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
, 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;
< 0.001). The median delay from first symptoms to diagnosis was 2 years longer in females (
= 0.015). Ages at diagnosis and first symptoms increased significantly over time (
< 0.001). Tumors were larger in males than females (
< 0.001); tumor size and invasion were inversely related to patient age (
< 0.001). Random GH at diagnosis correlated with nadir GH levels during OGTT (
< 0.001). GH was inversely related to age in both sexes (
< 0.001). Diabetes mellitus was present in 27.5%, hypertension in 28.8%, sleep apnea syndrome in 25.5% and cardiac hypertrophy in 15.5%. Serious cardiovascular outcomes like stroke, heart failure and myocardial infarction were present in <5% at diagnosis. Erythrocyte levels were increased and correlated with IGF-1 values. Thyroid nodules were frequent (34.0%); 820 patients had colonoscopy at diagnosis and 13% had polyps. Osteoporosis was present at diagnosis in 12.3% and 0.6-4.4% had experienced a fracture. In conclusion, this study of >3100 patients is the largest international acromegaly database and shows clinically relevant trends in the characteristics of acromegaly at diagnosis.
Glucocorticoids (GC), such as cortisol or dexamethasone, control various physiological functions, notably those involved in development, metabolism, inflammatory processes and stress, and exert most ...of their effects upon binding to the glucocorticoid receptor (GR, encoded by NR3C1 gene). GC signaling follows several consecutive steps leading to target gene transactivation, including ligand binding, nuclear translocation of ligand-activated GR complexes, DNA binding, coactivator interaction and recruitment of functional transcriptional machinery. Any step may be impaired and may account for altered GC signaling. Partial or generalized glucocorticoid resistance syndrome may result in a reduced level of functional GR, a decreased hormone affinity and binding, a defect in nuclear GR translocation, a decrease or lack of DNA binding and/or post-transcriptional GR modifications. To date, 26 loss-of-function NR3C1 mutations have been reported in the context of hypertension, hirsutism, adrenal hyperplasia or metabolic disorders. These clinical signs are generally associated with biological features including hypercortisolism without negative regulatory feedback loop on the hypothalamic-pituitary-adrenal axis. Patients had often low plasma aldosterone and renin levels despite hypertension. Only one GR gain-of-function mutation has been described associating Cushing's syndrome phenotype with normal urinary-free cortisol. Some GR polymorphisms (ER22/23EK, GR-9β) have been linked to glucocorticoid resistance and a healthier metabolic profile whereas some others seemed to be associated with GC hypersensitivity (N363S, BclI), increasing cardiovascular risk (diabetes type 2, visceral obesity). This review focuses on the earlier findings on the pathophysiology of GR signaling and presents criteria facilitating identification of novel NR3C1 mutations in selected patients.
Les glucocorticoïdes (GC) exercent de nombreux effets dans l’organisme, et sont impliqués dans le développement, le métabolisme, l’inflammation et le stress après liaison au récepteur des glucocorticoïdes (GR, codé par le gène NR3C1). Après activation par les GC, le complexe GC-GR est transféré dans le noyau où il s’homodimérise et se lie aux éléments de réponse sur l’ADN permettant la transcription de gènes cibles. La résistance aux GC peut être due à une altération de chacune des étapes de la signalisation du GR. À ce jour, 26 mutations perte de fonction du GR ont été rapportées devant des signes cliniques variés : hypertension artérielle, hirsutisme, hyperplasie surrénalienne ou troubles métaboliques. La plupart des patients ont un hypercortisolisme biologique sans rétrocontrôle négatif du cortisol sur l’axe hypothalamo-hypophyso-surrénalien. Les patients présentent également des concentrations plasmatiques d’aldostérone et de rénine normales ou basses, associées ou non à une hypertension artérielle. Chacune mutation altère la signalisation GC. Une seule mutation gain de fonction du GR a été décrite, conduisant à un profil métabolique défavorable (adiposité viscérale, diabète de type 2). Certains polymorphismes du GR (ER22/23EK, GR-9β) sont associés à une résistance partielle aux GC qui s’accompagne d’un meilleur profil métabolique. Enfin, d’autres polymorphismes (N363S, BclI) sont associés à une hypersensibilité GC et un profil métabolique plus défavorable. Cette revue résume les principales données récentes sur la physiopathologie du GR et présente les critères facilitant l’identification de nouvelles mutations du GR chez des patients sélectionnés.
Primary ovarian insufficiency (POI) is a frequent disorder that affects ~1% of women under 40 years of age. POI, which is characterized by the premature depletion of ovarian follicles and elevated ...plasma levels of follicle-stimulating hormone (FSH), leads to infertility. Although various etiological factors have been described, including chromosomal abnormalities and gene variants, most cases remain idiopathic. The aim of the present study was to identify and validate functionally new sequence variants in ATG (autophagy-related genes) leading to POI.
We have reanalyzed, in silico, the exome sequencing data from a previously reported work performed in 69 unrelated POI women. Functional experiments using a classical hallmark of autophagy, the microtubule-associated protein 1 light chain 3β (LC3), were then used to link these genes to this lysosomal degradation pathway.
We venture a functional link between ATG7 and ATG9A variants and POI. We demonstrated that variant ATG7 and ATG9A led to a decrease in autophagosome biosynthesis and consequently to an impairment of autophagy, a key biological process implicated in the preservation of the primordial follicles forming the ovarian reserve.
Our results unveil that impaired autophagy is a novel pathophysiological mechanism involved in human POI.
Only few retrospective studies have reported an efficacy rate of temozolomide (TMZ) in pituitary tumors (PT), all around 50%. However, the long-term survival of treated patients is rarely evaluated. ...We therefore aimed to describe the use of TMZ on PT in clinical practice and evaluate the long-term survival.
Multicenter retrospective study by members of the French Society of Endocrinology.
Forty-three patients (14 women) treated with TMZ between 2006 and 2016 were included. Most tumors were corticotroph (
= 23) or lactotroph (
= 13), and 14 were carcinomas. Clinical/pathological characteristics of PT, as well as data from treatment evaluation and from the last follow-up were recorded. A partial response was considered as a decrease in the maximal tumor diameter by more than 30% and/or in the hormonal rate by more than 50% at the end of treatment.
The median treatment duration was 6.5 cycles (range 2-24), using a standard regimen for most and combined radiotherapy for six. Twenty-two patients (51.2%) were considered as responders. Silent tumor at diagnosis was associated with a poor response. The median follow-up after the end of treatment was 16 months (0-72). Overall survival was significantly higher among responders (
= 0.002); however, ten patients relapsed 5 months (0-57) after the end of TMZ treatment, five in whom TMZ was reinitiated without success.
Patients in our series showed a 51.2% response rate to TMZ, with an improved survival among responders despite frequent relapses. Our study highlights the high variability and lack of standardization of treatment protocols.
Background
The natural history of multiple endocrine neoplasia type 1 (MEN1) is known through single-institution or single-family studies. We aimed to analyze the risk factors and causes of death in ...a large cohort of MEN1 patients.
Methods
Overall, 758 symptomatic MEN1 patients were identified through the GTE network (Groupe d’étude des Tumeurs Endocrines), which involves French and Belgian genetics laboratories responsible for MEN1 diagnosis and 80 clinical reference centers. The causes of death were analyzed. A frailty model, including time-dependent variables, was used to assess the impact of each clinical lesion, except for hyperparathyroidism, on survival.
Results
The median follow-up was 6.3 years. Female gender, family history of MEN1, and recent diagnosis were associated with a lower risk of death. Compared with nonaffected patients, those with thymic tumors (hazard ratio HR = 4.64, 95% CI = 1.73-12.41), glucagonomas–vipomas–somatostatinomas (HR = 4.29, 95% CI = 1.54-11.93), nonfunctioning pancreatic tumors (HR = 3.43, 95% CI = 1.71-6.88), and gastrinoma (HR = 1.89, 95% CI = 1.09-3.25) had a higher risk of death after adjustment for age, gender, and diagnosis period. The increased risk of death among patients with adrenal tumors was not significant, but three patients died from aggressive adrenal tumors. Pituitary tumors, insulinomas, and bronchial tumors did not increase the risk of death. The proportion of MEN1-related deaths decreased from 76.8 to 71.4% after 1990.
Conclusions
The prognosis of MEN1 disease has improved since 1980. Thymic tumors and duodenopancreatic tumors, including nonsecreting pancreatic tumors, increased the risk of death. Rare but aggressive adrenal tumors may also cause death. Most deaths were related to MEN1. New recommendations on abdominal and thoracic imaging are required.
Purpose
Acromegaly is characterized by a broad range of manifestations. Early diagnosis is key to treatment success, but is often delayed as symptomatology overlaps with common disorders. We ...investigated sign-and-symptom associations, demographics, and clinical characteristics at acromegaly diagnosis.
Methods
Observational, cross-sectional, multicenter non-interventional study conducted at 25 hospital departments in France that treat acromegaly (ClinicalTrials.gov: NCT02012127). Adults diagnosed with acromegaly < 5 years were enrolled. Demographic and clinical data were obtained from medical reports and patient questionnaires. Sign-and-symptom associations were assessed by multiple correspondence analysis (MCA).
Results
Overall, 472 patients were included in the analyses. MCA was unsuccessful in identifying sign-and-symptom associations at diagnosis. Endocrinologists (29.5% patients) and other clinical specialists (37.2% patients) were commonly first to suspect acromegaly. Morphologic manifestations (83.7–87.9% patients), snoring syndrome (81.4% patients), and asthenia (79.2% patients) were frequently present at diagnosis; differences were found between sexes for specific manifestations. Rates of discrepancy between patient- and physician-reported manifestations were highest for functional signs. Earliest manifestations prior to diagnosis, according to how they were detected, were enlarged hands and feet (6.4 ± 6.8 and 6.2 ± 6.9 years, functional signs), hypertension (6.6 ± 7.5 years, complementary examination) and carpal/cubital tunnel syndrome (5.7 ± 6.7 years, functional signs with complementary examination).
Conclusions
Results confirm the broad range of manifestations at diagnosis and delay in recognizing the disease. We identified early manifestations and sex differences that may aid physicians in diagnosing acromegaly. Discrepancy rates suggest physicians should obtain the patient’s perspective and seek functional signs during diagnosis.
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.
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.
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 (CAB(max/w)) was 3.5 mg (2.0-10.5). Despite a higher CAB(max/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 CAB(max/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 CAB(max/w) or disease control. Mortality was 4.8%, with four patients developing aggressive tumors (4.3%) and three a pituitary carcinoma (3.3%).
CAB-resistant prolactinomas remain a serious concern. Surgical debulking, newer therapeutic strategies, and early diagnosis of genetic forms could help to improve their outcome.
To assess the yield and the clinical value of systematic screening of susceptibility genes for patients with pheochromocytoma (pheo) or functional paraganglioma (pgl).
We studied 314 patients with a ...pheo or a functional pgl, including 56 patients having a family history and/or a syndromic presentation and 258 patients having an apparently sporadic presentation. Clinical data and blood samples were collected, and all five major pheo-pgl susceptibility genes (RET, VHL, SDHB, SDHD, and SDHC) were screened. Neurofibromatosis type 1 was diagnosed from phenotypic criteria.
We have identified 86 patients (27.4%) with a hereditary tumor. Among the 56 patients with a family/syndromic presentation, 13 have had neurofibromatosis type 1, and germline mutations on the VHL, RET, SDHD, and SDHB genes were present in 16, 15, nine, and three patients, respectively. Among the 258 patients with an apparently sporadic presentation, 30 (11.6%) had a germline mutation (18 patients on SDHB, nine patients on VHL, two patients on SDHD, and one patient on RET). Mutation carriers were younger and more frequently had bilateral or extra-adrenal tumors. In patients with an SDHB mutation, the tumors were larger, more frequently extra-adrenal, and malignant.
Genetic testing oriented by family/sporadic presentation should be proposed to all patients with pheo or functional pgl. We suggest an algorithm that would allow the confirmation of suspected inherited disease as well as the diagnosis of unexpected inherited disease.
Closed-loop insulin delivery systems are expected to become a standard treatment for patients with type 1 diabetes. We aimed to assess whether the Diabeloop Generation 1 (DBLG1) hybrid closed-loop ...artificial pancreas system improved glucose control compared with sensor-assisted pump therapy.
In this multicentre, open-label, randomised, crossover trial, we recruited adults (aged ≥18 years) with at least a 2 year history of type 1 diabetes, who had been treated with external insulin pump therapy for at least 6 months, had glycated haemoglobin (HbA
) of 10% or less (86 mmol/mol), and preserved hypoglycaemia awareness. After a 2-week run-in period, patients were randomly assigned (1:1) with a web-based system in randomly permuted blocks of two, to receive insulin via the hybrid closed-loop system (DBLG1; using a machine-learning-based algorithm) or sensor-assisted pump therapy over 12 weeks of free living, followed by an 8-week washout period and then the other intervention for 12 weeks. The primary outcome was the proportion of time that the sensor glucose concentration was within the target range (3·9-10·0 mmol/L) during the 12 week study period. Efficacy analyses were done in the modified intention-to-treat population, which included all randomly assigned patients who completed both 12 week treatment periods. Safety analyses were done in all patients who were exposed to either of the two treatments at least once during the study. This trial is registered with ClinicalTrials.gov, number NCT02987556.
Between March 3, 2017, and June 19, 2017, 71 patients were screened, and 68 eligible patients were randomly assigned to the DBLG1 group (n=33) or the sensor-assisted pump therapy group (n=35), of whom five dropped out in the washout period (n=1 pregnancy; n=4 withdrew consent). 63 patients completed both 12 week treatment periods and were included in the modified intention-to-treat analysis. The proportion of time that the glucose concentration was within the target range was significantly higher in the DBLG1 group (68·5% SD 9·4 than the sensor-assisted pump group (59·4% 10·2; mean difference 9·2% 95% CI 6·4 to 11·9; p<0·0001). Five severe hypoglycaemic episodes occurred in the DBLG1 group and three episodes occurred in the sensor-assisted pump therapy group, which were associated with hardware malfunctions or human error.
The DBLG1 system improves glucose control compared with sensor-assisted insulin pumps. This finding supports the use of closed-loop technology combined with appropriate health care organisation in adults with type 1 diabetes.
French Innovation Fund, Diabeloop.
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