Thierry Brue

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

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Publications (262)755.38 Total impact

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    ABSTRACT: ISL1 is a LIM homeodomain transcription factor necessary for development of the pituitary, retina, motor neurons, heart, and pancreas. Isl1 deficient mice (Isl1(-/-)) die early during embryogenesis at embryonic day 10.5 due to heart defects, and at that time, they have an undersized pituitary primordium. ISL1 is expressed in differentiating pituitary cells in early embryogenesis. Here we report the cell specific expression of ISL1 and assessment of its role in gonadotropes and thyrotropes. Isl1 expression is elevated in pituitaries of Cga(-/-) mice, a model of hypothyroidism with thyrotrope hypertrophy and hyperplasia. Thyrotrope-specific disruption of Isl1 with Tshb-cre is permissive for normal serum TSH, but T4 levels are decreased suggesting decreased thyrotrope function. Inducing hypothyroidism in normal mice causes a reduction in T4 levels and dramatically elevated TSH response, but mice with thyrotrope-specific disruption of Isl1 have a blunted TSH response. In contrast, deletion of Isl1 in gonadotropes with an Lhb-cre transgene has no obvious effect on gonadotrope function or fertility. These results show that ISL1 is necessary for maximal thyrotrope response to hypothyroidism, in addition to its role in development of Rathke's pouch.
    Molecular Endocrinology 08/2015; DOI:10.1210/me.2015-1192 · 4.02 Impact Factor
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    ABSTRACT: The management of hereditary pheochromocytoma has drastically evolved in the last 20 years. Bilateral pheochromocytoma does not increase mortality in multiple endocrine neoplasia type 2 (MEN 2) or von Hippel-Lindau (VHL) mutation carriers who are followed regularly, but these mutations induce major morbidities if total bilateral adrenalectomy is performed. Cortical sparing adrenal surgery may be proposed to avoid definitive adrenal insufficiency. The surgical goal is to leave sufficient cortical tissue to avoid glucocorticoid replacement therapy. This approach was achieved by the progressive experience of minimally invasive surgery via the transperitoneal or retroperitoneal route. Cortical sparing adrenal surgery exhibits less than 5% significant recurrence after 10 years of follow-up and normal glucocorticoid function in more than 50% of cases. Therefore, cortical sparing adrenal surgery should be systematically considered in the management of all patients with MEN 2 or VHL hereditary pheochromocytoma. Hereditary pheochromocytoma is a rare disease, and a randomized trial comparing cortical sparing vs. classical adrenalectomy is probably not possible. This lack of data most likely explains why cortical sparing surgery has not been adopted in most expert centers that perform at least 20 procedures per year for the treatment of this disease. This review examined recent data to provide insight into the technique, its indications, and results and subsequent follow-up in the management of patients with hereditary pheochromocytoma with a special emphasis on MEN 2.
    European Journal of Endocrinology 08/2015; DOI:10.1530/EJE-15-0549 · 4.07 Impact Factor
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    ABSTRACT: Despite being a classical growth disorder, pituitary gigantism has not been studied previously in a standardized way. We performed a retrospective, multicenter, international study to characterize a large series of pituitary gigantism patients. We included 208 patients (163 males; 78.4%) with growth hormone excess and current/previous abnormal growth velocity for age or final height >2SD above country normal means. The median onset of rapid growth was 13.0 years and occurred significantly earlier in females than in males; pituitary adenomas were diagnosed earlier in females than males (15.8 vs. 21.5 years, respectively). Adenomas were ≥10 mm (i.e. macroadenomas) in 84%, of which extrasellar extension occurred in 77% and invasion in 54%. GH/IGF-1 control was achieved in 39% during long-term follow-up. Final height was greater in those with younger age of onset, with larger tumors and higher GH levels. Later disease control was associated with a greater difference from mid-parental height (r=0.23, P=0.02). AIP mutations occurred in 29%; microduplication at Xq26.3 -X-linked acro-gigantism (X-LAG)- occurred in two familial isolated pituitary adenoma (FIPA) kindreds and in ten sporadic patients. Tumor size was not different in X-LAG, AIP mutated and genetically-negative patient groups. AIP-mutated and X-LAG patients had significantly younger age at onset and diagnosis, but disease control was worse in genetically-negative cases. Pituitary gigantism patients are characterized by male predominance and large tumors that are difficult to control. Treatment delay increases final height and symptom burden. AIP mutations and X-LAG explain many cases, but no genetic etiology is seen in >50% of cases.
    Endocrine Related Cancer 07/2015; DOI:10.1530/ERC-15-0320 · 4.81 Impact Factor
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    ABSTRACT: In couples presenting with retrograde ejaculation refractory to medical treatment, the first choice of fertility treatment should be Assisted Reproductive Techniques using rapidly purified spermatozoa retrieved from post-ejaculatory urine. The Hotchkiss technique and modified variants are simple and efficient for retrieving sperm from the bladder. We developed a new protocol, including a novel modified Hotchkiss technique involving sperm cryopreservation. The aim was to study the pregnancy rate and birth rate achieved by intra cytoplasmic sperm injection (ICSI) using frozen-thawed sperm retrieved from the bladder with this novel modified Hotchkiss technique in patients with refractory retrograde ejaculation. In this descriptive retrospective, single-center study, we analyzed the local database of all patients who banked sperm at the CECOS Laboratory Biology of Reproduction of La Conception University Hospital, Marseille, France, between 2004 and 2014. A total of 2171 patients banked sperm during this time, including 63 patients with retrograde ejaculation, of whom ten patients banked sperm that had been retrieved by the modified Hotchkiss technique. These ten couples underwent 26 ICSI cycles: nine clinical pregnancies were achieved in six couples, including eight after fresh embryo transfer and one after thawed embryo transfer, resulting in seven live births. The average live birth rate per transfer was 28 %. We report the largest series of births using frozen-thawed spermatozoa retrieved from post-ejaculatory urine by a modified Hotchkiss technique. This series of births demonstrates that this new modified Hotchkiss technique allows for successful association with sperm cryopreservation, leading to an efficient and easy management of couples with refractory retrograde ejaculation.
    05/2015; 2015(25):5. DOI:10.1186/s12610-015-0021-4
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    ABSTRACT: LHX4 is a LIM homeodomain transcription factor involved in the early steps of pituitary ontogenesis. To date, 8 heterozygous LHX4 mutations have been reported as responsible of combined pituitary hormone deficiency (CPHD) in Humans. We identified 4 new LHX4 heterozygous allelic variants in patients with congenital hypopituitarism: W204X, delK242, N271S and Q346R. Our objective was to determine the role of LHX4 variants in patients' phenotypes. Heterologous HEK293T cells were transfected with plasmids encoding for wild-type or mutant LHX4. Protein expression was analysed by Western Blot, and DNA binding by electro-mobility shift assay experiments. Target promoters of LHX4 were cotransfected with wild type or mutant LHX4 to test the transactivating abilities of each variant. Our results show that the W204X mutation was associated with early GH and TSH deficiencies and later onset ACTH deficiency. It led to a truncated protein unable to bind to alpha-Gsu promoter binding consensus sequence. W204X was not able to activate target promoters in vitro. Cotransfection experiments did not favour a dominant negative effect. In contrast, all other mutants were able to bind the promoters and led to an activation similar as that observed with wild type LHX4, suggesting that they were likely polymorphisms. To conclude, our study underlines the need for functional in vitro studies to ascertain the role of rare allelic variants of LHX4 in disease phenotypes. It supports the causative role of the W204X mutation in CPHD and adds up childhood onset ACTH deficiency to the clinical spectrum of the various phenotypes related to LHX4 mutations.
    PLoS ONE 05/2015; 10(5):e0126648. DOI:10.1371/journal.pone.0126648 · 3.23 Impact Factor
  • 05/2015; DOI:10.1530/endoabs.37.EP810
  • 05/2015; DOI:10.1530/endoabs.37.GP.19.09
  • Annales d Endocrinologie 05/2015; 76(2):188-189. DOI:10.1016/j.ando.2015.03.035 · 0.87 Impact Factor
  • 05/2015; DOI:10.1530/endoabs.37.EP743
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    ABSTRACT: ATL1103 is a second generation antisense oligomer directed at the GH receptor. It is a 20mer with a phosphorothioate backbone and 2′-O-methoxyethyl modifications of the five nucleotides at either end intended to increase its plasma half-life and affinity for the target RNA to allow post-hybridization RNaseH degradation. We report a phase 2 randomised, open-label, parallel group study of subcutaneously administered ATL1103 in patients with active acromegaly. Appropriate ethical approval was obtained in each centre and the study is registered as EudraCT 01200314730. Patients gave written informed consent. The protocol entailed appropriate washout from ongoing medical therapy after which IGF1 had to be at least >1.3 times age-related ULN. Patients were randomised to receive either ATL1103 200 mg once or twice weekly for 13 weeks. After completion of drug administration, patients were monitored for a further 8 weeks. The primary objectives were to evaluate the safety and pharmacokinetics. 34 patients were recruited in 13 centres and 26 (mean age 50.4 years; 11 male) were randomised, and all completed treatment. ATL1103 was well tolerated with mild to moderate injection site reactions being the most common drug-related AE. Four SAEs were reported (three in a single patient) but none were felt to be study drug related. Two patients withdrew at completion of dosing. There was a significant fall in serum IGF1 of 26% by week 14 with 200 mg twice weekly (577±198 vs 411±174 ng/ml (mean±S.D.), P<0.0001) although the nadir had not been reached. Once weekly dosing did not result in a significant fall in IGF1. The fall in IGF1 with twice weekly dosing was associated with a mean reduction ring size circumference of 1.150 mm (P=0.014) and an increase in GH (P=0.001). This study provides proof-of-concept that ATL1103 is able to significantly lower IGF1 in patients with acromegaly.
    05/2015; DOI:10.1530/endoabs.37.GP.19.10
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    ABSTRACT: Outcomes of congenital adrenal hyperplasia (CAH) due to classic 21-hydroxylase deficiency (21OHD) have been widely studied in children and women but less in men. To analyze data from a network of metropolitan French teaching hospitals on the clinical outcome of classic 21OHD in a large sample of CAH/21OHD genotyped adult men, and particularly the impact of 21OHD on the gonadotrope axis, testicular function and fertility. From April 2011 to June 2014, tertiary endocrinology departments provided data for 219 men with 21OHD (18-70 y; 73.6% salt wasters (SW) and 26.4% simple virilizers (SV)). Testicular sonography was performed in 164 men and sperm analysis in 71 men. Mean final height was 7.8 cm lower than in a reference population. Obesity was more common and mean blood pressure was lower than in the reference population. None of the patients was diabetic and lipid status was generally normal. Blood electrolyte status was normal in the vast majority of men, despite markedly elevated ACTH and renin levels. Serum progesterone (PROG), 17OHPROG and androstenedione levels were above-normal in the vast majority of cases. Hormonal profiling variously showed a normal gonadotrope-testicular axis, gonadotropin deficiency, or primary testicular insufficiency. Testicular sonography revealed adrenal rest tumors (TARTs) in 34% of 164 men. Serum inhibin B and FSH levels were respectively significantly lower and higher in patients with TARTs. Severe oligospermia or azoospermia was found in 42% of patients, and was significantly more prevalent in men with TARTs (70%) than in men with normal testes (3.6%;p<0.0001). Among men living with female partners, TARTs were significantly more prevalent in those who had not fathered children. We report the spectrum of testicular/gonadotrope axis impairment in the largest cohort of 21OHD men studied to date. Our results suggest that French men with 21OHD managed in specialized centers frequently have impaired exocrine testicular function but that its reproductive implications are often overlooked.
    The Journal of Clinical Endocrinology and Metabolism 03/2015; 100(6):jc20144124. DOI:10.1210/jc.2014-4124 · 6.21 Impact Factor
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    ABSTRACT: To test the role of wtPIT-1 (PITWT) or PIT-1 (R271W) (PIT271) in somatolactotroph cells, we established, using inducible lentiviral vectors, sublines of GH4C1 somatotroph cells that allow the blockade of the expression of endogenous PIT-1 and/or the expression of PITWT or PIT271, a dominant negative mutant of PIT-1 responsible for Combined Pituitary Hormone Deficiency in patients. Blocking expression of endogenous PIT-1 induced a marked decrease of cell proliferation. Overexpressing PITWT twofold led also to a dose-dependent decrease of cell proliferation that was accompanied by cell death. Expression of PIT271 induced a strong dose-dependent decrease of cell proliferation accompanied by a very pronounced cell death. These actions of PIT271 are independent of its interaction/competition with endogenous PIT-1, as they were unchanged when expression of endogenous PIT-1 was blocked. All these actions are specific for somatolactotroph cells, and could not be observed in heterologous cells. Cell death induced by PITWT or by PIT271 was accompanied by DNA fragmentation, but was not inhibited by inhibitors of caspases, autophagy or necrosis, suggesting that this cell death is a caspase-independent apoptosis. Altogether, our results indicate that under normal conditions PIT-1 is important for the maintenance of cell proliferation, while when expressed at supra-normal levels it induces cell death. Through this dual action, PIT-1 may play a role in the expansion/regression cycles of pituitary lactotroph population during and after lactation. Our results also demonstrate that the so-called "dominant-negative" action of PIT271 is independent of its competition with PIT-1 or a blockade of the actions of the latter, and are actions specific to this mutant variant of PIT-1.
    PLoS ONE 03/2015; 10(3):e0120010. DOI:10.1371/journal.pone.0120010 · 3.23 Impact Factor
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    ABSTRACT: Predicting the outcome of patients operated on for Cushing's disease (CD) is a challenging task. Our objective was to assess the accuracy of immediate post-surgical plasma cortisol, desmopressin test and the coupled dexamethasone desmopressin test (CDDT) as predictors of outcome. Sixty-seven patients with initial remission and a minimal post-surgical follow-up greater than 18 months were included in this retrospective bicenter study. Follow-up included 3-6 months followed by yearly 24-h urinary free cortisol, ACTH and cortisol plasmatic levels, a 1 mg overnight dexamethasone suppression test (1 mg DST), desmopressin test and the CDDT. ROC curves were performed to define the optimal threshold of immediate post-surgical cortisol level, and 3-6 month desmopressin test and CDDT, as predictors of final outcome in comparison with classical biological markers of recurrence. Eleven patients presented recurrence. The patient's median follow-up was 52 months (range, 18-180). As early predictors of outcome, immediate post-surgical plasma cortisol level < 35 nmol/l predicted the lack of recurrence with 93% negative predictive value (NPV), whereas predictive positive value (PPV) was 25%. During the follow-up, the CDDT was more precise than the desmopressin test in predicting the lack of recurrence (100% NPV) when performed in the first 3 years after surgery. Positivity of the CDDT was defined based on ROC curves by ACTH and cortisol increments > 50%. The CDDT was highly reproducible, as the same response was observed every year in 91% of the patients. Adding the CDDT the first 3 years after surgery to immediate post-surgical cortisol evaluation should allow obtaining an optimal follow-up management of patients operated for Cushing's disease. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Clinical Endocrinology 02/2015; 83(2). DOI:10.1111/cen.12739 · 3.46 Impact Factor
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    ABSTRACT: Background: Patients suffering from adrenal insufficiency, whether primary (PAI) or secondary (SAI) have an increased mortality risk and increased morbidity. There are no guidelines on hydrocortisone replacement therapy and little is known on patients' management in current practice. We described patients' profiles and treatment in a tertiary referral centre. Methods: Data were collected retrospectively from medical charts. PAI and SAI patients were described and compared. Results: Two hundred and one patients (79 PAI+122 SAI) were included. They had a mean duration of disease of 11.2years. Main causes of PAI were autoimmune diseases (31%) and adrenalectomy (26%). SAI was caused primarily by pituitary tumors (61%) and irradiation (20%). Mean dose of daily hydrocortisone (HC) was 27.5 and 19.9mg/day in PAI and SAI patients respectively, with a majority of patients dividing the dose into 2 intakes (46.8 and 72.2% in PAI and SAI groups, respectively). SAI patients exhibited more cardiovascular risk factors than PAI patients. The HC daily dose was slightly higher in patients with dyslipidemia (in both PAI and SAI groups) and in those with high blood pressure (in the SAI group only). One third of patients were out of work, due to unemployment, sick leaves, or disability. Conclusions: The management of AI is far from standardized, and individual tailorization is difficult with currently available means of treatment. Under- and overdose of hydrocortisone likely leads to complications, and altered quality of life reflected by a high rate of "out of work" patients.
    Annales d Endocrinologie 01/2015; 76(1). DOI:10.1016/j.ando.2014.11.004 · 0.87 Impact Factor
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    ABSTRACT: Objective: A number of factors can influence the reported outcomes of transsphenoidal surgery (TSS) for Cushing's disease - including different remission and recurrence criteria, for which there is no consensus. Therefore, a comparative analysis of the best treatment options and patient management strategies is difficult. In this review, we investigated the clinical outcomes of initial TSS in patients with Cushing's disease based on definitions of and assessments for remission and recurrence. Methods: We systematically searched PubMed and identified 44 studies with clear definitions of remission and recurrence. When data were available, additional analyses by time of remission, tumor size, duration of follow-up, surgical experience, year of study publication and adverse events related to surgery were performed. Results: Data from a total of 6400 patients who received microscopic TSS were extracted and analyzed. A variety of definitions of remission and recurrence of Cushing's disease after initial microscopic TSS was used, giving broad ranges of remission (42.0-96.6%; median, 77.9%) and recurrence (0-47.4%; median, 11.5%). Better remission and recurrence outcomes were achieved for microadenomas vs macroadenomas; however, no correlations were found with other parameters, other than improved safety with longer surgical experience. Conclusions: The variety of methodologies used in clinical evaluation of TSS for Cushing's disease strongly support the call for standardization and optimization of studies to inform clinical practice and maximize patient outcomes. Clinically significant rates of failure of initial TSS highlight the need for effective second-line treatments.
    European Journal of Endocrinology 01/2015; 172(6). DOI:10.1530/EJE-14-0883 · 4.07 Impact Factor
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    ABSTRACT: Context: Responses of GH-secreting adenomas to multimodal management of acromegaly varies widely between patients. Understanding the behavioral patterns of GH-secreting adenomas by identifying predictive factors of their evolution is a research priority. Objective: To clarify the relationship between adenoma T2-weighted signal on diagnostic MRI in acromegaly and clinical and biological features at diagnosis. Design: International, multicenter, retrospective analysis. Setting: 10 endocrine tertiary referral centers. Patients: 297 acromegalic recently diagnosed patients with available diagnostic MRI evaluations were included in the study. Main outcome measure: Clinical, biochemical characteristics and MRI signal findings. Results: T2-hypointense adenomas represented 52.9% of the series, were smaller than their T2-hyper- and isointense counterparts (p<0.0001), were associated with higher IGF1 levels (p=0.0001), invaded the cavernous sinus less frequently (p=0.0002) and rarely caused optic chiasm compression (p<0.0001). Acromegalic men tended to be younger at diagnosis than women (p=0.067) and presented higher IGF1 values (p=0.01). Although in total, adenomas had a predominantly inferior extension in 45.8% of cases, in men this was more frequent (p<0.0001), whereas in women optic chiasm compression of macroadenomas occurred more often (p=0.0067). Most adenomas (45.1%) measured between 11-20mm in maximal diameter and bigger adenomas were diagnosed at younger ages (p=0.0001). Conclusions: T2-weighted signal differentiates GH-secreting adenomas into subgroups with particular behaviors. This raises the question of whether T2-weighted signal could represent a factor in the classification of acromegalic patients in future studies.
    Endocrine Related Cancer 01/2015; 22(2). DOI:10.1530/ERC-14-0305 · 4.81 Impact Factor
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    ABSTRACT: BackgroundDAVID syndrome is a rare condition combining anterior pituitary hormone deficiency with common variable immunodeficiency. NFKB2 mutations have recently been identified in patients with ACTH and variable immunodeficiency. A similar mutation was previously found in Nfkb2 in the immunodeficient Lym1 mouse strain, but the effect of the mutation on endocrine function was not evaluated.Methods We ascertained six unrelated DAVID syndrome families. We performed whole exome and traditional Sanger sequencing to search for causal genes. Lym1 mice were propagated and examined for endocrine developmental anomalies.ResultsMutations in the NFKB2 gene were identified in three of our families through whole exome sequencing, and in a fourth by direct Sanger sequencing. De novo origin of the mutations could be demonstrated in three of the families. All mutations lie near the C-terminus of the protein-coding region, near signals required for processing of NF¿B2 protein by the alternative pathway. Two of the probands had anatomical pituitary anomalies, and one had growth and thyroid hormone as well as ACTH deficiency; these findings have not been previously reported. Two children of one of the probands carried the mutation and have to date exhibited only an immune phenotype. No mutations were found near the C-terminus of NFKB2 in the remaining two probands; whole exome sequencing has been performed for one of these. Lym1 mice, carrying a similar Nfkb2 C-terminal mutation, showed normal pituitary anatomy and expression of proopiomelanocortin (POMC).Conclusions We confirm previous findings that mutations near the C-terminus of NFKB2 cause combined endocrine and immunodeficiencies. De novo status of the mutations was confirmed in all cases for which both parents were available. The mutations are consistent with a dominant gain-of-function effect, generating an unprocessed NFKB2 super-repressor protein. We expand the potential phenotype of such NFKB2 mutations to include additional pituitary hormone deficiencies as well as anatomical pituitary anomalies. The lack of an observable endocrine phenotype in Lym1 mice suggests that the endocrine component of DAVID syndrome is either not due to a direct role of NFKB pathways on pituitary development, or else that human and mouse pituitary development differ in its requirements for NFKB pathway function.
    BMC Medical Genetics 12/2014; 15(1):139. DOI:10.1186/s12881-014-0139-9 · 2.08 Impact Factor
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    ABSTRACT: Objective: Few data are published on the long-term follow-up of ipilimumab-induced hypophysitis, a cytotoxic T-lymphocyte antigen-4 antibody. We characterized hypophysitis in terms of clinical signs, endocrinological profile, and imaging at diagnosis and during a long-term follow-up. Design and patients: Fifteen patients, treated for malignant melanoma and who presented ipilimumab-induced hypophysitis, were observed between June 2006 and August 2012 in Timone hospital, Marseille. Methods: Symptoms, pituitary function, and pituitary imaging at diagnosis of hypophysitis and during the follow-up were recorded. Results: 15 of 131 patients treated with ipilimumab (10 mg/kg in 11/15) or a placebo presented with hypophysitis (≥11.5%) at 9.5 ± 5.9 weeks (mean ± SD) after treatment start, occurring in 66% after the third infusion. Main initial symptoms were headache (n=13) and asthenia (n=11). All patients but one had at least one hormonal defect: thyrotroph (n=13), gonadotroph (n=12), or corticotroph (n=11) deficiencies. None had diabetes insipidus. Pituitary imaging showed a moderately enlarged gland in 12 patients. Clinical symptoms improved rapidly on high-dose glucocorticoids (n=11) or physiological replacement doses (n=4). At the end of follow-up (median 33.6 months, range 7-53.5), corticotroph deficiency remained in 13 patients, 11 recovered thyrotroph and 10 gonadotroph functions. Pituitary imaging remained abnormal in 11 patients. Conclusion: Ipilimumab-induced hypophysitis is a common side-effect with frequent hormonal deficiencies at diagnosis. Usually, hormonal deficiencies improved, except for corticotroph function. Patients receiving these immunomodulatory therapies should be closely monitored especially by systematic baseline hormone measurements after the third infusion and remain at risk of adrenal insufficiency in the long-term.
    European Journal of Endocrinology 11/2014; 172(2). DOI:10.1530/EJE-14-0845 · 4.07 Impact Factor

Publication Stats

4k Citations
755.38 Total Impact Points


  • 2005–2015
    • Aix-Marseille Université
      • Faculté de Médecine
      Marsiglia, Provence-Alpes-Côte d'Azur, France
    • Centre Hospitalier Universitaire de Limoges
      Limages, Limousin, France
  • 2001–2014
    • French National Centre for Scientific Research
      Lutetia Parisorum, Île-de-France, France
    • University Hospital Estaing of Clermont-Ferrand
      Clermont, Auvergne, France
  • 2008–2012
    • Assistance Publique Hôpitaux de Marseille
      • Service de neurochirurgie infantile
      Marsiglia, Provence-Alpes-Côte d'Azur, France
  • 2010
    • Institut de Recherche sur les Phénomènes Hors Equilibre
      Marsiglia, Provence-Alpes-Côte d'Azur, France
    • CHRU de Strasbourg
      Strasburg, Alsace, France
  • 2008–2010
    • Centre Hospitalier Universitaire de Montpellier
      Montpelhièr, Languedoc-Roussillon, France
  • 2009
    • Université Paul Cézanne
      Aix, Provence-Alpes-Côte d'Azur, France
    • Hospices Civils de Lyon
      Lyons, Rhône-Alpes, France
  • 2006
    • University of Chicago
      • Pritzker School of Medicine
      Chicago, Illinois, United States
    • McGill University
      • Department of Medicine
      Montréal, Quebec, Canada
  • 2004
    • University of Sousse
      Susa, Sūsah, Tunisia
  • 1999
    • University of Liège
      Luik, Walloon Region, Belgium
    • Beth Israel Deaconess Medical Center
      Boston, Massachusetts, United States