Thierry Brue

Aix-Marseille Université, Marsiglia, Provence-Alpes-Côte d'Azur, France

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Publications (198)664.16 Total impact

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    ABSTRACT: Gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs) raise difficult therapeutic problems despite the emergence of targeted therapies. Somatostatin analogues (SSA) remain pivotal therapeutic drugs. However, the tachyphylaxis and the limited antitumoral effects observed under the classical sst2 agonists (octreotide, lanreotide) led to the development of new SSA, such as the pan somatostatin receptor (sst) agonist pasireotide. Our aim was to compare pasireotide and octreotide effects on cell survival, chromogranin A (CgA) secretion, and sst2 phosphorylation/trafficking in pNET primary cells from 15 tumors. We established and characterized primary cultures of human pancreatic tumors (pNETs) as powerful preclinical models to understand the biological impacts of SSA. At clinically relevant concentrations (1-10 nM), pasireotide was at least as efficient as octreotide in inhibiting CgA secretion and cell viability through caspase-dependent apoptosis during short treatments, whatever the expression levels of the different sst receptors or the WHO grade of the parental tumor. Interestingly, contrary to octreotide, which induces a rapid and persistent partial internalization of sst2 associated to its phosphorylation on Ser341-343, pasireotide did not phosphorylate sst2 and induced a rapid and transient internalization of the receptor followed by a persistent recycling at the cell surface. These results provide the first evidence of striking differences in the dynamics of sst2 trafficking in pNET cells under the two SSA but similar efficiency in the control of CgA secretion and cell viability.
    Endocrine Related Cancer 10/2014; 21(5):691-704. · 5.26 Impact Factor
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    ABSTRACT: Context: The ghrelin receptor GHS-R1a, is highly expressed in human somatotroph adenomas and exhibits unusual high basal signaling activity. In humans, the suppression of this constitutive activity by mutation induces a short stature. Objective: Using a GHS-R1a inverse agonist, MSP, we explored the role of GHS-R1a constitutive activity in GH hypersecretion from somatotroph adenomas and as putative therapeutic target. Design: The effects of MSP were assessed on GH secretion from 19 human somatotroph tumors in vitro. Moreover, these effects were compared with those of octreotide (sst2 agonist) and with the combination of both drugs. Expression and localization of GHS-R1a and sst2 were studied. Results: For all tumors, MSP inhibited GH secretion in a dose dependent manner, from 13 to 64%. Moreover, MSP enhanced octreotide-induced GH inhibition. For 5 tumors, the effects of combined MSP + octreotide treatment were significantly higher than the sum of effects of each drug alone. MSP increased the membrane localization of GHS-R1a and of microdomains colocalizing sst2-GHS-R1a, highlighting the cooperation between the two drugs. Conclusions: The GHS-R1a inverse agonist could open new therapeutic options for acromegalic patients, particularly patients partially sensitive to octreotide whose GH secretion is not completely controlled by the sst2 agonist.
    The Journal of clinical endocrinology and metabolism. 10/2014;
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    ABSTRACT: Objectif L’objectif de cette étude était d’évaluer la pertinence du test couplé déxaméthasone desmopressine (TCDD) comme facteur prédictif de récidive de maladie de Cushing après chirurgie trans-sphénoïdale. Matériel et méthodes Nous avons rétrospectivement étudié 67 patients dans deux centres tertiaires (Marseille et Grenoble), en rémission initiale après chirurgie transsphénoïdale et suivis au moins 18 mois. Nous avons évalué à 3 mois puis annuellement le cortisol libre urinaire sur 24 h, les taux d’ACTH et de cortisol plasmatiques, la réponse aux tests de freinage minute et à la desmopressine et le TCDD. Après TCDD, un ratio d’ACTH (ACTHr) et de cortisol (cortisolr) étaient déterminés par la formule (pic – valeur basale)/valeur basale. Résultats Onze patients avaient récidivé après un suivi médian de 52 mois (18–180). L’association ACTHr et cortisole supérieur ou égal à 0,5 était présente chez tous les patients ayant récidivé et chez 14/56 patients en rémission (sensibilité = 100 %, spécificité = 75 %). La positivité du TCDD précédait de 6-76 mois les marqueurs classiques d’hypercorticisme chez 10/11 patients ayant récidivé. Six patients avaient récidivé malgré une cortisolémie à 8 h en postopératoire immédiat inférieur à 50 nmol/L : tous avaient un TCDD positif dans les 3 ans suivant la chirurgie. La réponse au TCDD était reproductible au cours des évaluations chez 91 % des patients. Conclusion Le TCDD est un facteur prédictif précoce et fiable de récidive de maladie de Cushing et a un intérêt majeur dans les 3 ans postopératoire pour optimiser la surveillance à long terme.
    Annales d'Endocrinologie. 10/2014; 75(s 5–6):264.
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    ABSTRACT: Background Many patients with acromegaly do not achieve biochemical control despite receiving high doses of the first-generation somatostatin analogues octreotide or lanreotide. In the PAOLA trial, we aimed to assess the efficacy and safety of two different doses of the somatostatin analogue pasireotide long-acting release compared with active control (octreotide or lanreotide) in patients with inadequately controlled acromegaly. Methods In a multicentre, randomised, phase 3 trial, we enrolled eligible patients aged 18 years or older with acromegaly who were inadequately controlled (5-point, 2 h mean growth hormone concentration >2·5 μg/L and insulin-like growth factor 1 [IGF-1] concentration >1·3 times the upper normal limit) and had received 30 mg octreotide long-acting repeatable or 120 mg lanreotide (Somatuline Autogel; Ipsen, UK) as monotherapy for 6 months or longer. We randomly assigned patients in a 1:1:1 ratio with an interactive voice-web response system to receive 40 mg pasireotide long-acting release once every 28 days for 24 weeks, 60 mg pasireotide long-acting release once every 28 days for 24 weeks, or continued treatment with octreotide or lanreotide (active control). Patients were stratified according to previous treatment (octreotide or lanreotide) and growth hormone concentrations at screening (2·5–10 μg/L and >10 μg/L). Patients and study investigators were not masked to study drug assignment but were masked to pasireotide dose allocation. The primary endpoint was number of patients achieving biochemical control, defined as mean growth hormone concentration less than 2·5 μg/L and normalised IGF-1 concentration. Efficacy analyses were based on intention to treat. This trial is registered with, number NCT01137682. Findings Between Dec 17, 2010, and Aug 6, 2012, 198 patients were enrolled and randomly assigned to pasireotide 40 mg (n=65), pasireotide 60 mg (n=65), or active control (n=68) groups. At 24 weeks, ten (15%) patients in the pasireotide 40 mg group and 13 (20%) patients in the pasireotide 60 mg group achieved biochemical control, compared with no patients in the active control group (absolute difference from control group 15·4%, 95% CI 7·6–26·5, p=0·0006 for pasireotide 40 mg group, 20·0%, 11·1–31·8, p<0·0001 for pasireotide 60 mg group). The most common adverse events were hyperglycaemia (21 [33%] for treatment with 40 mg pasireotide, 19 [31%] with 60 mg pasireotide, and nine [14%] with active control), diabetes (13 [21%], 16 [26%], and five [8%]), and diarrhoea (ten [16%], 12 [19%], and three [5%]); most were grade 1 or 2 in severity. Serious adverse events were reported in six (10%) patients in the pasireotide 40 mg group, two (3%) in the pasireotide 60 mg group, and three (5%) in the active control group. Interpretation Pasireotide provides superior efficacy compared with continued treatment with octreotide or lanreotide, and could become the new standard pituitary-directed treatment in patients with acromegaly who are inadequately controlled using first-generation somatostatin analogues. Funding Novartis Pharma AG. Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals Corporation.
    The Lancet Diabetes & Endocrinology. 09/2014;
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    ABSTRACT: Over the last two decades, the understanding of the mechanisms involved in pituitary ontogenesis has largely increased. Since the first description of POU1F1 human mutations responsible for a well-defined phenotype without extra-pituitary malformation, several other genetic defects of transcription factors have been reported with variable degrees of phenotype-genotype correlations. However, to date, despite the identification of an increased number of genetic causes of isolated or multiple pituitary deficiencies, the etiology of most (80-90 %) congenital cases of hypopituitarism remains unsolved. Identifying new etiologies is of importance as a post-natal diagnosis to better diagnose and treat the patients (delayed pituitary deficiencies, differential diagnosis of a pituitary mass on MRI, etc.), and as a prenatal diagnosis to decrease the risk of early death (undiagnosed corticotroph deficiency for instance). The aim of this review is to summarize the main etiologies and phenotypes of combined pituitary hormone deficiencies, associated or not with extra-pituitary anomalies, and to suggest how the identification of such etiologies could be improved in the near future.
    Journal of endocrinological investigation 09/2014; · 1.65 Impact Factor
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    ABSTRACT: To describe the results of growth hormone (GH) therapy in adult GH-deficient patients treated in a tertiary referral center, with a focus on quality of life and adherence.
    Annales d'endocrinologie. 07/2014;
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    ABSTRACT: The prevention of medullary thyroid cancer in patients with multiple endocrine neoplasia type 2 syndrome has demonstrated the ability of molecular diagnosis and prophylactic surgery to improve patient outcomes. However, the other major neoplasia associated with multiple endocrine neoplasia type 2, phaeochromocytoma, is not as well characterised in terms of occurrence and treatment outcomes. In this study, we aimed to systematically characterise the outcomes of management of phaeochromocytoma associated with multiple endocrine neoplasia type 2. This multinational observational retrospective population-based study compiled data on patients with multiple endocrine neoplasia type 2 from 30 academic medical centres across Europe, the Americas, and Asia. Patients were included if they were carriers of germline pathogenic mutations of the RET gene, or were first-degree relatives with histologically proven medullary thyroid cancer and phaeochromocytoma. We gathered clinical information about patients'RET genotype, type of treatment for phaeochromocytoma (ie, unilateral or bilateral operations as adrenalectomy or adrenal-sparing surgery, and as open or endoscopic operations), and postoperative outcomes (adrenal function, malignancy, and death). The type of surgery was decided by each investigator and the timing of surgery was patient driven. The primary aim of our analysis was to compare disease-free survival after either adrenal-sparing surgery or adrenalectomy. 1210 patients with multiple endocrine neoplasia type 2 were included in our database, 563 of whom had phaeochromocytoma. Treatment was adrenalectomy in 438 (79%) of 552 operated patients, and adrenal-sparing surgery in 114 (21%). Phaeochromocytoma recurrence occurred in four (3%) of 153 of the operated glands after adrenal-sparing surgery after 6-13 years, compared with 11 (2%) of 717 glands operated by adrenalectomy (p=0·57). Postoperative adrenal insufficiency or steroid dependency developed in 292 (86%) of 339 patients with bilateral phaeochromocytoma who underwent surgery. However, 47 (57%) of 82 patients with bilateral phaeochromocytoma who underwent adrenal-sparing surgery did not become steroid dependent. The treatment of multiple endocrine neoplasia type 2-related phaeochromocytoma continues to rely on adrenalectomies with their associated Addisonian-like complications and consequent lifelong dependency on steroids. Adrenal-sparing surgery, a highly successful treatment option in experienced centres, should be the surgical approach of choice to reduce these complications. European Union, German Cancer Foundation, Arthur Blank Foundation, Italian Government, Charles University, Czech Ministry of Health, Nanjing Military Command, National Science Centre Poland, National Research Council for Scientific and Technological Development, and State of São Paulo Research Foundation.
    The Lancet Oncology 04/2014; · 25.12 Impact Factor
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    ABSTRACT: Introduction:Focused parathyroidectomy is the treatment of choice for patients with concordant positive imaging. Bilateral cervical exploration is performed for cases with discordant imaging, yet more than 70% of those cases are the result of a single gland disease. As focused parathyroidectomy is generally costless and harmless, for cases with discordant imaging, we tried to determine whether pre-operative characteristics can lead to a diagnosis of single disease.Methods:This study included 182 patients treated for primary hyperparathyroidism by bilateral exploration from 2009 to 2012 at La Timone Hospital, Marseille, France. We classified the patients on preoperative images and pathological results (single or multiglandular disease). We then compared the demographical, laboratory and imaging results. We also asked a senior nuclear medicine practitioner who was blind to the ultrasound and pathological results to perform a second reading.Results:15.4% of patients had negative, 54.4% discordant, and 30.2% concordant imaging. After reviewing the scintigraphy results, 8% of the cases with discordant imaging would have been classified as concordant with ultrasound. Subtraction scintigraphy obtained better results than dual-phase scintigraphy (concordance with ultrasound in 50 vs 31% with classical scintigraphy). For the cases of discordant imaging, no predictive factors of single gland disease could be identified. Ultrasound and scintigraphy were similarly effective in determining the correct location of the abnormal gland.Conclusion:Discordant results of preoperative imaging modalities do not discriminate between uniglandular and multiglandular disease in hyperparathyroidism. Diagnostic differentiation between the different causes of hyperparathyroidism requires improvements in imaging techniques, and might benefit from subtraction scintigraphy.
    European Journal of Endocrinology 02/2014; · 3.14 Impact Factor
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    ABSTRACT: Background: The use of ketoconazole has been recently questioned after warnings from the European Medicine Agencies and the Food and Drug Administration due to potential hepatotoxicity. However, ketoconazole is frequently used as a drug to lower circulating cortisol levels. Several pharmacological agents have recently been approved for the treatment of Cushing's disease (CD) despite limited efficacy and significant side effects. Ketoconazole has been used worldwide for more than 30 years in CD but in the absence of large scale study, its efficacy and tolerance are still under debate. Patients and methods: We conducted a French retrospective, multicenter study reviewing data from patients treated by ketoconazole as a single agent for CD, with the aim of clarifying efficacy and tolerance in order to better determine the benefits/risk balance. Results: Data from 200 patients were included in this study. At the last follow-up, 49.3% of patients had normal urinary free cortisol (UFC) levels, 25.6% had at least a 50% decrease, and 25.4% had unchanged UFC levels. The median final dose of ketoconazole was 600 mg/day. Forty patients (20%) received ketoconazole as a pre-surgical treatment; 40-50% of these patients showed improvement of hypertension, hypokalemia and diabetes, and 48.7% had normal UFC before surgery. Overall, 41 patients (20.5%) stopped the treatment due to poor tolerance. Mild (< 5N) and major (>5N) increases in liver enzymes were observed in 13.5 % and 2.5% of patients respectively. No fatal hepatitis was observed. Conclusions: Ketoconazole is an effective drug with acceptable side effects. It should be used under close liver enzyme monitoring. Hepatotoxicity is usually mild and resolutive after drug withdrawal.
    The Journal of Clinical Endocrinology and Metabolism 01/2014; · 6.31 Impact Factor
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    The Lancet Oncology 01/2014; · 25.12 Impact Factor
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    ABSTRACT: Objectif Décrire les résultats du traitement par hormone de croissance (GH) chez des patients adultes déficitaires en GH, traités dans un centre de référence, en particulier les effets sur la qualité de vie et l’adhésion au traitement. Patients et méthodes Étude rétrospective portant sur des patients suivis sur une période de 11 ans. La qualité de vie (QOL) a été évaluée par le score de l’échelle QOL-Assessment of Growth Hormone Deficiency in Adults (QoL-AGHDA) et l’adhésion a été mesurée par un questionnaire spécifique. Nous avons aussi recueilli les données sur les paramètres cliniques, biologiques, la masse grasse et la minéralisation osseuse. Résultats Les données de 81 patients ont été analysées. Après une durée médiane de traitement de 7 ans, les deux tiers des patients ont rapporté une amélioration significative de la QOL (réduction moyenne de 3 points du score AGHDA, p < 0,001), plus fréquente (bien que non significativement) chez les patients d’âge moyen, les femmes, les patients ayant eu un GHD dans l’enfance et chez ceux ayant une QOL initiale plus altérée. Plus de 60 % des patients disaient poursuivre leur traitement sans interruption. Soixante-dix pour cent déclaraient une bonne adhésion (2 injections manquées ou moins/mois) et une majorité rapportaient une amélioration du bien être. Le poids moyen a augmenté de 2 kg alors que la masse grasse, le rapport tour de taille/tour de hanche et le bilan lipidique n’ont pas changé. La densité minérale osseuse a augmenté de façon significative au niveau du rachis et du col fémoral. Conclusion Notre étude confirme la persistance de l’amélioration de la QOL au long cours et a montré que la majorité des patients étaient toujours sous traitement après une durée médiane de 7 ans.
    Annales d'Endocrinologie. 01/2014;
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    ABSTRACT: In primary cultures of rat pituitary cells and in a pituitary sommatolactotroph cell line (GH4C1), endogenous core-clock- as well as hormone-genes such as prolactin displayed a rhythmic expression pattern, fitted by a sinusoidal equation in which the period value was close to the circadian one. This is consistent with the presence of a functional circadian oscillator in pituitary cells whose importance was ascertained in GH4C1 cell lines stably expressing a dominant negative mutant of BMAL1. In these cells, both endogenous core-clock- and prolactin-genes no more displayed a circadian pattern. Some genes we recently identified as mouse pituitary BMAL1-regulated genes in a DNA-microarray study, lost their circadian pattern in these cells, suggesting that BMAL1 controlled these genes locally in the pituitary. The intra-pituitary circadian oscillator could then play a role in the physiology of the gland that would not be seen anymore as a structure only driven by hypothalamic rhythmic control.
    Molecular and Cellular Endocrinology 11/2013; · 4.04 Impact Factor
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    ABSTRACT: Pituitary apoplexy is a rare event defined as the hemorrhagic necrosis of a pituitary adenoma(1) . Several risk factors have been reported, such as stimulation tests, anticoagulant therapy, surgery, hypertension, dopamine agonist given in prolactinoma(2) , or even octreotide in 3 cases of acromegaly(3-5) . To our knowledge, no case has ever been reported after the use of Lanreotide. Shortly after we had been made aware of such a case that was reported to our Reference Center for Rare Pituitary Diseases by colleagues from a different hospital in France, we observed a similar case in our center. A database search revealed 2 other isolated cases from other countries that had only been reported as short communications in endocrinology meetings (Riera M, European Neuro Endocrine Association, 2010; Herrera J, European Neuro Endocrine Association, 2006). Other centers were contacted, but only these 4 cases could be retrieved: we thus report here the cases of 4 patients with acromegaly, followed in 4 different Centers, treated with slow-release lanreotide (LR) or LR Autogel(®) , who presented pituitary apoplexy shortly after administration. This article is protected by copyright. All rights reserved.
    Clinical Endocrinology 10/2013; · 3.40 Impact Factor
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    ABSTRACT: BACKGROUND. Little is known about the Sheehan's syndrome (SS), even though it is believed that the incidence is low. The aim of our study was to determine the clinical features and diagnostic delay of SS and to ascertain whether early signs could have allowed earlier diagnosis.METHODS. All patients with SS diagnosed in reference units in the South-East of France between 1980 and 2011 were reported. Obstetric history, clinical symptoms suggestive of hypopituitarism, early signs, hormone analysis, and MRI data were collected.RESULTS. Thirty-nine of 40 women found with SS, were studied. Mean delay in SS diagnosis was 9 +/- 9.7 years. We found that 4 out of 35 assessable patients were diagnosed with agalactia, 16 out of 29 assessable ones with amenorrhea, 19 out of 39 with hypothyroidism, 8 with acute adrenal insufficiency and 15 with asthenia. Among the patients for whom there was a diagnostic delay of more than one year (n=28), 7 had headaches during the postpartum period, all assessable patients had agalactia, 6 out of 22 assessable ones amenorrhea, 7 out of 28 hypothyroidism and 12 out of 28 asthenia.CONCLUSION. Most signs of SS are aspecific and classical signs such as agalactia and amenorrhea are often difficult to collect, which can explain the long diagnostic delay. We suggest that all women failing to lactate after postpartum hemorrhage should be evaluated by measuring prolactin; and women with signs such as amenorrhea, asthenia, even several years after postpartum hemorrhage, should have a blood test including T4, TSH, 08:00h ACTH-cortisol and IGF-I.
    European Journal of Endocrinology 07/2013; · 3.14 Impact Factor
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    ABSTRACT: Pituitary adenomas are currently classified by histological, immunocytochemical and numerous ultrastructural characteristics lacking unequivocal prognostic correlations. We investigated the prognostic value of a new clinicopathological classification with grades based on invasion and proliferation. This retrospective multicentric case-control study comprised 410 patients who had surgery for a pituitary tumour with long-term follow-up. Using pituitary magnetic resonance imaging for diagnosis of cavernous or sphenoid sinus invasion, immunocytochemistry, markers of the cell cycle (Ki-67, mitoses) and p53, tumours were classified according to size (micro, macro and giant), type (PRL, GH, FSH/LH, ACTH and TSH) and grade (grade 1a: non-invasive, 1b: non-invasive and proliferative, 2a: invasive, 2b: invasive and proliferative, and 3: metastatic). The association between patient status at 8-year follow-up and age, sex, and classification was evaluated by two multivariate analyses assessing disease- or recurrence/progression-free status. At 8 years after surgery, 195 patients were disease-free (controls) and 215 patients were not (cases). In 125 of the cases the tumours had recurred or progressed. Analyses of disease-free and recurrence/progression-free status revealed the significant prognostic value (p < 0.001; p < 0.05) of age, tumour type, and grade across all tumour types and for each tumour type. Invasive and proliferative tumours (grade 2b) had a poor prognosis with an increased probability of tumour persistence or progression of 25- or 12-fold, respectively, as compared to non-invasive tumours (grade 1a). This new, easy to use clinicopathological classification of pituitary endocrine tumours has demonstrated its prognostic worth by strongly predicting the probability of post-operative complete remission or tumour progression and so could help clinicians choose the best post-operative therapy.
    Acta Neuropathologica 02/2013; · 9.73 Impact Factor
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    ABSTRACT: CONTEXT: germline mutations in the AIP gene have been identified in young patients (age ≤ 30 years old) with sporadic pituitary macroadenomas. Otherwise, there are few data concerning the prevalence of MEN1 mutations in such population. OBJECTIVE: We assessed the prevalence of both AIP and MEN1 genetic abnormalities (mutations and large gene deletions) in young patients (age ≤ 30 years old) diagnosed with sporadic and isolated macroadenoma, without hypercalcemia and/or MEN1-associated lesions. DESIGN: The entire coding sequences of AIP and MEN1 were screened for mutations. In cases of negative sequencing screening, multiplex ligation-dependent probe amplification was performed for the detection of large genetic deletions. PATIENTS AND SETTINGS: 174 patients from Endocrinology Departments of 15 French University Hospital Centers were eligible for this study. RESULTS: 21/174(12%) patients had AIP (n=15, 8.6%) or MEN1 (n=6, 3.4%) mutations. In pediatric patients (age ≤ 18 years old), AIP/MEN1 mutation frequency reached nearly 22% (n=10/46). AIPmut and MEN1mut were respectively identified in 8/79 (10.1%) and 1/79 (1.2%) somatotropinoma patients; they each accounted for 4/74 (5.4%) prolactinoma patients with mutations. Half of patients (n=3/6) with gigantism displayed mutations in AIP. Interestingly, 4/12 (33%) patients with non-secreting adenomas bore either AIP or MEN1 mutations, whereas none of the 8 corticotroph-adenomas and a single thyrotropinoma case had mutations. No large gene deletions were observed in sequencing-negative patients. CONCLUSION: mutations in MEN1 can be of significance in young patients with sporadic isolated pituitary macroadenomas, particularly prolactinomas, and together with AIP, we suggest genetic analysis of MEN1 in such population.
    European Journal of Endocrinology 01/2013; · 3.14 Impact Factor
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    ABSTRACT: Normosmic congenital hypogonadotropic hypogonadism (nCHH) is a rare reproductive disease leading to lack of puberty and infertility. Loss-of-function mutations of GNRH1 gene are a very rare cause of autosomal recessive nCHH. R31C GNRH1 is the only missense mutation that affects the conserved GnRH decapeptide sequence. This mutation was identified in a CpG islet in nine nCHH subjects from four unrelated families, giving evidence for a putative "hot spot". Interestingly, all the nCHH patients carry this mutation in heterozygosis that strikingly contrasts with the recessive inheritance associated with frame shift and non-sense mutations. Therefore, after exclusion of a second genetic event, a comprehensive functional characterization of the mutant R31C GnRH was undertaken. Using different cellular models, we clearly demonstrate a dramatic reduction of the mutant decapeptide capacity to bind GnRH-receptor, to activate MAPK pathway and to trigger inositol phosphate accumulation and intracellular calcium mobilization. In addition it is less able than wild type to induce lh-beta transcription and LH secretion in gonadotrope cells. Finally, the absence of a negative dominance in vitro offers a unique opportunity to discuss the complex in vivo patho-physiology of this form of nCHH.
    PLoS ONE 01/2013; 8(7):e69616. · 3.53 Impact Factor
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    ABSTRACT: Cushing's disease causes considerable morbidity and mortality, including cardiovascular, metabolic, respiratory and psychiatric complications, bone demineralization and increased susceptibility to infections. Metabolic complications include a high prevalence of impaired glucose tolerance, fasting hyperglycaemia and diabetes. Although pituitary surgery is the gold-standard treatment, other treatment strategies such as radiotherapy and medical therapy to reduce cortisol synthesis may be proposed in the event of recurrence or failure, or when surgery is not an option. Bilateral adrenalectomy can also be considered. One of the medical treatments used in Cushing's disease is the somatostatin analogue pasireotide, which acts on adrenocorticotropic hormone (ACTH) secretion by the pituitary. Its efficacy in reducing urinary free cortisol, plasma cortisol and ACTH, and in improving the clinical signs of the disease has been demonstrated. Its observed adverse effects are similar to the known effects of first-generation somatostatin analogues, although disturbances of carbohydrate metabolism are more frequent and more severe with pasireotide. The aim of the present review was to summarize the epidemiology and pathophysiology of the disturbances of glucose metabolism that arise in Cushing's disease, and to propose recommendations for detecting and monitoring glucose abnormalities and for managing pasireotide-induced hyperglycaemia.
    Diabetes & Metabolism 12/2012; · 2.39 Impact Factor
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    ABSTRACT: The anterior and intermediate lobes of the pituitary gland derive from the surface ectoderm. They provide a simple system to assess mechanisms of developmental identity established by tissue determinants. Each lobe contains a lineage expressing the hormone precursor pro-opiomelanocortin (POMC): the corticotropes and melanotropes. The T-box transcription factor Tpit controls terminal differentiation of both lineages. We now report on the unique role of Pax7 as a selector of intermediate lobe and melanotrope identity. Inactivation of the Pax7 gene results in loss of melanotrope gene expression and derepression of corticotrope genes. Pax7 acts by remodeling chromatin and allowing Tpit binding to a new subset of enhancers for activation of melanotrope-specific genes. Thus, the selector function of Pax7 is exerted through pioneer transcription factor activity. Genome-wide, the Pax7 pioneer activity is preferentially associated with composite binding sites that include paired and homeodomain motifs. Pax7 expression is conserved in human and dog melanotropes and defines two subtypes of pituitary adenomas causing Cushing's disease. In summary, expression of Pax7 provides a unique tissue identity to the pituitary intermediate lobe that alters Tpit-driven differentiation through pioneer and classical transcription factor activities.
    Genes & development 10/2012; 26(20):2299-310. · 12.08 Impact Factor
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    ABSTRACT: Dopamine agonist resistance in prolactinoma is an infrequent phenomenon. Doses of cabergoline (CAB) of up to 2.0 mg/week are usually effective in controlling prolactin (PRL) secretion and reducing tumor size in prolactinomas. The clinical presentation, management, and outcome of patients that are not well controlled by such commonly used doses of CAB-resistant patients are poorly understood. A multicenter retrospective study was designed to collect a large series of resistant prolactinoma patients, defined by uncontrolled hyperprolactinemia on CAB ≥2.0 mg weekly. Ninety-two patients (50 F, 42 M) were analyzed. At diagnosis, most had macroprolactinomas (82.6%); males were significantly older than females (P=0.0003) and presented with a more aggressive disease. A genetic basis was identified in 12 patients. Thirty-six patients (39.1%) received only medical therapy, most underwent surgery (60.9%, including multiple interventions in 10.9%), and 14.1% received postoperative radiotherapy. Eight patients developed late CAB resistance (8.7%). The median maximal weekly dose of CAB (CAB(max/w)) was 3.5 mg (2.0-10.5). Despite a higher CAB(max/w) in patients treated with multimodal therapy (P=0.003 vs exclusive pharmacological treatment), a debulking effect of surgery was shown in 14 patients, with a higher rate of PRL control (P=0.006) and a significant reduction in CAB(max/w) (P=0.001) postoperatively. At last follow-up (median 88 months), PRL normalization and tumor disappearance were achieved in 28 and 19.9% of the patients respectively, with no significant sex-related difference observed in CAB(max/w) or disease control. Mortality was 4.8%, with four patients developing aggressive tumors (4.3%) and three a pituitary carcinoma (3.3%). CAB-resistant prolactinomas remain a serious concern. Surgical debulking, newer therapeutic strategies, and early diagnosis of genetic forms could help to improve their outcome.
    European Journal of Endocrinology 08/2012; 167(5):651-62. · 3.14 Impact Factor

Publication Stats

3k Citations
664.16 Total Impact Points


  • 2005–2014
    • Aix-Marseille Université
      • Centre de Recherches en Cancérologie de Marseille (UM 105 UMR_S 1068 UMR 7258 CRCM)
      Marsiglia, Provence-Alpes-Côte d'Azur, France
    • Centre Hospitalier Universitaire de Limoges
      Limages, Limousin, France
    • Carol Davila University of Medicine and Pharmacy
      Bucureşti, Bucureşti, Romania
  • 1996–2014
    • French National Centre for Scientific Research
      Lutetia Parisorum, Île-de-France, France
  • 2008–2013
    • Assistance Publique Hôpitaux de Marseille
      • Service de neurochirurgie infantile
      Marsiglia, Provence-Alpes-Côte d'Azur, France
  • 2006–2012
    • Centre Hospitalier Universitaire de Liège
      Luik, Walloon Region, Belgium
    • University of Chicago
      • Department of Medicine
      Chicago, IL, United States
    • CHU de Lyon - Groupement Hospitalier Edouard Herriot
      Lyons, Rhône-Alpes, France
    • McGill University
      • Department of Medicine
      Montréal, Quebec, Canada
  • 2003–2012
    • Institut de recherches cliniques de Montréal
      Montréal, Quebec, Canada
  • 2011
    • Medical University of Vienna
      Wien, Vienna, Austria
  • 2010
    • University of Michigan
      Ann Arbor, Michigan, United States
    • University of Gothenburg
      • Endocrinology Unit
      Göteborg, Vaestra Goetaland, Sweden
    • Institut de Recherche sur les Phénomènes Hors Equilibre
      Marsiglia, Provence-Alpes-Côte d'Azur, France
  • 2009
    • Hospices Civils de Lyon
      Lyons, Rhône-Alpes, France
    • Università degli Studi dell'Aquila
      • Department of Experimental Medicine
      Aquila, Abruzzo, Italy
  • 2007
    • The Jikei University School of Medicine
      • Department of Pediatrics
      Tokyo, Tokyo-to, Japan
    • Centre Hospitalier Régional Universitaire de Lille
      Lille, Nord-Pas-de-Calais, France
  • 2001
    • University Hospital Estaing of Clermont-Ferrand
      Clermont, Auvergne, France
  • 1999
    • University of Liège
      Luik, Walloon Region, Belgium
  • 1992
    • Centre Hospitalier Universitaire de Nancy
      Nancy, Lorraine, France
    • Centre Hospitalier Universitaire Rouen
      • Service d'Endocrinologie, Diabète et Maladies Métaboliques
      Rouen, Upper Normandy, France
  • 1990
    • Hôpital Européen, Marseille
      Marsiglia, Provence-Alpes-Côte d'Azur, France