Publications by authors named "Philippe Chanson"

302 Publications

Cholecalciferol (vitamin D3) must not be considered as an endocrine disruptor

Geriatr Psychol Neuropsychiatr Vieil 2022 06;20(2):151-161

Membre du bureau et du Conseil scientifique de la Société française de gériatrie et gérontologie, Département de gériatrie et Centre mémoire ressources recherche, Centre de recherche sur l’autonomie et la longévité, Centre hospitalier universitaire, Angers, France ; UNIV ANGERS, UPRES EA 4638, Université d’Angers, Angers, France ; Gérontopôle Autonomie Longévité des Pays de la Loire, Nantes, France

A French ministerial decree planning to include cholecalciferol, i.e. vitamin D3 (VD3), in the endocrine disruptors (ED) list has generated a lot of concerns in French physicians and scientists. The aim of the present article was to discuss the scientific rationale that may support or not this decision, which seems to be due to the use of VD3 overdose as a rodenticide in some European countries. First, it is noticeable that cholecalciferol is not an “exogenous substance”, a term used in all the definitions of ED, as it is largely synthesized in the skin after UVB rays exposure. Second, we did not find any published article that may support the inclusion of VD3 in the ED list. The request “vitamin D AND endocrine disruptor” reported 33 references in the PubMed database on March, 10, 2022, most of them discussing disturbances of vitamin D metabolism by EDs. Third, a large amount of studies conclude that VD3 has or may have beneficial effects on many functions that are known to be altered by EDs. In addition, we warn that learning that VD3 could be legally considered as a PE may cause the general public to mistrust vitamin D supplementation, which is not desirable in terms of public health as it may increase the already too high prevalence of vitamin D deficient individuals. We consider the aberrant decision of including cholecalciferol in the ED list should be rapidly invalidated before being effective in France and possibly disseminated in the European Union.
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http://dx.doi.org/10.1684/pnv.2022.1031DOI Listing
June 2022

Life expectancy and likelihood of surgery in multiple endocrine neoplasia type 1: AFCE and GTE cohort study.

Br J Surg 2022 Jul 14. Epub 2022 Jul 14.

INSERM, U1231, Epidemiology and Clinical Research in Digestive Cancers Team, Dijon, France.

Background: The overall natural history, risk of death and surgical burden of patients with multiple endocrine neoplasia type 1 (MEN1) is not well known.

Methods: Patients with MEN1 from a nationwide cohort were included. The survival of patients with MEN1 was compared with that of the general population using simulated controls. The cumulative probabilities of MEN1-specific operations and postoperative mortality were assessed, and surgical sequences were analysed using sunburst charts and Venn diagrams.

Results: A total of 1386 patients with MEN1 were included. Life expectancy was significantly reduced in patients with MEN1 compared with simulated controls from the general population, with a lifetime difference of 15 years. Mutations affecting the JunD interaction domain had a significant negative impact on survival. Survival for patients with MEN1 compared with the general population improved over time. The probability of experiencing at least one specific MEN1 operation was above 95 per cent after 75 years, and most patients had surgery at least twice during their lifetime. Time to a 50 per cent risk of MEN1 surgery was 30.5 years for patients born after 1960, compared with 47.9 years for those born before 1960. Sex and mutations affecting the JunD interacting domain had no impact on time to first surgery. There was considerable heterogeneity in surgical sequences, with no specific clinical pathway.

Conclusion: Life expectancy was significantly lower among patients with MEN1 compared with the general population, and further decreased in patients with mutations affecting the JunD interacting domain. Almost all patients underwent at least one MEN1-specific operation during their lifetime, but there was no standardized sequence of surgery.
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http://dx.doi.org/10.1093/bjs/znac006DOI Listing
July 2022

Turner syndrome: French National Diagnosis and Care Protocol (NDCP; National Diagnosis and Care Protocol).

Orphanet J Rare Dis 2022 07 12;17(Suppl 1):261. Epub 2022 Jul 12.

Department of Endocrinology Pediatric and Adult, Reference Center for Rare Genital Development Disorders, Lyon Hospices Civils, Est Hospital Group, 69677, Bron, France.

Turner syndrome (TS; ORPHA 881) is a rare condition in which all or part of one X chromosome is absent from some or all cells. It affects approximately one in every 1/2500 liveborn girls. The most frequently observed karyotypes are 45,X (40-50%) and the 45,X/46,XX mosaic karyotype (15-25%). Karyotypes with an X isochromosome (45,X/46,isoXq or 45,X/46,isoXp), a Y chromosome, X ring chromosome or deletions of the X chromosome are less frequent. The objective of the French National Diagnosis and Care Protocol (PNDS; Protocole National de Diagnostic et de Soins) is to provide health professionals with information about the optimal management and care for patients, based on a critical literature review and multidisciplinary expert consensus. The PNDS, written by members of the French National Reference Center for Rare Growth and Developmental Endocrine disorders, is available from the French Health Authority website. Turner Syndrome is associated with several phenotypic conditions and a higher risk of comorbidity. The most frequently reported features are growth retardation with short adult stature and gonadal dysgenesis. TS may be associated with various congenital (heart and kidney) or acquired diseases (autoimmune thyroid disease, celiac disease, hearing loss, overweight/obesity, glucose intolerance/type 2 diabetes, dyslipidemia, cardiovascular complications and liver dysfunction). Most of the clinical traits of TS are due to the haploinsufficiency of various genes on the X chromosome, particularly those in the pseudoautosomal regions (PAR 1 and PAR 2), which normally escape the physiological process of X inactivation, although other regions may also be implicated. The management of patients with TS requires collaboration between several healthcare providers. The attending physician, in collaboration with the national care network, will ensure that the patient receives optimal care through regular follow-up and screening. The various elements of this PNDS are designed to provide such support.
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http://dx.doi.org/10.1186/s13023-022-02423-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9277788PMC
July 2022

Prolactin immunoassay: does the high-dose hook effect still exist?

Pituitary 2022 Aug 6;25(4):653-657. Epub 2022 Jul 6.

Fédération d'endocrinologie, Centre de Référence des Maladies Rares de l'Hypophyse HYPO, Faculté de Médecine Lyon Est, Hospices Civils de Lyon, Groupement Hospitalier Est, Université Claude Bernard Lyon1, F-69677, Bron cedex, France.

Purpose: Measurement of prolactin in clinical laboratories is an important component in the management of patients with pituitary adenoma. Prolactin measurement is known to be sensitive to the high-dose hook effect, in the presence of extremely high prolactin concentrations. This interference is referred to in most recent articles discussing prolactin assays and the management of prolactin-secreting pituitary adenomas. The objective of our study was to evaluate if the high-dose hook effect remains relevant in current practice, when using currently available assays.

Methods: Serum from a patient with a giant macroprolactinoma was assayed using all of the available prolactin assays in France in 2020, using native serum and after dilution. Technical inserts from assays were reviewed to assess the information on analytical principles, numbers of steps, and any reference to high dose hook effect.

Results: Fourteen assay kits were studied by 16 laboratories; all were two-site immunometric assays, mostly using one step (11/14). Results obtained after dilution varied from 17,900 µg/L to 86,900 µg/L depending on the assay used. One tested assay was sensitive to the high-dose hook effect leading to a falsely lower prolactin concentration when measuring native serum (150 µg/L compared to 17,900 µg/L after dilution).

Conclusion: The high-dose hook effect still exists in a very small minority of prolactin assays. The evolution of assay methods may lead to new assays that remain sensitive to this effect in the future. We therefore advise that the hook effect should still be mentioned in prolactin assay recommendations.
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http://dx.doi.org/10.1007/s11102-022-01246-8DOI Listing
August 2022

Second brain tumours after pituitary irradiation: lower risk than once thought.

Lancet Diabetes Endocrinol 2022 08 1;10(8):552-554. Epub 2022 Jul 1.

Université Paris-Saclay, Inserm, Physiologie et Physiopathologie Endocriniennes, Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Service d'Endocrinologie et des Maladies de la Reproduction, Centre de Référence des Maladies Rares de l'Hypophyse HYPO, Le Kremlin-Bicêtre, France. Electronic address:

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http://dx.doi.org/10.1016/S2213-8587(22)00171-1DOI Listing
August 2022

IGF-I variability over repeated measures in patients with acromegaly under long-acting somatostatin receptor ligands.

J Clin Endocrinol Metab 2022 Jul 1. Epub 2022 Jul 1.

Université Paris-Saclay, Inserm, Physiologie et Physiopathologie Endocriniennes, Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Service d'Endocrinologie et des Maladies de la Reproduction, Le Kremlin-Bicêtre, France.

Context: In patients with acromegaly on long-term treatment with long-acting somatostatin receptor ligands (SRLs), the time of blood collection for IGF-I measurement after injection is not well defined.

Aim: To assess serum IGF-I dynamics and variability in SRL-treated patients compared with surgically cured patients and healthy controls.

Patients And Methods: Thirty patients under SRLs considered controlled based on a normal previous IGF-I level, ten patients cured by pituitary surgery, and seven healthy subjects underwent four IGF-I weekly determinations.

Results: In SRL-treated patients, the IGF-I SDS (mean±SD) was higher just before injection (0.34±0.66) than at Day 7 (-0.33±0.61; p=0.0041) and Day 14 (-0.23±0.60; p=0.047) after injection, but it did not significantly vary in cured patients and healthy controls. The IGF-I CV was higher in SRL-treated patients than in cured patients or healthy controls (14.4±7.6% vs. 7.9±4.4% and 8.3±3.2%, respectively; p<0.05 for both). Among SRL-treated patients, IGF-I CV was higher in "nonoptimally controlled patients"-i.e., patients with at least one elevated IGF-I value out of four (n=9) compared with "optimally controlled" patients for whom all four IGF-I SDS values were <2.0 (21.3±9.3 vs. 11.6±6.0%; p=0.0019). The latter did not differ from surgically cured patients and healthy controls. The measurement at the farthest distance from the SRL injection was the most predictive of patients with nonoptimally controlled disease.

Conclusions: In patients treated with long-acting SRLs, IGF-I sampling at the farthest distance from SRL injection is the most informative and best predictor of optimal disease control.
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http://dx.doi.org/10.1210/clinem/dgac385DOI Listing
July 2022

Pituitary MRI Features in Acromegaly Resulting From Ectopic GHRH Secretion From a Neuroendocrine Tumor: Analysis of 30 Cases.

J Clin Endocrinol Metab 2022 07;107(8):e3313-e3320

Endocrinology and Nutrition Department, Complejo Hospitalario Universitario de Santiago de Compostela, 15706 Santiago de Compostela, Spain.

Context: Ectopic acromegaly is a consequence of rare neuroendocrine tumors (NETs) that secrete GHRH. This abnormal GHRH secretion drives GH and IGF-1 excess, with a clinical presentation similar to classical pituitary acromegaly. Identifying the underlying cause for the GH hypersecretion in the setting of ectopic GHRH excess is, however, essential for proper management both of acromegaly and the NET. Owing to the rarity of NETs, the imaging characteristics of the pituitary in ectopic acromegaly have not been analyzed in depth in a large series.

Objective: Characterize pituitary magnetic resonance imaging (MRI) features at baseline and after NET treatment in patients with ectopic acromegaly.

Design: Multicenter, international, retrospective.

Setting: Tertiary referral pituitary centers.

Patients: Thirty ectopic acromegaly patients having GHRH hypersecretion.

Intervention: None.

Main Outcome Measure: MRI characteristics of pituitary gland, particularly T2-weighted signal.

Results: In 30 patients with ectopic GHRH-induced acromegaly, we found that most patients had hyperplastic pituitaries. Hyperplasia was usually moderate but was occasionally subtle, with only small volume increases compared with normal ranges for age and sex. T2-weighted signal was hypointense in most patients, especially in those with hyperplastic pituitaries. After treatment of the NET, pituitary size diminished and T2-weighted signal tended to normalize.

Conclusions: This comprehensive study of pituitary MRI characteristics in ectopic acromegaly underlines the utility of performing T2-weighted sequences in the MRI evaluation of patients with acromegaly as an additional tool that can help to establish the correct diagnosis.
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http://dx.doi.org/10.1210/clinem/dgac274DOI Listing
July 2022

Reproductive Phenotypes in Men With Acquired or Congenital Hypogonadotropic Hypogonadism: A Comparative Study.

J Clin Endocrinol Metab 2022 06;107(7):e2812-e2824

University Paris-Saclay, F-91405 Orsay, France.

Context: In men with congenital hypogonadotropic hypogonadism (CHH), gonadotropin deficiency and testicular impairment exist since fetal development and persist throughout life. In a few reported cases of acquired HH (AHH), HH onset occurs mainly post pubertally.

Objective: This work aimed to compare the natural history and reproductive status in large series of CHH and lesional AHH evaluated in a single expert academic center.

Methods: We included 172 controls, 668 male HH patients (CHH: n = 201 [age 16.9 ± 9.0 years], lesional AHH: n = 467 [age 45.6 ± 18.4 years]) caused by hypothalamic and/or pituitary tumors (mainly adenomas and craniopharyngiomas) or infiltrative/traumatic diseases.

Results: At diagnosis, CHH were significantly younger, with 52.9% diagnosed before age 18 years, compared to only 9.6% of AHH patients. Cryptorchidism (21.9% vs 0.3%) and micropenis were more prevalent in CHH than AHH patients. Low testicular volume (TV) was present in 97% of patients with CHH (mean TV: 3.4 ± 2.7 mL) but in only 30% of those with AHH (mean TV: 20.8 ± 5.0 mL). Whereas no men with persistent CHH had spontaneous fertility, 70.4% of AHH men fathered at least one child without medical therapy. Total testosterone was lower both in CHH and AHH patients than in controls. Compared to controls, circulating gonadotropins and testicular peptides (insulin-like factor-3 and inhibin B) were decreased both in CHH and AHH, but were significantly higher in patients with AHH.

Conclusion: In AHH patients, the HH has later onset and is less severe than in CHH and the phenotype can overlap with that of individuals with normal laboratory values. Our data suggest that age at diagnosis is a predictor of the reproductive phenotype in AHH.
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http://dx.doi.org/10.1210/clinem/dgac194DOI Listing
June 2022

Role of 68Ga-DOTATOC PET/CT in Insulinoma According to 3 Different Contexts: A Retrospective Study.

Clin Nucl Med 2022 May;47(5):394-401

From the Service de Médecine Nucléaire, Hôpital Tenon AP-HP and Sorbonne University.

Objective: The aim of this study was to assess the performance of 68Ga-DOTATOC PET/CT in the detection and extension of insulinomas according to 3 different contexts: sporadic benign, sporadic metastatic, and multiple endocrine neoplasia type 1 (MEN1).

Patients And Methods: The data of 71 adult patients who underwent 68Ga-DOTATOC PET/CT for suspected or confirmed sporadic insulinoma, suspicion of insulinoma in the context of MEN1, follow-up of metastatic insulinoma, or suspicion of recurrence of insulinoma were retrospectively analyzed. Pathological examination or strong clinical and biological findings were used as standards of truth.

Results: For the assessment of a confirmed sporadic insulinoma in 17 patients, the sensitivity of SR-PET was 75%, including 2 patients for whom metastatic lesions had been revealed by SR-PET. For 35 patients with a suspicion of insulinoma, the sensitivity was 39%. In 10 patients followed up for metastatic insulinoma, the sensitivity was 100%. For 5 patients with a history of MEN1, interpretation of SR-PET was difficult, as 3 of them presented with multiple pancreatic uptake foci. The global sensitivity of SR-PET in all insulinomas excluding those with a MEN1 story was 64% (100% for metastatic insulinomas, 62% for benign insulinomas), with a specificity of 89%.

Conclusions: 68Ga-DOTATOC PET/CT is a useful examination tool for the assessment of insulinomas in selected contexts, with very high performance for the detection and extension workup of metastatic insulinomas and high specificity for the detection of sporadic benign insulinomas. The examination should be completed with GLP-1 receptor PET when it is negative or in a MEN1 context.
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http://dx.doi.org/10.1097/RLU.0000000000004126DOI Listing
May 2022

Prenatal dexamethasone treatment for classic 21-hydroxylase deficiency in Europe.

Eur J Endocrinol 2022 Mar 23;186(5):K17-K24. Epub 2022 Mar 23.

Laboratoire de Biochimie et Biologie Moléculaire, Hospices Civils de Lyon, Centre National de Référence 'Développement Génital: du fœtus à l'adulte DEV-GEN' Université Lyon I, Lyon, France.

Objective: To assess the current medical practice in Europe regarding prenatal dexamethasone (Pdex) treatment of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency.

Design And Methods: A questionnaire was designed and distributed, including 17 questions collecting quantitative and qualitative data. Thirty-six medical centres from 14 European countries responded and 30 out of 36 centres were reference centres of the European Reference Network on Rare Endocrine Conditions, EndoERN.

Results: Pdex treatment is currently provided by 36% of the surveyed centres. The treatment is initiated by different specialties, that is paediatricians, endocrinologists, gynaecologists or geneticists. Regarding the starting point of Pdex, 23% stated to initiate therapy at 4-5 weeks postconception (wpc), 31% at 6 wpc and 46 % as early as pregnancy is confirmed and before 7 wpc at the latest. A dose of 20 µg/kg/day is used. Dose distribution among the centres varies from once to thrice daily. Prenatal diagnostics for treated cases are conducted in 72% of the responding centres. Cases treated per country and year vary between 0.5 and 8.25. Registries for long-term follow-up are only available at 46% of the centres that are using Pdex treatment. National registries are only available in Sweden and France.

Conclusions: This study reveals a high international variability and discrepancy in the use of Pdex treatment across Europe. It highlights the importance of a European cooperation initiative for a joint international prospective trial to establish evidence-based guidelines on prenatal diagnostics, treatment and follow-up of pregnancies at risk for CAH.
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http://dx.doi.org/10.1530/EJE-21-0554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9010809PMC
March 2022

Consensus statement by the French Society of Endocrinology (SFE) and French Society of Pediatric Endocrinology & Diabetology (SFEDP) on diagnosis of Cushing's syndrome.

Ann Endocrinol (Paris) 2022 Apr 19;83(2):119-141. Epub 2022 Feb 19.

Service d'Endocrinologie Nutrition, Hôpital Ambroise-Paré, GHU Paris-Saclay, AP-HP Boulogne, EA4340, Université de Versailles-Saint-Quentin, Paris, France.

Cushing's syndrome is defined by prolonged exposure to glucocorticoids, leading to excess morbidity and mortality. Diagnosis of this rare pathology is difficult due to the low specificity of the clinical signs, the variable severity of the clinical presentation, and the difficulties of interpretation associated with the diagnostic methods. The present consensus paper by 38 experts of the French Society of Endocrinology and the French Society of Pediatric Endocrinology and Diabetology aimed firstly to detail the circumstances suggesting diagnosis and the biologic diagnosis tools and their interpretation for positive diagnosis and for etiologic diagnosis according to ACTH-independent and -dependent mechanisms. Secondly, situations making diagnosis complex (pregnancy, intense hypercortisolism, fluctuating Cushing's syndrome, pediatric forms and genetically determined forms) were detailed. Lastly, methods of surveillance and diagnosis of recurrence were dealt with in the final section.
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http://dx.doi.org/10.1016/j.ando.2022.02.001DOI Listing
April 2022

Parathyroid hormone in situ measurement in patients with hyperparathyroidism: single-centre experience of 179 patients.

Eur J Endocrinol 2022 Mar 8;186(4):489-501. Epub 2022 Mar 8.

Université Paris-Saclay, Inserm, Physiologie et Physiopathologie Endocriniennes, Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Service d'Endocrinologie et des Maladies de la Reproduction, Le Kremlin-Bicêtre, France.

Context: The measurement of parathyroid hormone(PTH) in situ (PTHis) by fine-needle aspiration (FNA) has been proposed as a tool to preoperatively help localize parathyroid glands detected on ultrasound. However, the accuracy of PTHis is highly variable according to the few available studies.

Aim: We aimed to develop and validate the PTHis procedure and assessed the performance of PTHis in a large series of patients with hyperparathyroidism and/or undetermined cervical lesions.

Patients And Methods: The technique set-up consisted of PTHis measurement in thyroid samples from patients with thyroid nodules and patients with high circulating PTH levels (tertiary hyperparathyroidism). Consecutive patients were recruited at one tertiary referral centre from 2017 to 2020 and submitted to ultrasound-guided FNA-PTHis determination.

Results: During the method set-up, we obtained undetectable PTHis levels in all non-parathyroid tissues after sample dilutions. PTHis was higher in patients with hyperparathyroidism (n = 145; 1817 ± 3739 ng/L; range: <4.6-31 140) than in those with thyroid or undetermined cervical lesions (n= 34; <4.6 ng/mL; P < 0.0001). When evaluating PTHis performance in histologically proven samples (158 lesions from 121 patients), PTHis was detectable in 85/97 parathyroid lesions (87%; range: 22-31;140 ng/L) and undetectable in all non-parathyroid lesions (n = 61; P < 0.0001). The specificity and positive predictive value were 100%, and the sensitivity was 87.6%. False-negative lesions (n= 12) were smaller (9.4 ± 5.9 mm) and more often consisted of hyperplasias (75%) than true-positive lesions (16.1 ± 8.4 mm and 33%, P = 0.009 and P = 0.0089, respectively). The method was safe and well tolerated. Four educational cases are also provided.

Conclusions: PTHis determination is a safe and well-tolerated procedure that enhances the specificity of ultrasound-detected lesions. If accurately set-up, it confirms the parathyroid origin of uncharacterized cervical lesions.
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http://dx.doi.org/10.1530/EJE-21-1249DOI Listing
March 2022

Plasma acetyl-l-carnitine and l-carnitine in major depressive episodes: a case-control study before and after treatment.

Psychol Med 2021 Oct 14:1-10. Epub 2021 Oct 14.

CESP, MOODS Team, INSERM, Faculté de Médecine, Univ Paris-Saclay, Le Kremlin BicêtreF-94275, France.

Background: Major depressive disorder (MDD) is the main cause of disability worldwide, its outcome is poor, and its underlying mechanisms deserve a better understanding. Recently, peripheral acetyl-l-carnitine (ALC) has been shown to be lower in patients with major depressive episodes (MDEs) than in controls. l-Carnitine is involved in mitochondrial function and ALC is its short-chain acetyl-ester. Our first aim was to compare the plasma levels of l-carnitine and ALC, and the l-carnitine/ALC ratio in patients with a current MDE and healthy controls (HCs). Our second aim was to assess their changes after antidepressant treatment.

Methods: l-Carnitine and ALC levels and the carnitine/ALC ratio were measured in 460 patients with an MDE in a context of MDD and in 893 HCs. Depressed patients were re-assessed after 3 and 6 months of antidepressant treatment for biology and clinical outcome.

Results: As compared to HC, depressed patients had lower ALC levels (p < 0.00001), higher l-carnitine levels (p < 0.00001) and higher l-carnitine/ALC ratios (p < 0.00001). ALC levels increased [coefficient: 0.18; 95% confidence interval (CI) 0.12-0.24; p < 0.00001], and l-carnitine levels (coefficient: -0.58; 95% CI -0.75 to -0.41; p < 0.00001) and l-carnitine/ALC ratios (coefficient: -0.41; 95% CI -0.47 to -0.34; p < 0.00001), decreased after treatment. These parameters were completely restored after 6 months of antidepressant. Moreover, the baseline l-carnitine/ALC ratio predicted remission after 3 months of treatment (odds ratio = 1.14; 95% CI 1.03-1.27; p = 0.015).

Conclusions: Our data suggest a decreased mitochondrial metabolism of l-carnitine into ALC during MDE. This decreased mitochondrial metabolism is restored after a 6-month antidepressant treatment. Moreover, the magnitude of mitochondrial dysfunction may predict remission after 3 months of antidepressant treatment. New strategies targeting mitochondria should be explored to improve treatments of MDD.
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http://dx.doi.org/10.1017/S003329172100413XDOI Listing
October 2021

Covid-19, the thyroid and the pituitary - The real state of play.

Ann Endocrinol (Paris) 2022 Apr 20;83(2):103-108. Epub 2022 Jan 20.

Service d'endocrinologie, maladies métaboliques et nutrition, pôle cardio-vasculaire et métabolique, CHU Larrey, 24, chemin de Pouvourville, TSA 30030, 31059 Toulouse cedex, France.

Thyroid and pituitary disorders linked to the coronavirus SARS-CoV-2, responsible for the COVID-19 epidemic, are mainly due to direct infection of the endocrine glands by the virus and to cell damage induced by the immune response. The two most frequent thyroid complications of COVID-19 are low T3 syndrome, or "non-thyroidal illness syndrome" (NTIS), and thyroiditis. Studies among in-patients with COVID-19 have shown that between one out of six and half of them have a low TSH level, related to NTIS and thyroiditis, respectively, sometimes found in the same patient. In NTIS, the decrease in free T3 concentration correlates with the severity of the infection and with a poor prognosis. Assessment of thyroid function in patients after a COVID-19 infection, shows normalization of thyroid function tests. Thyroiditis linked to COVID-19 can be divided into two groups, which probably differ in their pathophysiology. One is "destructive" thyroiditis occurring early in infection with SARS-CoV-2, with a severe form of COVID-19, usually observed in men. It is often asymptomatic and associated with lymphopenia. The other is subacute thyroiditis occurring, on average, one month after the COVID-19 episode, usually in clinically symptomatic women and associated with moderate hyperleukocytosis. Post-infection, one quarter to one third of patients remain hypothyroid. An Italian study demonstrated that low TSH in patients hospitalized for COVID-19 was associated with prolonged hospitalization and a higher mortality risk. Pituitary diseases associated with SARS-CoV-2 infection are much rarer and the causal relationship more difficult to ascertain. Several cases of pituitary apoplexy and diabetes insipidus during COVID-19 infection have been reported. Hyponatremia occurs in 20-50% of patients admitted to hospital for COVID-19. The prevalence of the syndrome of inappropriate antidiuretic hormone secretion (SIADH) amongst these hyponatremic cases is difficult to determine. These endocrine complications may influence the prognosis of infection with SARS-CoV-2. Although they rarely require specific treatment, it is important that endocrinologists recognize them to ensure appropriate management, particularly in the acute phase.
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http://dx.doi.org/10.1016/j.ando.2021.12.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8772063PMC
April 2022

Treatment of acromegaly has substantial effects on body composition: a long-term follow-up study.

Eur J Endocrinol 2021 Dec 10;186(2):173-181. Epub 2021 Dec 10.

Université Paris-Saclay, Inserm, Physiologie et Physiopathologie Endocriniennes, Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Service d'Endocrinologie et des Maladies de la Reproduction, Centre de Référence des Maladies Rares de l'Hypophyse, Le Kremlin-Bicêtre, France.

Background: Acromegaly is associated with changes in body composition. Long-term changes following acromegaly treatment and the impact of different treatments have been less investigated.

Methods: We performed a retrospective study in 201 patients with acromegaly. Body composition was assessed by dual-energy X-ray absorptiometry. To investigate the specific effects of treatment vs aging, changes in body composition were compared in one group of patients evaluated both at the time of active and controlled disease (active-to-controlled (A>C); n = 31) and in another group of patients evaluated two times while the disease was controlled (controlled-to-controlled (C>C); n = 32).

Results: In the whole cohort, insulin-like growth factor I (IGF-I) was correlated with fat (r = -0.369; P < 0.001) and lean mass (r = 0.383; P < 0.001). Patients from A>C and C>C groups were comparable for age, sex, BMI and follow-up duration (P = n.s.). Reduction in IGF-I levels was associated with an increase in fat mass and a decrease in lean mass in the A>C group, which was four and eight times more pronounced compared to the C>C group (fat mass: +39 ± 34% vs +10 ± 15%, P < 0.001; lean mass: -8 ± 8% vs -0.2 ± 6%, P < 0.001, respectively). Changes in fat mass were negatively associated with IGF-I (r = -0.450; P = 0.011) and independent of the individual therapy. The daily dose of pegvisomant correlated with fat mass (r = 0.421; P = 0.002) and insulin sensitivity index (r = -0.466; P < 0.001).

Conclusions: Treatment of acromegaly strongly impacts body composition until biochemical disease remission, characterized by an increase in fat mass and a decrease in lean mass. These changes are closely associated with the normalization of IGF-I. Thereafter, body composition changes are similar to what is observed with aging.
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http://dx.doi.org/10.1530/EJE-21-0900DOI Listing
December 2021

Recent insights in pituitary diseases.

Authors:
Philippe Chanson

Presse Med 2021 12 6;50(4):104094. Epub 2021 Nov 6.

Université Paris-Saclay, Inserm, Physiologie et Physiopathologie Endocriniennes, Assistance Publique Hôpitaux de Paris, Hôpital Bicêtre, Le Kremlin-Bicêtre France. Electronic address:

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http://dx.doi.org/10.1016/j.lpm.2021.104094DOI Listing
December 2021

Clinically non-functioning pituitary adenomas.

Presse Med 2021 Dec 28;50(4):104086. Epub 2021 Oct 28.

Université Paris-Saclay, Inserm, Physiologie et Physiopathologie Endocriniennes, Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Service d'Endocrinologie et des Maladies de la Reproduction, Centre de Référence des Maladies Rares de l'Hypophyse, 94275 Le Kremlin-Bicêtre, France; Medical University of Vienna, Department of Internal Medicine III, Division of Endocrinology and Metabolism, 1090 Vienna, Austria.

Clinically non functioning pituitary adenomas (NFPAs) include all pituitary adenomas that are not hormonally active. They are not associated with clinical syndromes such as amenorrhea-galactorrhea (prolactinomas), acromegaly, Cushing's disease or hyperthyroidism (TSH-secreting adenomas) and are therefore usually diagnosed by signs and symptoms related to a mass effect (headache, visual impairment, sometimes pituitary apoplexy), but also incidentally. Biochemical work up often documents several pituitary insufficiencies. In histopathology, the majority of NFPAs are gonadotroph. In the absence of an established medical therapy, surgery is the mainstay of treatment, unless contraindicated or in particular situations (e.g. small incidentalomas, distance from optic pathways). Resection, generally via a trans-sphenoidal approach (with the help of an endoscope), should be performed by a neurosurgeon with extensive experience in pituitary surgery, in order to maximize the chances of complete resection and to minimize complications. If a tumor remnant persists, watchful waiting is preferred to routine radiotherapy, as long as the tumor residue does not grow and is distant from the optic pathways. NFPA can sometimes recur even after complete resection, but predicting the individual risk of tumor remnant progression is difficult. Postoperative irradiation is only considered in case of residual tumor growth or relapse, due to its potential side effects.
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http://dx.doi.org/10.1016/j.lpm.2021.104086DOI Listing
December 2021

Lack of delayed neurocognitive side effects of Gamma Knife radiosurgery in acromegaly: the Later-Ac study.

Eur J Endocrinol 2021 Nov 30;186(1):37-44. Epub 2021 Nov 30.

Aix-Marseille Université, Institut National de la Santé et de la Recherche Médicale (INSERM), U1251, Marseille Medical Genetics (MMG), Institut Marseille Maladies Rares (MarMaRa), Marseille, France.

Introduction: Persistent growth hormone hypersecretion can be observed in roughly 50% of patients operated for somatotroph adenomas, requiring additional treatments. Despite its proven antisecretory efficacy, the use of Gamma Knife radiosurgery (GK) is limited probably due to the lack of data on long-term side effects, including potential cognitive consequences.

Methods: The LATe Effects of Radiosurgery in Acromegaly study was a cross-sectional exposed/unexposed non-randomized study. The primary objective was to determine the long-term neurocognitive effects of GK focusing on memory, executive functions, and calculation ability. Exposed patients had been treated by GK for acromegaly at least 5 years before inclusion. Unexposed patients (paired for age) had to be cured or controlled at last follow-up without any radiation technique. Patients of both groups were cured or controlled at the last follow-up.

Results: Sixty-four patients were evaluated (27 exposed and 37 unexposed). Mean follow-up after GK was 13 ± 6 years (including 24 patients followed for at least 10 years). While up to 23.8% of the patients of the whole cohort presented at least one abnormal cognitive test, we did not observe any significant difference in neurocognitive function between both groups. During the follow-up, 11 patients presented at least one new pituitary deficiency (P = 0.009 for thyroid-stimulating hormone deficiency with a higher rate in exposed patients), two presented a stroke (1 in each group), and one presented a meningioma (12 years after GK).

Conclusions: While GK exposes patients to a well-known risk of pituitary deficiency, it does not seem to induce long-term cognitive consequences in patients treated for acromegaly.
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http://dx.doi.org/10.1530/EJE-21-0826DOI Listing
November 2021

Cost-Utility of Acromegaly Pharmacological Treatments in a French Context.

Front Endocrinol (Lausanne) 2021 7;12:745843. Epub 2021 Oct 7.

Endocrinology Department, "Groupement Hospitalier Est" Hospices Civils de Lyon, Bron, France.

Objective: Efficacy of pharmacological treatments for acromegaly has been assessed in many clinical or real-world studies but no study was interested in economics evaluation of these treatments in France. Therefore, the objective of this study was to estimate the cost-utility of second-line pharmacological treatments in acromegaly patients.

Methods: A Markov model was developed to follow a cohort of 1,000 patients for a lifetime horizon. First-generation somatostatin analogues (FGSA), pegvisomant, pasireotide and pegvisomant combined with FGSA (off label) were compared. Efficacy was defined as the normalization of insulin-like growth factor-1 (IGF-1) concentration and was obtained from pivotal trials and adjusted by a network meta-analysis. Costs data were obtained from French databases and literature. Utilities from the literature were used to estimate quality-adjusted life year (QALY).

Results: The incremental cost-utility ratios (ICUR) of treatments compared to FGSA were estimated to be 562,463 € per QALY gained for pasireotide, 171,332 € per QALY gained for pegvisomant, and 186,242 € per QALY gained for pegvisomant + FGSA. Pasireotide seems to be the least cost-efficient treatment. Sensitivity analyses showed the robustness of the results.

Conclusion: FGSA, pegvisomant and pegvisomant + FGSA were on the cost-effective frontier, therefore, depending on the willingness-to-pay for an additional QALY, they are the most cost-effective treatments. This medico-economic analysis highlighted the consistency of the efficiency results with the efficacy results assessed in the pivotal trials. However, most recent treatment guidelines recommend an individualized treatment strategy based on the patient and disease profile.
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http://dx.doi.org/10.3389/fendo.2021.745843DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8531881PMC
February 2022

Consensus on diagnosis and management of Cushing's disease: a guideline update.

Lancet Diabetes Endocrinol 2021 12 20;9(12):847-875. Epub 2021 Oct 20.

San Raffaele Vita-Salute University, Milan, Italy.

Cushing's disease requires accurate diagnosis, careful treatment selection, and long-term management to optimise patient outcomes. The Pituitary Society convened a consensus workshop comprising more than 50 academic researchers and clinical experts to discuss the application of recent evidence to clinical practice. In advance of the virtual meeting, data from 2015 to present about screening and diagnosis; surgery, medical, and radiation therapy; and disease-related and treatment-related complications of Cushing's disease summarised in recorded lectures were reviewed by all participants. During the meeting, concise summaries of the recorded lectures were presented, followed by small group breakout discussions. Consensus opinions from each group were collated into a draft document, which was reviewed and approved by all participants. Recommendations regarding use of laboratory tests, imaging, and treatment options are presented, along with algorithms for diagnosis of Cushing's syndrome and management of Cushing's disease. Topics considered most important to address in future research are also identified.
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http://dx.doi.org/10.1016/S2213-8587(21)00235-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8743006PMC
December 2021

Loss of KDM1A in GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome: a multicentre, retrospective, cohort study.

Lancet Diabetes Endocrinol 2021 12 13;9(12):813-824. Epub 2021 Oct 13.

Division of Endocrinology, Department of Medicine and Research Center, Centre hospitalier de l'Université de Montréal, Montréal, QC, Canada.

Background: GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome is caused by aberrant expression of the GIP receptor in adrenal lesions. The bilateral nature of this disease suggests germline genetic predisposition. We aimed to identify the genetic driver event responsible for GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome.

Methods: We conducted a multicentre, retrospective, cohort study at endocrine hospitals and university hospitals in France, Canada, Italy, Greece, Belgium, and the Netherlands. We collected blood and adrenal samples from patients who had undergone unilateral or bilateral adrenalectomy for GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome. Adrenal samples from patients with primary bilateral macronodular adrenal hyperplasia who had undergone an adrenalectomy for overt or mild Cushing's syndrome without evidence of food-dependent cortisol production and those with GIP-dependent unilateral adrenocortical adenomas were used as control groups. We performed whole genome, whole exome, and targeted next generation sequencing, and copy number analyses of blood and adrenal DNA from patients with familial or sporadic disease. We performed RNA sequencing on adrenal samples and functional analyses of the identified genetic defect in the human adrenocortical cell line H295R.

Findings: 17 patients with GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome were studied. The median age of patients was 43·3 (95% CI 38·8-47·8) years and most patients (15 [88%]) were women. We identified germline heterozygous pathogenic or most likely pathogenic variants in the KDM1A gene in all 17 patients. We also identified a recurrent deletion in the short p arm of chromosome 1 harboring the KDM1A locus in adrenal lesions of these patients. None of the 29 patients in the control groups had KDM1A germline or somatic alterations. Concomitant genetic inactivation of both KDM1A alleles resulted in loss of KDM1A expression in adrenal lesions. Global gene expression analysis showed GIP receptor upregulation with a log2 fold change of 7·99 (95% CI 7·34-8·66; p=4·4 × 10), and differential regulation of several other G protein-coupled receptors in GIP-dependent primary bilateral macronodular hyperplasia samples compared with control samples. In vitro pharmacological inhibition and inactivation of KDM1A by CRISPR-Cas9 genome editing resulted in an increase of GIP receptor transcripts and protein in human adrenocortical H295R cells.

Interpretation: We propose that GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome results from a two-hit inactivation of KDM1A, consistent with the tumour suppressor gene model of tumorigenesis. Genetic testing and counselling should be offered to these patients and their relatives.

Funding: Agence Nationale de la Recherche, Fondation du Grand défi Pierre Lavoie, and the French National Cancer Institute.
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http://dx.doi.org/10.1016/S2213-8587(21)00236-9DOI Listing
December 2021

Pituitary adenoma in patients with multiple endocrine neoplasia type 1: a cohort study.

Eur J Endocrinol 2021 Nov 26;185(6):863-873. Epub 2021 Nov 26.

CHU de Nantes PHU2 Institut du Thorax et du Système Nerveux, Service d'Endocrinologie, Diabétologie et Nutrition, Nantes, France.

Objective: Pituitary adenoma (PA) is one of the three major components of multiple endocrine neoplasia type 1 (MEN1). Recent studies have suggested that MEN1-associated PAs are less aggressive than initially estimated. We propose an analysis of the outcome of PAs with a standard of care treatment in a nationwide cohort of MEN1 patients.

Design: Retrospective observational nationwide cohort study using the MEN1 patient registry from the French Group of Endocrine Tumours (GTE).

Methods: The GTE database population consists of 1435 patients with MEN1. This analysis focused on 551 patients recruited after 2000 with at least 3 years of follow-up. The study outcome was tumour progression of PA defined by an increase in Hardy classification (HC) during follow-up according to referring physician regular reports.

Results: Among 551 MEN1 patients (index and related), 202 (36.7%) had PA, with 114 (56.4%) diagnosed by MEN1-related screening. PAs were defined according to HC as microadenoma (grade I) in 117 cases (57.9%), macroadenoma in 59 (29.2%) with 20 HC grade II and 39 HC grades III-IV and unspecified in 26 (12.8%). They were prolactinomas in 92 cases (45.5%) and non-secreting in 73 (36.1%). After a median follow-up of 3 years among the 137 patients with HC grades I-II, 4 patients (2.9%) presented tumour progression.

Conclusion: PAs in patients with MEN1 are less aggressive than previously thought. Tumour progression is rare with a standard of care monitoring and treatment, especially in related patients who mostly present non-secreting microadenoma. MRI monitoring for asymptomatic MEN1 patients should be reduced accordingly.
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http://dx.doi.org/10.1530/EJE-21-0630DOI Listing
November 2021

Response to Letter to the Editor from Soghomonian: "Epicardial and Pericardial Adiposity Without Myocardial Steatosis in Cushing Syndrome".

J Clin Endocrinol Metab 2022 01;107(1):e443-e444

Université Paris-Saclay, Inserm, Physiologie et Physiopathologie Endocriniennes, Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Service d'Endocrinologie et des Maladies de la Reproduction, Centre de Référence des Maladies Rares de l'Hypophyse, 94275 Le Kremlin-Bicêtre, France.

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http://dx.doi.org/10.1210/clinem/dgab678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8684451PMC
January 2022

Diabetes Increases Severe COVID-19 Outcomes Primarily in Younger Adults.

J Clin Endocrinol Metab 2021 08 1;106(9):e3364-e3368. Epub 2021 Jun 1.

Cordeliers Research Centre, ImMeDiab team, INSERM, Université de Paris, 75006 Paris, France.

Context: Diabetes is reported as a risk factor for severe coronavirus disease 2019 (COVID-19), but whether this risk is similar in all categories of age remains unclear.

Objective: To investigate the risk of severe COVID-19 outcomes in hospitalized patients with and without diabetes according to age categories.

Design Setting And Participants: We conducted a retrospective observational cohort study of 6314 consecutive patients hospitalized for COVID-19 between February and 30 June 2020 in the Paris metropolitan area, France; follow-up was recorded until 30 September 2020.

Main Outcome Measure(s): The main outcome was a composite outcome of mortality and orotracheal intubation in subjects with diabetes compared with subjects without diabetes, after adjustment for confounding variables and according to age categories.

Results: Diabetes was recorded in 39% of subjects. Main outcome was higher in patients with diabetes, independently of confounding variables (hazard ratio [HR] 1.13 [1.03-1.24]) and increased with age in individuals without diabetes, from 23% for those <50 to 35% for those >80 years but reached a plateau after 70 years in those with diabetes. In direct comparison between patients with and without diabetes, diabetes-associated risk was inversely proportional to age, highest in <50 years and similar after 70 years. Similarly, mortality was higher in patients with diabetes (26%) than in those without diabetes (22%, P < 0.001), but adjusted HR for diabetes was significant only in patients younger than age 50 years (HR 1.81 [1.14-2.87]).

Conclusions: Diabetes should be considered as an independent risk factor for the severity of COVID-19 in young adults more so than in older adults, especially for individuals younger than 70 years.
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http://dx.doi.org/10.1210/clinem/dgab393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8195170PMC
August 2021

Reference values for IGF-I serum concentration in an adult population: use of the VARIETE cohort for two new immunoassays.

Endocr Connect 2021 Aug 26;10(9):1027-1034. Epub 2021 Aug 26.

Université Paris-Saclay, Inserm, Physiologie et Physiopathologie Endocriniennes, Assistance Publique-Hôpitaux de Paris, Hôpital de Bicêtre, Service d'Endocrinologie et des Maladies de la Reproduction, Centre de Référence des Maladies Rares de l'Hypophyse, Le Kremlin-Bicêtre, France.

Objective: Measurement of IGF-I is important in the management of patients with growth hormone disorders. Here we aim to establish normative data for two new IGF-I assay kits based on a large random sample of the French general adult population.

Subjects And Methods: We measured IGF-I in 911 healthy adults (18-90 years) with two immunoassays (ROCHE Elecsys® and IMMULITE-2000 calibrated against the new IS 02/2547). We compared the data with those of the six immunoassays (iSYS, LIAISON XL, IMMULITE-2000 calibrated against the first IS 87/518, IGF-I RIACT, Mediagnost ELISA, and Mediagnost RIA) that we reported previously. The pairwise concordance among the eight assays was assessed with Bland-Altman plots for both the IGF-1 raw data and the standard deviation scores (SDS), as well as with the percentage of observed agreement and the weighted Kappa coefficient for categorizing IGF-I SDS (ClinicalTrials.gov Identifier: NCT01831648).

Results: The normative data included the range of values (2.5-97.5 percentiles) given by the two new IGF-I assays according to age group and sex. A formula for the SDS calculation is provided. As for the previous six assays, the lower limits of the reference intervals of the two new assays were similar, but the upper limits varied markedly. The pairwise concordances were only moderate (kappa 0.57).

Conclusions: Data obtained for these two new IGF-I immunoassays confirm that despite being obtained in the same large healthy population, the reference intervals of the eight commercial IGF-1 assay kits showed noteworthy differences. The agreement among the various methods was moderate to good.
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http://dx.doi.org/10.1530/EC-21-0175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8428081PMC
August 2021

Epicardial and Pericardial Adiposity Without Myocardial Steatosis in Cushing Syndrome.

J Clin Endocrinol Metab 2021 11;106(12):3505-3514

Université Paris-Saclay, Inserm, Physiologie et Physiopathologie Endocriniennes, Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Service d'Endocrinologie et des Maladies de la Reproduction, Centre de Référence des Maladies Rares de l'Hypophyse, 94275 Le Kremlin-Bicêtre, France.

Context: Cardiovascular disease is the leading cause of death in patients with Cushing syndrome. Cortisol excess and adverse metabolic profile could increase cardiac fat, which can subsequently impair cardiac structure and function.

Objective: We aimed to evaluate cardiac fat mass and distribution in patients with Cushing syndrome.

Methods: In this prospective, cross-sectional study, 23 patients with Cushing syndrome and 27 control individuals of comparable age, sex, and body mass index were investigated by cardiac magnetic resonance imaging and proton spectroscopy. Patients were explored before and after biochemical disease remission. Myocardial fat measured by the Dixon method was the main outcome measure. The intramyocardial triglyceride/water ratio measured by spectroscopy and epicardial and pericardial fat volumes were secondary outcome measures.

Results: No difference was found between patients and controls in intramyocardial lipid content. Epicardial fat mass was increased in patients compared to controls (30.8 g/m2 [20.4-34.8] vs 17.2 g/m2 [13.1-23.5], P < .001). Similarly, pericardial fat mass was increased in patients compared to controls (28.3 g/m2 [17.9-38.0] vs 11.4 g/m2 [7.5-19.4], P = .003). Sex, glycated hemoglobin A1c, and the presence of hypercortisolism were independent determinants of epicardial fat. Pericardial fat was associated with sex, impaired glucose homeostasis and left ventricular wall thickness. Disease remission decreased epicardial fat mass without affecting pericardial fat.

Conclusion: Intramyocardial fat stores are not increased in patients with Cushing syndrome, despite highly prevalent metabolic syndrome, suggesting increased cortisol-mediated lipid consumption. Cushing syndrome is associated with marked accumulation of epicardial and pericardial fat. Epicardial adiposity may exert paracrine proinflammatory effects promoting cardiomyopathy.
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http://dx.doi.org/10.1210/clinem/dgab556DOI Listing
November 2021

International Multicenter Validation Study of the SAGIT® Instrument in Acromegaly.

J Clin Endocrinol Metab 2021 11;106(12):3555-3568

Pituitary Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

Context: The SAGIT® instrument (SAGIT) has been developed to enable accurate characterization of acromegaly disease activity.

Objective: We evaluated the ability of SAGIT to discriminate acromegaly disease control status.

Methods: This multicenter, noninterventional, prospective and retrospective, longitudinal study, conducted at academic and private clinical practice sites, included patients aged ≥ 18 years with a diagnosis of controlled (n = 109) or non-controlled (n = 105) acromegaly, assessed by clinical global evaluation of disease control (CGE-DC) questionnaire, investigator therapeutic decision, and international guidelines. Control status was not determined at baseline for 13 patients. Since 9 patients were enrolled retrospectively, all presented analyses are based on the prospective population (N = 227). Patients were assessed over a 2-year follow-up period. Classification and regression tree (CART) analyses were performed to investigate how SAGIT components at baseline (signs/symptoms [S], associated comorbidities [A], growth hormone levels [G], insulin-like growth factor 1 levels [I], tumor features [T]) discriminate between controlled and non-controlled acromegaly.

Results: Baseline mean subscores S, G, I, and T were significantly lower in patients with CGE-DC controlled vs CGE-DC non-controlled acromegaly. SAGIT components I and G for CGE-DC and S, A, G, I, and T for the clinician's therapeutic decision were retained by CART analyses. For international guidelines, only SAGIT component I was retained. The risk for undergoing ≥ 1 treatment change during the study was 3.44 times greater for CGE-DC non-controlled acromegaly relative to CGE-DC controlled acromegaly.

Conclusion: The SAGIT instrument is a valid and sensitive tool to comprehensively and accurately assess acromegaly severity.
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http://dx.doi.org/10.1210/clinem/dgab536DOI Listing
November 2021

Pegvisomant treatment in acromegaly in clinical practice: Final results of the French ACROSTUDY (312 patients).

Ann Endocrinol (Paris) 2021 Dec 10;82(6):582-589. Epub 2021 Jul 10.

CRESTIC EA 3804, université de Reims Champagne Ardenne, UFR Sciences Exactes et Naturelles, Moulin de la Housse, BP 1039, 51687 Reims cedex 2, France; Service d'Endocrinologie-Diabète-Nutrition, CHU de Reims, hôpital Robert Debré, avenue du Général Koenig, 51092 Reims cedex, France. Electronic address:

Objective: We report the final analysis of the French ACROSTUDY, using data revised and enriched since the 2013 interim analysis. Our objective was to validate the use of pegvisomant (PEGV) in the treatment of acromegaly and to determine efficacy and safety.

Patients And Methods: Patients with acromegaly treated with PEGV and followed up for at least 5 years were included. Eighty-eight investigators from 62 clinical centers in France included patients from April 2007 to April 2014. PEGV dose and administration frequency were determined by the physicians, based on their clinical evaluation and local habits. No additional examinations beyond those performed in normal follow-up were required. Minimum recommended follow-up included check-ups at treatment initiation, 6 months, 12 months and then annually.

Results: In total, 312 patients were enrolled. Mean age was 46.1±14.3 years at introduction of PEGV. Median PEGV treatment duration was 6.3 years and median follow-up was 5.6 years. Median dose at initiation was 10mg/day. The percentages of patients with IGF-1 ≤ ULN (upper limit of normal) were 10% (n=300) at baseline, 54% at 6 months (n=278), and 61.7% (n=253) at 2 years, then stabilizing at 64.4% (n=180) at 5 years. Mean PEGV dose was 17.4±11.7mg in patients with controlled disease versus 21.1±17.3mg in those without control at 5 years. At 5 years, 21.8% of patients (54/248) were receiving >30mg PEGV per day. In patients with at least one pituitary imaging procedure during the 5-year follow-up (n=292), the most recent image showed stable tumor volume in 212 subjects (72.6%), increased volume in 13 (4.5%), and decreased volume in 30 (10.3%). No PEGV treatments were permanently discontinued due to transaminase elevation. There were no cases of liver failure.

Conclusion: The French ACROSTUDY showed normalization of IGF-1 levels in 64.4% of a real-life cohort of patients, mostly with uncontrolled disease despite multiple prior therapies. Long-term follow-up showed a sustained effectiveness and good long-term safety.
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http://dx.doi.org/10.1016/j.ando.2021.05.004DOI Listing
December 2021

Blood microbiota and metabolomic signature of major depression before and after antidepressant treatment: a prospective case-control study.

J Psychiatry Neurosci 2021 05 19;46(3):E358-E368. Epub 2021 May 19.

From the INSERM UMRS 996 - Intestinal Microbiota, Macrophages and Liver Inflammation, DHU Hepatinov, Clamart, France (Ciocan, Cassard, Voican, Perlemuter); the University Paris-Saclay, University Paris-Sud, Faculty of Medicine, Le Kremlin-Bicêtre, France (Ciocan, Cassard, Becquemont, Verstuyft, Voican, El Asmar, Colle, Trabado, Chanson, Perlemuter, Corruble); the APHP, Hepato-Gastroenterology and Nutrition, Antoine-Béclère Hospital, Clamart, France (Ciocan, Voican, Perlemuter); the Centre for Clinical Research (CRC), Kremlin-Bicêtre Hospital, AP-HP, Le Kremlin-Bicêtre, France (Becquemont); the INSERM UMR-1178, CESP, "MOODS" Team, Le Kremlin-Bicêtre, France (Becquemont, Verstuyft, El Asmar, David, Corruble); the Department of Molecular Genetics, Pharmacogenetics and Hormones, Kremlin-Bicêtre Hospital, AP-HP, Le Kremlin-Bicêtre, 94275, France (Becquemont, Verstuyft, Trabado); the Psychiatry Department, Kremlin-Bicêtre Hospital, AP-HP, Le Kremlin-Bicêtre, 94275, France (Colle, Corruble); the University Paris-Saclay, University Paris-Sud, Faculty of Pharmacy, Chatenay-Malabry, 92 296, France (David); the INSERM 1185, University Paris-Saclay, University Paris-Sud, Faculty of Medicine, Le Kremlin-Bicêtre, 94276, France (Trabado, Chanson); the Department of Endocrinology, Saint-Antoine Hospital, AP-HP, Sorbonne University, University Paris 6, Paris, France (Feve); the INSERM UMR S_938, Saint-Antoine Research Centre, Paris, France (Feve); and the Department of Endocrinology and Reproductive Diseases, Kremlin-Bicêtre Hospital, AP-HP, Le Kremlin-Bicêtre, 94275, France (Chanson).

Background: The microbiota interacts with the brain through the gut-brain axis, and a distinct dysbiosis may lead to major depressive episodes. Bacteria can pass through the gut barrier and be found in the blood. Using a multiomic approach, we investigated whether a distinct blood microbiome and metabolome was associated with major depressive episodes, and how it was modulated by treatment.

Methods: In this case-control multiomic study, we analyzed the blood microbiome composition, inferred bacterial functions and metabolomic profile of 56 patients experiencing a current major depressive episode and 56 matched healthy controls, before and after treatment, using 16S rDNA sequencing and liquid chromatography coupled to tandem mass spectrometry.

Results: The baseline blood microbiome in patients with a major depressive episode was distinct from that of healthy controls (patients with a major depressive episode had a higher proportion of Janthinobacterium and lower levels of Neisseria) and changed after antidepressant treatment. Predicted microbiome functions confirmed by metabolomic profiling showed that patients who were experiencing a major depressive episode had alterations in the cyanoamino acid pathway at baseline. High baseline levels of Firmicutes and low proportions of Bosea and Tetrasphaera were associated with response to antidepressant treatment. Based on inferred baseline metagenomic profiles, bacterial pathways that were significantly associated with treatment response were related to xenobiotics, amino acids, and lipid and carbohydrate metabolism, including tryptophan and drug metabolism. Metabolomic analyses showed that plasma tryptophan levels are independently associated with response to antidepressant treatment.

Limitations: Our study has some limitations, including a lack of information on blood microbiome origin and the lack of a validation cohort to confirm our results.

Conclusion: Patients with depression have a distinct blood microbiome and metabolomic signature that changes after treatment. Dysbiosis could be a new therapeutic target and prognostic tool for the treatment of patients who are experiencing a major depressive episode.
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http://dx.doi.org/10.1503/jpn.200159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8327971PMC
May 2021
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