Italian guidelines for the management of adult individuals with overweight and obesity and metabolic comorbidities that are resistant to behavioral treatment.

AIM: This guideline (GL) is aimed at providing a clinical practice reference for the management of adult patients with overweight or obesity associated with metabolic complications who are resistant to lifestyle modification. METHODS: Surgeons, endocrinologists, gastroenterologists, psychologists, pharmacologists, a general practitioner, a nutritionist, a nurse and a patients' representative acted as multi-disciplinary panel. This GL has been developed following the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. A systematic review and network meta-analysis was performed by a methodologic group. For each question, the panel identified potentially relevant outcomes, which were then rated for their impact on therapeutic choices. Only outcomes classified as "critical" and "important" were considered in the systematic review of evidence. Those classified as "critical" were considered for clinical practice recommendations. Consensus on the direction (for or against) and strength (strong or conditional) of recommendations was reached through a majority vote. RESULTS: The present GL provides recommendations about the role of both pharmacological and surgical treatment for the clinical management of the adult patient population with BMI > 27 kg/m2 and < 40 kg/m2 associated with weight-related metabolic comorbidities, resistant to lifestyle changes. The panel: suggests the timely implementation of therapeutic interventions in addition to diet and physical activity; recommends the use of semaglutide 2.4 mg/week and suggests liraglutide 3 mg/day in patients with obesity or overweight also affected by diabetes or pre-diabetes; recommends semaglutide 2.4 mg/week in patients with obesity or overweight also affected by non-alcoholic fatty liver disease; recommends semaglutide 2.4 mg/week as first-line drug in patients with obesity or overweight that require a larger weight loss to reduce comorbidities; suggests the use of orlistat in patients with obesity or overweight also affected by hypertriglyceridemia that assume high-calorie and high-fat diet; suggests the use of naltrexone/bupropion combination in patients with obesity or overweight, with emotional eating; recommends surgical intervention (sleeve gastrectomy, Roux-en-Y gastric bypass, or metabolic gastric bypass/gastric bypass with single anastomosis/gastric mini bypass in patients with BMI ≥ 35 kg/m2 who are suitable for metabolic surgery; and suggests gastric banding as a possible, though less effective, surgical alternative. CONCLUSION: The present GL is directed to all physicians addressing people with obesity-working in hospitals, territorial services or private practice-and to general practitioners and patients. The recommendations should also consider the patient's preferences and the available resources and expertise.

Disease control of acromegaly does not prevent excess mortality in the long term: results of a nationwide survey in Italy.

OBJECTIVE: This study aimed to assess the long-term outcome of patients with acromegaly. DESIGN: This is a multicenter, retrospective, observational study which extends the mean observation period of a previously reported cohort of Italian patients with acromegaly to 15 years of follow-up. METHODS: Only patients from the centers that provided information on the life status of at least 95% of their original cohorts were included. Life status information was collected either from clinical records or from the municipal registry offices. Standardized mortality ratios (SMRs) were computed comparing data with those of the general Italian population. RESULTS: A total of 811 patients were included. There were 153 deaths, with 90 expected and an SMR of 1.7 (95% CI 1.4-2.0, p < 0.001). Death occurred after a median of 15 (women) or 16 (men) years from the diagnosis, without gender differences. Mortality remained elevated in the patients with control of disease (SMR 1.3, 95% CI 1.1-1.6). In the multivariable analysis, only older age and high IGF1 concentrations at last available follow-up visit were predictors of mortality. The oncological causes of death outweighed the cardiovascular ones, bordering on statistical significance with respect to the general population. CONCLUSIONS: Mortality remains significantly high in patients with acromegaly, irrespectively of disease status, as long as the follow-up is sufficiently long with a low rate of patients lost to follow-up. Therapy strategy including radiotherapy does not have an impact on mortality. Oncological causes of death currently outweigh the cardiovascular causes.

Calcium/phosphate ratio: an additional tool for the clinical management of asymptomatic primary hyperparathyroidism?

PURPOSE: Serum calcium/phosphate ratio (Ca/P) has been recently proposed as an additional tool to identify primary hyperparathyroidism (PHPT), especially in patients with subclinical presentation, with a proposed cut-off of 3.3 when both values are expressed in mg/dL. No data are available on the relationship between Ca/P and the clinical presentation of PHPT. We thus evaluated this relationship in a large, single-center, unselected series. METHODS: 515 consecutive PHPT patients (mean age 65 ± 13.15 years, 77.1% females) were retrospectively evaluated at diagnosis. RESULTS: Mean Ca/P was 4.54 ± 1.5 (range 2.36-13.9), being higher than 3.3 in 88.5% of patients. Ca/P was significantly higher in (1) males, (2) symptomatic PHPT, (3) patients with 25-hydroxy vitamin D levels lower than 20 µg/L, (4) patients with osteitis fibrosa cystica, (5) patients with T score < - 2.5 at the radial site. In a multivariate regression analysis, Ca/P resulted significantly associated with PTH levels. After the exclusion of 57 patients with asymptomatic PHPT (aPHPT) patients and serum Ca higher than 1 mg/dL above the upper limit of normal range, no differences were found in Ca/P between aPHPT meeting or not surgical criteria. CONCLUSIONS: In PHPT Ca/P ratio is associated with increased biochemical and clinical severity of disease and represents a direct indicator of clinical bone damage. However, it does not seem an additional tool to identify aPHPT patients reaching surgical indication.

Clinical presentation and management of patients with primary hyperparathyroidism in Italy.

PURPOSE: Evaluation of the phenotype of primary hyperparathyroidism (PHPT), adherence to International Guidelines for parathyroidectomy (PTx), and rate of surgical cure. METHOD: From January 2014-January 2016, we performed a prospective, multicenter study in patients with newly diagnosed PHPT. Biochemical and instrumental data were collected at baseline and during 1-year follow-up. RESULTS: Over the first year we enrolled 604 patients (age 61 ± 14 years), mostly women (83%), referred for further evaluation and treatment advice. Five hundred sixty-six patients had sporadic PHPT (93.7%, age 63 ± 13  years), the remaining 38 (6.3%, age 41 ± 17  years) had familial PHPT. The majority of patients (59%) were asymptomatic. Surgery was advised in 281 (46.5%). Follow-up data were available in 345 patients. Eighty-seven of 158 (55.1%) symptomatic patients underwent PTx. Sixty-five (53.7%) of 121 asymptomatic patients with at least one criterion for surgery underwent PTx and 56 (46.3%) were followed without surgery. Negative parathyroid imaging studies predicted a conservative approach [symptomatic PHPT: OR 18.0 (95% CI 4.2-81.0) P < 0.001; asymptomatic PHPT: OR 10.8, (95% CI 3.1-37.15) P < 0.001). PTx was also performed in 16 of 66 (25.7%) asymptomatic patients without surgical criteria. Young age, serum calcium concentration, 24 h urinary calcium, positive parathyroid imaging (either ultrasound or MIBI scan positive in 75% vs. 16.7%, P = 0.001) were predictors of parathyroid surgery. Almost all (94%) of patients were cured by PTx. CONCLUSIONS: Italian endocrinologists do not follow guidelines for the management of PHPT. Negative parathyroid imaging studies are strong predictors of a non-surgical approach. PTx is successful in almost all patients.

The basal to total insulin ratio in outpatients with diabetes on basal-bolus regimen.

OBJECTIVE: To evaluate the basal/total ratio of daily insulin dose (b/T) in outpatients with diabetes type 1 (DM1) and type 2 (DM2) on basal-bolus regimen, by investigating whether there is a relationship with HbA1c and episodes of hypoglycemia. METHODS: Multicentric, observational, cross-sectional study in Italy. Adult DM1 (n = 476) and DM2 (n = 541) outpatients, with eGFR >30 mL/min/1.73 m2, on a basal-bolus regimen for at least six months, were recruited from 31 Italian Diabetes services between March and September 2016. Clinicaltrials.govID: NCT03489031. RESULTS: Total daily insulin dose was significantly higher in DM2 patients (52.3 ± 22.5 vs. 46 ± 20.9 U/day), but this difference disappeared when insulin doses were normalized for body weight. The b/T ratio was lower than 0.50 in both groups: 0.46 ± 0.14 in DM1 and 0.43 ± 0.15 in DM2 patients (p = 0.0011). The b/T was significantly higher in the patients taking metformin in both groups, and significantly different according to the type of basal insulin (Degludec, 0.48 in DM1 and 0.44 in DM2; Glargine, 0.44 in DM1 and 0.43 in DM2; Detemir, 0.45 in DM1 and 0.39 in DM2). The b/T ratio was not correlated in either group to HbA1c or incidence of hypoglycemia (<40 mg/dL, or requiring caregiver intervention, in the last three months). In the multivariate analysis, metformin use and age were independent predictors of the b/T ratio in both DM1 and DM2 patients, while the type of basal insulin was an independent predictor only in DM1. CONCLUSION: The b/T ratio was independent of glycemic control and incidence of hypoglycemia.

Primary hyperparathyroidism and Klinefelter's syndrome in a young man.

UNLABELLED: We report the association of primary hyperparathyroidism (PHPT) and Klinefelter's syndrome (KS) in a 22-year-old male complaining of worsening fatigue. PHPT was asymptomatic at the diagnosis, but the patient had worsening hypercalcemia and osteoporosis, and developed acute renal colic. He then underwent parathyroidectomy with resection of a single adenoma and normalization of calcium and parathyroid hormone levels. Clinical and therapeutic implications of this rare association are discussed. LEARNING POINTS: The coexistence of KS and PHPT is very uncommon.Patients with mild PHPT often have nonspecific symptoms that may be confused and superimposed with those of hypogonadism.KS patients, especially when young and already osteoporotic at diagnosis, should be screened for other causes of secondary osteoporosis, in particular PHPT.

Predictors of morbidity and mortality in acromegaly: an Italian survey.

OBJECTIVE: To describe demographic and hormonal characteristics, comorbidities (diabetes mellitus and hypertension), therapeutic procedures and their effectiveness, as well as predictors of morbidity and mortality in a nationwide survey of Italian acromegalic patients. DESIGN: Retrospective multicenter epidemiological study endorsed by the Italian Society of Endocrinology and performed in 24 tertiary referral Italian centers. The mean follow-up time was 120 months. RESULTS: A total of 1512 patients, 41% male, mean age: 45±13 years, mean GH: 31±37 µg/l, IGF1: 744±318 ng/ml, were included. Diabetes mellitus was reported in 16% of cases and hypertension in 33%. Older age and higher IGF1 levels at diagnosis were significant predictors of diabetes and hypertension. At the last follow-up, 65% of patients had a controlled disease, of whom 55% were off medical therapy. Observed deaths were 61, with a standardized mortality ratio of 1.13 95% (confidence interval (CI): 0.87-1.46). Mortality was significantly higher in the patients with persistently active disease (1.93; 95% CI: 1.34-2.70). Main causes of death were vascular diseases and malignancies with similar prevalence. A multivariate analysis showed that older age, higher GH at the last follow-up, higher IGF1 levels at diagnosis, malignancy, and radiotherapy were independent predictors of mortality. CONCLUSIONS: Pretreatment IGF1 levels are important predictors of morbidity and mortality in acromegaly. The full hormonal control of the disease, nowadays reached in the majority of patients with modern management, reduces greatly the disease-related mortality.

AME position statement on adrenal incidentaloma.

OBJECTIVE: To assess currently available evidence on adrenal incidentaloma and provide recommendations for clinical practice. DESIGN: A panel of experts (appointed by the Italian Association of Clinical Endocrinologists (AME)) appraised the methodological quality of the relevant studies, summarized their results, and discussed the evidence reports to find consensus. RADIOLOGICAL ASSESSMENT: Unenhanced computed tomography (CT) is recommended as the initial test with the use of an attenuation value of ≤10 Hounsfield units (HU) to differentiate between adenomas and non-adenomas. For tumors with a higher baseline attenuation value, we suggest considering delayed contrast-enhanced CT studies. Positron emission tomography (PET) or PET/CT should be considered when CT is inconclusive, whereas fine needle aspiration biopsy may be used only in selected cases suspicious of metastases (after biochemical exclusion of pheochromocytoma). HORMONAL ASSESSMENT: Pheochromocytoma and excessive overt cortisol should be ruled out in all patients, whereas primary aldosteronism has to be considered in hypertensive and/or hypokalemic patients. The 1 mg overnight dexamethasone suppression test is the test recommended for screening of subclinical Cushing's syndrome (SCS) with a threshold at 138 nmol/l for considering this condition. A value of 50 nmol/l virtually excludes SCS with an area of uncertainty between 50 and 138 nmol/l. MANAGEMENT: Surgery is recommended for masses with suspicious radiological aspects and masses causing overt catecholamine or steroid excess. Data are insufficient to make firm recommendations for or against surgery in patients with SCS. However, adrenalectomy may be considered when an adequate medical therapy does not reach the treatment goals of associated diseases potentially linked to hypercortisolism.

Glomerular filtration rate and parathyroid hormone secretion in primary hyperparathyroidism.

CONTEXT: The recent Third International Workshop on the Management of Asymptomatic Primary Hyperparathyroidism (PHPT) set 60 ml/min as the precise level of glomerular filtration rate (GFR) below which surgery is recommended because it is considered a threshold of concern in patients with PHPT. OBJECTIVE: The aim of the study was to investigate the relationship between different stages of renal insufficiency and PTH levels in PHPT patients. DESIGN: We conducted a cross-sectional study. PATIENTS AND METHODS: We studied 294 consecutive PHPT patients. Biochemical evaluation included total and ionized serum calcium, phosphate, creatinine, immunoreactive intact PTH, and 25-hydroxyvitamin D3 levels in the fasting state. GFR was assessed with the Modification of Diet in Renal Disease Study formula. RESULTS: The mean GFR of the whole group of PHPT patients was 92.3 +/- 31.6 ml/min x 1.73 m(2). The patients were divided into four groups according to National Kidney Foundation Disease Outcomes Quality Initiative (K/DOQI) guidelines: group 1 with normal or increased GRF (>90 ml/min x 1.73 m(2); n = 153); group 2 with mild decreased GFR (60-89 ml/min x 1.73 m(2); n = 90); group 3 with moderately decreased GFR (30-59 ml/min x 1.73 m(2); n = 45); and group 4 with severely decreased GFR (<30 ml/min x 1.73 m(2); n = 6). PTH levels were comparable across groups 1-3, whereas group 4 showed significantly higher PTH levels (P < 0.0001). CONCLUSION: In our series of PHPT patients, only a severe impairment of GFR was characterized by a further PTH increase. These findings challenge the concept of a PTH elevation below the threshold of 60 ml/min of GFR.

Effects of extra virgin olive oil supplementation at two different low doses on lipid profile in mild hypercholesterolemic subjects: a randomised clinical trial.

Olive oil, the principal fat of Mediterranean Diet, is known to improve several cardiovascular risk factors at relatively high doses together with intensive modifications of dietary habits. Since this is hard to obtain in the long term, an intervention with encapsulated oil supplements might be more feasible. Aim of this preliminary study was to investigate the effects of the supplementation of a moderate amount of encapsulated extra virgin olive oil vs a lower dose in mildly hypercholesterolemic subjects, as part of their established diet, on blood lipid profile. A prospective randomized study was performed. Thirty-four mildly hypercholesterolemic subjects [age, mean+/-SD: 46+/-7 yr; total cholesterol (TC): 235+/-28 mg/dl] were randomly assigned to receive 2 g (group A) or 4 g (group B) per os of extra-virgin olive oil for 3 months. TC, triglycerides (TG), LDL cholesterol, HDL cholesterol, apolipoprotein A1 (Apo-AI), apolipoprotein B (Apo-B), and atherogenic index of plasma (AIP) were evaluated at the beginning and at the end of the study. In group B, but not in group A, a significant reduction of Apo-B values (7%) was observed; TG concentrations showed a trend towards reduction and Apo-A1 values a trend towards increase (9%). A significant decrease in Apo-B/Apo-A1 ratio (p<0.01) was also observed in group B. Extra virgin olive oil supplementation significantly decreased AIP from baseline in group B (p<0.05). The results of the present study seem to suggest that the daily supplementation, on top of the normal diet, of at least 4 g of extra virgin olive oil, in mildly hypercholesterolemic subjects, is associated to favorable modifications of the plasmatic lipid profile.

Dopamine D2 receptor gene polymorphisms and response to cabergoline therapy in patients with prolactin-secreting pituitary adenomas.

Dopamine-agonist cabergoline (CB) reduces prolactin (PRL) secretion and tumor size in 80% of patients with prolactin-secreting adenomas (PRL-omas) by binding type 2 dopamine receptor (DRD2). The mechanisms responsible for resistance to CB remain largely unknown. To assess the association of DRD2 with sensitivity to CB, TaqI-A1/A2, TaqI-B1/B2, HphI-G/T and NcoI-C/T genotypes were determined in a cross-sectional retrospective study, including 203 patients with PRL-oma. DRD2 alleles frequencies did not differ between patients and 212 healthy subjects. Conversely, NcoI-T allele frequency was higher in resistant rather than responsive patients, considering both PRL normalization (56.6 vs 45.3%, P=0.038) and tumor shrinkage (70.4 vs 41.4%, P=0.006). Finally, [TaqI A1-/TaqI B1-/HphI T-/NcoI T-] haplotype was found in 34.5% of patients normalizing PRL with < or =3 mg/week of CB vs 11.3% of resistants (P=0.021). In conclusion, resistance to CB was associated with DRD2 NcoI-T+ allele, consistent with evidence suggesting that this variant may lead to reduction and instability of DRD2 mRNA or protein.

Hypopituitarism and growth hormone deficiency (GHD) after traumatic brain injury (TBI).

In adults, hypopituitarism and growth hormone deficiency (GHD) should be suspected and diagnosed within an appropriate clinical context. It has been demonstrated that all patients with primary hypothalamic-pituitary diseases before and after any medical intervention (defined as neurosurgery, radiotherapy and medical therapy) are at obvious risk - more than just at high risk - for hypopituitarism (greater than 80% had severe GHD). The same obvious risk applies to patients diagnosed as having congenital or acquired GHD in childhood (between 30% and 50% of patients with severe GHD after retesting). Taking into account the fragility of the infundibular-hypothalamic structure, patients with other common pathological conditions of the central nervous system (CNS), such as traumatic brain injury (TBI), subarachnoid haemorrhage (SAH) or primary brain tumours (BT) with related medical intervention could be at risk for developing hypopituitarism, including GHD. GHD is the first and most common sign of pituitary impairment. Despite the risk of pituitary dysfunction and the results of some studies that these risks are greater than previously believed, neuroendocrine evaluations are still not routinely included as part of the clinical management plan for patients with TBI and SAH. Preliminary results of a multicenter study performed under the auspices of the Italian Society of Endocrinology underscore the high risk of hypopituitarism and GHD under these clinical conditions. Thus, careful screening of pituitary function should always be performed in patients following TBI and SAH.

A rare case of adulthood-onset growth hormone deficiency presenting as sporadic, symptomatic hypoglycemia.

Symptomatic hypoglycemia is described in children with severe GH deficiency (GHD), but is rare in adults with GHD. We describe the case of a 62- yr-old man, referred for recurrent hypoglycemic events. He reported a previous head trauma at the age of 20 yr and a diagnosis of reactive hypoglycemia at the age of 50 yr. In the last months, during a period of job-related stress, the hypoglycemic episodes became more frequent and severe (glucose <2.2 mmol/l), finally requiring hospitalization. On admission, the patient was in good general health, with normal renal and hepatic function. During hospitalization, no hypoglycemic episodes were recorded, also during a 72-h fasting test. Biochemical data and abdominal computed tomography (CT) excluded insulinoma. A tumor-induced hypoglycemia was ruled out. The 4-h oral glucose tolerance test (OGTT) showed an impaired glucose tolerance with a tendency toward asymptomatic hypoglycemia. Hormonal study disclosed low levels of GH (0.2 ng/ml) and IGF-I (51 ng/ml); the response of GH to GHRH plus arginine confirmed a severe GHD (GH peak 2.7 ng/ml). Other pituitary and counterregulation hormones were within the normal range and magnetic resonance imaging (MRI) of the pituitary gland was normal. Replacement therapy with a low dose of rhGH induced an increase of IGF-I up to low-normal values, accompanied by lasting regression of hypoglycemic events. In conclusion, hypoglycemia was the main clinical symptom of isolated adult onset GHD, in the present case. The possible pathogenesis of isolated adult onset GHD and the association of GHD with conditions predisposing to hypoglycemia are considered and discussed.

Proinsulin-secreting neuroendocrine tumor of the pancreas.

Insulinoma is characterized by spontaneous fasting hypoglycemia. Diagnosis relies on inappropriately increased insulin levels (>6 microU/ml), high insulin/glucose ratio (IGR >0.3), raised proinsulin values (>5 pMol/l). A 74-yr-old man was referred to us for episodes of symptomatic hypoglycemia without hyperinsulinemia and imaging [abdominal computed tomography (CT) and magnetic resonance scans] negative for neuroendocrine tumor (NET). During hospitalization severe hypoglycemic crises persisted requiring continuous glucose iv infusion. Insulin values (immunofluorimetric method) were not inappropriately increased, accordingly IGR was normal but C-peptide was in the upper-normal range. Proinsulin levels measured with specific radioimmunoassay were remarkably high. Octreoscan study was negative whereas endoscopic ultrasound disclosed a 10 mm lesion in the body of the pancreas, confirmed by rapid spiral CT scanning with dynamic images. Increased proinsulin levels allowed diagnosis of a secreting NET. After removal of the lesion, the patient experienced hyperglycemia. Histology confirmed a benign NET positively staining for insulin. In conclusion, proinsulin assay is of particular help when immunoreactive insulin, measured by specific new immunometric assays (immunoenzymometric and immunofluorimetric assays), is normal. These methods have good precision and specificity (no cross reactivity with intact or Des 31,32 proinsulin), but rare insulinomas secreting most, or all, of their insulin-like activity as proinsulins would go undetected if insulin levels alone were measured.

The limited value of the desmopressin test in the diagnostic approach to Cushing's syndrome.

OBJECTIVE: The desmopressin test is generally regarded as an alternative to the CRH test but it is unclear whether desmopressin is as effective as CRH in the differential diagnosis of ACTH-dependent Cushing's syndrome. However, a precise assessment of the operating characteristics of the desmopressin test in comparison with the CRH test has not been reported. The aim of the present study was to make a comparative evaluation of desmopressin and CRH tests in a consecutive cohort of patients with ACTH-dependent Cushing's syndrome and in a group of healthy subjects. DESIGN AND SUBJECTS: We studied 34 patients with Cushing's disease (CD) and nine patients with ectopic ACTH syndrome (EAS). The control group included 30 healthy subjects. Estimates of sensitivity and specificity were determined for a value of ACTH percent increment (Delta%) > 35% and for a Delta % > 50%, following either desmopressin or CRH, to differentiate CD from EAS. The sensitivity and specificity of a composite rule requiring an ACTH net increment (Delta) > 4.5 pmol/l at both values of Delta % was also calculated. When evaluating cortisol responses, the criteria were Delta % > 20% and Delta > 193 nmol/l. Moreover, to allow comparison of individual end points of the desmopressin and CRH tests at multiple levels of Delta % or Delta either for ACTH or cortisol without the bias of predetermined criteria, univariate curves of the receiver operating characteristics (ROC) were constructed by plotting the sensitivity against 1 - specificity at each level. RESULTS: In the patients with CD, the frequency of ACTH response was of 90% after both tests while the figures for cortisol were 73% after CRH and 77% after desmopressin, respectively. In the 15 patients who underwent both tests the magnitude of ACTH and cortisol responses induced by the 2 stimuli were fully comparable. In the patients with EAS a (false) positive ACTH response was found in 2/9 cases (22%) after the CRH test and in 2/5 patients (40%) after the desmopressin test. In the healthy subjects the CRH test was performed in 25 cases and the desmopressin test in 15 cases. The frequency of ACTH response was 52% following CRH and 13% following desmopressin. In the 10 healthy subjects who underwent both tests the ACTH response was significantly greater after CRH than desmopressin. The area under the ROC curve for the ACTH Delta % was significantly different than that occurring by chance following CRH but not desmopressin. The point on the ROC curve closest to 1 corresponded to an ACTH Delta % of 47% (sensitivity 87% and specificity 89%). However, a criterion of 100 % specificity would require an increase in the threshold for the ACTH Delta % to 259%. ROC analysis validated also the use of the ACTH Delta as a method to assess the response to CRH, but not after desmopressin. However, the diagnostic performance of this parameter was reduced in comparison to that of the ACTH Delta %, since the best cut-off for the Delta (6.2 pmol/l) had inferior specificity (79%). The operating characteristics of CRH and desmopressin were worse when considering cortisol responses. CONCLUSIONS: The present data suggest that the CRH test is more reliable than the desmopressin test in determining the aetiology of Cushing's syndrome. The desmopressin test resulted in a high frequency of false positive results in patients with ectopic ACTH secondary to carcinoid tumours. This finding may be due to the capability of these tumours to express the V3 vasopressin receptor through which desmopressin acts. However, the clinical endocrinologist may be confronted with some disturbing cases which are misdiagnosed because it is almost impossible to set a diagnostic criterion providing complete specificity in the differentiation of (occult) ectopic Cushing's syndrome using either CRH or desmopressin tests.

Left ventricular hypertrophy in primary hyperparathyroidism. Effects of successful parathyroidectomy.

OBJECTIVE: The association between primary hyperparathyroidism (PHPT) and increased mortality mainly from cardiovascular disease is still debated. The increased mortality previously reported in PHPT was not confirmed in a recent population based study. A high prevalence of left ventricular (LV) hypertrophy was, however, reported in this disease. Although arterial hypertension is regarded as the principal factor, the pathogenesis of LV hypertrophy in PHPT is complex and not completely defined, moreover the effects of successful parathyroidectomy (PTX) are not fully elucidated. The aims of this study were: to ascertain the prevalence of LV hypertrophy in a series of patients with PHPT in comparison to a control population, to seek for relationship between biochemical markers of disease, blood pressure (BP) levels and LV measurements and to evaluate the effects of successful PTX on LV hypertrophy during short-term follow-up. SUBJECTS AND DESIGN: Forty-three patients affected by active PHPT (16 males and 27 females, mean age 60.2 +/- 12.7 years) and 43 controls age- and sex-matched with the same prevalence of arterial hypertension were studied in a case-control analysis. Each subject underwent a M- and 2D mode echocardiographic evaluation and repeated BP measurement. In 21 PHPT submitted to surgery the echocardiographic measurement was repeated 6 months after successful PTX. MEASUREMENTS: Serum concentrations of parathyroid hormone (PTH), total-(Ca) and ionized calcium (iCa), phosphate, creatinine, total alkaline phosphatase (TALP) were measured in patients with PHPT at diagnosis and six months after PTX in the subgroup operated on; BP values were measured in three different occasion; mono and 2D echocardiographic evaluation was performed in control subjects and patients with PHPT either before and after PTX. RESULTS: LV hypertrophy, measured by LV mass index (LVMI), was present in 28/43 PHPT patients (65.1%) and in 15/43 (34.8%) controls, P < 0.05; among hypertensive subjects, 21/21 (100%) PHPT patients and 13/21 (61.9%) controls P < 0.05 were hypertrophic while among normotensive subjects, these figures were 7/22 (31.8%) for PHPT patients and 2/22 (9%) for controls, P = 0.67. At multiple regression analysis in a model including biochemical parameters and BP values, serum PTH levels were associated with LVMI values as the strongest predicting variable (0.46, P < 0.02). Six months after PTX, LVMI decreased (137.8 +/- 37.3 vs 113.0 +/- 28.5, P < 0.05) without changes in mean BP values and ratio of hypertensive patients. CONCLUSION: The present data confirm the high prevalence of LV hypertrophy in primary hyperparathyroidism also in a group of patients with an asymptomatic clinical presentation. The correlation between PTH values and left ventricular mass index suggests an action of the hormone in the pathogenesis of LV hypertrophy confirmed also by the decrease of left ventricular mass index after the reduction of PTH levels. The reversal of left ventricular mass index after parathyroidectomy could affect mortality in primary hyperparathyroidism. An echocardiographic study could be suggested in the clinical work-up of primary hyperparathyroidism in order to evaluate heart involvement and the response to successful parathyroidectomy.

Subclinical Cushing's syndrome in adrenal incidentaloma.

OBJECTIVE: Some patients with incidentally discovered adrenal adenomas display autonomous cortisol secretion not fully restrained by pituitary feedback, a condition that may be defined as subclinical Cushing's syndrome. We have evaluated the presence of subclinical Cushing's syndrome and its natural history in a cohort of patients with incidentally discovered adrenal adenomas. PATIENTS: Fifty-three consecutive patients (30 women and 23 men; median age 58 years, range 18-81 years) were studied. Diagnostic procedures were initiated for extra-adrenal complaints. Patients with known extra-adrenal malignancies or patients with hypertension of possible endocrine origin were excluded. MEASUREMENTS: All patients underwent the following endocrine evaluation: (1) measurement of DHEA-S at 0800 h, (2) measurement of serum cortisol at 0800 and 2400 h, (3) measurement of the 24-h excretion of urinary free cortisol (UFC), (4) overnight low-dose dexamethasone suppression test, (5) measurement of plasma ACTH at 0800 h (mean of at least two samples on different days), (6) oCRH stimulation test. Different groups of healthy subjects recruited from the hospital medical staff and their relatives served as controls for the various tests. The same endocrine work-up was repeated after 12 months in 25 patients. All patients were followed up at regular intervals for at least 12 months with clinical examination and abdominal computed tomography. Subclinical hypercortisolism was arbitrarily defined as definitive, probable or possible, according to the degree of endocrine abnormalities. RESULTS: UFC was significantly higher in patients with incidentaloma than in controls (262, 25-690 nmol/24 h versus 165, 25-772 nmol/24 h; P = 0.012). The percentage of subjects who did not suppress on dexamethasone was greater among patients than among healthy subjects (9/53 (17%) versus 5/103 (5%), P = 0.026). Plasma ACTH concentrations were lower in patients with adrenal incidentaloma than in controls (3, 1-9 pmol/l versus 5, 1-14 pmol/l; P = 0.014). These findings consistently point toward a functional autonomy of the adrenal adenomas even if the degree of cortisol excess is mild. Three patients fulfilled the criteria for definitive subclinical hypercortisolism, five for probable and two possible, but none of them experienced clinical and/or biochemical progression to overt hypercortisolism after 12 months. During follow-up, no signs of extra-adrenal malignancy became manifest and the size of the mass did not increase significantly in any patient. CONCLUSIONS: This study provides a clear demonstration of the current opinion that some patients with incidentally discovered adrenal adenomas may be exposed to a subtle, silent hypercortisolism. In some patients, in whom the clustering of more abnormalities in the hypothalamo-pituitary-adrenal axis occurs, subclinical Cushing's syndrome could be assumed. This term should be preferred to that of pre-clinical Cushing's syndrome since the biochemical abnormalities do not become clinically manifest, at least in the short term.

Combined cabergoline and recombinant human growth hormone treatment of an adolescent with a macroprolactinoma causing GH deficiency.

The rare macroprolactinomas seen in childhood frequently cause delayed puberty and GH deficiency. We report the combined use of cabergoline and recombinant human GH (rhGH) therapy in a male adolescent with macroprolactinoma and GH deficiency. Computed tomography and magnetic resonance imaging of the hypothalamic-pituitary region showed a macroadenoma with extrasellar extension. Neither bromocriptine nor dihydroergocryptine therapy was successful in decreasing serum PRL levels. On cabergoline treatment normal serum PRL levels were achieved within 3 months along with a marked shrinkage of the adenoma but growth rate did not increase nor did puberty start. The addition of exogenous rhGH therapy improved the growth rate, but complete pubertal development was obtained only after the administration of exogenous gonadotropins. During the combined treatment no expansion of the macroadenoma was observed. In conclusion, the combined therapy with cabergoline and rhGH seems to be safe and highly effective. Nevertheless, it warrants careful monitoring and on-going evaluation.

Different patterns of steroid secretion in patients with adrenal incidentaloma.

We previously found that a remarkable number of patients with adrenal incidentaloma display partially autonomous cortisol secretion. The amount of hypercortisolism is insufficient to give clinical expression, but enough to inhibit, in some cases, normal adrenal tissue. Other researchers found with high frequency a partial deficiency of 21-hydroxylase. The aim of the present study was to make a combined evaluation of these aspects of adrenal steroidogenesis. Twenty patients (6 men and 14 women, aged 25-74 yr; median, 59 yr) with incidentally discovered adrenal masses were studied. All had an adrenal adenoma histologically proven or diagnosed on the basis of size (< or = 4.0 cm in all but 1) and computed tomography picture (hypodense homogeneous mass with well defined margins). The following parameters were used to evaluate the ACTH-cortisol axis: overnight 1-mg dexamethasone suppression (4 nonsuppressors), ovine CRH stimulation (blunted ACTH-cortisol response in 2 cases), circadian serum cortisol rhythm (blunted night/day ratio in 4 and increased 24-h mean in 1), and 24-h urinary free cortisol excretion (always within the normal range). Three patients had 2 concomitant alterations, and 5 had a single abnormality. Partial deficiency of 21-hydroxylase was assumed in 6 patients who showed an exaggerated 17-hydroxyprogesterone response to ACTH, with a peak value of more than 10 ng/mL (> 30 nmol/L), according to New's nomogram. No abnormalities of the ACTH-cortisol axis were found in these patients, with the exception of low amplitude cortisol rhythm in 1 case. Therefore, 2 distinct patterns, dysregulated and partially autonomous cortisol secretion, on the one hand, and reduced 21-hydroxylase activity, on the other, can be found in a high number of patients bearing an adrenal incidentaloma. They appear mutually exclusive, and the differentiation by endocrine testing is quite clear. Serum dehydroepiandrosterone sulfate was below the third percentile in 13 of 20 patients and could represent a specific marker of cortical adenomas. This finding was evenly distributed among patients with subclinical hypercortisolism or partial enzymatic defect; therefore, low serum dehydroepiandrosterone sulfate is not readily attributable to suppressed ACTH secretion, which actually occurs in only some patients with subclinical hypercortisolism.