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Attanasio A.F.,Cascina del Rosone | Mo D.,Eli Lilly and Company | Erfurth E.M.,Lund University | Tan M.,Eli Lilly and Company | And 6 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2010

Context and Objective: Metabolic and body compositional consequences of GH deficiency (GHD) in adults are associated with a phenotype similar to the metabolic syndrome (MetS). Patients: We assessed MetS prevalence in adult GHD patients (n = 2531) enrolled in the Hypopituitary Control and Complications Study. Prevalence was assessed at baseline and after 3 yr of GH replacement in a subset of 346 adult-onset patients. Results: Baseline MetS crude prevalence was 42.3%; age-adjusted prevalence in the United States and Europe was 51.8 and 28.6% (P < 0.001), respectively. In the United States, age-adjusted prevalence was significantly higher (P < 0.001) than in a general population survey. Increased MetS risk at baseline was observed for age 40 yr or older (adjusted relative risk 1.34, 95% confidence interval 1.17-1.53, P < 0.001), females (1.15, 1.05-1.25, P = 0.002), and adult onset (1.77, 1.44-2.18, P < 0.001). In GH-treated adult-onset patients, MetS prevalence was not changed after 3 yr (42.5-45.7%, P = 0.172), but significant changes were seen for waist circumference (62.1-56.9%, P = 0.008), fasting glucose (26.0-32.4%, P < 0.001), and blood pressure (59.8-69.7%, P < 0.001). Significantly increased risk of MetS at yr 3 was associated with baseline MetS (adjusted relative risk 4.09, 95% confidence interval 3.02-5.53, P < 0.001) and body mass index 30 kg/m2 or greater (1.53, 1.17-1.99, P = 0.002) and increased risk (with a P value < 0.1) for GH dose 600 μg/d or greater (1.18, 95% confidence interval 0.98-1.44, P = 0.088). Conclusion: MetS prevalence in GHD patients was higher than in the general population in the United States and higher in the United States than Europe. Prevalence was unaffected by GH replacement, but baseline MetS status and obesity were strong predictors of MetS after GH treatment. Copyright © 2010 by The Endocrine Society.


De Martino M.C.,Institute Gustave Roussy | Al Ghuzlan A.,Institute Gustave Roussy | Aubert S.,Lille University Hospital Center | Assie G.,University of Paris Descartes | And 21 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2013

Context: Adrenocortical cancer (ACC) is a rare cancer with poor prognosis and scant treatment options. In ACC, no personalized approach has emerged but no extensive molecular screening has been performed to date. Objective: The objective of the study was toevaluate the presence of a large number of potentially targetable molecular events in a large cohort of advanced ACC. Design, Setting, and Participants: Weused hotspot gene sequencing (Ion Torrent, 40 patients) and comparative genomic hybridization (CGH; 28 patients; a subset of the entire cohort) in adult stage III-IV ACC samples to screen for mutations and copy number abnormalities of potential interest for therapeutic use in 46 and 130 genes, respectively. Results: At least one copy number alteration or mutation was found in 19 patients (47.5%). The most frequent mutations were detected on TP53, ATM, and CTNNB1 [6 of 40 (15%), 5 of 40 (12.5%), and 4 of 40 (10%), respectively]. The most frequent copy number alterations identified were: amplification of the CDK4 oncogene (5 of 28; 17.9%) and deletion of the CDKN2A (4 of 28; 14.3%) and CDKN2B (3 of 28; 10.7%) tumor suppressor genes. Amplifications of FGFR1, FGF9, or FRS2 were discovered in three subjects (10.7%). Associated alterations were: deletions of CDKN2A, CDKN2B with ATM mutations, and TP53 mutations with CTNNB1 mutations. Conclusions: No simple targetable molecular event emerged. Drugs targeting thecellcyclecould be the most relevant new therapeutic approach for patients with advanced ACC. Inhibitors of the fibroblast growth factor receptor pathway could also be a therapeutic option in a subset of patients, whereas other targeted therapies should be considered on a case-by-case basis. Copyright © 2013 by The Endocrine Society.


Caron P.,Center Hospitalier University Larrey | Broussaud S.,Center Hospitalier University Larrey | Bertherat J.,University of Paris Descartes | Borson-Chazot F.,Federation dEndocrinologie et des Maladies de la Nutrition | And 4 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2010

Context: Few data are available on pregnancy outcomes in women with acromegaly. Study Design: This was a retrospective multicenter study. Patients: The study included 46 women with GH-secreting pituitary microadenomas (n = 7) or macroadenomas (n = 39). Their mean age was 31.7 yr (±4.5 yr). Incomplete transsphenoidal surgical resection (n = 39) and pituitary radiation (n = 14) had been performed, respectively, 2.9 ± 2.6 and 7.3 ± 4.2 yr before pregnancy. The patients were receiving dopamine agonists (n = 25) and/or somatostatin analogs (n = 14), and GH/IGF-I hypersecretion was controlled and uncontrolled in, respectively, 23 and 34 cases. Five pregnancies followed the fertility treatment. Results: Fifty-nine pregnancies resulted in 64 healthy babies. Gestational diabetes and gravid hypertension occurred in four (6.8%) and eight (13.6%) pregnancies, respectively, and both were more frequent when GH/IGF-I hypersecretion was not controlled before pregnancy. Visual field defects were diagnosed during pregnancy in four women, three of whom were diagnosed with acromegaly during the pregnancy. Seven women had isolated headache. Magnetic resonance imaging performed 3.9 ± 0.3 months after delivery showed that the size of the adenoma had increased in three cases, decreased in two cases, and remained stable in 22 cases. Seventeen women breast-fed with no complications. Four women gave birth to a small-for-gestational-age infant; all had received somatostatin analogs, alone or in combination with dopamine agonists, during pregnancy. The mean IGF-I level fell significantly during the first trimester in 12 cases (before conception 588 ± 207 ng/ml, first trimester 319 ± 126 ng/ml, P = 0.002), whereas the GH concentration did not change significantly. Conclusion: The following conclusions were reached: 1) pregnancy in women with active or uncontrolled acromegaly may be associated with an increased risk of gestational diabetes and gravid hypertension; 2) pregnancy is occasionally associated with symptomatic enlargement of GH-secreting pituitary macroadenomas; 3) changes in serum GH and IGF-I concentrations are variable during pregnancy, indicating that routine monitoring is not mandatory if the pregnancy is uneventful; and 4) GH-suppressive treatment can be safely withdrawn after conception in most acromegalic women. Copyright © 2010 by The Endocrine Society.


Grynberg M.,Service dEndocrinologie et des Maladies de la Reproduction | Grynberg M.,University Paris - Sud | Salenave S.,Service dEndocrinologie et des Maladies de la Reproduction | Young J.,Service dEndocrinologie et des Maladies de la Reproduction | And 5 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2010

Context: The menstrual cycle is often abnormal in women with acromegaly. Gonadotropin deficiency may be due to a tumor mass effect (macroadenomas) and/or hyperprolactinemia and/or GH excess. Aim of the Study: The aim of the study was to analyze the causes of ovarian dysfunction in a large series of patients with acromegaly followed up in a single center. Patients and Methods: Gonadal function was assessed on the basis of menstrual status and hormone assays before and after treatment of acromegaly, between 1985 and 2005, in 55 patients aged from 17 to less than 45 yr. Results: Seventeen women (31%) were considered to be eugonadal because they had regular menstrual cycles and/or conceived spontaneously. The remaining 38 women had anovulatory cycles. Of these, 11 had hyperprolactinemia and six had hypogonadism due to a mass effect. The cause of the menstrual disturbances was mixed or unclassifiable in 14 cases. In the seven remaining cases, the gonadal dysfunction was likely related to the GH/IGF-I excess, which exerts a direct effect on the gonadotropic axis. Two had polycystic ovary syndrome, which disappeared after normalization of serum GH/IGF-I levels, suggesting that GH/IGF-I excess may also have a direct effect on the ovary. Thirty-eight women became pregnant, and all had healthy children, despite active acromegaly in 12 cases (31%). Conclusion: Gonadal dysfunction is very common in premenopausal women with acromegaly. The potential causes include the lactogenic effect of prolactin, GH, or both on gonadotropic axis. Tumor mass effect or direct effect of GH or IGF-I on the ovary may also participate in ovarian dysfunction. Copyright © 2010 by The Endocrine Society.


Chanson P.,University Paris - Sud | Chanson P.,Institute National Of La Sante Et Of La Recherche Medicale Unite 693 | Cailleux-Bounacer A.,University of Rouen | Kuhn J.-M.,University of Rouen | And 11 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2010

Context: The GHRH plus arginine (GHRH+Arg) test is a promising alternative to the insulin tolerance test (ITT) for diagnosis of adult GH deficiency (AGHD). Objectives: The objectives of the study were to validate the GHRH+Arg test for diagnosis of AGHD, using the ITT as comparator and a GH assay calibrated according to recent international recommendations, and to study the repeatability and tolerance of both tests. Design: This was a multicenter, randomized, open-label, phase III study. Setting: The study was conducted at 10 French university hospitals. Subjects: Sixty-nine subjects (38 and 15 with high and low probability of GH deficiency, respectively, and 16 healthy controls) were randomized: 35 to the GHRH+Arg-GHRH+Arg-ITT test sequence and 34 to the ITT-ITT-GHRH+Arg test sequence. Interventions: Each subject underwent three tests of GH secretion separated by 24 h or more. Main Outcome Measures: The primary variable used for response assessments was serum peak GH response. Test results were compared with the final AGHD diagnosis. Results: Peak GH responses in the two tests were strongly correlated. A cutoff value of 7.89 μg/liter for GHRH+Arg corresponding to 3 μg/liter for ITT was calculated. The cutoff value leading to 95% specificity with the GHRH+Arg test was measured at about 3.67 μg/liter (sensitivity 79.0%). Intermethod agreement and repeatability were high. Both tests were well tolerated. A preference for the GHRH+Arg test was expressed by 74% of subjects. Conclusions: The GHRH+Arg test demonstrated good accuracy and repeatability, was at least as sensitive as the ITT, and was associated with better subject acceptability. The GHRH+Arg test represents a good alternative to the ITT for the diagnosis of AGHD. Copyright © 2010 by The Endocrine Society.


Khan J.A.,Institute National Of La Sante Et Of La Recherche Medicale Unite 693 | Khan J.A.,University Paris - Sud | Amazit L.,Institute National Of La Sante Et Of La Recherche Medicale Unite 693 | Amazit L.,University Paris - Sud | And 8 more authors.
Molecular Endocrinology | Year: 2011

Progesterone receptor (PR) isoforms (PRA and PRB) are implicated in the progression of breast cancers frequently associated with imbalanced PRA/PRB expression ratio. Antiprogestins represent potential antitumorigenic agents for such hormone-dependent cancers. To investigate the mechanism(s) controlling PR isoforms degradation/stability in the context of agonist and antagonist ligands, we used endometrial and mammary cancer cells stably expressing PRA and/or PRB. We found that the antiprogestin RU486 inhibited the agonist-induced turnover of PR isoforms through active mechanism(s) involving distinct MAPK-dependent phosphorylations. p42/44 MAPK activity inhibited proteasome-mediated degradation of RU486-bound PRB but not PRA in both cell lines. Ligand-induced PRB turnover required neosynthesis of a mandatory down-regulating partner whose interaction/function is negatively controlled by p42/44 MAPK. Such regulation strongly influenced expression of various endogenous PRB target genes in a selective manner, supporting functional relevance of the mechanism. Interestingly, in contrast to PRB, PRA stability was specifically increased by MAPK kinase kinase 1-induced p38 MAPK activation. Selective inhibition of p42/p44 or p38 activity resulted in opposite variations of the PRA/PRB expression ratio. Moreover, MAPK-depen-dent PR isoforms stability was independent of PR serine-294 phosphorylation previously proposed as a major sensor of PR down-regulation. In sum, we demonstrate that MAPK-mediated cell signaling differentially controls PRA/PRB expression ratio at posttranslational level through ligand-sensitive processes. Imbalance in PRA/PRB ratio frequently associated with carcinogenesis might be a direct consequence of disorders in MAPK signaling that might switch cellular responses to hormonal stimuli and contribute towards pathogenesis. © 2011 by The Endocrine Society.


Brassard M.,Institute Gustave Roussy | Neraud B.,Endocrinology and Reproduction Diseases | Trabado S.,Molecular Genetics | Trabado S.,University Paris - Sud | And 15 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2011

Purpose: The purpose of the study was to assess the endocrine effects of vandetanib, a multikinase inhibitor targeting RET, vascular endothelial growth factor receptor, and epidermal growth factor receptor, in 39 patients with progressive thyroid cancer included in two randomized placebocontrolled trials using vandetanib 300 mg/d. Methods: Endocrine samplingswereperformed at baselineandthen every 6 months.Wecompared differences in endocrine parameters between baseline and on vandetanib therapy or placebo. Results: During vandetanib treatment, several changes were observed. 1) Calcium (P=0.0004) and vitaminD(P=0.001) mean replacement doses were increased; calcium level remained unchanged, but serum 25(OH) vitamin D level decreased (P = 0.001); and serum PTH (P = 0.01) and 1,25(OH) 2vitamin D (P = 0.01) levels increased, suggesting a decreased intestinal absorption of vitamin D or lack of sun exposure as a result of photosensitization. 2) L-T 4 doses were increased (P < 0.0001) to maintain serum TSH within the normal range. 3) In male patients, total testosterone (P = 0.048), bioavailable testosterone (P = 0.03), and SHBG (P = 0.02) levels increased. Serum inhibin B decreased (P=0.02) and stimulated FSH increased (P=0.006), suggesting a Sertoli cells insufficiency. 4) Cortisol level increased (P=0.007) as well as ACTH level (P=0.03) and cortisol-binding globulin (P = 0.02), but free urinary cortisol levels remained in the normal range. None of these changes were observed in patients randomized to the placebo arm. Conclusion: In patients with locally advanced or metastatic thyroid cancer, the tyrosine kinase inhibitor vandetanib has several endocrine effects. Thyroid hormone, calcium, and vitamin D analog requirements increased, but consequences of the biological alterations on phosphocalcic metabolism and gonadotrope and adrenal functions are unknown. Copyright © 2011 by The Endocrine Society.


Boussaid K.,Toulouse University Hospital Center | Meduri G.,Institute National Of La Sante Et Of La Recherche Medicale Unite 693 | Maiza J.-C.,Toulouse University Hospital Center | Gennero I.,Toulouse University Hospital Center | And 5 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2013

Context: McCune-Albright syndrome (MAS) is characterized by polyostotic fibrous dysplasia, café - au-lait skin pigmentations, and gonadotropin-independent sexual precocious puberty, resulting from a somatic postzygotic activating mutation of the GNAS1 gene. Setting: We report a virilizing sclerosing-stromal tumor of the ovary in a young female with MAS. Patient: She presented polyostotic fibrous dysplasia of the left upper and lower limbs and a café - au-lait skin spot in the posterior area of the neck. She had a history of precocious puberty, diagnosed at the age of 6 years and treated with cyproterone acetate until the age of 10 years; then she developed central puberty with severe oligomenorrhea. At the age of 23 years, she was hospitalized for a virilization syndrome including hirsutism, acne, deepening of the voice, amenorrhea, and clitoromegaly. Serum levels of T were dramatically increased (1293 ng/dl; normal range, 10-80). The abdominal computed tomography scan revealed a solid mass located on the left ovary. Intervention: An ovariectomy was performed, and histological examination revealed a sclerosingstromal tumor with pseudolobular pattern. Results: Immunohistochemical studies revealed that the tumor cells expressed all steroidogenic enzymes involved in androgen synthesis. Molecular analysis revealed that ovarian tumor cells harbored the Arg 201 activating mutation in the GNAS1 gene. After surgery, T levels returned to normal, the patient retrieved a normal gonadal function, and she was able to become pregnant. Conclusion: This observation extends the clinical spectrum of ovarian pathology of women with MAS. However, the mechanisms causing this ovarian tumor remain unclear, even if the gsp oncogene has been implicated in the pathogenesis of some gonadal tumors. Copyright © 2013 by The Endocrine Society.


PubMed | Institute National Of La Sante Et Of La Recherche Medicale Unite 693
Type: Journal Article | Journal: Endocrinology | Year: 2012

Mineralocorticoid receptor (MR), highly expressed in the hippocampus, binds corticosteroid hormones and coordinately participates, with the glucocorticoid receptor, to the control of stress responses, memorization, and behavior. To investigate the impact of MR in neuronal survival, we generated murine embryonic stem (ES) cells that overexpress human MR (hMR) (P1-hMR) and are induced to differentiate into mature neurons. We showed that recombinant MR expression increased throughout differentiation and is 2-fold higher in P1-hMR ES-derived neurons compared with wild-type controls, whereas glucocorticoid receptor expression was unaffected. Although proliferation and early neuronal differentiation were comparable in P1-hMR and wild-type ES cells, MR overexpression was associated with higher late neuronal marker expression (microtubule-associated protein 2 and -tubulin III). This was accompanied by a shift towards neuron survival with an increased ratio of anti- vs. proapoptotic molecules and 50% decreased caspase 3 activity. Knocking down MR overexpression by small interfering RNA drastically reversed neuroprotective effects with reduced Bcl(2)/Bax ratio and decreased microtubule-associated protein 2 expression. P1-hMR neurons were protected against oxidative stress-induced apoptosis through reduced caspase 3 activation and drastically increased Bcl(2)/Bax ratio and -tubulin III expression. We demonstrated the involvement of MR in neuronal differentiation and survival and identify MR as an important neuroprotective mediator opening potential pharmacological strategies.


PubMed | Institute National Of La Sante Et Of La Recherche Medicale Unite 693
Type: Journal Article | Journal: Molecular endocrinology (Baltimore, Md.) | Year: 2011

The progesterone receptor (PR), a ligand-activated transcription factor, recruits the primary coactivator steroid receptor coactivator-1 (SRC-1) gene promoters. It is known that PR transcriptional activity is paradoxically coupled to its ligand-dependent down-regulation. However, despite its importance in PR function, the regulation of SRC-1 expression level during hormonal exposure is poorly understood. Here we report that SRC-1 expression level (but not other p160 family members) is down-regulated by the agonist ligand R5020 in a PR-dependent manner. In contrast, the antagonist RU486 fails to induce down-regulation of the coactivator and impairs PR agonist-dependent degradation of SRC-1. We show that SRC-1 proteolysis is a proteasome- and ubiquitin-mediated process that, predominantly but not exclusively, occurs in the cytoplasmic compartment in which SRC-1 colocalizes with proteasome antigens as demonstrated by confocal imaging. Moreover, SRC-1 was stabilized in the presence of leptomycin B or several proteasomal inhibitors. Two degradation motifs, amino-acids 2-16 corresponding to a PEST motif and amino acids 41-136 located in the basic helix loop helix domain of the coactivator, were identified and shown to control the stability as well as the hormone-dependent down-regulation of the coactivator. SRC-1 degradation is of physiological importance because the two nondegradable mutants that still interacted with PR as demonstrated by coimmunoprecipitation failed to stimulate transcription of exogenous and endogenous target genes, suggesting that concomitant PR/SRC-1 ligand-dependent degradation is a necessary step for PR transactivation activity. Collectively our findings are consistent with the emerging role of proteasome-mediated proteolysis in the gene-regulating process and indicate that the ligand-dependent down-regulation of SRC-1 is critical for PR transcriptional activity.

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