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CONTEXT: Renin-angiotensin-aldosterone system (RAAS) activation is closely linked to obesity; however, the sex-specific associations between RAAS activity and body composition among individuals without obesity are not well understood. OBJECTIVE: To investigate the associations of aldosterone and renin with body composition according to sex in the general population. DESIGN: Population-based cohort study. SETTING: Québec (Canada). PARTICIPANTS: Adults aged 40-69 years enrolled to CARTaGENE between 2009 and 2010 (N=3,687). EXPOSURES: Plasma aldosterone and renin concentrations. MAIN OUTCOME MEASURES: Body composition assessed via anthropometrics (waist circumference and waist-to-hip ratio), bioelectrical impedance (lean body mass, fat mass, and muscle mass), and cardiac magnetic resonance imaging (epicardial and pericardial adipose tissue volumes). RESULTS: The mean (SD) age and body mass index were 55 (8) years and 27.3 (4.8) kg/m2, respectively. Among males, higher aldosterone and renin were associated with increased waist circumference, increased waist-to-hip ratio, increased fat mass, decreased lean body mass, and decreased muscle mass (p<0.05). Aldosterone (p=0.02), but not renin (p=0.43), was associated with increased ectopic cardiac adiposity in males. In contrast, higher renin (p<0.05), but not aldosterone (p≥0.05), was associated with increased waist circumference, increased waist-to-hip ratio, and increased cardiac adiposity in females. Among females, higher renin and aldosterone were associated with increased fat mass (p<0.05) but were not associated with lean body mass or muscle mass (p≥0.05). All aforementioned associations were independent of body weight. CONCLUSIONS: Independent of body weight, increased RAAS activity is associated with unfavorable differences in body composition; however, the strength and pattern of association varies by sex.
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OBJECTIVE: Primary aldosteronism (PA) is one of the most frequent causes of secondary hypertension. Although clinical practice guidelines recommend a diagnostic process, details of the steps remain incompletely standardized. DESIGN: In the present SCOT-PA survey, we have investigated the diversity of approaches utilized for each diagnostic step in different expert centers through a survey using Google questionnaires. A total of 33 centers from 3 continents participated. RESULTS: We demonstrated a prominent diversity in the conditions of blood sampling, assay methods for aldosterone and renin, and the methods and diagnostic cutoff for screening and confirmatory tests. The most standard measures were modification of antihypertensive medication and sitting posture for blood sampling, measurement of plasma aldosterone concentration (PAC) and active renin concentration by chemiluminescence enzyme immunoassay, a combination of aldosterone-to-renin ratio with PAC as an index for screening, and saline infusion test in a seated position for confirmatory testing. The cutoff values for screening and confirmatory testing showed significant variation among centers. CONCLUSIONS: Diversity of the diagnostic steps may lead to an inconsistent diagnosis of PA among centers and limit comparison of evidence for PA between different centers. We expect the impact of this diversity to be most prominent in patients with mild PA. The survey raises 2 issues: the need for standardization of the diagnostic process and revisiting the concept of mild PA. Further standardization of the diagnostic process/criteria will improve the quality of evidence and management of patients with PA.
Sujet(s)
Hyperaldostéronisme , Hypertension artérielle , Humains , Aldostérone , Rénine , Hypertension artérielle/diagnostic , Hypertension artérielle/étiologie , Enquêtes et questionnairesRÉSUMÉ
Endogenous Cushing's syndrome (CS) is rare during pregnancy, probably because hypercortisolism induces anovulation and infertility. To date, slightly above 200 cases have been reported in the literature. The most frequent etiology of CS diagnosed during gestation is from primary adrenal causes, namely adrenal adenomas and an entity called pregnancy-induced CS. The latter can be secondary to the aberrant adrenal expression of luteinizing hormone/human chorionic gonadotropin receptor (LHCGR) in the adrenal lesions. Diagnosis of CS during pregnancy is extremely challenging, as a consequence of the physiologic hypercortisolism normally present during pregnancy. Assessment of excess cortisol production tests should be interpreted cautiously using adapted upper limits of normal criteria for pregnant patients and a high index of suspicion is required for diagnosis. Imaging is also limited due to high risk of radiation exposure with computed tomography and teratogenicity with contrast agents. The optimal treatment strategy is surgical resection of adrenal adenoma or pituitary adenoma, ideally before 24 weeks of gestation to reduce the risk of maternal and fetal complications. In mild cases, surgery can be postponed until after delivery and treatment should focus on controlling metabolic complications of hypercortisolism, such as hypertension and dysglycemia. Maternal and fetal outcomes of excess cortisol exposure, except fetal loss, are not readily improved by successful treatment of hypercortisolism.
Sujet(s)
Adénomes , Syndrome de Cushing , Hypertension artérielle , Grossesse , Femelle , Humains , Syndrome de Cushing/diagnostic , Syndrome de Cushing/étiologie , HydrocortisoneRÉSUMÉ
Cushing's syndrome (CS) is associated with multisystemic complications; the hematological system is not spared. Alteration in hemostatic parameters and in vivo endothelial dysfunction lead to increased thrombotic events. Arterial and venous thrombotic events carry significant morbidity and mortality. Death from cardiovascular and pulmonary embolism account for more than 50% of mortality. Surgery is a critical period; close to 50% of events occur in the 1-2 months after intervention. The evaluation and risk stratification of patients with CS is key to prevent events, balancing the risk-benefit of anticoagulation in this population. This current review will focus on up-to-date data on epidemiology, pathophysiology and management of hypercoagulability in CS.
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Syndrome de Cushing , Thrombophilie , Thromboembolisme veineux , Syndrome de Cushing/complications , Syndrome de Cushing/épidémiologie , Humains , Morbidité , Appréciation des risques , Thrombophilie/épidémiologie , Thrombophilie/étiologie , Thromboembolisme veineux/épidémiologie , Thromboembolisme veineux/étiologieRÉSUMÉ
CONTEXT: In primary aldosteronism (PA), aldosterone secretion is relatively independent of the renin-angiotensin system, but can be regulated by several other stimuli. OBJECTIVE: To evaluate aldosterone response to several stimuli in a series of patients with PA secondary either to bilateral adrenal hyperplasia (BAH) or unilateral aldosterone-producing adenoma (APA). DESIGN AND SETTING: Prospective cohort study conducted in a university teaching hospital research center. PATIENTS: Forty-three patients with confirmed PA and subtyped by adrenal vein sampling (n = 39) were studied, including 11 with BAH, 28 with APA, and 4 with undefined etiology. We also studied 4 other patients with aldosterone and cortisol cosecretion. INTERVENTIONS: We systematically explored aberrant regulation of aldosterone using an in vivo protocol that included the following stimulation tests performed over 3 days under dexamethasone suppression: upright posture, mixed meal, adrenocorticotropin (ACTH) 1-24, gonadotropin-releasing hormone (GnRH), vasopressin, and serotonin R4 agonist. MAIN OUTCOME MEASURES: Positive response was defined as >50% renin or ACTH-independent increase in plasma aldosterone/cortisol concentration following the various stimulation tests. RESULTS: Renin-independent aldosterone secretion increased in response to several aberrant stimuli (upright posture, GnRH) in up to 83% of patients with APA or BAH in whom ACTH 1-24 and HT4R agonists also produced aldosterone oversecretion in all patients. The mean significant aberrant responses per patient was similar in BAH (4.6) and in APA (4.0). CONCLUSIONS: Aldosterone secretion in PA is relatively autonomous from the renin-angiotensin system, but is highly regulated by several other stimuli, which contributes to the large variability of aldosterone levels in PA patients.
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Aldostérone/métabolisme , Hyperaldostéronisme/épidémiologie , Hyperaldostéronisme/métabolisme , Tumeurs corticosurrénaliennes/épidémiologie , Tumeurs corticosurrénaliennes/métabolisme , Glandes surrénales/métabolisme , Glandes surrénales/anatomopathologie , Adénome corticosurrénalien/épidémiologie , Adénome corticosurrénalien/métabolisme , Adulte , Sujet âgé , Aldostérone/sang , Techniques de diagnostic endocrinien , Femelle , Hormone de libération des gonadotrophines , Humains , Hydrocortisone/sang , Hyperaldostéronisme/sang , Hyperaldostéronisme/diagnostic , Hyperplasie/métabolisme , Hyperplasie/anatomopathologie , Mâle , Voies et réseaux métaboliques/physiologie , Adulte d'âge moyen , Stimulation physique/méthodes , Prévalence , Études prospectives , Québec/épidémiologie , Rénine/sangRÉSUMÉ
CONTEXT: Unilateral aldosteronomas should suppress renin and contralateral aldosterone secretion. Complete aldosterone suppression in contralateral adrenal vein sample (AVS) could predict surgical outcomes. OBJECTIVES: To retrospectively evaluate the prevalence of basal contralateral suppression using Aldosterone (A)contralateral(CL)/Aperipheral(P) as compared to (A/Cortisol(C)CL)/(A/C)P ratio in primary aldosteronism (PA) patients studied in two Canadian centers. To determine the best cut-off to predict clinical and biochemical surgical cure. To compare the accuracy of ACL/AP to the basal and post-ACTH lateralization index (LI) in predicting surgical cure. METHODS: In total, 330 patients with PA and successful AVS were included; 124 lateralizing patients underwent surgery. Clinical and biochemical cure at 3 and 12 months were evaluated using the PASO criteria. RESULTS: Using ACL/AP and (A/C)CL/(A/C)P at the cut-off of 1, the prevalence of contralateral suppression was 6 and 45%, respectively. Using ROC curves, the ACL/AP ratio is associated with clinical cure at 3 and 12 months and biochemical cure at 12 months. (A/C)CL/(A/C)P is associated with biochemical cure only. The cut-offs for ACL/AP offering the best sensitivity (Se) and specificity (Sp) for clinical and biochemical cures at 12 months are 2.15 (Se: 63% and Sp: 71%) and 6.15 (Se: 84% and Sp: 77%), respectively. Basal LI and post-ACTH LI are associated with clinical cure but only the post-ACTH LI is associated with biochemical cure. CONCLUSIONS: In lateralized PA, basal contralateral suppression defined by ACL/AP is rare and incomplete compared to the (A/C)CL/(A/C)P ratio and is associated with clinical and biochemical postoperative outcome, but with modest accuracy.
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Tumeurs de la surrénale/sang , Glandes surrénales/métabolisme , Adénome corticosurrénalien/sang , Aldostérone/sang , Prélèvement d'échantillon sanguin/méthodes , Hyperaldostéronisme/sang , Hyperaldostéronisme/épidémiologie , Tumeurs de la surrénale/diagnostic , Tumeurs de la surrénale/épidémiologie , Tumeurs de la surrénale/chirurgie , Glandes surrénales/anatomopathologie , Surrénalectomie/statistiques et données numériques , Adénome corticosurrénalien/diagnostic , Adénome corticosurrénalien/épidémiologie , Adénome corticosurrénalien/chirurgie , Adulte , Aldostérone/analyse , Canada/épidémiologie , Études de cohortes , Techniques de diagnostic endocrinien , Régulation négative , Femelle , Humains , Hydrocortisone , Hyperaldostéronisme/anatomopathologie , Hyperaldostéronisme/chirurgie , Mâle , Adulte d'âge moyen , Pronostic , Études rétrospectives , Résultat thérapeutiqueRÉSUMÉ
CONTEXT: Previous studies suggested that plasma aldosterone (PAC) response to ACTH stimulation could predict the subtypes of primary aldosteronism (PA) and avoid adrenal venous sampling (AVS). OBJECTIVE: Assess the usefulness of peripheral (P) PAC response to ACTH stimulation during AVS to identify the source of aldosterone in patients with PA. METHODS: Two hundred and fifteen patients were assigned to four different lateralization ratio (LR) groups based on different combinations of basal (≥ or <2) and post-ACTH LR (≥ or <4). The P vein parameters analysed included as follows: mean basal PAC, maximal PAC (PACmax ), and PAC/C ratio (PACmax /C), PAC absolute increase, PAC relative increase following ACTH bolus (250 mcg IV) and maximal variation of PAC/C ratio between post-ACTH and basal measures. RESULTS: Mean basal PAC was significantly higher in group 1 (basal LR > 2 and post-ACTH > 4) than in group 2 (basal LR > 2, post-ACTH < 4) or group 4 (basal LR < 2 post-ACTH < 4) (P < .001). PACmax , PACmax /C and PAC absolute increase following ACTH were higher in group 1 than the others (P < .017). Using receiver operating characteristic (ROC) curves analysis of groups 1 and 4, best AUC were obtained with mean basal PAC (AUC: 0.757 95% IC: 0.653-0.861), PACmax (AUC: 0.753 95% IC: 0.646-0.860) and PACmax /C (AUC: 0.750 95% IC: 0.646-0.853). CONCLUSION: P mean basal PAC and PACmax and PACmax /C are higher in basal and ACTH lateralized PA than in other groups. Peripheral PAC cut-off values fail to adequately distinguish all groups and cannot replace the requirement to conduct AVS.
Sujet(s)
Glandes surrénales/vascularisation , Hormone corticotrope/pharmacologie , Aldostérone/sang , Prélèvement d'échantillon sanguin/méthodes , Hydrocortisone/métabolisme , Hyperaldostéronisme/diagnostic , Glandes surrénales/effets des médicaments et des substances chimiques , Adulte , Sujet âgé , Aldostérone/métabolisme , Techniques de diagnostic endocrinien , Femelle , Humains , Hyperaldostéronisme/sang , Hyperaldostéronisme/métabolisme , Mâle , Adulte d'âge moyen , Valeur prédictive des tests , Pronostic , Études rétrospectives , VeinesRÉSUMÉ
A 29-year-old G4A3 woman presented at 25 weeks of pregnancy with progressive signs of Cushing's syndrome (CS), gestational diabetes requiring insulin and hypertension. A 3.4 × 3.3 cm right adrenal adenoma was identified during abdominal ultrasound imaging for nephrolithiasis. Investigation revealed elevated levels of plasma cortisol, 24 h urinary free cortisol (UFC) and late-night salivary cortisol (LNSC). Serum ACTH levels were not fully suppressed (4 and 5 pmol/L (N: 2-11)). One month post-partum, CS regressed, 24-h UFC had normalised while ACTH levels were now less than 2 pmol/L; however, dexamethasone failed to suppress cortisol levels. Tests performed in vivo 6 weeks post-partum to identify aberrant hormone receptors showed no cortisol stimulation by various tests (including 300 IU hLH i.v.) except after administration of 250 µg i.v. Cosyntropin 1-24. Right adrenalectomy demonstrated an adrenocortical adenoma and atrophy of adjacent cortex. Quantitative RT-PCR analysis of the adenoma revealed the presence of ACTH (MC2) receptor mRNA, while LHCG receptor mRNA was almost undetectable. This case reveals that CS exacerbation in the context of pregnancy can result from the placental-derived ACTH stimulation of MC2 receptors on the adrenocortical adenoma. Possible contribution of other placental-derived factors such as oestrogens, CRH or CRH-like peptides cannot be ruled out. Learning points: Diagnosis of Cushing's syndrome during pregnancy is complicated by several physiological alterations in hypothalamic-pituitary-adrenal axis regulation occurring in normal pregnancy. Cushing's syndrome (CS) exacerbation during pregnancy can be associated with aberrant expression of LHCG receptor on primary adrenocortical tumour or hyperplasia in some cases, but not in this patient. Placental-derived ACTH, which is not subject to glucocorticoid negative feedback, stimulated cortisol secretion from this adrenal adenoma causing transient CS exacerbation during pregnancy. Following delivery and tumour removal, suppression of HPA axis can require several months to recover and requires glucocorticoid replacement therapy.
RÉSUMÉ
The regulation of cortisol or aldosterone production when ACTH of pituitary origin or the renin-angiotensin systems are suppressed in primary adrenal Cushing's syndrome or in primary aldosteronism is exerted by diverse genetic and molecular mechanisms. In addition to recently identified mutations in various genes implicated in the cyclic AMP or ion channel pathways, steroidogenesis is not really autonomous as it is frequently regulated by the aberrant adrenocortical expression of diverse hormone receptors, particularly G-protein coupled hormone receptors (GPCR) which can substitute for the normal function of ACTH or angiotensin-II. In addition, paracrine or autocrine production of ligands for the aberrant GPCR such as ACTH or serotonin is found in some adrenal tumors or hyperplasias and participates in a complex regulatory loop causing steroid excess. Targeted therapies to block the aberrant ligands or their receptors could become useful in the future, particularly for patients with bilateral source of steroid excess.
Sujet(s)
Maladies des surrénales/génétique , Récepteurs couplés aux protéines G/génétique , Récepteurs couplés aux protéines G/physiologie , Maladies des surrénales/physiopathologie , Tumeurs de la surrénale/étiologie , Tumeurs de la surrénale/métabolisme , Tumeurs de la surrénale/physiopathologie , Glandes surrénales/physiopathologie , Hormone corticotrope/métabolisme , Syndrome de Cushing/génétique , Syndrome de Cushing/métabolisme , Syndrome de Cushing/physiopathologie , Humains , Hydrocortisone/métabolisme , Hyperaldostéronisme/génétique , Hyperaldostéronisme/métabolisme , Hyperaldostéronisme/physiopathologie , Hyperplasie/génétique , Hyperplasie/physiopathologie , Mutation/physiologie , Hypophyse/anatomopathologie , Hypophyse/physiopathologie , Récepteurs couplés aux protéines G/métabolismeRÉSUMÉ
PURPOSE: Hepatocyte nuclear factor 1 alpha (HNF1α) defects cause Mature Onset Diabetes of the Young type 3 (MODY3), characterized by defects in beta-cell insulin secretion. However, HNF1α is involved in many other metabolic pathways with relevance for monogenic or polygenic type 2 diabetes. We aimed to investigate gut hormones, lipids, and insulin regulation in response to a meal test in HNF1α defect carriers (MODY3) compared to non-diabetic subjects (controls) and type 2 diabetes (T2D). METHODS: We administered a standardized liquid meal to each participant. Over 6 hours, we measured post-meal responses of insulin regulation (blood glucose, c-peptide, insulin), gut hormones (ghrelin, glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1) and lipids (non-esterified fatty acids [NEFA] and triglycerides). RESULTS: We found that MODY3 participants had lower insulin secretion indices than controls and T2D participants, showing the expected ß-cell defect. MODY3 had similar glycated hemoglobin levels (HbA1c median [IQR]: 6.5 [5.6-7.6]%) compared to T2D (median: 6.6 [6.2-6.9]%; P<0.05). MODY3 had greater insulin sensitivity (Matsuda index: 71.9 [29.6; 125.5]) than T2D (3.2 [4.0; 6.0]; P<0.05). MODY3 experienced a larger decrease in the ratio of NEFA to insulin (NEFA 30-0 / insulin 30-0: -39 [-78; -30] x104) in the early post-prandial period (0-30 minutes) compared to controls and to T2D (-2.0 [-0.6; -6.4] x104; P<0.05). MODY3 had lower fasting (0.66 [0.46; 1.2] mM) and post-meal triglycerides levels compared to T2D (fasting: 2.3 [1.7; 2.7] mM; P<0.05). We did not detect significant post-meal differences in ghrelin and incretins between MODY3 and other groups. CONCLUSION: In response to a standard meal test, MODY3 showed greater early post-prandial NEFA diminution in response to relatively low early insulin secretion, and they maintained very low post-prandial triglycerides levels.