) and before 5 years old in five cases (3%). Surgery was performed before age 21 in 66 patients (41%) with a total of 74 operations: pituitary adenoma (n=9, 16%), hyperparathyroidism (n=38, 31%), gastrinoma (n=1, 33%), NSPT (n=5, 36%), and all cases of insulinoma, adrenal tumors and thymic-NET. One patient died before age 21 due to a thymic-NET. Overall, lesions were malignant in four cases. Conclusions: Various MEN1 lesions occurred frequently before 21 years old, but mainly after 10 years of age. Rare, aggressive tumors may develop at any age. Hyperparathyroidism was the most frequently encountered lesion but was not always the first biological or clinical abnormality to appear during the course of MEN1.
    Journal of Clinical Endocrinology &amp Metabolism 01/2015; 100(4):jc20143659. DOI:10.1210/jc.2014-3659 · 6.21 Impact Factor
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  • V Bernard · C Bouvattier · S Christin-Maitre
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    ABSTRACT: Men reproductive health has long been ignored although it is responsible for 50% of couple's infertility. However, in recent years, the understanding of endocrine physiology underlying testis development and spermatogenesis has enabled the development of new therapeutic strategies. Some concern the management of male infertility. Others are dealing with finding an effective male contraceptive. In this review, we first present the management of infertility, in patients with congenital hypogonadotropic hypogonadism. We then describe the major improvements for Klinefelter patient's infertility. Finally, we review the different hormonal and non-hormonal methods for male contraception, currently in development. Efficacy and safety of the some non-hormonal methods remain to be demonstrated so far in humans. Copyright © 2014 Elsevier Masson SAS. All rights reserved.
    Annales d Endocrinologie 10/2014; 75S1:S13-S20. DOI:10.1016/S0003-4266(14)70023-X · 0.87 Impact Factor
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    Annales de biologie clinique 08/2014; 72(4):385-389. DOI:10.1684/abc.2014.0972 · 0.28 Impact Factor
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    ABSTRACT: Context: Mutations in CHD7, a gene previously implicated in CHARGE syndrome, have been reported in patients presenting with Kallmann syndrome (KS) or congenital hypogonadotropic hypogonadism (CHH). Most mutations causing CHARGE syndrome result in premature stop codons and occur de novo, but the proportion of truncating versus non-truncating mutations in KS and CHH patients is still unknown. Objective: To determine the nature, prevalence, mode of transmission, and clinical spectrum of CHD7 mutations in a large series of patients. Design: We studied 209 KS and 94 CHH patients. These patients had not been diagnosed as CHARGE syndrome according to the current criteria. We searched for mutations in 16 KS and CHH genes including CHD7. Results: We found presumably pathogenic mutations in CHD7 in 24 KS patients, but not in CHH patients. Non-truncating mutations (16 missense, and a two-codon duplication) were more prevalent than truncating mutations (three nonsense, three frame-shift, and a splice site), which contrasts with patients presenting with typical CHARGE syndrome. Thus the clinical spectrum associated with CHD7 mutations may be partly explained by genotype/phenotype correlations. Eight patients also had congenital deafness and one had a cleft lip/palate, whereas six had both. For 10 patients, the presence of diverse features of the CHARGE spectrum in at least one relative argues against a de novo appearance of the missense mutation, and this was confirmed by genetic analysis in five families. Conclusion: Considering the large prevalence and clinical spectrum of CHD7 mutations, it will be particularly relevant to genetic counseling to search for mutations in this gene in KS patients seeking fertility treatment, especially if KS is associated with deafness and cleft lip/palate.
    Journal of Clinical Endocrinology &amp Metabolism 07/2014; 99(10):jc20142110. DOI:10.1210/jc.2014-2110 · 6.21 Impact Factor
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    ABSTRACT: Contexte La néoplasie endocrinienne multiple de type 1, NEM1, est une affection à transmission autosomique dominante qui associe chez un même patient ou ses apparentés des tumeurs des parathyroïdes, du pancréas endocrine et de l’hypophyse. Des données controversées suggèrent que le variant Ala541Thre pourrait avoir un rôle pathogénique, et pourrait être associé à un risque accru de développer des lésions de MEN1. Objectifs Le but de cette étude était d’évaluer les atteintes cliniques et fonctionnelles du variant p.Ala541Thr. Patients et méthodes Nous avons analysé une série de 55 patients porteurs du variant p.Ala541Thr. Leur présentation clinique a été comparée à celle de 117 patients MEN1. L’effet biologique de ce variant sur la croissance cellulaire a été également étudié dans un modèle cellulaire issus de tumeurs de cellules de Leydig déficientes en MEN1 (LCT10). Résultats L’âge moyen à la première lésion est similaire dans les 2 groupes p.Ala541Thr et MEN1, mais aucun des patients p.Ala541Thr n’avait plus d’une lésion au diagnostic. Une deuxième lésion a été diagnostiquée chez 13 % des MEN1 et 7 % des p.Ala541Thr l’année qui a suivi le diagnostic initial. Les études fonctionnelles montrent que la réexpression du variant p.Ala541Thr ne permet pas d’inhiber la croissance cellulaire, contrairement à ce qui a été observé avec la protéine sauvage. Conclusions Ce travail vient perturber le concept de polymorphisme et de leur potentielle non-pathogénicité. Des études complémentaires sont cependant nécessaires afin de déterminer si ce variant peut-être impliqué dans la survenue d’un phénotype MEN1 de faible pénétrance.
    Annales d Endocrinologie 07/2014; 75(3). DOI:10.1016/j.ando.2014.05.003 · 0.87 Impact Factor
  • Célia Ravel · Capucine Hyon · Jean-Pierre Siffroi · Sophie Christin-Maitre
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    ABSTRACT: DAX-1 stands for Dosage sensitive sex-reversal, Adrenal hypoplasia congenital (AHC), on the X chromosome. DAX-1 mutations usually cause primary adrenal insufficiency or congenital adrenal hypoplasia in early childhood and hypogonadotropic hypogonadism (MIM # 300200). DAX-1 protein is necessary to maintain normal spermatogenesis. In humans, male fertility has been studied in few patients carrying DAX-1 mutations. Cases of azoospermia have been reported, as well as unsuccessful gonadotropin treatments. The clinician should be informed that TESE-ICSI technique carries a potential hope to father non-affected children, as shown in this review.
    Annales d Endocrinologie 04/2014; 75(2). DOI:10.1016/j.ando.2014.03.003 · 0.87 Impact Factor
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    ABSTRACT: Background: The use of ketoconazole has been recently questioned after warnings from the European Medicine Agencies and the Food and Drug Administration due to potential hepatotoxicity. However, ketoconazole is frequently used as a drug to lower circulating cortisol levels. Several pharmacological agents have recently been approved for the treatment of Cushing's disease (CD) despite limited efficacy or significant side effects. Ketoconazole has been used worldwide for more than 30 years in CD, but in the absence of a large-scale study, its efficacy and tolerance are still under debate. Patients and methods: We conducted a French retrospective multicenter study reviewing data from patients treated by ketoconazole as a single agent for CD, with the aim of clarifying efficacy and tolerance to better determine the benefit/risk balance. Results: Data from 200 patients were included in this study. At the last follow-up, 49.3% of patients had normal urinary free cortisol (UFC) levels, 25.6% had at least a 50% decrease, and 25.4% had unchanged UFC levels. The median final dose of ketoconazole was 600 mg/d. Forty patients (20%) received ketoconazole as a presurgical treatment; 40% to 50% of these patients showed improvement of hypertension, hypokalemia, and diabetes, and 48.7% had normal UFC before surgery. Overall, 41 patients (20.5%) stopped the treatment due to poor tolerance. Mild (<5N, inferior to 5-fold normal values) and major (>5N, superior to 5-fold normal values) increases in liver enzymes were observed in 13.5% and 2.5% of patients, respectively. No fatal hepatitis was observed. Conclusions: Ketoconazole is an effective drug with acceptable side effects. It should be used under close liver enzyme monitoring. Hepatotoxicity is usually mild and resolves after drug withdrawal.
    The Journal of Clinical Endocrinology and Metabolism 01/2014; 99(5):jc20133628. DOI:10.1210/jc.2013-3628 · 6.21 Impact Factor
  • Célia Ravel · Capucine Hyon · Jean-Pierre Siffroi · Sophie Christin-Maitre
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    ABSTRACT: DAX-1 signifie inversion sexuelle dosage sensible, hypoplasie congénitale des surrénales sur le chromosome X. Les mutations de DAX-1 entraînent une insuffisance surrénale primitive ou une hypoplasie congénitale des surrénales dans la petite enfance ainsi qu’un hypogonadisme hypogonadotrope (MIM#300200). La protéine DAX-1 est nécessaire au maintien d’une spermatogénèse normale. Chez l’homme la fertilité masculine a été étudiée chez quelques patients porteurs de la mutation. Des cas d’azoospermis ont été rapportés ainsi que des échecs de traitement par les gonadotrophines. Le clinicien doit être informé que la technique TESE-ICSI offre un espoir de paternité permettant la naissance d’enfants non atteints comme il est montré dans cette revue.
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    ABSTRACT: Background Bilateral macronodular adrenal hyperplasia is a rare cause of primary adrenal Cushing's syndrome. In this form of hyperplasia, hypersecretion of cortisol suppresses the release of corticotropin by pituitary corticotrophs, which results in low plasma corticotropin levels. Thus, the disease has been termed corticotropin-independent macronodular adrenal hyperplasia. We examined the abnormal production of corticotropin in these hyperplastic adrenal glands. Methods We obtained specimens of hyperplastic macronodular adrenal tissue from 30 patients with primary adrenal disease. The corticotropin precursor proopiomelanocortin and corticotropin expression were assessed by means of a polymerase-chain-reaction assay and immunohistochemical analysis. The production of corticotropin and cortisol was assessed in 11 specimens with the use of incubated explants and cell cultures coupled with hormone assays. Corticotropin levels were measured in adrenal and peripheral venous blood samples from 2 patients. ResultsThe expression of proopiomelanocortin messenger RNA (mRNA) was detected in all samples of hyperplastic adrenal tissue. Corticotropin was detected in steroidogenic cells arranged in clusters that were disseminated throughout the adrenal specimens. Adrenal corticotropin levels were higher in adrenal venous blood samples than in peripheral venous samples, a finding that was consistent with local production of the peptide within the hyperplastic adrenals. The release of adrenal corticotropin was stimulated by ligands of aberrant membrane receptors but not by corticotropin-releasing hormone or dexamethasone. A semiquantitative score for corticotropin immunostaining in the samples correlated with basal plasma cortisol levels. Corticotropin-receptor antagonists significantly inhibited in vitro cortisol secretion. Conclusions Cortisol secretion by the adrenals in patients with macronodular hyperplasia and Cushing's syndrome appears to be regulated by corticotropin, which is produced by a subpopulation of steroidogenic cells in the hyperplastic adrenals. Thus, the hypercortisolism associated with bilateral macronodular adrenal hyperplasia appears to be corticotropin-dependent. (Funded by the Agence Nationale de la Recherche and others.)
    New England Journal of Medicine 11/2013; 369(22):2115-2125. DOI:10.1056/NEJMoa1215245 · 55.87 Impact Factor
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    ABSTRACT: L’insuffisance ovarienne prématurée (IOP) est suspectée cliniquement devant une aménorrhée et affirmée biologiquement chez une femme âgée de moins de 40 ans par un taux de FSH > 40 mUI/L (voire 20 mUI/L) à deux reprises. Sa prévalence est estimée à 1 à 2 % chez les femmes de moins de 40 ans. Dans 90 % des cas, aucune étiologie n’est retrouvée. Il convient d’éliminer une cause secondaire (radiothérapie pelvienne, chimiothérapie, chirurgie ovarienne, exposition in utero au distilbène) et d’effectuer un caryotype pour rechercher un syndrome de Turner (cause génétique la plus fréquente) ou une anomalie de l’X. Une recherche de pré-mutation du gène FMR1 (syndrome de l’X fragile) est souhaitable, même en l’absence de retard mental dans la famille. D’autres anomalies génétiques pourront être recherchées en fonction des symptômes associés (ex. : mutation de FOXL2, SF1). Une origine auto-immune est évoquée dans un contexte d’auto-immunité associé car il n’existe pas de dosage d’anticorps fiable pour établir le diagnostic d’IOP auto-immune. La prise en charge thérapeutique repose sur le traitement hormonal substitutif pour pallier la carence estrogénique : faire disparaître les bouffées de chaleur, diminuer la perte osseuse et le risque cardiovasculaire. Il associe des estrogènes à de la progestérone ou un progestatif jusqu’à l’âge d’au moins 51 ans. Il est souhaitable d’informer les patientes que le taux de grossesses spontanées n’est pas nul (5 %). En cas de désir de grossesse, elles doivent être adressées dans un centre spécialisé pour bénéficier d’une fécondation in vitro avec don d’ovocytes. La prise en charge psychologique doit faire intégralement partie du traitement. Les taux d’anxiété et de dépression sont, chez ces femmes, supérieurs à la population générale. Aucun traitement préventif efficace n’est à ce jour disponible.
    La Presse Médicale 11/2013; 42(11):1500–1507. DOI:10.1016/j.lpm.2013.04.018 · 1.08 Impact Factor
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    ABSTRACT: Premature ovarian failure (POF) is clinically suspected by amenorrhea and confirmed by an elevated FSH serum level above 40mUI/L (even 20mUI/L) twice, in a woman before the age of 40. Prevalence of POF is between 1 to 2% in women. In 90% of cases, no aetiology is identified. Obvious causes are chemotherapy, pelvic radiotherapy, ovarian surgery and diethylstilbestrol exposure in utero. A karyotype should be performed as Turner Syndrome is the most frequent genetic cause of POF. Some X abnormalities such as X deletion or X autosome translocation can be found. FMR1 pre-mutation (fragile X syndrome) should be searched for, even though no cases of mental retardation are known, in the family. Other genetic abnormalities can be suggested by associated symptoms (i.e.: FOXL2, SF1 mutations). Auto-immune aetiology can be suspected if other auto-immune features are present, however, there are no reliable auto-antibodies to confirm auto-immunity in POF. Treatment of POF is based on hormonal replacement therapy in order to avoid estrogen deficiency, suppress vasomotor symptoms and avoid bone loss as well as cardiovascular risk. Estrogens should be associated with progesterone or a progestin, at least up to the age of 51. Patients with POF should be informed that spontaneous pregnancies may occur (in 5% of cases). In case of desire of pregnancy, the patient should be oriented to a specialized unit for in vitro fertilization with oocyte donation. Psychological support is essential and should be part of the treatment. POF is associated with an increased risk of emotional distress and depression. No preventive treatment of POF is available so far.
    La Presse Médicale 10/2013; · 1.08 Impact Factor
  • Annales d Endocrinologie 09/2013; 74(4):279-280. DOI:10.1016/j.ando.2013.07.127 · 0.87 Impact Factor

Publication Stats

2k Citations
572.58 Total Impact Points


  • 1998–2015
    • Assistance Publique – Hôpitaux de Paris
      Lutetia Parisorum, Île-de-France, France
  • 2012–2014
    • Unité Inserm U1077
      Caen, Lower Normandy, France
  • 2007–2013
    • Hôpital Saint-Antoine (Hôpitaux Universitaires Est Parisien)
      Lutetia Parisorum, Île-de-France, France
  • 2000–2013
    • Pierre and Marie Curie University - Paris 6
      • Équipe Génétique de la reproduction (EA 1533)
      Lutetia Parisorum, Île-de-France, France
    • Cornell University
      • Department of Medicine
      Итак, New York, United States
  • 2004
    • Hôpitaux Universitaires La Pitié salpêtrière - Charles Foix
      Lutetia Parisorum, Île-de-France, France
  • 2003
    • University of Liège
      Luik, Walloon, Belgium
  • 1999
    • Hôpital Saint-Vincent-de-Paul – Hôpitaux universitaires Paris Centre
      Lutetia Parisorum, Île-de-France, France
  • 1994
    • Massachusetts General Hospital
      • Reproductive Endocrine Unit
      Boston, Massachusetts, United States