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Adrenocortical carcinoma (ACC) is an orphan disease lacking effective systemic treatment options. The low incidence of the disease and high cost of clinical trials are major obstacles in the search for improved treatment strategies. As a novel approach, registry-based clinical trials have been introduced in clinical research, so allowing for significant cost reduction, but without compromising scientific benefit. Herein, we describe how the European Network for the Study of Adrenal Tumours (ENSAT) could transform its current registry into one fit for a clinical trial infrastructure. The rationale to perform randomized registry-based trials in ACC is outlined including an analysis of relevant limitations and challenges. We summarize a survey on this concept among ENSAT members who expressed a strong interest in the concept and rated its scientific potential as high. Legal aspects, including ethical approval of registry-based randomization were identified as potential obstacles. Finally, we describe three potential randomized registry-based clinical trials in an adjuvant setting and for advanced disease with a high potential to be executed within the framework of an advanced ENSAT registry. Thus we, therefore, provide the basis for future registry-based trials for ACC patients. This could ultimately provide proof-of-principle of how to perform more effective randomized trials for an orphan disease.

The aim of our study was to investigate the effects of a combined treatment with alpha-lipoic acid (ALA) and myoinositol (MYO) on clinical, endocrine and metabolic features of women affected by polycystic ovary syndrome (PCOS). In this pilot cohort study, forty women with PCOS were enrolled and clinical, hormonal and metabolic parameters were evaluated before and after a six-months combined treatment with ALA and MYO daily. Studied patients experienced a significant increase in the number of cycles in six months (p < 0.01). The free androgen index (FAI), the mean androstenedione and DHEAS levels significantly decreased after treatment (p < 0.05). Mean SHBG levels significantly raised (p < 0.01). A significant improvement in mean Ferriman–Gallwey (F–G) score (p < 0.01) and a significant reduction of BMI (p < 0.01) were also observed. A significant reduction of AMH levels, ovarian volume and total antral follicular count were observed in our studied women (p< 0.05). No significant changes occurred in gluco-insulinaemic and lipid parameters after treatment. The combined treatment of ALA and MYO is able to restore the menstrual pattern and to improve the hormonal milieu of PCOS women, even in the absence of apparent changes in insulin metabolism.

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OBJECTIVE: To develop and validate a specific simple measure of insulin sensitivity using oral glucose tolerance test (OGTT) values for lean polycystic ovary syndrome (PCOS) women. DESIGN: Retrospective study. SETTING: Gynecologic Outpatient Clinic of University Hospital, affiliated with Unit of Gynecologic Endocrinology. PATIENT(S): Totals of 201 lean and 198 overweight/obese (ov-ob) nondiabetic PCOS patients were retrospectively selected. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): All patients underwent OGTT, euglycemic-hyperinsulinemic clamp, and androgenic and biochemical assays. The predictive performance of each insulin resistance (IR) index was analyzed with the use of receiver operating characteristic (ROC) curves. RESULT(S): Higher correlation coefficients with clamp studies were obtained with the Belfiore Area (RS=0.579) and the homeostasis-model assessment (HOMA)-M120 (RS=-0.576) in lean PCOS patients and with the Sib (RS=0.697) in ov-ob PCOS patients. The best predictive index of IR in lean PCOS was a HOMA-M120 value of ≥12.8 or more (area under the ROC curve [AUC] 92.4%). In the ov-ob PCOS population, the best predictive performance was obtained by a Sib of ≤10.2 or less (AUC 85.7%). CONCLUSION(S): IR should be assessed in all PCOS women, both lean and ov-ob subjects. The HOMA-M120 resulted as a very simple tool, validated specifically for the lean PCOS woman whose cardiometabolic impairment is more frequently misunderstood.

The long-term consequences of subclinical hypercortisolism (SH) in patients with adrenal incidentalomas (AIs) are unknown.

An emerging branch of research is examining the linkage between Vitamin D and nonskeletal disorders, including endocrine diseases. In this regard, a still little studied aspect concerns the involvement of vitamin D in adrenal gland disorders. Adrenal gland disorders, which might be theoretically affected by vitamin D unbalance, include adrenal insufficiency, Cushing's syndrome, adrenocortical tumors and hyperaldosteronism. In this review, we provide an updated document, which tries to collect and discuss the limited evidence to be found in the literature about the relationship between vitamin D and adrenal disorders. We conclude that there is insufficient evidence proving a causal relationship between vitamin D levels and adrenal disorders. Evidence coming from cross-sectional clinical studies can hardly clarify what comes first between vitamin D unbalance and adrenal disease. On the other hand, longitudinal studies monitoring the levels of vitamin D in patients with adrenal disorders or, conversely, the possible development of adrenal pathologies in subjects affected by impaired vitamin D levels would be able to elucidate this still unclear issue.

Clinical evidences reported subclinical alterations of thyroid function in obesity, although the relationship between thyroid status and obesity remains unclear. We cross-sectionally investigated the influence of metabolic features on hypothalamic-pituitary-thyroid axis in obesity.

Osteoporosis in men is less frequent than in women and is more often due to an underlying cause, such as nutritional deficiencies or lifestyle factors, endocrinological or systemic affections, long-term specific therapies. The growing attention on male osteoporosis is mainly explained by the increasing use of some drugs producing bone loss as frequent side effect, like gonadotropin-releasing hormone (GnRH) agonists for prostate cancer, immunosuppressive agents, or glucocorticoids. Glucocorticoids are largely used for the cure of lots of haematological, rheumatological, dermatological, pneumological, and other systemic diseases. It is well known glucocorticoid-induced osteoporosis (GIOP) develops rapidly at prednisone > 5mg/d or equivalent levels but recurrence is recently also observed in patients receiving low dose and intermittent therapy. However, the possible side effects of corticosteroids at low dose on bone are not completely understood and rightly prevented. We present the case of a young man with precocious bone loss. His improper and irregular use of corticosteroids at low dose was finally recognized as the underlying cause of his unexplainable bone demineralization. The following short review about effects of glucocorticoids on bone suggests fracture incidence and bone mineral density should be assessed even in young people and men perceiving glucocorticoids at undefined dose for long period.

It is largely recognized that Growth Hormone (GH) plays an important role in linear growth during childhood and subsequent completion of appropriate height in early adulthood. It has also significant influence on a variety of metabolic activities, as well as the cardiovascular system and quality of life (QoL) in adults. GH is involved in the attainment of optimal Bone Mineral Density (BMD), the most important predictor of osteoporotic fractures, during the transition from paediatric to adult age. The time interval between paediatric and adult age is a critical period of life to clinically assess persistence of GHD in patients affected by childhood onset GHD (COGHD) and determine the need for continuing treatment with recombinant human Growth Hormone (rhGH) even in the face of closure of epiphyseal growth plates. It has been reported GHD is associated with higher fracture's risk in COGHD patients and GH therapy should minimize, if not prevent, osteoporosis in adulthood. We report the case of a COGHD young man, rhGH treated until final height completion, presenting a wrist fracture and precocious bone density loss.

In patients with adrenal incidentalomas (AIs), cross-sectional studies suggested the presence of an association between subclinical hypercortisolism (SH) and an increased prevalence of vertebral fractures (VFx) and spinal deformity index (SDI), which is a clinical index of bone quality. No longitudinal studies investigated the incidence of VFx and SDI changes over time in SH. The aim of this study was to evaluate VFx risk and SDI changes in SH over time. One-hundred-three consecutive AI patients were studied at baseline and after 12 and 24 months. Patients were divided into SH(+) (n = 27) and SH(-) (n = 76) groups on the basis of the presence of two or more among urinary free cortisol greater than 70 µg/24 hours, serum cortisol after 1-mg dexamethasone suppression test greater than 3.0 µg/dL, and adrenocorticotropic hormone (ACTH) less than 10 pg/mL in 2 or more of the 3 evaluations. At baseline and after 24 months, bone mineral density (BMD) by dual-energy X-ray absorptiometry and the presence of VFx and SDI by summing the grade of deformity for each vertebra were evaluated. At the end of follow-up, the SH(+) group showed a higher prevalence of VFx (81.5%) as compared with baseline (55.6%, p = .04) and a worsening of SDI (2.11 ± 1.85 versus 1.11 ± 1.47, p = .032) associated with SH regardless of age, gender, body mass index , BMD, baseline SDI, menopause duration [odds ratio (OR) = 12.3, 95% confidence interval (CI) 4.1-36.5, p = .001]. The incidence of new vertebral fractures was higher in the SH(+) group (48%) than in the SH(-) group (13%; p = .001). It is concluded that subclinical hypercortisolism is associated with an increased risk of VFx and a possible deterioration of bone quality.

CONTEXT: The aim of treatment in patients affected by anorexia nervosa (AN) is weight recovery. However, during weight gain, anorectic patients' body composition is changed, with an increase in abdominal fat, particularly in the visceral compartment. OBJECTIVE: We hypothesized that changes in body composition, particularly in abdominal fat, are responsible for the variability in insulin sensitivity (IS) in different stages of AN. DESIGN AND MEASUREMENTS: We compared 20 anorectic patients in the acute stage, 19 in the weight-recovery stage and 21 controls. All subjects underwent an oral glucose tolerance test, hyperinsulinaemic euglycaemic clamp and dual energy X-ray absorptiometry to measure body composition. RESULTS: The percentage of trunk fat was higher in weight recovery than in the acute phase (47·7 ± 8·4%vs 34·6 ± 7·6%; P ≤ 0·01) and in the control group (33·4 ± 7·6; P < 0·01 vs weight recovery). Although the recovery group gained weight, their body mass index (BMI) was not statistically different from that of the acute group (14·4 ± 1·1 vs 13·6 ± 1·8 kg/m(2) ). Insulin sensitivity was lower in the weight-recovery group than the acute group (4·7 ± 1·5 vs 7·8 ± 1·6 mg/kg/min; P < 0·01) and controls (7·7 ± 1·4 mg/kg/min; P < 0·01). A linear negative correlation was found between IS and the percentage of abdominal fat in the weight-recovery and acute groups (r = -0·51; P = 0·04 and r = -0·53; P = 0·04 respectively), while IS did not correlate with BMI. CONCLUSION: Although weight-recovery represents the main aim of treatment in AN, refeeding is associated with an increase in abdominal fat which might be responsible of the onset of insulin resistance. As BMI and weight-recovery were associated with impaired IS, they cannot be considered the only aim of treatment of AN.

We read with interest the article by Alvarez et al, which aimed to investigate the relations of circulating 25-hydroxyvitamin D [25(OH)D] and parathyroid hormone (PTH) concentrations with direct measurements of insulin sensitivity, after robust measures of body composition and fat distribution were accounted for. We would like to express our opinion and a different interpretation of the data provided by authors, with the hope that other points for discussion are brought up. In a very recent publication, Alvarez et al provided novel findings suggesting that dietary vitamin D is independently associated with insulin sensitivity in African Americans (AAs) but not in European Americans (EAs). Interestingly, the 2 groups were identical for hepatic insulin sensitivity [homeostatic model assessment (HOMA)], whereas Si, a method for measuring insulin sensitivity that encompasses both hepatic and peripheral tissues, was lower in AAs, therefore suggesting a pivotal role for insulin resistance in skeletal muscle [especially in the presence of identical body mass index (BMI)] in correlation with 25(OH)D. In the present article, the authors suggest that 25(OH)D and PTH concentrations are independently associated with whole-body insulin sensitivity and suggest that these variables may influence insulin sensitivity through independent mechanisms. In fact, multiple linear regression analysis indicated that 25(OH)D and PTH concentrations were independently related to Si after adjustment for age, race, and intraabdominal adipose tissue. It is well known, however, that adipose tissue is the natural reservoir for lipo-soluble 25(OH)D. The higher BMI and the higher subcutaneous fat content found in AAs (although the latter difference was not statistically significant) could therefore explain the differences in 25(OH)D concentration, as well as in HOMA index, found by the authors. We examined the effect of 25(OH)D on insulin sensitivity in obese subjects and found a linear correlation be

The aim of this retrospective study was to evaluate the efficacy, safety, and tolerability of lanreotide autogel given to metastatic well-differentiated (WD) neuroendocrine tumors (NET) patients observed in our Institute between 2005 and 2008. Patients with metastatic NET referred to our tertiary referral center were given lanreotide autogel 120 mg/month by deep sc injection for a period of at least 24 months. The efficacy was evaluated by the relief of disease symptoms, behavior of tumor markers and response rate in terms of time to tumor progression. Safety and tolerability were evaluated by assessing the onset of adverse events and treatment feasibility. Twenty-three patients (13 males), median age 62 yr (range 32-87) were considered for the study. All patients were affected by WD metastatic NET and had tumor progression in the last 6 months before the enrolment in the study. Median duration of response was 28 months (range 6-50 months). Fourteen patients (60.9%) showed flushing and diarrhea which improved by 85.7% and 55.6%, respectively, bronchoconstrinction and abdominal pain also ameliorated. A complete, partial or no-changed response in the tumor markers behavior was observed, respectively, in 42.9%, 22.9%, and 17.1% of cases. According to RECIST (Response Evaluation Criteria In Solid Tumors) criteria (version 1.1), there were 2 partial regression (8.7%) and 15 stable disease (65.3%); 6 patients (26.0%) progressed. No patient complained from any severe adverse reaction. The results of our study suggest that lanreotide autogel is effective in the symptoms, biochemical markers, and tumor progression control of WD metastatic NET and confirm that the treatment is well tolerated.

We read with interest the article by Kayaniyil et al. that supplied elegant data suggesting that 25- hydroxyvitamin D [25(OH)D] is related to insulin resistance and _-cell function in a large population at high risk for type 2 diabetes and/or metabolic syndrome, thus concluding that 25(OH)D may be an independent risk factor for diabetes. We have, however, some concerns. First, the studied population was mainly composed of obese subjects (the mean BMI was 30.5 kg/m2). Clearly, within a population with such a high BMI, the major variable influencing insulin sensitivity is fat mass. An increased fat mass (within the same BMI) could determine both the reduced insulin sensitivity and 25(OH)D. The two variables therefore correlate, but are not causally related. In our recently published article, we approached this important question by comparing two groups of obese subjects matched by BMI but different in terms of insulin sensitivity: no differences in 25(OH)D concentrations could be found, suggesting that the adipose tissue is its reservoir. Kayaniyil et al. themselves reported a weaker correlation in their obese (BMI 30 kg/m2) subpopulation but, unfortunately, they did not provide data on body composition. Second, although the correlation within the high risk (for diabetes) population is intriguing, a control population is missing. In particular, it is not reported whether the studied population has lower 25(OH)D concentration than an hypothetical control cohort. If this was not the case, the working hypothesis fails. How could normal 25(OH)D determine insulin resistance? Third, if 25(OH)D is involved in the pathogenesis of type 2 diabetes, one would expect that a supplementation of calcitriol or its analogues would ameliorate the glucose metabolism. This was not the case either in insulin-resistant diabetic patients or in healthy subjects (4). As we and others reported, 25(OH)D concentration mainly reflects body fat mass; the reduction of fat mass, rather than vitamin

The prevalence of hypovitaminosis D is high among obese subjects. Further, low 25-hydroxyvitamin D (25(OH)D) concentration has been postulated to be a risk factor for type 2 diabetes, although its relation with insulin-sensitivity is not well investigated. Thus, we aimed to investigate the relationship between 25(OH)D concentration and insulin-sensitivity, using the glucose clamp technique. In total, 39 subjects with no known history of diabetes mellitus were recruited. The association of 25(OH)D concentration with insulin-sensitivity was evaluated by hyperinsulinemic euglycemic clamp. Subjects with low 25(OH)D (<50 nmol/l) had higher BMI (P = 0.048), parathyroid hormone (PTH) (P = 0.040), total cholesterol (P = 0.012), low-density lipoprotein (LDL) cholesterol (P = 0.044), triglycerides (P = 0.048), and lower insulin-sensitivity as evaluated by clamp study (P = 0.047). There was significant correlation between 25(OH)D and BMI (r = -0.58; P = 0.01), PTH (r = -0.44; P < 0.01), insulin-sensitivity (r = 0.43; P < 0.01), total (r = -0.34; P = 0.030) and LDL (r = -0.40; P = 0.023) (but not high-density lipoprotein (HDL)) cholesterol, and triglycerides (r = 0.45; P = 0.01). Multivariate analysis using 25(OH)D concentration, BMI, insulin-sensitivity, HDL cholesterol, LDL cholesterol, total cholesterol, and triglycerides, as the cofactors was performed. BMI was found to be the most powerful predictor of 25(OH)D concentration (r = -0.52; P < 0.01), whereas insulin-sensitivity was not significant. Our study suggested that there is no cause-effect relationship between vitamin D and insulin-sensitivity. In obesity, both low 25(OH)D concentration and insulin-resistance appear to be dependent on the increased body size.

Context: Subtle hypercortisolism is associated with an increased risk of vertebral fracture (VFx). Objective: The objective was to determine the best parameters of cortisol secretion for detecting the VFx risk in patients with adrenal incidentalomas (AI). Design: This was a retrospective (cross-sectional arm) and prospective (longitudinal arm) design. In the cross-sectional arm, we assessed the accuracy of the cortisol secretion indexes in identifying the patients with VFx (prevalent VFx). In the longitudinal arm, we tested the cortisol secretion parameters, which were able to identify the prevalent VFx, for the prediction of the occurrence of a new VFx (incident VFx) in AI patients followed-up for at least 2 years. Setting: Four referral Italian endocrinology units participated in this study. Patients: A total of 444 and 126 AI patients without symptoms of hypercortisolism enrolled in the cross-sectional arm and longitudinal arm, respectively. Main Outcome Measures: Serum cortisol after a 1-mg dexamethasone suppression test (1 mg DST), urinary free cortisol, ACTH, bone mineral density at lumbar spine and femoral neck (by dual-energy X-ray absorptiometry), and the VFx presence (by X-ray). Results: The cortisol levels after 1 mg DST that were greater than 2.0-g/dl (55 nmol/liter) were the best criteria for detecting patients with both prevalent (73.6% sensitivity, 70.5% specificity) and incident VFx (80% sensitivity, 68.8% specificity) and were associated with a 10-fold increased risk of a new VFx (odds ratio,10.27; 95% confidence interval, 3.39-31.12; P <.0001), regardless of age, gender, bone mineral density at lumbar spine, and prevalent VFx. Conclusions: In AI patients without symptoms of overt hypercortisolism, the cortisol levels after 1 mg DST greater than 2.0-g/dl (55 nmol/liter) represent the best criterion for detecting prevalent and incident VFx.

1. Monotherapy with mitotane is recommended in patients after incomplete surgical resection or in patients not fit for surgery or chemotherapy 1 ⊕⊕OO. 2. Monotherapy with mitotane may be recommended in advanced ACC with involvement of few organs and low-grade mitotic index, particularly when RFS after removal of the primary tumor has been longer than 12 months 1 ⊕OOOO. 3. The chemotherapeutic regimen EDP in combination with mitotane is recommended in most patients with advanced or metastatic ACC 1 ⊕⊕⊕⊕. 4. There are insufficient data to recommend a particular targeted therapy in patients with advanced ACC beyond ongoing clinical trials.

Prolactin and cortisol responses to d-fenfluramine challenge of central serotonin are reduced in depressed and suicidal patients. Low serum cholesterol levels are also reported in suicidal behavior. Thus, we examined for a relationship between serum cholesterol and fenfluramine challenge responses in patients with depression and/or attempted suicide.