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Annales d'Endocrinologie - In Press. Accepted Manuscript Available online since lundi 4 mai 2020

Aldosterone, produced by the adrenals and under the control of plasma angiotensin and potassium levels, regulates hydromineral homeostasis and blood pressure. Here we report that the neuropeptide substance P (SP) released by intraadrenal nerve fibres, stimulates aldosterone secretion via binding to neurokinin type 1 receptors (NK1R) expressed by aldosterone-producing adrenocortical cells. The action of SP is mediated by the extracellular signal-regulated kinase pathway and involves upregulation of steroidogenic enzymes. We also conducted a prospective proof-of-concept, double blind, placebo-controlled clinical trial aimed to investigate the impact of the NK1R antagonist aprepitant on aldosterone secretion in healthy male volunteers (EudraCT: 2008-003367-40, ClinicalTrial.gov: NCT00977223). Participants received during two 7-day treatment periods aprepitant (125 mg on the 1st day and 80 mg during the following days) or placebo in a random order at a 2-week interval. The primary endpoint was plasma aldosterone levels during posture test. Secondary endpoints included basal aldosterone alterations, plasma aldosterone variation during metoclopramide and hypoglycaemia tests, and basal and stimulated alterations of renin, cortisol and ACTH during the three different stimulatory tests. The safety of the treatment was assessed on the basis of serum transaminase measurements on days 4 and 7. All pre-specified endpoints were achieved. Aprepitant decreases aldosterone production by around 30% but does not influence the aldosterone response to upright posture. These results indicate that the autonomic nervous system exerts a direct stimulatory tone on mineralocorticoid synthesis through SP, and thus plays a role in the maintenance of hydromineral homeostasis. This regulatory mechanism may be involved in aldosterone excess syndromes., Adrenal aldosterone production is regulated by plasma angiotensin and potassium levels. Here the authors report that the neuropeptide substance P stimulates aldosterone production via neurokinin type 1 receptors (NK1R), and report a proof-of-concept placebo controlled clinical trial showing that a NK1R antagonist decreases aldosterone levels.

International audience; PurposeAcromegaly 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.MethodsObservational, cross-sectional, multicenter non-interventional study conducted at 25 hospital departments in France that treat acromegaly (ClinicalTrials.gov: NCT02012127). Adults diagnosed with acromegaly

Octreotide SC depot is a novel, ready-to-use formulation administered via a thin needle. In a phase 1 study in healthy volunteers, this formulation provided higher bioavailability of octreotide with faster onset and stronger suppression of IGF-1 in healthy volunteers versus long-acting intramuscular (IM) octreotide. This phase 2 study evaluated the pharmacokinetics, efficacy, and safety of octreotide SC depot in patients with acromegaly and functioning NETs, previously treated with octreotide IM.Adult patients with acromegaly or functioning NETs treated for ≥ 2 months with octreotide IM [10/20/30 mg every 4 weeks (q4w)] received the last dose of octreotide IM treatment in study period 0 and were randomized 28 days later to receive octreotide SC depot 10 mg q2w, or 20 mg q4w for 3 months (period 1). The primary objective was to characterize the PK profile of octreotide SC depot after each injection vs PK for octreotide IM (period 0).Twelve patients were randomized to receive octreotide SC depot 10 mg q2w (acromegaly n = 3; NET n = 1) or 20 mg q4w (acromegaly n = 4; NET n = 4). Plasma levels of octreotide were higher with octreotide SC depot as compared to octreotide IM. Adverse events were reported in 6 and 8 patients during period 0 and period 1, respectively; most common in period 1 were gastrointestinal disorders.Octreotide SC depot provided higher exposure (AUC) than octreotide IM, maintained biochemical control in patients with acromegaly and symptom control in patients with functioning NETs, and was well tolerated with a safety profile consistent with octreotide IM. CLINICALTRIALS.NCT02299089.

Le cortex surrenalien est innerve par des fibres du systeme nerveux autonome. Des facteurs neuronaux, liberes au contact des cellules steroidogenes, controlent la secretion hormonale. Notamment, la substance P (SP), un neuropeptide de la famille des tachykinines, stimule la production d’aldosterone chez le rat. Le but de l’etude est d’examiner le role de la SP dans la regulation des secretions surrenaliennes chez l’homme. Nos resultats montrent que les genes codant la SP (TAC1) et le recepteur NK1 (TACR1) sont exprimes dans la surrenale humaine. Des fibres nerveuses a SP sont situees dans la zone glomerulee a proximite des cellules productrices d’aldosterone exprimant le recepteur NK1. L’activation du NK1R par la SP stimule la production d’aldosterone par des cellules corticosurrenaliennes en culture. Cet effet stimulant est bloque par l’aprepitant, un antagoniste du NK1R. La liaison de la SP sur le NK1R active la voie ERK et augmente la transcription de genes codant des enzymes de la steroidogenese. Une etude clinique en double insu contre placebo revele que l’aprepitant abaisse le taux d’adosterone plasmatique en position couchee et reduit la production globale d’aldosterone (aldosteronurie des 24 heures), sans affecter la reponse de l’aldosterone a l’orthostatisme chez le volontaire sain. La reponse de l’aldosterone a l’aprepitant est independante de la renine. Nos donnees demontrent que la substance P intrasurrenalienne exerce un tonus stimulant sur la production d’aldosterone chez l’homme. La regulation nerveuse de la fonction mineralocorticoide par la SP interviendrait en position couchee, en complement du systeme renine-angiotensine qui est active par l’orthostatisme.

International audience; In the normal human adrenal gland, serotonin (5-HT) stimulates aldosterone secretion through the 5-HT4 receptor (5-HT4R). However, the physiological role of the serotonergic control of adrenocortical function is not known. In the present study, we have investigated the ability of l-Lysine, which has been shown to act as a 5-HT4 receptor antagonist, to counteract in vitro and in vivo the stimulatory effect of 5-HT4R agonists on aldosterone production. l-Lysine was found to inhibit aldosterone production induced by 5-HT and the 5-HT4R agonists BIMU8 from cultured human adrenocortical cells. The action of l-Lysine (4.95 g/day orally) on the adrenal cortex was also evaluated in 20 healthy volunteers in a double blind, cross-over, placebo controlled study. l-Lysine had no significant influence on basal plasma aldosterone levels and the aldosterone responses to upright posture, tetracosactide, and low sodium diet (10 mmol/day for 3 days). Conversely, l-Lysine significantly reduced the surge of plasma aldosterone induced by metoclopramide indicating that l-Lysine is able to efficiently antagonize the adrenal 5-HT4 receptors in vivo. These results suggest that l-Lysine supplementation may represent a new treatment of primary adrenal diseases in which corticosteroid hypersecretion is driven by overexpressed 5-HT4 receptors.

Physical activity (PA) improves insulin sensitivity and is particularly important for type 2 diabetes (T2D) management; however, patient adherence is poor. Neuromuscular electrostimulation (NMES) is widely used for rehabilitation issues, but the metabolic impact of provoked involuntary muscular contractions has never been investigated. ELECTRODIAB is a prospective, bi-centric, and 4-week-long pilot study that enrolled 18 patients with T2D who did not require insulin treatment. Insulin sensitivity was evaluated by euglycemic hyperinsulinemic clamp before and after (1) a single NMES session and (2) a week of daily NMES training. Energy expenditure (EE) at baseline and during NMES was evaluated by indirect calorimetry. Dietary and background PA were monitored to avoid bias. After a single session (T1) or a week (T2) of NMES training, insulin sensitivity (M value) increased by 9.3 ± 38.2 % (ns) and 24.9 ± 35.8 % (p = 0.009), respectively, compared with the baseline (T0). Insulin sensitivity increased up to 46.2 ± 33.8 % (p = 0.002) at T2 in the more insulin-resistant subjects (baseline M value ≤4 mg/Kg/min, n = 10). The NMES session-generated EE was 1.42 ± 9.27 kcal/h, which was not significantly increased from the baseline. Insulin sensitivity was significantly improved in patients with T2D after 1 week of daily NMES training, with very low EE. NMES could be an alternative to conventional PA, but the putative mechanisms of action must still be investigated.

L’etude ACRONIS (CSOM230CIC05) a pour objectif de fournir des donnees de vraie-vie de l’utilisation de PAS-LP, chez des patients traites depuis ≥ 6 mois (partie retrospective) ou traites a partir de l’inclusion (partie prospective). Nous presentons ici les resultats de la partie retrospective. L’âge moyen des patients recrutes (n = 60) etait de 45,4 ans avec 55 % de femmes. La duree moyenne de suivi depuis le diagnostic etait de 53,2 mois (σ = 54,5 mois) ; 83,3 % avaient eu une chirurgie hypophysaire, 40,0 % une radiotherapie et 98,3 % un traitement medicamenteux (73,3 % octreotide, 31,7 % lanreotide, 53,3 % pegvisomant, 48,3 % d’agonistes dopaminergiques). Parmi les patients, 23,3 % et 13,3 % etaient diabetiques ou prediabetiques respectivement avant la prescription de PAS-LP. Au total, 81,4 % des patients ont debute PAS-LP a 40 mg. Apres une duree moyenne de 8,2 mois, 32,2 % avaient vu leur dose augmentee et 5,1 % diminuee. Apres 6 mois, l’IGF-1 etait normalise chez 42,5 % des patients (n = 40). La normalisation de l’IGF-1 et une GH Ces resultats preliminaires de l’etude ACRONIS confirment en pratique clinique l’efficacite et la tolerance de PAS-LP chez les patients acromegales precedemment non controles par SSA de premiere generation.

Resume La loi Jarde n o 2012-300 du 5 mars 2012 met en place un cadre juridique unique pour l’ensemble des recherches impliquant la personne humaine, en tenant compte du risque auquel les personnes sont exposees. Ce nouveau dispositif devrait permettre de renforcer la protection des personnes, tout en simplifiant l’organisation des recherches.

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

Dihydrotestosterone (DHT) the physiologically most potent androgen cannot be aromatised into oestrogen. DHT is used as a treatment for idiopathic gynaecomastia. In order to investigate the different sites of action of DHT on the hypothalamic-pituitary-testicular axis, two groups of adult men were studied. Group I included 10 gonadotropin-releasing hormone (GnRH)-deficient men who were evaluated before and during a pulsatile infusion of GnRH alone for 2 weeks and then in association with DHT given transdermally at doses used in the treatment of gynaecomastia for further two weeks. Luteinizing hormone (LH) pulsatility was assessed at the end of each step of the study. Plasma LH levels were measured every 15 min. Plasma testosterone (T), DHT, oestradiol (E2), free alpha-subunit (FAS) of glycoproteic hormones and LH bioactivity were measured on pooled plasma samples. Group II included 12 healthy men in whom plasma T, DHT and E2 were measured before and then 24, 48 and 72 h after the injection of 5000 IU hCG alone or in combination with either DHT or the pure anti-androgen nilutamide. Two weeks separated each of the 3 hCG testing. In group I, except for bioactive/immunoreactive (B/I) LH ratio which was unchanged, GnRH treatment induced significant rises (p < 0.01) in all plasma hormone levels, LH pulse amplitude and frequency. During treatment with GnRH+DHT, plasma DHT levels increased up to 16.8 +/- 2.5 nm, while plasma hormone levels, B/I LH ratio, LH pulse amplitude and frequency were similar to those obtained with GnRH alone. In group II, the peak of hCG-induced T rise was not modified by either DHT or nilutamide. In contrast, DHT reduced by 50% (p < 0.01) the E2 peak in response to hCG. These data show that DHT exerts no direct action on the pituitary to retroregulate LH secretion and to modify either B/I LH ratio or FAS secretion. Its reducing effect on LH secretion is likely mediated at the hypothalamic level. DHT does not appear to have a physiological influence on Leydig cells steroidogenesis. Administered at therapeutic doses, DHT directly reduces testicular aromatase activity that combined with its antigonadotropic effect leads to the gain in the symptomatic treatment of gynaecomastia.

Introduction Dans une large cohorte de patients diagnostiques entre 2009 et 2014, etudier les symptomes et comorbidites au diagnostic de l’acromegalie. Methodologie Etude observationnelle, transversale, multicentrique conduite en France entre septembre 2013 et juin 2014. Ont ete inclus des adultes dont l’acromegalie a ete diagnostiquee depuis moins de 5 ans. Les donnees ont ete collectees de facon retrospective a partir du dossier medical du patient et ont ete confirmees a l’aide de questionnaires patients. Resultats L’âge moyen (moy ± DS) des 472 patients etait de 51,9 (± 14,3) ans et 57,2 % etaient des femmes. L’acromegalie etait diagnostiquee par les endocrinologues (29,5 %) et les medecins generalistes (16,1 %). Au diagnostic, la GH etait de 18,7 (± 30,1) mg/L, l’IGF-1 de 295 (± 160) % LSN, l’acromegalie etait liee a un macro-adenome (80,3 %) pur (78,8 %) ou a GH/PRL (18,2 %). Les patients presentaient des signes morphologiques [modifications du visage, elargissement des mains et des pieds] (96,2 %), cutanes (85,8 %), respiratoires (83,5 %), une asthenie (79,2 %), des signes rhumatologiques (76,1 %), des complications endocriniennes (73,3 %), des signes ORL (62,1 %), un syndrome du canal carpien (58,1 %), des troubles cardiovasculaires (62,9 %), gastro-intestinaux (57,8 %), sexuels (47,7 %), des perturbations metaboliques (42,8 %) [diabete (27,5 %), intolerance au glucose (9,5 %)], des troubles psychologiques (28,8 %), ou une neoplasie (11,9 %). Le delai entre l’apparition des symptomes/comorbidites et le diagnostic d’acromegalie etait de 5,1 (± 4,3) ans. Conclusion Ces resultats confirment la frequence des signes et comorbidites presents au diagnostic d’acromegalie, et met en evidence un raccourcissement des delais pour le diagnostic, soulignant l’importance des efforts pour ameliorer le diagnostic precoce de l’acromegalie.

Context: The GHRH plus arginine (GHRH+Arg) test is a promising alternative to the insulin tolerance test (ITT) for diagnosis of adult GH deficiency (AGHD). Objectives: The objectives of the study were to validate the GHRH+Arg test for diagnosis of AGHD, using the ITT as comparator and a GH assay calibrated according to recent international recommendations, and to study the repeatability and tolerance of both tests. Design: This was a multicenter, randomized, open-label, phase III study. Setting: The study was conducted at 10 French university hospitals. Subjects: Sixty-nine subjects (38 and 15 with high and low probability of GH deficiency, respectively, and 16 healthy controls) were randomized: 35 to the GHRH+Arg-GHRH+Arg-ITT test sequence and 34 to the ITT-ITT-GHRH+Arg test sequence. Interventions: Each subject underwent three tests of GH secretion separated by 24 h or more. Main Outcome Measures: The primary variable used for response assessments was serum peak GH response. Test results were compared with the final AGHD diagnosis. Results: Peak GH responses in the two tests were strongly correlated. A cutoff value of 7.89 μg/liter for GHRH+Arg corresponding to 3 μg/liter for ITT was calculated. The cutoff value leading to 95% specificity with the GHRH+Arg test was measured at about 3.67 μg/liter (sensitivity 79.0%). Intermethod agreement and repeatability were high. Both tests were well tolerated. A preference for the GHRH+Arg test was expressed by 74% of subjects. Conclusions: The GHRH+Arg test demonstrated good accuracy and repeatability, was at least as sensitive as the ITT, and was associated with better subject acceptability. The GHRH+Arg test represents a good alternative to the ITT for the diagnosis of AGHD.

BackgroundThe functional testing of endocrine testis uses extractive human chorionic gonadotropin (ehCG). Recombinant human hCG (rhCG), avoiding any contamination, should replace ehCG. Moreover, a functional evaluation with recombinant human LH (rhLH) would be closer to physiology than a pharmacological testing with hCG.MethodsThe study was conducted in normal men. We first evaluated the dose–effect of ehCG on plasma testosterone and estradiol levels, before and after injection of either hCG or vehicle. Secondly, the responses to the optimal dose of ehCG were compared with those of rhCG. Thirdly, we investigated the dose–effect of rhLH, on steroid hormone secretion. LH, testosterone, and estradiol plasma levels were measured after the injection of either rhLH or placebo.ResultsehCG induced dose-dependent increases in plasma estradiol and testosterone levels. They respectively peaked at 24 and 72 h after the injection. The most potent dose of ehCG (5000 IU) induced results similar to those observed with 250 μg (6500 IU) rhCG. By comparison with placebo, rhLH induced a significant and dose-dependent increase in plasma testosterone levels 4 h after the injection. Peak response of testosterone to rhLH and rhCG was significantly correlated. rhLH did not induce significant change in plasma estradiol level.ConclusionsIn normal men, a single i.v. injection of 150 IU rhLH induces a 25% rise in plasma testosterone levels by comparison with placebo. At the moment, the dynamic evaluation using hCG remains the gold standard test to explore the Leydig cell function. The use of 250 μg rhCG avoiding any contamination should be recommended.

Objective: The diagnosis of primary hyperparathyroidism (PHP) can be difficult in patients with normal plasma calcium or parathyroid hormone (PTH) levels. We perfected a standardized short-time i.v. calcium loading test in healthy controls (HC) and compared the results with those of patients with PHP. Methods: Sixteen HC received 0.33 mmol/kg calcium gluconate intravenously for 3 h. Plasma calcium and serum PTH levels (assayed with immunoluminescent sandwich methods) were measured before, at the end of the infusion and 3 h later. Results were compared with those of 16 PHP patients. Results: In HC, basal total plasma calcium (mean ± s.e.m.) was 2.33 ± 0.02 mmol/l. At the end of calcium loading, calcemia reached 3.21 ± 0.05 mmol/l and decreased to 2.94 ± 0.08 mmol/l 3 h later. In PHP patients, basal plasma calcium was 2.54 ± 0.03 mmol/l and reached similar values as in HC during the testing. Basal serum PTH levels were 32.5 ± 3.3 ng/l in HC and 86.9 ± 6.3 ng/l in PHP. At the end of calcium loading, they dropped to 8.8 ± 0.6 ng/l (HC) and to 31.4 ± 4.2 ng/l (PHP). Three hours later, they were 11.6 ± 0.8 and 39.8 ± 4.0 ng/l respectively. There was a cut-off in serum PTH values between the two groups at the end of calcium loading and 3 h later. Conclusion: The standardized short-time PTH suppression test appears reliable to differentiate healthy subjects from PHP whose serum PTH levels remain >14 and >23 ng/ml respectively at the end of loading and 3 h later. This well-tolerated and easily performed test could be used for the diagnosis of PHP in patients suspected for the disease despite the normality of some basal biological markers.

Objectif Les incretines influencent la motricite digestive. Une secretion et/ou une sensibilite anormale a ces hormones pourraient favoriser la gastroparesie definie par un ralentissement de la vidange gastrique. L’etude a evalue la secretion des incretines et le profil metabolique apres charge orale en glucose (HGPO) chez des patients sans diabete connu et atteints d’une gastroparesie documentee. Patients et methodes 20 patients se plaignant d’un incomfort post-prandrial suggerant une gastroparesie ont ete inclus et compares a une population de 10 sujets temoins. Ont ete exclus 4 patients a vidange gastrique normale (breath test) et un patient atteint d’un diabete meconnu (glycemie a jeun > 7 mmol/l). Les taux plasmatiques de glucose, insuline, GLP-1 et GIP ont ete mesures toutes les 30 minutes lors d’une HGPO (75 g) sur 5 heures. Resultats L’âge et le BMI moyens ne sont pas significativement differents entre les 2 groupes. Glycemie, insulinemie et HOMA-R ne sont pas differents a jeun. L’Index de sensibilite a l’insuline calcule a partir de l’HGPO est significativement diminue dans le groupe « gastroparesie » (6,14 ± 0,93 versus 10,85 ± 1,38 UI-1.ml. mg-1.ml, p = 0,004). L’aire sous la courbe (AUC) de la glycemie et de l’insulinemie au cours de l’HGPO sont significativement superieures dans le groupe « gastroparesie » (P Conclusion Cette etude preliminaire suggere que l’HGPO permette de detecter un etat d’insulino-resistance et d’hyper-insulinisme francs et de frequentes anomalies de la tolerance au glucose chez des patients ayant une gastroparesie confirmee. L’augmentation des taux plasmatiques de GIP et d’insuline pourraient participer a la physiopathologie du trouble de la vidange gastrique.

Benzene derivatives can induce severe liver cell necrosis in animals. A case of a 40-year-old man whose daily consumption of alcohol was 200 g and who had a severe monochlorobenzene-induced liver necrosis is described. Liver biopsy specimen showed centrilobular and mediolobular necrosis, similar to that in mice after experimental bromobenzene administration. Monochlorobenzene serum concentration, assayed from day 3 to day 15 after poisoning, decreased monoexponentially with a half-life of 40.3 hours. Prostaglandin E1 was administered from day 3 to day 8. The patient ultimately recovered. The mechanism of monochlorobenzene-induced liver injury and the possible aggravating role of chronic alcohol consumption are discussed.