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1. Understanding the genetic complexity of puberty timing across the allele frequency spectrum

Author

Kentistou, KA, Kaisinger, LR, Stankovic, S, Vaudel, M, Mendes de Oliveira, E, Messina, A, Walters, RG, Liu, X, Busch, AS, Helgason, H, Thompson, DJ, Santoni, F, Petricek, KM, Zouaghi, Y, Huang-Doran, I, Gudbjartsson, DF, Bratland, E, Lin, K, Gardner, EJ, Zhao, Y, Jia, RY, Terao, C, Riggan, MJ, Bolla, MK, Yazdanpanah, M, Yazdanpanah, N, Bradfield, JP, Broer, L, Campbell, A, Chasman, DI, Cousminer, DL, Franceschini, N, Franke, LH, Girotto, G, He, C, Järvelin, M-R, Joshi, PK, Kamatani, Y, Karlsson, R, Luan, J, Lunetta, KL, Mägi, R, Mangino, M, Medland, SE, Meisinger, C, Noordam, R, Nutile, T, Concas, MP, Polašek, O, Porcu, E, Ring, SM, Sala, C, Smith, AV, Tanaka, T, van der Most, PJ, Vitart, V, Wang, CA, Willemsen, G, Zygmunt, M, Ahearn, TU, Andrulis, IL, Anton-Culver, H, Antoniou, AC, Auer, PL, Barnes, CLK, Beckmann, MW, Berrington de Gonzalez, A, Bogdanova, NV, Bojesen, SE, Brenner, H, Buring, JE, Canzian, F, Chang-Claude, J, Couch, FJ, Cox, A, Crisponi, L, Czene, K, Daly, MB, Demerath, EW, Dennis, J, Devilee, P, De Vivo, I, Dörk, T, Dunning, AM, Dwek, M, Eriksson, JG, Fasching, PA, Fernandez-Rhodes, L, Ferreli, L, Fletcher, O, Gago-Dominguez, M, García-Closas, M, García-Sáenz, JA, González-Neira, A, Grallert, H, Guénel, P, Haiman, CA, Hall, P, Hamann, U, Hakonarson, H, Hart, RJ, Hickey, M, Hooning, MJ, Hoppe, R, Hopper, JL, Hottenga, J-J, Hu, FB, Huebner, H, Hunter, DJ, ABCTB Investigators, Jernström, H, John, EM, Karasik, D, Khusnutdinova, EK, Kristensen, VN, Lacey, JV, Lambrechts, D, Launer, LJ, Lind, PA, Lindblom, A, Magnusson, PKE, Mannermaa, A, McCarthy, MI, Meitinger, T, Menni, C, Michailidou, K, Millwood, IY, Milne, RL, Montgomery, GW, Nevanlinna, H, Nolte, IM, Nyholt, DR, Obi, N, O'Brien, KM, Offit, K, Oldehinkel, AJ, Ostrowski, SR, Palotie, A, Pedersen, OB, Peters, A, Pianigiani, G, Plaseska-Karanfilska, D, Pouta, A, Pozarickij, A, Radice, P, Rennert, G, Rosendaal, FR, Ruggiero, D, Saloustros, E, Sandler, DP, Schipf, S, Schmidt, CO, Schmidt, MK, Small, K, Spedicati, B, Stampfer, M, Stone, J, Tamimi, RM, Teras, LR, Tikkanen, E, Turman, C, Vachon, CM, Wang, Q, Winqvist, R, Wolk, A, Zemel, BS, Zheng, W, van Dijk, KW, Alizadeh, BZ, Bandinelli, S, Boerwinkle, E, Boomsma, DI, Ciullo, M, Chenevix-Trench, G, Cucca, F, Esko, T, Gieger, C, Grant, SFA, Gudnason, V, Hayward, C, Kolčić, I, Kraft, P, Lawlor, DA, Martin, NG, Nøhr, EA, Pedersen, NL, Pennell, CE, Ridker, PM, Robino, A, Snieder, H, Sovio, U, Spector, TD, Stöckl, D, Sudlow, C, Timpson, NJ, Toniolo, D, Uitterlinden, A, Ulivi, S, Völzke, H, Wareham, NJ, Widen, E, Wilson, JF, Lifelines Cohort Study, Danish Blood Donor Study, Ovarian Cancer Association Consortium, Breast Cancer Association Consortium, Biobank Japan Project, China Kadoorie Biobank Collaborative Group, Pharoah, PDP, Li, L, Easton, DF, Njølstad, PR, Sulem, P, Murabito, JM, Murray, A, Manousaki, D, Juul, A, Erikstrup, C, Stefansson, K, Horikoshi, M, Chen, Z, Farooqi, IS, Pitteloud, N, Johansson, S, Day, FR, Perry, JRB, Ong, KK, Kentistou, KA, Kaisinger, LR, Stankovic, S, Vaudel, M, Mendes de Oliveira, E, Messina, A, Walters, RG, Liu, X, Busch, AS, Helgason, H, Thompson, DJ, Santoni, F, Petricek, KM, Zouaghi, Y, Huang-Doran, I, Gudbjartsson, DF, Bratland, E, Lin, K, Gardner, EJ, Zhao, Y, Jia, RY, Terao, C, Riggan, MJ, Bolla, MK, Yazdanpanah, M, Yazdanpanah, N, Bradfield, JP, Broer, L, Campbell, A, Chasman, DI, Cousminer, DL, Franceschini, N, Franke, LH, Girotto, G, He, C, Järvelin, M-R, Joshi, PK, Kamatani, Y, Karlsson, R, Luan, J, Lunetta, KL, Mägi, R, Mangino, M, Medland, SE, Meisinger, C, Noordam, R, Nutile, T, Concas, MP, Polašek, O, Porcu, E, Ring, SM, Sala, C, Smith, AV, Tanaka, T, van der Most, PJ, Vitart, V, Wang, CA, Willemsen, G, Zygmunt, M, Ahearn, TU, Andrulis, IL, Anton-Culver, H, Antoniou, AC, Auer, PL, Barnes, CLK, Beckmann, MW, Berrington de Gonzalez, A, Bogdanova, NV, Bojesen, SE, Brenner, H, Buring, JE, Canzian, F, Chang-Claude, J, Couch, FJ, Cox, A, Crisponi, L, Czene, K, Daly, MB, Demerath, EW, Dennis, J, Devilee, P, De Vivo, I, Dörk, T, Dunning, AM, Dwek, M, Eriksson, JG, Fasching, PA, Fernandez-Rhodes, L, Ferreli, L, Fletcher, O, Gago-Dominguez, M, García-Closas, M, García-Sáenz, JA, González-Neira, A, Grallert, H, Guénel, P, Haiman, CA, Hall, P, Hamann, U, Hakonarson, H, Hart, RJ, Hickey, M, Hooning, MJ, Hoppe, R, Hopper, JL, Hottenga, J-J, Hu, FB, Huebner, H, Hunter, DJ, ABCTB Investigators, Jernström, H, John, EM, Karasik, D, Khusnutdinova, EK, Kristensen, VN, Lacey, JV, Lambrechts, D, Launer, LJ, Lind, PA, Lindblom, A, Magnusson, PKE, Mannermaa, A, McCarthy, MI, Meitinger, T, Menni, C, Michailidou, K, Millwood, IY, Milne, RL, Montgomery, GW, Nevanlinna, H, Nolte, IM, Nyholt, DR, Obi, N, O'Brien, KM, Offit, K, Oldehinkel, AJ, Ostrowski, SR, Palotie, A, Pedersen, OB, Peters, A, Pianigiani, G, Plaseska-Karanfilska, D, Pouta, A, Pozarickij, A, Radice, P, Rennert, G, Rosendaal, FR, Ruggiero, D, Saloustros, E, Sandler, DP, Schipf, S, Schmidt, CO, Schmidt, MK, Small, K, Spedicati, B, Stampfer, M, Stone, J, Tamimi, RM, Teras, LR, Tikkanen, E, Turman, C, Vachon, CM, Wang, Q, Winqvist, R, Wolk, A, Zemel, BS, Zheng, W, van Dijk, KW, Alizadeh, BZ, Bandinelli, S, Boerwinkle, E, Boomsma, DI, Ciullo, M, Chenevix-Trench, G, Cucca, F, Esko, T, Gieger, C, Grant, SFA, Gudnason, V, Hayward, C, Kolčić, I, Kraft, P, Lawlor, DA, Martin, NG, Nøhr, EA, Pedersen, NL, Pennell, CE, Ridker, PM, Robino, A, Snieder, H, Sovio, U, Spector, TD, Stöckl, D, Sudlow, C, Timpson, NJ, Toniolo, D, Uitterlinden, A, Ulivi, S, Völzke, H, Wareham, NJ, Widen, E, Wilson, JF, Lifelines Cohort Study, Danish Blood Donor Study, Ovarian Cancer Association Consortium, Breast Cancer Association Consortium, Biobank Japan Project, China Kadoorie Biobank Collaborative Group, Pharoah, PDP, Li, L, Easton, DF, Njølstad, PR, Sulem, P, Murabito, JM, Murray, A, Manousaki, D, Juul, A, Erikstrup, C, Stefansson, K, Horikoshi, M, Chen, Z, Farooqi, IS, Pitteloud, N, Johansson, S, Day, FR, Perry, JRB, and Ong, KK

Abstract

Pubertal timing varies considerably and is associated with later health outcomes. We performed multi-ancestry genetic analyses on ~800,000 women, identifying 1,080 signals for age at menarche. Collectively, these explained 11% of trait variance in an independent sample. Women at the top and bottom 1% of polygenic risk exhibited ~11 and ~14-fold higher risks of delayed and precocious puberty, respectively. We identified several genes harboring rare loss-of-function variants in ~200,000 women, including variants in ZNF483, which abolished the impact of polygenic risk. Variant-to-gene mapping approaches and mouse gonadotropin-releasing hormone neuron RNA sequencing implicated 665 genes, including an uncharacterized G-protein-coupled receptor, GPR83, which amplified the signaling of MC3R, a key nutritional sensor. Shared signals with menopause timing at genes involved in DNA damage response suggest that the ovarian reserve might signal centrally to trigger puberty. We also highlight body size-dependent and independent mechanisms that potentially link reproductive timing to later life disease.

Published
2024

4. Navigating Disrupted Puberty: Development and Evaluation of a Mobile-Health Transition Passport for Klinefelter Syndrome

Author

Dwyer, A. A., Heritier, V., Llahana, S., Edelman, L., Papadakis, G. E., Vaucher, L., Pitteloud, N., and Hauschild, M.

Subjects
Male, Adolescent, Puberty, BF, RT, Telemedicine, Young Adult, Klinefelter Syndrome, Health Transition, Child, Preschool, Chronic Disease, Child, Humans, Klinefelter Syndrome/diagnosis, Klinefelter Syndrome/therapy, Retrospective Studies, Klinefelter syndrome (KS), adolescent, continuity of care, puberty, transition, RC
Abstract

Klinefelter syndrome (KS) is the most common aneuploidy in men and has long-term sequelae on health and wellbeing. KS is a chronic, lifelong condition and adolescents/young adults (AYAs) with KS face challenges in transitioning from pediatric to adult-oriented services. Discontinuity of care contributes to poor outcomes for health and wellbeing and transition programs for KS are lacking. We aimed to develop and test a mobile health tool (KS Transition Passport) to educate patients about KS, encourage self-management and support successful transition to adult-oriented care. First, we conducted a retrospective chart review and patient survey to examine KS transition at a university hospital. Second, we conducted a systematic scoping review of the literature on AYAs with KS. Last, we developed a mobile health transition passport and evaluated it with patient support groups. Participants evaluated the tool using the System Usability Scale and Patient Education Materials Assessment Tool (PEMAT). Chart review identified 21 AYAs diagnosed between 3.9-16.8 years-old (median 10.2 years). The survey revealed only 4/10 (40%) were on testosterone therapy and fewer (3/10, 30%) had regular medical care. The scoping review identified 21 relevant articles highlighting key aspects of care for AYAs with KS. An interprofessional team developed the mobile-health KS transition passport using an iterative process. Support group members (n=35) rated passport usability as 'ok' to 'good' (70 ± 20, median 73.5/100). Of PEMAT dimensions, 5/6 were deemed 'high quality' (86-90/100) and participants knew what to do with the information (actionability = 83/100). In conclusion, many patients with KS appear to have gaps in transition to adult-oriented care. Iterative development of a KS transition passport produced a mobile health tool that was usable, understandable and had high ratings for actionability.

Published
2022

7. Precision medicine in the era of artificial intelligence: implications in chronic disease management

Author

Subramanian, M., Wojtusciszyn, A., Favre, L., Boughorbel, S., Shan, J., Letaief, K.B., Pitteloud, N., and Chouchane, L.

Subjects
Artificial intelligence, Big-data analytics, Chronic diseases, Chronic inflammation, Deep phenotyping, Exposome, Machine leaning, Personalized treatment, Precision medicine
Abstract

Aberrant metabolism is the root cause of several serious health issues, creating a huge burden to health and leading to diminished life expectancy. A dysregulated metabolism induces the secretion of several molecules which in turn trigger the inflammatory pathway. Inflammation is the natural reaction of the immune system to a variety of stimuli, such as pathogens, damaged cells, and harmful substances. Metabolically triggered inflammation, also called metaflammation or low-grade chronic inflammation, is the consequence of a synergic interaction between the host and the exposome-a combination of environmental drivers, including diet, lifestyle, pollutants and other factors throughout the life span of an individual. Various levels of chronic inflammation are associated with several lifestyle-related diseases such as diabetes, obesity, metabolic associated fatty liver disease (MAFLD), cancers, cardiovascular disorders (CVDs), autoimmune diseases, and chronic lung diseases. Chronic diseases are a growing concern worldwide, placing a heavy burden on individuals, families, governments, and health-care systems. New strategies are needed to empower communities worldwide to prevent and treat these diseases. Precision medicine provides a model for the next generation of lifestyle modification. This will capitalize on the dynamic interaction between an individual's biology, lifestyle, behavior, and environment. The aim of precision medicine is to design and improve diagnosis, therapeutics and prognostication through the use of large complex datasets that incorporate individual gene, function, and environmental variations. The implementation of high-performance computing (HPC) and artificial intelligence (AI) can predict risks with greater accuracy based on available multidimensional clinical and biological datasets. AI-powered precision medicine provides clinicians with an opportunity to specifically tailor early interventions to each individual. In this article, we discuss the strengths and limitations of existing and evolving recent, data-driven technologies, such as AI, in preventing, treating and reversing lifestyle-related diseases.

Published
2020

14. Neuron-derived neurotrophic factor (NDNF) is mutated in patients with Congenital Hypogonadotropic Hypogonadism

Author

Messina, A., Pulli, K., Santini, S., Acierno, J., Känsäkoski, J., Cassatella, D., Xu, C., Casoni, F., Malone, S. A., Ternier, G., Conte, D., Sidis, Y., Tommiska, J., Vaaralahti, K., Dwyer, A., Gothilf, Y., Merlo, G. R., Santoni, F., Niederländer, N. J., Giacobini, P., Raivio, T., and Pitteloud, N

Subjects
Gonadotropin Kallmann Disease GnRH Animal Model of Disease Neurotrophic Factor
Published
2020

15. Clinical Management of Congenital Hypogonadotropic Hypogonadism

Author

Young, J., Xu, C., Papadakis, G.E., Acierno, J.S., Maione, L., Hietamäki, J., Raivio, T., Pitteloud, N., HUS Children and Adolescents, Raivio Group, Children's Hospital, Research Programs Unit, and STEMM - Stem Cells and Metabolism Research Program

Subjects
GONADOTROPIN-RELEASING-HORMONE, RECOMBINANT HUMAN FSH, HUMAN CHORIONIC-GONADOTROPIN, QUALITY-OF-LIFE, 3123 Gynaecology and paediatrics, Adolescent, Adult, Female, Gonadotropin-Releasing Hormone/administration & dosage, Gonadotropin-Releasing Hormone/deficiency, Gonadotropin-Releasing Hormone/metabolism, Gonadotropins/administration & dosage, Humans, Hypogonadism/congenital, Hypogonadism/diagnosis, Hypogonadism/drug therapy, Hypogonadism/metabolism, Infant, Infant, Newborn, Male, ANTI-MULLERIAN HORMONE, 3121 General medicine, internal medicine and other clinical medicine, HUMAN MENOPAUSAL GONADOTROPIN, FUNCTIONAL HYPOTHALAMIC AMENORRHEA, BONE-MINERAL DENSITY, FOLLICLE-STIMULATING-HORMONE, TESTOSTERONE REPLACEMENT THERAPY
Abstract

The initiation and maintenance of reproductive capacity in humans is dependent on pulsatile secretion of the hypothalamic hormone GnRH. Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder that results from the failure of the normal episodic GnRH secretion, leading to delayed puberty and infertility. CHH can be associated with an absent sense of smell, also termed Kallmann syndrome, or with other anomalies. CHH is characterized by rich genetic heterogeneity, with mutations in >30 genes identified to date acting either alone or in combination. CHH can be challenging to diagnose, particularly in early adolescence where the clinical picture mirrors that of constitutional delay of growth and puberty. Timely diagnosis and treatment will induce puberty, leading to improved sexual, bone, metabolic, and psychological health. In most cases, patients require lifelong treatment, yet a notable portion of male patients (approximate to 10% to 20%) exhibit a spontaneous recovery of their reproductive function. Finally, fertility can be induced with pulsatile GnRH treatment or gonadotropin regimens in most patients. In summary, this review is a comprehensive synthesis of the current literature available regarding the diagnosis, patient management, and genetic foundations of CHH relative to normal reproductive development.

Published
2019

18. Developing and evaluating rare disease educational materials co-created by expert clinicians and patients: the paradigm of congenital hypogonadotropic hypogonadism

Author

COST Action BM1105, Badiu, C, Bonomi, M, Borshchevsky, I, Cools, M, Craen, M, Ghervan, C, Hauschild, M, Hershkovitz, E, Hrabovszky, E, Juul, A, Kim, S, Kumanov, P, Lecumberri, B, Lemos, MC, Neocleous, V, Niedziela, M, Pekic, S, Persani, L, Phan-Hug, F, Pignatelli, D, Pitteloud, N, Popovic, V, Quinton, R, Skordis, N, Smith, N, Stefanija, MA, Xu, C, Young, J, and Dwyer, AA

Abstract

Background\ud \ud Patients with rare diseases face health disparities and are often challenged to find accurate information about their condition. We aimed to use the best available evidence and community partnerships to produce patient education materials for congenital hypogonadotropic hypogonadism (CHH) and the olfacto-genital (Kallmann) syndrome (i.e., CHH and defective sense of smell), and to evaluate end-user acceptability. Expert clinicians, researchers and patients co-created the materials in a multi-step process. Six validated algorithms were used to assess reading level of the final product. Comprehensibility and actionability were measured using the Patient Education Materials Assessment Tool via web-based data collection. Descriptive statistics were employed to summarize data and thematic analysis for analyzing open-ended responses. Subsequently, translation and cultural adaption were conducted by clinicians and patients who are native speakers.\ud Results\ud \ud Co-created patient education materials reached the target 6th grade reading level according to 2/6 (33%) algorithms (range: grade 5.9–9.7). The online survey received 164 hits in 2 months and 63/159 (40%) of eligible patients completed the evaluation. Patients ranged in age from 18 to 66 years (median 36, mean 39 ± 11) and 52/63 (83%), had adequate health literacy. Patients scored understandability at 94.2% and actionability at 90.5%. The patient education materials were culturally adapted and translated into 20 languages (available in Additional file 1).\ud Conclusions\ud \ud Partnering with patients enabled us to create patient education materials that met patient- identified needs as evidenced by high end-user acceptability, understandability and actionability. The web-based evaluation was effective for reaching dispersed rare disease patients. Combining dissemination via traditional healthcare professional platforms as well as patient-centric sites can facilitate broad uptake of culturally adapted translations. This process may serve as a roadmap for creating patient education materials for other rare diseases.

Published
2017

20. Testosterone restoration using enclomiphene citrate in men with secondary hypogonadism: a pharmacodynamic and pharmacokinetic study

Author

Wiehle, R., Cunningham, G.R., Pitteloud, N., Wike, J., Hsu, K., Fontenot, G.K., Rosner, M., Dwyer, A., and Podolski, J.

Subjects
LH, secondary hypogonadism, Sexual Medicine, transdermal testosterone, testosterone restoration, serum testosterone
Abstract

Objectives To determine the pharmacodynamic profile of serum total testosterone and luteinizing hormone (LH) levels in men with secondary hypogonadism after initial and chronic daily oral doses of enclomiphene citrate vs transdermal testosterone. To determine the effects of daily oral doses of enclomiphene citrate in comparison with transdermal testosterone on other hormones and markers in men with secondary hypogonadism. Patients and Methods This was a randomized, single-blind, two-centre, phase II study to evaluate the effects of three different doses of enclomiphene citrate (6.25, 12.5 and 25 mg) vs transdermal testosterone on 24-h LH and total testosterone in otherwise normal healthy men with secondary hypogonadism. Forty-eight men were enrolled in the trial (the intent-to-treat population), but four men had testosterone levels >350 ng/dL at baseline. Forty-four men completed the study per protocol. All subjects enrolled in this trial had serum total testosterone in the low range (

Published
2013

21. Patients avec variation du développement sexuel : un exemple de prise en charge interdisciplinaire [Patients with variations of sex development : an example of interdisciplinary care]

Author

Phan-Hug, F., Kraus, C., Paoloni-Giacobino, A., Fellmann, F., Typaldou, S.A., Ansermet, F., Alamo, L., Eggert, N., Pelet, O., Vial, Y., Muehlethaler, V., Birraux, J., Ramseyer, P., Renteria, S.C., Dwyer, A., Pitteloud, N., and Meyrat, B.J.

Subjects
Disorders of Sex Development/physiopathology, Disorders of Sex Development/therapy, Ethics, Medical, Humans, Interdisciplinary Communication, Male, Specialization, Switzerland
Abstract

The medical, psychological and social aspects of disorders of sex development (DSD) represent a challenge for the management of these patients. However, advances in our understanding of the etiology and genetics of this condition, novel surgical approaches and the growing influence of patient groups as well as wider recognition of ethical issues have helped improve the care of patients with a DSD. Importantly, a multidisciplinary approach involving specialists is crucial for understanding and treating such rare and complex cases. According to the recommendations of the Swiss National Ethical Commission, we shall use the term « Variation of Sex Development » rather than « Disorder of Sex Development » in this publication. This article addresses the care of DSD patients throughout development from the point of view of specialists in complementary fields.

Published
2016

23. Two missense mutations in KCNQ1 cause pituitary hormone deficiency and maternally inherited gingival fibromatosis

Author

Tommiska, J. (Johanna), Känsäkoski, J. (Johanna), Skibsbye, L. (Lasse), Vaaralahti, K. (Kirsi), Liu, X. (Xiaonan), Lodge, E. J. (Emily J.), Tang, C. (Chuyi), Yuan, L. (Lei), Fagerholm, R. (Rainer), Kanters, J. K. (Jørgen K.), Lahermo, P. (Päivi), Kaunisto, M. (Mari), Keski-Filppula, R. (Riikka), Vuoristo, S. (Sanna), Pulli, K. (Kristiina), Ebeling, T. (Tapani), Valanne, L. (Leena), Sankila, E.-M. (Eeva-Marja), Kivirikko, S. (Sirpa), Lääperi, M. (Mitja), Casoni, F. (Filippo), Giacobini, P. (Paolo), Phan-Hug, F. (Franziska), Buki, T. (Tal), Tena-Sempere, M. (Manuel), Pitteloud, N. (Nelly), Veijola, R. (Riitta), Lipsanen-Nyman, M. (Marita), Kaunisto, K. (Kari), Mollard, P. (Patrice), Andoniadou, C. L. (Cynthia L.), Hirsch, J. A. (Joel A.), Varjosalo, M. (Markku), Jespersen, T. (Thomas), Raivio, T. (Taneli), Tommiska, J. (Johanna), Känsäkoski, J. (Johanna), Skibsbye, L. (Lasse), Vaaralahti, K. (Kirsi), Liu, X. (Xiaonan), Lodge, E. J. (Emily J.), Tang, C. (Chuyi), Yuan, L. (Lei), Fagerholm, R. (Rainer), Kanters, J. K. (Jørgen K.), Lahermo, P. (Päivi), Kaunisto, M. (Mari), Keski-Filppula, R. (Riikka), Vuoristo, S. (Sanna), Pulli, K. (Kristiina), Ebeling, T. (Tapani), Valanne, L. (Leena), Sankila, E.-M. (Eeva-Marja), Kivirikko, S. (Sirpa), Lääperi, M. (Mitja), Casoni, F. (Filippo), Giacobini, P. (Paolo), Phan-Hug, F. (Franziska), Buki, T. (Tal), Tena-Sempere, M. (Manuel), Pitteloud, N. (Nelly), Veijola, R. (Riitta), Lipsanen-Nyman, M. (Marita), Kaunisto, K. (Kari), Mollard, P. (Patrice), Andoniadou, C. L. (Cynthia L.), Hirsch, J. A. (Joel A.), Varjosalo, M. (Markku), Jespersen, T. (Thomas), and Raivio, T. (Taneli)

Abstract

Familial growth hormone deficiency provides an opportunity to identify new genetic causes of short stature. Here we combine linkage analysis with whole-genome resequencing in patients with growth hormone deficiency and maternally inherited gingival fibromatosis. We report that patients from three unrelated families harbor either of two missense mutations, c.347G>T p.(Arg116Leu) or c.1106C>T p.(Pro369Leu), in KCNQ1, a gene previously implicated in the long QT interval syndrome. Kcnq1 is expressed in hypothalamic GHRH neurons and pituitary somatotropes. Co-expressing KCNQ1 with the KCNE2 β-subunit shows that both KCNQ1 mutants increase current levels in patch clamp analyses and are associated with reduced pituitary hormone secretion from AtT-20 cells. In conclusion, our results reveal a role for the KCNQ1 potassium channel in the regulation of human growth, and show that growth hormone deficiency associated with maternally inherited gingival fibromatosis is an allelic disorder with cardiac arrhythmia syndromes caused by KCNQ1 mutations.

Published
2017

24. [How do Swiss family physicians treat subclinical hypothyroidism?]

Author

Virgini V, Baumgartner C, Bischoff T, Dagmar Haller, Frey P, Rosemann T, Th, Collet, Sykiotis G, Pitteloud N, and Rodondi N

Subjects
Thyroxine, Hypothyroidism, Hormone Replacement Therapy, Surveys and Questionnaires, Humans, Physicians, Family, Practice Patterns, Physicians', Switzerland, Randomized Controlled Trials as Topic
Abstract

Subclinical hypothyroidism is a common condition, and its prevalence increases with age. Currently, guidelines regarding the screening and treatment of subclinical hypothyroidism are controversial. An international survey of general practitioners (GPs), to which Swiss GPs also contributed, showed large inter-country variations in treatment strategies for subclinical hypothyroidism. These differences are mainly explained by the lack of strong evidence for the management of this condition. The European randomized-controlled clinical trial TRUST should help clarify recommendations for screening and thyroxin replacement for the elderly with subclinical hypothyroidism. Working in close collaboration with GPs in Switzerland for the recruitment of patients will ensure that the findings from this study will be applicable to primary care settings.

Published
2014

27. How do Swiss family physicians treat subclinical hypothyroidism?

Author

Frey, P, Rosemann, T, Bischoff, T, Haller, D M, Rodondi, Nicolas, Collet, T-H, Baumgartner, Christine, Pitteloud, N, Virgini, V, and Sykiotis, G

Subjects
610 Medicine & health, 360 Social problems & social services
Abstract

L’hypothyroïdie infraclinique est fréquemment rencontrée et sa prévalence augmente avec l’âge. Les recommandations relatives au dépistage et au traitement de l’hypothyroïdie infraclinique sont controversées. Une enquête internationale auprès des médecins de famille, à laquelle la Suisse a participé, a mis en évidence de fortes variations dans la prise en charge de l’hypothyroïdie infraclinique entre les pays. Ces différences de traitement traduisent avant tout le manque de données fiables quant à la prise en charge de cette condition. L’essai clinique randomisé européen TRUST devrait permettre de clarifier les indications pour le dépistage et la substitution par thyroxine. Une collaboration avec les médecins de famille et le soutien des Instituts universitaires de médecine générale à Lausanne et à Berne pour le recrutement des patients devraient permettre d’obtenir des données directement applicables à une population représentative de la médecine ambulatoire., Subclinical hypothyroidism is a common condition, and its prevalence increases with age. Currently, guidelines regarding the screening and treatment of subclinical hypothyroidism are controversial. An international survey of general practitioners (GPs), to which Swiss GPs also contributed, showed large inter-country variations in treatment strategies for subclinical hypothyroidism. These differences are mainly explained by the lack of strong evidence for the management of this condition. The European randomized-controlled clinical trial TRUST should help clarify recommendations for screening and thyroxin replacement for the elderly with subclinical hypothyroidism. Working in close collaboration with GPs in Switzerland for the recruitment of patients will ensure that the findings from this study will be applicable to primary care settings.

Published
2014
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28. [Caring for patients with pediatric endocrinopathies and diabetes into adulthood: challenges of an often difficult transition]

Author

Phan-Hug F, Hauschild M, Andrew Dwyer, and Pitteloud N

Subjects
Adult, Health Services Needs and Demand, Time Factors, Adolescent, Communication, Age Factors, Endocrine System Diseases, Self Care, Patient-Centered Care, Personal Autonomy, Practice Guidelines as Topic, Diabetes Mellitus, Humans, Cooperative Behavior, Child
Abstract

The success of therapies for a number of pediatric disorders has posed new challenges for the long-term follow-up of adolescents with chronic endocrinopathies. Unfortunately, too many patients are lost during the transfer from pediatric to adult clinics. The transition process should be well-organized and include the young person and family. Recognizing the special needs of these adolescents is an important step in developing patient-centered approaches to care that enable patients to develop autonomy and self care skills. Key elements in this process include structured policies and guidelines, communication and close collaboration between pediatric and adult clinics, and integrating nurse clinicians in the transition process to help close the gaps in care.

Published
2012

30. GNRH1 mutations in patients with idiopathic hypogonadotropic hypogonadism

Author

Chan, Y M, de Guillebon, A, Lang-Muritano, M, Plummer, L, Cerrato, F, Tsiaras, S, Gaspert, A, Lavoie, H B, Wu, C-H, Crowley Jr., W F, Amory, J K, Pitteloud, N, Seminara, S B, and University of Zurich

Subjects
1000 Multidisciplinary, 10036 Medical Clinic, 10049 Institute of Pathology and Molecular Pathology, 610 Medicine & health
Published
2009

32. Variations in, But Not, Are Associated With Hypopituitarism and Septo-optic Dysplasia

Author

McCabe, MJ, Gaston-Massuet, C, Gregory, LC, Alatzoglou, KS, Tziaferi, V, Sbai, O, Rondard, P, Masumoto, K-H, Nagano, M, Shigeyoshi, Y, Pfeifer, M, Hulse, T, Buchanan, CR, Pitteloud, N, Martinez-Barbera, J-P, Dattani, MT, McCabe, MJ, Gaston-Massuet, C, Gregory, LC, Alatzoglou, KS, Tziaferi, V, Sbai, O, Rondard, P, Masumoto, K-H, Nagano, M, Shigeyoshi, Y, Pfeifer, M, Hulse, T, Buchanan, CR, Pitteloud, N, Martinez-Barbera, J-P, and Dattani, MT

Published
2013

33. Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism

Author

Miraoui, H., Dwyer, A.A., Hughes, V.A., Sidis, Y., Pitteloud, N., Sykiotis, G.P., Plummer, L., Feng, B., Keefe, K., Crowley Jr., W.F., Seminara, S.B., Hall, J.E., Chung, W., Tsai, P.-S., Beenken, A., Mohammadi, M., Clarke, J., Rubenstein, J., Pers, T.H., Dworzynski, Piotr, Hansen, Kasper Lage, Niedziela, M., Raivio, T., Quinton, R., Kumanov, P., Young, Jette Feveile, Yialamas, M.A., Van Vliet, G., Chanoine, J.-P., Miraoui, H., Dwyer, A.A., Hughes, V.A., Sidis, Y., Pitteloud, N., Sykiotis, G.P., Plummer, L., Feng, B., Keefe, K., Crowley Jr., W.F., Seminara, S.B., Hall, J.E., Chung, W., Tsai, P.-S., Beenken, A., Mohammadi, M., Clarke, J., Rubenstein, J., Pers, T.H., Dworzynski, Piotr, Hansen, Kasper Lage, Niedziela, M., Raivio, T., Quinton, R., Kumanov, P., Young, Jette Feveile, Yialamas, M.A., Van Vliet, G., and Chanoine, J.-P.

Abstract

Congenital hypogonadotropic hypogonadism (CHH) and its anosmia-associated form (Kallmann syndrome [KS]) are genetically heterogeneous. Among the >15 genes implicated in these conditions, mutations in FGF8 and FGFR1 account for ∼12% of cases; notably, KAL1 and HS6ST1 are also involved in FGFR1 signaling and can be mutated in CHH. We therefore hypothesized that mutations in genes encoding a broader range of modulators of the FGFR1 pathway might contribute to the genetics of CHH as causal or modifier mutations. Thus, we aimed to (1) investigate whether CHH individuals harbor mutations in members of the so-called "FGF8 synexpression" group and (2) validate the ability of a bioinformatics algorithm on the basis of protein-protein interactome data (interactome-based affiliation scoring [IBAS]) to identify high-quality candidate genes. On the basis of sequence homology, expression, and structural and functional data, seven genes were selected and sequenced in 386 unrelated CHH individuals and 155 controls. Except for FGF18 and SPRY2, all other genes were found to be mutated in CHH individuals: FGF17 (n = 3 individuals), IL17RD (n = 8), DUSP6 (n = 5), SPRY4 (n = 14), and FLRT3 (n = 3). Independently, IBAS predicted FGF17 and IL17RD as the two top candidates in the entire proteome on the basis of a statistical test of their protein-protein interaction patterns to proteins known to be altered in CHH. Most of the FGF17 and IL17RD mutations altered protein function in vitro. IL17RD mutations were found only in KS individuals and were strongly linked to hearing loss (6/8 individuals). Mutations in genes encoding components of the FGF pathway are associated with complex modes of CHH inheritance and act primarily as contributors to an oligogenic genetic architecture underlying CHH.

Published
2013

34. Genetic overlap in Kallmann syndrome, combined pituitary hormone deficiency, and septo-optic dysplasia

Author

Raivio, T, Avbelj, M, McCabe, MJ, Romero, CJ, Dwyer, AA, Tommiska, J, Sykiotis, GP, Gregory, LC, Diaczok, D, Tziaferi, V, Elting, MW, Padidela, R, Plummer, L, Martin, C, Feng, B, Zhang, C, Zhou, QY, Chen, H, Mohammadi, M, Quinton, R, Sidis, Y, Radovick, S, Dattani, MT, Pitteloud, N, Raivio, T, Avbelj, M, McCabe, MJ, Romero, CJ, Dwyer, AA, Tommiska, J, Sykiotis, GP, Gregory, LC, Diaczok, D, Tziaferi, V, Elting, MW, Padidela, R, Plummer, L, Martin, C, Feng, B, Zhang, C, Zhou, QY, Chen, H, Mohammadi, M, Quinton, R, Sidis, Y, Radovick, S, Dattani, MT, and Pitteloud, N

Abstract

Context: Kallmann syndrome (KS), combined pituitary hormone deficiency (CPHD), and septo-optic dysplasia (SOD) all result from development defects of the anterior midline in the human forebrain. Objective: The objective of the study was to investigate whether KS, CPHD, and SOD have shared genetic origins. Design and Participants: A total of 103 patients with either CPHD (n = 35) or SOD (n = 68) were investigated for mutations in gene simplicated in the etiology of KS (FGFR1, FGF8, PROKR2, PROK2, and KAL1). Consequences of identified FGFR1, FGF8, and PROKR2 mutations were investigated in vitro. Results: Three patients with SOD had heterozygous mutations in FGFR1; these were either shown to alter receptor signaling (p.S450F, p.P483S) or predicted to affect splicing (c.336C>T, p.T112T). One patient had a synonymous change in FGF8 (c.216G>A, p.T72T) that was shown to affect splicing and ligand signaling activity. Four patients with CPHD/SOD were found to harbor heterozygous rare loss-of-function variants in PROKR2 (p.R85G, p.R85H, p.R268C). Conclusions: Mutations in FGFR1/FGF8/PROKR2 contributed to 7.8% of our patients with CPHD/ SOD. These data suggest a significant genetic overlap between conditions affecting the development of anterior midline in the human forebrain. Copyright © 2012 by The Endocrine Society.

Published
2012

35. NovelMutations Associated with Recessive Holoprosencephaly, Craniofacial Defects, and Hypothalamo-Pituitary Dysfunction

Author

McCabe, MJ, Gaston-Massuet, C, Tziaferi, V, Gregory, LC, Alatzoglou, KS, Signore, M, Puelles, E, Gerrelli, D, Farooqi, IS, Raza, J, Walker, J, Kavanaugh, SI, Tsai, P-S, Pitteloud, N, Martinez-Barbera, J-P, Dattani, MT, McCabe, MJ, Gaston-Massuet, C, Tziaferi, V, Gregory, LC, Alatzoglou, KS, Signore, M, Puelles, E, Gerrelli, D, Farooqi, IS, Raza, J, Walker, J, Kavanaugh, SI, Tsai, P-S, Pitteloud, N, Martinez-Barbera, J-P, and Dattani, MT

Published
2011

36. Novel FGF8 mutations associated with recessive holoprosencephaly, craniofacial defects, and hypothalamo-pituitary dysfunction

Author

McCabe, Mark James, Gaston-Massuet, Carles, Tziaferi, Vaitsa, Gregory, Louise C., Alatzoglou, Kyriaki S., Puelles, Eduardo, Gerrelli, Dianne, Farooqi, I. Sadaf, Raza, Jamal, Walker, Joanna, Kavanaugh, Scott I., Tsai, Pei-San, Pitteloud, N., Martínez-Barberá, Juan P., Signore, Massimo, Dattani, Mehul T., McCabe, Mark James, Gaston-Massuet, Carles, Tziaferi, Vaitsa, Gregory, Louise C., Alatzoglou, Kyriaki S., Puelles, Eduardo, Gerrelli, Dianne, Farooqi, I. Sadaf, Raza, Jamal, Walker, Joanna, Kavanaugh, Scott I., Tsai, Pei-San, Pitteloud, N., Martínez-Barberá, Juan P., Signore, Massimo, and Dattani, Mehul T.

Abstract

Context: Fibroblast growth factor (FGF) 8 is important for GnRH neuronal development with human mutations resulting in Kallmann syndrome. Murine data suggest a role for Fgf8 in hypothalamo- pituitary development; however, its role in the etiology of wider hypothalamo-pituitary dysfunction in humans is unknown. Objective: The objective of this study was to screen for FGF8 mutations in patients with septo-optic dysplasia (n = 374) or holoprosencephaly (HPE)/midline clefts (n = 47). Methods: FGF8 was analyzed by PCR and direct sequencing. Ethnically matched controls were then screened for mutated alleles (n = 480-686). Localization of Fgf8/FGF8 expression was analyzed by in situ hybridization in developing murine and human embryos. Finally, Fgf8 hypomorphic mice (Fgf8 loxPNeo/-) were analyzed for the presence of forebrain and hypothalamo-pituitary defects. Results: A homozygous p.R189H mutation was identified in a female patient of consanguineous parentage with semilobar HPE, diabetes insipidus, and TSH and ACTH insufficiency. Second, a heterozygous p.Q216E mutation was identified in a female patient with an absent corpus callosum, hypoplastic optic nerves, and Moebius syndrome. FGF8 was expressed in the ventral diencephalon and anterior commissural plate but not in Rathke's pouch, strongly suggesting early onset hypothalamic and corpus callosal defects in these patients. This was consolidated by significantly reduced vasopressin and oxytocin staining neurons in the hypothalamus of Fgf8 hypomorphic mice compared with controls along with variable hypothalamo-pituitary defects and HPE. Conclusion: We implicate FGF8 in the etiology of recessive HPE and potentially septo-optic dysplasia/ Moebius syndrome for the first time to our knowledge. Furthermore, FGF8 is important for the development of the ventral diencephalon, hypothalamus, and pituitary. Copyright © 2011 by The Endocrine Society.

Published
2011

37. CHD7 mutations in patients initially diagnosed with Kallmann syndrome--the clinical overlap with CHARGE syndrome.

Author

Jongmans, M.C.J., Ravenswaaij-Arts, C.M.A. van, Pitteloud, N., Ogata, T., Sato, N., Claahsen-van der Grinten, H.L., Donk, K. van der, Seminara, S., Bergman, J.E., Brunner, H.G., Crowley, W.F., Hoefsloot, L.H., Jongmans, M.C.J., Ravenswaaij-Arts, C.M.A. van, Pitteloud, N., Ogata, T., Sato, N., Claahsen-van der Grinten, H.L., Donk, K. van der, Seminara, S., Bergman, J.E., Brunner, H.G., Crowley, W.F., and Hoefsloot, L.H.

Abstract

Contains fulltext : 80605.pdf (publisher's version ) (Closed access), Kallmann syndrome (KS) is the combination of hypogonadotropic hypogonadism and anosmia or hyposmia, two features that are also frequently present in CHARGE syndrome. CHARGE syndrome is caused by mutations in the CHD7 gene. We performed analysis of CHD7 in 36 patients with KS and 20 patients with normosmic idiopathic hypogonadotropic hypogonadism (nIHH) in whom mutations in KAL1, FGFR1, PROK2 and PROKR2 genes were excluded. Three of 56 KS/nIHH patients had de novo mutations in CHD7. In retrospect, these three CHD7-positive patients showed additional features that are seen in CHARGE syndrome. CHD7 mutations can be present in KS patients who have additional features that are part of the CHARGE syndrome phenotype. We did not find mutations in patients with isolated KS. These findings imply that patients diagnosed with hypogonadotropic hypogonadism and anosmia should be screened for clinical features consistent with CHARGE syndrome. If such features are present, particularly deafness, dysmorphic ears and/or hypoplasia or aplasia of the semicircular canals, CHD7 sequencing is recommended.

Published
2009

39. CHD7 mutations in patients initially diagnosed with Kallmann syndrome – the clinical overlap with CHARGE syndrome

Author

Jongmans, MCJ, primary, Van Ravenswaaij‐Arts, CMA, additional, Pitteloud, N, additional, Ogata, T, additional, Sato, N, additional, Claahsen‐van der Grinten, HL, additional, Van Der Donk, K, additional, Seminara, S, additional, Bergman, JEH, additional, Brunner, HG, additional, Crowley, WF, additional, and Hoefsloot, LH, additional

Published
2008
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42. [Follow-up and management of children born small for gestational age a endocrine and metabolic aspects]

Author

Elowe-Gruau E, Phan-Hug F, Stoppa-Vaucher S, Pitteloud N, and Michael Hauschild

Subjects
Risk, Metabolic Diseases, Human Growth Hormone, Child, Preschool, Infant, Small for Gestational Age, Puberty, Infant, Newborn, Humans, Infant, Growth, Insulin Resistance, Child, Endocrine System Diseases
Abstract

Children born premature and/or small for gestational age (SGA) are at risk of growth and metabolic abnormalities. Catch-up growth occurs usually before the age of 2. In the absence of sufficient catch up growth, growth hormone (GH) treatment should be evaluated under certain conditions. Children who were born premature and/or SGA are at higher risk of insulin resistance and metabolic abnormalities, especially in case of excessive weight gain during the first months of life. Puberty in these children occurs normally or slightly advanced, with no effect on gonadic function or fertility. Each step of the development of premature and/or SGA children present specific risks, which the pediatrician has to follow. If necessary, the pediatric endocrinologist will initiate a specific management.

44. Congenital hypogonadotropic hypogonadism with split hand/foot malformation: a clinical entity with a high frequency of FGFR1 mutations

Author

Villanueva C, Jacobson-Dickman E, Xu C, ManouvrierS, DwyerA, Sykiotis GP, Beenken A, Liu Y, Tommiska J, Hu Y, Tiosano D, Gerard M, Leger J, Drouin-Garraud V, Lefebvre H, Polak M, Carel J, Phan-Hug F, Hauschild M, Raivio T, Bouloux P, Sidis Y, Mohammadi M, de Roux N, and Pitteloud N

Abstract

Purpose:Congenital hypogonadotropic hypogonadism (CHH) and split hand/foot malformation (SHFM) are two rare genetic conditions. Here we report a clinical entity comprising the two.Methods:We identified patients with CHH and SHFM through international collaboration. Probands and available family members underwent phenotyping and screening for FGFR1 mutations. The impact of identified mutations was assessed by sequence and structure based predictions and/or functional assays.Results:We identified eight probands with CHH with (n = 3; Kallmann syndrome) or without anosmia (n = 5) and SHFM seven of whom (88) harbor FGFR1 mutations. Of these seven one individual is homozygous for p.V429E and six individuals are heterozygous for p.G348R p.G485R p.Q594 p.E670A p.V688L or p.L712P. All mutations were predicted by in silico analysis to cause loss of function. Probands with FGFR1 mutations have severe gonadotropin releasing hormone deficiency (absent puberty and/or cryptorchidism and/or micropenis). SHFM in both hands and feet was observed only in the patient with the homozygous p.V429E mutation; V429 maps to the fibroblast growth factor receptor substrate 2a binding domain of FGFR1 and functional studies of the p.V429E mutation demonstrated that it decreased recruitment and phosphorylation of fibroblast growth factor receptor substrate 2a to FGFR1 thereby resulting in reduced mitogen activated protein kinase signaling.Conclusion:FGFR1 should be prioritized for genetic testing in patients with CHH and SHFM because the likelihood of a mutation increases from 10 in the general CHH population to 88 in these patients.Genet Med advance online publication 13 November 2014Genetics in Medicine (2014); doi:10.1038/gim.2014.166.

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47. Reversal of idiopathic hypogonadotropic hypogonadism.

Author

Raivio T, Falardeau J, Dwyer A, Quinton R, Hayes FJ, Hughes VA, Cole LW, Pearce SH, Lee H, Boepple P, Crowley WF Jr., Pitteloud N, Raivio, Taneli, Falardeau, John, Dwyer, Andrew, Quinton, Richard, Hayes, Frances J, Hughes, Virginia A, Cole, Lindsay W, and Pearce, Simon H

Abstract

Background: Idiopathic hypogonadotropic hypogonadism, which may be associated with anosmia (the Kallmann syndrome) or with a normal sense of smell, is a treatable form of male infertility caused by a congenital defect in the secretion or action of gonadotropin-releasing hormone (GnRH). Patients have absent or incomplete sexual maturation by the age of 18. Idiopathic hypogonadotropic hypogonadism was previously thought to require lifelong therapy. We describe 15 men in whom reversal of idiopathic hypogonadotropic hypogonadism was sustained after discontinuation of hormonal therapy.Methods: We defined the sustained reversal of idiopathic hypogonadotropic hypogonadism as the presence of normal adult testosterone levels after hormonal therapy was discontinued.Results: Ten sustained reversals were identified retrospectively. Five sustained reversals were identified prospectively among 50 men with idiopathic hypogonadotropic hypogonadism after a mean (+/-SD) duration of treatment interruption of 6+/-3 weeks. Of the 15 men who had a sustained reversal, 4 had anosmia. At initial evaluation, 6 men had absent puberty, 9 had partial puberty, and all had abnormal secretion of GnRH-induced luteinizing hormone. All 15 men had received previous hormonal therapy to induce virilization, fertility, or both. Among those whose hypogonadism was reversed, the mean serum level of endogenous testosterone increased from 55+/-29 ng per deciliter (1.9+/-1.0 nmol per liter) to 386+/-91 ng per deciliter (13.4+/-3.2 nmol per liter, P<0.001), the luteinizing hormone level increased from 2.7+/-2.0 to 8.5+/-4.6 IU per liter (P<0.001), the level of follicle-stimulating hormone increased from 2.5+/-1.7 to 9.5+/-12.2 IU per liter (P<0.01), and testicular volume increased from 8+/-5 to 16+/-7 ml (P<0.001). Pulsatile luteinizing hormone secretion and spermatogenesis were documented.Conclusions: Sustained reversal of normosmic idiopathic hypogonadotropic hypogonadism and the Kallmann syndrome was noted after discontinuation of treatment in about 10% of patients with either absent or partial puberty. Therefore, brief discontinuation of hormonal therapy to assess reversibility of hypogonadotropic hypogonadism is reasonable. (ClinicalTrials.gov number, NCT00392756 [ClinicalTrials.gov].). [ABSTRACT FROM AUTHOR]

Published
2007

48. Genetic testing facilitates prepubertal diagnosis of congenital hypogonadotropic hypogonadism

Author

Nelly Pitteloud, Cheng Xu, Franziska Phan-Hug, James S Acierno, Daniele Cassatella, Andrew A. Dwyer, Gerasimos P. Sykiotis, Mariarosaria Lang-Muritano, Moosa Mohammadi, University of Zurich, and Pitteloud, N

Subjects
Male, 0301 basic medicine, medicine.medical_specialty, 2716 Genetics (clinical), Fibroblast Growth Factor 8, 030209 endocrinology & metabolism, 610 Medicine & health, Biology, Article, Congenital Abnormalities, Gonadotropin-Releasing Hormone, 03 medical and health sciences, 0302 clinical medicine, 1311 Genetics, Internal medicine, Cryptorchidism, Genetics, medicine, Humans, Genetic Testing, Receptor, Fibroblast Growth Factor, Type 1, Genetics (clinical), Testosterone, Genetic testing, medicine.diagnostic_test, Hypogonadism, Fibroblast growth factor receptor 1, Infant, Newborn, Genetic disorder, Micropenis, medicine.disease, 030104 developmental biology, Endocrinology, 10036 Medical Clinic, Congenital Hypogonadotropic Hypogonadism, Luteinizing hormone, Signal Transduction, Hormone
Abstract

Neonatal micropenis and cryptorchidism raise the suspicion of congenital hypogonadotropic hypogonadism (CHH), a rare genetic disorder caused by gonadotropin-releasing hormone deficiency. Low plasma testosterone levels and low gonadotropins during minipuberty provide a clinical diagnostic clue, yet these tests are seldomly performed in general practice. We report a male neonate with no family history of reproductive disorders who was born with micropenis and cryptorchidism. Hormonal testing at age 2.5 months showed low testosterone (0.3 nmol/L) and undetectable gonadotropins (luteinizing hormone and follicle-stimulating hormone both

Published
2017

49. Estradiol levels in men with congenital hypogonadotropic hypogonadism and the effects of different modalities of hormonal treatment

Author

Anne Guiochon-Mantel, Nelly Pitteloud, Philippe Chanson, Stéphanie Baron, Antonio Agostino Sinisi, Luigi Maione, Françoise Galland, Jacques Young, Sylvie Brailly-Tabard, Hélène Bry-Gauillard, Séverine Trabado, Sylvie Salenave, Trabado, S, Maione, L, Salenave, S, Baron, S, Galland, F, Bry Gauillard, H, Guiochon Mantel, A, Chanson, P, Pitteloud, N, Sinisi, Antonio Agostino, Brailly Tabard, S, and Young, J.

Subjects
Adult, Male, medicine.medical_specialty, Paris, Adolescent, medicine.drug_class, Kallmann syndrome, Hormone Replacement Therapy, Population, Chorionic Gonadotropin, Young Adult, Sex hormone-binding globulin, Klinefelter Syndrome, Hypogonadotropic hypogonadism, Internal medicine, Sex Hormone-Binding Globulin, medicine, Humans, Testosterone, Prospective Studies, education, Retrospective Studies, education.field_of_study, Analysis of Variance, biology, Estradiol, business.industry, Hypogonadism, Obstetrics and Gynecology, Dihydrotestosterone, Luteinizing Hormone, Middle Aged, Androgen, medicine.disease, Endocrinology, Treatment Outcome, Reproductive Medicine, biology.protein, Androgens, Congenital Hypogonadotropic Hypogonadism, Klinefelter syndrome, Follicle Stimulating Hormone, business, Biomarkers
Abstract

Objective To evaluate the degree of E 2 deficiency in male congenital hypogonadotropic hypogonadism (CHH), and its response to different hormonal treatments. Design Retrospective and prospective studies. Setting Academic institution. Patient(s) Untreated or treated CHH, healthy men, untreated men with Klinefelter syndrome (KS). Intervention(s) Serum sex hormone-binding globulin (SHBG) and total E 2 (TE2) as well as bioavailable (BE2) and free (FE2) levels were measured and determined. Main Outcome Measure(s) Total, bioavailable, and free testosterone, TE2, BE2, FE2 were compared in normal men, untreated and treated CHH and in untreated KS. Result(s) TE2, BE2, and FE2 levels were very significantly lower in untreated patients with CHH (n = 91) than in controls (n = 63) and in patients with KS (n = 45). The TE2 correlated positively with serum total T in patients with CHH. The TE2 also correlated very positively with serum LH in the combined population of patients with CHH and healthy men, suggesting that low E 2 levels in CHH are due to severe LH-driven T deficiency. All fractions of circulating E 2 were very significantly higher in patients with CHH receiving T enanthate (n = 101) or the FSH–hCG combination (n = 88) than in untreated patients with CHH. Contrary to dihydrotestosterone (DHT), both T enanthate and combined FSH-hCG therapy significantly and prospectively increased TE2 levels in patients with CHH. Conclusion(s) Contrary to KS, the male hypogonadism observed in CHH is associated with profound E 2 deficiency, which can be overcome by aromatizable androgen or combined gonadotropin therapy.

Published
2011

50. Heavy metal in radiation therapy: A simple method to differentiate hip prosthesis materials.

Author

Miéville FA, Pitteloud N, Pisaturo O, Tercier PA, Lamanna G, Achard V, and Allal AS

Subjects
Humans, Radiotherapy Planning, Computer-Assisted methods, Radiotherapy Dosage, Artifacts, Metals, Heavy, Calibration, Titanium, Image Processing, Computer-Assisted methods, Hip Prosthesis, Tomography, X-Ray Computed
Abstract

Background: In recent years, the number of hip replacement patients receiving radiation therapy has steadily increased. In parallel, strategies have been developed to reduce metal artifacts in computed tomography (CT) images and improve the accuracy of dose calculation algorithms. However, in certain situations, knowledge of the type of prosthesis material is required to accurately determine the dose distribution., Purpose: This study aims to identify physical materials in hip prostheses to correctly assign them in the treatment planning system and improve dose calculation accuracy., Methods: We first verified the validity of the extended CT mass density calibration curve measured on titanium (Ti) and stainless steel (SS) metal inserts of two different diameters. Then using dedicated reference objects of various circular diameters, we developed a method based on interpolation functions to differentiate between Ti and SS material groups. Forty data sets from 18 patients were used to validate our method on two different reconstruction kernels: a standard Br44f and the electron DirectDensity (Sd40f) kernels from Siemens., Results: Hounsfield units (HU) of Ti and SS inserts were found to vary widely depending on insert diameter, CT spectrum, and reconstruction kernels due to cupping artifacts. The largest HU difference (-79%) was obtained for SS at 70 kV with Br44f when the diameter increased from 8 to 30 mm. Therefore, under these conditions, the extended CT-density calibration curve is not recommended for heavy metal density determination. Using our interpolation-based method, we achieved excellent detection (100%) and material differentiation (100%) results for stems in both reconstruction kernels. At CT energies between 110 and 140 kV, the detection and material differentiation rates were 93.3% and 92.9% for the heads and 93.3% and 92.9% for the acetabular cups, respectively, with the Br44f. Similarly, the use of Sd40f resulted in detection and differentiation rates of 94.7% and 100% for the heads and 100% and 95.0% for the acetabular cups, respectively., Conclusion: This method makes it possible to differentiate between hip prosthesis materials and correctly assign them to the Ti or SS group without prior knowledge of the prosthesis type, regardless of the reconstruction kernels. In combination with the Acuros XB (Varian) or Monte Carlo dose algorithms, excellent dosimetric accuracy can be achieved even in the vicinity of hip prostheses. By performing basic measurements, the method can be adapted to other CT units and reconstruction kernels, replacing the use of an extended CT-density calibration curve., (© 2024 American Association of Physicists in Medicine.)

Published
2024
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