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1. Age at diagnosis in patients with chronic congenital endocrine conditions: a regional cohort study from a reference center for rare diseases

Author: Wafa Kallali, Claude Messiaen, Roumaisah Saïdi, Soucounda Lessim, Magali Viaud, Jerome Dulon, Mariana Nedelcu, Dinane Samara, Muriel Houang, Bruno Donadille, Carine Courtillot, GianPaolo de Filippo, Jean-Claude Carel, Sophie Christin-Maitre, Philippe Touraine, Irene Netchine, Michel Polak, and Juliane Léger
Subjects: Diagnosis, Congenital endocrine disease, Cohort, Female, Male, Medicine
Abstract: Abstract Background For chronic congenital endocrine conditions, age at diagnosis is a key issue with implications for optimal management and psychological concerns. These conditions are associated with an increase in the risk of comorbid conditions, particularly as it concerns growth, pubertal development and fertility potential. Clinical presentation and severity depend on the disorder and the patient’s age, but diagnosis is often late. Objective To evaluate age at diagnosis for the most frequent congenital endocrine diseases affecting growth and/or development. Patients and Methods This observational cohort study included all patients (n = 4379) with well-defined chronic congenital endocrine diseases—non-acquired isolated growth hormone deficiency (IGHD), isolated congenital hypogonadotropic hypogonadism (ICHH), ectopic neurohypophysis (NH), Turner syndrome (TS), McCune-Albright syndrome (MAS), complete androgen insensitivity syndrome (CAIS) and gonadal dysgenesis (GD)—included in the database of a single multisite reference center for rare endocrine growth and developmental disorders, over a period of 14 years. Patients with congenital hypothyroidism and adrenal hyperplasia were excluded as they are generally identified during neonatal screening. Results Median age at diagnosis depended on the disease: first year of life for GD, before the age of five years for ectopic NH and MAS, 8–10 years for IGHD, TS (11% diagnosed antenatally) and CAIS and 17.4 years for ICHH. One third of the patients were diagnosed before the age of five years. Diagnosis occurred in adulthood in 22% of cases for CAIS, 11.6% for TS, 8.8% for GD, 0.8% for ectopic NH, and 0.4% for IGHD. A male predominance (2/3) was observed for IGHD, ectopic NH, ICHH and GD. Conclusion The early recognition of growth/developmental failure during childhood is essential, to reduce time-to-diagnosis and improve outcomes.
Published: 2021
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2. Pituitary function and the response to GH therapy in patients with Langerhans cell histiocytosis: analysis of the KIMS database

Author: Philippe Touraine, Yempabou Sagna, Anders F Mattsson, Pia Burman, André P Van Beek, Martin Ove Carlsson, Ferah Aydin, Ulla Feldt-Rasmussen, Cecilia Camacho-Hübner, and Center for Liver, Digestive and Metabolic Diseases (CLDM)
Subjects: Adult, Male, Hormone Replacement Therapy, Human Growth Hormone, Endocrinology, Diabetes and Metabolism, General Medicine, Hypopituitarism, Histiocytosis, Langerhans-Cell, Cross-Sectional Studies, Endocrinology, Quality of Life, Humans, Female, Child, Dwarfism, Pituitary
Abstract: Objective To analyze the effectiveness and safety of growth hormone (GH) replacement treatment in adult patients with Langerhans cell histiocytosis (LCH) and GH deficiency (GHD) enrolled in KIMS (Pfizer International Metabolic Database). Patients and methods Patients with LCH and GHD were studied at baseline and some of them after 1 year of GH treatment. The effectiveness of GH is presented as change after 1 year of treatment (mean, 95% CI). The LCH population was compared to two other groups of patients enrolled in KIMS, granulomatous and lymphocytic hypophysitis. Results At baseline, 81 adults with LCH (27 with childhood onset, 56% females), mean age at GHD onset of 29 (15) years were studied. Diabetes insipidus was diagnosed in 86% of patients. Analysis of 1 year of GH treatment was possible in 37 patients. One-year cross-sectional values for the GH dose were 0.39 (s.d.± 0.21) mg and −0.5 (−1.2 to 0.2) for insulin-like growth factor-1 s.d. Total cholesterol decreased 0.9 (−1.5 to −0.3 (mmol/L); P n = 20) was improved by 2.8 points (−5.6 to 0.0; P 2 (95% CI: −0.2 to 1.4). All these effects did not differ from the two other groups after adjusting for age, gender, and baseline values. In 20 of 77 patients included in the safety analysis, 36 serious adverse events were reported during 435 patient-years (82.8/1000); no new safety signals were reported. Conclusion After 1 year of GH treatment in patients with LCH, metabolic variables and quality of life improved, with no new safety signals.
Published: 2022
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3. Dominant TP63 missense variants lead to constitutive activation and premature ovarian insufficiency

Author: Elena J. Tucker, Niklas Gutfreund, Marc‐Antoine Belaud‐Rotureau, David Gilot, Tiffany Brun, Brianna L. Kline, Katrina M. Bell, Mathilde Domin‐Bernhard, Camille Théard, Philippe Touraine, Gorjana Robevska, Jocelyn van van den Bergen, Katie L. Ayers, Andrew H. Sinclair, Volker Dötsch, Sylvie Jaillard, University of Melbourne, Murdoch Children's Research Institute (MCRI), Institute of Biochemistry and Signal Transduction [Hamburg, Germany], Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), École des Hautes Études en Santé Publique [EHESP] (EHESP), CHU Pontchaillou [Rennes], CRLCC Eugène Marquis (CRLCC), Oncogenesis, Stress, Signaling (OSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de référence Maladies Rares CLAD-Ouest [Rennes], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and This study was supported by a CHU Rennes grant (Appel à Projets Innovations 2019 to SJ), an Australian National Health and Medical Research Council (NHMRC) program grant (1074258 to AHS), NHMRC fellowships (1054432 to EJT, 1062854 to AHS), a Suzi Carp postdoctoral scholarship (to EJT) and the Deutsche Forschungsgemeinschaft (DO 545/18-1). The research conducted at the Murdoch Children's Research Institute was supported by the Victorian government's operational infrastructure support program. We thank the Bioinformatic department of Rennes University Hospital (Pr M. De Tayrac and Dr W. Carré) for technical assistance. Open access publishing facilitated by The University of Melbourne, as part of the Wiley - The University of Melbourne agreement via the Council of Australian University Librarians.
Subjects: premature ovarian insufficiency, [SDV]Life Sciences [q-bio], Tumor Suppressor Proteins, Mutation, Missense, Primary Ovarian Insufficiency, TAp63α, genomic diagnosis, Genetics, Humans, Female, TP63, infertility, p63 isoforms, Genetics (clinical), Transcription Factors
Abstract: International audience; Premature ovarian insufficiency (POI) is a leading form of female infertility, characterised by menstrual disturbance and elevated follicle-stimulating hormone before age 40. It is highly heterogeneous with variants in over 80 genes potentially causative, but the majority of cases having no known cause. One gene implicated in POI pathology is TP63. TP63 encodes multiple p63 isoforms, one of which has been shown to have a role in the surveillance of genetic quality in oocytes. TP63 C-terminal truncation variants and N-terminal duplication have been described in association with POI, however, functional validation has been lacking. Here we identify three novel TP63 missense variants in women with nonsyndromic POI, including one in the N-terminal activation domain, one in the C-terminal inhibition domain, and one affecting a unique and poorly understood p63 isoform, TA*p63. Via blue-native page and luciferase reporter assays we demonstrate that two of these variants disrupt p63 dimerization, leading to constitutively active p63 tetramer that significantly increases the transcription of downstream targets. This is the first evidence that TP63 missense variants can cause isolated POI and provides mechanistic insight that TP63 variants cause POI due to constitutive p63 activation and accelerated oocyte loss in the absence of DNA damage.
Published: 2022
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4. Evaluation of a new transition organization for young adults with endocrine or metabolic diseases

Author: Enora Le Roux, Agathe Turpin, Morgane Michel, Isabelle Tejedor, Florence Menesguen, Sabine Malivoir, Sandrine Bottius, Hélène Mellerio, Michel Polak, and Philippe Touraine
Subjects: Male, Adolescent, Endocrinology, Diabetes and Metabolism, Transitional Care, General Medicine, Endocrine System Diseases, Young Adult, Endocrinology, Metabolic Diseases, Patient Satisfaction, Humans, Female, Lost to Follow-Up, France, Referral and Consultation
Abstract: Objective To evaluate the effect of a new care organization on multiple outcomes of transition success and its cost-effectiveness in patients with any endocrine or metabolic disease diagnosed during childhood and transferred to adult care. Design Non-randomized controlled trial in a French university hospital. Methods Patients transferred to adult care during the control period (04/2014–08/2016) and the intervention period (09/2016–06/2018) were included. The intervention is based on case management involving liaising with pediatric services, personalizing care pathways, and liaising with structures outside hospital (general practitioner, educational and social sector). The primary endpoint was the percentage of patients lost to follow-up at 24 months post transfer. Other outcomes were collected from medical files, consultation software, and questionnaires. A cost analysis was performed. Results Two hundred two patients were included (101 per period), the most represented pathologies were congenital and non-congenital hypopituitarism (respectively n = 34 (17%) and n = 45 (22%)) and thyroid diseases (n = 21, 10%). Patients were aged 22.5 in median at 24 months post transfer where 12 were lost to follow-up in the control group vs 9 with the intervention (P = 0.49). The percentage of honored consultation among those planned during 24 months was higher with intervention (P = 0.0065). Patient satisfaction, physician trust, and transfer delay did not differ between the groups. The incremental cost-effectiveness ratio was €179 per patient not lost to follow-up. Conclusions At 24 months post transfer, the rate of lost to follow-up did not differ significantly, but indicators of a steadier follow-up were increased and the intervention appeared to be cost-effective.
Published: 2022
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5. High Prevalence of Early Endocrine Disorders After Childhood Brain Tumors in a Large Cohort

Author: Laura Gabriela González Briceño, Dulanjalee Kariyawasam, Dinane Samara-Boustani, Elisa Giani, Jacques Beltrand, Stéphanie Bolle, Brice Fresneau, Stéphanie Puget, Christian Sainte-Rose, Claire Alapetite, Graziella Pinto, Marie-Liesse Piketty, Séverine Brabant, Samuel Abbou, Isabelle Aerts, Kevin Beccaria, Marie Bourgeois, Thomas Roujeau, Thomas Blauwblomme, Federico Di Rocco, Caroline Thalassinos, Christian Pauwels, Charlotte Rigaud, Syril James, Kanetee Busiah, Albane Simon, Franck Bourdeaut, Lauriane Lemelle, Léa Guerrini-Rousseau, Daniel Orbach, Philippe Touraine, François Doz, Christelle Dufour, Jacques Grill, and Michel Polak
Subjects: Adult, Male, Brain Neoplasms, Endocrinology, Diabetes and Metabolism, Biochemistry (medical), Clinical Biochemistry, Endocrine System Diseases, Biochemistry, Endocrinology, Prevalence, Humans, Female, Pituitary Neoplasms, Cerebellar Neoplasms, Child, Retrospective Studies
Abstract: Context Endocrine complications are common in pediatric brain tumor patients. Objective We aimed to describe the endocrine follow-up of patients with primary brain tumors. Methods This is a noninterventional observational study based on data collection from medical records of 221 patients followed at a Pediatric Endocrinology Department. Results Median age at diagnosis was 6.7 years (range, 0-15.9), median follow-up 6.7 years (0.3-26.6), 48.9% female. Main tumor types were medulloblastoma (37.6%), craniopharyngioma (29.0%), and glioma (20.4%). By anatomic location, 48% were suprasellar (SS) and 52% non-suprasellar (NSS). Growth hormone deficiency (GHD) prevalence was similar in both groups (SS: 83.0%, NSS: 76.5%; P = 0.338), appearing at median 1.8 years (−0.8 to 12.4) after diagnosis; postradiotherapy GHD appeared median 1.6 years after radiotherapy (0.2-10.7). Hypothyroidism was more prevalent in SS (76.4%), than NSS (33.9%) (P < 0.001), as well as ACTH deficiency (SS: 69.8%, NSS: 6.1%; P < 0.001). Early puberty was similar in SS (16%) and NSS (12.2%). Hypogonadotropic hypogonadism was predominant in SS (63.1%) vs NSS (1.3%), P < 0.001, and postchemotherapy gonadal toxicity in NSS (29.6%) vs SS (2.8%), P < 0.001. Adult height was lower for NSS compared to target height (−1.0 SD, P < 0.0001) and to SS patients (P < 0.0001). Thyroid nodules were found in 13/45 patients (28.8%), including 4 cancers (4.8-11.5 years after radiotherapy). Last follow-up visit BMI was higher in both groups (P = 0.0001), and obesity incidence was higher for SS (46.2%) than NSS (17.4%). Conclusion We found a high incidence of early-onset endocrine disorders. An endocrine consultation and nutritional evaluation should be mandatory for all patients with a brain tumor, especially when the tumor is suprasellar or after hypothalamus/pituitary irradiation.
Published: 2021
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6. Whole exome sequencing in a cohort of familial premature ovarian insufficiency cases reveals a broad array of pathogenic or likely pathogenic variants in 50% of families

Author: Alexandre Rouen, Eli Rogers, Véronique Kerlan, Brigitte Delemer, Sophie Catteau-Jonard, Yves Reznik, Anne Gompel, Isabelle Cedrin, Anne-Marie Guedj, Virginie Grouthier, Thierry Brue, Catherine Pienkowski, Anne Bachelot, Sandra Chantot-Bastaraud, Alexandra Rousseau, Tabassome Simon, Esther Kott, Jean-Pierre Siffroi, Philippe Touraine, Sophie Christin-Maitre, Maladies génétiques d'expression pédiatrique (U933), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Universitaire de Reims (CHU Reims), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Hopital port Royal, Partenaires INRAE, Hôpital Jean Verdier [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Marseille Maladies Rares (MarMaRa), Aix Marseille Université (AMU), Service d'endocrinologie, diabète, maladies métaboliques [Hôpital de la Conception - APHM], CHU Saint-Antoine [AP-HP], and Programme Hospitalier de Recherche Clinique AOM08084, NI07022 FAMIOP
Subjects: premature ovarian insufficiency, Genes in POI, [SDV]Life Sciences [q-bio], Menopause, Premature, Obstetrics and Gynecology, Primary Ovarian Insufficiency, hypergonadotropic hypogonadism, whole exome sequencing, Cohort Studies, Fragile X Mental Retardation Protein, Cross-Sectional Studies, primary amenorrhea, Reproductive Medicine, Exome Sequencing, Humans, Female
Abstract: International audience; Objective: To study the diagnostic yield, including variants in genes yet to be incriminated, of whole exome sequencing (WES) in familial cases of premature ovarian insufficiency (POI). Design: Cross-sectional study. Setting: Endocrinology and reproductive medicine teaching hospital departments. Patients: Familial POI cases were recruited as part of a nationwide multicentric cohort. A total of 36 index cases in 36 different families were studied. Fifty-two relatives were available, including 25 with POI and 27 affected who were nonaffected. Karyotype analysis, FMR1 screening, single nucleotide polymorphism array analysis, and WES were performed in all subjects. Interventions: None. Main Outcome Measures: The primary outcome was a molecular etiology, as diagnosed by karyotype, FMR1 screening, single nucleotide polymorphism array, and WES. Results: A likely molecular etiology (pathogenic or likely pathogenic variant) was identified in 18 of 36 index cases (50% diagnostic yield). In 12 families, we found a pathogenic or likely pathogenic variant in a gene previously incriminated in POI, and in 6 families, we found a pathogenic or likely pathogenic variant in new candidate genes. Most of the variants identified were located in genes involved in cell division and meiosis (n = 11) or DNA repair (n = 4). Conclusions: The genetic etiologic diagnosis in POI allows for genetic familial counseling, anticipated pregnancy planning, and ovarian tissue preservation or oocyte preservation. Identifying new genes may lead to future development of therapeutics in reproduction based on disrupted molecular pathways. Clinical Trial Registration Number: NCT 01177891. ((C) 2021 by American Society for Reproductive Medicine.) El resumen esta disponible en Espanol al final del articulo.
Published: 2022
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7. Turner syndrome: French National Diagnosis and Care Protocol (NDCP; National Diagnosis and Care Protocol)

Author: Elodie Fiot, Bertille Alauze, Bruno Donadille, Dinane Samara-Boustani, Muriel Houang, Gianpaolo De Filippo, Anne Bachelot, Clemence Delcour, Constance Beyler, Emilie Bois, Emmanuelle Bourrat, Emmanuel Bui Quoc, Nathalie Bourcigaux, Catherine Chaussain, Ariel Cohen, Martine Cohen-Solal, Sabrina Da Costa, Claire Dossier, Stephane Ederhy, Monique Elmaleh, Laurence Iserin, Hélène Lengliné, Armelle Poujol-Robert, Dominique Roulot, Jerome Viala, Frederique Albarel, Elise Bismuth, Valérie Bernard, Claire Bouvattier, Aude Brac, Patricia Bretones, Nathalie Chabbert-Buffet, Philippe Chanson, Regis Coutant, Marguerite de Warren, Béatrice Demaret, Lise Duranteau, Florence Eustache, Lydie Gautheret, Georges Gelwane, Claire Gourbesville, Mickaël Grynberg, Karinne Gueniche, Carina Jorgensen, Veronique Kerlan, Charlotte Lebrun, Christine Lefevre, Françoise Lorenzini, Sylvie Manouvrier, Catherine Pienkowski, Rachel Reynaud, Yves Reznik, Jean-Pierre Siffroi, Anne-Claude Tabet, Maithé Tauber, Vanessa Vautier, Igor Tauveron, Sebastien Wambre, Delphine Zenaty, Irène Netchine, Michel Polak, Philippe Touraine, Jean-Claude Carel, Sophie Christin-Maitre, Juliane Léger, Centre de Référence des Maladies Endocriniennes Rares de la Croissance [APHP Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Cité (UPCité), Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'endocrinologie, gynécologie et diabétologie pédiatriques [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Trousseau [APHP], CHU Pitié-Salpêtrière [AP-HP], Département d'obstétrique et de gynécologie [Hôpital Robert Debré], Université Paris Diderot - Paris 7 (UPD7)-AP-HP Hôpital universitaire Robert-Debré [Paris], AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Charles Foix [AP-HP], Service de Rhumatologie [CHU Lariboisière], Hôpital Lariboisière-Fernand-Widal [APHP], Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Hôpital Avicenne [AP-HP], Service d'endocrinologie, diabète, maladies métaboliques [Hôpital de la Conception - APHM], Aix Marseille Université (AMU), CHU de Bordeaux Pellegrin [Bordeaux], AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Hospices Civils de Lyon (HCL), CHU Tenon [AP-HP], Endocrinologie pédiatrique[CHU Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Hôpital Jean Verdier [AP-HP], Service Endocrinologie - Diabétologie [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), AP-HP - Hôpital Antoine Béclère [Clamart], Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Hôpital Jeanne de Flandre [Lille], Service de pédiatrie multidisciplinaire [Hôpital de la Timone Enfants - APHM], Hôpital de la Timone [CHU - APHM] (TIMONE), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Maladies génétiques d'expression pédiatrique (U933), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], CHU Clermont-Ferrand, Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), and Ministère de la Santé
Subjects: Adult, Chromosomes, Human, X, Karyotype, Turner’s syndrome, Turner Syndrome, General Medicine, Recommendation, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Adulthood, Childhood, Management, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Diabetes Mellitus, Type 2, Karyotyping, Diagnosis, Humans, Pharmacology (medical), Female, Genetics (clinical)
Abstract: Turner syndrome (TS; ORPHA 881) is a rare condition in which all or part of one X chromosome is absent from some or all cells. It affects approximately one in every 1/2500 liveborn girls. The most frequently observed karyotypes are 45,X (40–50%) and the 45,X/46,XX mosaic karyotype (15–25%). Karyotypes with an X isochromosome (45,X/46,isoXq or 45,X/46,isoXp), a Y chromosome, X ring chromosome or deletions of the X chromosome are less frequent. The objective of the French National Diagnosis and Care Protocol (PNDS; Protocole National de Diagnostic et de Soins) is to provide health professionals with information about the optimal management and care for patients, based on a critical literature review and multidisciplinary expert consensus. The PNDS, written by members of the French National Reference Center for Rare Growth and Developmental Endocrine disorders, is available from the French Health Authority website. Turner Syndrome is associated with several phenotypic conditions and a higher risk of comorbidity. The most frequently reported features are growth retardation with short adult stature and gonadal dysgenesis. TS may be associated with various congenital (heart and kidney) or acquired diseases (autoimmune thyroid disease, celiac disease, hearing loss, overweight/obesity, glucose intolerance/type 2 diabetes, dyslipidemia, cardiovascular complications and liver dysfunction). Most of the clinical traits of TS are due to the haploinsufficiency of various genes on the X chromosome, particularly those in the pseudoautosomal regions (PAR 1 and PAR 2), which normally escape the physiological process of X inactivation, although other regions may also be implicated. The management of patients with TS requires collaboration between several healthcare providers. The attending physician, in collaboration with the national care network, will ensure that the patient receives optimal care through regular follow-up and screening. The various elements of this PNDS are designed to provide such support.
Published: 2022
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8. Impact of cancer chemotherapy before ovarian cortex cryopreservation on ovarian tissue transplantation

Author: Thierry Leblanc, S Egels, Catherine Genestie, Pauline Brice, Jean Gabarre, Jean-Marc Lacorte, Céline Chalas, Sebastien Gouy, Nathalie Dhedin, Véronique Drouineaud, Gilles Lefebvre, Yasmina Badachi, Jean-Paul Akakpo, G Lebègue, Frédérique Capron, Nicolas Boissel, Catherine Poirot, Alain Delmer, Jean-Philippe Wolf, Anne Fortin, Jean-Paul Vernant, Philippe Touraine, Philippe Morice, and M Dommergues
Subjects: Adult, Oncology, medicine.medical_specialty, Time Factors, Adolescent, Ovarian Cortex, medicine.medical_treatment, Ovary, Transplantation, Autologous, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Cancer Survivors, Pregnancy, Neoplasms, Internal medicine, Follicular phase, medicine, Humans, Cumulative incidence, Ovarian tissue cryopreservation, Autografts, Birth Rate, Antineoplastic Agents, Alkylating, Cryopreservation, Chemotherapy, 030219 obstetrics & reproductive medicine, business.industry, Graft Survival, Rehabilitation, Fertility Preservation, Obstetrics and Gynecology, Recovery of Function, Chemotherapy regimen, Menstruation, Transplantation, Treatment Outcome, medicine.anatomical_structure, Reproductive Medicine, Female, business, Live Birth
Abstract: STUDY QUESTION How efficacious is transplantation of ovarian cortex previously exposed to chemotherapy? SUMMARY ANSWER Prior exposure to chemotherapy did not disrupt the function of cryopreserved ovarian tissue after transplantation. WHAT IS KNOWN ALREADY Ovarian tissue cryopreservation (OTC) followed by ovarian tissue transplantation (OTT) is an efficacious technique for restoration of female fertility. At least 130 children have been born following this procedure. To date, little is known about the efficacy of OTT in patients exposed to cancer chemotherapy prior to OTC. STUDY DESIGN, SIZE, DURATION This study evaluates the recovery of ovarian function and fertility in 31 consecutive patients who had received OTT, between 2005 and 2015. PARTICIPANTS/MATERIALS, SETTING, METHODS Thirty one patients, wanting children, were transplanted with autologous ovarian cortex, among which 22 patients (71%) had been exposed to chemotherapy before OTC. Recovery of ovarian function was considered total once menstruation occurred. Ovarian function recovery (OFR), ovarian graft survival, and incidence of pregnancy were related to previous chemotherapy exposure, type of chemotherapy and graft characteristics (number of grafted fragments and follicular density). MAIN RESULTS AND ROLE OF CHANCE The amount of ovarian tissue collected was the only parameter to show any significant change between patients with versus without previous chemotherapy. At 1 year after OTT, the cumulative incidence of OFR was 83% (93% in patients exposed to chemotherapy and 67% in others (P = 0.14)). A low follicular density (
Published: 2019
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9. Causal and Candidate Gene Variants in a Large Cohort of Women with Primary Ovarian Insufficiency

Author: Lawrence M. Nelson, Mika Moriwaki, Corrine K. Welt, Elaine R. Mardis, Clement Y. Chow, Amber R. Cooper, Elaine Taylor, Bushra Gorsi, Aleksander Rajkovic, Marvin B Moore, Philippe Touraine, Claire Lu, Edgar Javier Hernandez, Mark Yandell, Emily Coelho, and Amanda Walker
Subjects: Adult, medicine.medical_specialty, Heterozygote, Candidate gene, Adolescent, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, Primary ovarian insufficiency, DNA Mutational Analysis, Context (language use), Primary Ovarian Insufficiency, Biology, Biochemistry, Young Adult, Endocrinology, Transcription (biology), Internal medicine, Exome Sequencing, medicine, Humans, 1000 Genomes Project, Gene, Exome, Exome sequencing, Whole genome sequencing, Genetics, Clinical Research Article, Biochemistry (medical), Genetic architecture, Large cohort, WDR33, Case-Control Studies, Mutation, Female
Abstract: Context A genetic etiology likely accounts for the majority of unexplained primary ovarian insufficiency (POI). Objective We hypothesized that heterozygous rare variants and variants in enhanced categories are associated with POI. Design The study was an observational study. Setting Subjects were recruited at academic institutions. Patients Subjects from Boston (n = 98), the National Institutes of Health and Washington University (n = 98), Pittsburgh (n = 20), Italy (n = 43), and France (n = 32) were diagnosed with POI (amenorrhea with an elevated follicle-stimulating hormone level). Controls were recruited for health in old age or were from the 1000 Genomes Project (total n = 233). Intervention We performed whole exome sequencing (WES), and data were analyzed using a rare variant scoring method and a Bayes factor-based framework for identifying genes harboring pathogenic variants. We performed functional studies on identified genes that were not previously implicated in POI in a D. melanogaster model. Main Outcome Genes with rare pathogenic variants and gene sets with increased burden of deleterious variants were identified. Results Candidate heterozygous variants were identified in known genes and genes with functional evidence. Gene sets with increased burden of deleterious alleles included the categories transcription and translation, DNA damage and repair, meiosis and cell division. Variants were found in novel genes from the enhanced categories. Functional evidence supported 7 new risk genes for POI (USP36, VCP, WDR33, PIWIL3, NPM2, LLGL1, and BOD1L1). Conclusions Candidate causative variants were identified through WES in women with POI. Aggregating clinical data and genetic risk with a categorical approach may expand the genetic architecture of heterozygous rare gene variants causing risk for POI.
Published: 2021
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10. Whole exome sequencing reveals copy number variants in individuals with disorders of sex development

Author: Rajini Sreenivasan, Katrina Bell, Jocelyn van den Bergen, Gorjana Robevska, Daniele Belluoccio, Rachana Dahiya, Gary M. Leong, Jérôme Dulon, Philippe Touraine, Elena J. Tucker, Katie Ayers, and Andrew Sinclair
Subjects: Male, Comparative Genomic Hybridization, Endocrinology, DNA Copy Number Variations, Exome Sequencing, High-Throughput Nucleotide Sequencing, Humans, Exome, Female, Androgen-Insensitivity Syndrome, Molecular Biology, Biochemistry
Abstract: Complete androgen insensitivity syndrome (CAIS), where 46,XY individuals present as female, is caused by variants in the androgen receptor gene (AR). We analyzed the DNA of a patient with suspected CAIS using a targeted gene sequencing panel and whole exome sequencing (WES) but did not detect any small nucleotide variants in AR. Analysis of WES data using our bioinformatics pipeline designed to detect copy number variations (CNV) uncovered a rare duplication of exon 2 of AR. Using array comparative genomic hybridization, the duplication was found to span 43.6 kb and is predicted to cause a frameshift and loss of AR protein. We confirmed the power of our WES-CNV detection protocol by identifying pathogenic CNVs in FSHR and NR5A1 in previously undiagnosed patients with disorders of sex development. Our findings illustrate the usefulness of CNV analysis in WES data to detect pathogenic genomic changes that may go undetected using only standard analysis protocols.
Published: 2021

11. A recessive variant in TFAM causes mtDNA depletion associated with primary ovarian insufficiency, seizures, intellectual disability and hearing loss

Author: Farid, Ullah, Waqar, Rauf, Kamal, Khan, Sheraz, Khan, Katrina M, Bell, Vanessa Cristina, de Oliveira, Muhammad, Tariq, Shabnam, Bakhshalizadeh, Philippe, Touraine, Nicholas, Katsanis, Andrew, Sinclair, Sijie, He, Elena J, Tucker, Shahid M, Baig, and Erica E, Davis
Subjects: Male, Genes, Recessive, Primary Ovarian Insufficiency, DNA, Mitochondrial, Pedigree, DNA-Binding Proteins, Mitochondrial Proteins, Seizures, Intellectual Disability, Animals, Humans, Female, Gonads, Hearing Loss, Cells, Cultured, Zebrafish, Transcription Factors
Abstract: Mitochondrial disorders are collectively common, genetically heterogeneous disorders in both pediatric and adult populations. They are caused by molecular defects in oxidative phosphorylation, failure of essential bioenergetic supply to mitochondria, and apoptosis. Here, we present three affected individuals from a consanguineous family of Pakistani origin with variable seizures and intellectual disability. Both females display primary ovarian insufficiency (POI), while the male shows abnormal sex hormone levels. We performed whole exome sequencing and identified a recessive missense variant c.694C T, p.Arg232Cys in TFAM that segregates with disease. TFAM (mitochondrial transcription factor A) is a component of the mitochondrial replisome machinery that maintains mtDNA transcription and replication. In primary dermal fibroblasts, we show depletion of mtDNA and significantly altered mitochondrial function and morphology. Moreover, we observed reduced nucleoid numbers with significant changes in nucleoid size or shape in fibroblasts from an affected individual compared to controls. We also investigated the effect of tfam impairment in zebrafish; homozygous tfam mutants carrying an in-frame c.141_149 deletion recapitulate the mtDNA depletion and ovarian dysgenesis phenotypes observed in affected humans. Together, our genetic and functional data confirm that TFAM plays a pivotal role in gonad development and expands the repertoire of mitochondrial disease phenotypes.
Published: 2021

12. Modified-Release Hydrocortisone in Congenital Adrenal Hyperplasia

Author: Alessandro Prete, F. Peter Treasure, Nicole Reisch, Wiebke Arlt, John Porter, Aude Brac de la Perriere, Colin Perry, Angelica Lindén Hirschberg, Richard J. Ross, Ashwini Mallappa, Philippe Touraine, Deborah P. Merke, Anders Juul, Nike M. M. L. Stikkelbroeck, Kerry Maltby, D. Aled Rees, John Newell-Price, National Institutes of Health [Bethesda] (NIH), Queens Elizabeth Hospital [Birmingham], University of Birmingham [Birmingham], Hospices Civils de Lyon (HCL), Karolinska University Hospital [Stockholm], Rigshospitalet [Copenhagen], Copenhagen University Hospital, University of Sheffield [Sheffield], Queen Elizabeth University Hospital (Glasgow), Cardiff University, University-Hospital Munich-Großhadern [München], Radboud University Medical Centre [Nijmegen, The Netherlands], Service d’endocrinologie et médecine de la reproduction [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Diurnal Ltd, and University of Cambridge [UK] (CAM)
Subjects: Male, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, Anti-Inflammatory Agents, Phases of clinical research, Biochemistry, Gastroenterology, 0302 clinical medicine, Endocrinology, 030212 general & internal medicine, Vascular damage Radboud Institute for Molecular Life Sciences [Radboudumc 16], Middle Aged, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Prognosis, 3. Good health, Tolerability, Female, adrenal insufficiency, Glucocorticoid, AcademicSubjects/MED00250, medicine.drug, Cortisol secretion, Adult, medicine.medical_specialty, 030209 endocrinology & metabolism, Context (language use), 21-hydroxylase deficiency, 03 medical and health sciences, Young Adult, All institutes and research themes of the Radboud University Medical Center, Internal medicine, Adrenal insufficiency, medicine, congenital adrenal hyperplasia, Humans, Congenital adrenal hyperplasia, hydrocortisone, Online Only Articles, Clinical Research Articles, Aged, Hydrocortisone, Adrenal Hyperplasia, Congenital, business.industry, Biochemistry (medical), medicine.disease, glucocorticoid, business, Follow-Up Studies
Abstract: Context Standard glucocorticoid therapy in congenital adrenal hyperplasia (CAH) regularly fails to control androgen excess, causing glucocorticoid overexposure and poor health outcomes. Objective We investigated whether modified-release hydrocortisone (MR-HC), which mimics physiologic cortisol secretion, could improve disease control. Methods A 6-month, randomized, phase 3 study was conducted of MR-HC vs standard glucocorticoid, followed by a single-arm MR-HC extension study. Primary outcomes were change in 24-hour SD score (SDS) of androgen precursor 17-hydroxyprogesterone (17OHP) for phase 3, and efficacy, safety and tolerability of MR-HC for the extension study. Results The phase 3 study recruited 122 adult CAH patients. Although the study failed its primary outcome at 6 months, there was evidence of better biochemical control on MR-HC, with lower 17OHP SDS at 4 (P = .007) and 12 (P = .019) weeks, and between 07:00h to 15:00h (P = .044) at 6 months. The percentage of patients with controlled 09:00h serum 17OHP ( Conclusion MR-HC improved biochemical disease control in adults with reduction in steroid dose over time and patient-reported benefit.
Published: 2021
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13. Meiotic genes in premature ovarian insufficiency: variants in HROB and REC8 as likely genetic causes

Author: Solène Duros, Bénédicte Nouyou, Rajini Sreenivasan, Sultana M.H. Faradz, Jocelyn van den Bergen, Andrew H. Sinclair, Shabnam Bakhshalizadeh, Jérôme Dulon, Elena J. Tucker, Linda Akloul, Wilfrid Carré, Katrina M. Bell, Nurin Aisyiyah Listyasari, Mathilde Domin-Bernhard, Marc-Antoine Belaud-Rotureau, Sylvie Jaillard, Gorjana Robevska, Katie L. Ayers, Philippe Touraine, Murdoch Children's Research Institute (MCRI), University of Melbourne, Centre des Pathologies gynécologiques Rares [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Pontchaillou [Rennes], Institut de recherche en santé, environnement et travail (Irset), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA), École des Hautes Études en Santé Publique [EHESP] (EHESP), NHMRC programNational Health and Medical Research Council of Australia [1074258], NHMRC fellowshipsNational Health and Medical Research Council of Australia [1054432, 1126995, 1062854], Melbourne Research Scholarship, Victorian Government's Operational Infrastructure Support Program, CHU Rennes grant, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: Infertility, Cohesin complex, In silico, [SDV]Life Sciences [q-bio], Cell Cycle Proteins, Primary Ovarian Insufficiency, Biology, Premature ovarian insufficiency, Article, Chromosomes, Mice, 03 medical and health sciences, 0302 clinical medicine, Exome Sequencing, Genetics, medicine, Animals, Humans, Gene, Genetics (clinical), Exome sequencing, 030304 developmental biology, 0303 health sciences, 030219 obstetrics & reproductive medicine, MCM8, DNA Helicases, medicine.disease, Phenotype, 3. Good health, DNA-Binding Proteins, Meiosis, Female
Abstract: International audience; Premature ovarian insufficiency (POI), affecting 1 in 100 women, is characterised by loss of ovarian function associated with elevated gonadotropin, before the age of 40. In addition to infertility, patients face increased risk of comorbidities such as heart disease, osteoporosis, cancer and/or early mortality. We used whole exome sequencing to identify the genetic cause of POI in seven women. Each had biallelic candidate variants in genes with a primary role in DNA damage repair and/or meiosis. This includes two genes, REC8 and HROB, not previously associated with autosomal recessive POI. REC8 encodes a component of the cohesin complex and HROB encodes a factor that recruits MCM8/9 for DNA damage repair. In silico analyses, combined with concordant mouse model phenotypes support these as new genetic causes of POI. We also identified novel variants in MCM8, NUP107, STAG3 and HFM1 and a known variant in POF1B. Our study highlights the pivotal role of meiosis in ovarian function. We identify novel variants, consolidate the pathogenicity of variants previously considered of unknown significance, and propose HROB and REC8 variants as new genetic causes while exploring their link to pathogenesis.
Published: 2021
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14. Long-term outcomes of lentiviral gene therapy for the β-hemoglobinopathies: the HGB-205 trial

Author: Elisa Magrin, Michaela Semeraro, Nicolas Hebert, Laure Joseph, Alessandra Magnani, Anne Chalumeau, Aurélie Gabrion, Cécile Roudaut, Jouda Marouene, Francois Lefrere, Jean-Sebastien Diana, Adeline Denis, Bénédicte Neven, Isabelle Funck-Brentano, Olivier Negre, Sylvain Renolleau, Valentine Brousse, Laurent Kiger, Fabien Touzot, Catherine Poirot, Philippe Bourget, Wassim El Nemer, Stéphane Blanche, Jean-Marc Tréluyer, Mohammed Asmal, Courtney Walls, Yves Beuzard, Manfred Schmidt, Salima Hacein-Bey-Abina, Vahid Asnafi, Isabelle Guichard, Maryline Poirée, Fabrice Monpoux, Philippe Touraine, Chantal Brouzes, Mariane de Montalembert, Emmanuel Payen, Emmanuelle Six, Jean-Antoine Ribeil, Annarita Miccio, Pablo Bartolucci, Philippe Leboulch, and Marina Cavazzana
Subjects: Male, Young Adult, Treatment Outcome, Adolescent, Lentivirus, beta-Thalassemia, Humans, Female, General Medicine, Anemia, Sickle Cell, Genetic Therapy, General Biochemistry, Genetics and Molecular Biology
Abstract: Sickle cell disease (SCD) and transfusion-dependent β-thalassemia (TDT) are the most prevalent monogenic disorders worldwide. Trial HGB-205 ( NCT02151526 ) aimed at evaluating gene therapy by autologous CD34
Published: 2020

15. Genomic sequencing highlights the diverse molecular causes of Perrault syndrome: a peroxisomal disorder (PEX6), metabolic disorders (CLPP, GGPS1), and mtDNA maintenance/translation disorders (LARS2, TFAM)

Author: Sandra Whalen, Juliette Dupont, Sandrine Vuillaumier-Barrot, Chloe Hanna, Gorjana Robevska, Phillipa J. Lamont, Lurdes Sampaio, John Christodoulou, Rocio Rius, Elena J. Tucker, André Travessa, Jocelyn van den Bergen, Andrew H. Sinclair, Arnaud Isapof, Katrina M. Bell, Andrea Simpson, Jérôme Dulon, Sylvie Jaillard, Tanya Stojkovic, Susana Quijano-Roy, David R. Thorburn, Katie L. Ayers, Philippe Touraine, Murdoch Children's Research Institute (MCRI), University of Melbourne, CHU Pontchaillou [Rennes], Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Filière Neuromusculaire (FILNEMUS), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), National Health and Medical Research Council (NHMRC)National Health and Medical Research Council of Australia [1113531], NHMRCNational Health and Medical Research Council of Australia [1074258, 1054432, 1062854, 1155244], CONACYTConsejo Nacional de Ciencia y Tecnologia (CONACyT), Victorian Government's Operational Infrastructure Support Program, Université d'Angers (UA)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: Adult, Male, Candidate gene, Adolescent, Mitochondrial translation, Hearing Loss, Sensorineural, [SDV]Life Sciences [q-bio], Gene Expression, Biology, DNA, Mitochondrial, Amino Acyl-tRNA Synthetases, Mitochondrial Proteins, 03 medical and health sciences, Peroxisomal disorder, Genetics, medicine, Peroxisomes, Farnesyltranstransferase, Humans, Genetic Predisposition to Disease, Child, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Base Sequence, 030305 genetics & heredity, Ovary, High-Throughput Nucleotide Sequencing, Geranyltranstransferase, Endopeptidase Clp, TFAM, medicine.disease, Dimethylallyltranstransferase, Human genetics, Premature ovarian failure, Gonadal Dysgenesis, 46,XX, Pedigree, DNA-Binding Proteins, Protein prenylation, ATPases Associated with Diverse Cellular Activities, Female, PEX6, Transcription Factors
Abstract: International audience; Perrault syndrome is a rare heterogeneous condition characterised by sensorineural hearing loss and premature ovarian insufficiency. Additional neuromuscular pathology is observed in some patients. There are six genes in which variants are known to cause Perrault syndrome; however, these explain only a minority of cases. We investigated the genetic cause of Perrault syndrome in seven affected individuals from five different families, successfully identifying the cause in four patients. This included previously reported and novel causative variants in known Perrault syndrome genes, CLPP and LARS2, involved in mitochondrial proteolysis and mitochondrial translation, respectively. For the first time, we show that pathogenic variants in PEX6 can present clinically as Perrault syndrome. PEX6 encodes a peroxisomal biogenesis factor, and we demonstrate evidence of peroxisomal dysfunction in patient serum. This study consolidates the clinical overlap between Perrault syndrome and peroxisomal disorders, and highlights the need to consider ovarian function in individuals with atypical/mild peroxisomal disorders. The remaining patients had variants in candidate genes such as TFAM, involved in mtDNA transcription, replication, and packaging, and GGPS1 involved in mevalonate/coenzyme Q(10) biosynthesis and whose enzymatic product is required for mouse folliculogenesis. This genomic study highlights the diverse molecular landscape of this poorly understood syndrome.
Published: 2020
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16. Effect of congenital adrenal hyperplasia treated by glucocorticoids on plasma metabolome: a machine-learning-based analysis

Author: Joe-Elie Salem, Edi Prifti, Monique Leban, Anne Bachelot, Lee S. Nguyen, Farid Ichou, Christian Funck-Brentano, Philippe Touraine, Centre d'investigation clinique Paris Est [CHU Pitié Salpêtrière] (CIC Paris-Est), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), CMC Ambroise Paré [Neuilly-sur-Seine], Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Centre d'investigation clinique Biothérapie [CHU Pitié-Salpêtrière] (CIC-BTi), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Integromics [Paris], Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unité de modélisation mathématique et informatique des systèmes complexes [Bondy] (UMMISCO), Université de Yaoundé I-Institut de la francophonie pour l'informatique-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Université Gaston Bergé (Saint-Louis, Sénégal)-Université Cadi Ayyad [Marrakech] (UCA)-Sorbonne Université (SU)-Institut de Recherche pour le Développement (IRD [France-Nord]), ICANalytics [Paris], The study sponsor was Assistance Publique – Hôpitaux de Paris (Département de la Recherche Clinique et du Développement)., CIC Paris Est, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CIC Pitié BT, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Institut de Recherche pour le Développement (IRD [France-Nord])-Institut de la francophonie pour l'informatique-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Université Gaston Bergé (Saint-Louis, Sénégal)-Université Cadi Ayyad [Marrakech] (UCA)-Université de Yaoundé I-Sorbonne Université (SU), Service d’endocrinologie et médecine de la reproduction [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de référence des maladies endocriniennes rares de la croissance et du développement [CHU Pitié-Salpêtrière], Centre des Pathologies gynécologiques Rares [CHU Pitié-Salpêtrière], Centre d'investigation clinique pluridisciplinaire [CHU Pitié Salpêtrière] (CIC-P 1421), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Service d'Endocrinologie et Médecine de la Reproduction [CHU Pitié-Salpêtrière], and Bodescot, Myriam
Subjects: 0301 basic medicine, Purine, Male, Hydrocortisone, lcsh:Medicine, Machine Learning, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, Purine metabolism, lcsh:Science, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Multidisciplinary, Endocrine system and metabolic diseases, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 3. Good health, Aminosugar, Area Under Curve, Metabolome, Female, Glucocorticoid, medicine.drug, Adult, medicine.medical_specialty, Multihormonal system disorders, Article, 03 medical and health sciences, Young Adult, Metabolomics, Internal medicine, medicine, Humans, Indoleamine-Pyrrole 2,3,-Dioxygenase, Congenital adrenal hyperplasia, Glucocorticoids, Adrenal Hyperplasia, Congenital, business.industry, lcsh:R, Metabolism, medicine.disease, 030104 developmental biology, Pyrimidines, chemistry, ROC Curve, Purines, Case-Control Studies, lcsh:Q, business, 030217 neurology & neurosurgery
Abstract: Background. Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency leads to impaired cortisol biosynthesis. Treatment includes glucocorticoid supplementation. We studied the specific metabolomics signatures in CAH patients using two different algorithms. Methods. In a case-control study of CAH patients matched on sex and age with healthy control subjects, two metabolomic analyses were performed: one using MetaboDiff, a validated differential metabolomic analysis tool and the other, using Predomics, a novel machine-learning algorithm. Results. 168 participants were included (84 CAH patients). There was no correlation between plasma cortisol levels during glucocorticoid supplementation and metabolites in CAH patients. Indoleamine 2,3-dioxygenase enzyme activity was correlated with ACTH (rho coefficient = −0.25, p-value = 0.02), in CAH patients but not in controls subjects. Overall, 33 metabolites were significantly altered in CAH patients. Main changes came from: purine and pyrimidine metabolites, branched aminoacids, tricarboxylic acid cycle metabolites and associated pathways (urea, glucose, pentose phosphates). MetaboDiff identified 2 modules that were significantly different between both groups: aminosugar metabolism and purine metabolism. Predomics found several interpretable models which accurately discriminated the two groups (accuracy of 0.86 and AUROC of 0.9). Conclusion. CAH patients and healthy control subjects exhibit significant differences in plasma metabolomes, which may be explained by glucocorticoid supplementation.
Published: 2020
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17. Increased long QT and torsade de pointes reporting on tamoxifen compared with aromatase inhibitors

Author: Dan M. Roden, Andrew M. Glazer, Joe-Elie Salem, Anne Bachelot, Carine Courtillot, Javid Moslehi, Bénédicte Lebrun-Vignes, Antoine Pariente, Christian Funck-Brentano, Philippe Touraine, Virginie Grouthier, Centre de référence des maladies endocriniennes rares de la croissance et du développement [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d’endocrinologie et médecine de la reproduction [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Vanderbilt University [Nashville], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], CIC Bordeaux, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux [Bordeaux], Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Pierre et Marie Curie - Paris 6 (UPMC)
Subjects: Oncology, Databases, Factual, [SDV]Life Sciences [q-bio], Action Potentials, 030204 cardiovascular system & hematology, chemistry.chemical_compound, 0302 clinical medicine, Exemestane, Heart Rate, Risk Factors, Torsades de Pointes, Aged, 80 and over, Aromatase Inhibitors, Letrozole, Middle Aged, Prognosis, 3. Good health, Europe, Long QT Syndrome, 030220 oncology & carcinogenesis, Female, Cardiology and Cardiovascular Medicine, hormones, hormone substitutes, and hormone antagonists, medicine.drug, Adult, Selective Estrogen Receptor Modulators, medicine.medical_specialty, Adolescent, Long QT syndrome, Anastrozole, Torsades de pointes, Risk Assessment, QT interval, Article, Young Adult, 03 medical and health sciences, Heart Conduction System, Internal medicine, medicine, Adverse Drug Reaction Reporting Systems, Humans, cardiovascular diseases, Aged, business.industry, ventricular arrhythmias, medicine.disease, Cardiotoxicity, Tamoxifen, chemistry, sex steroid hormones, torsade de pointes, business, Adverse drug reaction
Abstract: ObjectiveA prolonged QTc (LQT) is a surrogate for the risk of torsade de pointes (TdP). QTc interval duration is influenced by sex hormones: oestradiol prolongs and testosterone shortens QTc. Drugs used in the treatment of breast cancer have divergent effects on hormonal status.MethodsWe performed a disproportionality analysis using the European database of suspected adverse drug reaction (ADR) reports to evaluate the reporting OR (ROR χ2) of LQT, TdP and ventricular arrhythmias associated with selective oestrogen receptor modulators (SERMs: tamoxifen and toremifene) as opposed to aromatase inhibitors (AIs: anastrozole, exemestane and letrozole). When the proportion of an ADR is greater in patients exposed to a drug (SERMs) compared with patients exposed to control drug (AIs), this suggests an association between the specific drug and the reaction and is a potential signal for safety. Clinical and demographic characterisation of patients with SERMs-induced LQT and ventricular arrhythmias was performed.ResultsSERMs were associated with higher proportion of LQT reports versus AIs (26/8318 vs 11/14851, ROR: 4.2 (2.11–8.55), pConclusionsSERMs are associated with more reports of drug-induced LQT, TdP and ventricular arrhythmias compared with AIs. This finding is consistent with oestradiol-like properties of SERMs on the heart as opposed to effects of oestrogen deprivation and testosterone increase induced by AIs.Trial registration numberNCT03259711.
Published: 2018
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18. Premature ovarian insufficiency: step-by-step genetics bring new insights

Author: Philippe Touraine
Subjects: Minichromosome Maintenance Proteins, business.industry, Primary ovarian insufficiency, Menopause, Premature, Obstetrics and Gynecology, Primary Ovarian Insufficiency, medicine.disease, Premature ovarian insufficiency, Bioinformatics, Menopause, Minichromosome Maintenance Complex Component 9, Reproductive Medicine, Mutation, Mutation (genetic algorithm), medicine, Humans, Female, business
Published: 2020
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19. GGPS1 Mutations Cause Muscular Dystrophy/Hearing Loss/Ovarian Insufficiency Syndrome

Author: Udo Oppermann, Richard S. Finkel, Sandra Donkervoort, Edoardo Malfatti, Mariarita Santi, Leila Qebibo, Thomas Voit, Carsten G. Bönnemann, Kamel Mamchaoui, Michio Hirano, Kate Bushby, Philippe Touraine, Isabelle Nelson, Volker Straub, Hui Xiong, Tanya Stojkovic, Jahannaz Dastgir, A. Reghan Foley, Stephanie Duguez, Thomas C. Markello, Jyoti K. Jaiswal, Jachinta Rooney, Thierry Maisonobe, Ying Hu, Imelda Hughes, Jocelyn Laporte, Norma B. Romero, Katherine G. Meilleur, Johann Böhm, Adam Horn, Yaqun Zou, James E. Dunford, Yanbin Fan, Goutam Chandra, Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Handicap neuromusculaire : Physiopathologie, Biothérapie et Pharmacologies appliquées (END-ICAP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Neurophysiologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Chirurgie Générale, Viscérale et Endocrinienne [CHU Pitié-Sapêtrière], Unit of Neuromuscular Morphology [CHU Pitié-Salpêtrière], Institut de Myologie, Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), ANR-10-INBS-09 Fondation Maladies Rares, FMR National Institute of Neurological Disorders and Stroke, NINDS, This study was supported by intramural funds from the NIH National Institute of Neurological Disorders and Stroke (grant to C.G.B). J.E.D. is supported by National Institute for Health Research Oxford Biomedical Research Centre, Oxford, United Kingdom. J.L. and J.B. are supported by France G?nomique (ANR-10-INBS-09) and Fondation Maladies Rares within the framework of the ?Myocapture? sequencing project. We thank the patients and their families for their generous participation in this study, Dr P. Mohassel for his help in evaluating the patients, and M. Pizzimenti for technical assistance., ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Myologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut de Myologie, and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, 0301 basic medicine, Pathology, Geranylgeranyl pyrophosphate, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Primary Ovarian Insufficiency, Muscular Dystrophies, Protein Structure, Secondary, Mice, chemistry.chemical_compound, 0302 clinical medicine, Medicine, Gene Knock-In Techniques, Muscular dystrophy, Research Articles, Exome sequencing, Sanger sequencing, Geranyltranstransferase, Middle Aged, Phenotype, Pedigree, 3. Good health, Neurology, symbols, Female, Sensorineural hearing loss, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], GGPS1, medicine.symptom, Research Article, Adult, medicine.medical_specialty, Adolescent, Hearing loss, Mice, Transgenic, Young Adult, 03 medical and health sciences, symbols.namesake, Exome Sequencing, Animals, Farnesyltranstransferase, Humans, Hearing Loss, business.industry, Sequence Analysis, DNA, Dimethylallyltranstransferase, medicine.disease, 030104 developmental biology, chemistry, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract: International audience; Objective: A hitherto undescribed phenotype of early onset muscular dystrophy associated with sensorineural hearing loss and primary ovarian insufficiency was initially identified in 2 siblings and in subsequent patients with a similar constellation of findings. The goal of this study was to understand the genetic and molecular etiology of this condition. Methods: We applied whole exome sequencing (WES) superimposed on shared haplotype regions to identify the initial biallelic variants in GGPS1 followed by GGPS1 Sanger sequencing or WES in 5 additional families with the same phenotype. Molecular modeling, biochemical analysis, laser membrane injury assay, and the generation of a Y259C knock-in mouse were done. Results: A total of 11 patients in 6 families carrying 5 different biallelic pathogenic variants in specific domains of GGPS1 were identified. GGPS1 encodes geranylgeranyl diphosphate synthase in the mevalonate/isoprenoid pathway, which catalyzes the synthesis of geranylgeranyl pyrophosphate, the lipid precursor of geranylgeranylated proteins including small guanosine triphosphatases. In addition to proximal weakness, all but one patient presented with congenital sensorineural hearing loss, and all postpubertal females had primary ovarian insufficiency. Muscle histology was dystrophic, with ultrastructural evidence of autophagic material and large mitochondria in the most severe cases. There was delayed membrane healing after laser injury in patient-derived myogenic cells, and a knock-in mouse of one of the mutations (Y259C) resulted in prenatal lethality. Interpretation: The identification of specific GGPS1 mutations defines the cause of a unique form of muscular dystrophy with hearing loss and ovarian insufficiency and points to a novel pathway for this clinical constellation. ANN NEUROL 2020;88:332–347.
Published: 2020
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20. Illicit Upregulation of Serotonin Signaling Pathway in Adrenals of Patients With High Plasma or Intra-Adrenal ACTH Levels

Author: Olivier Chabre, Céline Duparc, Mathilde Sibony, Mari Suzuki, Philippe Touraine, Fideline Bonnet-Serrano, Estelle Louiset, Constantine A. Stratakis, Françoise Gobet, Jacques Young, Julie Le Mestre, Hervé Lefebvre, Jérôme Bertherat, Yves Reznik, Gérald Raverot, Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Normandie Université (NU), Service Endocrinologie - Diabétologie [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Service d’endocrinologie et médecine de la reproduction [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Biologie du Cancer et de l'Infection (BCI ), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut National de la Santé et de la Recherche Médicale (INSERM), Récepteurs stéroïdiens : physiopathologie endocrinienne et métabolique, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR93-Université Paris-Sud - Paris 11 (UP11), Service d'anatomie pathologique [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'Anatomie et Cytologie Pathologique [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), National Institutes of Health [Bethesda] (NIH), Santé Lyon Est - Louis Léopold Ollier, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Paris-Sud - Paris 11 (UP11)-IFR93-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Tenon [AP-HP], Service d'Endocrinologie et Médecine de la Reproduction [CHU Pitié-Salpêtrière], Service d'Anatomie et cytologie pathologiques [CHU Tenon], and DUPARC, Céline
Subjects: 0301 basic medicine, Male, [SDV.MHEP.PHY] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Endocrinology, Diabetes and Metabolism, Receptor expression, Clinical Biochemistry, Adrenal Gland Neoplasms, Stimulation, Tryptophan Hydroxylase, Biochemistry, Cushing syndrome, 0302 clinical medicine, Endocrinology, Adrenal Glands, Cyclic AMP, Cushing Syndrome, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Chemistry, Adrenal cortex, Middle Aged, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 3. Good health, Up-Regulation, medicine.anatomical_structure, Female, Signal Transduction, Cortisol secretion, Adenoma, Adult, medicine.medical_specialty, Serotonin, endocrine system, Primary Cell Culture, 030209 endocrinology & metabolism, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Serotonergic, 03 medical and health sciences, Adrenocorticotropic Hormone, Internal medicine, medicine, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Humans, Pituitary ACTH Hypersecretion, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Clinical Research Articles, Biochemistry (medical), medicine.disease, Cushing Disease, 030104 developmental biology, Receptors, Serotonin, Steroid 21-Hydroxylase, Protein Kinases
Abstract: Context In the human adrenal, serotonin (5-HT), released by mast cells stimulates corticosteroid secretion through activation of type 4 serotonin receptors (5-HT4R). In primary pigmented nodular adrenocortical disease cells, activation of the cAMP/protein kinase A (PKA) pathway by PRKAR1A mutations triggers upregulation of the 5-HT synthesizing enzyme tryptophan hydroxylase (TPH) and the 5-HT4, 5-HT6, and 5-HT7 receptors. Because ACTH stimulates cortisol secretion through activation of PKA, adrenocortical tissues exposed to sustained stimulation by ACTH may harbor increased expression of TPH and 5-HT4/6/7 receptors. Objective To investigate the effects of long-term ACTH stimulation on the serotonergic pathway in adrenals of patients with high plasma or intra-adrenal ACTH levels. Methods Adrenal tissues were obtained from patients with Cushing disease, ectopic secretion of ACTH [paraneoplastic Cushing syndrome; (paraCS)], 21-hydroxylase deficiency (21-OHD), primary bilateral macronodular adrenal hyperplasia with intra-adrenal ACTH presence, or cortisol-producing adenomas. TPH and 5-HT4/6/7 receptor expression was investigated using RT-PCR and immunochemistry in comparison with normal adrenals. Primary cultured adrenocortical cells originating from a patient with paraCS were incubated with 5-HT and 5-HTR agonists/antagonists. Results TPH and/or 5-HT4/6/7 receptors were overexpressed in the different types of tissues. In paraCS cultured cells, the cortisol response to 5-HT was exaggerated compared with normal adrenal cells and the stimulatory action of 5-HT was reduced by 5-HT4R antagonist. Conclusion Our results indicate that prolonged activation of the cAMP/PKA pathway by ACTH induces an aberrant serotonergic stimulatory loop in the adrenal cortex that likely participates in the pathogenesis of corticosteroid hypersecretion.
Published: 2019
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21. TP63-truncating variants cause isolated premature ovarian insufficiency

Author: Katrina M. Bell, Gorjana Robevska, Jérôme Dulon, Philippe Touraine, Andrew H. Sinclair, Chloe Hanna, Sylvie Jaillard, Sonia Grover, Elena J. Tucker, Simon Sadedin, Jocelyn van den Bergen, Murdoch Children's Research Institute (MCRI), Institut de recherche en santé, environnement et travail (Irset), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA), CHU Pontchaillou [Rennes], University of Melbourne, Hôpital Raymond Poincaré [AP-HP], Centre des Pathologies gynécologiques Rares [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 1062854, National Health and Medical Research Council, 1074258, National Health and Medical Research Council, 1054432, Peter Doherty Early Career Fellowship, Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: premature ovarian insufficiency, media_common.quotation_subject, [SDV]Life Sciences [q-bio], Nonsense, Primary Ovarian Insufficiency, Biology, Premature ovarian insufficiency, medicine.disease_cause, 03 medical and health sciences, Exon, Protein Domains, Exome Sequencing, TP63, Genotype, Genetics, medicine, Humans, Genetic Predisposition to Disease, whole-exome sequencing, Genetics (clinical), Exome sequencing, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, media_common, 0303 health sciences, Mutation, ovarian dysgenesis, Tumor Suppressor Proteins, Serine Endopeptidases, 030305 genetics & heredity, Phenotype, PREPL, Pedigree, 3. Good health, POI cohort, Codon, Nonsense, Female, Prolyl Oligopeptidases, Transcription Factors
Abstract: Premature ovarian insufficiency involves amenorrhea and elevated follicle-stimulating hormone before age 40, and its genetic basis is poorly understood. Here, we study 13 premature ovarian insufficiency (POI) patients using whole-exome sequencing. We identify PREPL and TP63 causative variants, and variants in other potentially novel POI genes. PREPL deficiency is a known cause of syndromic POI, matching the patients' phenotype. A role for TP63 in ovarian biology has previously been proposed but variants have been described in multiorgan syndromes, and not isolated POI. One patient with isolated POI harbored a de novo nonsense TP63 variant in the terminal exon and an unrelated patient had a different nonsense variant in the same exon. These variants interfere with the repression domain while leaving the activation domain intact. We expand the phenotypic spectrum of TP63-related disorders, provide a new genotype:phenotype correlation for TP63 and identify a new genetic cause of isolated POI.
Published: 2019
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22. Gain-of-function Prolactin Receptor Variants Are Not Associated With Breast Cancer and Multiple Fibroadenoma Risk

Author: Rémi Pierre, Isabelle Tejedor, Aurélie Chiche, Zeina Chakhtoura, Carine Courtillot, Florence Boutillon, P. Camparo, Fabienne Rakotozafy, Vincent Goffin, Natascha Pigat, Jacques-Emmanuel Guidotti, Marie-Laure Tanguy, Sophie Vacher, Fatima Laki, Anne Bissery, Ivan Bièche, Marc Foretz, Marie Bernadet, Jean Tichet, Virginie Grouthier, Philippe Touraine, Sophie Bernichtein, Marcio Do Cruzeiro, Brigitte Sigal-Zafrani, and Ibtissem Cherifi
Subjects: Adult, 0301 basic medicine, Genetically modified mouse, medicine.medical_specialty, Adolescent, Receptors, Prolactin, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, Breast Neoplasms, Mice, Transgenic, Context (language use), Biochemistry, Germline, Cohort Studies, Mice, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Breast cancer, Breast Fibroadenoma, Internal medicine, medicine, Animals, Humans, business.industry, Prolactin receptor, Biochemistry (medical), Middle Aged, medicine.disease, Fibroadenoma, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, 030220 oncology & carcinogenesis, Cohort, Female, business
Abstract: In a cohort of 95 women with multiple breast fibroadenomas (MFAs), we recently identified patients harboring germline heterozygous variants of the prolactin receptor (PRLR) exhibiting constitutive activity (PRLRThis study sought to better delineate the potential role of PRLR gain-of-function variants in benign and malignant mammary tumorigenesis.This was an observational study and transgenic mouse model analysis.The study took place at the Department of Endocrinology, Reproductive Disorders and Rare Gynecologic Diseases, Pitié Salpêtrière, Paris, and Inserm Unit 1151, Paris.We generated a second MFA cohort (n = 71) as well as a group of control subjects (n = 496) and a cohort of women with breast cancer (n = 119). We also generated two transgenic mouse models carrying the coding sequences of human PRLRWe aimed to determine the prevalence of PRLR variants in these three populations and to uncover any association of the latter with specific tumor pattern, especially in patients with breast cancer.This study did not highlight a higher prevalence of PRLR variants in the MFA group and in the breast cancer group compared with control subjects. Transgenic mice expressing PRLRPRLR
Published: 2016
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23. Deletion ofCPEB1Gene: A Rare but Recurrent Cause of Premature Ovarian Insufficiency

Author: S. Christin-Maitre, L. Mansour-Hendili, Anne Gompel, Véronique Kerlan, Philippe Touraine, Yves Reznik, Sandra Chantot-Bastaraud, Jean-Pierre Siffroi, Bruno Donadille, B. Delemer, S. Jonard, Catherine Dodé, and Capucine Hyon
Subjects: Adult, 0301 basic medicine, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, Menopause, Premature, Context (language use), Primary Ovarian Insufficiency, Biology, Premature ovarian insufficiency, medicine.disease_cause, Bioinformatics, Biochemistry, law.invention, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, law, medicine, Humans, Gene, Polymerase chain reaction, mRNA Cleavage and Polyadenylation Factors, Mutation, 030219 obstetrics & reproductive medicine, Biochemistry (medical), Breakpoint, FMR1, 030104 developmental biology, Female, Gene Deletion, Transcription Factors, Cohort study
Abstract: Premature ovarian insufficiency (POI) may be secondary to chemotherapy, radiotherapy, or environmental factors. Genetic causes are identified in 20-25% of cases, but most POI cases remain idiopathic.This study aimed to identify new genes involved in POI and to characterize the implication of CPEB1 gene in POI.This was a case report and cohort study replicate conducted in academic medical centers.A deletion including CPEB1 gene was first identified in a patient with primary amenorrhea. Secondly, 191 sporadic POI cases and 68 familial POI cases were included. For each patient, karyotype was normal and FMR1 premutation was excluded. Search for CPEB1 deletions was performed by quantitative multiplex PCR of short fluorescent fragments or DNA microarray analysis. Gene sequencing of CPEB1 was performed for 95 patients.We identified three patients carrying a microdeletion in band 15q25.2. The proximal breakpoint, for the three patients, falls within a low-copy repeat region disrupting the CPEB1 gene, which represents a strong candidate gene for POI as it is known to be implicated in oocyte meiosis. No mutation was identified by sequencing CPEB1 gene. Therefore, heterozygous deletion of CPEB1 gene leading to haploinsufficiency could be responsible for POI in humans.Microdeletions of CPEB1 were identified in 1.3% of patients with POI, whereas no mutation was identified. This microdeletion is rare but recurrent as it is mediated by nonallelic homologous recombination due to the existence of low-copy repeats in the region. This result demonstrates the importance of DNA microarray analysis in etiological evaluation and counseling of patients with POI.
Published: 2016
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24. Post-transplant outcome of ovarian tissue cryopreserved after chemotherapy in hematological malignancies

Author: Céline Chalas, Nicolas Boissel, Yasmina Badachi, Catherine Genestie, Gérard Socié, Gilles Lefebvre, Jean-Philippe Wolf, Frédérique Capron, Jean-Paul Akakpo, Véronique Drouineaud, Pauline Brice, Catherine Poirot, Géraldine Lebègue, Jean-Marc Lacorte, Thierry Leblanc, Alain Delmer, Nathalie Dhedin, Jean Gabarre, Jean-Paul Vernant, Marc Dommergues, Sophie Egels, Anne Fortin, Philippe Touraine, CHU Saint Louis [APHP], Sorbonne Université (SU), Service de Gynécologie et Obstétrique [Groupe Hospitalier Pitié-Salpêtrière], CHU Pitié-Salpêtrière [APHP], Service d'hématologie-oncologie adultes, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Service de Biochimie Endocrinienne et Oncologique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Service de Radiologie [CHU Pitié-Salpétrière], Service de pathologie [CHU Pitié-Salpêtrière], Service d'Hématologie Clinique [CHU Pitié-Salpêtrière], Centre Hospitalier Universitaire de Reims (CHU Reims), Service d'hématologie [Reims], Hôpital Robert Debré, Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims (CHU Reims)-Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims (CHU Reims), CHU Cochin [AP-HP], Institut E3M [CHU Pitié-Salpêtrière], Service d'endocrinologie et maladies métaboliques [CHU Pitié-Salpêtrière], Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Gynécologie-Obstétrique, Maternité, Chirurgie Gynécologique [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Service de Biochimie Endocrinienne et Oncologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'Hématologie clinique [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Cochin [AP-HP], Service d’Endocrinologie, Métabolisme et Prévention des Risques Cardio-Vasculaires [CHU Pitié-Salpêtrière], and Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris]
Subjects: Oncology, medicine.medical_specialty, Ovary transplantation, medicine.medical_treatment, [SDV]Life Sciences [q-bio], MEDLINE, [SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, Cryopreservation, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Fertility preservation, Online Only Articles, ComputingMilieux_MISCELLANEOUS, Chemotherapy, 030219 obstetrics & reproductive medicine, Ovarian tissue transplantation, business.industry, Ovarian tissue, Ovary, Ovarian tissue cryopreservation, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Organ Transplantation, Recovery of Function, Hematology, Post transplant, 3. Good health, Hematologic Neoplasms, 030220 oncology & carcinogenesis, Quality of Life, Female, business
Abstract: International audience
Published: 2019
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25. Endocrine manifestations in a cohort of 63 adulthood and childhood onset patients with Langerhans cell histiocytosis

Author: Philippe Touraine, Fleur Cohen, Joseph Y Drabo, Abdellatif Tazi, Carine Courtillot, Ahmed Idbaih, Jean Donadieu, Zahir Amoura, Julien Haroche, Yempabou Sagna, Gestionnaire, Hal Sorbonne Université, Centre Hospitalier Universitaire Yalgado Ouédraogo (CHUYO), Service d'Endocrinologie et Médecine de la Reproduction [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de pneumologie [Saint-Louis], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'hématologie-immunologie-oncologie pédiatrique [CHU Trousseau], CHU Trousseau [APHP], Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service d'Onco-neurologie = Département de neurologie 2 [CHU Pitié Salpêtrière], Service de médecine interne [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service d’endocrinologie et médecine de la reproduction [CHU Pitié-Salpêtrière], Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université - Département de neurologie 2 - Mazarin, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Male, Pediatrics, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Cohort Studies, 0302 clinical medicine, Endocrinology, Langerhans cell histiocytosis, Age of Onset, Child, Aged, 80 and over, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, General Medicine, Middle Aged, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 3. Good health, [SDV] Life Sciences [q-bio], Histiocytosis, Child, Preschool, 030220 oncology & carcinogenesis, Cohort, Female, France, Thyroid function, Adult, Thyroid Hormones, medicine.medical_specialty, Adolescent, Endocrine System, 030209 endocrinology & metabolism, Endocrine System Diseases, Young Adult, 03 medical and health sciences, Internal medicine, medicine, Humans, Endocrine system, Aged, Retrospective Studies, business.industry, Retrospective cohort study, medicine.disease, Histiocytosis, Langerhans-Cell, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Gonadotropins, Pituitary, Diabetes insipidus, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Age of onset, business, Follow-Up Studies
Abstract: Objective Langerhans cell histiocytosis (LCH) is a rare inflammatory myeloid neoplasm which can infiltrate any organ or tissue. Endocrine involvement has mostly been described in case reports and small retrospective studies. We aimed to describe endocrine manifestations in a large cohort of adulthood onset (AO) and childhood onset (CO) patients with LCH. Design Single-center observational study conducted between January 2002 and December 2017 at Pitié-Salpêtrière University Hospital (Paris, France), a tertiary care hospital. Method Clinical, biological and morphological evaluations of pituitary, gonadal, adrenal and thyroid function evaluations performed in 63 consecutive patients with LCH (AO patients: 40, CO patients: 23). Fifty-eight patients underwent follow-up assessments. Results Complete pituitary evaluation was performed in 38/63 patients (60.3%); at least one anterior pituitary dysfunction (APD) was found in 63.2% of them. In this subgroup of patients, the most prevalent deficiencies were diabetes insipidus (DI) and GHD (55.3% each), followed by gonadotropin deficiency (34.2%) and thyrotropin deficiency (23.7%). In the subgroup of the 25 incompletely evaluated patients, we found DI in 44%, GHD in 50%, gonadotropin deficiency in 30.4% and thyrotropin deficiency in 16%. APD was more common in CO patients (P = 0.003) but was not systematically associated with DI regardless of the age of onset. Endocrine dysfunction was most often permanent; moreover, occurrence of new deficiencies has been described during follow-up. Conclusion The spectrum of endocrine disorders appears to be large in LCH (both in AO and CO patients) and should be evaluated carefully at diagnosis and during follow-up. APD was not always associated with DI.
Published: 2019
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26. Postprandial GLP-1 Secretion After Bariatric Surgery in Three Cases of Severe Obesity Related to Craniopharyngiomas

Author: M. Bretault, Philippe Touraine, Charles Barsamian, Jean-Luc Bouillot, Marie-Laure Raffin-Sanson, Jean-Marc Lacorte, Sébastien Czernichow, Claire Carette, Michel Polak, and Suzanne Laroche
Subjects: Male, 0301 basic medicine, Sleeve gastrectomy, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Bariatric Surgery, 030209 endocrinology & metabolism, Pituitary neoplasm, Craniopharyngioma, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Insulin resistance, Glucagon-Like Peptide 1, Weight loss, medicine, Humans, Pituitary Neoplasms, Obesity, Nutrition and Dietetics, business.industry, Middle Aged, Postprandial Period, medicine.disease, Surgery, 030104 developmental biology, Postprandial, Female, medicine.symptom, business, Hyperinsulinism
Abstract: Craniopharyngiomas are rare cerebral tumors associated with severe obesity after hypothalamic surgery. A meta-analysis showed significant weight loss at 1 year after bariatric surgery in these patients even though more modest than in common causes of obesity. We hypothesized that this discrepancy could be partly explained by differences in GLP-1 secretion after surgery since patients with craniopharyngioma present a significantly higher degree of insulin resistance and hyperinsulinism than common obese control. We report three cases of bariatric surgery in patients presenting with hypothalamique obesity related to craniopharyngiomas. At 18 months, the mean weight loss was 20 kg with expected insulin resistance decrease. Before surgery, standardized test meal shows abolition of postprandial GLP-1 secretion in all patients with a progressive restoration in the patients with gastric bypass (GBP) surgery.
Published: 2016
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27. Endocrine Manifestations in a Monocentric Cohort of 64 Patients With Erdheim-Chester Disease

Author: Z. Amoura, M. Leban, J. Haroche, S. Laugier Robiolle, F. Cohen Aubart, Frédéric Charlotte, Carine Courtillot, Raphaële Renard-Penna, Philippe Touraine, and Aurélie Drier
Subjects: Adult, Male, Erdheim-Chester Disease, medicine.medical_specialty, genetic structures, Endocrinology, Diabetes and Metabolism, Pituitary Function Tests, Clinical Biochemistry, 030209 endocrinology & metabolism, Disease, Thyroid Function Tests, Biochemistry, Cohort Studies, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Bone Density, Endocrine Glands, Internal medicine, Adrenal Glands, medicine, Humans, Endocrine system, Young adult, Gonads, Aged, Aged, 80 and over, business.industry, Biochemistry (medical), Middle Aged, medicine.disease, Histiocytosis, Erdheim–Chester disease, Cohort, Diabetes insipidus, Disease Progression, Female, France, business, Diabetes Insipidus, 030217 neurology & neurosurgery, Follow-Up Studies, Cohort study
Abstract: Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis, characterized by infiltration of foamy histiocytes in multiple organs. Endocrine involvement has mostly been described in case reports.We performed systematic endocrine evaluation in a large cohort of patients with ECD.This was a single-center observational study conducted between October 2007 and May 2013.The evaluation was conducted in Pitié-Salpêtrière Hospital (Paris, France), a tertiary care hospital.Sixty-four consecutive patients with ECD (sex ratio, 3.6; mean age, 57.6 years [range, 20-80 years]). Thirty-six patients had follow-up assessments.There were no interventions.Clinical, biological, and morphological evaluations of pituitary, gonadal, adrenal, and thyroid functions, as well as metabolic evaluation, were performed.Diabetes insipidus was found in 33.3% of patients, frequently as the first manifestation of ECD. Anterior pituitary dysfunction was found in 91.3% of patients with full anterior pituitary evaluation, including somatotropic deficiency (78.6%), hyperprolactinemia (44.1%), gonadotropic deficiency (22.2%), thyrotropic deficiency (9.5%), and corticotropic deficiency (3.1%). Thirty-five patients (54.7%) had ≥2 anterior pituitary dysfunctional axes, rising to 69.6% (16 of 23) when only patients with complete evaluations were considered. Two patients had panhypopituitarism. Infiltration of the pituitary and stalk was found with magnetic resonance imaging in 24.4% of patients. Testicular insufficiency was found in 53.1% of patients, with sonographic testicular infiltration in 29% of men, mostly bilateral. Computed tomography adrenal infiltration was found in 39.1% of patients, and 1 case of adrenal insufficiency was observed. No patient was free of endocrine hormonal or morphological involvement. Endocrine dysfunctions were most often permanent, and new deficits appeared during follow-up.Endocrine involvement is very frequent in ECD and should be evaluated carefully at diagnosis and during follow-up.
Published: 2016
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28. Prevalence of and Risk Factors for Anal Oncogenic Human Papillomavirus Infection Among HIV-Infected Women in France in the Combination Antiretroviral Therapy Era

Author: Valérie Potard, Isabelle Etienney, Catherine Moore, Isabelle Heard, Catherine Crenn-Hebert, Philippe Touraine, Isabelle Poizot-Martin, Dominique Costagliola, Heather Cubie, Centre National de Référence pour les Papillomavirus - Rétrovirologie moléculaire - Génétique,Papillomavirus et Cancer humain, Institut Pasteur [Paris] (IP), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U912 INSERM - Aix Marseille Univ - IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Immuno-hématologie clinique [Hôpital Sainte Marguerite - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud ), Inserm-Transfert [Paris], Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Dpt proctologie [CHU Croix St Simon], Groupe Hospitalier Diaconesses Croix Saint-Simon, Hôpital Louis Mourier - AP-HP [Colombes], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Scottish HPV Reference Laboratory [Edinburgh, UK], Lissalde, Claire, Institut Pasteur [Paris], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Institut de Recherche pour le Développement (IRD)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)
Subjects: Adult, 0301 basic medicine, HPV, medicine.medical_specialty, Adolescent, Cross-sectional study, 030106 microbiology, HIV Infections, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cervix Uteri, Young Adult, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Risk Factors, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Prevalence, medicine, Humans, Immunology and Allergy, Anal cancer, anal canal, 030212 general & internal medicine, Cervix, Gynecology, Anus Diseases, business.industry, Obstetrics, Papillomavirus Infections, cervical, HPV infection, virus diseases, Odds ratio, Middle Aged, Anal canal, medicine.disease, 3. Good health, Cross-Sectional Studies, Infectious Diseases, medicine.anatomical_structure, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, HIV-positive women, Cohort, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Population study, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, France, business
Abstract: International audience; Background. Little is known about the type-specific prevalence of anal human papillomavirus (HPV) infection and risk factors for anal high-risk (HR) HPV infection in human immunodeficiency virus (HIV)-infected women. Methods. A cross-sectional study of anal and cervical HPV infection was nested within a gynecological cohort of HIV-infected women. Specimens were tested for type-specific DNA using a polymerase chain reaction-based assay. Results. The study population consisted of 311 women with a median age of 45.3 years, of whom 42.8% originated from sub-Saharan Africa and 96.8% were receiving combination antiretroviral therapy. The median CD4 + cell count was 612/μL, and the HIV load was
Published: 2015
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29. The prolactin receptor as a therapeutic target in human diseases: browsing new potential indications

Author: Vincent Goffin and Philippe Touraine
Subjects: Male, Receptors, Prolactin, medicine.medical_treatment, Clinical Biochemistry, Antineoplastic Agents, Breast Neoplasms, Disease, Bioinformatics, Targeted therapy, Prostate, Drug Discovery, medicine, Animals, Humans, Molecular Targeted Therapy, Receptor, STAT5, Pharmacology, biology, Prolactin receptor, Prostatic Neoplasms, Cancer, medicine.disease, Prolactin, medicine.anatomical_structure, Drug Design, Immunology, biology.protein, Molecular Medicine, Female
Abstract: Prolactin (PRL) signaling has emerged as a relevant target in breast and prostate cancers. This has encouraged various laboratories to develop compounds targeting the PRL receptor (PRLR). As the latter is widely distributed, it is timely to address whether other conditions could also benefit from such inhibitors.The authors briefly overview the two classes of PRLR blockers, which involve: i) PRL-core based analogs that have been validated as competitive antagonists in various preclinical models, and ii) anti-PRLR neutralizing antibodies that are currently in clinical Phase I for advanced breast and prostate cancers. The main purpose of this review is to discuss the multiple organs/diseases that may be considered as potential targets/indications for such inhibitors. This is done in light of reports suggesting that PRLR expression/signaling is increased in disease, and/or that systemic or locally elevated PRL levels correlate with (or promote) organ pathogenesis.The two immediate challenges in the field are i) to provide the scientific community with potent anti-prolactin receptor antibodies to map prolactin receptor expression in target organs, and ii) to take advantage of the availability of functionally validated PRLR blockers to establish the relevance of these potential indications in humans.
Published: 2015
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30. Gynecologic follow up of 129 women on dialysis and after kidney transplantation: a retrospective cohort study

Author: Zeina Chakhtoura, Lucile Mercadal, Benoit Barrou, Marie Meunier, Nadia Arzouk, Jacqueline Caby, and Philippe Touraine
Subjects: Adult, medicine.medical_specialty, Metrorrhagia, medicine.medical_treatment, Population, Intrauterine device, Cohort Studies, Chlormadinone acetate, chemistry.chemical_compound, Pregnancy, Renal Dialysis, medicine, Humans, education, Menstruation Disturbances, Kidney transplantation, Dialysis, Retrospective Studies, Gynecology, education.field_of_study, business.industry, Obstetrics and Gynecology, Retrospective cohort study, Middle Aged, medicine.disease, Kidney Transplantation, Menstruation, Pregnancy Complications, Transplantation, Contraception, Reproductive Medicine, chemistry, Kidney Failure, Chronic, Female, medicine.symptom, business, Genital Diseases, Female, Follow-Up Studies
Abstract: To describe the gynecologic issues and follow-up in our referral center of women on dialysis and after kidney transplantation.This retrospective cohort study included 129 dialysed women among whom 102 had had transplants. Data on menstrual pattern, pregnancies, contraception, and cervical cytology were retrieved from patients' files.The follow-up started at age 41.6±14.2 years and lasted for 9.5±10.2 years. Of the women, 78.7% had regular menses before dialysis, decreasing to 30.6% on dialysis (p0.001), when 43.1% were amenorrheic (p0.001). After transplantation, more patients had regular menstruation and fewer were amenorrheic (respectively 57.1% and 23.1%, p0.001). On dialysis and after transplantation, 25% and 30.5% of patients suffered from metrorrhagia (compared to 17.1% before, p0.01). Concerning pregnancies, rates of spontaneous abortions (33.3%, p=0.01), intrauterine growth retardation (28.5%, p0.001) and prematurity (23.8%, p=0.008) were significantly higher after transplantation than before dialysis. Prescriptions for the combined contraceptive pill and intrauterine device decreased whereas chlormadinone acetate was widely used: it treated metrorrhagia and relieved mastodynia in 80% and 12% of the cases. Smear tests showed more inflammation (33% vs 0.8%, p0.05), condylomas (13.6% vs 3.1%, p=0.005) and intraepithelial neoplasias (12.6% vs 2.3%, p=0.003) among patients after renal graft than before dialysis.Women on dialysis and after kidney transplantation suffered more from irregular menses and metrorrhagia which was improved by chlormadinone acetate. We noted high rates of obstetrical complications and abnormal smear tests. Consequently, this population must have close follow-up to identify and treat gynecologic issues.
Published: 2015
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31. Early central blood pressure elevation in adult patients with 21-hydroxylase deficiency

Author: Randa Bittar, Jérôme Dulon, Nora Dahmoune, Marie Laure Tanguy, Philippe Touraine, Gaelle Lethielleux, Joe-Elie Salem, Bernard I. Levy, Antonio Gallo, David Rosenbaum, Monique Leban, Eric Bruckert, Xavier Girerd, Anne Bachelot, Service d’Endocrinologie, Métabolisme et Prévention des Risques Cardio-Vasculaires [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU), Laboratoire d'Imagerie Biomédicale (LIB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre des Pathologies gynécologiques Rares [CHU Pitié-Salpêtrière], Centre de référence des maladies endocriniennes rares de la croissance et du développement [CHU Pitié-Salpêtrière], Service d’endocrinologie et médecine de la reproduction [CHU Pitié-Salpêtrière], Institut E3M [CHU Pitié-Salpêtrière], Dyslipidémies, inflammation et athérosclérose dans les maladies métaboliques, Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Lariboisière, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de pharmacologie médicale [CHU Pitié-Salpêtrière], Service de Biochimie Endocrinienne et Oncologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Université Paris Diderot - Paris 7 (UPD7)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de biochimie et hormonologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Service d'endocrinologie-métabolisme [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU), Centre de référence des maladies endocriniennes rares de la croissance [CHU Pitié-Salpêtrière], Service d'endocrinologie et de la médecine reproductive [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Lariboisière-Université Paris Diderot - Paris 7 (UPD7), and Service de pharmacologie biologique [CHU Pitié-Salpâtrière]
Subjects: Adult, medicine.medical_specialty, Physiology, [SDV]Life Sciences [q-bio], Context (language use), Blood Pressure, 030204 cardiovascular system & hematology, Pulse Wave Analysis, Carotid Intima-Media Thickness, Microcirculation, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Internal Medicine, medicine, Humans, Congenital adrenal hyperplasia, 030212 general & internal medicine, Prospective Studies, Prospective cohort study, Child, Pulse wave velocity, biology, Adrenal Hyperplasia, Congenital, business.industry, 21-Hydroxylase, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, medicine.disease, 3. Good health, Blood pressure, biology.protein, Cardiology, Female, Cardiology and Cardiovascular Medicine, business, Rare disease
Abstract: International audience; CONTEXT:Controversial data exist on cardiovascular damages in patients with congenital adrenal hyperplasia (CAH).OBJECTIVE:To assess blood pressure and early cardiovascular damages on a large cohort of adult CAH patients and control individuals.DESIGN:Case-control study.SETTING:Referral Center for Rare Disease, Pitié Salpêtrière Hospital, Paris, France.PATIENTS OR OTHER PARTICIPANTS:Fifty-eight women and 26 men with CAH diagnosed in childhood and 85 controls matched-paired for sex, age and smoking status were prospectively included.INTERVENTION:Measurement of large arteries and microcirculatory anatomical and functional indices as well as hormonal status and cardiovascular risk factors evaluation.MAIN OUTCOME MEASURE:The primary objective was to compare carotid intima-media thickness (cIMT) in CAH patients and controls. The secondary objectives were to compare blood pressure (BP), radial augmentation index (rAI), central BP, carotid-femoral pulse wave velocity (PWV), skin microcirculation indices and inflammation parameters in CAH patients and controls.RESULTS:Although PWV and cIMT were identical in patients and controls, higher rAI (64.6 ± 1.7 vs. 59.9 ± 1.6%, P = 0.02) and higher central SBP (101.8 ± 1.5 vs. 95.1 ± 1.5 mmHg, P
Published: 2018
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32. Complex Association of Sex Hormones on Left Ventricular Systolic Function: Insight into Sexual Dimorphism

Author: Philippe Touraine, Sylvie Salenave, Jean-Sébastien Hulot, Anne Bachelot, Christian Funck-Brentano, Joe-Elie Salem, N. Bourcigaux, Philippe Chanson, Monique Leban, Michel Polak, Gisèle Preud’Homme, Juliane Léger, Richard Isnard, Jérôme Dulon, Nadjib Hammoudi, Nora Dahmoune, Sophie Christin Maitre, Lee S. Nguyen, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de pharmacologie médicale [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Cardiologie [CHU Pitié-Salpêtrière], Centre de Référence des Maladies Endocriniennes Rares de la Croissance [APHP Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Centre des Pathologies gynécologiques Rares [CHU Pitié-Salpêtrière], Institut E3M [CHU Pitié-Salpêtrière], Service d’endocrinologie et médecine de la reproduction [CHU Pitié-Salpêtrière], Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Gestionnaire, Hal Sorbonne Université, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Pharmacologie médicale [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Service d'Endocrinologie et Médecine de la Reproduction [CHU Pitié-Salpêtrière]
Subjects: Adult, Male, Cardiac function curve, medicine.medical_specialty, Systole, Physiology, Heart Ventricles, 030204 cardiovascular system & hematology, Ventricular Function, Left, 030218 nuclear medicine & medical imaging, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Sex hormone-binding globulin, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Interquartile range, Internal medicine, medicine, Humans, Radiology, Nuclear Medicine and imaging, Congenital adrenal hyperplasia, Sex hormones, Gonadal Steroid Hormones, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Ejection fraction, biology, business.industry, Stroke Volume, Stroke volume, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, medicine.disease, Ventricular functions, Healthy Volunteers, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Echocardiography, Heart failure, Cardiology, biology.protein, Female, Cardiology and Cardiovascular Medicine, business
Abstract: International audience; BACKGROUND: Normal values of left ventricular ejection fraction (LVEF) and absolute values of global longitudinal strain (GLS) are lower in men than in women. Data concerning the association of sex hormone levels on these left ventricular systolic function surrogates are scarce. The aim of this study was to determine the association of sex hormones with systolic left ventricular function in healthy subjects and patients with congenital adrenal hyperplasia (CAH) as a model of testosterone dysregulation.METHODS: Eighty-four adult patients with CAH (58 women; median age, 27 years; interquartile range, 23-36 years) and 84 healthy subjects matched for sex and age were prospectively included. Circulating concentrations of sex hormones were measured within 48 hours of echocardiography with assessment of LVEF and left ventricular longitudinal, radial, and circumferential strain.RESULTS: LVEF and GLS were higher in healthy women than in healthy men (63.9 ± 4.2% vs 60.9 ± 5.1% [P < .05] and 20.0 ± 1.9% vs 17.9 ± 2.4% [P < .001], respectively), while there was no difference in LVEF or GLS between women and men with CAH (63.9 ± 4.5% vs 63.0 ± 4.6% [P = NS] and 19.4 ± 2.2% vs 18.3 ± 1.8% [P = NS], respectively). Bioavailable testosterone levels were higher in women with CAH than in female control subjects (0.08 ng/mL [interquartile range, 0.04-0.14 ng/mL] vs 0.16 ng/mL [interquartile range, 0.04-0.3 ng/mL], P < .001) and lower in men with CAH than in male control subjects (2.3 ng/mL [interquartile range, 1.3-3 ng/mL] vs 2.9 ng/mL [interquartile range, 2.5-3.4 ng/mL], P < .05). In men, LVEF and GLS were negatively correlated with bioavailable testosterone levels (r = -0.3, P ≤ .05, and r = -0.45, P < .01, respectively), while midventricular radial strain was positively correlated with bioavailable testosterone level (r = 0.38, P < .05). The absolute value of circumferential strain was positively correlated with follicle-stimulating hormone (r = 0.65, P < .0001).CONCLUSIONS: These data support that the existence of sex dimorphism concerning left ventricular systolic cardiac function is significantly associated with testosterone levels.
Published: 2018
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33. A common African variant of human connexin 37 is associated with Caucasian primary ovarian insufficiency and has a deleterious effect in vitro

Author: Anne, Bachelot, Jerome, Gilleron, Geri, Meduri, Mihelai, Guberto, Jerome, Dulon, Sylviane, Boucherie, Philippe, Touraine, and Micheline, Misrahi
Subjects: Heterozygote, Black People, Cell Communication, Primary Ovarian Insufficiency, Caucasian, GJA4, confocal microscopy, Connexins, White People, Mice, Animals, Humans, Granulosa Cells, Cell Membrane, African, Gap Junctions, candidate gene, Articles, connexin 37, Rats, variant, Oocytes, Gap-fluorescence recovery after photobleaching, Female, mutation, primary ovarian failure, HeLa Cells
Abstract: Folliculogenesis requires communication between granulosa cells and oocytes, mediated by connexin-based gap junctions. Connexin 37 (Cx37)-deficient female mice are infertile. The present study assessed Cx37 deficiency in patients with primary ovarian insufficiency (POI). A candidate gene study was performed in patients and controls from the National Genotyping Center (Evry, France) including 58 Caucasian patients with idiopathic isolated POI and 142 Caucasian controls. Direct genomic sequencing of the coding regions of the GJA4 gene (encoding Cx37) was performed with the aim to identify a deleterious variant associated with POI and absent in ethnically matched controls. A single Cx37 variant absent in the control population was identified, namely a c.946G>A heterozygous substitution leading to a p.Gly316Ser variant that was present in two POI patients. This variant was absent in all Caucasian controls from various databases, and has been observed exclusively in African populations. This variant was identified to have a dominant negative effect in HeLa cells in vitro to alter connexon function (by 67.2±7.17%), as determined by Gap-fluorescence recovery after photobleaching. The alteration principally resulted from a decrease of cell surface connexons due to altered trafficking (by 47.73±8.59%). In marked contrast to this observation, a p.Pro258Ser variant frequent in all ethnic populations in databases had no functional effect in vitro. In conclusion, the present study reported on a Cx37 variant in two Caucasian POI patients, which was absent in control Caucasian populations, and which had a deleterious effect in vitro. It is therefore suggested that in the genetic context of the Caucasian population, this variant may contribute to POI.
Published: 2017

34. Monocentric study of 112 consecutive patients with childhood onset GH deficiency around and after transition

Author: Carine Courtillot, Roselyne Baudoin, Tatiana Du Souich, Lucile Saatdjian, Isabelle Tejedor, Graziella Pinto, Juliane Léger, Michel Polak, Jean-Louis Golmard, and Philippe Touraine
Subjects: Adult, Male, Aging, Pediatrics, medicine.medical_specialty, Adolescent, Bone density, Endocrinology, Diabetes and Metabolism, Pituitary Function Tests, Hypopituitarism, Cohort Studies, Young Adult, Absorptiometry, Photon, Endocrinology, Bone Density, Internal medicine, Humans, Medicine, Insulin-Like Growth Factor I, Young adult, Child, Retrospective Studies, Bone mineral, medicine.diagnostic_test, Human Growth Hormone, business.industry, Magnetic resonance imaging, Retrospective cohort study, General Medicine, Lipids, Recombinant Proteins, Discontinuation, Multivariate Analysis, Female, business, Lipid profile, Follow-Up Studies, Cohort study
Abstract: ObjectivesOur aim was to analyze a large cohort of childhood onset GH deficiency (CO-GHD) adults from a unique adult center, in order to analyze their clinical management and to study the metabolic and bone status in relation to GHD and to the other pituitary deficits, and to evaluate these parameters during the long-term follow-up.Design and methodsObservational retrospective cohort study on 112 consecutive CO-GHD adults transferred to our unit from 1st January 1994 to 1st March 2012. Evaluation of GHD in pediatrics and after transition was conducted following consensus guidelines. Data recorded from pediatric and adult files were GH doses, pituitary magnetic resonance imaging and function, and metabolic and bone status.ResultsMost patients presented with severe CO-GHD (64%) associated with other pituitary deficits (66%). CO-GHD was acquired in 56%, congenital in 33%, and idiopathic in 11% cases. Most patients (83%) stopped GH before transfer, at 16.3 years (median), despite persistence of GHD. Median age at transfer was 19.4 years. After transfer, GHD persisted in 101 patients and four of the 11 resolutive GHD were non idiopathic. IGF1 level was ConclusionsThis study raises concern about discontinuation of GH replacement therapy in pediatrics in severely persistent GHD patients and about the often insufficient dose of GH in the treatment of adult patients.
Published: 2013
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35. DNA Methylation Is an Independent Prognostic Marker of Survival in Adrenocortical Cancer

Author: Anne, Jouinot, Guillaume, Assie, Rossella, Libe, Martin, Fassnacht, Thomas, Papathomas, Olivia, Barreau, Bruno, de la Villeon, Simon, Faillot, Nadim, Hamzaoui, Mario, Neou, Karine, Perlemoine, Fernande, Rene-Corail, Stéphanie, Rodriguez, Mathilde, Sibony, Frédérique, Tissier, Bertrand, Dousset, Silviu, Sbiera, Cristina, Ronchi, Matthias, Kroiss, Esther, Korpershoek, Ronald, de Krijger, Jens, Waldmann, Detlef, K, Bartsch, Marcus, Quinkler, Magalie, Haissaguerre, Antoine, Tabarin, Olivier, Chabre, Nathalie, Sturm, Michaela, Luconi, Franco, Mantero, Massimo, Mannelli, Regis, Cohen, Véronique, Kerlan, Philippe, Touraine, Gaelle, Barrande, Lionel, Groussin, Xavier, Bertagna, Eric, Baudin, Laurence, Amar, Felix, Beuschlein, Eric, Clauser, Joel, Coste, Jérôme, Bertherat, Pathology, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5), CHU Cochin [AP-HP], Department of Psychiatry, Chirurgie digestive, hépato-biliaire et endocrinienne [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München (LMU), Comprehensive Cancer Center Mainfranken, Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU), Department of Pathology, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Clinical Genetics, Département d'endocrinologie - Bordeaux 2, Université Bordeaux Segalen - Bordeaux 2, Groupement Hospitalier Lyon-Est (GHE), Hospices Civils de Lyon (HCL), Laboratoire de Cytologie, Département d'Anatomie et de Cytologie Pathologiques, CHU Grenoble-Hôpital Michallon, Department of Endocrinology and Diabetes Mellitus, Hôpital Delafontaine, Service d'Endocrinologie (CHRU - Endocrino), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Groupe d'Etude de la Thrombose de Bretagne Occidentale (GETBO), Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Département d'endocrinologie et Médecine Reproductive [AP-HP Hôpital Pitié-Salpétrière], AP-HP Hôpital Universitaire Pitié Salpêtrière - GHU Pitié Salpêtrière, Centre Hospitalier Régional d'Orléans (CHR), Médecine nucléaire, Département d'imagerie médicale [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Université de Brest (UBO)-Université de Brest (UBO), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Régional d'Orléans (CHRO), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)
Subjects: 0301 basic medicine, Male, [SDV]Life Sciences [q-bio], Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, medical, Biochemistry, 0302 clinical medicine, Endocrinology, Adrenocortical Carcinoma, Methylation, DNA, Neoplasm, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Middle Aged, Prognosis, 3. Good health, Tumor Burden, Diabetes and Metabolism, Survival Rate, CpG site, 030220 oncology & carcinogenesis, Cohort, DNA methylation, Female, Adult, medicine.medical_specialty, Context (language use), Biology, Disease-Free Survival, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Journal Article, Humans, Survival rate, Aged, Neoplasm Staging, Proportional Hazards Models, Retrospective Studies, Biochemistry, medical, Proportional hazards model, Biochemistry (medical), Retrospective cohort study, DNA Methylation, Adrenal Cortex Neoplasms, 030104 developmental biology, Ki-67 Antigen, Multivariate Analysis, CpG Islands, Multiplex Polymerase Chain Reaction, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Context:Adrenocortical cancer (ACC) is an aggressive tumor with a heterogeneous outcome. Prognostic stratification is difficult even based on tumor stage and Ki67. Recently integrated genomics studies have demonstrated that CpG islands hypermethylation is correlated with poor survival.Objective:The goal of this study was to confirm the prognostic value of CpG islands methylation on an independent cohort.Design:Methylation was measured by methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA).Setting:MS-MLPA was performed in a training cohort of 50 patients with ACC to identify the best set of probes correlating with disease-free survival (DFS) and overall survival (OS). These outcomes were validated in an independent cohort from 21 ENSAT centers.Patients:The validation cohort included 203 patients (64% women, median age 50 years, 80% localized tumors).Main Outcome Measures:DFS and OS.Results:In the training cohort, mean methylation of 4 genes (PAX5, GSTP1, PYCARD, PAX6) was the strongest methylation marker. In the validation cohort, methylation was a significant prognostic factor of DFS (P < 0.0001) and OS (P < 0.0001). Methylation, Ki67, and ENSAT stage were combined in multivariate models. For DFS, methylation (P = 0.0005) and stage (P < 0.0001) but not Ki67 (P = 0.19) remained highly significant. For OS, methylation (P = 0.0006), stage (P < 0.0001), and Ki67 (P = 0.024) were independent prognostic factors.Conclusions:Tumor DNA methylation emerges as an independent prognostic factor in ACC. MS-MLPA is readily compatible with clinical routine and should enhance our ability for prognostication and precision medicine.
Published: 2017
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36. Contribution of LHX4 Mutations to Pituitary Deficits in a Cohort of 417 Unrelated Patients

Author: Michel Polak, Enzo Cohen, Sophie Rose, Frédéric Brioude, Nathalie Collot, Daniela Larizza, Marie Legendre, Florence Dastot, Juliane Léger, Anne Marie Bertrand, Philippe Duquesnoy, Marie Laure Sobrier, Philippe Touraine, Mohamad Maghnie, Bruno Copin, Maïté Tauber, Irène Netchine, Serge Amselem, Isabelle Oliver-Petit, Laura González Briceño, Thomas Edouard, Physiopathologie des maladies génétiques d'expression pédiatrique, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Università degli studi di Genova = University of Genoa (UniGe), Service de génétique et embryologie médicales [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Référence des Maladies Endocriniennes Rares de la Croissance [APHP Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Service d'endocrinologie, gynécologie et diabétologie pédiatriques [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Chirurgie Digestive et Endocrinienne [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Service de Diabétologie - Endocrinologie [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Service d'explorations fonctionnelles [CHU Trousseau], Fondazione IRCCS Policlinico San Matteo [Pavia], Università degli Studi di Pavia = University of Pavia (UNIPV), Couvet, Sandrine, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], and Societe Francaise d'Endocrinologie et Diabetologie PediatriqueFondation pour la Recherche Medicale PLP20131028838
Subjects: 0301 basic medicine, Male, Pituitary gland, MESH: Sequence Homology, Amino Acid, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Clinical Biochemistry, Sequence Homology, Hypopituitarism, MESH: Amino Acid Sequence, medicine.disease_cause, MESH: Hypopituitarism, Biochemistry, Cohort Studies, 0302 clinical medicine, Endocrinology, MESH: Child, Child, MESH: Cohort Studies, Genetics, Sanger sequencing, Mutation, Blotting, MESH: Infant, Newborn, MESH: Transcription Factors, MESH: Follow-Up Studies, Prognosis, MESH: Infant, Ectopic Posterior Pituitary, Pedigree, Diabetes and Metabolism, [SDV] Life Sciences [q-bio], Amino Acid, medicine.anatomical_structure, Sella turcica, Child, Preschool, symbols, Female, Western, medicine.medical_specialty, MESH: Mutation, Adolescent, MESH: Pedigree, Blotting, Western, LIM-Homeodomain Proteins, 030209 endocrinology & metabolism, Context (language use), Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, MESH: Prognosis, 03 medical and health sciences, symbols.namesake, Internal medicine, medicine, Humans, Immunoprecipitation, MESH: Blotting, Western, Amino Acid Sequence, Preschool, Biomarkers, Follow-Up Studies, Infant, Infant, Newborn, Sequence Homology, Amino Acid, Transcription Factors, Biochemistry (medical), MESH: Adolescent, MESH: LIM-Homeodomain Proteins, MESH: Humans, MESH: Immunoprecipitation, MESH: Child, Preschool, Heterozygote advantage, medicine.disease, Newborn, MESH: Male, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, MESH: Biomarkers, MESH: Female
Abstract: Context:LHX4 encodes a LIM-homeodomain transcription factor that is implicated in early pituitary development. In humans, only 13 heterozygous LHX4 mutations have been associated with congenital hypopituitarism.Objective:The aims of this study were to evaluate the prevalence of LHX4 mutations in patients with hypopituitarism, to define the associated phenotypes, and to characterize the functional impact of the identified variants and the respective role of the 2 LIM domains of LHX4.Design and Patients:We screened 417 unrelated patients with isolated growth hormone deficiency or combined pituitary hormone deficiency associated with ectopic posterior pituitary and/or sella turcica anomalies for LHX4 mutations (Sanger sequencing). In vitro studies were performed to assess the functional consequences of the identified variants.Results:We identified 7 heterozygous variations, including p.(Tyr131*), p.(Arg48Thrfs*104), c.606+1G>T, p.Arg65Val, p.Thr163Pro, p.Arg221Gln, and p.Arg235Gln), that were associated with variable expressivity; 5 of the 7 were also associated with incomplete penetrance. The p.(Tyr131*), p.(Arg48Thrfs*104), p.Ala65Val, p.Thr163Pro, and p.Arg221Gln LHX4 variants are unable to transactivate the POU1F1 and GH promoters. As suggested by transactivation, subcellular localization, and protein-protein interaction studies, p.Arg235Gln is probably a rare polymorphism. Coimmunoprecipitation studies identified LHX3 as a potential protein partner of LHX4. As revealed by functional studies of LIM-defective recombinant LHX4 proteins, the LIM1 and LIM2 domains are not redundant.Conclusion:This study, performed in the largest cohort of patients screened so far for LHX4 mutations, describes 6 disease-causing mutations that are responsible for congenital hypopituitarism. LHX4 mutations were found to be associated with variable expressivity, and most of them with incomplete penetrance; their contribution to pituitary deficits that are associated with an ectopic posterior pituitary and/or a sella turcica defect is ∼1.4% in the 417 probands tested.
Published: 2017
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37. French law: what about a reasoned reimbursement of serum vitamin D assays?

Author: Jean-Claude Souberbielle, Claude Laurent Benhamou, Bernard Cortet, Mickael Rousière, Christian Roux, Vered Abitbol, Cédric Annweiler, Maurice Audran, Justine Bacchetta, Pierre Bataille, Olivier Beauchet, Rémi Bardet, Alexandra Benachi, Francis Berenbaum, Hubert Blain, Françoise Borson-Chazot, Véronique Breuil, Karine Briot, Philippe Brunet, Jean-Claude Carel, Philippe Caron, Olivier Chabre, Philippe Chanson, Roland Chapurlat, Pierre Cochat, Régis Coutant, Sophie Christin-Maitre, Martine Cohen-Solal, Christian Combe, Catherine Cormier, Marie Courbebaisse, Grégory Debrus, Brigitte Delemer, Georges Deschenes, Marc Duquenne, Guillaume Duval, Patrice Fardellone, Denis Fouque, Gérard Friedlander, Jean-Bernard Gauvain, Lionel Groussin, Pascal Guggenbuhl, Pascal Houillier, Thierry Hannedouche, William Jacot, Rose-Marie Javier, Guillaume Jean, Claude Jeandel, Dominique Joly, Peter Kamenicky, Bertrand Knebelmann, Marie-Hélène Lafage-Proust, Yves LeBouc, Erick Legrand, Florence Levy-Weil, Agnès Linglart, Laurent Machet, Emmanuel Maheu, Eric Mallet, Christian Marcelli, Pierre Marès, Christophe Mariat, Gérard Maruani, Yves Maugars, France Montagnon, Bruno Moulin, Philippe Orcel, Henri Partouche, Virginie Personne, Charles Pierrot-Deseilligny, Michel Polak, Claire Pouteil-Noble, Dominique Prié, Agathe Raynaud-Simon, Yves Rolland, Jean-Louis Sadoul, Bernard Salle, Corinne Sault, Anne-Marie Schott, Isabelle Sermet-Gaudelus, Martin Soubrier, Ivan Tack, Eric Thervet, Isabelle Tostivint, Philippe Touraine, Florence Tremollières, Pablo Urena-Torres, Jean-Paul Viard, Jean-Louis Wemeau, Georges Weryha, Norbert Winer, Jacques Young, Thierry Thomas, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire d'Informatique de Nantes Atlantique (LINA), Mines Nantes (Mines Nantes)-Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS), Service de rhumatologie[Lille], Hôpital Roger Salengro [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Laboratoire d'aérologie (LAERO), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Observatoire Midi-Pyrénées (OMP), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Centre National de la Recherche Scientifique (CNRS), Laboratoire des Matériels Électriques (EDF R&D LME), EDF R&D (EDF R&D), EDF (EDF)-EDF (EDF), Centre d'Analyse et d'Intervention Sociologiques (CADIS), École des hautes études en sciences sociales (EHESS)-Centre National de la Recherche Scientifique (CNRS), Département de Médecine Interne et Gérontologie clinique, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Service de gynécologie-obstétrique, médecine de la reproduction [Béclère], Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Antoine Béclère [Clamart], Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Department of Geriatrics - Efficiency and Deficiency Laboratory, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de rhumatologie, Centre Hospitalier Universitaire de Nice (CHU Nice)-Hôpital l'Archet, Vascular research center of Marseille (VRCM), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Trigone-CIREL, Centre Interuniversitaire de Recherche en Education de Lille - ULR 4354 (CIREL), Université de Lille-Université de Lille, Signalisation Hormonale, Physiopathologie Endocrinienne et Métabolique, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Service de rhumatologie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Biologie de l'Os et du Cartilage : Régulations et Ciblages Thérapeutiques (BIOSCAR (UMR_S_1132 / U1132)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Rhumatologie [CHU Lariboisière], Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Unité Expérimentale Recherches Intégrées - Gotheron (UERI), Institut National de la Recherche Agronomique (INRA), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de Néphrologie Pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Université de Bordeaux (UB), Mécanismes physiopathologiques et conséquences des calcifications vasculaires - UR UPJV 7517 (MP3CV), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, Motricité - Plasticité, Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Centre de recherche sur le développement territorial (CRDT), Centre de recherche sur le développement territorial, CHU Pontchaillou [Rennes], Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut Pascal (IP), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-SIGMA Clermont (SIGMA Clermont)-Centre National de la Recherche Scientifique (CNRS), Service de rhumatologie [Nantes], Université de Nantes (UN)-Hôtel-Dieu-Centre hospitalier universitaire de Nantes (CHU Nantes), Information – Technologies – Analyse Environnementale – Procédés Agricoles (UMR ITAP), Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Centre de Physique Théorique [Palaiseau] (CPHT), École polytechnique (X)-Centre National de la Recherche Scientifique (CNRS), Département de Médecine Générale, Université Paris Descartes - Paris 5 (UPD5), CHU Pitié-Salpêtrière [AP-HP], Service de néphrologie et transplantation, Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Centre de recherche Croissance et signalisation (UMR_S 845), Service d'Endocrinologie (NICE - Endocrino), Centre Hospitalier Universitaire de Nice (CHU Nice), CIC Cochin Pasteur (CIC 1417), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôtel-Dieu-Université Paris Descartes - Paris 5 (UPD5)-Groupe hospitalier Broca-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand, CPMF2 - Flemish Cluster Predictive Microbiology in Foods - www.cpmf2.be BioTeC - Chemical and Biochemical Process Technology and Control Department of Chemical Engineering, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Université Pierre et Marie Curie - Paris 6 (UPMC), Centre de ménopause, Centre de Diagnostic et de Thérapeutique, Hôpital de l’Hôtel-Dieu [Paris], Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Service d'Endocrinologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service d'obstétrique-gynécologie [Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Institut für Kernphysik der Universität zu Köln, Universität zu Köln = University of Cologne, Centre National de la Recherche Scientifique (CNRS)-Mines Nantes (Mines Nantes)-Université de Nantes (UN), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Observatoire Midi-Pyrénées (OMP), Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS), Service de rhumatologie [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Eq 4, Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Groupement Hospitalier Lyon-Est (GHE), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL)-Centre de médecine nucléaire, Fédération d'endocrinologie-Groupement hospitalier Lyon-Est-Fédération d'endocrinologie-Groupement hospitalier Lyon-Est, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Centre National de la Recherche Scientifique (CNRS)-École polytechnique (X), Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre des Pathologies gynécologiques Rares [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut E3M [CHU Pitié-Salpêtrière], Hôpital Paule de Viguier, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Universität zu Köln, Hôpital Roger Salengro-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Laboratoire d'aérologie (LA), Centre National de la Recherche Scientifique (CNRS)-Observatoire Midi-Pyrénées (OMP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Antoine Béclère, Centre de Recherche Saint-Antoine (CR Saint-Antoine), Service de rhumatologie, inflammation-immunopathologie- biothérapie [CHU Saint-Antoine] (DHU i2B ), CHU Saint-Antoine [APHP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Groupement Hospitalier Lyon-Est (GHE), Centre Interuniversitaire de Recherche en Education de Lille (CIREL) - EA 4354 (CIREL), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP], Hôpital Lariboisière, Unité de Recherches Intégrées - Gotheron (GOTH RI UERI), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré, Laboratoire de génie chimique [ancien site de Basso-Cambo] (LGC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Sigma CLERMONT (Sigma CLERMONT)-Centre National de la Recherche Scientifique (CNRS), Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Lariboisière, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP]-Hôtel-Dieu-Université Paris Descartes - Paris 5 (UPD5)-Groupe hospitalier Broca-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Gabriel Montpied (CHU), CHU Pitié-Salpêtrière [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Institut für Kernphysik - Universität zu Köln, Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Université Fédérale Toulouse Midi-Pyrénées-Météo-France -Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Centre National de la Recherche Scientifique (CNRS), Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], AP-HP - Hôpital Antoine Béclère [Clamart], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11), Laboratoire d'Informatique de Nantes Atlantique ( LINA ), Centre National de la Recherche Scientifique ( CNRS ) -Mines Nantes ( Mines Nantes ) -Université de Nantes ( UN ), Hôpital Roger Salengro-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Laboratoire d'aérologie - LA ( LA ), Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut national des sciences de l'Univers ( INSU - CNRS ) -Observatoire Midi-Pyrénées ( OMP ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire des Matériels Électriques ( EDF R&D LME ), EDF R&D ( EDF R&D ), EDF ( EDF ) -EDF ( EDF ), Centre d'Analyse et d'Intervention Sociologiques ( CADIS ), École des hautes études en sciences sociales ( EHESS ) -Centre National de la Recherche Scientifique ( CNRS ), CHU Angers, Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Antoine Béclère, Centre de Recherche Saint-Antoine ( CR Saint-Antoine ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), Service de rhumatologie, inflammation-immunopathologie- biothérapie [CHU Saint-Antoine] ( DHU i2B ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Saint-Antoine [APHP], Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ), Centre de Recherche en Cancérologie de Lyon ( CRCL ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Groupement Hospitalier Lyon-Est ( GHE ), Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ) -Centre de médecine nucléaire, CHU Nice-Hôpital l'Archet, Vascular research center of Marseille ( VRCM ), Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Interuniversitaire de Recherche en Education de Lille (CIREL) - EA 4354 ( CIREL ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP], Biologie de l'Os et du Cartilage : Régulations et Ciblages Thérapeutiques ( BIOSCAR ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Lariboisière-Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Unité de Recherches Intégrées - Gotheron ( GOTH RI UERI ), Institut National de la Recherche Agronomique ( INRA ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré, Laboratoire de génie chimique ( LGC ), Institut National Polytechnique [Toulouse] ( INP ) -Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique ( CNRS ), Université de Bordeaux ( UB ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Necker Enfants-Malades (INEM) ( INEM - UM 111 (UMR 8253 / U1151) ), Centre de recherche sur le développement territorial ( CRDT ), Institut Pascal ( IP ), Université Blaise Pascal - Clermont-Ferrand 2 ( UBP ) -Sigma CLERMONT ( Sigma CLERMONT ) -Centre National de la Recherche Scientifique ( CNRS ), Université de Nantes ( UN ) -Hôtel-Dieu-Centre hospitalier universitaire de Nantes ( CHU Nantes ), Information – Technologies – Analyse Environnementale – Procédés Agricoles ( UMR ITAP ), Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture ( IRSTEA ) -Institut national d’études supérieures agronomiques de Montpellier ( Montpellier SupAgro ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Lariboisière, Centre de Physique Théorique [Palaiseau] ( CPHT ), École polytechnique ( X ) -Centre National de la Recherche Scientifique ( CNRS ), Université Paris Descartes - Paris 5 ( UPD5 ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Université de Lyon-Université de Lyon-Hospices Civils de Lyon ( HCL ) -Centre Hospitalier Lyon Sud [CHU - HCL] ( CHLS ), Hospices Civils de Lyon ( HCL ), Centre de recherche Croissance et signalisation ( UMR_S 845 ), Service d'Endocrinologie ( NICE - Endocrino ), CHU Nice, CIC Cochin Pasteur ( CIC 1417 ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP]-Hôtel-Dieu-Université Paris Descartes - Paris 5 ( UPD5 ) -Groupe hospitalier Broca-Institut National de la Santé et de la Recherche Médicale ( INSERM ), CHU Gabriel Montpied ( CHU ), Katholieke Universiteit Leuven ( KU Leuven ), Université Pierre et Marie Curie - Paris 6 ( UPMC ), Assistance publique - Hôpitaux de Paris (AP-HP), Université Paris Descartes - Faculté de Médecine ( UPD5 Médecine ), Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Centre hospitalier universitaire de Nantes ( CHU Nantes ), and CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, recommendation, Pediatrics, medicine.medical_specialty, Malabsorption, Legislation, Medical, [SDV]Life Sciences [q-bio], Osteoporosis, 030209 endocrinology & metabolism, Rickets, vitamin D, osteomalacia, vitamin D deficiency, 03 medical and health sciences, 0302 clinical medicine, rickets, medicine, Vitamin D and neurology, Humans, 030212 general & internal medicine, Biological Psychiatry, Reimbursement, Aged, Aged, 80 and over, Osteomalacia, Hematologic Tests, [ SDV ] Life Sciences [q-bio], business.industry, Hydroxycholecalciferols, assay, medicine.disease, Obesity, reimbursement, osteoporosis, 3. Good health, Surgery, clinical practice, Neuropsychology and Physiological Psychology, Insurance, Health, Reimbursement, Female, Neurology (clinical), France, Geriatrics and Gerontology, business, calcium phosphorus evaluation, chronic kidney disease
Abstract: International audience; The number of serum 25-hydroxyvitamin D (25OHD) assays has increased tenfold in France in less than 10 years, sometimes for invalidated reasons. In 2013, the French National Authority for Health (Haute autorité de santé, or HAS) limited the indications for serum 25OHD measurements to rickets/osteomalacia, older adults with recurrent falls, monitoring of kidney transplant in adults, and surgical treatment of obesity in adults. Our aim here was to note that other indications for serum 25OHD measurements are supported by previous literature and by a number of national and international recommendations, in particular the following: any situation of bone fragility, any chronic renal failure
Published: 2016
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38. Poor Compliance to Hormone Therapy and Decreased Bone Mineral Density in Women with Premature Ovarian Insufficiency

Author: Jérôme Dulon, Monique Leban, Carole Nicolas, Philippe Touraine, Jean Louis Golmard, Anne Bachelot, Solenne Gricourt, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC), Centre d'investigation clinique Paris Est [CHU Pitié Salpêtrière] (CIC Paris-Est), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Institut E3M [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de biochimie et hormonologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de recherche clinique [CHU Pitié-Salpêtrière], and Service de Biochimie Endocrinienne et Oncologie [CHU Pitié-Salpêtrière]
Subjects: Bone density, Physiology, medicine.medical_treatment, Osteopenia and Osteoporosis, Osteoporosis, Menopause, Premature, lcsh:Medicine, Turner Syndrome, Primary Ovarian Insufficiency, Chromosomal Disorders, Endocrinology, 0302 clinical medicine, Bone Density, Medicine and Health Sciences, lcsh:Science, Connective Tissue Diseases, Osteoporosis, Postmenopausal, Univariate analysis, 030219 obstetrics & reproductive medicine, Multidisciplinary, Pharmaceutics, Estrogen Replacement Therapy, Hormonal Therapy, 3. Good health, Menopause, Connective Tissue, Transgender hormone therapy, Female, Anatomy, Research Article, Adult, medicine.medical_specialty, Hormone Replacement Therapy, 030209 endocrinology & metabolism, Premature ovarian insufficiency, 03 medical and health sciences, Rheumatology, Drug Therapy, Internal medicine, medicine, Humans, Bone, Clinical Genetics, Gynecology, Endocrine Physiology, business.industry, lcsh:R, Biology and Life Sciences, medicine.disease, Osteopenia, Biological Tissue, Women's Health, lcsh:Q, Hormone therapy, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Follow-Up Studies
Abstract: International audience; Premature ovarian insufficiency leads to through infertility and estrogen deficiency. Optimal management encompasses estrogen replacement therapy. Long-term outcome of women with POI is not known. We design a study to evaluate the medical care, hormone replacement therapy compliance and bone mineral density (BMD) in POI women with at least a five-year follow-up after the first evaluation. One hundred and sixty-two patients (37.3±8.0 years) were evaluated (follow-up 7.9±2.8 years). Sixty-nine patients (42.6%) had stopped their hormone replacement therapy (HRT) for at least one year during the follow up period. BMD determination at initial evaluation and at follow-up visit was completed in 92 patients. At first evaluation, 28 patients (30%) had osteopenia and 7 (8%) had osteoporosis. At follow up, 31 women (34%) had BMD impairment with osteopenia in 61% and osteoporosis in 5%. In univariate analysis and multivariate analysis, there was a significant loss of femoral BMD in women who had stopped their HRT for over a year. In conclusion, this first study concerning long-term follow-up of POI patients shows the poor compliance to their HRT, despite its importance in the prevention of bone demineralization. This study reinforces the need for follow up and specific care for POI women.
Published: 2016
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39. MCM8 and MCM9 Nucleotide Variants in Women With Primary Ovarian Insufficiency

Author: Jelena Matic, Michelle A. Wood-Trageser, Massimiliano Cocca, Selma F. Witchel, Huaiyang Jiang, Caterina Barbieri, Jérôme Dulon, Anne Bachelot, Swapna S. Desai, Philippe Touraine, Jaqueline Chipkin, Aleksandar Rajkovic, Daniela Toniolo, Cinzia Sala, Desai, Swapna, Wood Trageser, Michelle, Matic, Jelena, Chipkin, Jaqueline, Jiang, Huaiyang, Bachelot, Anne, Dulon, Jerome, Sala, Cinzia, Barbieri, CATERINA MARIA, Cocca, Massimiliano, Toniolo, Daniela, Touraine, Philippe, Witchel, Selma, and Rajkovic, Aleksandar
Subjects: 0301 basic medicine, Endocrinology, Diabetes and Metabolism, Biochemistry, Endocrinology, Clinical Biochemistry, Biochemistry (medical), Adult, medicine.medical_specialty, Aging, DNA Repair, DNA repair, DNA damage, Biology, Primary Ovarian Insufficiency, Bioinformatics, 03 medical and health sciences, Exon, Follicle-stimulating hormone, Internal medicine, medicine, Humans, Nucleotide, Gene, Clinical Research Articles, chemistry.chemical_classification, Genetics, MCM8, Minichromosome Maintenance Proteins, Heterozygote advantage, Sequence Analysis, DNA, Diabetes and Metabolism, 030104 developmental biology, chemistry, Female, DNA Damage
Abstract: OBJECTIVE: To assess the frequency of variants, including biallelic pathogenic variants, in MCM8 and MCM9, other genes related to MCM8/9 and DNA damage repair (DDR) pathway in participants with primary ovarian insufficiency (POI). DESIGN: MCM8, MCM9 and genes encoding DDR proteins that have been implicated in reproductive aging were sequenced among POI participants. SETTING: Academic research institution Participants: All were diagnosed with POI prior to the age of 40 and presented with elevated FSH levels. INTERVENTIONS: None Main Outcome Measures: We identified nucleotide variants in MCM8, MCM9, and genes thought to be involved in the DNA damage response pathway and/or implicated in reproductive aging. RESULTS: MCM8 was sequenced in 155 POI participants, while MCM9 was sequenced in 151 participants. Three out of 155 (2%) participants carried possibly damaging heterozygous variants in MCM8, while 7 of 151 (5%) individuals carried possibly damaging heterozygous variants in MCM9. One participant carried a novel homozygous variant, c.1651C>T, p.Gln551* in MCM9 which is predicted to introduce a premature stop codon in exon 9. Biallelic damaging heterozygous variants in both MCM8 and MCM9 were identified in one participant. Out of a total of 10 participants carrying damaging heterozygous variants in either MCM8 or MCM9, two individuals carried heterozygous damaging variants in genes associated with either MCM8-MCM9 or DDR pathway Conclusions: We identified a significant number of potentially damaging and novel variants in MCM8 and MCM9 among participants with POI, and examined multi-allelic association with variants in DDR and MCM8/MCM9 interactome genes.
Published: 2016

40. MRI follow-up is unnecessary in patients with macroprolactinomas and long-term normal prolactin levels on dopamine agonist treatment

Author: Thomas Cuny, Thierry Brue, Isabelle Tejedor, Georges Weryha, Albert Beckers, Philippe Touraine, J F Bonneville, Henry Dufour, Iulia Potorac, Juliette Eroukhmanoff, Frederic Castinetti, Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Service d'Endocrinologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Science et Ingénierie des Matériaux et Procédés (SIMaP ), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Centre de recherche en neurobiologie - neurophysiologie de Marseille (CRN2M), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), centre hospitalier universitaire de liège, and Service d'endocrinologie clinique
Subjects: Adult, Male, medicine.medical_specialty, Cabergoline, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], 030209 endocrinology & metabolism, Asymptomatic, Dopamine agonist, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Belgium, Dopamine, Internal medicine, medicine, Humans, Pituitary Neoplasms, Prolactinoma, 030212 general & internal medicine, Macroprolactinoma, Ergolines, Bromocriptine, Retrospective Studies, medicine.diagnostic_test, business.industry, Magnetic resonance imaging, General Medicine, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Prolactin, 3. Good health, Dopamine Agonists, Aminoquinolines, Female, France, medicine.symptom, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, medicine.drug, Follow-Up Studies
Abstract: Objective Both antitumor and antisecretory efficacies of dopamine agonists (DA) make them the first-line treatment of macroprolactinomas. However, there is no guideline for MRI follow-up once prolactin is controlled. The aim of our study was to determine whether a regular MRI follow-up was necessary in patients with long-term normal prolactin levels under DA. Patients and methods We conducted a retrospective multicenter study (Marseille, Paris La Pitie Salpetriere and Nancy, France; Liege, Belgium) including patients with macroprolactinomas (largest diameter: >10 mm and baseline prolactin level: >100 ng/mL) treated by dopamine agonists, and regularly followed (pituitary MRI and prolactin levels) during at least 48 months once normal prolactin level was obtained. Results In total, 115 patients were included (63 men and 52 women; mean age at diagnosis: 36.3 years). Mean baseline prolactin level was 2224 ± 6839 ng/mL. No significant increase of tumor volume was observed during the follow-up. Of the 21 patients (18%) who presented asymptomatic hemorrhagic changes of the macroprolactinoma on MRI, 2 had a tumor increase (2 and 7 mm in the largest size). Both were treated by cabergoline (1 mg/week) with normal prolactin levels obtained for 6 and 24 months. For both patients, no further growth was observed on MRI during follow-up at the same dose of cabergoline. Conclusion No significant increase of tumor size was observed in our patients with controlled prolactin levels on DA. MRI follow-up thus appears unnecessary in patients with biologically controlled macroprolactinomas.
Published: 2016
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41. Premature Ovarian Insufficiency: New Perspectives on Genetic Cause and Phenotypic Spectrum

Author: Anne Bachelot, Andrew H. Sinclair, Elena J. Tucker, Philippe Touraine, and Sonia Grover
Subjects: 0301 basic medicine, Genetics, 030219 obstetrics & reproductive medicine, Endocrinology, Diabetes and Metabolism, Female infertility, Disease mechanisms, Personalized treatment, Anti-Müllerian hormone, Biology, Primary Ovarian Insufficiency, Bioinformatics, medicine.disease, Premature ovarian insufficiency, Phenotype, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Endocrinology, Low estradiol, medicine, biology.protein, Animals, Humans, Identification (biology), Female
Abstract: Premature ovarian insufficiency (POI) is one form of female infertility, defined by loss of ovarian activity before the age of 40 and characterized by amenorrhea (primary or secondary) with raised gonadotropins and low estradiol. POI affects up to one in 100 females, including one in 1000 before the age of 30. Substantial evidence suggests a genetic basis for POI; however, the majority of cases remain unexplained, indicating that genes likely to be associated with this condition are yet to be discovered. This review discusses the current knowledge of the genetic basis of POI. We highlight genes typically known to cause syndromic POI that can be responsible for isolated POI. The role of mouse models in understanding POI pathogenesis is discussed, and a thorough list of candidate POI genes is provided. Identifying a genetic basis for POI has multiple advantages, such as enabling the identification of presymptomatic family members who can be offered counseling and cryopreservation of eggs before depletion, enabling personalized treatment based on the cause of an individual's condition, and providing better understanding of disease mechanisms that ultimately aid the development of improved treatments.
Published: 2016

42. An Application of NGS for Molecular Investigations in Perrault Syndrome: Study of 14 Families and Review of the Literature

Author: Justine, Lerat, Laurence, Jonard, Natalie, Loundon, Sophie, Christin-Maitre, Didier, Lacombe, Cyril, Goizet, Cécile, Rouzier, Lionel, Van Maldergem, Souad, Gherbi, Eréa-Nöel, Garabedian, Jean-Paul, Bonnefont, Philippe, Touraine, Isabelle, Mosnier, Arnold, Munnich, Françoise, Denoyelle, and Sandrine, Marlin
Subjects: Adolescent, Hearing Loss, Sensorineural, DNA Helicases, Mutation, Missense, High-Throughput Nucleotide Sequencing, Infant, Endopeptidase Clp, Sequence Analysis, DNA, Gonadal Dysgenesis, 46,XX, Pedigree, Amino Acyl-tRNA Synthetases, Mitochondrial Proteins, Child, Preschool, Humans, Exome, Female, Genetic Predisposition to Disease, Child, Peroxisomal Multifunctional Protein-2
Abstract: Perrault syndrome (PS) is a rare autosomal recessive condition characterized by deafness and gonadic dysgenesis. Recently, mutations in five genes have been identified: C10orf2, CLPP, HARS2, HSD17B4, and LARS2. Probands included are presented with sensorineural deafness associated with gonadic dysgenesis. DNA was sequenced using next-generation sequencing (NGS) with a panel of 35 deafness genes including the five Perrault genes. Exonic variations known as pathogenic mutations or detected with1% frequency in public databases were extracted and subjected to segregation analysis within each family. Both mutations and low coverage regions were analyzed by Sanger sequencing. Fourteen female index patients were included. The screening in four cases has been extended to four family members presenting with PS phenotype. For four unrelated patients (28.6%), causative mutations were identified: three homozygous mutations in C10orf2, CLPP, and HARS2, and one compound heterozygous mutation in LARS2. Three additional heterozygous mutations in LARS2 and HSD17B4 were found in three independent familial cases. All these missense mutations were verified by Sanger sequencing. Familial segregation analyses confirmed the molecular diagnosis in all cases carrying biallelic mutations. Because of NGS, molecular analysis confirmed the clinical diagnosis of PS in 28.6% of our cohort and four novel mutations were found in four Perrault genes. For the unsolved cases, exome sequencing should be performed to search for a sixth unknown PS gene.
Published: 2016

43. Complex Influence of Gonadotropins and Sex Steroid Hormones on QT Interval Duration

Author: Philippe Touraine, Martine Lebot, Anne Bachelot, Christian Funck-Brentano, Fabio Badilini, Clement Favet, Joe-Elie Salem, Laurence Koehl, Guillaume Abehsira, Service de pharmacologie médicale [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CIC Paris Est, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Service de Cardiologie [CHU Pitié-Salpêtrière], Service d’Endocrinologie, Métabolisme et Prévention des Risques Cardio-Vasculaires [CHU Pitié-Salpêtrière], Centre de Référence des Maladies Endocriniennes Rares de la Croissance [APHP Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Centre des Pathologies gynécologiques Rares [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), AMPS, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre d'investigation clinique Paris Est [CHU Pitié Salpêtrière] (CIC Paris-Est), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), HAL-UPMC, Gestionnaire, Service de Pharmacologie médicale [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre d'investigation clinique pluridisciplinaire [CHU Pitié Salpêtrière] (CIC-P 1421), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], and Service d'Endocrinologie, Métabolisme et Prévention des Maladies Cardio-vasculaires [CHU Pitié-Salpêtrière]
Subjects: Adult, Male, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, 030204 cardiovascular system & hematology, Biochemistry, QT interval, 03 medical and health sciences, Electrocardiography, 0302 clinical medicine, Endocrinology, Heart Rate, Internal medicine, medicine, Humans, Congenital adrenal hyperplasia, Testosterone, 030212 general & internal medicine, Gonadal Steroid Hormones, QT interval duration, Progesterone, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Sex Steroid Hormones, Free testosterone, Adrenal Hyperplasia, Congenital, Estradiol, business.industry, Biochemistry (medical), Healthy subjects, Case-control study, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Luteinizing Hormone, medicine.disease, 3. Good health, Case-Control Studies, Female, Follicle Stimulating Hormone, business, Gonadotropins
Abstract: International audience; QT interval duration is longer in women than in men. Sex steroid hormones have inconsistently been suggested to explain this difference. Implication of gonadotropins has never been studied.Objective:We here report the combined influence of sex steroid hormones and gonadotropins on QT interval duration in healthy subjects and patients with congenital adrenal hyperplasia (CAH) as a model of testosterone and progesterone overexpression.Design:Patients. Eighty four CAH patients (58 women) and 84 healthy subjects matched-paired for sex and age were prospectively included. Circulating concentrations of 17-OH-progesterone, progesterone, testosterone, estradiol, FSH and LH, were measured concomitantly to recording of a digitized electrocardiogram.Results:QTcFridericia(QTcF) was shorter in women with CAH than in control women (404±2 msec vs. 413±2.1 msec, p≤0.001). 17-OH-progesterone, progesterone, progesterone/estradiol ratio and total testosterone were higher in women with CAH than in women controls (p
Published: 2016
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44. Impact of clinical, hormonal, radiological, and immunohistochemical studies on the diagnosis of postmenopausal hyperandrogenism

Author: Julie Sarfati, Philippe Touraine, Anne Bachelot, Christiane Coussieu, and Geri Meduri
Subjects: medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Urology, Basal (phylogenetics), Endocrinology, Internal medicine, medicine, Humans, Testosterone, Aged, Retrospective Studies, Ovarian Neoplasms, Gynecology, medicine.diagnostic_test, business.industry, Ultrasound, Hyperandrogenism, Obstetrics and Gynecology, Histology, Magnetic resonance imaging, Retrospective cohort study, General Medicine, Middle Aged, medicine.disease, Postmenopause, Radiography, Androgens, Immunohistochemistry, Female, business, Biomarkers, Hormone
Abstract: ObjectiveEvaluation of postmenopausal women with suspicion of androgen-secreting tumor.Design and patientsWe retrospectively studied 22 postmenopausal women referred to our center for suspicion of androgen-secreting tumor. All patients had clinical, biological, and morphological evaluation. In absence of adrenal tumors, ovarian surgery was most often proposed and immunohistochemistry (IHC) studies were performed.ResultsOvarian tumors were detected by ultrasound and/or magnetic resonance imaging in eight patients. Two adrenal androgen-secreting tumors were diagnosed by an adrenal computed tomography (CT) scan. The clinical presentation of the women with or without tumors was similar. Nevertheless, women with tumor exhibited significantly higher testosterone levels and lower basal FSH and LH levels than the other women (2.6±2.7 vs 0.9±0.9 ng/ml,PPPConclusionsAndrogen-secreting tumors are clinically difficult to discriminate from other causes of postmenopausal hyperandrogenism. Testosterone and FSH were the two discriminative markers in a multivariate analysis. Ovarian and adrenal tumors were detected by imaging studies. However, ovarian non-tumoral causes of hyperandrogenism may be difficult to detect with conventional histology.
Published: 2011
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45. Sequence variation analysis of the prolactin receptor C-terminal region in women with premature ovarian failure

Author: Céline Leux, Frédérique Kuttenn, Anne Bachelot, Justine Bouilly, Diane Rebourcet, Nadine Binart, Philippe Touraine, and Yuchen Liu
Subjects: Adult, Male, Gene isoform, endocrine system, medicine.medical_specialty, endocrine system diseases, Receptors, Prolactin, DNA Mutational Analysis, Cell Count, Mice, Transgenic, Primary Ovarian Insufficiency, medicine.disease_cause, Mice, Exon, Internal medicine, medicine, Animals, Humans, Protein Isoforms, Receptor, Mutation, Base Sequence, business.industry, Prolactin receptor, Genetic Variation, Obstetrics and Gynecology, medicine.disease, Prolactin, Protein Structure, Tertiary, Premature ovarian failure, Endocrinology, Reproductive Medicine, Oocytes, Female, Signal transduction, business
Abstract: Using a mouse model expressing only the PRL receptor short isoform mimicking premature ovarian failure, signaling pathways induced by PRL were analyzed in mouse ovaries. Sequencing of the coding portion of exons 10 and 11, specific to the long and short receptor isoform, respectively, did not revealed any mutation in 101 women with premature ovarian failure.
Published: 2010
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46. Surgery is not superior to dilation for the management of vaginal agenesis in Mayer-Rokitansky-Küster-Hauser syndrome: a multicenter comparative observational study in 131 patients

Author: Alaa Cheikhelard, Maud Bidet, Amandine Baptiste, Magali Viaud, Christine Fagot, Naziha Khen-Dunlop, Christine Louis-Sylvestre, Sabine Sarnacki, Philippe Touraine, Caroline Elie, Yves Aigrain, Michel Polak, Jean-Luc Brun, Emile Darai, Philippe Descamps, Karinne Gueniche, Pierre Leguevaque, Patrice Lopes, Claude Louis-Borrione, Karine Morcel, Chloe Ouallouche, Bernard-Jean Paniel, Aline Ranke, Romain Rouzier, and Catherine Pienkowski
Subjects: Adult, medicine.medical_specialty, 46, XX Disorders of Sex Development, Population, 030232 urology & nephrology, Congenital Abnormalities, Young Adult, 03 medical and health sciences, Gynecologic Surgical Procedures, 0302 clinical medicine, Humans, Medicine, Mayer-Rokitansky-Kuster-Hauser Syndrome, education, Mullerian Ducts, education.field_of_study, 030219 obstetrics & reproductive medicine, business.industry, Obstetrics and Gynecology, Plastic Surgery Procedures, Dilatation, Surgery, Exact test, Distress, Dyspareunia, Treatment Outcome, Vagina, Quality of Life, Vaginoplasty, Female, Observational study, Analysis of variance, Sexual Health, business, Psychosocial
Abstract: Vaginal agenesis in Mayer-Rokitansky-Küster-Hauser syndrome can be managed either by various surgeries or dilation. The choice still depends on surgeon's preferences rather than on quality comparative studies and validated protocols.We sought to compare dilation and surgical management of vaginal agenesis in Mayer-Rokitansky-Küster-Hauser syndrome, in terms of quality of life, anatomical results, and complications in a large multicenter population.Our multicenter study included 131 patients18 years, at least 1 year after completing vaginal agenesis management. All had an independent gynecological evaluation including a standardized pelvic exam, and completed the World Health Organization Quality of Life instrument (general quality of life) as well as the Female Sexual Function Index and Female Sexual Distress Scale-Revised (sexual quality of life) scales. Groups were: surgery (N = 84), dilation therapy (N = 26), and intercourse (N = 20). One patient was secondarily excluded because of incomplete surgical data. For statistics, data were compared using analysis of variance, Student, Kruskal-Wallis, Wilcoxon, and Student exact test.Mean age was 26.5 ± 5.5 years at inclusion. In all groups, World Health Organization Quality of Life scores were not different between patients and the general population except for lower psychosocial health and social relationship scores (which were not different between groups). Global Female Sexual Function Index scores were significantly lower in the surgery and dilation therapy groups (median 26 range [2.8-34.8] and 24.7 [2.6-34.4], respectively) than the intercourse group (30.2 [7.8-34.8], P = .044), which had a higher score only in the satisfaction dimension (P = .004). However, the scores in the other dimensions of Female Sexual Function Index were not different between groups. The Female Sexual Distress Scale-Revised median scores were, respectively, 17 [0-52], 20 [0-47], and 10 [10-40] in the surgery, dilation therapy, and intercourse groups (P = .38), with sexual distress in 71% of patients. Median vaginal depth was shorter in dilatation therapy group (9.6 cm [5.5-12]) compared to surgery group (11 cm [6-15]) and intercourse group (11 cm [6-12.5]) (P = .039), but remained within normal ranges. One bias in the surgery group was the high number of sigmoid vaginoplasties (57/84, 68%), but no differences were observed between surgeries. Only 4 patients achieved vaginas6.5 cm. Delay between management and first intercourse was 6 months (not significant). Seventy patients (53%) had dyspareunia (not significant), and 17 patients all from the surgery group had an abnormal pelvic exam. In the surgery group, 34 patients (40.5%) had complications, requiring 20 secondary surgeries in 17 patients, and 35 (42%) needed postoperative dilation. In the dilation therapy group, 13 (50%) needed maintenance dilation.Surgery is not superior to therapeutic or intercourse dilation, bears complications, and should therefore be only a second-line treatment. Psychological counseling is mandatory at diagnosis and during therapeutic management.
Published: 2018
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47. New concepts in prolactin biology

Author: Vincent Goffin, Sophie Bernichtein, and Philippe Touraine
Subjects: Male, endocrine system, medicine.medical_specialty, Receptors, Prolactin, Dopamine, Endocrinology, Diabetes and Metabolism, Breast Neoplasms, Biology, medicine.disease_cause, Prolactin cell, Endocrinology, Breast cancer, Risk Factors, Internal medicine, STAT5 Transcription Factor, medicine, Animals, Humans, Endocrine system, Autocrine signalling, Receptor, Mutation, Prostatic Neoplasms, medicine.disease, Prolactin, Hyperprolactinemia, Female, hormones, hormone substitutes, and hormone antagonists, Hormone
Abstract: Human prolactin (PRL) is currently viewed as a hormone of pituitary origin, whose production (i.e. serum levels) is controlled by dopamine, whose biological actions relate exclusively to lactation and reproductive functions, for which any genetic disorder is yet to be identified, and whose unique associated pathology is hyperprolactinemia. Both experimental studies and human sample/cohort-based investigations performed during the past decade have considerably widened our perception of PRL biology: i) there are now strong epidemiological arguments supporting the fact that circulating PRL is a risk factor for breast cancer, ii) in addition to the endocrine hormone, locally produced PRL has been documented in several human tissues; there is increasing evidence supporting the tumor growth potency of local PRL, acting via autocrine/paracrine mechanisms, in both rodent models, and human breast and prostate tumors, iii) the first functional germinal polymorphisms of the PRL receptor were recently identified in patients presenting with breast tumors, which involve single amino acid substitution variants exhibiting constitutive activity, iv) human PRL analogs have been engineered, which were shown in experimental models to down-regulate the effects triggered by local PRL (competitive antagonism) or by the constitutively active receptor variants (inverse agonism). The aim of this review is to discuss these novel concepts in PRL biology, including their potential pathophysiological outcomes.
Published: 2010
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48. Hormonal status and ICU-acquired paresis in critically ill patients

Author: Pablo Rodriguez, Philippe Touraine, Sylvie Bastuji-Garin, Tarek Sharshar, Andrea Polito, Robert Stevens, Hervé Outin, Bernard De Jonghe, Virginie Maxime, Kathleen Laborde, and Charles Cerf
Subjects: Male, medicine.medical_specialty, Resuscitation, Neurological disorder, Critical Care and Intensive Care Medicine, Intensive care, Anesthesiology, medicine, Humans, Prospective Studies, Intensive care medicine, Severe complication, Aged, Paresis, Aged, 80 and over, Cross Infection, Critically ill, business.industry, Middle Aged, medicine.disease, Hormones, Intensive Care Units, Female, France, medicine.symptom, business, Hormone
Abstract: The pathogenesis of intensive care unit-acquired paresis (ICUAP), a frequent and severe complication of critical illness, is poorly understood. Since ICUAP has been associated with female gender in some studies, we hypothesized that hormonal dysfunction might contribute to ICUAP.To determine the relationship between hormonal status, ICUAP and mortality in patients with protracted critical illness.Prospective observational study.Four medical and surgical ICUs.ICU patients mechanically ventilated for7 days.None.Plasma levels of insulin growth factor-1 (IgF1), prolactin, thyroid stimulating hormone (TSH), follicular stimulating hormone (FSH), luteinizing hormone (LH), estradiol, progesterone, testosterone, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulphate (DHEAS) and cortisol were measured on the first day patients were awake (day 1). Mean blood glucose from admission to day 1 was calculated. ICUAP was defined as Medical Research Council sum score48/60 on day 7.We studied 102 patients (65 men and 37 women, 29 post-menopausal), of whom 24 (24%) died during hospitalization. Among the 86 patients tested at day 7, 39 (49%) had ICUAP, which was more frequent in women (63% versus men 36%, p = 0.02). Mean blood glucose was higher in patients with ICUAP. Estradiol/testosterone ratio was greater in men with ICUAP.ICUAP 7 days after awakening was associated with increased blood glucose and with biological evidence of hypogonadism in men, while an association with hormonal dysfunction was not detected in women.
Published: 2010
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49. Fertility in Women with Nonclassical Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency

Author: F. Kuttenn, Marie-Béatrice Galand-Portier, Christiane Coussieu, Irene Mowzowicz, Séverine Clauin, Maud Bidet, Philippe Boudou, Véronique Tardy, Yves Morel, Anne Bachelot, Philippe Touraine, Christine Bellanné-Chantelot, and Jean-Louis Golmard
Subjects: Adult, Infertility, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, endocrine system diseases, Endocrinology, Diabetes and Metabolism, media_common.quotation_subject, Clinical Biochemistry, Fertility, urologic and male genital diseases, Biochemistry, Endocrinology, Congenital adrenal hyperplasia due to 21-hydroxylase deficiency, Pregnancy, Internal medicine, Humans, Medicine, Congenital adrenal hyperplasia, Glucocorticoids, Menstrual cycle, hirsutism, media_common, Hydrocortisone, Gynecology, Chi-Square Distribution, Adrenal Hyperplasia, Congenital, business.industry, Biochemistry (medical), Pregnancy Outcome, nutritional and metabolic diseases, medicine.disease, Pedigree, Abortion, Spontaneous, Mutation, Female, Steroid 21-Hydroxylase, business, Infertility, Female, medicine.drug
Abstract: In contrast to subfertility often reported in women suffering from the classical form of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, fertility in nonclassical CAH (NC-CAH) has been rarely studied. Our objective was to evaluate fertility in NC-CAH women.We studied 190 NC-CAH women (161 probands + 29 first degree relatives). Only 20 probands had consulted for infertility (12%), either alone or associated with hirsutism or menstrual cycle disorders. The diagnosis was established on post-ACTH 17-hydroxyprogesterone 10 ng/ml or greater and further characterized by CYP21A2 gene analysis.Ninety-five of the 190 women wanted pregnancy (aged 26.7 +/- 8.9 yr); 187 pregnancies occurred in 85 women, which resulted in 141 births in 82 of them. Ninety-nine pregnancies (52.9%) occurred before the diagnosis of NC-CAH (96 spontaneously and three with ovulation inducers) whereas 98 occurred after diagnosis (11 spontaneously and 77 with hydrocortisone treatment); 83% of pregnancies were obtained within 1 yr. The rate of miscarriages was 6.5% for pregnancies obtained with glucocorticoid treatment vs. 26.3% without. Two of the 141 infants (1.5%) were born with classical CAH.Subfertility is mild in NC-CAH. However, the rate of miscarriages is lower in pregnancies occurring with glucocorticoid treatment and argues for treating NC-CAH women wanting pregnancy. In addition, considering the high rate of heterozygotes for CYP21A2 mutations in the general population, it is essential to genotype the partner of patients with a severe mutation to predict the risk of classical CAH and offer genetic counseling.
Published: 2010
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50. FOXL2 mutations lead to different ovarian phenotypes in BPES patients: Case Report

Author: Elfride De Baere, Catherine Genestie, Anne Bachelot, Catherine Duflos, Philippe Touraine, Reiner A. Veitia, Catherine Poirot, Bettina Bständig, and Geri Meduri
Subjects: Adult, Forkhead Box Protein L2, Infertility, medicine.medical_specialty, Pathology, endocrine system diseases, Ovary, Blepharophimosis, Primary Ovarian Insufficiency, Biology, medicine.disease_cause, FOXL2 Gene, Ovarian Follicle, Internal medicine, Follicular phase, medicine, Humans, Mutation, Rehabilitation, Obstetrics and Gynecology, Forkhead Transcription Factors, Syndrome, medicine.disease, Immunohistochemistry, female genital diseases and pregnancy complications, Premature ovarian failure, Phenotype, Forkhead box L2, Endocrinology, medicine.anatomical_structure, Reproductive Medicine, Female
Abstract: FOXL2 mutations cause the autosomal dominant Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) that may be associated with premature ovarian failure (POF). However, little is known about the molecular mechanisms of FOXL2 actions in the human ovary. We conducted an extensive clinical, hormonal and ovarian histological study in two patients carrying a FOXL2 mutation associated with the typical eyelid malformations and infertility. This observational study was conducted at referral centres for POF. Histological and immunohistological studies were conducted on ovarian biopsies from two women with POF carrying a FOXL2 mutation resulting in putative polyalanine expansions of the protein. Abnormalities similar to those observed in mice with FOXL2 gene inactivation were present in the first patient's ovary, although the ovarian histology of the second patient was apparently normal. Different ovarian phenotypes, follicular defects and distribution of FOXL2 protein were observed in two patients carrying a FOXL2 mutation.
Published: 2009
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