Publications by authors named "Gaetan Prevost"

34 Publications

The impact of diabetes on heart failure development: the cardio-renal-metabolic connection.

Diabetes Res Clin Pract 2021 Apr 22:108831. Epub 2021 Apr 22.

Department of Cardiology, University of Rennes, CHU Rennes, INSERM, LTSI-UMR 1099, Rennes, France.

Heart failure (HF) and chronic kidney disease (CKD) are often associated in type 2 diabetes (T2D), aggravate each other and exert synergistic effects to increase the risk of cardiac and renal events. The risks of renal worsening in HF patients and HF in CKD patients need to be evaluated to tailor preventive therapy. The recent CV and renal trials enriched our knowledge about the natural history of HF and CKD in T2D and provided evidence for the benefit of sodium-glucose cotransporter 2 inhibitors (SGLT2is) in HF and renal decline prevention. SGLT-2is are the best choice in patients with HFrEF to improve CV prognosis and HF-related outcomes and also to prevent kidney-related outcomes, and in CKD patients to slow down renal failure and also reduce hHF and CV death. In both situations the number of patients to treat in order to prevent such events in one patient is lower than in the general T2D population at high CV risk. GLP1-receptor agonists could be an alternative in a patient who is intolerant or has a contraindication to SGLT-2is. A tight collaboration between diabetologists, nephrologists and cardiologists should be encouraged for a holistic and effective strategy to reduce the burden of cardio-renal-metabolic interaction.
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http://dx.doi.org/10.1016/j.diabres.2021.108831DOI Listing
April 2021

Rare Forms of Lipomatosis: Dercum's Disease and Roch-Leri Mesosomatous Lipomatosis.

J Clin Med 2021 Mar 21;10(6). Epub 2021 Mar 21.

Endocrinology, Diabetology and Metabolism, CHU Lille, 59000 Lille, France.

In contrast to obesity, which is very frequent, lipomatosis and lipodystrophy syndromes are rare diseases of adipose tissue. Lipodystrophy syndromes are characterized by metabolic abnormalities associated with partial or generalized lipoatrophy. Lipomatosis is defined by the presence of several body lipomas without lipoatrophy. Dercum's disease (DD) and Roch-Leri mesosomatous lipomatosis (RLML) are rare and poorly characterized forms of lipomatosis. They have raised little clinical interest despite the non-negligible consequences of DD on quality of life. The main clinical presentation of these diseases includes multiple lipomas, which are painful in DD (in contrast to RLML). The two diseases are frequently associated with obesity and metabolic syndrome, with hypertension, diabetes, or dyslipidemia. The long-term course of the diseases remains poorly described. DD affects mainly women, whereas RLML mostly affects men. In both diseases lipomas are found on the back and thighs, as well as on the abdomen in DD and the forearms in RLML. The painful lipomas tend to recur after surgery in DD (in contrast to RLML). Most cases are sporadic. No specific treatment has been identified, as the pathophysiology remains unknown. Nevertheless, low-grade fat inflammation and specific abnormalities such as hyperbasophilia deserve further investigation. The aim of this review is to analyze the available literature on the topic.
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http://dx.doi.org/10.3390/jcm10061292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8003963PMC
March 2021

Use of dipeptidyl peptidase-4 inhibitors and prognosis of COVID-19 in hospitalized patients with type 2 diabetes: A propensity score analysis from the CORONADO study.

Diabetes Obes Metab 2021 05 16;23(5):1162-1172. Epub 2021 Feb 16.

Département d'Endocrinologie, Diabétologie et Maladies Métaboliques, CHU de Rouen, Université de Rouen, Rouen, France.

Aim: To investigate the association between routine use of dipeptidyl peptidase-4 (DPP-4) inhibitors and the severity of coronavirus disease 2019 (COVID-19) infection in patient with type 2 diabetes in a large multicentric study.

Materials And Methods: This study was a secondary analysis of the CORONADO study on 2449 patients with type 2 diabetes (T2D) hospitalized for COVID-19 in 68 French centres. The composite primary endpoint combined tracheal intubation for mechanical ventilation and death within 7 days of admission. Stabilized weights were computed for patients based on propensity score (DPP-4 inhibitors users vs. non-users) and were used in multivariable logistic regression models to estimate the average treatment effect in the treated as inverse probability of treatment weighting (IPTW).

Results: Five hundred and ninety-six participants were under DPP-4 inhibitors before admission to hospital (24.3%). The primary outcome occurred at similar rates in users and non-users of DPP-4 inhibitors (27.7% vs. 28.6%; p = .68). In propensity analysis, the IPTW-adjusted models showed no significant association between the use of DPP-4 inhibitors and the primary outcome by Day 7 (OR [95% CI]: 0.95 [0.77-1.17]) or Day 28 (OR [95% CI]: 0.96 [0.78-1.17]). Similar neutral findings were found between use of DPP-4 inhibitors and the risk of tracheal intubation and death.

Conclusions: These data support the safety of DPP-4 inhibitors for diabetes management during the COVID-19 pandemic and they should not be discontinued.
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http://dx.doi.org/10.1111/dom.14324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8013481PMC
May 2021

Assessment of pyloric sphincter distensibility and pressure in patients with diabetic gastroparesis.

Neurogastroenterol Motil 2020 Dec 14:e14064. Epub 2020 Dec 14.

Digestive Physiology Department, Rouen University Hospital, Rouen, France.

Background: Recent studies have shown that pyloric distensibility is altered in 30-50% of gastroparetic patients but the number of diabetic patients included in prior reports has been small. The aim of the present study was to assess pyloric sphincter measurements in diabetic patients with gastroparesis and to determine whether diabetes characteristics were correlated to pyloric disfunction.

Methods: Pyloric distensibility and pressure were measured using EndoFLIP system in 46 patients with diabetic gastroparesis (DGP) and compared with 21 healthy volunteers (HV), and 33 patients with idiopathic gastroparesis (IGP). Altered pyloric distensibility was defined as the measurement below 10 mm /mmHg at 40 ml of inflation. In diabetic patients, blood glucose, glycated hemoglobin, duration, complications, and treatments were collected.

Key Results: Mean pyloric distensibility at 40 ml of inflation was lower in DGP and IGP groups with, respectively, 10.8 ± 0.9 mm /mmHg and 14.8 ± 2.2 mm /mmHg in comparison with the HV group (25.2 ± 2.3 mm /mmHg; p < 0.005). 56.5% of patients had a decreased pyloric distensibility in the DGP group, 51.5% of patients in the IGP group, and 10% of patients in the HV group. No correlation was found between pyloric sphincter measurements and diabetes characteristics, including blood glucose, glycated hemoglobin, diabetes mellitus type, neuropathy, or GLP1 agonists intake.

Conclusion And Interferences: Pyloric sphincter distensibility and pressure were altered both in diabetic and idiopathic gastroparesis. Pyloric sphincter distensibility was not correlated to diabetes parameters.
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http://dx.doi.org/10.1111/nmo.14064DOI Listing
December 2020

Metformin use is associated with a reduced risk of mortality in patients with diabetes hospitalised for COVID-19.

Diabetes Metab 2020 Dec 10;47(5):101216. Epub 2020 Dec 10.

Department of Endocrinology, Diabetes Mellitus and Nutrition, Amiens University Hospital, 80054 Amiens, France; PériTox = UMR_I 01, University of Picardie Jules Verne, Amiens, France.

Aims: Metformin exerts anti-inflammatory and immunosuppressive effects. We addressed the impact of prior metformin use on prognosis in patients with type 2 diabetes hospitalised for COVID-19.

Methods: CORONADO is a nationwide observational study that included patients with diabetes hospitalised for COVID-19 between March 10 and April 10, 2020 in 68 French centres. The primary outcome combined tracheal intubation and/or death within 7 days of admission. A Kaplan-Meier survival curve was reported for death up to day 28. The association between metformin use and outcomes was then estimated in a logistic regression analysis after applying a propensity score inverse probability of treatment weighting approach.

Results: Among the 2449 patients included, 1496 were metformin users and 953 were not. Compared with non-users, metformin users were younger with a lower prevalence of diabetic complications, but had more severe features of COVID-19 on admission. The primary endpoint occurred in 28.0% of metformin users (vs 29.0% in non-users, P =  0.6134) on day 7 and in 32.6% (vs 38.7%, P = 0.0023) on day 28. The mortality rate was lower in metformin users on day 7 (8.2 vs 16.1%, P <  0.0001) and on day 28 (16.0 vs 28.6%, P < 0.0001). After propensity score weighting was applied, the odds ratios for primary outcome and death (OR [95%CI], metformin users vs non-users) were 0.838 [0.649-1.082] and 0.688 [0.470-1.007] on day 7, then 0.783 [0.615-0.996] and 0.710 [0.537-0.938] on day 28, respectively.

Conclusion: Metformin use appeared to be associated with a lower risk of death in patients with diabetes hospitalised for COVID-19.
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http://dx.doi.org/10.1016/j.diabet.2020.101216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832745PMC
December 2020

Risk stratification and screening for coronary artery disease in asymptomatic patients with diabetes mellitus: Position paper of the French Society of Cardiology and the French-speaking Society of Diabetology.

Arch Cardiovasc Dis 2021 Feb 9;114(2):150-172. Epub 2020 Dec 9.

Department of Interventional Cardiology for Coronary, Valves and Structural Heart Diseases, Institut Coeur Poumon, Centre Hospitalier Universitaire de Lille, Lille, France; Inserm, U1011, Institut Pasteur de Lille, EGID, Lille, France; Department of Medicine, Université de Lille, Lille, France.

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http://dx.doi.org/10.1016/j.acvd.2020.07.003DOI Listing
February 2021

Risk stratification and screening for coronary artery disease in asymptomatic patients with diabetes mellitus: Position paper of the French Society of Cardiology and the French-speaking Society of Diabetology.

Diabetes Metab 2021 Mar 23;47(2):101185. Epub 2020 Aug 23.

Department of Interventional Cardiology for Coronary, Valves and Structural Heart Diseases, Institut Coeur Poumon, Centre Hospitalier Universitaire de Lille, Lille, France; Inserm, U1011, Institut Pasteur de Lille, EGID, Lille, France; Department of Medicine, Université de Lille, Lille, France.

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http://dx.doi.org/10.1016/j.diabet.2020.08.002DOI Listing
March 2021

Phenotypic characteristics and prognosis of inpatients with COVID-19 and diabetes: the CORONADO study.

Diabetologia 2020 08 29;63(8):1500-1515. Epub 2020 May 29.

Département Diabète et Endocrinologie, Hôpital Lariboisière, Assistance Publique Hôpitaux de Paris, Paris, France.

Aims/hypothesis: Coronavirus disease-2019 (COVID-19) is a life-threatening infection caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virus. Diabetes has rapidly emerged as a major comorbidity for COVID-19 severity. However, the phenotypic characteristics of diabetes in COVID-19 patients are unknown.

Methods: We conducted a nationwide multicentre observational study in people with diabetes hospitalised for COVID-19 in 53 French centres in the period 10-31 March 2020. The primary outcome combined tracheal intubation for mechanical ventilation and/or death within 7 days of admission. Age- and sex-adjusted multivariable logistic regressions were performed to assess the prognostic value of clinical and biological features with the endpoint. ORs are reported for a 1 SD increase after standardisation.

Results: The current analysis focused on 1317 participants: 64.9% men, mean age 69.8 ± 13.0 years, median BMI 28.4 (25th-75th percentile: 25.0-32.7) kg/m; with a predominance of type 2 diabetes (88.5%). Microvascular and macrovascular diabetic complications were found in 46.8% and 40.8% of cases, respectively. The primary outcome was encountered in 29.0% (95% CI 26.6, 31.5) of participants, while 10.6% (9.0, 12.4) died and 18.0% (16.0, 20.2) were discharged on day 7. In univariate analysis, characteristics prior to admission significantly associated with the primary outcome were sex, BMI and previous treatment with renin-angiotensin-aldosterone system (RAAS) blockers, but not age, type of diabetes, HbA, diabetic complications or glucose-lowering therapies. In multivariable analyses with covariates prior to admission, only BMI remained positively associated with the primary outcome (OR 1.28 [1.10, 1.47]). On admission, dyspnoea (OR 2.10 [1.31, 3.35]), as well as lymphocyte count (OR 0.67 [0.50, 0.88]), C-reactive protein (OR 1.93 [1.43, 2.59]) and AST (OR 2.23 [1.70, 2.93]) levels were independent predictors of the primary outcome. Finally, age (OR 2.48 [1.74, 3.53]), treated obstructive sleep apnoea (OR 2.80 [1.46, 5.38]), and microvascular (OR 2.14 [1.16, 3.94]) and macrovascular complications (OR 2.54 [1.44, 4.50]) were independently associated with the risk of death on day 7.

Conclusions/interpretations: In people with diabetes hospitalised for COVID-19, BMI, but not long-term glucose control, was positively and independently associated with tracheal intubation and/or death within 7 days.

Trial Registration: clinicaltrials.gov NCT04324736.
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http://dx.doi.org/10.1007/s00125-020-05180-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7256180PMC
August 2020

Glucose homeostasis is impaired in mice deficient in the neuropeptide 26RFa (QRFP).

BMJ Open Diabetes Res Care 2020 02;8(1)

U1239, INSERM, Rouen, France.

Introduction: 26RFa (pyroglutamyl RFamide peptide (QRFP)) is a biologically active peptide that has been found to control feeding behavior by stimulating food intake, and to regulate glucose homeostasis by acting as an incretin. The aim of the present study was thus to investigate the impact of 26RFa gene knockout on the regulation of energy and glucose metabolism.

Research Design And Methods: 26RFa mutant mice were generated by homologous recombination, in which the entire coding region of prepro26RFa was replaced by the iCre sequence. Energy and glucose metabolism was evaluated through measurement of complementary parameters. Morphological and physiological alterations of the pancreatic islets were also investigated.

Results: Our data do not reveal significant alteration of energy metabolism in the 26RFa-deficient mice except the occurrence of an increased basal metabolic rate. By contrast, 26RFa mutant mice exhibited an altered glycemic phenotype with an increased hyperglycemia after a glucose challenge associated with an impaired insulin production, and an elevated hepatic glucose production. Two-dimensional and three-dimensional immunohistochemical experiments indicate that the insulin content of pancreatic β cells is much lower in the 26RFa mice as compared with the wild-type littermates.

Conclusion: Disruption of the 26RFa gene induces substantial alteration in the regulation of glucose homeostasis, with in particular a deficit in insulin production by the pancreatic islets. These findings further support the notion that 26RFa is an important regulator of glucose homeostasis.
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http://dx.doi.org/10.1136/bmjdrc-2019-000942DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7050347PMC
February 2020

CVOTs: What did the endocrinologist learn?

Diabetes Res Clin Pract 2020 Jan 26;159:107947. Epub 2019 Nov 26.

Department of Endocrinology, Diabetes and Metabolic Diseases, Normandie Univ, UNIROUEN, Rouen University Hospital, Rouen, France. Electronic address:

The recent CVOTs which tested the new glucose-lowering drugs (GLD) show that in patients with type 2 diabetes mellitus (T2DM) it is now possible to reduce cardiovascular complications including ischemic events and hospitalization for heart failure, and mortality, and, to some extent, microvascular complications of diabetes, in particular renal outcomes. Additionally CVOTs provide major informations on safety and metabolic effects for long-term use of these drugs. The benefits with GLP-1 RAs are most likely derived through the reduction of atherosclerosis-related events while SGLT-2is seem mostly to reduce heart failure-related events. Specific mechanisms independent from glucose control are involved. Based on CVOTs results it is time, as stated in the new EASD-ADA and ESC/EASD guidelines, to take into consideration such opportunities in the decision-making process when treating T2DM patients, favoring the use of drugs that have shown clear cardiovascular and renal benefits. The treatment decisions require more expertise in the evaluation of cardiovascular and renal risk which becomes a major determinant for the choice of GLD treatment, the target for lipids, the adjustment of anti-hypertensive treatments and the prescription of aspirin. In this context it is essential that endocrinologists-diabetologists communicate more with cardiologists and nephrologists and with the primary care practitioners.
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http://dx.doi.org/10.1016/j.diabres.2019.107947DOI Listing
January 2020

Targets for blood glucose: What have the trials told us.

Eur J Prev Cardiol 2019 Dec;26(2_suppl):64-72

Department of Cardiovascular and Metabolic Diseases, IRCCS MultiMedica, Italy.

The challenges of diabetes treatment are to prevent or delay microangiopathic complications and macrovascular disease. Early, effective and sustained glycaemic control is advocated by all diabetes guidelines to mitigate the risks of prolonged hyperglycaemia. The post-hoc analyses of the large randomised glucose intervention trials and the long-term results of these trials have shown clearly that intensive glycaemic control may have more favourable cardiovascular effects when initiated earlier in the course of diabetes, particularly among in patients without cardiovascular disease. Based on the intervention trials a haemoglobin A1c level of less than 7.0% (<53 mmol/mol) is a generally accepted target to reduce microvascular disease and should be initiated early in the course of the diabetes. However, haemoglobin A1c targets should be individualised. Achieving a good glycaemic control without detrimental effect and preferably with benefit to the cardiovascular system and to renal function is an important challenge. When targeting a tight glycaemic control, avoidance of hypoglycaemia is crucial particularly in patients with coronary artery disease and in patients with heart failure. The cardiovascular outcomes trials performed to test the cardiovascular safety of the new glucose-lowering therapies offer compelling evidence in favour of the role of these drugs for cardiovascular prevention. Thus, both the glycaemic target and the choice of therapies should now be defined on an individual basis.
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http://dx.doi.org/10.1177/2047487319885456DOI Listing
December 2019

The neuropeptide 26RFa in the human gut and pancreas: potential involvement in glucose homeostasis.

Endocr Connect 2019 Jul;8(7):941-951

Normandie Univ, UNIROUEN, INSERM U1239, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication (DC2N), Rouen, France.

Objective: Recent studies performed in mice revealed that the neuropeptide 26RFa regulates glucose homeostasis by acting as an incretin and by increasing insulin sensitivity. However, in humans, an association between 26RFa and the regulation of glucose homeostasis is poorly documented. In this study, we have thus investigated in detail the distribution of 26RFa and its receptor, GPR103, in the gut and the pancreas, and determined the response of this peptidergic system to an oral glucose challenge in obese patients.

Design And Methods: Distribution of 26RFa and GPR103 was examined by immunohistochemistry using gut and pancreas tissue sections. Circulating 26RFa was determined using a specific radioimmunoassay in plasma samples collected during an oral glucose tolerance test.

Results: 26RFa and GPR103 are present all along the gut but are more abundant in the stomach and duodenum. In the stomach, the peptide and its receptor are highly expressed in the gastric glands, whereas in the duodenum, ileum and colon they are present in the enterocytes and the goblet cells. In the pancreatic islets, the 26RFa/GPR103 system is mostly present in the β cells. During an oral glucose tolerance test, plasma 26RFa profile is different between obese patients and healthy volunteers, and we found strong positive correlations between 26RFa blood levels and the BMI, and with various parameters of insulin secretion and insulin resistance.

Conclusion: The present data suggest an involvement of the 26RFa/GPR103 peptidergic system in the control of human glucose homeostasis.
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http://dx.doi.org/10.1530/EC-19-0247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6612231PMC
July 2019

Neuropeptide 26RFa (QRFP) is a key regulator of glucose homeostasis and its activity is markedly altered in obese/hyperglycemic mice.

Am J Physiol Endocrinol Metab 2019 07 14;317(1):E147-E157. Epub 2019 May 14.

Normandie University, UNIROUEN, INSERM U1239, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication (DC2N) , Rouen , France.

Recent studies have shown that the hypothalamic neuropeptide 26RFa regulates glucose homeostasis by acting as an incretin and increasing insulin sensitivity. In this study, we further characterized the role of the 26RFa/GPR103 peptidergic system in the global regulation of glucose homeostasis using a 26RFa receptor antagonist and also assessed whether a dysfunction of the 26RFa/GPR103 system occurs in obese hyperglycemic mice. First, we demonstrate that administration of the GPR103 antagonist reduces the global glucose-induced incretin effect and insulin sensitivity whereas, conversely, administration of exogenous 26RFa attenuates glucose-induced hyperglycemia. Using a mouse model of high-fat diet-induced obesity and hyperglycemia, we found a loss of the antihyperglcemic effect and insulinotropic activity of 26RFa, accompanied with a marked reduction of its insulin-sensitive effect. Interestingly, this resistance to 26RFa is associated with a downregulation of the 26RFa receptor in the pancreatic islets, and insulin target tissues. Finally, we observed that the production and release kinetics of 26RFa after an oral glucose challenge is profoundly altered in the high-fat mice. Altogether, the present findings support the view that 26RFa is a key regulator of glucose homeostasis whose activity is markedly altered under obese/hyperglycemic conditions.
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http://dx.doi.org/10.1152/ajpendo.00540.2018DOI Listing
July 2019

Altered bioavailability of epoxyeicosatrienoic acids is associated with conduit artery endothelial dysfunction in type 2 diabetic patients.

Cardiovasc Diabetol 2019 03 18;18(1):35. Epub 2019 Mar 18.

Department of Pharmacology, Rouen University Hospital, 76000, Rouen Cedex, France.

Background: This pathophysiological study addressed the hypothesis that soluble epoxide hydrolase (sEH), which metabolizes the vasodilator and anti-inflammatory epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatrienoic acids (DHETs), contributes to conduit artery endothelial dysfunction in type 2 diabetes.

Methods And Results: Radial artery endothelium-dependent flow-mediated dilatation in response to hand skin heating was reduced in essential hypertensive patients (n = 9) and type 2 diabetic subjects with (n = 19) or without hypertension (n = 10) compared to healthy subjects (n = 36), taking into consideration cardiovascular risk factors, flow stimulus and endothelium-independent dilatation to glyceryl trinitrate. Diabetic patients but not non-diabetic hypertensive subjects displayed elevated whole blood reactive oxygen species levels and loss of NO release during heating, assessed by measuring local plasma nitrite variation. Moreover, plasma levels of EET regioisomers increased during heating in healthy subjects, did not change in hypertensive patients and decreased in diabetic patients. Correlation analysis showed in the overall population that the less NO and EETs bioavailability increases during heating, the more flow-mediated dilatation is reduced. The expression and activity of sEH, measured in isolated peripheral blood mononuclear cells, was elevated in diabetic but not hypertensive patients, leading to increased EETs conversion to DHETs. Finally, hyperglycemic and hyperinsulinemic euglycemic clamps induced a decrease in flow-mediated dilatation in healthy subjects and this was associated with an altered EETs release during heating.

Conclusions: These results demonstrate that an increased EETs degradation by sEH and altered NO bioavailability are associated with conduit artery endothelial dysfunction in type 2 diabetic patients independently from their hypertensive status. The hyperinsulinemic and hyperglycemic state in these patients may contribute to these alterations. Trial registration NCT02311075. Registered December 8, 2014.
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http://dx.doi.org/10.1186/s12933-019-0843-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6423843PMC
March 2019

Effect of food deprivation on the hypothalamic gene expression of the secretogranin II-derived peptide EM66 in rat.

Neuroreport 2017 Nov;28(16):1049-1053

aUNIROUEN, INSERM U1239, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication (DC2N), Normandie University, Rouen, France bLaboratory of Neuroendocrinology and Nutritional and Climatic Environment, Faculty of Sciences, University Sidi Mohamed Ben Abdellah, Fez, Morocco.

EM66 is a peptide derived from the chromogranin, secretogranin II (SG-II). Recent findings in mice indicate that EM66 is a novel anorexigenic neuropeptide that regulates hypothalamic feeding behavior, at least in part, by activating the POMC neurons of the arcuate nucleus. The present study aimed to investigate the mechanism of action of EM66 in the control of feeding behavior and, more specifically, its potential interactions with the NPY and POMC systems in rat. We analyzed by Q-PCR the gene expression of the EM66 precursor, SG-II, in hypothalamic extracts following 2, 3, or 4 days of food deprivation and compared it with the expression levels of the two major neuropeptidergic systems, that is, POMC and NPY, modulating feeding behavior. Our results show that fasting for 2 and 3 days has no effect on SG-II mRNA levels. However, 4 days of food deprivation induced a significant alteration in the expression levels of the three genes studied, with a significant increase in SG-II and NPY mRNAs, and conversely, a significant decrease in POMC mRNA. These data indicate that the EM66 gene expression is modulated by a negative energy status and suggest interactions between EM66 and NPY to regulate food intake through the POMC system.
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http://dx.doi.org/10.1097/WNR.0000000000000889DOI Listing
November 2017

Excess Body Mass Index Loss at 3 Months: A Predictive Factor of Long-Term Result after Sleeve Gastrectomy.

J Obes 2017 29;2017:2107157. Epub 2017 Jan 29.

Department of Digestive Surgery, Rouen University Hospital, 1 rue de Germont, 76031 Rouen, France.

Laparoscopic Sleeve Gastrectomy (SG) is considered as successful if the percentage of Excess Body Mass Index Loss (% EBMIL) remains constant over 50% with long-term follow-up. The aim of this study was to evaluate whether early % EBMIL was predictive of success after SG. This retrospective study included patients who had SG with two years of follow-up. Patients had follow-up appointments at 3 (M3), 6, 12, and 24 months (M24). Data as weight and Body Mass Index (BMI) were collected systematically. We estimated the % EBMIL necessary to establish a correlation between M3 and M24 compared to % EBMIL speeds and calculated a limit value of % EBMIL predictive of success. Data at operative time, M3, and M24 were available for 128 patients. Pearson test showed a correlation between % EBMIL at M3 and that at M24 ( = 0.74; < 0.0001). % EBMIL speed between surgery and M3 ( = 0.0011) was significant but not between M3 and M24. A linear regression analysis proved that % EBMIL over 20.1% at M3 ( < 0.0001) predicted a final % EBMIL over 50%. % EBMIL at M3 after SG is correlated with % EBMIL in the long term. % EBMIL speed was significant in the first 3 months. % EBMIL over 20.1% at M3 leads to the success of SG.
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http://dx.doi.org/10.1155/2017/2107157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5303591PMC
September 2017

The Neuropeptide 26RFa (QRFP) and Its Role in the Regulation of Energy Homeostasis: A Mini-Review.

Front Neurosci 2016 29;10:549. Epub 2016 Nov 29.

INSERM U982, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, Institute for Research and Innovation in Biomedicine, University of Rouen, Normandy UniversityMont-Saint-Aignan, France; Department of Endocrinology, Diabetes and Metabolic Diseases, Institute for Research and Innovation in Biomedecine, University Hospital of Rouen, University of Rouen, Normandy UniversityRouen, France.

This mini-review deals with the neuropeptide 26RFa (or QRFP) which is a member of the RFamide peptide family discovered simultaneously by three groups in 2003. 26RFa (or its N-extended form 43RFa) was subsequently shown to be the endogenous ligand of the human orphan receptor GPR103. In the brain, 26RFa and GPR103mRNA are primarily expressed in hypothalamic nuclei involved in the control of feeding behavior, and at the periphery, the neuropeptide and its receptor are present in abundance in the gut and the pancreatic islets, suggesting that 26RFa is involved in the regulation of energy metabolism. Indeed, 26RFa stimulates food intake when injected centrally, and its orexigenic effect is even more pronounced in obese animals. The expression of 26RFa is up-regulated in the hypothalamus of obese animals, supporting that the 26RFa/GPR103 system may play a role in the development and/or maintenance of the obese status. Recent data indicate that 26RFa is also involved in the regulation of glucose homeostasis. 26RFa reduces glucose-induced hyperglycemia, increases insulin sensitivity and insulinemia. Furthermore, an oral ingestion of glucose strongly stimulates 26RFa release by the gut, indicating that 26RFa is a novel incretin. Finally, 26RFa is able to prevent pancreatic β cell death and apoptosis. This brief overview reveals that 26RFa is a key neuropeptide in the regulation of energy metabolism. Further fields of research are suggested including the pathophysiological implication of the 26RFa/GPR103 system.
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http://dx.doi.org/10.3389/fnins.2016.00549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5126098PMC
November 2016

Dipotassium ethylenediaminetetraacetic acid is better than tripotassium salt for electrochemiluminescence insulin measurement.

Clin Chim Acta 2016 Dec 29;463:45-46. Epub 2016 Sep 29.

Medical Biochemistry, Rouen University Hospital, Rouen, France, 1 rue de Germont, 76031 Rouen, France. Electronic address:

Previous studies reported that stability of insulin was better on ethylenediaminetetraacetic acid (EDTA) plasma sample than serum sample. However, those studies used tripotassium EDTA (K3-EDTA) tubes, rather than dipotassium EDTA (K2-EDTA) tubes which are more commonly used in laboratories. We investigated the impact of preservative type of EDTA (K2 or K3) on the stability of C-peptide and insulin at 4°C and at room temperature room. Our study has identified that K2-EDTA achieves longer stability of insulin but does not improve the stability of C-peptide. Insulin and C-peptide are stable 24h on the same K2-EDTA sample at room temperature.
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http://dx.doi.org/10.1016/j.cca.2016.09.014DOI Listing
December 2016

Selenoprotein T Deficiency Leads to Neurodevelopmental Abnormalities and Hyperactive Behavior in Mice.

Mol Neurobiol 2016 11 26;53(9):5818-5832. Epub 2015 Oct 26.

Inserm, U982, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, Institute for Research and Innovation in Biomedicine, University of Rouen, Normandy University, Mont-Saint-Aignan, 76821, France.

Selenoprotein T (SelT) is a newly discovered thioredoxin-like protein, which is abundantly but transiently expressed in the neural lineage during brain ontogenesis. Because its physiological function in the brain remains unknown, we developed a conditional knockout mouse line (Nes-Cre/SelT) in which SelT gene is specifically disrupted in nerve cells. At postnatal day 7 (P7), these mice exhibited reduced volume of different brain structures, including hippocampus, cerebellum, and cerebral cortex. This phenotype, which is observed early during the first postnatal week, culminated at P7 and was associated with increased loss of immature neurons but not glial cells, through apoptotic cell death. This phenomenon was accompanied by elevated levels of intracellular reactive oxygen species, which may explain the increased neuron demise and reduced brain structure volumes. At the second postnatal week, an increase in neurogenesis was observed in the cerebellum of Nes-Cre/SelT mice, suggesting the occurrence of developmental compensatory mechanisms in the brain. In fact, the brain volume alterations observed at P7 were attenuated in adult mice. Nevertheless, SelT mutant mice exhibited a hyperactive behavior, suggesting that despite an apparent morphological compensation, SelT deficiency leads to cerebral malfunction in adulthood. Altogether, these results demonstrate that SelT exerts a neuroprotective role which is essential during brain development, and that its loss impairs mice behavior.
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http://dx.doi.org/10.1007/s12035-015-9505-7DOI Listing
November 2016

[The neuropeptide 26RFa and its role in the regulation of energy metabolism].

Biol Aujourdhui 2016 22;210(4):227-235. Epub 2017 Mar 22.

INSERM U982, Laboratoire de Différenciation et Communication Neuronale et Neuroendocrine, Institut de Recherche et d'Innovation Biomédicale (IRIB), Université de Rouen, Normandie Université, 76821 Mont-Saint-Aignan, France.

The neuropeptide 26RFa, also referred to as QRFP (for pyroglutamilated RFamide peptide), is the latest member of the RFamide peptide family to be discovered. 26RFa and its N-extended form, 43RFa, have been characterized in all vertebrate classes as the endogenous ligands of the human orphan receptor GPR103. In the brain, 26RFa and GPR103mRNA are primarily expressed in hypothalamic nuclei involved in the control of feeding behavior, and in the periphery, the neuropeptide and its receptor are present in abundance in the gut and the pancreatic islets, suggesting that 26RFa is involved in the regulation of energy metabolism. Indeed, 26RFa stimulates food intake when centrally injected, and its orexigenic effect is even more pronounced in obese animals. The expression of 26RFa is up-regulated in the hypothalamus of obese animals, supporting the view that 26RFa may play a role in the development and/or maintenance of the obese status. Recent data indicate that 26RFa is also involved in the regulation of glucose homeostasis. 26RFa reduces glucose-induced hyperglycemia, increases insulin sensitivity and insulinemia. Furthermore, an oral ingestion of glucose strongly stimulates 26RFa release by the gut, indicating that 26RFa is a novel incretin. Finally, 26RFa is able to prevent pancreatic β cell death and apoptosis. In conclusion, this overview of the literature reveals that 26RFa is a key neuropeptide in the regulation of energy metabolism. Further fields of research are suggested including the pathophysiological implication of the 26RFa/GPR103 system.
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http://dx.doi.org/10.1051/jbio/2016024DOI Listing
September 2017

Cell-to-cell communication in bilateral macronodular adrenal hyperplasia causing hypercortisolism.

Front Endocrinol (Lausanne) 2015 20;6:34. Epub 2015 Apr 20.

INSERM Unité 982, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication , Mont-Saint-Aignan , France ; Institute for Research and Innovation in Biomedicine, Rouen University , Mont-Saint-Aignan , France.

It has been well established that, in the human adrenal gland, cortisol secretion is not only controlled by circulating corticotropin but is also influenced by a wide variety of bioactive signals, including conventional neurotransmitters and neuropeptides, released within the cortex by various cell types such as chromaffin cells, neurons, cells of the immune system, adipocytes, and endothelial cells. These different types of cells are present in bilateral macronodular adrenal hyperplasia (BMAH), a rare etiology of primary adrenal Cushing's syndrome, where they appear intermingled with adrenocortical cells in the hyperplastic cortex. In addition, the genetic events, which cause the disease, favor abnormal adrenal differentiation that results in illicit expression of paracrine regulatory factors and their receptors in adrenocortical cells. All these defects constitute the molecular basis for aberrant autocrine/paracrine regulatory mechanisms, which are likely to play a role in the pathophysiology of BMAH-associated hypercortisolism. The present review summarizes the current knowledge on this topic as well as the therapeutic perspectives offered by this new pathophysiological concept.
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http://dx.doi.org/10.3389/fendo.2015.00034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4403554PMC
May 2015

Hypothalamic Neuropeptide 26RFa Acts as an Incretin to Regulate Glucose Homeostasis.

Diabetes 2015 Aug 9;64(8):2805-16. Epub 2015 Apr 9.

INSERM U982, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, Institute for Research and Innovation in Biomedicine, Rouen, France Normandy University, Caen, France University of Rouen, Rouen, France

26RFa is a hypothalamic neuropeptide that promotes food intake. 26RFa is upregulated in obese animal models, and its orexigenic activity is accentuated in rodents fed a high-fat diet, suggesting that this neuropeptide might play a role in the development and maintenance of the obese status. As obesity is frequently associated with type 2 diabetes, we investigated whether 26RFa may be involved in the regulation of glucose homeostasis. In the current study, we show a moderate positive correlation between plasma 26RFa levels and plasma insulin in patients with diabetes. Plasma 26RFa concentration also increases in response to an oral glucose tolerance test. In addition, we found that 26RFa and its receptor GPR103 are present in human pancreatic β-cells as well as in the gut. In mice, 26RFa attenuates the hyperglycemia induced by a glucose load, potentiates insulin sensitivity, and increases plasma insulin concentrations. Consistent with these data, 26RFa stimulates insulin production by MIN6 insulinoma cells. Finally, we show, using in vivo and in vitro approaches, that a glucose load induces a massive secretion of 26RFa by the small intestine. Altogether, the present data indicate that 26RFa acts as an incretin to regulate glucose homeostasis.
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http://dx.doi.org/10.2337/db14-1864DOI Listing
August 2015

Neuropeptide Y and α-MSH circadian levels in two populations with low body weight: anorexia nervosa and constitutional thinness.

PLoS One 2015 23;10(3):e0122040. Epub 2015 Mar 23.

Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 982, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, Institute for Research and Innovation in Biomedecine (IRIB), University of Rouen, Mont-Saint-Aignan, France.

Context: Anorexia nervosa (AN) presents an adaptive appetite regulating profile including high levels of ghrelin and 26RFa (orexigenic) and low levels of leptin and PYY (anorexigenic). However, this adaptive mechanism is not effective in promoting food intake. The NPY/proopiomelanocortin (POMC) system plays a crucial role in the regulation of feeding behavior as NPY is the most potent orexigenic neuropeptide identified so far and as the POMC-derived peptide α-MSH drastically reduces food intake, and this peptidergic system has not been thoroughly studied in AN.

Objective: The aim of the present study was thus to investigate whether a dysfunction of the NPY/POMC occurs in two populations with low body weight, AN and constitutional thinness (CT).

Design And Settings: This was a cross-sectional study performed in an endocrinological unit and in an academic laboratory.

Investigated Subjects: Three groups of age-matched young women were studied: 23 with AN (AN), 22 CT and 14 normal weight controls.

Main Outcome Measures: Twelve-point circadian profiles of plasma NPY and α-MSH levels were measured in the three groups of investigated subjects.

Results: No significant circadian variation of NPY was detected between the three groups. Plasma α-MSH levels were significantly lower in AN (vs controls) all over the day. The CT group, compared to controls, presented lower levels of α-MSH in the morning and the evening, and an important rise during lunchtime.

Conclusion: In AN patients, the NPY system is not up-regulated under chronic undernutrition suggesting that this may play a role in the inability of anorectic women to adapt food intake to their energy demand. In contrast, low circadian α-MSH levels integrate the adaptive profile of appetite regulation of this disease. Finally, in CT women, the important α-MSH peak detected during lunchtime could explain why these patients are rapidly food satisfied.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0122040PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4370702PMC
February 2016

Neuromuscular electrostimulation and insulin sensitivity in patients with type 2 diabetes: the ELECTRODIAB pilot study.

Acta Diabetol 2015 Apr 9;52(2):285-91. Epub 2014 Aug 9.

Diabetes Care Unit, University Hospital of Caen, Caen, France,

Aim: 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.

Materials And Methods: 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.

Results: 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.

Conclusions: 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.
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http://dx.doi.org/10.1007/s00592-014-0636-5DOI Listing
April 2015

Comparison of the effectiveness of four bariatric surgery procedures in obese patients with type 2 diabetes: a retrospective study.

J Obes 2014 22;2014:638203. Epub 2014 May 22.

Department of Endocrinology, Diabetes and Metabolic Diseases, University Hospital of Rouen, 76031 Rouen, France ; INSERM U982 Neuronal and Neuroendocrine Differentiation and Communication, Institut de Recherche et d'Innovation Biomédicale, Normandie University, University of Rouen, 76821 Mont Saint Aignan, France.

Aim: The aim of the present retrospective study was to evaluate the efficacy of four bariatric surgical procedures to induce diabetes remission and lower cardiovascular risk factors in diabetic obese patients. Moreover, the influence of surgery on weight evolution in the diabetic population was compared with that observed in a nondiabetic matched population.

Methods: Among 970 patients who were operated on in our center since 2001, 81 patients were identified as type 2 diabetes. Laparoscopic adjustable gastric banding (GB), intervention type Mason (MA), gastric bypass (RYGB), and sleeve gastrectomy (SG) were performed, respectively, in 25%, 17%, 28%, and 30% of this diabetic population.

Results: The resolution rate of diabetes one year after surgery was significantly higher after SG than GB (62.5% versus 20%, P < 0.01), but not significantly different between SG and RYGB. In terms of LDL-cholesterol reduction, RYGB was equivalent to SG and superior to CGMA or GB. Considering the other cardiovascular risk factors, there was no significant difference according to surgical procedures. The weight loss was not statistically different between diabetic and nondiabetic matched patients regardless of the surgical procedures used.

Conclusion: Our data confirm that the efficacy of surgery to treat diabetes is variable among the diverse procedures and SG might be an interesting option in this context.
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http://dx.doi.org/10.1155/2014/638203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4055665PMC
November 2014

[How to manage the interruption of a treatment with anti-inflammatory corticosteroids?].

Presse Med 2014 Apr 6;43(4 Pt 1):453-9. Epub 2014 Mar 6.

CHU de Rouen, service d'endocrinologie, diabète et maladies métaboliques, 76230 Bois-Guillaume, France.

A prolonged treatment with anti-inflammatory corticosteroids induces an inhibition of ACTH secretion from pituitary corticotroph cells. An abrupt interruption of such a treatment potentially leads to the risk of an acute adrenal failure, in particular in stressing situations. The inertia in reactivation of the secretion of the stimulating hypothalamic factors (CRH and AVP) and consecutively of ACTH can be responsible for an inability to adapt the secretion of glucocorticoids in response to stress. A short-time treatment (<3 weeks) with anti-inflammatory corticoids does not expose to this risk. On the contrary, a more prolonged treatment, especially with high daily doses, needs to perform an evaluation of the level of corticotroph secretion. This evaluation should be done before to consider that either stopping the treatment is out of risk or if the initiation of a substitutive treatment with hydrocortisone is required. The measurement of morning plasma cortisol level already provides a significant information. As to whether that is needed, a dynamic evaluation can be performed. Among the available tests, the Synacthen(®)test, easy to perform and using at best 1μg of β1-24 ACTH, appears the most finely informative to answer this question and to choose the most adapted follow-up.
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http://dx.doi.org/10.1016/j.lpm.2014.01.007DOI Listing
April 2014

Tumor shrinkage with lanreotide Autogel 120 mg as primary therapy in acromegaly: results of a prospective multicenter clinical trial.

J Clin Endocrinol Metab 2014 Apr 1;99(4):1282-90. Epub 2013 Jan 1.

Department of Endocrinology and Metabolic Diseases (P.J.C.), Centre Hospitalier Universitaire Larrey, F-31059 Toulouse, France; Department of Endocrinology (J.S.B.), Aberdeen Royal Infirmary, Aberdeen AB25 2ZP, United Kingdom; ENDOC Center for Endocrine Tumors (S.P.), 20357 Hamburg, Germany; Department of Endocrinology (D.F.), Derriford Hospital, Plymouth PL6 8DH, United Kingdom; Department of Endocrinology, Diabetes, Metabolic Diseases, and Nutrition (A.T.), University of Bordeaux 2, CHU Bordeaux, 33076 Bordeaux, France; Department of Endocrinology, Diabetes, and Metabolic Diseases (G.P.), CHU Rouen, 76031 Rouen, France; Ipsen Pharma (P.M., A.C.), 92100 Boulogne-Billancourt, France.

Context: Methodological shortcomings often compromise investigations into the effects of primary somatostatin-analog treatment on tumor size in acromegaly. There are also limited data for the long-acting lanreotide formulation.

Objective: The aim of the study was to better characterize the effects of primary lanreotide Autogel treatment on tumor size in patients with GH-secreting macroadenomas.

Design: PRIMARYS was a 48-week, multicenter, open-label, single-arm study.

Setting: The study was conducted at specialist endocrine centers.

Patients: Treatment-naïve acromegalic patients with GH-secreting macroadenomas participated in the study.

Intervention: Lanreotide Autogel 120 mg was administered sc every 28 days (without dose titration).

Outcome Measures: The primary endpoint was the proportion of patients with clinically significant (≥20%) tumor volume reduction (TVR) at week 48/last post-baseline value available using central assessments from three readers. The null hypothesis (H0) for the primary endpoint was that the proportion with TVR was ≤55%. Secondary endpoints included: TVR at other time points, GH and IGF-1, acromegalic symptoms, quality of life (QoL), and safety.

Results: Sixty-four of 90 (71.1%) patients completed the study. Clinically significant TVR at 48 weeks/last post-baseline value available was achieved by 62.9% (95% confidence interval, 52.0, 72.9) of 89 patients in the primary analysis (intention-to-treat population; H0 not rejected) and 71.9-75.3% in sensitivity (n = 89) and secondary analyses (n = 63) (H0 rejected). At 12 weeks, 54.1% had clinically significant TVR. Early and sustained improvements also occurred in GH and IGF-1, acromegalic symptoms, and QoL. No patients withdrew due to gastrointestinal intolerance.

Conclusions: Primary treatment with lanreotide Autogel, administered at 120 mg (highest available dose) without dose titration, in patients with GH-secreting macroadenomas provides early and sustained reductions in tumor volume, GH and IGF-1, and acromegalic symptoms, and improves QoL.
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http://dx.doi.org/10.1210/jc.2013-3318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4009579PMC
April 2014

[Androgenic treatment of male hypogonadism].

Presse Med 2014 Feb 21;43(2):196-204. Epub 2013 Nov 21.

CHU de Rouen, hôpital de Bois-Guillaume, service d'endocrinologie, diabète et maladies métaboliques, 76230 Bois-Guillaume, France.

The diagnosis of male hypogonadism should be clearly established on a clinical and biological basis before considering the initiation of a substitutive treatment with androgens. A careful evaluation of advantages, constraints and limitations of the treatment should be done previously. The potential advantages of an androgenic substitution include an improvement of the symptoms of hypogonadism and the prevention of its bone and metabolic consequences. Absolute (namely prostatic) or relative contraindications should be detected before starting any substitution. The modalities of treatment will be adapted to both the patient's age and the goals to reach. The different available formulations do not induce a similar pattern of plasma testosterone levels. Patches, gel applications and long-acting intramuscular formulations [injected every 3 months] result in stable plasma levels in the physiologic range. The main limitation to their use is linked to a financial aspect as they are not the object of any refund. A careful survey (on clinical, biological and radiological basis) should be established after starting the substitutive treatment with androgens.
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http://dx.doi.org/10.1016/j.lpm.2013.06.021DOI Listing
February 2014