Publications by authors named "Véronique Raverot"

37 Publications

Letter to the Editor: "Changes in Thyroid Function Across Adolescence: a Longitudinal Study".

J Clin Endocrinol Metab 2020 08;105(8)

Hospices Civils de Lyon, Groupement Hospitalier Est, Fédération d'Endocrinologie, Bron cedex.

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http://dx.doi.org/10.1210/clinem/dgaa313DOI Listing
August 2020

Management of thyroid dysfunctions in the elderly. French Endocrine Society consensus 2019 guidelines. Short version.

Ann Endocrinol (Paris) 2020 10 21;81(5):511-515. Epub 2020 May 21.

Service d'endocrinologie et maladies métaboliques, CHU de Larrey, 31059 Toulouse, France. Electronic address:

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http://dx.doi.org/10.1016/j.ando.2020.05.002DOI Listing
October 2020

Age- and Sex-Specific TSH Upper-Limit Reference Intervals in the General French Population: There Is a Need to Adjust Our Actual Practices.

J Clin Med 2020 Mar 14;9(3). Epub 2020 Mar 14.

Hospices Civils de Lyon, Fédération d'Endocrinologie, Groupement Hospitalier Est, F-69677 Bron cedex, France.

It is well known that thyroid dysfunction increases with age. This study is aimed to determine reference intervals, in males and females, suitable for thyroid disease exploration during adult life using routinely collected serum thyrotropin (TSH) data in a tertiary center from 2007 to 2018. Over 11 years, 295,775 TSH levels were measured in a single lab. Among the 156,025 TSH results available for analysis, 90,538 values were from female subjects, 82,019 were from patients aged >60 years and 26,825 were from patients aged >80 years. By using an indirect approach, we determined reference values of TSH adapted to age and sex, and we then evaluated the proportion of patients who would have been reclassified with these reference values. The median TSH ranged from 1.2-1.4 mUI/L during the study period. The upper limit of reference range of TSH increased with age; in females the median to 97.5th percentile values increased continuously from the age of 30 years to the oldest age group. Using new calculated reference values in patients with TSH above the conventional upper-limit reference value (4 mUI/L), the proportion of results reclassified as within the reference interval among patients aged >60 years ranged, according to age group, from 50.5% to 65.1% of females and from 33.0% to 37.7% of males. The use of TSH age-specific and sex-specific upper-limit reference values led to the reclassification of a great number of samples, notably among women. This suggests that age-specific TSH upper-limit reference intervals in daily practice should be used in order to avoid misclassification.
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http://dx.doi.org/10.3390/jcm9030792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141356PMC
March 2020

SST5 expression and USP8 mutation in functioning and silent corticotroph pituitary tumors.

Endocr Connect 2020 Feb 1. Epub 2020 Feb 1.

H Lasolle, Service d'Endocrinologie, Centre de Référence des Maladies Rares de l'Hypophyse HYPO, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France.

Objective: Somatostatin receptor type 5 (SST5) is inconsistently expressed by corticotroph tumors, with higher expression found in corticotropinomas having ubiquitin-specific protease 8 (USP8) mutations. Aims were to study the correlation between characteristics of corticotropinomas and SST5 expression/USP8 mutation status and to describe the response to pasireotide in 5 patients.

Design: Retrospective cohort study.

Methods: Clinico-biochemical, radiological and pathological data of 62 patients, operated for a functioning or silent corticotropinoma between 2013 and 2017, were collected. SST5 expression was measured by immunohistochemistry (clone UMB-4, Abcam, IRS>1 being considered positive) and Sanger sequencing was performed on 50 tumors to screen for USP8 mutations.

Results: SST5 expression was positive in 26/62 pituitary tumors. A moderate or strong IRS was found in 15/58 corticotropinomas and in 13/35 functioning corticotropinomas. Among functioning tumors, those expressing SST5 were more frequent in women (22/24 vs 9/15, P=0.04) and had a lower grade (P=0.04) compared to others. USP8 mutations were identified in 13/50 pituitary tumors and were more frequent in functioning compared to silent tumors (11/30 vs 2/20, P=0.05). SST5 expression was more frequent in USP8mut vs USP8wt tumors (10/11 vs 7/19, P=0.007). Among treated patients, normal urinary free cortisol levels were obtained in 3 patients (IRS 0, 2, 6) while a 4-fold decrease was observed in one patient (IRS 4).

Conclusion: SST5 expression appears to be associated with functioning, USP8mut and lower grade corticotropinomas. A correlation between SST5 expression or USP8mut and response to pasireotide remains to be confirmed.
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http://dx.doi.org/10.1530/EC-20-0035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7077525PMC
February 2020

Melatonin rhythm and other outputs of the master circadian clock in the desert goat (Capra hircus) are entrained by daily cycles of ambient temperature.

J Pineal Res 2020 Apr 16;68(3):e12634. Epub 2020 Feb 16.

Comparative Anatomy Unit, Department of Biological and Pharmaceutical Veterinary Sciences, Hassan II Agronomy and Veterinary Medicine Institute, Rabat, Morocco.

In desert areas, mammals such as camel and goat are exposed to harsh environmental conditions. The ambient temperature (Ta) cycles have been shown to entrain the circadian clock in the camel. In the present work, we assumed that, in the goat living in a desert biotope, Ta cycles would have the same synchronizing effect on the central clock. Therefore, the effects of Ta cycles on body temperature (Tb), locomotor activity (LA) and melatonin (Mel) rhythms as outputs of the master circadian clock have been studied. The study was performed on bucks kept first under constant conditions of total darkness (DD) and constant Ta, then maintained under DD conditions but exposed to Ta cycles with heat period during subjective day and cold period during subjective night. Finally, the Ta cycles were reversed with highest temperatures during the subjective night and the lowest temperatures during the subjective day. Under constant conditions, the circadian rhythms of Tb and LA were free running with an endogenous period of 25.3 and 25.0 hours, respectively. Ta cycles entrained the rhythms of Tb and LA to a period of exactly 24.0 hours; while when reversed, the Ta cycles led to an inversion of Tb and LA rhythms. Similarly, Ta cycles were also able to entrain Mel rhythm, by adjusting its secretion to the cooling phase before and after Ta cycles inversion. All together, these results show that the Ta cycles entrain the master circadian clock in the goat.
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http://dx.doi.org/10.1111/jpi.12634DOI Listing
April 2020

Diagnosis, pathology, and management of TSH-secreting pituitary tumors. A single-center retrospective study of 20 patients from 1981 to 2014.

Ann Endocrinol (Paris) 2019 Sep 26;80(4):216-224. Epub 2019 Jul 26.

Université de Lyon, Lyon1, 69372 Lyon, France; Inserm U1052, CNRS UMR5286, Cancer Research Center of Lyon, Lyon, France; Fédération d'endocrinologie, centre de référence maladies rares hypophysaire HYPO, groupement hospitalier Est, hospices Civils de Lyon, 59, boulevard Pinel, 69677 Bron cedex, France. Electronic address:

TSH (thyroid-stimulating hormone)-secreting tumors are the rarest type of pituitary tumor. The objective of this study was to describe initial presentation and follow-up in patients presenting TSH-secreting tumors and to characterize the pathological features, based on a cohort of 20 patients treated in our referral center, between 1981 and 2014. Most of the patients (75%) were female, aged around 50 years (mean: 50±13 years). Initial symptoms were hyperthyroidism (8/20) and/or tumor mass-related symptoms. Median time to diagnosis was 18 months. Biochemical hyperthyroidism was found in 15 patients. Most of the tumors were macroadenomas (75%) and 30% were invasive. Seventeen patients underwent transsphenoidal surgery. All tumors expressed TSH, with>50% positive cells. Eleven were monohormonal and 6 plurihormonal, expressing βTSH plus growth hormone (GH) and/or prolactin (PRL). Both subtypes showed high expression of Pit-1 and SSTR somatostatin receptors. SSTR was slightly expressed in the plurihormonal subtype. Ki-67 index was elevated (≥3%) in only one tumor. Signs of hyperthyroidism were more frequent in the plurihormonal than in the monohormonal subtype. At final follow-up (median: 34.79±66.7 months), 75% of the patients were in complete remission after surgery; persistent hyperthyroidism was controlled by somatostatin analogs, alone (n=3) or associated to radiotherapy (n=1). The multidisciplinary approach promoted early diagnosis and control of hyperthyroidism by neurosurgical treatment, associated to somatostatin analogs or not. Clinical/pathological correlations highlighted the variations in immune profiles and in clinical and biological symptoms.
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http://dx.doi.org/10.1016/j.ando.2019.06.006DOI Listing
September 2019

Smith-Magenis Syndrome: Molecular Basis of a Genetic-Driven Melatonin Circadian Secretion Disorder.

Int J Mol Sci 2019 Jul 19;20(14). Epub 2019 Jul 19.

GénoPsy, Reference Center for Diagnosis and Management of Genetic Psychiatric Disorders, Centre Hospitalier le Vinatier and EDR-Psy Q19 Team (Centre National de la Recherche Scientifique & Lyon 1 Claude Bernard University), 69678 Bron, France.

Smith-Magenis syndrome (SMS), linked to () haploinsufficiency, is a unique model of the inversion of circadian melatonin secretion. In this regard, this model is a formidable approach to better understand circadian melatonin secretion cycle disorders and the role of the gene in this cycle. Sleep-wake cycle disorders in SMS include sleep maintenance disorders with a phase advance and intense sleepiness around noon. These disorders have been linked to a general disturbance of sleep-wake rhythm and coexist with inverted secretion of melatonin. The exact mechanism underlying the inversion of circadian melatonin secretion in SMS has rarely been discussed. We suggest three hypotheses that could account for the inversion of circadian melatonin secretion and discuss them. First, inversion of the circadian melatonin secretion rhythm could be linked to alterations in light signal transduction. Second, this inversion could imply global misalignment of the circadian system. Third, the inversion is not linked to a global circadian clock shift but rather to a specific impairment in the melatonin secretion pathway between the suprachiasmatic nuclei (SCN) and pinealocytes. The development of diurnal SMS animal models that produce melatonin appears to be an indispensable step to further understand the molecular basis of the circadian melatonin secretion rhythm.
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http://dx.doi.org/10.3390/ijms20143533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6679101PMC
July 2019

Cabergoline in severe ectopic or occult Cushing's syndrome.

Eur J Endocrinol 2019 Jul;181(1):K1-K9

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

Context: Cabergoline has been shown to have some effect in the treatment of moderate Cushing's disease, but its effectiveness in Cushing's syndrome of ectopic or occult origin remains to be investigated.

Case Series: In this case series, cabergoline was used in combination with steroidogenesis inhibitors in nine patients with severe Cushing's syndrome of ectopic or occult origin. Cabergoline's effectiveness enabled rapid withdrawal of the steroidogenesis inhibitors and long-term control of the hypercortisolism in three of the cases.

Review Of The Literature: In the literature, we found only 11 cases of ectopic or occult Cushing's syndrome treated with dopamine receptor agonists, alone or in combination. Yet of these 11 cases, 10 responded.

Conclusions: Although limited, the existing experience highlights the potential value of cabergoline in the treatment of ectopic or occult Cushing's syndrome.
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http://dx.doi.org/10.1530/EJE-18-1014DOI Listing
July 2019

Letter to the editor: A case of laboratory-generated "thyroid dysfunction".

Ann Endocrinol (Paris) 2019 Apr 31;80(2):140-141. Epub 2018 Oct 31.

Fédération d'endocrinologie, CHU de Lyon, 59, boulevard Pinel, 69677 Bron, France.

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http://dx.doi.org/10.1016/j.ando.2018.10.001DOI Listing
April 2019

Is circadian rhythmicity a prerequisite to coma recovery? Circadian recovery concomitant to cognitive improvement in two comatose patients.

J Pineal Res 2019 Apr 6;66(3):e12555. Epub 2019 Feb 6.

Lyon Neuroscience Research Center (CRNL), Integrative Physiology of the Brain Arousal Systems (Waking) team, INSERM UMRS 1028, CNRS UMR 5292, Université Claude Bernard Lyon 1, Université de Lyon, F-69000, Lyon, France.

Circadian rhythmicity (CR) is involved in the regulation of all integrated functions, from sleep-wake cycle regulation to metabolic function, mood and cognition. However, the interdependence of CR, cognition and consciousness has been poorly addressed. To clarify the state of CR in coma and to determine the chronological relationship between its recovery and consciousness after brain lesions, we conducted a longitudinal observational study investigating how the state of CR was chronologically related with the recovery of behavioural wakefulness, cognition and/or awareness. Among 16 acute comatose patients, we recruited two 37-year-old patients with a persistent disorder of consciousness, presenting diencephalic lesions caused by severe traumatic brain injuries. Two biological urinary markers of CR were explored every 2 hours during 24 hours (6-sulfatoxymelatonin, free cortisol) with a dedicated methodology to extract the endogenous component of rhythmicity (environmental light recording, near-constant-routine protocol, control of beta-blockers). They presented an initial absence of rhythmic secretions and a recovered CR 7-8 months later. This recovery was not associated with the restoration of behavioural wakefulness, but with an improvement of cognition and awareness (up to the minimally conscious state). MRI showed a lesion pattern compatible with the interruption of either the main hypothalamic-sympathetic pathway or the accessory habenular pathway. These results suggest that CR may be a prerequisite for coma recovery with a potential but still unproven favourable effect on brain function of the resorted circadian melatonin secretion and/or the functional recovery of the suprachiasmatic nucleus (SCN). Assessing circadian functions by urinary melatonin should be further explored as a biomarker of cognition reappearance and investigated to prognosticate functional recovery.
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http://dx.doi.org/10.1111/jpi.12555DOI Listing
April 2019

Brain processing of pictures of children in men with pedophilic disorder: A positron emission tomography study.

Neuroimage Clin 2019 24;21:101647. Epub 2018 Dec 24.

Hospices Civils de Lyon, Groupement Hospitalier Est, Fédération d'Endocrinologie, 59 Boulevard Pinel, Bron F-69500, France; CESP, Fac. de médecine - Univ. Paris-Sud, Fac. de médecine - UVSQ, INSERM, Université Paris-Saclay, Hôpital Paul Brousse, Porte 45, 16 avenue Paul Vaillant-Couturier, Villejuif Cedex 94807, France; Corresponding author at: Inserm U1178, Hôpital Paul Brousse, Porte 45, 16 avenue Paul Vaillant-Couturier, Villejuif Cedex 94807, France.. Electronic address:

Although structural and functional neuroimaging techniques have recently been used to investigate the mechanisms of sexual attraction to children, a hallmark of pedophilic disorder, the differences in the processing of child sexual stimuli between men attracted to children and those attracted to adults remain unclear. Here, our purpose was to identify through positron emission tomography the brain responses of 15 male outpatients with pedophilic disorder to validated visual sexual stimuli depicting children (VSSc) and to compare them with 15 male healthy controls matched for sexual orientation (to female or male adults), age, and handedness. The patients' sample comprised both offenders and non-offenders. In response to VSSc, the between-groups analysis showed that activation in the right inferior temporal cortex [Brodmann area (BA) 20] was lower in patients than in controls. Moreover, in patients but not in controls, the presentation of VSSc induced an activation in a more caudal region of the right inferior temporal gyrus (BA 37) and in the left middle occipital gyrus (BA 19). In addition, in patients the level of activation in the caudal right inferior temporal gyrus was positively correlated with ratings of sexual arousal elicited by VSSc, whereas this correlation was negative in BA 20. These results implicate the right inferior temporal gyrus as a possible candidate area mediating sexual arousal in patients with pedophilic disorder and suggest that two of its areas play opposite, i.e., activating and inhibitory, roles.
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http://dx.doi.org/10.1016/j.nicl.2018.101647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6412007PMC
December 2019

A challenging case: highly variable TSH in a mother and her two children.

Clin Chem Lab Med 2019 05;57(6):e114-e117

Laboratoire de Biochimie et biologie moléculaire, Centre de Biologie Sud Centre Hospitalier Lyon Sud, 69495 Pierre Bénite Cedex, France.

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http://dx.doi.org/10.1515/cclm-2018-0871DOI Listing
May 2019

Isolated elevation of thyroglobulin in the follow-up of differentiated thyroid cancer, does it always indicate true persistent disease?

Ann Endocrinol (Paris) 2019 Feb 25;80(1):61. Epub 2018 Sep 25.

Fédération d'endocrinologie, CHU de Lyon, 59, boulevard Pinel, 69677 Bron, France.

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http://dx.doi.org/10.1016/j.ando.2018.09.005DOI Listing
February 2019

Impaired histaminergic neurotransmission in children with narcolepsy type 1.

CNS Neurosci Ther 2019 03 17;25(3):386-395. Epub 2018 Sep 17.

Integrative Physiology of the Brain Arousal System, CRNL, INSERM-U1028, CNRS, UMR5292, University Lyon1, Lyon, France.

Objective: Narcolepsy is a sleep disorder characterized in humans by excessive daytime sleepiness and cataplexy. Greater than fifty percent of narcoleptic patients have an onset of symptoms prior to the age of 18. Current general agreement considers the loss of hypothalamic hypocretin (orexin) neurons as the direct cause of narcolepsy notably cataplexy. To assess whether brain histamine (HA) is also involved, we quantified the cerebrospinal fluid (CSF) levels of HA and tele-methylhistamine (t-MeHA), the direct metabolite of HA between children with orexin-deficient narcolepsy type 1 (NT1) and controls.

Methods: We included 24 children with NT1 (12.3 ± 3.6 years, 11 boys, 83% cataplexy, 100% HLA DQB1*06:02) and 21 control children (11.2 ± 4.2 years, 10 boys). CSF HA and t-MeHA were measured in all subjects using a highly sensitive liquid chromatographic-electrospray/tandem mass spectrometric assay. CSF hypocretin-1 values were determined in the narcoleptic patients.

Results: Compared with the controls, NT1 children had higher CSF HA levels (771 vs 234 pmol/L, P < 0.001), lower t-MeHA levels (879 vs 1924 pmol/L, P < 0.001), and lower t-MeHA/HA ratios (1.1 vs 8.2, P < 0.001). NT1 patients had higher BMI z-scores (2.7 ± 1.6 vs 1.0 ± 2.3, P = 0.006) and were more often obese (58% vs 29%, P = 0.05) than the controls. Multivariable analyses including age, gender, and BMI z-score showed a significant decrease in CSF HA levels when the BMI z-score increased in patients (P = 0.007) but not in the controls. No association was found between CSF HA, t-MeHA, disease duration, age at disease onset, the presence of cataplexy, lumbar puncture timing, and CSF hypocretin levels.

Conclusions: Narcolepsy type 1 children had a higher CSF HA level together with a lower t-MeHA level leading to a significant decrease in the t-MeHA/HA ratios. These results suggest a decreased HA turnover and an impairment of histaminergic neurotransmission in narcoleptic children and support the use of a histaminergic therapy in the treatment against narcolepsy.
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http://dx.doi.org/10.1111/cns.13057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6488909PMC
March 2019

Diagnostic procedure in suspected Graves' disease.

Ann Endocrinol (Paris) 2018 Dec 18;79(6):608-617. Epub 2018 Aug 18.

Service d'endocrinologie, CHU de Rabat, Rabat, Morocco.

Diagnostic procedure in suspected Graves' disease has never been studied scientifically and actual practice seems quite variable, notably between countries. Recommendations are few and weak (expert opinion). This article presents the recommendations of an expert consensus meeting organized by the French Society of Endocrinology in 2016. In case of clinically suspected thyrotoxicosis, the first-line biological assessment is of thyroid-stimulating hormone (TSH). Free T4 and possibly free T3 assays assess biological severity and are necessary for treatment efficacy monitoring. Positive diagnosis of Graves' disease after biological confirmation of thyrotoxicosis does not always require complementary etiological examinations if clinical presentation is unambiguous, notably including extra-thyroid signs. Otherwise, first-line anti-TSH-receptor (TSH-R) antibody screening is recommended for its good intrinsic performance (sensitivity and specificity) and ease of access in France. Scintigraphy is reserved to rare cases of Graves' disease with negative antibody findings or when another etiology is suspected. Thyroid ultrasound scan may be contributive, but is not recommended in first line.
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http://dx.doi.org/10.1016/j.ando.2018.08.002DOI Listing
December 2018

Expert opinions on endocrine toxicity induced by new anticancer therapies: Precautions to be taken in performing and interpreting hormonal assays under immunotherapy.

Ann Endocrinol (Paris) 2018 Oct 11;79(5):550-554. Epub 2018 Jul 11.

Laboratoire d'hormonologie, service de biochimie et biologie moléculaire, CHU de Lyon, groupement hospitalier Est, 69008 Lyon, France.

As well as tyrosine kinase and mTOR inhibitors, new anticancer therapies make use of antibodies targeting tyrosine kinase receptors or blocking anti-tumor immune response checkpoints. These are always monoclonal; in their international non-proprietary names, the origin is prefixed to "-mab": e.g., mouse antibodies end in "o-mab", chimeric antibodies in "xi-mab", humanized antibodies in "zu-mab" and human antibodies in "u-mab". When the analytic principle of the assay involves a murine monoclonal antibody and the therapeutic antibody contains a murine sequence, analytic interference is to be feared if the patient develops antibodies against the therapeutic antibody. The interfering heterophilic antibody may be a HAMA (anti-mouse), a HACA (anti-chimeric) or a HAHA (anti-humanized-antibody). In immunoassay for patients under immunotherapy, it is therefore recommended to check the type of therapeutic antibody: if it is liable to contain murine sequences, heterophilic antibodies should be screened for and neutralized.
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http://dx.doi.org/10.1016/j.ando.2018.07.004DOI Listing
October 2018

Endocrine side-effects of new anticancer therapies: Overall monitoring and conclusions.

Ann Endocrinol (Paris) 2018 Oct 11;79(5):591-595. Epub 2018 Jul 11.

HESPER EA 7425, université Claude-Bernard Lyon 1, hospices civils de Lyon, fédération d'endocrinologie, 69008 Lyon, France.

The present final consensus statement of the French Society of Endocrinology lays out the assessments that are to be systematically performed before and during anticancer treatment by immunotherapy, tyrosine kinase inhibitors or mTOR inhibitors, even without onset of any endocrinopathy. It also discusses the CTCAE adverse event grading system in oncology and the difficulty of implementing it for endocrine side-effects of these anticancer treatments. Notably, this is why certain treatment steps applied in other side-effects (e.g., high-dose corticosteroids, contraindications to immunotherapy, etc.) need to be discussed before implementation for endocrine side-effects.
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http://dx.doi.org/10.1016/j.ando.2018.07.005DOI Listing
October 2018

MANAGEMENT OF ENDOCRINE DISEASE Hyperandrogenic states in women: pitfalls in laboratory diagnosis.

Eur J Endocrinol 2018 Apr 16;178(4):R141-R154. Epub 2018 Feb 16.

Laboratoire d'Hormonologie, d'Endocrinologie Moléculaire et des Maladies Rares, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France.

Measuring total testosterone level is the first-line approach in assessing androgen excess in women. The main pitfalls in measuring testosterone relate to its low concentration and to the structural similarity between circulating androgens and testosterone, requiring accurate techniques with high specificity and sensitivity. These goals can be achieved by immunoassay using a specific anti-testosterone monoclonal antibody, ideally after an extraction step. Liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) will be commonly used for measuring testosterone, providing optimal accuracy with a low limit of detection. Yet, the pitfalls of these two techniques are well identified and must be recognized and systematically addressed. In general, laboratories using direct testosterone immunoassay and mass spectrometry need to operate within a quality framework and be actively engaged in external quality control processes and standardization, so as to ensure appropriate interpretation irrespective of the particular laboratory. Circulating testosterone is strongly bound to sex-hormone-binding globulin (SHBG), and SHBG levels are typically low in overweight hyperandrogenic patients. Thus, low SHBG may decrease circulating testosterone to normal values, which will mask androgen excess status. One way to avoid this pitfall, awaiting direct free testosterone assays that are yet to be developed, is to measure SHBG and calculate free testosterone. A few other pitfalls will be discussed in this review, including those of adrenal androgen exploration, with the aim of helping clinicians to better handle laboratory investigation of androgen excess disorders in women.
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http://dx.doi.org/10.1530/EJE-17-0776DOI Listing
April 2018

Multi-System Deconditioning in 3-Day Dry Immersion without Daily Raise.

Front Physiol 2017 13;8:799. Epub 2017 Oct 13.

Centre de Recherche Clinique, Centre Hospitalier Universitaire d'Angers, Angers, France.

Dry immersion (DI) is a Russian-developed, ground-based model to study the physiological effects of microgravity. It accurately reproduces environmental conditions of weightlessness, such as enhanced physical inactivity, suppression of hydrostatic pressure and supportlessness. to study the integrative physiological responses to a 3-day strict DI protocol in 12 healthy men, and to assess the extent of multi-system deconditioning. We recorded general clinical data, biological data and evaluated body fluid changes. Cardiovascular deconditioning was evaluated using orthostatic tolerance tests (Lower Body Negative Pressure + tilt and progressive tilt). Metabolic state was tested with oral glucose tolerance test. Muscular deconditioning was assessed via muscle tone measurement. Orthostatic tolerance time dropped from 27 ± 1 to 9 ± 2 min after DI. Significant impairment in glucose tolerance was observed. Net insulin response increased by 72 ± 23% on the third day of DI compared to baseline. Global leg muscle tone was approximately 10% reduced under immersion. Day-night changes in temperature, heart rate and blood pressure were preserved on the third day of DI. Day-night variations of urinary K diminished, beginning at the second day of immersion, while 24-h K excretion remained stable throughout. Urinary cortisol and melatonin metabolite increased with DI, although within normal limits. A positive correlation was observed between lumbar pain intensity, estimated on the second day of DI, and mean 24-h urinary cortisol under DI. , DI represents an accurate and rapid model of gravitational deconditioning. The extent of glucose tolerance impairment may be linked to constant enhanced muscle inactivity. Muscle tone reduction may reflect the reaction of postural muscles to withdrawal of support. Relatively modest increases in cortisol suggest that DI induces a moderate stress effect. , this advanced ground-based model is extremely suited to test countermeasures for microgravity-induced deconditioning and physical inactivity-related pathologies.
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http://dx.doi.org/10.3389/fphys.2017.00799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5645726PMC
October 2017

Low cerebrospinal fluid hypocretin levels during sudden infant death syndrome (SIDS) risk period.

Sleep Med 2017 05 8;33:57-60. Epub 2017 Feb 8.

Integrative Physiology of Brain Arousal System, CRNL, INSERM-U1028, CNRS UMR5292, University Lyon 1, Lyon, France; Centre de biologie et d'anatomopathologie, Groupement Hospitalier Est, Lyon, France. Electronic address:

Objectives: The temporal association between sudden infant death syndrome (SIDS) and sleep suggests that the arousability from sleep provides a protective mechanism for survival. Recently, the hypocretin system, which promotes wakefulness, has been implicated in SIDS, since it has been reported that SIDS victims have fewer hypocretin neurons than infants who have died from other causes. To understand the role of hypocretin in SIDS, it is essential to better understand how this system matures. The present study compared cerebrospinal fluid (CSF) hypocretin in children aged 2-6 months, which is the age of peak incidence for SIDS, to both younger and older children.

Method: Hypocretin levels were measured in CSF samples from 101 children who underwent a clinically relevant lumbar puncture. Children were separated into five age groups: 0-2 months, 2-6 months, 1-5 years, 5-10 years, and 10-18 years.

Results: Hypocretin levels were not significantly different between 1-5 years, 5-10 years, and 10-18 years. Therefore, these three groups were pooled into a single one (1-18 years) for further analysis. Between the 0-2 month, 2-6 month, and 1-18 year groups, a significant difference in CSF hypocretin levels existed (p = 0.001). Simple comparisons showed that CSF hypocretin levels in the 2-6 month age group were significantly lower than hypocretin levels in both the 0-2 month and 1-18 year group (p < 0.001 and p = 0.008, respectively), but not significantly between 0-2 month and 1-18 year children.

Conclusions: The CSF hypocretin levels were lower at the age of peak incidence for SIDS. This could underlie an increased vulnerability to SIDS at this specific age.
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http://dx.doi.org/10.1016/j.sleep.2016.12.027DOI Listing
May 2017

Establishment of revised diagnostic cut-offs for adrenal laboratory investigation using the new Roche Diagnostics Elecsys Cortisol II assay.

Ann Endocrinol (Paris) 2016 Oct 19;77(5):620-622. Epub 2016 Jul 19.

Fédération d'endocrinologie, hospices civils de Lyon, 59, boulevard Pinel, 69677 Bron cedex, France; Faculté de médecine Lyon-Est, université Lyon 1, 69372 Lyon, France.

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http://dx.doi.org/10.1016/j.ando.2016.05.002DOI Listing
October 2016

Differential Effects of PI3K and Dual PI3K/mTOR Inhibition in Rat Prolactin-Secreting Pituitary Tumors.

Mol Cancer Ther 2016 06 16;15(6):1261-70. Epub 2016 Mar 16.

INSERM U1052, CNRS UMR5286, Cancer Research Center of Lyon, Lyon, France. Université Lyon 1, Lyon, France. Fédération d'Endocrinologie, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France.

Aggressive pituitary tumors are rare but difficult to manage, as there is no effective chemotherapy to restrict their growth and cause their shrinkage. Within these tumors, growth-promoting cascades, like the PI3K/mTOR pathway, appear to be activated. We tested the efficacy of two inhibitors of this pathway, NVP-BKM120 (Buparlisib; pan-PI3K) and NVP-BEZ235 (dual PI3K/mTOR), both in vitro on immortalized pituitary tumor cells (GH3) and on primary cell cultures of human pituitary tumors and in vivo on a rat model of prolactin (PRL) tumors (SMtTW3). In vitro, NVP-BEZ235 had a potent apoptotic and cytostatic effect that was characterized by decreased cyclin D/E and Cdk4/2 protein levels and subsequent accumulation of cells in G1 In vivo, the effect was transient, with a decrease in mitotic index and increase in apoptosis; long-term treatment had no significant inhibitory effect on tumor growth. In contrast, while NVP-BKM120 had little effect in vitro, it dramatically limited tumor growth in vivo Increased Akt phosphorylation observed only in the NVP-BEZ235-treated tumors may explain the differential response to the two inhibitors. Primary cell cultures of human PRL pituitary tumors responded to NVP-BEZ235 with reduced cell viability and decreased hormone secretion, whereas NVP-BKM120 had little effect. Altogether, these results show a potential for PI3K inhibitors in the management of aggressive pituitary tumors. Mol Cancer Ther; 15(6); 1261-70. ©2016 AACR.
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http://dx.doi.org/10.1158/1535-7163.MCT-15-0891DOI Listing
June 2016

pNET co-secreting GHRH and calcitonin: ex vivo hormonal studies in human pituitary cells.

Endocrinol Diabetes Metab Case Rep 2016 5;2016:150134. Epub 2016 Feb 5.

Endocrinology, Diabetes and Metabolic Unit, Kaplan Medical Center, Hebrew University Medical School of Jerusalem , Bilu 176100, Rehovot , Israel.

Unlabelled: Acromegaly due to ectopic GHRH secretion from a neuroendocrine tumor (NET) is rare and comprises <1% of all acromegaly cases. Herein we present a 57-year-old woman with clinical and biochemical features of acromegaly and a 6 cm pancreatic NET (pNET), secreting GHRH and calcitonin. Following surgical resection of the pancreatic tumor, IGF1, GH and calcitonin normalized, and the clinical features of acromegaly improved. In vitro studies confirmed that the tumor secreted large amounts of both GHRH and calcitonin, and incubation of pNET culture-derived conditioned media stimulated GH release from a cultured human pituitary adenoma. This is a unique case of pNET secreting both GHRH and calcitonin. The ability of the pNET-derived medium to stimulate in vitro GH release from a human pituitary-cell culture, combined with the clinical and hormonal remission following tumor resection, confirmed the ectopic source of acromegaly in this patient.

Learning Points: Signs, symptoms and initial work-up of acromegaly due to ectopic GHRH secretion are similar to pituitary-dependent acromegaly. However, if no identifiable pituitary lesion is found, somatostatin receptor scan and further imaging (CT, MRI) should be performed.Detection of GHRH in the blood and in the tumor-derived medium supports the diagnosis of ectopic GHRH secretion.Functional bioactivity of pNET-secreted GHRH can be proved in vitro by releasing GH from human pituitary cells.
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http://dx.doi.org/10.1530/EDM-15-0134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4762224PMC
February 2016

GHRH excess and blockade in X-LAG syndrome.

Endocr Relat Cancer 2016 Mar 15;23(3):161-70. Epub 2015 Dec 15.

Department of EndocrinologyCentre Hospitalier Universitaire de Liège, University of Liège, Domaine Universitaire du Sart-Tilman, 4000 Liège, BelgiumDepartment of Human GeneticsCentre Hospitalier Universitaire de Liège, University of Liège, Domaine Universitaire du Sart-Tilman, 4000 Liège, BelgiumPediatric Endocrinology UnitUniversité Catholique de Louvain, Avenue Hippocrate 10, 1200 Brussels, BelgiumCliniques Universitaires Saint Luc and Department of PathologyUniversité Catholique de Louvain, Avenue Hippocrate 10, 1200 Brussels, BelgiumLaboratory of Molecular BiologyAPHM, Hôpital la Conception, 13385, Marseille, FranceAix Marseille UniversitéCRNS, CRN2M-UMR 7286, 13344, Marseille, FranceSection on Endocrinology and GeneticsProgram on Developmental Endocrinology and Genetics (PDEGEN) and Pediatric Endocrinology Inter-institute Training Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland 20892, USALaboratoire d'Hormonologie - CBPEGroupement Hospitalier Est, Hospices Civils de Lyon, 59 bd Pinel - 69677 Bron Cedex, FranceUniversité Catholique de LouvainPole d'endocrinologie, diabete et nutrition (EDIN), Brussels, BelgiumDepartment of NeurosurgeryUniversité Catholique de Louvain, Brussels, Belgium.

X-linked acrogigantism (X-LAG) syndrome is a newly described form of inheritable pituitary gigantism that begins in early childhood and is usually associated with markedly elevated GH and prolactin secretion by mixed pituitary adenomas/hyperplasia. Microduplications on chromosome Xq26.3 including the GPR101 gene cause X-LAG syndrome. In individual cases random GHRH levels have been elevated. We performed a series of hormonal profiles in a young female sporadic X-LAG syndrome patient and subsequently undertook in vitro studies of primary pituitary tumor culture following neurosurgical resection. The patient demonstrated consistently elevated circulating GHRH levels throughout preoperative testing, which was accompanied by marked GH and prolactin hypersecretion; GH demonstrated a paradoxical increase following TRH administration. In vitro, the pituitary cells showed baseline GH and prolactin release that was further stimulated by GHRH administration. Co-incubation with GHRH and the GHRH receptor antagonist, acetyl-(d-Arg(2))-GHRH (1-29) amide, blocked the GHRH-induced GH stimulation; the GHRH receptor antagonist alone significantly reduced GH release. Pasireotide, but not octreotide, inhibited GH secretion. A ghrelin receptor agonist and an inverse agonist led to modest, statistically significant increases and decreases in GH secretion, respectively. GHRH hypersecretion can accompany the pituitary abnormalities seen in X-LAG syndrome. These data suggest that the pathology of X-LAG syndrome may include hypothalamic dysregulation of GHRH secretion, which is in keeping with localization of GPR101 in the hypothalamus. Therapeutic blockade of GHRH secretion could represent a way to target the marked hormonal hypersecretion and overgrowth that characterizes X-LAG syndrome.
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http://dx.doi.org/10.1530/ERC-15-0478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6300999PMC
March 2016

Performance of the 4-mg intravenous dexamethasone suppression test in differentiating Cushing disease from pseudo-Cushing syndrome.

Ann Endocrinol (Paris) 2016 Feb 3;77(1):30-6. Epub 2015 Dec 3.

Fédération d'endocrinologie, groupement hospitalier Est, Hospices Civils de Lyon, 69500 Bron, France; Service de biostatistique, Hospices Civils de Lyon, 69003 Lyon, France; Université de Lyon, 69000 Lyon, France; Inserm, U1028, 69008 Lyon, France. Electronic address:

Context: Discriminating Cushing disease (CD) from pseudo-Cushing syndrome (PCS) is a challenging task that may be overcome with the 4-mg intravenous (IV) dexamethasone suppression test (DST).

Objective: Assess the performance of the 4-mg IV DST in the differential diagnosis between CD and PCS in well-characterized patients.

Design: Retrospective comparative study of subjects seen in a tertiary care unit (November 2008 to July 2011).

Methods: Thirty-six patients with PCS and 32 patients with CD underwent 4-mg IV dexamethasone infusions from 11 am to 3 pm. Areas Under ROC Curves (AUCs) were estimated and compared for ACTH and cortisol measured at 4 pm the same day (day 1) and 8 am the next day (day 2). The ROC curve of the marker with the highest AUC was used to determine the threshold with the highest specificity for 100% sensitivity.

Results: The AUC of ACTH at 8 am on day 2 was estimated at 98.4% (95% CI: [92.1-100]), which is significantly greater than that of ACTH at 4 pm on day 1 (P=0.04) and that of cortisol at 8 am on day 2 (P=0.05). For ACTH at 8 am on day 2, the threshold with the highest specificity for 100% sensitivity was estimated at 14.8 ng/L. At this threshold, the sensitivity was estimated at 100% [89-100] and the specificity at 83.3% [67-94].

Conclusion: The 4-mg IV DST is an easy and accurate tool in distinguishing CD from PCS. It deserves thus a better place in establishing the diagnosis of CD.
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http://dx.doi.org/10.1016/j.ando.2015.11.001DOI Listing
February 2016

Effect of dietary protein on plasma insulin-like growth factor-1, growth, and body composition in healthy term infants: a randomised, double-blind, controlled trial (Early Protein and Obesity in Childhood (EPOCH) study).

Br J Nutr 2016 Jan 20;115(2):271-84. Epub 2015 Nov 20.

1Service de Neonatologie,Hopital de la Croix-Rousse,Hospices Civils de Lyon,F-69004 Lyon,France.

The effect of protein intake on growth velocity in infancy may be mediated by insulin-like growth factor-1 (IGF-1). This study aimed to determine the effects of formulae containing 1·8 (F1·8) or 2·7 g (F2·7) protein/418·4 kJ (100 kcal) on IGF-1 concentrations and growth. Healthy term infants were randomly assigned to receive F1·8 (n 74) or F2·7 (n 80) exclusively for the first 4 months of life. A group of breast-fed infants (n 84) was followed-up simultaneously (reference). Growth and body composition were measured at 0·5, 4, 6, 12, 36, 48 and 60 months of life. The IGF-1 concentrations at 4 months (primary outcome) were similar in the F1·8 (67·1 (sd 20·8) ng/l; n 70) and F2·7 (71·2 (sd 27·5) ng/l; n 73) groups (P=0·52). Both formula groups had higher IGF-1 concentrations than the breast-fed group at 4 and 9 months of age (P≤0·0001). During the first 60 months of life, anthropometric parameters in the F1·8 group were lower compared with the F2·7 group, and the differences were significant for head circumference from 2 to 60 months, body weight at 4 and 6 months and length at 9, 12 and 36 months of age. There were no significant differences in body composition between these two groups at any age. We conclude that, in formula-fed infants, although increased protein intake did not affect the IGF-1 concentration during the first 12 months of life, it did affect length and head circumference growth, suggesting that factors other than IGF-1 could play roles in determining growth velocity.
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http://dx.doi.org/10.1017/S0007114515004456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4697297PMC
January 2016

High bicarbonate levels in narcoleptic children.

J Sleep Res 2016 Apr 17;25(2):194-202. Epub 2015 Nov 17.

Integrative Physiology of Brain Arousal System, CRNL, INSERM-U1028, University Lyon1, Lyon, France.

The objective of this study was to evaluate the levels of plasma bicarbonate levels in narcoleptic children. Clinical, electrophysiological data and bicarbonate levels were evaluated retrospectively in children seen in our paediatric national reference centre for hypersomnia. The cohort included 23 control subjects (11.5 ± 4 years, 43% boys) and 51 patients presenting de-novo narcolepsy (N) (12.7 ± 3.7 years, 47% boys). In narcoleptic children, cataplexy was present in 78% and DQB1*0602 was positive in 96%. The control children were less obese (2 versus 47%, P = 0.001). Compared with control subjects, narcoleptic children had higher bicarbonate levels (P = 0.02) as well as higher PCO2 (P < 0.01) and lower venous pH gas (P < 0.01). Bicarbonate levels higher than 27 mmol L(-1) were found in 41.2% of the narcoleptic children and 4.2% of the controls (P = 0.001). Bicarbonate levels were correlated with the Adapted Epworth Sleepiness Scale (P = 0.01). Narcoleptic patients without obesity often had bicarbonate levels higher than 27 mmol L (-1) (55 versus 25%, P = 0.025). No differences were found between children with and without cataplexy. In conclusion, narcoleptic patients had higher bicarbonate plasma levels compared to control children. This result could be a marker of hypoventilation in this pathology, provoking an increase in PCO2 and therefore a respiratory acidosis, compensated by an increase in plasma bicarbonates. This simple screening tool could be useful for prioritizing children for sleep laboratory evaluation in practice.
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http://dx.doi.org/10.1111/jsr.12357DOI Listing
April 2016