B Ambrosi, C Dall'Asta, L Barbetta and R Libe
R Libe, C Dall'Asta, L Barbetta, A Baccarelli, P Beck-Peccoz and B Ambrosi
BACKGROUND: The incidence of adrenal incidentalomas has sharply increased in recent decades and concurrent subtle endocrine abnormalities, or even subclinical conditions, have been identified. Nonetheless, data concerning possible changes in adrenal size and/or hormonal pattern during follow-up are still inadequate. OBJECTIVE: To evaluate long-term morphological and functional evolution of adrenal incidentalomas after initial diagnosis and to identify possible risk factors for hormonal hyperactivity and mass enlargement. PATIENTS: Sixty-four patients (34-79 years) were followed-up for 12-120 months (median 25.5 months). Initial computerized tomography scan showed a unilateral mass in 51 patients and bilateral lesions in 13 patients. Average mass diameter at diagnosis was 2.5+/-0.1 cm (range 1.0-4.0). Twelve patients had subclinical Cushing's syndrome, 41 had mild hormonal alterations, and 11 had normal adrenal function at baseline. All patients were investigated by morphological and functional evaluation 6 and 12 months after diagnosis, and then at 1-year intervals. RESULTS: During follow-up, a mass size increase >/=1 cm was observed in 13 patients, and 18 developed further subtle endocrine alterations. Cumulative risk of developing endocrine abnormalities was 17% at 1 year, 29% at 2 years, and 47% at 5 years. The risk was higher in the first 2 years of follow-up if the initial tumor diameter was >or=3 cm. Overall, cumulative risk of mass enlargement was 6% at 1 year, 14% at 2 years, and 29% at 5 years, and it was greater in patients with normal adrenal function than in those with subtle hormonal abnormalities (P<0.05). One female subject showed a mass enlargement after 6 months of follow-up and was eventually diagnosed with non-Hodgkin's lymphoma. CONCLUSIONS: Patients with an adrenal incidentaloma are at risk for tumor growth and development of hormonal alterations. The risk of adrenal malignancy, although not elevated, also indicates the need for long-term follow-up.
R Dall, J Kanaley, TK Hansen, N Moller, JS Christiansen, H Hosoda, K Kangawa and JO Jorgensen
OBJECTIVE: To characterise plasma levels of the recently identified endogenous ligand for the GH secretagogue receptor (ghrelin) during submaximal aerobic exercise in healthy adults and in GH-deficient adults. DESIGN: Eight healthy males (mean+/-s.e. age, 40.8+/-2.9 years) and eight hypopituitary males with verified GH deficiency (mean+/-s.e. age, 40.8+/-4.7 years) underwent a baseline test of their peak aerobic capacity (VO(2) peak) and lactate threshold (LT) on a cycle ergometer, as well as an evaluation of body composition. The patients were then studied on two occasions in random order when they exercised for 45 min at their LT. On one occasion, GH replacement had been discontinued from the evening before, whereas on the other occasion they received their evening GH in addition to an intravenous infusion of GH (0.4 IU) during exercise the following day. The healthy subjects exercised at their LT on one occasion without GH. RESULTS: The patients were significantly more obese and had lower VO(2) max (corrected for body weight) and LT as compared with the control subjects. Exercise induced a peak in serum GH concentrations after 45 min in the control group (11.43+/-3.61 microg/l). Infusion of GH in the patients resulted in a peak level after 45 min, whereas no increase was detected when exercising without GH (9.77+/-2.40 (GH) vs 0.11+/-0.07 microg/l (no GH)). Plasma ghrelin levels did not change significantly with time in either study, and no correlations were detected between ghrelin levels and parameters such as GH and IGF-I levels, age or body composition. Plasma ghrelin levels were significantly lower during the study period with GH as compared with the study with no GH. CONCLUSIONS: Submaximal aerobic exercise of an intensity sufficient to stimulate GH release was not associated with significant alterations in plasma ghrelin concentrations, which indicated that systemic ghrelin is not involved in the exercise-induced stimulation of GH secretion. The observation that ghrelin levels were lower during GH replacement suggests that GH may feedback-inhibit systemic ghrelin release.
P. Cavallo-Perin, A. Bruno, P. Nuccio, A. M. Dall'omo, G. R. Fronda, P. Avagnina, G. Molino, C. Bozzo and G. Pagano
Abstract. Cirrhosis of the liver is characterized by glucose intolerance and hyperinsulinaemia. It is considered an insulin resistant state with both a receptor and a post-receptor defect of insulin activity. It would appear that reduced hepatic degradation rather than increased B-cell production is responsible for hyperinsulinaemia. The effect of surgical portosystemic shunt on insulin resistance was studied in 18 cirrhotics with impaired glucose tolerance (12 males, 6 females; mean age 46.9 ± 0.7 years) by measuring: glucose production (3H-glucose infusion), glucose utilisation (euglycaemic clamp at ~ 100, ~ 1000 and ~ 10000 μU/l), plasma insulin and C-peptide levels, and liver function indices (serum bilirubin, albumin, ALT, GGT) before and 2 months after surgery. Liver sorbitol clearance was also employed to measure variations in the functional liver plasma flow induced by the shunt. No significant changes were noted in: glucose production (1.94 ± 0.17 sem vs 1.96 ± 0.17 mg/kg/min), glucose utilisation (metabolic clearance rate: 3.32 ± 0.48 vs 3.42 ± 0.43 at ~ μU/ml; 9.70 ± 1.0 vs 9.16 ± 0.9 at~ 1000 μU/ml; 10.92 ± 1.1 vs 11.07 ± 0.8 ml/kg/min at ~ 10000 μU/ml), fasting plasma insulin, C-peptide and C-peptide/insulin molar ratio (4.66 ± 0.47 vs 5.50 ± 0.54), and the liver function indices. By contrast, there was a significant decrease in functional liver plasma flow (813 ± 34 vs 604 ± 34 ml/min, P < 0.001). These results suggest that surgical shunt does not modify the mechanisms and the degree of insulin resistance in human liver cirrhosis and that hyperinsulinaemia can not be primarily referred to change of liver perfusion, but is most probably related to liver cell damage.
B Ambrosi, C Dall'Asta, S Cannavo, R Libe, T Vigo, P Epaminonda, I Chiodini, S Ferrero, F Trimarchi, M Arosio and P Beck-Peccoz
OBJECTIVE: Rosiglitazone, a thiazolidinedione compound with peroxisome proliferator-activated receptor-gamma (PPAR-gamma)-binding affinity, is able to suppress adrenocorticotropic hormone (ACTH) secretion in treated mice and in AtT20 pituitary tumor cells. These observations suggested that thiazolidinediones may be effective as therapy for Cushing's disease (CD). PATIENTS AND METHODS: Rosiglitazone (8 mg/day) was administered to 14 patients with active CD (13 women, one man, 18-68 years). Plasma ACTH, serum cortisol (F) and urinary free cortisol (UFC) levels were measured before and then monthly during rosiglitazone administration. RESULTS: In six patients a reduction of ACTH and F levels and a normalization of UFC were observed 30-60 days after the beginning of rosiglitazone administration: there was a significant difference between basal and post-treatment values for UFC (1238+/-211 vs 154+/-40 nmol/24 h, P<0.03), but not for ACTH (15.9+/-3.7 vs 7.9+/-0.9 pmol/l) and F levels (531+/-73 vs 344+/-58 nmol/l). Two of six cases, followed up for 7 months, showed a mild clinical improvement. Eight patients were nonresponders after 30-60 days of rosiglitazone treatment: their ACTH, F and UFC levels did not differ before and during drug administration. Immunohistochemical analysis of pituitary tumors removed from two responder and two nonresponder patients showed a similar intense immunoreactivity for PPAR-gamma in about 50% of cells. CONCLUSIONS: The administration of rosiglitazone seems able to normalize cortisol secretion in some patients with CD, at least for short periods. Whether the activation of PPAR-gamma by rosiglitazone might be effective as chronic pharmacologic treatment of CD needs a more extensive investigation through a randomized and controlled study.
S Belli, D Santi, E Leoni, E Dall’Olio, F Fanelli, M Mezzullo, C Pelusi, L Roli, S Tagliavini, T Trenti, A R Granata, U Pagotto, R Pasquali, V Rochira, C Carani and M Simoni
Men with Klinefelter syndrome (KS) show hypergonadotropic hypogonadism, but the pathogenesis of hypotestosteronemia remains unclear. Testicular steroidogenesis in KS men was evaluated over three decades ago after human chorionic gonadotropin (hCG) stimulation, but inconclusive results were obtained. Intriguingly, some recent studies show increased intratesticular testosterone concentrations in men with KS.
To analyze serum steroid profile, as a proxy of testicular steroidogenesis, after hCG stimulation in KS compared with control men.
A prospective, longitudinal, case–control, clinical trial.
Thirteen KS patients (36±9 years) not receiving testosterone (TS) replacement therapy and 12 eugonadic controls (32±8 years) were enrolled. Serum steroids were measured by liquid chromatography–tandem mass spectrometry (LC–MS/MS) at baseline and for five consecutive days after intramuscular injection of 5000IU hCG.
Progesterone (P), 17-hydroxyprogesterone (17OHP), TS, and estradiol (E2) showed a significant increase (P<0.001) after hCG stimulation in both groups. On the contrary, androstenedione (AS) and dehydroepiandrosterone did not increase after hCG stimulation. The 17OHP/P ratio increased in both groups (P<0.001), the TS/AS ratio (17β-hydroxysteroid dehydrogenase type 3 (17βHSD3) activity) did not increase after hCG in any group, and the E2/TS ratio (aromatase activity) increased significantly in both groups (P=0.009 in KS and P<0.001 in controls). Luteinizing hormone decreased after hCG in both groups (P=0.014 in KS and P<0.001 in controls), whereas follicle-stimulating hormone decreased only in control men (P<0.001).
This study demonstrates for the first time using LC–MS/MS that Leydig cells of KS men are able to respond to hCG stimulation and that the first steps of steroidogenesis are fully functional. However, the TS production in KS men is impaired, possibly related to reduced hydroxysteroid deydrogenase activity due to an unfavorable intratesticular metabolic state.