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See detailCorrection of vitamin D insufficiency with combined strontium ranelate and vitamin D3 in osteoporotic patients.
Rizzoli, R.; Dawson-Hughes, B.; Kaufman, J.-M. et al

in European Journal of Endocrinology (2014), 170(3), 441-50

OBJECTIVE: This study aims to investigate the efficacy and safety of oral fixed-dose combination of strontium ranelate 2 g/vitamin D3 1000 IU daily vs strontium ranelate 2 g daily for correcting vitamin D ... [more ▼]

OBJECTIVE: This study aims to investigate the efficacy and safety of oral fixed-dose combination of strontium ranelate 2 g/vitamin D3 1000 IU daily vs strontium ranelate 2 g daily for correcting vitamin D insufficiency in osteoporosis. DESIGN: A 6-month international, randomized, double-blind, parallel-group, phase 3 study. METHODS: A total of 518 men and postmenopausal women aged >/=50 years with primary osteoporosis (T-score </=-2.5 s.d.) and serum 25-hydroxyvitamin D (25(OH)D) >22.5 nmol/l were included. Patients were allocated to strontium ranelate 2 g/vitamin D3 1000 IU daily (n=413) or strontium ranelate 2 g daily (n=105). The participants received calcium 1 g daily. The primary endpoint was serum 25(OH)D at last post-baseline evaluation during 3 months. RESULTS: Both groups were comparable at baseline. Mean baseline of 25(OH)D was 44.1+/-14.6 nmol/l. After 3 months, the percentage of patients with 25(OH)D >/=50 nmol/l was higher with strontium ranelate/vitamin D3 vs strontium ranelate (84 vs 44%, P<0.001; adjusted between-group odds ratio=6.7; 95% CI, 4.2-10.9). The efficacy of the fixed-dose combination on 25(OH)D was maintained at 6 months (86 vs 40%, P<0.001). Mean 25(OH)D was 65.1 and 49.5 nmol/l, respectively, after 3 months and 66.9 and 45.4 nmol/l after 6 months. Physical performance improved in both groups. Falls were 17 and 20% in the strontium ranelate/vitamin D3 and strontium ranelate groups respectively. Parathyroid hormone levels were inversely correlated with 25(OH)D. No clinically relevant differences in safety were observed. CONCLUSIONS: This study confirms the efficacy and safety of fixed-dose combination of strontium ranelate 2 g/vitamin D3 1000 IU for correction of vitamin D insufficiency in osteoporotic patients. [less ▲]

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See detailGenetic analysis in young patients with sporadic pituitary macroadenomas:Beside AIP don't forget MEN1 genetic analysis.
Cuny, Thomas; Pertuit, Morgane; Sahnoun-Fathallah, Mouna et al

in European Journal of Endocrinology (2013)

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 ... [more ▼]

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. [less ▲]

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See detailSerum sclerostin levels in men with idiopathic osteoporosis
Lapauw, Bruno; Vandewalle, S.; Taes, Y. et al

in European Journal of Endocrinology (2013), 168(4), 615-620

Objective: Sclerostin inhibits osteoblast differentiation and bone formation. If aberrant sclerostin action is involved in less efficient bone acquisition in men with idiopathic low bone mass, this might ... [more ▼]

Objective: Sclerostin inhibits osteoblast differentiation and bone formation. If aberrant sclerostin action is involved in less efficient bone acquisition in men with idiopathic low bone mass, this might be reflected in higher serum sclerostin levels. Methods: In 116 men with idiopathic osteoporosis (%65 years old), 40 of their sons and healthy controls, areal bone parameters were measured using dual-energy X-ray absorptiometry, and volumetric and geometric bone parameters were measured using peripheral quantitative computed tomography. Serum analytes were measured using immunoassays and estradiol (E2) levels using liquid chromatography–tandem mass spectrometry. Results: Men with idiopathic low bone mass had lower levels of sclerostin than the controls (0.54G 0.17 vs 0.66G0.23 ng/ml; P!0.001). In both groups, sclerostin levels were strongly associated with age; when adjusting for age, no associations with anthropometrics were observed (PO0.14). In multivariate analyses, sclerostin levels displayed a positive association with whole-body bone mineral content (BMC) and areal BMD (aBMD), as well as with trabecular and cortical volumetric bone mineral density (vBMD) at the tibia in the probands. No clear associations were observed in the control group, neither were sclerostin levels associated with BMC at the radius or lumbar spine (all PO0.11). Testosterone, but not E2, was inversely related to sclerostin levels in the probands. No difference in sclerostin levels was found in their sons when compared with their controls. Conclusion: Lower rather than higher serum sclerostin levels in the probands with idiopathic low bone mass suggest that aberrant sclerostin secretion is not involved in the pathogenesis of low bone mass in these subjects. [less ▲]

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See detailAdrenal involvement in MEN1. Analysis of 715 cases from the Groupe d'etude des Tumeurs Endocrines database.
Gatta-Cherifi, B.; Chabre, O.; Murat, A. et al

in European Journal of Endocrinology (2012), 166(2), 269-279

Objective Limited data regarding adrenal involvement in multiple endocrine neoplasia type 1 (MEN1) is available. We describe the characteristics of MEN1-associated adrenal lesions in a large cohort to ... [more ▼]

Objective Limited data regarding adrenal involvement in multiple endocrine neoplasia type 1 (MEN1) is available. We describe the characteristics of MEN1-associated adrenal lesions in a large cohort to provide a rationale for their management. Methods Analysis of records from 715 MEN1 patients from a multicentre database between 1956 and 2008. Adrenal lesions were compared with those from a multicentre cohort of 144 patients with adrenal sporadic incidentalomas. Results Adrenal enlargement was reported in 20.4% (146/715) of patients. Adrenal tumours (>10 mm in size) accounted for 58.1% of these cases (10.1% of the whole patient cohort). Tumours were bilateral and >40 mm in size in 12.5 and 19.4% of cases respectively. Hormonal hypersecretion was restricted to patients with tumours and occurred in 15.3% of them. Compared with incidentalomas, MEN1-related tumours exhibited more cases of primary hyperaldosteronism, fewer pheochromocytomas and more adrenocortical carcinomas (ACCs; 13.8 vs 1.3%). Ten ACCs occurred in eight patients. Interestingly, ACCs occurred after several years of follow-up of small adrenal tumours in two of the eight affected patients. Nine of the ten ACCs were classified as stage I or II according to the European Network for the Study of Adrenal Tumors. No evident genotype/phenotype correlation was found for the occurrence of adrenal lesions, endocrine hypersecretion or ACC. Conclusions Adrenal pathology in MEN1 differs from that observed in sporadic incidentalomas. In the absence of relevant symptoms, endocrine biology can be restricted to patients with adrenal tumours and should focus on steroid secretion including the aldosterone-renin system. MEN1 is a high-risk condition for the occurrence of ACCs. It should be considered regardless of the size of the tumour. [less ▲]

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See detailProlactinomas Resistant to Standard Doses of Cabergoline : A multicenter study of 92 patients
VROONEN, Laurent ULg; Jaffrain-Rea, ML; PETROSSIANS, Patrick ULg et al

in European Journal of Endocrinology (2012), 167

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See detailHigh prevalence of AIP gene mutations following focused screening in young patients with sporadic pituitary macroadenomas.
Tichomirowa, Maria A; Barlier, Anne; Daly, Adrian ULg et al

in European Journal of Endocrinology (2011), 165(4), 509-15

BACKGROUND: Aryl hydrocarbon receptor interacting protein (AIP) mutations (AIPmut) cause aggressive pituitary adenomas in young patients, usually in the setting of familial isolated pituitary adenomas ... [more ▼]

BACKGROUND: 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. METHODS: We included 163 sporadic pituitary macroadenoma patients irrespective of clinical phenotype diagnosed at <30 years of age. RESULTS: 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. CONCLUSION: 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. [less ▲]

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See detailGender-related differences in MEN1 lesion occurrence and diagnosis: a cohort study of 734 cases from the Groupe d''etude des Tumeurs Endocrines
goudet, p; Bonithon-Kopp, C.; Murat, A. et al

in European Journal of Endocrinology (2011)

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See detailMutations of calcium-sensing receptor gene: two novel mutations and overview of impact on calcium homeostasis
Livadariu, E.; Auriemma, R. S.; Rydlewski, C. et al

in European Journal of Endocrinology (2011)

Objective: Genetic disorders of calcium metabolism arise in a familial or sporadic setting. The calcium-sensing receptor (CaSR) plays a key role in maintaining calcium homeostasis and study of the CASR ... [more ▼]

Objective: Genetic disorders of calcium metabolism arise in a familial or sporadic setting. The calcium-sensing receptor (CaSR) plays a key role in maintaining calcium homeostasis and study of the CASR gene can be clinically useful in determining etiology and appropriate therapeutic approaches. We report two cases of novel CASR gene mutations that illustrate the varying clinical presentations and discuss these in terms of the current understanding of CaSR function. Patients and Methods: A 16 yr-old patient had mild hypercalcemia associated with low-normal urinary calcium excretion and normal-to-high parathyroid hormone (PTH) levels. Because of negative family history, familial hypocalciuric hypercalcemia (FHH) was originally excluded. The second patient was a 54 yr-old man with symptomatic hypocalcemia, hyperphosphatemia, low PTH, and mild hypercalciuria. Familial investigation revealed the same phenotype in the patient's sister. The coding region of the CaSR gene was sequenced in both probands and their available first-degree relatives. Results: The first patient had a novel heterozygous inactivating CASR mutation in exon 4, which predicted a p.A423K change; genetic analysis was negative in the parents. The second patient had a novel heterozygous activating CASR mutation in exon 6, which predicted a p.E556K change; the affected sister of the proband was also positive. Conclusions: We reported two novel heterozygous mutations of the CASR gene, an inactivating mutation in exon 4 and the first activating mutation reported to date in exon 6. These cases illustrate the importance of genetic testing of CASR gene to aid correct diagnosis and to assist in clinical management. [less ▲]

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See detailAdult final height after GH therapy for irradiation-induced GH deficiency in childhood survivors of brain tumors: the Belgian experience.
Beckers, D.; THOMAS, M.; Jamart, J. et al

in European Journal of Endocrinology (2010), 162(3), 483-90

OBJECTIVES: The treatment of brain tumors in childhood is frequently complicated by growth retardation with a high proportion of irradiation (Irr)-induced GH deficiency (GHD) resulting in reduced adult ... [more ▼]

OBJECTIVES: The treatment of brain tumors in childhood is frequently complicated by growth retardation with a high proportion of irradiation (Irr)-induced GH deficiency (GHD) resulting in reduced adult final height (AFH) even after GH therapy (GHT). In order to optimize future GHT protocols, more information on the factors influencing the growth response to GH in these children is needed. This retrospective study evaluated AFH and influencing auxological and treatment factors of a standardized daily biosynthetic GHT in childhood survivors of brain tumors with documented GHD after brain Irr. DESIGN AND METHODS: From the Belgian GH Registry, 57 children survivors of a brain tumor outside the hypothalamo-pituitary area with available AFH were stratified into two groups depending on cranial (C-Irr; n=25) or craniospinal (CS-Irr; n=32) Irr. RESULTS: In the C-Irr patients, results showed an AFH of -0.8 (-2.5, 1.4) SDS (median (range)) and in the CS-Irr patients, results showed a significantly (P<0.001) lower AFH of -1.8 (-4.2, 0.0) SDS. AFH SDS corrected for mid-parental height (MPH) in the C-Irr group was -0.5 (-2.2, 0.9) and -1.5 (-3.6, 0.0) SDS in the CS-Irr group. AFH was positively correlated with age at end of tumor therapy, height SDS at start GHT, height gain SDS first year GHT, and negatively correlated with CS-Irr. CONCLUSIONS: GHT failed to restore adult height to MPH in nearly half of Irr-induced GHD patients for brain tumor, especially those receiving CS-Irr, irradiated at a younger age or shorter at start GHT. [less ▲]

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See detailAggressive pituitary adenomas occurring in young patients in a large Polynesian kindred with a germline R271W mutation in the AIP gene.
Jennings, J. E.; Georgitsi, M.; Holdaway, I. et al

in European Journal of Endocrinology (2009), 161(5), 799-804

OBJECTIVE: Mutations in the aryl hydrocarbon receptor-interacting protein (AIP) were recently shown to confer a pituitary adenoma predisposition in patients with familial isolated pituitary adenomas (FIPA ... [more ▼]

OBJECTIVE: Mutations in the aryl hydrocarbon receptor-interacting protein (AIP) were recently shown to confer a pituitary adenoma predisposition in patients with familial isolated pituitary adenomas (FIPA). We report a large Samoan FIPA kindred from Australia/New Zealand with an R271W mutation that was associated with aggressive pituitary tumors. DESIGN AND METHODS: Case series with germline screening of AIP and haplotype analyses among R271W families. RESULTS: This previously unreported kindred consisted of three affected individuals that either presented with or had first symptoms of a pituitary macroadenoma in late childhood or adolescence. The index case, a 15-year-old male with incipient gigantism and his maternal aunt, had somatotropinomas, and the maternal uncle of the index case had a prolactinoma. All tumors were large (15, 40, and 60 mm maximum diameter) and two required transcranial surgery and radiotherapy. All three affected subjects and ten other unaffected relatives were found to be positive for a germline R271W AIP mutation. Comparison of the single nucleotide polymorphism patterns among this family and two previously reported European FIPA families with the same R271W mutation demonstrated no common ancestry. CONCLUSIONS: This kindred exemplifies the aggressive features of pituitary adenomas associated with AIP mutations, while genetic analyses among three R271W FIPA families indicate that R271W represents a mutational hotspot that should be studied further in functional studies. [less ▲]

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See detailSmall effect of the androgen receptor gene GGN repeat polymorphism on serum testosterone levels in healthy men
Bogaert, V.; Vanbillemont, G.; Taes, Y. et al

in European Journal of Endocrinology (2009), 161(1), 171-7

OBJECTIVE: The human androgen receptor (AR) contains a polyglutamine and a polyglycine stretch which are highly polymorphic and are coded respectively by a CAG and GGN repeat in exon 1 of the AR gene ... [more ▼]

OBJECTIVE: The human androgen receptor (AR) contains a polyglutamine and a polyglycine stretch which are highly polymorphic and are coded respectively by a CAG and GGN repeat in exon 1 of the AR gene. Although the in vitro studies indicated a possible effect of the GGN repeat polymorphism on the AR gene transcription and clinical observations suggest that it might modulate the androgen action, its functional significance remains unclear. We wanted to assess whether the GGN repeat affects the serum testosterone levels in healthy men, which is the expected outcome through feedback regulation if it influences androgen action as has been shown to be the case for the CAG repeat. DESIGN AND PATIENTS: A population based cross-sectional cohort study including 1476 healthy young, middle-aged, and elderly men. MEASUREMENT: Testosterone and LH levels were determined by immunoassay; free testosterone (FT) levels were calculated. Genotyping of the GGN repeat was performed using the sequencing technique. RESULTS: The GGN repeat number was significantly associated with circulating testosterone and FT levels (P=0.017 and P=0.013 respectively). However, taking into account that age, body mass index, and CAG are already in the regression model, the GGN repeat could explain only a small part of the variation of both testosterone and FT. CONCLUSION: To our knowledge, this study is the first to demonstrate a significant positive association between the GGN repeat and androgen levels in a large cohort of healthy men. Although the present study thus adds credence to the view that the polyglycine tract in the AR can modulate AR action, this effect appears to be only small so that its clinical relevance remains questionable. [less ▲]

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See detailCabergoline and the risk of valvular lesions in endocrine disease.
Lancellotti, Patrizio ULg; Livadariu, E.; Markov, M. et al

in European Journal of Endocrinology (2008), 159(1), 1-5

AIMS: The cardiac valvular risk associated with lower exposure to cabergoline in common endocrine conditions such as hyperprolactinemia is unknown. METHODS AND RESULTS: We performed a cross-sectional ... [more ▼]

AIMS: The cardiac valvular risk associated with lower exposure to cabergoline in common endocrine conditions such as hyperprolactinemia is unknown. METHODS AND RESULTS: We performed a cross-sectional, case-control echocardiographic study to assess the valvular status in 102 subjects receiving cabergoline for endocrine disorders and 51 matched control subjects. Cabergoline treatment ranged from 12 to 228 months, with a cumulative dose of 18-1718 mg. Valvular regurgitation was equally prevalent in both groups and was almost exclusively mild. Two cabergoline-treated subjects had moderate mitral regurgitation; there was no relationship between cabergoline dose and the presence or severity of mitral valve regurgitation (P=NS). Mitral valve tenting area was significantly greater in the cabergoline group when compared with the control subjects (P=0.03). Mitral valve leaflet thickening was observed in 5.9% of cabergoline-treated subjects; no relationship with the cumulative cabergoline dose was found. No patient had aortic or tricuspid valvular restriction. CONCLUSION: No significantly increased risk of clinically relevant cardiac valve disorders was found in subjects treated with long-term cabergoline therapy at the doses used in endocrine practice. While exposure to cabergoline appears to be safe during low-dose long-term therapy, an association with subclinical changes in mitral valve geometry cannot be completely excluded. [less ▲]

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See detailVariable pathological and clinical features of a large Brazilian family harboring a mutation in the aryl hydrocarbon receptor-interacting protein gene
Naves, L. A.; Daly, Adrian ULg; Vanbellinghen, Jean-François ULg et al

in European Journal of Endocrinology (2007), 157(4), 383-391

Background: Germline aryl hydrocarbon receptor-interacting protein (AIP) mutations occur in 15% of familial isolated pituitary adenoma (FIPA) cases. To date, studies have focused on the identification of ... [more ▼]

Background: Germline aryl hydrocarbon receptor-interacting protein (AIP) mutations occur in 15% of familial isolated pituitary adenoma (FIPA) cases. To date, studies have focused on the identification of such mutations in large international cohorts. Detailed genetic and clinical studies within AIP mutation-positive families have been limited. Aim: To undertake a comprehensive study of a large Brazilian FIPA kindred with an E174 frameshift (E174fs) AIP mutation to assess clinical, hormonal, and radiological features in mutation carriers. Methods: The kindred included 122 subjects across six generations; all underwent clinical examination. Genetic studies were performed to identify E174fs mutation carriers. E174fs-positive subjects underwent magnetic resonance imaging (MRI) and hormonal assessments. Results: Of the ten germline AIP mutation carriers, three had pituitary tumors, while seven were asymptomatic carriers. Three patients with pituitary tumors showed variability in terms of tumor phenotype (two with acromegaly, one with prolactinoma, or mixed prolactin/GH-secreting tumor) and age at diagnosis; both patients with acromegaly had poor responses to octreotide. Tumor AIP immunohistochemistry from the operated patient showed decreased expression when compared with normal tissue. Two adult subjects with normal MRI had elevated IGF-I in the absence of other causes. A 2-year-old child with the E174fs mutation and a normal MRI had premature thelarche, ovarian development, and advanced bone age in the absence of other underlying causes. Conclusions: The penetrance of pituitary tumors in AIP mutation-positive adult subjects was 33.3%, while clinical/hormonal features were variable. The features noted in AIP-mutation carriers in this kindred suggest that clinical characteristics of such carriers may extend beyond pituitary tumors. [less ▲]

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See detailThe clinical, pathological, and genetic features of familial isolated pituitary adenomas
Beckers, Albert ULg; Daly, Adrian ULg

in European Journal of Endocrinology (2007), 157(4), 371-382

Pituitary adenomas occur in a familial setting in multiple endocrine neoplasia type 1 (MEN1) and Carney's complex (CNC), which occur due to mutations in the genes MEN1 and PRKAR1A respectively. Isolated ... [more ▼]

Pituitary adenomas occur in a familial setting in multiple endocrine neoplasia type 1 (MEN1) and Carney's complex (CNC), which occur due to mutations in the genes MEN1 and PRKAR1A respectively. Isolated familial somatotropinoma (IFS) is also a well-described clinical syndrome retated only to patients with acrogigantism. Pituitary adenomas of all types - not limited to IFS - can occur in a familial setting in the absence of MEN1 and CNC; this phenotype is tcrmed familial isolated pituitary adenomas (FIPA). Over the past 7 years, we have described over 90 FIPA kindreds. In FIPA, both homogeneous and heterogeneous pituitary adenoma phenotypes can occur within families; virtually all FIPA kindreds contain at least one prolactinoma or somatotropinoma. FIPA differs from MEN1 in terms of a lower proportion of prolactinomas and more frequent somatotropinomas in the FIPA cohort. Patients with FIPA are significantly younger at diagnosis and have significantly larger pituitary adenomas than matched sporadic pituitary adenoma counterparts. A minority of FIPA families overall (15%) exhibit mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene; AIP mutations are present in only half of IFS kindreds occurring as part of the FIPA cohort. In families with AIP mutations, pituitary adenomas have a penetrance of over 50%. AIP mutations are extremely rare in patients with sporadic pituitary adenomas. This review deals with pituitary adenomas that occur in a familial setting, describes in detail the clinical, pathological, and genetic features of FIPA, and addresses aspects of the clinical approach to FIPA families with and without AIP mutations. [less ▲]

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See detailAssessment and mechanism of variations in pubertal timing in internationally adopted children: a developmental hypothesis
Domine, Françoise ULg; Parent, Anne-Simone ULg; Rasier, Gregory et al

in European Journal of Endocrinology (2006), 155(Suppl. 1), 17-25

During the past decades, children migrating for international adoption have increased in number, creating an original condition of dramatic environmental change during development. In several countries ... [more ▼]

During the past decades, children migrating for international adoption have increased in number, creating an original condition of dramatic environmental change during development. In several countries, cohorts of these subjects have been shown to experience a global advancement in age at the onset of puberty, and sexual precocity is seen more frequently than in other conditions. Such early or precocious development has been assessed in relatively small cohorts or individual patients using well-defined physical indicators in comparison with updated references in the foster country. Family and adolescent evaluation of pubertal timing could allow for the study of large series of internationally adopted subjects. Also, this type of assessment integrates the physical changes of puberty with the adolescent changes in psychological and social functioning. The pathophysiological mechanisms leading to advancement of puberty in migrating children are still unclear and possibly involve several factors. In the present paper, we hypothesize that the sexual precocity in children migrating for international adoption could represent a developmentally programmed disorder resulting from cumulative anomalies in early remodeling of the central nervous system by communicational, social, nutritional, and hormonal inputs. There is some evidence that the deviations in those inputs can result in altered brain structure, particularly in the limbic system. We discuss the possible association with further disorders of developmental functions, such as cognitive, psychosocial, and sexual maturation. Along this hypothesis, some forms of idiopathic sexual precocity could result from dysfunction of one or several of the environmental programming factors, while other forms may involve predominantly genetic or familial factors. [less ▲]

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See detailPredictors and rates of treatment-resistant tumor growth in acromegaly
Besser, G. M.; Burman, P.; Daly, Adrian ULg

in European Journal of Endocrinology (2005), 153(2), 187-193

Background: Multimodal therapy for acromegaly affords adequate disease control for many patients; however, there remains a subset of individuals that exhibit treatment-resistant disease. The issue of ... [more ▼]

Background: Multimodal therapy for acromegaly affords adequate disease control for many patients; however, there remains a subset of individuals that exhibit treatment-resistant disease. The issue of treatment-resistant pituitary tumor growth remains relatively under-explored. Methods: We assessed the literature for relevant data regarding the surgical, medical and radio-therapeutic treatment of acromegaly in order to identify the factors that were predictive of aggressive or treatment-resistant pituitary tumor behavior in acromegaly and undertook an assessment of the rates of failure to control tumor progression with available treatment modalities. Results: Young age at diagnosis, large tumor size, high growth hormone secretion and certain histological markers are predictors of future aggressive tumor behavior in acromegaly. Significant tumor regrowth occurs in less than 10% of cases thought to be cured surgically, whereas failure to control tumor growth is seen in less than 1% of patients receiving radiotherapy. Somatostatin analogs induce a variable degree of tumor shrinkage in acromegaly but up to 2.2% of somatostatin analog-treated tumors continue to grow. Relative to other therapies, limited data are available for pegvisomant, but these indicate that persistent tumor growth occurs in 1.6-2.9% of cases followed up regularly with serial magnetic resonance imaging scans. Conclusions: Treatment-resistant tumor progression occurs in a small minority of patients with acromegaly, regardless of treatment modality. Young patients with large tumors or those with high pre-treatment levels of growth hormone particularly warrant close monitoring for continued tumor progression during treatment for acromegaly. [less ▲]

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See detailThe multi-ligand somatostatin analogue SOM230 inhibits ACTH secretion by cultured human corticotroph adenomas via somatostatin receptor type 5.
Hofland, Leo J.; van der Hoek, Joost; Feelders, Richard et al

in European Journal of Endocrinology (2005), 152(4), 645-654

Objective: Currently, there is no effective medical treatment for patients with pituitary-dependent Cushing’s disease. A novel somatostatin (SS) analogue, named SOM230, with high binding affinity to SS ... [more ▼]

Objective: Currently, there is no effective medical treatment for patients with pituitary-dependent Cushing’s disease. A novel somatostatin (SS) analogue, named SOM230, with high binding affinity to SS receptor subtypes sst1, sst2, sst3 and sst5 was recently introduced. We compared the in vitro effects of the sst2-preferring SS analogue octreotide (OCT) and the multi-ligand SOM230 on ACTH release by human and mouse corticotroph tumour cells. Methods: By quantitative RT-PCR the sst subtype expression level was determined in human corticotroph adenomas. In vitro, the inhibitory effect of OCT and SOM230 on ACTH release by dispersed human corticotroph adenoma cells and mouse AtT20 corticotroph adenoma cells was determined. In addition, the influence of dexamethasone on the responsiveness to OCT and SOM230 was studied. Results: Corticotroph adenomas expressed predominantly sst5 mRNA (six out of six adenomas), whereas sst2 mRNA expression was detected at significantly lower levels. In a 72 h incubation with 10 nmol/l SOM230, ACTH release was inhibited in three out of five cultures (range –30 to –40%). Ten nmol/l OCT slightly inhibited ACTH release in only one of five cultures (– 28%). In AtT20 cells, expressing sst2, sst3 and sst5, SOM230 inhibited ACTH secretion with high potency (IC50 0.2 nmol/l). Dexamethasone (10 nmol/l) pre-treatment did not influence the sensitivity of the cells to the inhibitory effect of SOM230, suggesting that sst5 is relatively resistant to negative control by glucocorticoids. Conclusions: The selective expression of sst5 receptors in corticotroph adenomas and the preferential inhibition of ACTH release by human corticotroph adenoma cells by SOM230 in vitro, suggest that SOM230 may have potential in the treatment of patients with pituitary-dependent Cushing’s disease. [less ▲]

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See detailGross total resection or debulking of pituitary adenomas improves hormonal control of acromegaly by somatostatin analogs
Petrossians, Patrick ULg; Borges-Martins, L.; Espinoza, C. et al

in European Journal of Endocrinology (2005), 152(1), 61-66

Introduction: Invasive GH-secreting pituitary adenomas are rarely cured by surgery and although long-term therapy with somatostatin analogs (SSAs) may be employed, hormonal control is achieved in only 60 ... [more ▼]

Introduction: Invasive GH-secreting pituitary adenomas are rarely cured by surgery and although long-term therapy with somatostatin analogs (SSAs) may be employed, hormonal control is achieved in only 60% of cases. The impact of tumor debulking on subsequent control of acromegaly with SSAs has not been studied previously. Methods: We studied retrospectively the response to SSA therapy in acromegalic patients before and after incomplete surgical tumor excision. A case review identified 24 acromegalic patients who had received SSA therapy for 1 month before and after gross total resection or debulking of adenomas. No patient received radiotherapy or combination treatment with SSAs and dopamine agonists during the study. GH and IGF-I responses to SSAs were recorded pre- and postoperatively. Postoperative SSA therapy was begun after a washout period of 1–3 months to assess the hormonal effects of the surgery alone. Results: Before preoperative SSA treatment, 24/24 (100%) patients had elevated GH levels and IGF-I levels were elevated in 19/21 (90.5%) patients with recorded values. During preoperative SSA treatment, GH and IGF-I levels were normalized in 7/24 (29.2%) and 11/24 (45.8%) patients respectively. Following postoperative washout, GH was controlled in only 3/24 (12.5%) patients, while IGF-I was controlled in 8/19 (42.1%) patients with available data. During the second SSA treatment period, normal GH levels were seen in 13/24 (54.2%) patients, while IGF-I control was noted in 18/23 (78.3%). Conclusion: Gross total tumor resection or debulking increases the likelihood of achieving biochemical disease control with SSAs in acromegalic patients with adenomas that were not amenable to complete surgical resection and in whom primary SSA therapy was unable to achieve good biochemical control. [less ▲]

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See detailInterest of the androgen deficiency in aging males (ADAM) questionnaire for the identification of hypogonadism in elderly community-dwelling male volunteers
Tancredi, Annalisa ULg; Reginster, Jean-Yves ULg; Schleich, FLorence ULg et al

in European Journal of Endocrinology (2004), 151(3), 355-360

Objective: To date, serum free testosterone measurement is considered to be the gold standard for the diagnosis of hypogonadism in elderly males but it is not available to all subjects suspected of a ... [more ▼]

Objective: To date, serum free testosterone measurement is considered to be the gold standard for the diagnosis of hypogonadism in elderly males but it is not available to all subjects suspected of a decrease in testicular function. Therefore, we evaluated whether the Androgen Deficiency in Aging Males (ADAM) questionnaire, in its original or in a modified 'quantitative' version (qADAM), could be used as a surrogate to biochemical determinations for the identification of hypogonadism in elderly males. Methods: 5028 men, aged 50-70 years, spontaneously consulting for the assessment of their gonadal function were studied. ADAM and qADAM, allocating a value of 1 point for any positive answer to each of the 10 questions of the ADAM test, were assessed for their ability to discriminate between males with free testosterone levels below or above 70 ng/l. Results: The sensitivity and specificity of the ADAM score were 81% and 21.6% respectively. The use of ADAM resulted in an appropriate classification of our population in normal or hypogonadal subjects in 44.5% of the cases. The area under the receiver operating characteristics (ROC) curve for the qADAM (0.529) revealed a highly marginal interest of this quantitative approach compared with the original scoring system. Conclusions: The ADAM test has a high sensitivity to identify aging males with low free testosterone levels. However, due to its lack of specificity, this test cannot be used as a surrogate to serum free testosterone testing for the identification of androgen deficiency in elderly, community-dwelling males. [less ▲]

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See detailPrevalence and demographic features of childhood growth hormone deficiency in Belgium during the period 1986-2001
Thomas, Muriel; Massa, Guy; Craen, Margarita et al

in European Journal of Endocrinology (2004), 151(1), 67-72

Objective: Since the availability of recombinant human growth hormone (rhGH) all children with growth hormone deficiency (GHD) living in Belgium are offered rhGH treatment after approval by a peer-review ... [more ▼]

Objective: Since the availability of recombinant human growth hormone (rhGH) all children with growth hormone deficiency (GHD) living in Belgium are offered rhGH treatment after approval by a peer-review board. In this study, we evaluated the prevalence and demographic features of childhood GHD in Belgium during the period 1986-2001 and we compared them with the data from other countries. Methods: Diagnostic, demographic and baseline auxological data of 714 children diagnosed as having GHD between 1986 and 2001 were retrieved from the database of the Belgian Study Group for Paediatric Endocrinology. Results: The prevalence of GHD in Belgium was estimated to be 1/5600. The origin of GHD was idiopathic (idGHD) in 41% of the patients, congenital (congGHD) in 20% and acquired (acqGHD) in 35%. During the first 4 years (1986-1989) more patients were classified as idGHD; thereafter the distribution between the three aetiology groups did not change. In all groups, boys outnumbered girls but this preponderance was especially pronounced in congGHD patients (male:female = 4:1) with a central malformation that associates an anterior pituitary hypoplasia, a missing, fine or normal pituitary stalk and an ectopic posterior pituitary. Thirteen percent of the patients with idGHD, 50% with congGHD and 52% with acqGHD had multiple pituitary deficiencies. Patients with congGHD were the youngest (mean+/-S.D. age: 6.5+/-4.7 years) and were the shortest (-3.0+/-1.3 standard deviation score (SDS)) at the start of rhGH treatment. There was no time trend over the studied period for age and height at onset of GH therapy. Conclusion: In Belgium, the prevalence of childhood GHD can be estimated as 1/5600 which is comparable to other recent surveys. The yearly number of new patients for the different aetiologies and the auxological parameters have remained relatively constant over the last 16 years. [less ▲]

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