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Maria A Tichomirowa,
Anne Barlier,
Adrian F Daly,
Marie-Lise Jaffrain-Rea,
Cristina Ronchi,
Maria Yaneva,
Jonathan D Urban,
Patrick Petrossians,
Atanaska Elenkova,
Antoine Tabarin, [......],
Emmanuel Sonnet,
Angel Ferrandez Longás,
Marie-Thérèse Hagelstein,
Philippe Caron,
Günter K Stalla,
Vincent Bours,
Sabina Zacharieva,
Anna Spada,
Thierry Brue,
Albert Beckers
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ABSTRACT: Aryl hydrocarbon receptor interacting protein (AIP) mutations (AIPmut) cause aggressive pituitary adenomas in young patients, usually in the setting of familial isolated pituitary adenomas. The prevalence of AIPmut among sporadic pituitary adenoma patients appears to be low; studies have not addressed prevalence in the most clinically relevant population. Hence, we undertook an international, multicenter, prospective genetic, and clinical analysis at 21 tertiary referral endocrine departments.
We included 163 sporadic pituitary macroadenoma patients irrespective of clinical phenotype diagnosed at <30 years of age.
Overall, 19/163 (11.7%) patients had germline AIPmut; a further nine patients had sequence changes of uncertain significance or polymorphisms. AIPmut were identified in 8/39 (20.5%) pediatric patients. Ten AIPmut were identified in 11/83 (13.3%) sporadic somatotropinoma patients, in 7/61 (11.5%) prolactinoma patients, and in 1/16 non-functioning pituitary adenoma patients. Large genetic deletions were not seen using multiplex ligation-dependent probe amplification. Familial screening was possible in the relatives of seven patients with AIPmut and carriers were found in six of the seven families. In total, pituitary adenomas were diagnosed in 2/21 AIPmut-screened carriers; both had asymptomatic microadenomas.
Germline AIPmut occur in 11.7% of patients <30 years with sporadic pituitary macroadenomas and in 20.5% of pediatric patients. AIPmut mutation testing in this population should be considered in order to optimize clinical genetic investigation and management.
European Journal of Endocrinology 07/2011; 165(4):509-15. · 3.42 Impact Factor
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ABSTRACT: Retrospective follow-up study on patients suffering from macroprolactinomas which were treated with agonists of D2 receptors; the MRI results were correlated with the clinical symptomatology and with the level of prolactin in the blood.
From 1996 to 2006 we followed 38 patients diagnosed with macroprolactinoma. All patients underwent MRI in same protocol two times. The indication for MRI was based on the clinical symptomatology (signs of hormonal dysfunction, visual fields impairment) or increased blood level of prolactin.
The first predominant clinical signs in males were local manifestations of expansive process and in women hormonal dysfunction. Intratumorous haemorrhage in patients undergoing the treatment with the agonists of D2 receptors is common, it was encountered in 25 cases, but only in two cases it was followed by a more serious clinical symptomatology, which had to be referred to the department of the neurosurgery. Even when there were pronounced regressions or near complete disappearance of the tumour and normalisation of the blood level of prolactin, withdrawal of the treatment with agonists of D2 receptors caused increase in size of the adenoma and increase of level of prolactinaemia.
Only two patients presented with serious clinical symptomatology associated with intratumoral hemorrhage. The hemorrhages are more common during the first weeks of therapy, but can happen at any time thought out the treatment with D2 receptor agonists. Our hypothesis: the prolactinomas with higher level of prolactin have greater tendency for larger hemorrhages.
Neuro endocrinology letters 01/2008; 28(6):841-5. · 1.30 Impact Factor
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Adrian F Daly,
Jean-François Vanbellinghen,
Sok Kean Khoo,
Marie-Lise Jaffrain-Rea,
Luciana A Naves,
Mirtha A Guitelman,
Arnaud Murat,
Philippe Emy,
Anne-Paule Gimenez-Roqueplo,
Guido Tamburrano, [......], Vaclav Hana,
Angela Solano,
Dreanina Delettieres,
Douglas C Luccio-Camelo,
Armando Basso,
Vincent Rohmer,
Thierry Brue,
Vincent Bours,
Bin Tean Teh,
Albert Beckers
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ABSTRACT: An association between germline aryl hydrocarbon receptor-interacting protein (AIP) gene mutations and pituitary adenomas was recently shown.
The objective of the study was to assess the frequency of AIP gene mutations in a large cohort of patients with familial isolated pituitary adenoma (FIPA).
This was a multicenter, international, collaborative study.
The study was conducted in 34 university endocrinology and genetics departments in nine countries.
Affected members from each FIPA family were studied. Relatives of patients with AIP mutations underwent AIP sequence analysis.
Presence/absence and description of AIP gene mutations were the main outcome measures.
There was no intervention.
Seventy-three FIPA families were identified, with 156 patients with pituitary adenomas; the FIPA cohort was evenly divided between families with homogeneous and heterogeneous tumor expression. Eleven FIPA families had 10 germline AIP mutations. Nine mutations, R16H, G47_R54del, Q142X, E174frameshift, Q217X, Q239X, K241E, R271W, and Q285frameshift, have not been described previously. Tumors were significantly larger (P = 0.0005) and diagnosed at a younger age (P = 0.0006) in AIP mutation-positive vs. mutation-negative subjects. Somatotropinomas predominated among FIPA families with AIP mutations, but mixed GH/prolactin-secreting tumors, prolactinomas, and nonsecreting adenomas were also noted. Approximately 85% of the FIPA cohort and 50% of those with familial somatotropinomas were negative for AIP mutations.
AIP mutations, of which nine new mutations have been described here, occur in approximately 15% of FIPA families. Although pituitary tumors occurring in association with AIP mutations are predominantly somatotropinomas, other tumor types are also seen. Further study of the impact of AIP mutations on protein expression and activity is necessary to elucidate their role in pituitary tumorigenesis in FIPA.
Journal of Clinical Endocrinology & Metabolism 06/2007; 92(5):1891-6. · 6.50 Impact Factor
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ABSTRACT: In this study we examined the anti-Helicobacter pylori (anti-H. pylori) antibodies in patients with autoimmune thyroiditis, with and without different polyglandular involvement, and in healthy controls.
Patients with autoimmune thyroiditis (AT) were divided into three groups: Group A: 23 patients with isolated AT, Group B: 30 patients with AT as a part of polyglandular activation of autoimmunity, and Group C: 7 patients with AT as a part of autoimmune polyglandular syndrome type II. Thirty healthy individuals served as controls (Group D). Anti-H. pylori antibodies were determined first by ELISA for classes IgG, IgA, and IgM, and subsequently by immunoblot for classes IgG and IgA.
ELISA: The number of patients with IgA antibodies in Group A (39%) and Group B (30%) differed significantly from controls (7%, p<0.05). Immunoblot: Anti-CagA antibodies were found in 13% of patients in Group A, 7% of Group B, 0% of Group C, and 20% of Group D. A higher seroprevalence, as compared to controls, was found for IgG to the VacA (p=0.01), 30 kDa (p=0.001), and 17 kDa (p=0.008) antigens in Group A and for IgG to the 30 kDa antigen in Group C (p=0.037). A significantly higher seroprevalence, as compared to controls, was likewise found for IgA to the 17 kDa antigen in Group A (p=0.015).
A different distribution of antibodies to H. pylori antigens was found in patients with isolated AT compared to patients with AT coupled with a polyglandular syndrome.
Neuro endocrinology letters 01/2007; 27 Suppl 1:41-5. · 1.30 Impact Factor
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ABSTRACT: Vascular growth factors are important not only in angiogenesis but also for the maintenance of normal endothelial integrity and function. Elevated levels of vascular endothelial growth factor (VEGF), angiopoietin-2, hepatocyte growth factor (HGF), endostatin and angiogenin have been associated with endothelial dysfunction and atherosclerosis. Both acromegaly and growth hormone deficiency (GHD) are associated with endothelial dysfunction and changes in blood vessel morphology.
To investigate the effect of GH status on the circulating levels of angiogenic factors.
We measured the levels of six endothelial growth modulators, four angiogenic growth factors and two inhibitors of angiogenesis in 35 untreated acromegalics, 36 untreated GH-deficient subjects and 101 normal control subjects. Fifteen GH-deficient subjects were also studied before and 1 year after treatment with GH.
Mean angiogenin concentrations were increased in acromegaly and decreased in GH-deficient subjects compared to control subjects. Endostatin levels showed a similar pattern although the elevated levels in acromegalic subjects did not achieve statistical significance. Angiogenin and endostatin levels both correlated significantly with IGF-I levels (R = 0.61, P < 0.001 and R = 0.22, P < 0.01, respectively). The relationship between angiogenin and IGF-I levels remained significant even after correction for gender, age, body mass index (BMI) and insulin resistance. There were no significant differences in the levels of HGF, VEGF, VEGF-C or angiopoietin-2 between the three groups. VEGF-D levels were elevated in both acromegalic and GH-deficient male subjects. A similar pattern was apparent in female subjects. After GH treatment, a significant reduction in VEGF-D levels and a significant rise in endostatin levels were observed in GH-deficient subjects. A nonsignificant increase in angiogenin levels was also observed.
These data indicate that significant perturbations in the levels of vascular growth modulators are present in both acromegaly and GHD. While changes in endostatin and angiogenin levels appear to correlate with IGF-I levels, VEGF-D levels show similar perturbations in both acromegaly and GHD. Further studies are required to determine the relationship of the perturbations to endothelial dysfunction in these conditions.
Clinical Endocrinology 08/2005; 63(1):79-86. · 3.17 Impact Factor
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ABSTRACT: Growth hormone deficiency (GHD) in adult life has been associated with increased central adiposity, decreased insulin sensitivity, dyslipidaemia and increased risk of cardiovascular disease. The effects of GH replacement on adiponectin and resistin, adipokines which have a role in modulating insulin sensitivity have not been previously reported.
To examine the effects of GH replacement on adipokine levels and insulin resistance in GHD patients.
Seventeen adult GHD patients were examined at baseline and after 1 year of treatment with recombinant human GH (mean dose 0.31 mg/day, range 0.13-0.67 mg/day).
GH replacement significantly increased IGF-I levels. The mean IGF-I SD score increased from -1.98 at baseline to 0.76 at study end. GH replacement was associated with a significant reduction in percentage body fat (34.11 +/- 1.33 vs. 30.65 +/- 1.27%, P < 0.0005) and a significant increase in lean body mass (63.57 +/- 1.24 vs. 66.96 +/- 1.18%, P < 0.0004), before and after treatment, respectively. Surprisingly, there was no effect of GH replacement on the plasma levels of leptin, resistin or adiponectin or on plasma lipid profile. Insulin sensitivity did not deteriorate during GH replacement despite the known 'anti-insulin' effect of GH. Fasting glucose, insulin and insulin resistance as calculated using the homeostasis model assessment insulin resistance index (HOMA-R) were unchanged by GH treatment.
These data demonstrate GH replacement in adult subjects with GHD is effective in changing body composition and restoring IGF-I levels over a 12-month period; however, in our study, these changes were not accompanied by changes in adipokine levels or beneficial effects on plasma lipids or insulin resistance.
Clinical Endocrinology 04/2004; 60(4):442-50. · 3.17 Impact Factor
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ABSTRACT: With the aim to investigate histopathological changes and proliferative and apoptotic activity in GH-secreting adenomas we compared 14 cases pre-treated with somatostatin analogues before surgery with a reference group of 17 un-pretreated ones. Besides routine histology, immunocytochemical detection of all pituitary hormones, caspase-3, cytokeratin-18, and "M30 antigen", its apoptosis-specific fragment was performed. Proliferation activity of the tumour was determined by the Ki-67 antigen expression. In treated adenomas more prominent regressive changes were found accompanied by compensatory increase in perivascular fibrosis. The Ki-67 labelling index was lower in treated group (mean 2.5, median 1.6 per mille) than in untreated patients (mean 9.4, median 5.0 per mille). The difference was statistically significant (p=0.049 using Mann-Whitney Rank Sum Test). Apoptosis was detected in only 2 of the 14 pre-treated adenomas, and it was more frequent (9/17) and more prominent in the untreated group.
Journal of Clinical Neuroscience 08/2003; 10(4):444-8. · 1.25 Impact Factor
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ABSTRACT: Insulin resistance, impaired glucose tolerance and type 2 diabetes are common in acromegalic subjects. The mechanism underlying this insulin resistance is unclear.
We investigated the levels of the adipocytokines, resistin, adiponectin and leptin in a group of 18 acromegalic subjects and 18 control subjects matched for age, gender and body mass index.
Here we demonstrate for the first time significant elevation in adiponectin levels in acromegalic subjects compared to control subjects 12.5 +/- 1.2 vs. 8.97 +/- 1.1 mg/l, P = 0.029. The resistin levels were similar in acromegalic subjects and controls; 20.65 +/- 2.99 vs. 19.03 +/- 4.72 micro g/l. No evidence of a correlation between adiponectin and insulin resistance as calculated from HOMA-R was found. No correlation was observed either between adiponectin or resistin levels and GH levels, total IGF-I or free IGF-I levels. Leptin levels were significantly reduced in acromegalic subjects, 8.22 +/- 2.26 vs. 18.3 +/- 4.1 micro g/l, P = 0.004. In control subjects, significant correlations between leptin levels and HOMA-R and between resistin levels and HOMA-R were observed. These relationships were not apparent in acromegalic subjects.
From these data we conclude that changes in resistin and adiponectin levels are unlikely to account for the insulin resistance of acromegaly.
Clinical Endocrinology 07/2003; 58(6):736-42. · 3.17 Impact Factor
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ABSTRACT: Summarybackground Insulin resistance, impaired glucose tolerance and type 2 diabetes are common in acromegalic subjects. The mechanism underlying this insulin resistance is unclear.design We investigated the levels of the adipocytokines, resistin, adiponectin and leptin in a group of 18 acromegalic subjects and 18 control subjects matched for age, gender and body mass index.results Here we demonstrate for the first time significant elevation in adiponectin levels in acromegalic subjects compared to control subjects 12·5 ± 1·2 vs. 8·97 ± 1·1 mg/l, P = 0·029. The resistin levels were similar in acromegalic subjects and controls; 20·65 ± 2·99 vs. 19·03 ± 4·72 µg/l. No evidence of a correlation between adiponectin and insulin resistance as calculated from HOMA-R was found. No correlation was observed either between adiponectin or resistin levels and GH levels, total IGF-I or free IGF-I levels. Leptin levels were significantly reduced in acromegalic subjects, 8·22 ± 2·26 vs. 18·3 ± 4·1 µg/l, P = 0·004. In control subjects, significant correlations between leptin levels and HOMA-R and between resistin levels and HOMA-R were observed. These relationships were not apparent in acromegalic subjects.conclusion From these data we conclude that changes in resistin and adiponectin levels are unlikely to account for the insulin resistance of acromegaly.
Clinical Endocrinology 06/2003; 58(6):736 - 742. · 3.17 Impact Factor
