Vesicular monoamine transporters expression in pheochromocytomas and paragangliomas according to scintigraphy and positron emission tomography behavior.

BACKGROUND: The expression of vesicular catecholamine transporters (VMAT1 and 2) in pheochromocytomas (PHEOs) and paragangliomas (PGLs) and the possible relationships with [18F]FDOPA PET/CT and [123I]MIBG scintigraphy uptake are unknown. Our purpose was to investigate possible correlations of either VMAT1 and VMAT2 expression with the functional imaging in patients with PHEOs and PGLs. METHODS: An observational 3-year time study was performed by enrolling 31 consecutive patients with PHEO (N.=17) or PGL (N.=14). They underwent the same diagnostic work-up; moreover, [123I]MIBG SPECT/CT (N.=20) and [18F]FDOPA PET/CT (N.=14) were performed in a subset of patients. After surgery, routine histology and semiquantitative analysis of VMAT1/VMAT2 immunoreactivity were carried out in all cases. RESULTS: VMAT1 immunoreactivity was found in all tumors, but two PHEOs. VMAT1 immunoreactivity was higher in PGLs than in PHEOs, though at not significant extent. Elevated VMAT2 immunoreactivity score was present in all but two negative tumors. Normal [123I]-MIBG uptake was independent from VMAT1/2 immunoreactivity. Patients undergoing [18F]FDOPA PET/CT showed a high score level of both VMATs and were detected by the technique in all cases. CONCLUSIONS: VMAT1 and VMAT2 are highly expressed in most tumors, though VMAT1 immunoreactivity is apparently prevalent in PGLs as compared to PHEOs. Presence and expression of VMAT1 and VMAT2 are not limiting factors for MIBG uptake. The status of VMAT expression might help to understand why the more frequently used radiotracers do not always have the expected diagnostic performance. Finally, the present study points out the importance of developing new radiotracers with higher sensitivity, specificity and accuracy consequently reducing healthcare costs.

Endocrine and haemodynamic stress responses to an arithmetic cognitive challenge.

OBJECTIVE: We aimed at developing and validating a simple, highly repeatable computer-based tool, which could be employed to simulate the effects of an acute mental stress on endocrine and haemodynamic stress responses. METHODS: Fifteen subjects underwent a mental cognitive challenge, employing an ad hoc designed web tool (available at http://bagame.altervista.org) that proposed a series of random arithmetic operations (addictions or subtractions) between one- to three-digit numbers for 10 minutes. We measured plasma epinephrine, norepinephrine, cortisol, and ACTH, in addition to heart rate (HR), systolic (SBP) and diastolic (DBP) blood pressure throughout the test. RESULTS: The arithmetic mental challenge promptly activated the sympatho-adrenomedullary axis (epinephrine +112±24%, p<0.05; norepinephrine +37±13%, p<0.004) and the hypothalamic-pituitary-adrenocortical axis (cortisol +25±7%, p<0.008; ACTH +97±44%, p<0.008), which in turn exerted stimulatory effects on the cardiovascular system (HR +18±4%, p<0.05; SBP +112±24%, p<0.05; DBP +34±8%, p<0.05) in all subjects, without any symptoms and regardless of the individuals' mental arithmetic ability. CONCLUSIONS: We developed and validated a computer-based tool that is effective for simulating endocrine and haemodynamic responses to an acute mental stress. This novel tool is easy-to-use, freely-accessible, and it can be employed to further investigate stress-related pathophysiological mechanisms and their role in cardiovascular diseases.

Tumoral EPAS1 (HIF2A) mutations explain sporadic pheochromocytoma and paraganglioma in the absence of erythrocytosis.

Pheochromocytomas (PCCs) and paragangliomas (PGLs) are chromaffin-cell tumors that arise from the adrenal medulla and extra-adrenal paraganglia, respectively. The dysfunction of genes involved in the cellular response to hypoxia, such as VHL, EGL nine homolog 1, and the succinate dehydrogenase (SDH) genes, leads to a direct abrogation of hypoxia inducible factor (HIF) degradation, resulting in a pseudo-hypoxic state implicated in PCC/PGL development. Recently, somatic post-zygotic mutations in EPAS1 (HIF2A) have been found in patients with multiple PGLs and congenital erythrocytosis. We assessed 41 PCCs/PGLs for mutations in EPAS1 and herein describe the clinical, molecular and genetic characteristics of the 7 patients found to carry somatic EPAS1 mutations; 4 presented with multiple PGLs (3 of them also had congenital erythrocytosis), whereas 3 were single sporadic PCC/PGL cases. Gene expression analysis of EPAS1-mutated tumors revealed similar mRNA EPAS1 levels to those found in SDH-gene- and VHL-mutated cases and a significant up-regulation of two hypoxia-induced genes (PCSK6 and GNA14). Interestingly, single nucleotide polymorphism array analysis revealed an exclusive gain of chromosome 2p in three EPAS1-mutated tumors. Furthermore, multiplex-PCR screening for small rearrangements detected a specific EPAS1 gain in another EPAS1-mutated tumor and in three non-EPAS1-mutated cases. The finding that EPAS1 is involved in the sporadic presentation of the disease not only increases the percentage of PCCs/PGLs with known driver mutations, but also highlights the relevance of studying other hypoxia-related genes in apparently sporadic tumors. Finally, the detection of a specific copy number alteration affecting chromosome 2p in EPAS1-mutated tumors may guide the genetic diagnosis of patients with this disease.

Effect of aliskiren treatment on endothelium-dependent vasodilation and aortic stiffness in essential hypertensive patients.

AIMS: Aliskiren is a new oral non-peptide renin inhibitor. Its effects on vascular function in human hypertension are unknown. We assessed whether aliskiren may improve peripheral endothelial function and arterial stiffness in essential hypertensive patients (EH), when compared with the angiotensin-converting enzyme-inhibitor ramipril. METHODS AND RESULTS: Fifty EH received treatment with aliskiren (150-300 mg/daily) or ramipril (5-10 mg/daily) for 12 weeks, according to a randomized, open with blind endpoints, parallel group design. We studied the forearm blood flow (straingauge plethysmography) response to intrabrachial acetylcholine, repeated under the nitric oxide synthase inhibitor N(G)-monomethyl-l-arginine (l-NMMA) (4 µmol/min), or the antioxidant ascorbic acid (8 mg/100 mL/min). Carotid-to-femoral pulse wave velocity (PWV), central blood pressure and augmentation index (AIx) were obtained by applanation tonometry. Brachial blood pressure was similarly normalized by aliskiren (from 149/94 to 136/86 mmHg) and ramipril (from 148/92 to 135/85 mmHg), as well as central blood pressure. Aliskiren increased (P < 0.001) the vasodilation to acetylcholine and restored the inhibitory effect of l-NMMA on acetylcholine. Ascorbic acid, which at baseline potentiated the response to acetylcholine, no longer improved endothelium-dependent relaxation after aliskiren treatment. In contrast, ramipril failed to affect the response to acetylcholine, the lacking inhibitory effect of l-NMMA, or the potentiating effect of ascorbic acid. Pulse wave velocity was significantly (P < 0.05) and similarly reduced by both drugs. Aliskiren induced a significantly (P < 0.05) greater AIx reduction than ramipril. CONCLUSION: Aliskiren increased nitric oxide availability in the forearm resistance arterioles of EH, an effect probably determined by an antioxidant activity, which can also contribute to improved peripheral wave reflection.

Peroxisome proliferator-activated receptor α agonists modulate Th1 and Th2 chemokine secretion in normal thyrocytes and Graves' disease.

Until now, no data are present about the effect of peroxisome proliferator-activated receptor (PPAR)α activation on the prototype Th1 [chemokine (C-X-C motif) ligand (CXCL)10] (CXCL10) and Th2 [chemokine (C-C motif) ligand 2] (CCL2) chemokines secretion in thyroid cells. The role of PPARα and PPARγ activation on CXCL10 and CCL2 secretion was tested in Graves' disease (GD) and control primary thyrocytes stimulated with interferon (IFN)γ and tumor necrosis factor (TNF)α. IFNγ stimulated both CXCL10 and CCL2 secretion in primary GD and control thyrocytes. TNFα alone stimulated CCL2 secretion, while had no effect on CXCL10. The combination of IFNγ and TNFα had a synergistic effect both on CXCL10 and CCL2 chemokines in GD thyrocytes at levels comparable to those of controls. PPARα activators inhibited the secretion of both chemokines (stimulated with IFNγ and TNFα) at a level higher (for CXCL10, about 60-72%) than PPARγ agonists (about 25-35%), which were confirmed to inhibit CXCL10, but not CCL2. Our data show that CCL2 is modulated by IFNγ and TNFα in GD and normal thyrocytes. Furthermore we first show that PPARα activators inhibit the secretion of CXCL10 and CCL2 in thyrocytes, suggesting that PPARα may be involved in the modulation of the immune response in the thyroid.

Sclerosing Paragangliomas: Correlations of Histological Features with Patients' Genotype and Vesicular Monoamine Transporter Expression.

Paragangliomas and pheochromocytomas are rare neuroendocrine tumors, carrying a germ-line mutation in 40% patients. Sclerosis is a rare histological feature in these tumors. We investigated the possible correlations between histological findings, first sclerosis, immunoreactivity for vesicular catecholamine transporters (VMAT1/VMAT2) and patients' genotype in a consecutive series of 57 tumors (30 paragangliomas and 27 pheochromocytomas) from 55 patients. The M-GAPP grading system, sclerosis (0-3 scale) and VMAT1/VMAT2 (0-6 scale) immunoreactivity scores were assessed. Germ-line mutations of Succinate Dehydrogenase genes, RET proto-oncogene and Von Hippel Lindau tumor suppressor gene were searched. A germ-line mutation was found in 25/55 (45.5%) patients, mainly with paraganglioma (N = 14/30, 46,66%). Significant (score ≥ 2) tumor sclerosis was found in 9 (16.1%) tumors, i.e., 7 paragangliomas and 2 pheochromocytomas, most of them (8/9) from patients with a germ-line mutation. M-GAPP score was higher in the mutation status (in 76% of patients involving the SDHx genes, in 12% the RET gene and in the remaining 12% the VHL gene) and in tumors with sclerosis (p < 0.05). Spearman's rank correlation showed a strong correlation of germ-line mutations with M-GAPP (p < 0.0001) and sclerosis (p = 0.0027) scores; a significant correlation was also found between sclerosis and M-GAPP scores (p = 0.029). VMAT1 expression was higher in paragangliomas than in pheochromocytomas (p = 0.0006), the highest scores being more frequent in mutation-bearing patients' tumors (p < 0.01). VMAT2 was highly expressed in all but two negative tumors. Sclerosis and VMAT1 expression were higher in paragangliomas than in pheochromocytomas; tumor sclerosis, M-GAPP and VMAT1 scores were associated to germ-line mutations. Sclerosis might represent a histological marker of tumor susceptibility, prompting to genetic investigations in paragangliomas.

A case of pheochromocytoma presenting as secondary hyperaldosteronism, hyperparathyroidism, diabetes and proteinuric renal disease.

A 35-year-old woman was admitted to the Nephrology and Dialysis Unit of Pisa University for hypertension, hypokalaemia, renal impairment, proteinuria and hyperglycaemia. plasma renin activity (PRA) and plasma aldosterone were elevated, but Doppler ultrasound and angio-computed tomography (CT) of renal arteries were normal. Abdomen CT revealed only a left adrenal mass, and measurement of catecholamines suggested the diagnosis of pheochromocytoma. Biochemical findings suggestive of hyperparathyroidism were also detected, but a multiple endocrine disorder was excluded by genetic analysis. Pathology examination confirmed the pheochromocytoma and immunohistochemistry also showed positivity for parathyroid hormone. After surgery, disappearance of the symptoms and normalization of all haemodynamic and humoral parameters was observed. This is a rare case of pheochromocytoma responsible for secondary hyperaldosteronism, hyperparathyroidism, proteinuric renal disease and diabetes mellitus.

A case report of a TDM-guided optimization of mitotane for a safe and effective long-term treatment.

A 43-years old woman was diagnosed an adrenocortical carcinoma (AC) that was excised, whereas two lung metastases were un-operable. Mitotane 6 g/day was started as standard therapy but it was responsible for severe central nervous system (CNS) and gastrointestinal toxicities associated with a 10 kg body weight loss. A therapeutic drug monitoring (TDM) protocol demonstrated that mitotane plasma concentrations (>30 mg/L) exceeded the therapeutic range (14-20 mg/L) and increased even when drug daily dose was reduced by 50%. The increase in drug plasma concentrations was probably due to body slimming. Under continuous TDM control, a reduced mitotane dose (1.5 g/day) was definitively administered and it proved to be tolerable and effective. Indeed, lung metastases were excised and two years later there was no evidence of other neoplastic lesions. In conclusion, the adoption of therapeutic mitotane monitoring allowed the treatment of an AC patient with a reduced, tolerable and effective dose.

Body mass index predicts plasma aldosterone concentrations in overweight-obese primary hypertensive patients.

CONTEXT: Body mass index (BMI) shows a direct correlation with plasma aldosterone concentration (PAC) and urinary aldosterone excretion in normotensive individuals; whether the same applies to hypertensive patients is unknown. OBJECTIVE: Our objective was to determine if BMI predicts PAC and the PAC/plasma renin activity ratio [aldosterone renin ratio (ARR)] in hypertensive patients, and if this affects the identification of primary aldosteronism (PA). DESIGN: This was a prospective evaluation of consecutive hypertensive patients referred nationwide to specialized hypertension centers. MAIN OUTCOME MEASURES: Sitting PAC, plasma renin activity, and the ARR, baseline and after 50 mg captopril orally with concomitant assessment of parameters, including BMI and daily sodium intake, were calculated. RESULTS: Complete biochemical data and a definite diagnosis were obtained in 1125 consecutive patients. Of them 999 had primary (essential) hypertension (PH) and 126 (11.2%) PA caused by an aldosterone-producing adenoma in 54 (4.8%). BMI independently predicted PAC (beta = 0.153; P < 0.0001) in PH, particularly in the overweight-obese, but not in the PA group. Covariance analysis and formal comparison of the raw, and the BMI-, sex-, and sodium intake-adjusted ARR with receiver operator characteristic curves, showed no significant improvement for the discrimination of aldosterone-producing adenoma from PH patients with covariate-adjusted ARR. CONCLUSIONS: BMI correlated with PAC independent of age, sex, and sodium intake in PH, but not in PA patients. This association of BMI is particularly evident in overweight-obese PH patients, and suggests a pathophysiological link between visceral adiposity and aldosterone secretion. However, it does not impact on the diagnostic accuracy of the ARR for discriminating PA from PH patients.

Plasma and urine aldosterone to plasma renin activity ratio in the diagnosis of primary aldosteronism.

OBJECTIVE: To establish the best cut-off value of the aldosterone (ALD)/plasma renin activity (PRA) ratio when screening patients for primary aldosteronism. One hundred and six patients with primary aldosteronism and 100 essential hypertensive patients were investigated in rigorous standardized conditions. METHODS: The ALD/PRA cut-off values were calculated from both the plasma and urine ALD/PRA ratio and analyzed by receiver operating characteristic (ROC) curve. In patients with PRA below 0.2 ng/ml/h [our radioimmunoassay detection limit], values were calculated both with PRA levels set at 0.2 ng/ml/h ('adjusted') and with PRA levels detected ('unadjusted') in the assay. RESULTS: ROC analysis on the ALD/PRA ratio indicated that the best performance was obtained when the plasma ALD (ng/dl)/PRA ratio was used in comparison with that observed in the urine ALD (microg/day)/PRA ratio. In patients with primary aldosteronism, as a whole group, the cut-off value of 69 corresponded to the best compromise value between sensitivity (96%) and specificity (85%), with and without PRA adjustment. In patients with aldosterone-producing adenoma, the cut-off to obtain 100% sensitivity with high specificity (85%) proved to be 69, with and without PRA adjustment. In patients with bilateral adrenal hyperplasia, both with and without PRA adjustment, the best compromise between sensitivity (94%) and specificity (86%) was a cut-off value of 71. CONCLUSION: The best cut-off to identify patients with primary aldosteronism, corresponding to 69, was obtained by using the plasma ALD/PRA ratio. Adjustment of PRA to 0.2 ng/ml/h does not interfere with calculation of the plasma ALD/PRA ratio cut-off.

Arterial stiffness, intima-media thickness and carotid artery fibrosis in patients with primary aldosteronism.

OBJECTIVES: To evaluate vascular wall structure and conduit artery stiffness in patients with primary aldosteronism. METHODS: This observational study, conducted in a University Hypertension Center, evaluated the carotid wall by 2-D ultrasonography and ultrasonic tissue characterization, and analyzed arterial stiffness by applanation tonometer. Twenty-three consecutive patients with primary aldosteronism, 24 matched patients with essential hypertension and 15 controls were studied. Intima-media thickness and corrected integrated backscatter signal of the carotid arteries were evaluated. Radial and femoral pulse wave velocity and aortic augmentation index were also investigated. RESULTS: Intima-media thickness in patients with essential hypertension (0.69 +/- 0.03 mm) was higher (P < 0.04) than that in controls (0.59 +/- 0.02 mm). This finding was more evident in primary aldosteronism patients (0.84 +/- 0.03 mm), in whom intima-media thickness was greater than that in controls (P < 0.0001) or in patients with essential hypertension (P < 0.01). Similarly, corrected integrated backscatter signal in patients with essential hypertension (-23.6 +/- 0.35 dB) was higher (P < 0.0001) than that in controls (-26.2 +/- 0.44 dB), but it was even more elevated in patients with primary aldosteronism (-22.1 +/- 0.46 dB), who showed greater corrected integrated backscatter signal than was the case in patients with essential hypertension (P < 0.009) or in controls (P < 0.0001). Femoral pulse wave velocity was higher in primary aldosteronism patients (10.8 +/- 0.57 m/s) than in patients with essential hypertension (9.1 +/- 0.34 m/s, P < 0.03) or in controls (7.1 +/- 0.51 m/s, P < 0.0001). Femoral pulse wave velocity was lower in controls than in patients with essential hypertension (P < 0.0001). The same pattern was observed for radial pulse wave velocity. Aortic augmentation index was higher in primary aldosteronism patients (28.2 +/- 2.1%) than in patients with essential hypertension (26.0 +/- 1.8%) or in controls (16.8 +/- 2.0%, P < 0.001). Patients with essential hypertension likewise exhibited higher aortic augmentation index than controls (P < 0.001). CONCLUSION: Aldosterone excess is responsible per se for vascular morphological (wall thickening and carotid artery fibrosis) and functional (central stiffness) damage.

Preclinical cardiac involvement in phaeochromocytoma: a study with integrated backscatter.

OBJECTIVE: It is well known that vascular and cardiac structure may be influenced by circulating neurohormonal factors. Our aim was to study the myocardial wall texture by integrated backscatter (IBS) analysis in patients with phaeochromocytoma (PHEO). DESIGN: Fourteen patients with PHEO, 15 matched high-normal blood pressure (BP) subjects, 15 mild essential hypertensives and 15 normotensive controls underwent two-dimensional conventional ultrasonography and ultrasonic IBS of the myocardial wall. IBS analysis was performed at both interventricular septum and posterior wall levels. IBS values were expressed in decibels and corrected for the IBS values obtained within the pericardium (C-IBS). The systo-diastolic cyclical variations in IBS (CV-IBS), an index of myocardial contractile performance, were also evaluated. RESULTS: Patients with PHEO showed C-IBS values comparable to those of hypertensive patients, and significantly higher than those of high-normal BP subjects and controls at both septum and posterior wall levels (P < 0.001 for all). In PHEO patients, CV-IBS was lower than that of normotensive, high-normal BP subjects and hypertensive patients, at both septum and posterior wall levels (P < 0.001 for all). An inverse relationship was found in the PHEO group between 24-h urinary normetanephrine and CV-IBS of both septum (r(2) = -0.29, P < 0.05) and posterior wall (r(2) = -0.46, P < 0.05). CONCLUSIONS: Our results show that patients with PHEO have myocardial remodelling characterized by increased myocardial fibrosis, confirmed by an increase in the overall myocardial backscatter level measured. The observed decrease in the magnitude of CV-IBS suggests an impairment of myocardial contractile performance. These results may provide insights into the role of catecholamines in left ventricular (LV) structure and function in PHEO.

Adrenalectomy Lowers Incident Atrial Fibrillation in Primary Aldosteronism Patients at Long Term.

Primary aldosteronism (PA) causes cardiovascular damage in excess to the blood pressure elevation, but there are no prospective studies proving a worse long-term prognosis in adrenalectomized and medically treated patients. We have, therefore, assessed the outcome of PA patients according to treatment mode in the PAPY study (Primary Aldosteronism Prevalence in Hypertension) patients, 88.8% of whom were optimally treated patients with primary (essential) hypertension (PH), and the rest had PA and were assigned to medical therapy (6.4%) or adrenalectomy (4.8%). Total mortality was the primary end point; secondary end points were cardiovascular death, major adverse cardiovascular events, including atrial fibrillation, and total cardiovascular events. Kaplan-Meier and Cox analysis were used to compare survival between PA and its subtypes and PH patients. After a median of 11.8 years, complete follow-up data were obtained in 89% of the 1125 patients in the original cohort. Only a trend (P=0.07) toward a worse death-free survival in PA than in PH patients was observed. However, at both univariate (90.0% versus 97.8%; P=0.002) and multivariate analyses (hazard ratio, 1.82; 95% confidence interval, 1.08-3.08; P=0.025), medically treated PA patients showed a lower atrial fibrillation-free survival than PH patients. By showing that during a long-term follow-up adrenalectomized aldosterone-producing adenoma patients have a similar long-term outcome of optimally treated PH patients, whereas, at variance, medically treated PA patients remain at a higher risk of atrial fibrillation, this large prospective study emphasizes the importance of an early identification of PA patients who need adrenalectomy as a key measure to prevent incident atrial fibrillation.

Prospective evaluation of the saline infusion test for excluding primary aldosteronism due to aldosterone-producing adenoma.

BACKGROUND: Data on the performance of the tests used to confirm the diagnosis of primary aldosteronism (PA) are limited. OBJECTIVE: To prospectively investigate the accuracy of the saline infusion test (SIT). METHODS: Three hundred and seventeen (26.9%) out of 1125 patients screened in the PAPY study underwent measurement of plasma aldosterone, cortisol and renin activity after infusion of 2 l of isotonic saline intravenously over 4 h. They comprised patients with a baseline aldosterone/renin ratio (ARR) > 40 and one every four patients not fulfilling such criterion. The area under the receiver-operator characteristic curves (AUC) of aldosterone values after SIT was used as a measure of accuracy for diagnosing PA, aldosterone-producing adenoma (APA) or idiopathic hyperaldosteronism (IHA). RESULTS: One hundred and twenty (37.9%) patients had PA that was due to an APA in 46 (38.3%) and to IHA in 74 (61.7%). No untoward effect occurred with the SIT. The AUC (0.811 +/- 0.026, 0.878 +/- 0.040 and 0.784 +/- 0.034 for identification of PA, APA and IHA, respectively) was higher (P < 0.0001) than that under the diagonal. By sensitivity/specificity versus criterion values plot, the best aldosterone cut-off values for identifying APA and IHA were 6.75 and 6.91 ng/dl, respectively. However, even at these optimal cut-offs, sensitivity and specificity were moderate because of values overlapping between patients with and without the disease. Moreover, there were no differences of AUC and aldosterone cut-offs between APA and IHA. CONCLUSION: In a multicenter study the SIT was safe and specific for excluding PA, but had no place for discriminating between an APA and IHA.

Maffucci Syndrome Associated With Adrenocorticotropic Hormone-Independent Bilateral Macronodular Adrenal Hyperplasia.

CONTEXT: Maffucci syndrome is a rare, nonhereditary, mesodermal dysplastic disease characterized by the presence of multiple hemangiomas and enchondromas. This pathological condition, which is often unrecognized, is associated with a high prevalence of benign and malignant endocrine tumors involving pituitary, adrenal, thyroid, and parathyroid glands. CASE DESCRIPTION: We describe the case of a young patient presenting a history suggestive of secondary arterial hypertension and typical features of Maffucci syndrome (multiple hemangiomas and enchondromas), which were unrecognized over the previous 3 decades. Given that endocrine diseases are common causes of secondary arterial hypertension and are often associated with Maffucci syndrome, a comprehensive diagnostic workup was performed, revealing the presence of large bilateral adrenal masses (70 mm right, 35 mm left) and autonomous cortisol secretion (adrenocorticotropic hormone-independent Cushing syndrome). The patient underwent a bilateral adrenalectomy, and steroid replacement therapy was initiated. Surgery resulted in a normalization of arterial blood pressure, and antihypertensive treatment was discontinued. Histological examinations revealed morphological features of primary bilateral macronodular adrenal hyperplasia. CONCLUSIONS: Early recognition and lifelong monitoring of Maffucci syndrome is required to identify and treat possible associated endocrine diseases and malignancies. Among them, unilateral cortical adrenal masses have been previously described, but to our knowledge, this is the first reported case of Maffucci syndrome associated with primary bilateral macronodular adrenal hyperplasia. Additional studies are needed to establish the etiopathological link between these 2 entities and, more in general, between Maffucci syndrome and endocrine diseases, but possible common genetic alterations may be suggested.

Carotid vascular remodeling in patients with pheochromocytoma.

CONTEXT: The influence of catecholamines on vascular remodeling in humans was investigated. OBJECTIVE: The objective was to study the carotid vascular wall in patients with pheochromocytoma (PHEO). DESIGN AND SETTING: An observational study was conducted in a university referral center for blood pressure diseases. PATIENTS: Fourteen patients with PHEO, 15 matched high-normal essential hypertensives, 15 mild essential hypertensives, and 15 controls underwent two-dimensional conventional ultrasonography and ultrasonic tissue characterization of the carotid wall. MAIN OUTCOME MEASURES: Intimal media thickness (IMT), diameter, and corrected ultrasonic integrated backscatter signal (C-IBS) of carotid arteries were evaluated. RESULTS: IMT in PHEOs (0.844 +/- 0.18 mm, mean +/- sd) was greater than not only controls (0.596 +/- 0.09 mm, P < 0.0002) but also high-normal (0.710 +/- 0.17 mm, P < 0.03), and even mild (0.727 +/- 0.20 mm, P = 0.06) hypertensives. IMT in the latter was higher than in controls (P < 0.03), without difference in comparison with high-normal hypertensives. C-IBS values in PHEOs (-21.71 +/- 2.0 dB, mean +/- sd) were greater than in controls (-26.20 +/- 1.73 dB, P < 0.0001) but also than in high-normal (-23.84 +/- 1.16 dB, P < 0.002) and mild (-23.37 +/- 1.99 dB, P < 0.01) hypertensives. C-IBS values in controls were lower than in high-normal (P < 0.0005) and mild (P < 0.0001) hypertensives. Carotid diameter was not significantly different in the four groups. In PHEOs, C-IBS was associated with urinary noradrenaline (r = 0.640, P < 0.01) and normethanephrine (r = 0.737, P < 0.009). CONCLUSIONS: Carotid IMT of PHEOs is higher than in controls and matched groups of hypertensives with comparable or even higher blood pressure. This vascular rearrangement is characterized by increased IBS values due to collagen deposition and vascular fibrosis. Therefore, our data show that abnormal catecholamine levels take part per se in carotid wall remodeling of patients with PHEO.

Vascular reactivity in congenital hypogonadal men before and after testosterone replacement therapy.

CONTEXT: The contribution of endogenous testosterone (TS) in the functional integrity of peripheral circulation in men was studied. OBJECTIVE: The objective of this study was to observe vascular reactivity in male congenital hypogonadal patients before and after prolonged exposure to normal TS levels. DESIGN: This was a longitudinal study in which, basically and after 6-month (range, 6-8 months) androgen treatment, we investigated forearm blood flow (strain-gauge plethysmography) changes induced by intraarterial acetylcholine (Ach), alone or in the presence of N(G)-monomethyl-l-arginine infusion, and by sodium nitroprusside. We also evaluated, by Doppler ultrasound, flow-mediated dilation of the brachial artery (BA) in response to reactive hyperemia (RH) and glyceryl trinitrate (GTN). SETTING: The studies were conducted at university referral centers for andrologic and blood pressure diseases. PATIENTS: Eight adult male Caucasian hypogonadal patients and nine healthy matched control subjects were studied. INTERVENTION: Intervention was TS enanthate (250 mg in 1 ml oily solution) by im injection every 3 wk. RESULTS: At baseline, BA diameter and RH, flow-mediated dilation, and GTN responses showed no difference between the two groups. TS therapy increased plasma total TS (P < 0.02) and reduced high-density lipoprotein (P < 0.01) and total cholesterol (P < 0.04). It did not affect vasodilation to sodium nitroprusside (355 +/- 47%), but it further reduced the vascular response to Ach (187 +/- 29%, P < 0.01 vs. baseline) and abolished the inhibition by N(G)-monomethyl-l-arginine on Ach (inhibition, 3.2%). Moreover, TS therapy decreased (P < 0.01) flow-mediated dilation, whereas it did not modify BA diameter and responses to RH and GTN. CONCLUSIONS: Hypogonadal patients show impaired vascular reactivity, including endothelial-dependent vasodilation due to reduced nitric oxide availability. TS administration further impairs nitric oxide availability in these patients.

Cushing's Syndrome and Steroid Dementia.

Cushing's Syndrome (CS) is associated with a specific spectrum of dementia-like symptoms, including psychiatric disorders, such as major depression, anxiety and mania, and neurocognitive alterations, like impairment of memory and concentration. This pattern of clinical complications, which significantly impair the health-related quality of life of CS patients, is sometimes referred to as "steroid dementia syndrome" (SDS). The SDS is the result of anatomical and functional anomalies in brain areas involved in the processing of emotion and cognition, which are only partially restored after the biochemical remission of the disease. Therefore, periodical neuropsychiatric evaluations are recommended in all CS patients, and a long-term follow-up is required after normalization of hypercortisolism. Recent evidences demonstrate that three classes of drugs (glucocorticoid receptor antagonists, steroidogenesis inhibitors, and pituitary tumor-targeted drugs), which are used for medical treatment of CS, can rapidly relief neuropsychiatric symptoms of SDS. Furthermore, several psychoactive medications have demonstrated effectiveness in the treatment of symptoms induced by the acute or chronic glucocosteroid administration. In this paper, a review of the current and future patents for the treatment and prevention of CS and SDS will be presented.

Cholecalciferol treatment downregulates renin-angiotensin system and improves endothelial function in essential hypertensive patients with hypovitaminosid D.

BACKGROUND: Vitamin D deficiency is related to an increased prevalence of cardiovascular disease. Renin-angiotensin-aldosterone system suppression and vascular dysfunction are considered among the main mechanisms implicated in this association. However, interventional studies demonstrating that vitamin D replacement reduces circulating renin-angiotensin-aldosterone components and improves vascular function in humans are still lacking. METHODS: Thirty-three consecutive patients with essential hypertension and hypovitaminosis D underwent therapy with cholecalciferol 50 000 IU/week orally for 8 weeks. Thirty-three hypertensive patients with normal vitamin D levels and 20 normotensive individuals were also enrolled as control groups. At baseline and at the end of the study, we evaluated plasma renin activity, circulating renin, angiotensin II, aldosterone and plasma vitamin D levels. Endothelial function [flow-mediated dilation (FMD)], carotid-femoral pulse wave velocity and augmentation index, peripheral and central blood pressure were also acquired. RESULTS: After 8-week cholecalciferol administration, all treated patients normalized plasma 25(OH)D values. Furthermore, a reduction in plasma levels of plasma renin activity (1.17 ±â€Š0.3 vs 1.51 ±â€Š0.4 ng/ml per h, P = 0.02), renin (13.4 ±â€Š1.7 vs 19.2 ±â€Š2.9 pg/ml, P < 0.001), angiotensin II (11.6 ±â€Š1.6 vs 15.8 ±â€Š2.7 pg/ml, P = 0.02) was observed at the end of the study. FMD was significantly increased after cholecalciferol treatment (4.4 ±â€Š2.6 vs 3.3 ±â€Š2.1%, P < 0.05), in the absence of changes of brachial artery diameter and endothelium-independent vasodilation. Carotid-femoral pulse wave velocity and augmentation index were not modified, as well peripheral and central blood pressure. CONCLUSION: The restoration of normal vitamin D levels after 8-week cholecalciferol treatment is able to inhibit peripheral renin-angiotensin system and improve FMD in essential hypertensive patients with hypovitaminosis D.