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To study the utility of T2-weighted MRI sequences in the identification of the inferior intercavernous sinus (IICS), a potential source of bleeding during transsphenoidal surgery of pituitary adenomas.Pituitary sagittal T1W and coronal T2W MRI sequences were analyzed in 237 consecutive patients, after the exclusion of postoperative MRIs and those revealing an empty sella or a pituitary macroadenoma. Sphenoid sinus pneumatization was defined as incomplete (group 1) if it did not reach the nadir of the sella turcica, as complete (group 2) if it extended beyond the nadir of the sella or asymmetric (group 3), when only one side of the sinus was completely pneumatized.In Group 2 (70% of the patients), the IICS was rarely visualized on coronal T2W MRI (6/167 patients-3.6%), whereas in Group 1 it was identified in nearly all patients (55/57 patients - 96.5%, p 0.001). In Group 3, the IICS was only visible above the non-pneumatized part of the sphenoid sinus.The IICS can be identified on coronal T2W images in patients with an incompletely pneumatized sphenoid sinus, but very rarely in patients with a totally pneumatized sinus. This information can help to increase awareness among pituitary surgeons of the need to potentially manage IICS bleeding during transsphenoidal surgery in patients with an incompletely pneumatized sphenoid sinus.

Pituitary adenomas (PAs) are common, usually benign tumors of the anterior pituitary gland which, for the most part, have no known genetic cause. PAs are associated with major clinical effects due to hormonal dysregulation and tumoral impingement on vital brain structures. Following the identification of a loss-of-function variant (p.Arg703Gln) in thePAMgene in a family with pituitary gigantism, we investigated 299 individuals with sporadic PAs and 17 familial isolated pituitary adenomas kindreds forPAMvariants.PAMencodes a multifunctional protein responsible for the essential C-terminal amidation of secreted peptides.Genetic screening was performed by germline and tumor sequencing and germline copy number variation (CNV) analysis. No germline CNVs or somatic single nucleotide variants (SNVs) were identified. We detected seven likely pathogenic heterozygous missense, truncating, and regulatory SNVs. These SNVs were found in sporadic subjects with GH excess (p.Gly552Arg and p.Phe759Ser), pediatric Cushing disease (c.-133T>C and p.His778fs), or with different types of PAs (c.-361G>A, p.Ser539Trp, and p.Asp563Gly). The SNVs were functionally testedin vitrofor protein expression and trafficking by Western blotting, for splicing by minigene assays, and for amidation activity in cell lysates and serum samples. These analyses confirmed a deleterious effect on protein expression and/or function. By interrogating 200,000 exomes from the UK Biobank, we confirmed a significant association of thePAMgene and rarePAMSNVs to diagnoses linked to pituitary gland hyperfunction.Identification ofPAMas a candidate gene associated with pituitary hypersecretion opens the possibility of developing novel therapeutics based on altering PAM function.

Background: Patients with acromegaly require lifelong medication; a longer dosing interval would reduce treatment burden. This study investigated the pharmacokinetics, pharmacodynamics and safety profile of a new prolonged-release formulation (PRF) of lanreotide every 12 weeks. Research design and methods: In this multicenter, open-label, dose-ascending study, cohorts of nine patients with acromegaly received single doses of lanreotide PRF according to a 3 + 3 + 3 scheme in order to determine the maximum tolerated dose (MTD). Following a 12-week treatment period, patients were followed up for a further 12 weeks. Serum lanreotide, insulin-like growth factor-1 and growth hormone concentrations were analyzed. Adverse events were monitored throughout the study. Results: The MTD was not reached. Peak lanreotide serum concentration values were similar in all cohorts, whereas area under the curve values from time zero to 85 days increased but were not dose-proportional. The apparent elimination half-life of lanreotide PRF was approximately 54–63 days, in line with the expected prolonged-release characteristics. Growth hormone and insulin-like growth factor-1 levels were generally stable. Conclusions: The safety and tolerability profile was in-line with the known safety profile of lanreotide autogel. Lanreotide PRF was well tolerated and the pharmacokinetic profile suggests that a dosing interval of 12 weeks could be achievable. Clinical trial registration: www.clinicaltrials.gov identifier is NCT02396953; EudraCT 2014–002389-62.

X-linked acrogigantism (X-LAG) is the most severe form of pituitary gigantism and is characterized by aggressive growth hormone (GH)-secreting pituitary tumors that occur in early childhood. X-LAG is associated with chromosome Xq26.3 duplications (the X-LAG locus typically includes VGLL1, CD40LG, ARHGEF6, RBMX, and GPR101) that lead to massive pituitary tumoral expression of GPR101, a novel regulator of GH secretion. The mechanism by which the duplications lead to marked pituitary misexpression of GPR101 alone was previously unclear. Using Hi-C and 4C-seq, we characterized the normal chromatin structure at the X-LAG locus. We showed that GPR101 is located within a topologically associating domain (TAD) delineated by a tissue-invariant border that separates it from centromeric genes and regulatory sequences. Next, using 4C-seq with GPR101, RBMX, and VGLL1 viewpoints, we showed that the duplications in multiple X-LAG-affected individuals led to ectopic interactions that crossed the invariant TAD border, indicating the existence of a similar and consistent mechanism of neo-TAD formation in X-LAG. We then identified several pituitary active cis-regulatory elements (CREs) within the neo-TAD and demonstrated in vitro that one of them significantly enhanced reporter gene expression. At the same time, we showed that the GPR101 promoter permits the incorporation of new regulatory information. Our results indicate that X-LAG is a TADopathy of the endocrine system in which Xq26.3 duplications disrupt the local chromatin architecture forming a neo-TAD. Rewiring GPR101-enhancer interaction within the new regulatory unit is likely to cause the high levels of aberrant expression of GPR101 in pituitary tumors caused by X-LAG., The work was supported by the following funding sources: Fondazione Telethon, Italy grant no. GGP20130 (to G.T.); Society for Endocrinology equipment grant (to G.T.); Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH) Research project Z01-HD008920 (to C.A.S., supporting G.T., F.R.F.); Fonds d’Investissement pour la Recherche Scientifique (FIRS) of the Centre Hospitalier Universitaire de Liège (to A.F.D. and A.B.); the JABBS Foundation, UK (to A.B.); and Novo Nordisk Belgium Educational Grant, Belgium (to A.F.D. and A.B.). M.F. was funded by the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement (#800396) and a Juan de la Cierva-Formación fellowship from the Spanish Ministry of Science and Innovation (FJC2018-038233-I). G.T. was funded by the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement (#843843). A.F.D. and D.A. were supported by Action de Recherche Concertée (ARC) Grant 17/21-01 from Liège University. D.A. was supported by grants from Télévie (7461117 F, 7454719 F) and the Léon Fredericq Foundation, Belgium.

Objective Screening studies have established genetic risk profiles for diseases such as multiple endocrine neoplasia type 1 (MEN1) and pheochromocytoma–paraganglioma (PPGL). Founder effects play an important role in the regional/national epidemiology of endocrine cancers, particularly PPGL. Founder effects in the Netherlands have been described for various diseases, some of which established themselves in South Africa due to Dutch emigration. The role of Dutch founder effects in South Africa has not been explored in PPGL. Design We performed a single-center study in South Africa of the germline genetic causes of isolated/syndromic neuroendocrine tumors. Methods Next-generation panel, Sanger sequencing and multiplex ligand-dependent probe amplification for endocrine neoplasia risk genes. Results From a group of 13 patients, we identified 6 with PPGL, 4 with sporadic or familial isolated pituitary adenomas, and 3 with clinical MEN1; genetic variants were identified in 9/13 cases. We identified the Dutch founder exon 3 deletion in SDHB in two apparently unrelated individuals with distinct ethnic backgrounds that had metastatic PPGL. Asymptomatic carriers with this Dutch founder SDHBexon 3 deletion were also identified. Other PPGL patients had variants in SDHB, and SDHD and three MEN1variants were identified among MEN1 and young-onset pituitary adenoma patients. Conclusions This is the first identification of a Dutch founder effect for PPGL in South Africa. Awareness of the presence of this exon 3 SDHB deletion could promote targeted screening at a local level. Insights into PPGL genetics in South Africa could be achieved by studying existing patient databases for Dutch founder mutations in SDHx genes.

Context Ectopic acromegaly is a consequence of rare neuroendocrine tumors (NETs) that secrete GHRH. This abnormal GHRH secretion drives GH and IGF-1 excess, with a clinical presentation similar to classical pituitary acromegaly. Identifying the underlying cause for the GH hypersecretion in the setting of ectopic GHRH excess is, however, essential for proper management both of acromegaly and the NET. Owing to the rarity of NETs, the imaging characteristics of the pituitary in ectopic acromegaly have not been analyzed in depth in a large series. Objective Characterize pituitary magnetic resonance imaging (MRI) features at baseline and after NET treatment in patients with ectopic acromegaly. Design Multicenter, international, retrospective. Setting Tertiary referral pituitary centers. Patients Thirty ectopic acromegaly patients having GHRH hypersecretion. Intervention None. Main outcome measure MRI characteristics of pituitary gland, particularly T2-weighted signal. Results In 30 patients with ectopic GHRH-induced acromegaly, we found that most patients had hyperplastic pituitaries. Hyperplasia was usually moderate but was occasionally subtle, with only small volume increases compared with normal ranges for age and sex. T2-weighted signal was hypointense in most patients, especially in those with hyperplastic pituitaries. After treatment of the NET, pituitary size diminished and T2-weighted signal tended to normalize. Conclusions This comprehensive study of pituitary MRI characteristics in ectopic acromegaly underlines the utility of performing T2-weighted sequences in the MRI evaluation of patients with acromegaly as an additional tool that can help to establish the correct diagnosis.

Objective T2-signal intensity and somatostatin (SST) receptor expression are recognized predictors of therapy response in acromegaly. We investigated the relationship between these predictors and the hormonal and tumoral responses to long-acting pasireotide (PAS-LAR) therapy, which were also compared with responsiveness to first-generation somatostatin receptor ligands (SRLs). Design The PAPE study is a cohort study. Methods We included 45 acromegaly patients initially receiving SRLs, followed by combination therapy with pegvisomant, and finally PAS-LAR. We assessed tumor volume reduction (≥25% from baseline), IGF-1 levels (expressed as the upper limit of normal), and T2-weighted MRI signal and SST receptor expression of the adenoma. Results Patients with significant tumor shrinkage during PAS-LAR showed higher IGF-1 levels during PAS-LAR (mean (S.D.): 1.36 (0.53) vs 0.93 (0.43), P = 0.020), less IGF-1 reduction after first-generation SRLs (mean (S.D.): 0.55 (0.71) vs 1.25 (1.07), P = 0.028), and lower SST2 receptor expression (median (IQR): 2.0 (1.0–6.0) vs 12.0 (7.5–12.0), P = 0.040). Overall, T2-signal intensity ratio was increased compared with baseline (mean (S.D.): 1.39 (0.56) vs 1.25 (0.52), P = 0.017) and a higher T2-signal was associated with lower IGF-1 levels during PAS-LAR (β: −0.29, 95% CI: −0.56 to −0.01, P = 0.045). A subset of PAS-LAR treated patients with increased T2-signal intensity achieved greater reduction of IGF-1 (mean (S.D.): 0.80 (0.60) vs 0.45 (0.39), P = 0.016). Conclusions Patients unresponsive to SRLs with a lower SST2 receptor expression are more prone to achieve tumor shrinkage during PAS-LAR. Surprisingly, tumor shrinkage is not accompanied by a biochemical response, which is accompanied with a higher T2-signal intensity.

Gigantism has always been the subject of interest among the general public due to connotations of otherworldly strength and abilities. Until quite recently, the study of gigantism as an illness has not received concerted scientific attention, probably due to its very rare nature. International collaborative research has now led to significant advances in the understanding of the molecular mechanisms responsible for some forms of excessively tall stature. The clinical presentation of pituitary gigantism will be detailed here with emphasis on the specific aspects that are typical to the different genetic causes underlying the disease.

This paper proposes an approach and demonstrates its application for cross-border exchange of clinical documents oriented towards the use of archetype concepts and international patient summary standards adopted in the European Union. A novelty in this approach is the management of native XML instances of an archetype concept in the CEN 13606 standard by means of a native XML database and XML technologies. The computer experiments demonstrate that it is suitable for representing relatively small clinical datasets such as those describing rare diseases like the Acromegaly illness, where the semantic context in the relatively small number of symptoms is practicable to tag in terms of SNOMED-CT terminology codes. Additionally, we demonstrate that the semantically enriched information model can facilitate secondary use of clinical data by visualizing the execution of queries based on standard terminologies. Finally, the compatibility of the information model with the IPS standard enables sharing of clinical data among different information models.

Introduction: Acromegaly is a rare disease due to growth hormone (GH)-secreting pituitary adenoma. GH and IGF-1 levels are usually congruent, indicating either remission or active disease, however a discrepancy between GH and IGF-1 may occur. We aimed to evaluate the outcome of acromegalic comorbidities in patients with congruent GH and/or IGF-1 levels vs discordant biochemical parameters. Methods: Retrospective analysis of the data of 3173 patients from the Liège Acromegaly Survey (LAS) allowed to include 190 patients from 8 tertiary referral centers across Europe, treated by surgery, with available data concerning diabetes mellitus (DM) and hypertension (HT) both at diagnosis and at last follow-up. We recorded for all the patients the number of antihypertensive and antidiabetic drugs used at the first evaluation and at last follow-up. Results: Ninety-nine patients belonged to the REM group (Concordant parameters), sixty-five patients were considered as GHdis and 26 patients were considered as IGF-1dis. At diagnosis, 63 patients (33.1%) had HT and 54 patients had DM (28.4%). There was no statistically significant difference in terms of number of anti-HT and anti-diabetic drugs at diagnosis versus last follow-up (mean duration=7.3+/-4.5years) between all 3 groups. Discussion: The results highlight that the long-term outcome of acromegaly does not tend to be more severe in patients with biochemical discordance in comparison with patients considered as in remission on the basis of concordant biological parameters, suggesting that patients with biochemical discordance do not require a closer follow-up.

Introduction Initialement impliquee dans la regulation du metabolisme adipocytaire, la voie FGF21/KLB/FGFR1 a des effets pleiotropiques. La perte de fonction du recepteur FGFR1 est la cause la plus frequente d’hypogonadisme hypogonadotrope. Cas clinique Un garcon de 15 ans, avec une surdite congenitale de l’oreille droite, sans troubles de l’olfaction, consulte pour retard pubertaire et de croissance (1,59 m, 47 kg). Âge osseux de 14 ans, GH : 6,4 ng/mL apres ITT, gonadotrophines stimulables par LHRH, testosterone-totale 99 ng/dL (28–1110 ng/dL). Une RMN hypophysaire est normale. Son pere et sa sœur ont presente une puberte tardive vers 16 ans. Le patient traite par GH et Sustanon, atteint 1,77 m et 79 kg. A 16 ans, atteint de SEP, comme son pere. A 18 ans, le bilan gonadique est reevalue, normal (volume testiculaire bilateral : 14 mL). Un panel de 80 genes d’hypogonadisme hypogonadotrope retrouve un variant heterozygote KLB c.3092T > A, p.(Leu1031*). Ce nouveau variant (vraisemblablement pathogene, classe IV), provoque l’apparition d’un codon stop premature dans l’exon 5 du gene KLB. Discussion Selon Xu. et al. (EMBO Mol Med 2017), 4 % des patients avec un hypogonadisme hypogonadotrope congenital presentent une mutation faux-sens du gene KLB. Les patients avec des mutations KLB presentaient (n = 9/13) un syndrome metabolique aussi, a difference de notre patient, porteur d’une mutation non-sens. Chez la souris, la perte du gene KLB entraine un retard de la puberte, une alteration du cycle oestrogenique, une hypofertilite. L’association avec une sclerose en plaques est intrigante : les autres membres de la famille seront donc etudies.

Context First-generation somatostatin receptor ligands (fg-SRLs) represent the mainstay of medical therapy for acromegaly, but they provide biochemical control of disease in only a subset of patients. Various pretreatment biomarkers might affect biochemical response to fg-SRLs. Objective To identify clinical predictors of the biochemical response to fg-SRLs monotherapy defined as biochemical response (insulin-like growth factor (IGF)-1 ≤ 1.3 × ULN (upper limit of normal)), partial response (>20% relative IGF-1 reduction without normalization), and nonresponse (≤20% relative IGF-1 reduction), and IGF-1 reduction. Design Retrospective multicenter study. Setting Eight participating European centers. Methods We performed a meta-analysis of participant data from 2 cohorts (Rotterdam and Liège acromegaly survey, 622 out of 3520 patients). Multivariable regression models were used to identify predictors of biochemical response to fg-SRL monotherapy. Results Lower IGF-1 concentration at baseline (odds ratio (OR) = 0.82, 95% confidence interval (CI) 0.72–0.95 IGF-1 ULN, P = .0073) and lower bodyweight (OR = 0.99, 95% CI 0.98–0.99 kg, P = .038) were associated with biochemical response. Higher IGF-1 concentration at baseline (OR = 1.40, (1.19–1.65) IGF-1 ULN, P ≤ .0001), the presence of type 2 diabetes (oral medication OR = 2.48, (1.43–4.29), P = .0013; insulin therapy OR = 2.65, (1.02–6.70), P = .045), and higher bodyweight (OR = 1.02, (1.01–1.04) kg, P = .0023) were associated with achieving partial response. Younger patients at diagnosis are more likely to achieve nonresponse (OR = 0.96, (0.94–0.99) year, P = .0070). Baseline IGF-1 and growth hormone concentration at diagnosis were associated with absolute IGF-1 reduction (β = 0.90, standard error (SE) = 0.02, P ≤ .0001 and β = 0.002, SE = 0.001, P = .014, respectively). Conclusion Baseline IGF-1 concentration was the best predictor of biochemical response to fg-SRL, followed by bodyweight, while younger patients were more likely to achieve nonresponse.

Pituitary adenomas are frequently occurring neoplasms that produce clinically significant disease in 1:1000 of the general population. The pathogenesis of pituitary tumors is a matter of interest as it could help to improve diagnosis and treatment. Until recently, however, disruptions in relatively few genes were known to predispose to pituitary tumor formation. In the last decade, several more genes and pathways have been described. Germline pathogenic variants in the aryl hydrocarbon receptor-interacting protein (AIP) gene were found in familial or sporadic pituitary adenomas, usually with an aggressive clinical course. Cyclin-dependent kinase inhibitor 1B (CDKN1B) pathogenic variants lead to multiple endocrine neoplasia type 4 (MEN4) syndrome, in which pituitary adenomas can occur. Xq26.3 duplications involving the gene GPR101 cause X-linked acrogigantism. The pheochomocytoma and/or paraganglioma with pituitary adenoma association (3PAs) syndrome suggests that pathogenic variants in the genes of the succinate dehydrogenase complex or MYC-associated factor X (MAX) might be involved in pituitary tumorigenesis. New recurrent somatic alterations were also discovered in pituitary adenomas, such as, ubiquitin-specific protease 8 (USP8) and USP48 pathogenic variants in corticotropinomas. The aim of the present review is to provide an overview of the genetic pathophysiology of pituitary adenomas and their clinical relevance.

Background: Previous studies indicate that PAS-LAR can achieve control of insulin-like growth factor I (IGF-I) levels and may reduce tumor size, however a subset of acromegaly patients responds poorly. T2-signal intensity, somatostatin receptor (SST) subtype 2 and 5 expression, and the response to first-generation somatostatin receptor ligands (SRLs) are recognized predictors of therapy response. Valid prediction of the response to PAS-LAR can alter treatment stratification. Aim: To analyze T2-signal intensity and SST receptor expression in relation to the hormone and tumor response during PAS-LAR treatment, and to determine to what extent this equals SRLs responsiveness. Methods: We included 45 patients initially receiving SRLs, followed by a combination therapy including pegvisomant, and finally treated with PAS-LAR. The hormone response to PAS-LAR was evaluated using IGF-I (x ULN) levels at 24 weeks. T2-weighted MRI signal intensity of the adenoma was visually assessed and quantified by region of interest measurement. A tumor volume change of ≥25% from baseline was considered significant. SST receptor expression in adenomas was evaluated in 13 out of 45 patients using a validated immunoreactivity score (IRS). The clinical characteristics and the hormone and tumor response to PAS-LAR were assessed using multivariable regressions. Results: Patients with the lowest percentage IGF-I (x ULN) reduction during SRLs also showed weak IGF-I (x ULN) control during PAS-LAR and, however, more significant tumor shrinkage (r=0.41, p=0.006; p=0.036). Lower IGF-I (x ULN) levels during PAS-LAR were associated with higher T2-signal intensity and less significant tumor shrinkage (ß=-0.29, p=0.045; ß=0.34, p=0.035). With regards to tumor response, adenoma volume at baseline was associated with higher random GH levels at diagnosis and greater absolute tumor shrinkage during PAS-LAR (ß=69, p=0.0018; ß=1.05, p=0.020). Significant tumor shrinkage was associated with female patients, higher IGF-I (x ULN) levels during PAS-LAR and borderline significant with non-hypointense adenomas at baseline (OR=6.35, 95% CI=1.42-36.4; OR=13.2, 95% CI=2.14-129.1; OR=5.97, 95% CI=0.91-65.5 respectively). Lower IGF-I (x ULN) levels after PAS-LAR correlated with higher (r=-0.68, p=0.011; r=-0.52, p=0.083), while significant tumor shrinkage correlated with lower SST2 levels as well as SST2/SST5 ratio expression (p=0.040; p=0.024). Conclusions: Patients not responding to somatostatin analogs with particularly large adenomas, low SST2 receptor expression and higher T2-signal intensity are more prone to show tumor shrinkage during PAS-LAR than patients with high SST2 receptor expression and T2-hypointense adenomas. Surprisingly, tumor shrinkage is not accompanied by lower IGF-I (x ULN) levels, which are associated with a high SST2 receptor expression and a higher T2-signal intensity. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

Familial pituitary adenomas account for approximately 5–8% of all pituitary adenomas. Besides the adenomas occurring as part of syndromic entities that group several endocrine or nonendocrine disorders (multiple endocrine neoplasia type 1 or 4, Carney complex and McCune–Albright syndrome), 2–3% of familial pituitary adenomas fit into the familial isolated pituitary adenomas (FIPA) syndrome, an autosomal dominant condition with incomplete penetrance. About 20% of FIPA cases are due to mutations in the AIP gene and have distinct clinical characteristics. Recent findings have isolated a new non-AIP FIPA syndrome called X-linked acrogigantism, resulting from a microduplication that always includes the GPR101 gene. These new advances in the field of pituitary disease are opening up a new challenging domain to both clinicians and researchers. This review will focus on these recent findings and their contribution to the diagnosis and the management of familial pituitary adenomas.

Objectif Dans l’acromegalie, le controle des concentrations de GH et d’IGF-1 definit la remission biochimique. Ces derniers sont generalement congruents, refletant soit une maladie active soit la remission, cependant, une discordance entre GH et IGF-1 peut s’observer. Nous avons compare le suivi de l’hypertension arterielle (HTA) et du diabete (DIA) chez des patients acromegales avec des taux de GH et d’IGF-1 congruents vs discordants. Materiel et methodes Une analyse retrospective des donnees de 3173 patients du Liege Acromegaly Survey (LAS) a permis d’inclure 190 patients de 8 centres de reference europeen, traites exclusivement par chirurgie, et avec des donnees concernant DIA et HTA au diagnostic et au dernier suivi. Nous avons recueilli pour chaque patient le nombre de traitement antiHTA et antiDIA au diagnostic et au dernier suivi. Resultats 99 patients appartenaient au groupe REM (parametres congruents), 65 etaient consideres GHdis (GH random elevee et IGF-1 normale) et 26 etaient consideres IGF-1dis (IGF-1 elevee et GH ranodm normale). Au diagnostic, 63 patients (33,1 %) etaient hypertendus et 54 patients etaient diabetiques (28,4 %). Il n’y avait pas de difference statistiquement significative en terme de nombre de traitement antuHTA ou antiDIA au diagnostic comparativement au dernier suivi (suivi moyen 7,3±4,5 ans) entre les 3 groupes. Discussion L’evolution a long terme de l’acromegalie n’est pas plus pejorative chez les patients presentant une discordance des parametres biochimiques en comparaison avec ceux consideres en remission, suggerant qu’il n’est pas necessaire de realiser de suivi plus rapproche dans cette population de patients acromegales.

[Background] Pituitary adenomas have a high disease burden due to tumor growth/invasion and disordered hormonal secretion. Germline mutations in genes such as MEN1 and AIP are associated with early onset of aggressive pituitary adenomas that can be resistant to medical therapy., [Aims] We performed a retrospective screening study using published risk criteria to assess the frequency of AIP and MEN1 mutations in pituitary adenoma patients in a tertiary referral center., [Methods] Pituitary adenoma patients with pediatric/adolescent onset, macroadenomas occurring ≤30 years of age, familial isolated pituitary adenoma (FIPA) kindreds and acromegaly or prolactinoma cases that were uncontrolled by medical therapy were studied genetically. We also assessed whether immunohistochemical staining for AIP (AIP-IHC) in somatotropinomas was associated with somatostatin analogs (SSA) response., [Results] Fifty-five patients met the study criteria and underwent genetic screening for AIP/MEN1 mutations. No mutations were identified and large deletions/duplications were ruled out using MLPA. In a cohort of sporadic somatotropinomas, low AIP-IHC tumors were significantly larger (P = 0.002) and were more frequently sparsely granulated (P = 0.046) than high AIP-IHC tumors. No significant relationship between AIP-IHC and SSA responses was seen., [Conclusions] Germline mutations in AIP/MEN1 in pituitary adenoma patients are rare and the use of general risk criteria did not identify cases in a large tertiary-referral setting. In acromegaly, low AIP-IHC was related to larger tumor size and more frequent sparsely granulated subtype but no relationship with SSA responsiveness was seen. The genetics of pituitary adenomas remains largely unexplained and AIP screening criteria could be significantly refined to focus on large, aggressive tumors in young patients., This research was supported by a grant from the Fonds d’Investissement pour la Recherche (FIRS) of the CHU de Liège, the JABBS Foundation, United Kingdom (to A B) and the ISCIII-Subdirección General de Evaluación y Fomento de la Investigación co-funded with Fondos FEDER (PI13/02043 to A S-M and PI16/00175 to A S-M and D A C). A S-M and D A C were also supported by grants from the Andalusian Ministry of Health (A-0003-2016, A-0006-2015, C-0015-2014 and RC-0006-2018).

In the general population, height is determined by a complex interplay between genetic and environmental factors. Pituitary gigantism is a rare but very important subgroup of patients with excessive height, as it has an identifiable and clinically treatable cause. The disease is caused by chronic growth hormone and insulin-like growth factor 1 secretion from a pituitary somatotrope adenoma that forms before the closure of the epiphyses. If not controlled effectively, this hormonal hypersecretion could lead to extremely elevated final adult height. The past 10 years have seen marked advances in the understanding of pituitary gigantism, including the identification of genetic causes in ~50% of cases, such as mutations in the AIP gene or chromosome Xq26.3 duplications in X-linked acrogigantism syndrome. Pituitary gigantism has a male preponderance, and patients usually have large pituitary adenomas. The large tumour size, together with the young age of patients and frequent resistance to medical therapy, makes the management of pituitary gigantism complex. Early diagnosis and rapid referral for effective therapy appear to improve outcomes in patients with pituitary gigantism; therefore, a high level of clinical suspicion and efficient use of diagnostic resources is key to controlling overgrowth and preventing patients from reaching very elevated final adult heights.

Previous years, the incidence of autoimmune thyroid diseases has increased worldwide. The presence of many pollutants in the environment suspected to be thyroid disruptors may have contributed to the observed increase. Unfortunately, the results from epidemiological studies assessing the association between pollution and thyroid disorders remain inconsistent, maybe due to a nearly complete neglect of the mixture effect. The blood levels of 12 brominated flame retardants, 3 polychlorinated biphenyls, 16 organochlorine pesticides, 7 perfluoroalkyl substances and 16 phenolic organohalogens were measured in 35 hypothyroid and 44 hyperthyroid volunteers and in 160 individuals from the general population designed as controls. Weighted quantile sum (WQS) regressions were performed to compute indexes representing the mixture of POPs, and we assessed the relations with thyroid disorders. Nineteen pollutants were detected in more than 40% of the individuals and were thus included in the WQS indexes. The WQS index was statistically significantly associated with an increased odds of hypothyroidism (odds ratio (OR) = 98.1; 95% CI: 5.51–1747) with the highest weights attributed to PCB 138 (w = 0.210), 3-OH-CB 180 (w = 0.197), 4-OH-CB 146 (w = 0.188), 4’,4-DDE (w = 0.156) while there were no evidence of a relation with increased odds of hyperthyroidism. Given the relative low number of individuals included in the present investigation, standard WQS methodology could not be used, this study should thus be considered as a preliminary, hypothesis-generating study. Nevertheless, these results highlighted the importance of considering the potential effect of chemical mixture when studying endocrine disruptors.

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). Design Two retrospective cohorts (Rotterdam + Liège Acromegaly Survey (LAS), total n = 188) were meta-analyzed 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. Results For PEGV dosing in combination with LA-SSA, IGF-I levels, weight, height and age, were associated with the PEGV normalization dosage (P ≤ 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 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.

Acromegaly is a rare disorder caused by chronic growth hormone (GH) hypersecretion. While diagnostic and therapeutic methods have advanced, little information exists on trends in acromegaly characteristics over time. The Liège Acromegaly Survey (LAS) Database, a relational database, is designed to assess the profile of acromegaly patients at diagnosis and during long-term follow-up at multiple treatment centers. The following results were obtained at diagnosis. The study population consisted of 3173 acromegaly patients from ten countries; 54.5% were female. Males were significantly younger at diagnosis than females (43.5 vs 46.4 years; P P = 0.015). Ages at diagnosis and first symptoms increased significantly over time (P P P P P 3100 patients is the largest international acromegaly database and shows clinically relevant trends in the characteristics of acromegaly at diagnosis.

Since the 1990's cabergoline has been the treatment of choice in prolactinoma, as it permits rapid and effective hormonal and tumor control in most cases. Evidence of cardiac valvulopathy was demonstrated in Parkinson's disease patients treated with dopamine agonists. Retrospective studies in prolactinoma patients treated with cabergoline at lower doses did not show such an effect. However, few prospective data with long-term follow-up are available. The aim of this study was to assess the safety of cabergoline regarding cardiac valvular status during prospective follow-up in patients treated for prolactinoma or idiopathic hyperprolactinemia. We report here a series of 100 patients (71F; median age at diagnosis: 41.5 years) treated with cabergoline for endocrine diseases (prolactinoma n = 89, idiopathic hyperprolactinemia n = 11). All patients underwent complete transthoracic echocardiographic studies at baseline and during long-term prospective surveillance using the same equipment and performed by the same technicians. The median interval between baseline and last follow-up echocardiographic studies while on cabergoline was 62.5 months (interquartile range: 34.75-77.0). The median total duration of cabergoline treatment was 124.5 months (interquartile range: 80.75-188.75) and the median cumulative total dose of cabergoline was 277.8 mg (interquartile range : 121.4-437.8 mg) at last follow-up. We found no clinically relevant alterations in cardiac valve function or valvular calcifications with cabergoline treatment. Our data suggest that findings from retrospective analyses are correct and that cabergoline is a safe chronic treatment at the doses used typically in endocrinology.

International audience; Since the 1990's cabergoline has been the treatment of choice in prolactinoma, as it permits rapid and effective hormonal and tumor control in most cases. Evidence of cardiac valvulopathy was demonstrated in Parkinson's disease patients treated with dopamine agonists. Retrospective studies in prolactinoma patients treated with cabergoline at lower doses did not show such an effect. However, few prospective data with long-term follow-up are available. The aim of this study was to assess the safety of cabergoline regarding cardiac valvular status during prospective follow-up in patients treated for prolactinoma or idiopathic hyperprolactinemia. We report here a series of 100 patients (71F; median age at diagnosis: 41.5 years) treated with cabergoline for endocrine diseases (prolactinoma n = 89, idiopathic hyperprolactinemia n = 11). All patients underwent complete transthoracic echocardiographic studies at baseline and during long-term prospective surveillance using the same equipment and performed by the same technicians. The median interval between baseline and last follow-up echocardiographic studies while on cabergoline was 62.5 months (interquartile range: 34.75-77.0). The median total duration of cabergoline treatment was 124.5 months (interquartile range: 80.75-188.75) and the median cumulative total dose of cabergoline was 277.8 mg (interquartile range : 121.4-437.8 mg) at last follow-up. We found no clinically relevant alterations in cardiac valve function or valvular calcifications with cabergoline treatment. Our data suggest that findings from retrospective analyses are correct and that cabergoline is a safe chronic treatment at the doses used typically in endocrinology.

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 to 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 the 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.

Background Dopamine agonist resistance in prolactinoma is an infrequent phenomenon. Doses of cabergoline (CAB) of up to 2.0 mg/week are usually effective in controlling prolactin (PRL) secretion and reducing tumor size in prolactinomas. The clinical presentation, management, and outcome of patients that are not well controlled by such commonly used doses of CAB-resistant patients are poorly understood. Design and methods A multicenter retrospective study was designed to collect a large series of resistant prolactinoma patients, defined by uncontrolled hyperprolactinemia on CAB ≥2.0 mg weekly. Results Ninety-two patients (50 F, 42 M) were analyzed. At diagnosis, most had macroprolactinomas (82.6%); males were significantly older than females (P=0.0003) and presented with a more aggressive disease. A genetic basis was identified in 12 patients. Thirty-six patients (39.1%) received only medical therapy, most underwent surgery (60.9%, including multiple interventions in 10.9%), and 14.1% received postoperative radiotherapy. Eight patients developed late CAB resistance (8.7%). The median maximal weekly dose of CAB (CABmax/w) was 3.5 mg (2.0–10.5). Despite a higher CABmax/w in patients treated with multimodal therapy (P=0.003 vs exclusive pharmacological treatment), a debulking effect of surgery was shown in 14 patients, with a higher rate of PRL control (P=0.006) and a significant reduction in CABmax/w (P=0.001) postoperatively. At last follow-up (median 88 months), PRL normalization and tumor disappearance were achieved in 28 and 19.9% of the patients respectively, with no significant sex-related difference observed in CABmax/w or disease control. Mortality was 4.8%, with four patients developing aggressive tumors (4.3%) and three a pituitary carcinoma (3.3%). Conclusion CAB-resistant prolactinomas remain a serious concern. Surgical debulking, newer therapeutic strategies, and early diagnosis of genetic forms could help to improve their outcome.

Acromegaly is a chronic rare disease associated with negative pathological effects on multiple systems and organs. We designed a new informatics tool to study data from patients with acromegaly, the Liege Acromegaly Survey (LAS). This relational database permits the inclusion of anonymous historical and prospective data on patients and includes pathophysiology, clinical features, responses to therapy and long term outcomes of acromegaly. We deployed the LAS in a validation study at a single center in order to study the characteristics of patients with acromegaly diagnosed at our center from 1970-2011. A total of 290 patients with acromegaly were included (147 males and 143 females). There was a linear relationship between age at diagnosis and the date of diagnosis, indicating that older patients are being diagnosed with acromegaly more frequently. A majority presented with macroadenomas (77.5%) and the median diameter was 14 mm. Patients with macroadenomas were significantly younger than patients with microadenomas (P=0.01). GH values at diagnosis decreased with the age of the patients (P=0.01) and there was a correlation between GH values and tumor size at diagnosis (P=0.02). No correlation existed between insulin-like growth factor 1 (IGF-1) levels and tumor characteristics. The prevalence of diabetes was 21.4% in this population and 41.0% had hypertension. The presence of hypertension and diabetes were significantly associated with one another (P

Objective: To summarize current knowledge on the clinical and genetic characteristics of familial pituitary tumor syndromes. Methods: This review is based on a comprehensive search through the English-language literature with use of the following terms: “familial,” “pituitary,” “adenomas,” and “tumors.” Results: Familial pituitary tumors are rare and constitute approximately 5% of all pituitary adenomas. Currently, there are 4 recognized inherited syndromes that involve pituitary tumorigenesis—multiple endocrine neoplasia type 1 (MEN 1), multiple endocrine neoplasia type 4 (MEN 4), Carney complex (CNC), and familial isolated pituitary adenomas (FIPA). MEN 1 and CNC have been known for several decades, and their clinical and molecular characteristics have been comprehensively studied. Many familial cases of pituitary adenomas can be attributed to mutations in MEN1 and PRKAR1A genes. The recently defined MEN 4 is extremely rare. Familial pituitary tumors that are not associated with MEN 1 and CNC have been united under a new term introduced in the 1990s—FIPA. About 15% to 25% of patients with FIPA harbor mutations in the AIP gene. Conclusion: Although rare, familial pituitary tumors present an opportunity to study inherited molecular and genetic mechanisms of pituitary tumorigenesis. A comprehensive understanding of their characteristics may provide a basis for early diagnosis and better management of affected patients. (Endocr Pract. 2011;17[Suppl 3]:41-46) Abbreviations: AhR = aryl hydrocarbon receptor; AIP = aryl hydrocarbon receptor interacting protein; CNC = Carney complex; FIPA = familial isolated pituitary adenomas; GH = growth hormone; MEN 1 = multiple endocrine neoplasia type 1; MEN 4 = multiple endocrine neoplasia type 4

Pituitary adenomas usually present sporadically, with a multifactorial pathogenesis including somatic mutational events in cancer-related genes. Genetic predisposition implies the presence of germline DNA alterations with a range of impacts on pituitary cell biology, translating into a variable penetrance of the disease. Genetic causes must be considered in the presence of specific clinical settings, such as familial occurrence of pituitary adenoma, with or without extrapituitary diseases, and may also be suspected in young patients (

Dopamine (DA) is a catecholamine with a wide range of functions and whose five subtype receptors are found in different organs where they exert a mainly inhibitory action. Since this action may also appear in a number of secretory tumors in various locations, DA agonists have elicited some interest as a medical treatment for hypercorticism. Non-iatrogenic Cushing’s syndromes are due in 70% of the cases to a pituitary adrenocorticotropic hormone (ACTH)-producing adenoma, and, less frequently, to an adrenal adenoma or an ectopic ACTH secretion by a neuroendocrine tumor. First-line treatment in Cushing’s syndrome consists of the surgical removal of the secreting tumor. However, surgery may not achieve a complete cure in a number of cases, hence emphasizing the potential benefit of a medical complementary treatment, which could also benefit patients as an alternative approach, either when waiting for, or when the patient is not eligible for surgery. Studies of corticotropic adenomas have shown that 80% of these tumors express D2 receptors. Clinical trials of DA agonists in Cushing’s disease have shown an inhibitory effect of these drugs with an inhibition of ACTH secretion and/or a decrease of tumor size. There are only a few cases of documented use of DA agonists in ectopic ACTH secretion, but when the tumor expresses DA receptors, DA agonists may represent a useful complementary treatment. DA receptors are also expressed in normal and tumoral adrenals, suggesting a potential use of DA agonists in Cushing’s syndrome secondary to adrenal tumors. However, clinical data regarding this specific situation are very scarce, maybe due to the relatively high rate of surgical cure of adrenal adenomas. In conclusion, DA agonists represent a potential preparatory or complementary treatment for endogenous Cushing’s syndrome, especially in Cushing’s disease. These compounds may be underused as suggested by the scarce number of publication and case reports in the literature. In the future, association of these drugs with somatostatin analogs may also prove beneficial.

UNLABELLED Multicentric registers such as The French Acromegaly Register provide data on rare disorders that are otherwise difficult to obtain, so avoiding extrapolation from limited data sets. This study focuses on clinical, hormonal and therapy characteristics of acromegaly in people over 70 years old. The objective was to compare this population with the youngest to disclose if the medical management was similar. PATIENTS AND METHODS The data were obtained from the 30 centres that have registered patients in the Acromegaly Register since 1999. RESULTS The register listed 644 acromegaly patients on 1st January 2005, of whom 68 (22 men and 46 women) were over 70 years old, independently of the diagnosis date of their disease. Their average age was 76.8 + or - 5 years (range: 70-95) and they had suffered from acromegaly for 11 + or - 6 years (compared to 7 years in those aged less than 70). Their BMI were similar. Diabetes and hypertension were more frequent than in younger acromegalic patients and in the general French population matched for age. Circulating GH and IGF-1 concentrations were lower than in the younger acromegalic patients on inclusion and 1 year after treatment. There was no significant difference in the tumor size. Only 44% of the patients over 70 underwent surgery, against 90% of patients under 70 years. However, the fractions of young and elderly patients with a controlled disease 1 year after inclusion were the same (51%). CONCLUSION In the limits of the use of register, these data reveal a high prevalence of diabetes and hypertension in the eldest acromegalic patients. Despite much less frequent surgical intervention, patients' disease under control is equivalent to the younger population 1 year after the initial interview, confirming the effectiveness of the choices of treatment.

Somatostatin analogs (SSA) with their potent antise cretory and antiproliferative effects are the main medical treatment option for patients with neuroendocrine t umors, such as gastroenteropancreatic and acromegalyassociated growth hormone secreting pituitary tumor s. Although a good portion of acromegalic patients gets normalized after SSA treatment, strict hormonal con trol is not achieved in a sizeable proportion of th ese patients. The reasons for this incomplete response to SSA trea tment are unclear. We have found that the tumor sup pressor ZAC1 (LOT1/PLAGL1) is essential for the antiproliferative effect of SSA in pituitary tumor cells. The aim of the present retrospective cohort study was to deter mine whether ZAC1 immunoreactivity in archival somatotrophinoma tissue derived from 45 patients with acromegaly routinely pretreated with SSA before surgery, was associated with response to SSA (normalization of GH, IGF-I and presence of tumor shrinka ge). All tumors displayed ZAC1 immunoreactivity [weak (+ ; n = 15), moderate (+ + ; n = 16) and strong (+ + + ; n = 14)]. A significant positive correlation was found between strong ZAC1 immunoreactivity and IGF-I normalization and presence of tumor shrinkage after SSA treatment, which was not affected by age at di agnosis, gender or duration of SSA treatment. These in vivo data combined with the antiproliferative properties of ZAC1/Zac1 provide evidence of a mechanistic role for this transcription factor on SSA induced tumor shri nkage and hormone normalization.

Objective There is ample clinical evidence that skin is responsive to physiopathological levels of circulating thyroid hormones. The aim of the study was to assess some physical changes of the skin in the presence of moderate thyroid dysfunction. Setting University Hospital. Patients and methods A total of 119 adults suffering from hypothyroidism or hyperthyroidism and 60 healthy controls were enrolled in this study. Hormonal dosages (TSH, fT3, fT4) were assessed in the serum. A series of biometrological assessments were also performed on the volar and dorsal aspects of the forearms. These included electrometric assessments (Nova Dermal Phase Meter®, Corneometer®), evaporimetry (Tewameter®), colorimetry (Mexameter®), ultrasound shear wave propagation (Reviscometer®) and squamometry X. Correlations were searched between each of the serum hormonal dosages and each of the biometrological parameters. Results The hormonal changes in the untreated patients with thyroid dysfunction were modest in intensity. A few outlier values with regard to the normal range were found for each biometrological parameter. No correlations were found between fT3 or fT4 and each of the physical parameters. By contrast, significant negative linear correlations were found between thyroid-stimulating hormone (TSH) and skin hydration measured by the Corneometer® and the Nova DPM®. Conclusion This multipronged exploratory study shows that direct or indirect effects of TSH may influence the stratum corneum hydration. This correlation seemed very sensitive, as no other specific biophysical parameter was significantly correlated with the thyroid hormonal concentrations in the serum. However, our findings do not exclude the possibility of some other skin changes supervening in case of more severe thyroid dysfunction. The mechanism by which TSH alters the stratum corneum hydration is yet unknown.

GH-secreting pituitary adenomas can be hypo-, iso- or hyper-intense on T2-weighted MRI sequences. We conducted the current multicenter study in a large population of patients with acromegaly to analyze the relationship between T2-weighted signal intensity on diagnostic MRI and hormonal and tumoral responses to somatostatin analogs (SSA) as primary monotherapy. Acromegaly patients receiving primary SSA for at least 3 months were included in the study. Hormonal, clinical and general MRI assessments were performed and assessed centrally. We included 120 patients with acromegaly. At diagnosis, 84, 17 and 19 tumors were T2-hypo-, iso- and hyper-intense, respectively. SSA treatment duration, cumulative and mean monthly doses were similar in the three groups. Patients with T2-hypo-intense adenomas had median SSA-induced decreases in GH and IGF-1 of 88% and 59% respectively, which were significantly greater than the decreases observed in the T2-iso- and hyper-intense groups (P P P r = 0.22), IGF-1 (P r = 0.14) and adenoma volume (P r = 0.33). The T2-weighted signal intensity of GH-secreting adenomas at diagnosis correlates with hormone reduction and tumor shrinkage in response to primary SSA treatment in acromegaly. This study supports its use as a generally available predictive tool at diagnosis that could help to guide subsequent treatment choices in acromegaly.