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See detailChanges in the management and comorbidities of acromegaly over three decades. The French Acromegaly Registry.
Maione, Luigi; Brue, Thierry; Beckers, Albert ULg et al

in European Journal of Endocrinology (2017), 176(5), 645-655

CONTEXT: Acromegaly is a rare disease associated with chronic multisystem complications. National registries have been created in several countries. DESIGN: The French registry contains data on acromegaly ... [more ▼]

CONTEXT: Acromegaly is a rare disease associated with chronic multisystem complications. National registries have been created in several countries. DESIGN: The French registry contains data on acromegaly epidemiology, management and comorbidities recorded over more than three decades, retrospectively until 1999 and prospectively from 1999 until 2012. RESULTS: Data could be analyzed for 999 of the 1034 patients included in the registry (46% males). Disease control, defined as IGF-I normalization (adjusted for age and sex), was achieved in 75% of patients at the last follow-up visit. Half the patients with uncontrolled disease had IGF-I levels below 1.5 times the upper limit of normal (ULN). The proportion of patients with surgically cured disease did not change markedly over time, whereas the proportion of patients with uncontrolled disease fell and the proportion of patients with medically controlled disease rose. Cardiovascular, metabolic, respiratory and rheumatologic comorbidities and their outcomes were recorded for most patients, and no noteworthy overall deterioration was noted over time. Cancer occurred in 10% of patients, for a standardized incidence ratio of 1.34 (95% CI, 0.94-1.87) in men and 1.24 (0.77-1.73) in women. Forty-one patients died during follow-up, for a standardized mortality ratio of 1.05 (0.70-1.42). Most deaths were due to cancer. CONCLUSIONS: The majority of patients with acromegaly now have successful disease control thanks to multistep management. The incidence of comorbidities following diagnosis of acromegaly is very low. Life expectancy is now close to that of the general population, probably owing to better management of the GH/IGF-I excess and comorbidities. [less ▲]

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See detailA multivariable prediction model for pegvisomant dosing: monotherapy and in combination with long-acting somatostatin analogues
Franck, Sanne Elisabeth; Korevaar, Tim; PETROSSIANS, Patrick ULg et al

in European Journal of Endocrinology (2017)

Background: Effective treatment of acromegaly with pegvisomant (PEGV), a growth hormone receptor antagonist, requires an appropriate dose titration. PEGV doses vary widely among individual patients, and ... [more ▼]

Background: Effective treatment of acromegaly with pegvisomant (PEGV), a growth hormone receptor antagonist, requires an appropriate dose titration. PEGV doses vary widely among individual patients, and various covariates may affect its dosing and pharmacokinetics. Objective: To identify predictors of the PEGV dose required to normalize insulin-like growth factor I (IGF-I) levels during PEGV monotherapy and in combination with long-acting somatostatin analogues (LA-SSAs). 188) were meta-analysed as a form of external replication to study the predictors of PEGV dosing in addition to LA-SSA, the LAS (n=83) was used to study the predictors of PEGV monotherapy dosing. Multivariable regression models were used to identify predictors of the PEGV dose required to normalize IGF-I levels. <0.001, p=<0.001, p=0.028 and p=0.047, respectively). Taken together, these characteristics predicted the PEGV normalization dose correctly in 63.3% of all patients within a range of +/- 60 mg/week (21.3% within a range of +/- 20 mg/week). For monotherapy, only weight was associated with the PEGV normalization dose (p=<0.001) and predicted this dosage correctly in 77.1% of all patients within a range of +/- 60 mg/week (31.3% within a range of +/- 20 mg/week). Conclusion: In this study, we show that IGF-I levels, weight, height and age can contribute to define the optimal PEGV dose in order to normalize IGF-I levels in addition to LA-SSA. For PEGV monotherapy, only the patient's weight was associated with the IGF-I normalization PEGV dosage. [less ▲]

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See detailMRI follow-up is unnecessary in patients with macroprolactinomas and long-term normal prolactin levels on dopamine agonist treatment.
Eroukhmanoff, J.; Tejedor, I.; Potorac, Iulia ULg et al

in European Journal of Endocrinology (2017), 176(3), 323-328

OBJECTIVE: Both antitumor and antisecretory efficacies of dopamine agonists (DA) make them the first-line treatment of macroprolactinomas. However, there is no guideline for MRI follow-up once prolactin ... [more ▼]

OBJECTIVE: Both antitumor and antisecretory efficacies of dopamine agonists (DA) make them the first-line treatment of macroprolactinomas. However, there is no guideline for MRI follow-up once prolactin is controlled. The aim of our study was to determine whether a regular MRI follow-up was necessary in patients with long-term normal prolactin levels under DA. PATIENTS AND METHODS: We conducted a retrospective multicenter study (Marseille, Paris La Pitie Salpetriere and Nancy, France; Liege, Belgium) including patients with macroprolactinomas (largest diameter: >10 mm and baseline prolactin level: >100 ng/mL) treated by dopamine agonists, and regularly followed (pituitary MRI and prolactin levels) during at least 48 months once normal prolactin level was obtained. RESULTS: In total, 115 patients were included (63 men and 52 women; mean age at diagnosis: 36.3 years). Mean baseline prolactin level was 2224 +/- 6839 ng/mL. No significant increase of tumor volume was observed during the follow-up. Of the 21 patients (18%) who presented asymptomatic hemorrhagic changes of the macroprolactinoma on MRI, 2 had a tumor increase (2 and 7 mm in the largest size). Both were treated by cabergoline (1 mg/week) with normal prolactin levels obtained for 6 and 24 months. For both patients, no further growth was observed on MRI during follow-up at the same dose of cabergoline. CONCLUSION: No significant increase of tumor size was observed in our patients with controlled prolactin levels on DA. MRI follow-up thus appears unnecessary in patients with biologically controlled macroprolactinomas. [less ▲]

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See detailCabergoline for Cushing's disease: a large retrospective multicenter study.
Ferriere, A.; Cortet, C.; Chanson, P. et al

in European Journal of Endocrinology (2017), 176(3), 305-314

OBJECTIVE: The efficacy of cabergoline in Cushing's disease (CD) is controversial. The aim of this study was to assess the efficacy and tolerability of cabergoline in a large contemporary cohort of ... [more ▼]

OBJECTIVE: The efficacy of cabergoline in Cushing's disease (CD) is controversial. The aim of this study was to assess the efficacy and tolerability of cabergoline in a large contemporary cohort of patients with CD. DESIGN: We conducted a retrospective multicenter study from thirteen French and Belgian university hospitals. METHODS: Sixty-two patients with CD received cabergoline monotherapy or add-on therapy. Symptom score, biological markers of hypercortisolism and adverse effects were recorded. RESULTS: Twenty-one (40%) of 53 patients who received cabergoline monotherapy had normal urinary free cortisol (UFC) values within 12 months (complete responders), and five of these patients developed corticotropic insufficiency. The fall in UFC was associated with significant reductions in midnight cortisol and plasma ACTH, and with clinical improvement. Compared to other patients, complete responders had similar median baseline UFC (2.0 vs 2.5xULN) and plasma prolactin concentrations but received lower doses of cabergoline (1.5 vs 3.5 mg/week, P < 0.05). During long-term treatment (>12 months), cabergoline was withdrawn in 28% of complete responders because of treatment escape or intolerance. Overall, sustained control of hypercortisolism was obtained in 23% of patients for 32.5 months (19-105). Nine patients on steroidogenesis inhibitors received cabergoline add-on therapy for 19 months (1-240). Hypercortisolism was controlled in 56% of these patients during the first year of treatment with cabergoline at 1.0 mg/week (0.5-3.5). CONCLUSIONS: About 20-25% of CD patients are good responders to cabergoline therapy allowing long-term control of hypercortisolism at relatively low dosages and with acceptable tolerability. No single parameter, including the baseline UFC and prolactin levels, predicted the response to cabergoline. [less ▲]

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See detailMANAGEMENT OF ENDOCRINE DISEASE: Pituitary "incidentaloma": Neuroradiological assessment and differential diagnosis.
Vasilev, Vladimir; Rostomyan, Liliya ULg; Daly, Adrian ULg et al

in European Journal of Endocrinology (2016), 175(4), 171184

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See detailTriiodothyronine-predominant Graves’ disease in childhood: detection and therapeutic implications
HARVENGT, Julie ULg; boizeau, priscilla; chevenne, didier et al

in European Journal of Endocrinology (2015), 172(6), 715-723

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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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