Jean-Benoît Corcuff

Fat distribution in obese women is associated with subtle alterations of the hypothalamic–pituitary–adrenal axis activity and sensitivity to glucocorticoids

OBJECTIVES Obesity with abdominal body fat distribution (A‐BFD) and hypothalamic‐pituitary‐adrenal (HPA) axis activity are somehow linked, but the exact interactions still need clarification. Obese subjects display normal circulating plasma cortisol concentrations with normal circadian rhythms. However, when the HPA axis is pharmacologically challenged, body fat distribution matters and then A‐BFD obese women differ from those with subcutaneous body fat distribution (P‐BFD). We hypothesized that lower dose provocative and suppressive tests than those used to diagnose hypercortisolism of tumour origin or adrenal insufficiency would shed some light on the characteristics of the HPA axis activity in relation with body fat distribution.

Molecular genetics of hypothalamic–pituitary–adrenal axis activity and function

The hypothalamic–pituitary–adrenocortical (HPA) axis is a major neuroendocrine system involved in the regulation of numerous physiological processes and in adaptation to stress. A wide range of variability can be observed in all the components of the system, and the contribution of genetic factors has been shown in the central regulation of the axis, the production of glucocorticoid hormones by the adrenal cortex, their bioavailability, and the efficiency of their action at the level of receptor and postreceptor mechanisms. Numerous molecular polymorphisms have been described that contribute to physiological variation as well as to HPA axis‐related pathological conditions. Although most studies focus on single gene polymorphisms, future studies should aim to integrate the different sources of variation into a systems genetic model to take into account the strong interdependence of the different components of the axis.

Lessons from an unpleasant surprise: a biochemical strategy for the diagnosis of pheochromocytoma.

Objective To audit the performances of the analytes used in the diagnosis of pheochromocytoma and to present a graphical guideline to help the diagnosis. Design A 5 year retrospective study. Settings Laboratory and departments of a university hospital. Participants In-patients, suspected of bearing a pheochromocytoma, were investigated for urinary metanephrines and catecholamines (photometric method) and vanillylmandelic acid, fractionated catecholamines and metanephrines [high pressure liquid chromatography (HPLC) coupled to electrochemical detection (ED)] urinary excretion. Main outcome Patients with a pheochromocytoma (24 out of 2003 patients) were diagnosed by the combination of normetanephrine and metanephrine determination. Results All analytes but dopamine were significantly elevated in patients with a pheochromocytoma. The area under the receiver operating characteristics (ROC) curves were the highest for total metanephrines, normetanephrine and metanephrine determinations. Because of analytical interferences in the metanephrines determination, the normetanephrine and metanephrine performed better. It is noteworthy that all pheochromocytomas had either normetanephrine or metanephrine levels above their respective optimal threshold (sensitivity 100%). The best optimal threshold performance was reached by the mean of three daily samples. Total or fractionated catecholamines or vanillylmandelic acid were less accurate tools. Conclusion Amongst urinary tests, the combined use of HPLC/ED determination of normetanephrine and metanephrine seems the most effective screening strategy for the diagnosis of pheochromocytoma. The older total metanephrine photometric assay is grieved by analytical interferences.

Overnight urinary free cortisol determination: A screening test for the diagnosis of Cushing's syndrome

The collection of urine over 24 h to measure free cortisol (UFC) is used to diagnose Cushings syndrome. However, a complete collection of urine is not easy to achieve and the sampling is frequently inaccurate, so a 24 h collection for the determination of UFC excretion is used as a confirmatory rather than a screening test for Cushings syndrome. Our objective was to evaluate a more convenient urine collection for screening patients suspected of Cushings syndrome.

Comparative values of catecholamines and metabolites for the diagnosis of neuroblastoma

In order to diagnose neuroblastomas, we assayed the three adrenal hormones and five of their metabolites by high-performance liquid chromatography followed by electrochemical detection in urine samples of 395 children with tumours of unknown nature (including 29 neuroblastomas). The analytes (expressed as analyte/creatinine ratios) performances were determined by calculating the related sensitivity and specificity and receiver operating characteristics curves within the different age groups. Normetanephrine (NME), vanillylmandelic and homovanillic acids (VMA, HVA) were the best analytes. Calculated optimal thresholds (best specificity/sensitivity couples) of these analytes minimised the number of false-positive diagnosis. Conclusion: combined determination of normetanephrine with vanillylmandelic acid (0–1 year) or homovanillic acid (1–5 years and 5–10 years) further enhanced the diagnostic power up to 100% sensitivity and specificity of the testing depending on the age group. Plotting individual levels (normetanephrine versus vanillylmandelic acid or homovanillic acid) allowed a rapid visual analysis that would have missed only one small low grade non-secreting tumour.

Assessment of brain natriuretic peptide in patients with suspected heart failure: comparison with radionuclide ventriculography data

BACKGROUND The aim of the study was to prospectively evaluate patients with suspected or known heart disease using plasma brain natriuretic peptide (BNP) measurement and radionuclide ventriculography to examine whether left ventricular dysfunction is associated with an abnormal rise of BNP concentration. METHODS Patients (n=153) and controls (n=14) underwent radionuclide ventriculography to determine Left ventricular Ejection Fraction (LVEF) and measurement of plasma BNP concentration using a commercial kit. RESULTS Plasma BNP concentration in controls was significantly lower than that in patients whatever the stage of the disease, significantly lower than that of patients with normal LVEF (LVEF>55%); than that of patients with altered LVEF (LVEF< or =40%); and than that of patients with moderately reduced LVEF (40%<LVEF< or =5%). Comparisons between groups of patients showed that the more severe the disease, the higher the BNP level. From the ROC curve, a plasma BNP concentration of 52 pg/ml was attached to a 85% sensitivity and 82% specificity in identifying patients with LVEF< or =40%. CONCLUSIONS Plasma BNP concentration provides a reliable and sensitive marker of LV systolic dysfunction evaluated by a nuclear medicine technique, and could be a potential screening test to identify patients for additional investigations.

Oral contraception but not menstrual cycle phase is associated with increased free cortisol levels and low hypothalamo-pituitary-adrenal axis reactivity

Background: In females, estrogen is a potential modulator of cortisol response to stressors. The aim of this study was to determine the influence of menstrual cycle phase, oral contraception (OC) use and exercise training on hypothalamo-pituitary-adrenal (HPA) axis activity and reactivity after physical stress. Aim: We investigated the effects of the menstrual cycle and OC use on exhaustive exercise-induced changes in free salivary cortisol concentrations and free urinary cortisol/cortisone excretion in healthy young women. Materials and subjects: Twenty-eight women were allocated to an untrained group (no.=16) or a trained group (no.=12), depending on their physical training background. The untrained group was composed of nine OC users (UNT-OC+) and seven eumenorrheic women (UNT-OC−) tested in the follicular and luteal phases, while the trained group was entirely composed of OC+ subjects (T-OC+). Methods: Three laboratory sessions were conducted in a randomised order: a prolonged exercise test, a short-term exercise test, and a control session. For each session, urine and saliva specimens were collected at rest (09: 00 h) and then, 30, 60 and 90 min later. Results: Estradiol fluctuation during the menstrual cycle phase did not alter free cortisol baseline values and responses to exercise. OC use was associated with increased free resting salivary concentrations and urinary cortisol excretion with blunted salivary cortisol response to prolonged exercise stimulation. No training effect was noted. Conclusions: OC but not menstrual cycle phase is associated with increased free cortisol levels and low HPA axis reactivity.

Per-operative Hemodynamic Instability in Normotensive Patients With Incidentally Discovered Pheochromocytomas

CONTEXT The per-operative hemodynamic behavior of normotensive incidentally discovered pheochromocytomas is poorly documented. OBJECTIVE To compare the per-operative hemodynamic instability and early postoperative outcome of normotensive pheochromocytomas, hypertensive pheochromocytomas, and benign non-pheochromocytoma adrenal incidentalomas (AIs). DESIGN Retrospective cohort treated in a single center. PATIENTS AND METHODS Fifty patients (10 normotensive pheochromocytomas, 24 hypertensive pheochromocytomas, and 16 AIs) were anesthetized and operated on by the same team, using laparoscopy in 78% of cases. Before surgery, 60% of normotensive and 95.8% of hypertensive pheochromocytomas received pretreatment with α-receptor or calcium channel blockers. All of the patients received the same intraoperative hemodynamic monitoring, including continuous direct intra-arterial pressure recording. RESULTS All the features of hemodynamic instability, with the exception of the diastolic pressure nadir and fluid volume requirements, differed between hypertensive pheochromocytomas and AIs. Conversely, all features of hemodynamic instability were similar in hypertensive and normotensive pheochromocytomas. More specifically, by comparison with AIs, normotensive pheochromocytomas displayed higher maximal systolic pressure; more hypertensive, severe hypertensive, and hypotensive episodes; and a higher minimal heart rate, and also required more interventions to treat undesirable blood pressure elevations. Postoperative complications, all of which were mild, were more frequent in hypertensive pheochromocytomas than in normotensive pheochromocytomas (P < .03). CONCLUSIONS Normotensive pheochromocytomas have roughly comparable per-operative hemodynamic instability to hypertensive pheochromocytomas and differ markedly from non-pheochromocytoma AIs. It is therefore crucial to identify normotensive pheochromocytomas among AIs when surgery is scheduled and to apply the standard of care for pheochromocytoma anesthesia.

Retinoids and glucocorticoids target common genes in hippocampal HT22 cells.

Vitamin A metabolite retinoic acid (RA) plays a major role in the aging adult brain plasticity. Conversely, chronic excess of glucocorticoids (GC) elicits some deleterious effects in the hippocampus. We questioned here the involvement of RA and GC in the expression of target proteins in hippocampal neurons. We investigated proteins involved either in the signaling pathways [RA receptor β (RARβ) and glucocorticoid receptor (GR)] or in neuron differentiation and plasticity [tissue transglutaminase 2 (tTG) and brain‐derived neurotrophic factor (BDNF)] in a hippocampal cell line, HT22. We applied RA and/or dexamethasone (Dex) as activators of the pathways and investigated mRNA and protein expression of their receptors and of tTG and BDNF as well as tTG activity and BDNF secretion. Our results confirm the involvement of RA‐ and GC‐dependent pathways and their interaction in our neuronal cell model. First, both pathways regulate the transcription and expression of own and reciprocal receptors: RA and Dex increased RARβ and decreased GR expressions. Second, Dex reduces the expression of tTG when associated with RA despite stimulating its expression when used alone. Importantly, when they are combined, RA counteracts the deleterious effect of glucocorticoids on BDNF regulation and thus may improve neuronal plasticity under stress conditions. In conclusion, GC and RA both interact through regulations of the two receptors, RARβ and GR. Furthermore, they both act, synergistically or oppositely, on other target proteins critical for neuronal plasticity, tTG and BDNF.

Bioavailable estradiol in man: Relationship with age and testosterone

Sex hormones undergo decreases in aging men. Several studies have shown the association of low levels of bioavailable estradiol with osteoporosis in man. To allow a better approach of sex hormones influences, we evaluated bioavailable estradiol concentrations in men and its correlation with age and testosterone. We show that bioavailable estradiol decreases significantly with age. We provide reference values in men with normal testosterone levels.