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Background: Weight loss is a milestone in the prevention of chronic diseases associated with high morbility and mortality in industrialized countries. Very-low calorie ketogenic diets (VLCKDs) are increasingly used in clinical practice for weight loss and management of obesity-related comorbidities. Despite evidence on the clinical benefits of VLCKDs is rapidly emerging, some concern still exists about their potential risks and their use in the long-term, due to paucity of clinical studies. Notably, there is an important lack of guidelines on this topic, and the use and implementation of VLCKDs occurs vastly in the absence of clear evidence-based indications. Purpose: We describe here the biochemistry, benefits and risks of VLCKDs, and provide recommendations on the correct use of this therapeutic approach for weight loss and management of metabolic diseases at different stages of life.

Cushing's disease (CD) is a severe endocrine condition caused by an adrenocorticotropin (ACTH)-pro- ducing pituitary adenoma that chronically stimulates adrenocortical cortisol production and with potentially serious complications if not or inadequately treated. Active CD may produce a fourfold increase in mortality and is associated with significant morbidities. Moreover, excess mortality risk may persist even after CD treatment. Although predictors of risk in treated CD are not fully understood, the importance of early recognition and ade- quate treatment is well established. Surgery with resection of a pituitary adenoma is still the first line therapy, being successful in about 60-70 % of patients; however, recur- rence within 2-4 years may often occur. When surgery fails, medical treatment can reduce cortisol production and ameliorate clinical manifestations while more definitive therapy becomes effective. Compounds that target hypo- thalamic-pituitary axis, glucocorticoid synthesis or adre- nocortical function are currently used to control the deleterious effects of chronic glucocorticoid excess. In this review we describe and analyze the molecular basis of the drugs targeting the disease at central level, suppressing ACTH secretion, as well as at peripheral level, acting as adrenal inhibitors, or glucocorticoid receptor antagonists. Understanding of the underlying molecular mechanisms in CD and of glucocorticoid biology should promote the development of new targeted and more successful therapies in the future. Indeed, most of the drugs discussed have been tested in limited clinical trials, but there is potential ther- apeutic benefit in compounds with better specificity for the class of receptors expressed by ACTH-secreting tumors. However, long-term follow-up with management of per- sistent comorbidities is needed even after successful treatment of CD.

In the management of adrenocorticotropic hormone (ACTH)–dependent Cushing's syndrome, inferior petrosal sinus sampling (IPSS) provides information for the endocrinologist, the neurosurgeon, and the neuroradiologist. To the endocrinologist who performs the etiological diagnosis, results of IPSS confirm or exclude the diagnosis of Cushing's disease with 80%–100% sensitivity and over 95% specificity. Baseline central-peripheral gradients have suboptimal accuracy, and stimulation with corticotropin-releasing hormone (CRH), possibly desmopressin, has to be performed. The rationale for the use of IPSS in this context depends on other diagnostic means, taking availability of CRH and reliability of dynamic testing and pituitary imaging into account. As regards the other specialists, the neuroradiologist may collate results of IPSS with findings at imaging, while IPSS may prove useful to the neurosurgeon to chart a surgical course. The present review illustrates the current standpoint of these 3 specialists on the role of IPSS.

Pasireotide is the first medical therapy officially approved for the treatment of adult patients with Cushing's disease (CD) who experienced a failure of pituitary surgery or are not candidates for surgery and require medical therapeutic intervention. The current study aimed at investigating the effects of long-term treatment with pasireotide (up to 24 months) on tumor mass in a group of patients with CD, participating to a phase III study. Fourteen CD patients entered the phase III clinical trial CSOM230B2305 at Naples Center, and eight (seven women, one man, aged 38.9 ± 17.6 years), including seven with a microadenoma and one with a macroadenoma, received treatment with pasireotide at the dose of 600-1200 µg bid for at least 6 months, and were considered for the analysis of the study. These eight patients were subjected to the evaluation of pituitary tumor volume by pituitary MRI, together with the evaluation of urinary cortisol levels, at baseline and every 6 months for the entire period of treatment. Pasireotide treatment induced full disease control in 37.5 % and partial disease control in 37.5 % after 6 months, whereas full and partial disease control after 12 months was obtained in 28.6 % and in 57.1 % of patients, respectively. A significant (>25 %) reduction in tumor volume was found in 62.5 % and in 100 % of patients, after 6 and 12 months, respectively. In particular, after 6 months, a slight tumor shrinkage (between 25.1 and 50 %) was observed in 25 %, moderate (50.1-75 %) in 25 %, and marked (>75 %) in 12.5 % of patients, whereas after 12 months, a slight tumor shrinkage was observed in 43 %, moderate in 14 %, and marked in 43 % of patients. In 25 % of patients (two patients), a marked tumor shrinkage was recorded, with tumor mass disappearance in one case; this tumor shrinkage was associated to rapid and sustained biochemical remission up to 24 months of continuous pasireotide treatment. These two cases represent the first cases with a documentation of such a notable effect of pasireotide on tumor mass. Pasireotide induces significant tumor shrinkage in 62.5 % of patients after 6 months and in 100 % of patients after 12 months, and occasionally induces a radiological disappearance of the tumor. This evidence supports and strengthens the role of pasireotide as medical treatment specifically addressed to patients with CD, particularly in those who had unsuccessful pituitary surgery, or are not candidates for surgery.

Background: Cushing disease (CD) is associated with increased morbidity and mortality caused by cardiometabolic alterations. Visceral Adiposity Index (VAI) expresses impaired adipose distribution and function which are related to the cardiometabolic risk. Aim: To evaluate in a cohort of CD patients the correlation between VAI and other parameters, such as gender, etiology, age, cortisol values measured in the morning (8 am) and at the midnight, urinary free cortisol (24h sample of urine, average of three samples) and glucose tolerance as normal glucose tolerance (NGT), impaired fasting glucose (IFG), impaired glucose tolerance (IGT), IFG+IGT and diabetes mellitus. Materials and methods: We performed a retrospective study in 140 CD patients consecutively afferent in outpatients clinic of the Universities of Naples and Palermo. Patients were divided by VAI tertiles and trend analysis was evaluated. Results: 27 men and 113 women, mean age of 40.98±16,61 years and BMI of 30.86 ± 6.01 Kg/m2 were studied. 62.7% of patients had a metabolic syndrome, 30.7% diabetes mellitus, 5.7% IFG, 12.1% IGT and 0.7% IFG+IGT. Among all parameters evaluated, only the midnight cortisol showed a significant increasing trend according to VAI tertiles (I tertile 172.57±77.24, II tertile 168.40±73.67, III tertile 227.06±119.42; p=0.045). Significant correlations between HOMA IR increase and VAI tertiles (I tertile 2.16±1.18, II tertile 3.13±1.49, III tertile 2.81±1.37 p=0.020), HbA1c increase and VAI tertiles (I tertile 5.87±0.84%, II tertile 6.40±1.23%, III tertile 6.60±1.19% p=0.018) were found. No significant trend for HOMA-b was observed. Conclusions: CD women have a higher cardiometabolic risk than men and this risk becomes more higher more older is the patient. Therefore these patients have a condition of visceral adiposity dysfunction that contributes to decrease of insulin sensitivity, but not at a reduction in betacell function, like the typical diabetes mellitus at onset. Thus, visceral fat dysfunction seems to be a key factor not only in favouring diabetes mellitus onset but also in worsening glycaemic control in Cushing diabetic patients.

Introduction: Hyperprolactinemia is reportedly associated with an impaired metabolic profile, particularly in patients with concomitant hypogonadism. The current study aimed at investigating the effects of short (12 months) and long (60 months) treatment with cabergoline (CAB) on metabolic complications, metabolic syndrome (MS) prevalence and visceral adiposity index (VAI) in hyperprolactinemic patients (pts). Patients and Methods: Seventy-one pts (51 F, 20 M, aged 35.4±11.7 yrs), including 36 with microprolactinomas, 32 with macroprolactinomas and 3 with non-tumoral hyperprolactinemia, entered the study. In all pts, PRL and metabolic parameters (BMI, waist circumference, lipid and glucose profile, insulin, VAI) were assessed at diagnosis and after 12 and 60 months of continuous CAB treatment. MS was evaluated in line with NCEP-ATP III criteria. Results: Compared to baseline, CAB induced a significant decrease in PRL levels after 12 months (p=0.000) and a further decrease after 60 months (p=0.000) with complete normalization in 93% of pts. At baseline, MS prevalence was significantly higher in pts with PRL above significantly decreased after 12 (12.6%, p= 0.009) and 60 (7%, p=0.000) months of treatment compared to baseline (32.4%). Total cholesterol and triglycerides were significantly reduced after 12-month CAB compared to baseline (p=0.03), and further decreased (p=0.000) after 60-month follow-up. HDL cholesterol resulted significantly increased after 60-month CAB compared to baseline (p=0.000) and 12 months (p=0.000). Glucose and insulin significantly decreased after 12 months of CAB (p=0.001), and were further improved after long-term CAB (p=0.03 and p=0.000 respectively) compared to short-term therapy. Compared to baseline, a slight but not significant decrease in VAI was found at 12-month evaluation, whereas VAI was significantly decreased after 60 months of treatment (p=0.000). Conclusions: Short-term CAB treatment significantly improves metabolic profile, so that to reduce MS prevalence, whereas longer treatment is required to achieve a significant improvement of VAI.

Background: Patients with Congenital Adrenal Hypeplasia (CAH) due to 21-hydroxylase deficiency need a life-long therapy with glucocorticoids (GCs) and tend to have a cluster of metabolic risk factors, which are consistent with metabolic syndrome (MS). Most frequently used GCs are Hydrocortisone (HC) and Prednisone (P), different for both pharmacodynamic and pharmacokynetic characteristics. Aim: The aim of this study was to evaluate the impact of HC and P on VAI, a new indicator of visceral fat function, and on metabolic profile in CAH patients long term treated with GC. Materials and Methods: Thirty-two patients (22 F, 10 M, 18-46 yrs), among which 16 (11 F, 5 M) treated with HC (dose 10-45 mg/die) and 16 (11 F, 5 M) treated with P (dose 5-15 mg/die), were retrospectively enrolled in the study. VAI was calculated according to Amato and colleagues. Metabolic profile was evaluated measuring each component of MS, in line with IDF criteria, as well as the area under the curve (AUC) of glucose and insulin during 120 min oral glucose tolerance test (OGTT), the homeostasis model assessment of the insulin resistance index (HOMA-IR) and the insulin sensitivity index (ISI). Results: Patients treated with P showed higher VAI (p< 0.001), waist circumference (p=0,03), triglycerides (P

Cushing's syndrome is associated with increased mortality, mainly due to cardiovascular complications, which are sustained by the common development of systemic arterial hypertension and metabolic syndrome, which partially persist after the disease remission. Cardiovascular diseases and hypertension associated with endogenous hypercortisolism reveal underexplored peculiarities. The use of exogenous corticosteroids also impacts on hypertension and cardiovascular system, especially after prolonged treatment. The mechanisms involved in the development of hypertension differ, whether glucocorticoid excess is acute or chronic, and the source endogenous or exogenous, introducing inconsistencies among published studies. The pleiotropic effects of glucocorticoids and the overlap of the several regulatory mechanisms controlling blood pressure suggest that a rigorous comparison of in-vivo and in-vitro studies is necessary to draw reliable conclusions. This review, developed during the first ‘Altogether to Beat Cushing's syndrome’ workshop held in Capri in 2012, evaluates the most important peculiarities of hypertension associated with CS, with a particular focus on its pathophysiology. A critical appraisal of most significant animal and human studies is compared with a systematic review of the few available clinical trials. A special attention is dedicated to the description of the clinical features and cardiovascular damage secondary to glucocorticoid excess. On the basis of the consensus reached during the workshop, a pathophysiology-oriented therapeutic algorithm has been developed and it could serve as a first attempt to rationalize the treatment of hypertension in Cushing's syndrome.

Guidelines for the management of osteoporosis induced by endogenous hypercortisolism are not available. Both the American College of Rheumatology and the International Osteoporosis Foundation recommend to modulate the treatment of exogenous glucocorticoid-induced osteoporosis (GIO) based on the individual fracture risk profile (calculated by FRAX) and dose of glucocorticoid used, but it is difficult to translate corticosteroid dosages to different degrees of endogenous hypercortisolism, and there are no data on validation of FRAX stratification method in patients with endogenous hypercortisolism. Consequently, it is unclear whether such recommendations may be adapted to patients with endogenous hypercortisolism. Moreover, patients with exogenous GIO take glucocorticoids since suffering a disease that commonly affects bone. On the other hand, the correction of coexistent risk factors, which may contribute to increase the fracture risk in patients exposed to glucocorticoid excess, and the removal of the cause of endogenous hypercortisolism, may lead to the recovery of bone health. Although the correction of hypercortisolism and of possible coexistent risk factors is necessary to favor the normalization of bone turnover with recovery of bone mass; in some patients, the fracture risk could not be normalized and specific anti-osteoporotic drugs should be given. Who, when, and how the patient with endogenous hypercortisolism should be treated with bone-active therapy is discussed.

Deficiency of 17β-hydroxysteroid dehydrogenase type 3 (17βHSD3), an enzyme converting androstenedione (A) to testosterone (T), is a rare cause of autosomal recessive 46,XY disorder of sexual development (DSD). A 18-years phenotypically female patient from southern Italy presented with primary amenorrhea. She had deep voice, macrocephaly, enlarged and bulbous nasal tip, macrostomia, facial acne, breast asymmetry, hypoplasia of the first finger of right hand, proximal implant of the fifth metatarsus bilaterally as well as an increased muscle mass and hirsutism, with hair distribution on face, neck, chest, abdomen, pubic region and on upper and lower limbs. Genital exam showed thickened labra majora with absence of labra minora and a blind-ending pseudo-vagina with clitoris enlargement. Karyotype analysis showed a male genotype (46,XY). Hormonal evaluation showed decreased T (188 ng/dL-6.5 nmol/L) and increased A (10 ng/mL-34,96 nmol/L), considering male reference ranges, resulting in a decreased T/A ratio (0,186). MRI identified testicles in inguinal regions. Human Chorionic Gonadotropin test showed T/A ratio permanently under 0,8. These evidences were suggestive of a 46,XY DSD due to 17βHSD3 deficiency. An homozygous mutation (IVS3 -1 G>C or c.326-1G>C) of the 17βHSD3 gene was discovered. Psychologist identified a well determined female gender identity. It was decided to proceed with gonadectomy and vaginal enlargement by use of dilatators. Conclusion: The case described represents a new case of DSD due to 17βHSD3 deficiency. This patient, raised as a girl, is diagnosed in a very late stage. The identified mutation, previously reported only in Dutch and Brazilian population, is one of 27 presently known mutations of 17βHSD3 gene and is never reported in Italian population.

Context: Glucocorticoid (GC) replacement therapy in patients with adrenal insufficiency (AI) is life saving. After over 50years of conventional GC treatment, novel formulations are now entering routine clinical practice. Methods: Given the spectrum of medications currently available and new insights into the understanding of AI, the authors reviewed relevant medical literature with emphasis on original studies, prospective observational data and randomized controlled trials performed in the past 35years. The Expert Opinion of a panel of selected endocrinologists was sought to answer specific clinical questions. The objective was to provide an evidence-supported guide, for the use of GC in various settings from university hospitals to outpatient clinics, that offers specific advice tailored to the individual patient. Results: The Panel reviewed available GC replacement therapies, comprising short-acting, intermediate and long-acting oral formulations, subcutaneous formulations and the novel modified-release hydrocortisone. Advantages and disadvantages of these formulations were reviewed. Conclusions: In the Panel’s opinion, achieving the optimal GC timing and dosing is needed to improve the outcome of AI. No-single formulation offers the best option for every patients. Recent data suggest that more emphasis should be given to the timing of intake. Tailoring of GS should be attempted in all patients—by experts—on a case-by-case basis. The Panel identified specific subgroups of AI patients that could be help by this process. Long-term studies areneeded to confirm the short-term benefits associated with the modified-release GCs. The impact of GC tailoring has yet to be proven in terms of hospitalization rate, morbidity and mortality.

Background and ObjectivesEndocrine complications have been described in patients affected by RASopathies but no systematic assessment has been reported. In this study, we investigate the prevalence of endocrine disorders in a consecutive unselected cohort of patients with RASopathies.Study Design72 patients with a genetically confirmed RASopathy (Noonan syndrome [NS], N=53; 29 LEOPARD syndrome [LS], N=2; cardiofaciocutaneous syndrome [CFCS], N=14; subjects showing co-occurring pathogenic variants in PTPN11 and NF1, N=3) and an age- and sex-matched healthy controls were included in the study. Endocrine system involvement was investigated by assessing the thyroid function, pubertal development, auxological parameters, adrenal function and bone metabolism.ResultsShort stature was detected in 40% and 64% of the NS and CFCS subcohorts, respectively. Patients showed lower Z-scores at DXA than controls (pConclusionsThe collected data demonstrate a high prevalence of thyroid autoimmunity, confirming an increased risk to develop autoimmune disorders both in NS and CFCS. Reduced BMD, probably associated to reduced physical activity and inflammatory cytokines, also occurs. These findings are expected to have implications for the follow-up and prevention of osteopenia/osteoporosis in both NS and CFCS.

Background Glycogen storage disease type I (GSDI) is an inborn error of carbohydrate metabolism caused by mutations of either the G6PC gene (GSDIa) or the SLC37A4 gene (GSDIb). Glucose 6-phosphate (G6P) availability has been shown to modulate 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1), an ER-bound enzyme catalyzing the local conversion of inactive cortisone into active cortisol. Adrenal cortex assessment has never been performed in GSDI. The aim of the current study was to evaluate the adrenal cortex hormones levels in GSDI patients. Methods Seventeen GSDI (10 GSDIa and 7 GSDIb) patients and thirty-four age and sex-matched controls were enrolled. Baseline adrenal cortex hormones and biochemical markers of metabolic control serum levels were analyzed. Low dose ACTH stimulation test was also performed. Results Baseline cortisol serum levels were higher in GSDIa patients (p = 0.042) and lower in GSDIb patients (p = 0.041) than controls. GSDIa patients also showed higher peak cortisol response (p = 0.000) and Cortisol AUC (p = 0.029). In GSDIa patients, serum cholesterol (p = 0.000), triglycerides (p = 0.000), lactate (p = 0.000) and uric acid (p = 0.008) levels were higher and bicarbonate (p = 0.000) levels were lower than controls. In GSDIb patients, serum cholesterol levels (p = 0.016) were lower and lactate (p = 0.000) and uric acid (p = 0.000) levels were higher than controls. Baseline cortisol serum levels directly correlated with cholesterol (ρ = 0.65, p = 0.005) and triglycerides (ρ = 0.60, p = 0.012) serum levels in GSDI patients. Conclusions The present study showed impaired cortisol levels in GSDI patients, with opposite trend between GSDIa and GSDIb. The otherwise preserved adrenal cortex function suggests that this finding might be secondary to local deregulation rather than hypothalamo-pituitary-adrenal axis dysfunction in GSDI patients. We hypothesize that 11βHSD1 might represent the link between endocrine regulation and metabolic derangement in GSDI, constituting new potential therapeutic target in GSDI patients.

Bone metabolism has been rarely investigated in children affected by Neurofibromatosis type 1 (NF1). Aim of the present study was to assess bone mineral metabolism in children and adults NF1 patients, to determine the relevant factors potentially involved in the development of reduced bone mineral density (BMD), and provide possible therapeutic intervention in NF1 patients. 114 NF1 patients and sex and age matched controls were enrolled into the study. Clinical and biochemical factors reflecting bone metabolism were evaluated. Factors potentially affecting BMD were also investigated including: physical activity, sun exposure, vitamin D intake. Whenever the presence of vitamin D deficiency was recorded, cholecalciferol supplementation was started and z-score data obtained at Dual-Energy X-ray Absorptiometry (DXA) during supplementation were compared with previous ones. NF1 patients showed lower Z-scores at Dual-Energy X-ray Absorptiometry DXA than controls. Physical activity was significantly reduced in NF1 patients than in controls. Sun exposure was significantly lower in NF1 compared to control subjects. At linear regression analysis vitamin D was the most predictive factor of reduced z-score at DXA (p = 0.0001). Cholecalciferol supplementation significantly increased BMD z-score (p

Aim: To ascertain the predictors of remission and relapse in patients of Cushing’s disease (CD) undergoing pituitary transsphenoidal surgery (TSS). Methods: Patients with CD subjected to TSS over 35 years at a tertiary care center were included. Patients were grouped into remission and persistent disease at 1 year after surgery, and were further followed up for relapse. Demographic, clinical, biochemical, histological, radiological and post-operative follow-up parameters were analyzed. Results: Of the 152 patients of CD, 145 underwent TSS. Remission was achieved in 95 (65.5%) patients at 1 year. Patients in remission had shorter duration of symptoms prior to presentation (p = 0.009), more frequent presence of proximal myopathy (p = 0.038) and a tumor size of < 2.05 cm (p = 0.016) in comparison to those with persistent disease. Post-TSS, immediate post-operative 0800-h cortisol (< 159.85 nmol/L; p = 0.001), histological confirmation of tumor (p = 0.045), duration of glucocorticoid replacement (median 90 days; p = 0.001), non-visualization of tumor on MRI (p = 0.003), new-onset hypogonadism (p = 0.001), 3-month 0800-h cortisol (< 384.9 nmol/L; p = 0.001), resolution of diabetes (p = 0.001) and hypertension (p = 0.001), and recovery of hypothalamic–pituitary–adrenal axis (p = 0.018) favored remission. In logistic regression model, requirement of glucocorticoid replacement (p = 0.033), and resolution of hypertension post-TSS (p = 0.003) predicted remission. None of the parameters could predict relapse. Conclusion: The study could ascertain the predictors of remission in CD. Apart from the tumor characteristics, surgical aspects and low post-operative 0800-h cortisol, the results suggest that baseline clinical parameters, longer glucocorticoid replacement, and resolution of metabolic complications post-TSS predict remission in CD. Long-term follow-up is essential to look for relapse.

Cushing’s Syndrome (CS), or chronic endogenous hypercortisolism, is a rare and serious disease due to corticotroph pituitary (Cushing’s disease, CD) and extra-pituitary (ectopic CS) tumours overproducing ACTH, or cortisol-secreting adrenal tumours or lesions (adrenal CS). The first-line treatment for CS is represented by the surgical removal of the responsible tumour, but surgery might be unfeasible or ineffective and medical treatment can be required in a relevant percentage of patients with CS, especially CD and ectopic CS. Corticotroph pituitary and extra-pituitary tumours, as well as adrenal tumours and lesions responsible for CS express dopamine receptors (DRs), which have been found to mediate inhibition of hormone secretion and/or cell proliferation in experimental setting, suggesting that dopaminergic system, particularly DRs, might represent a target for the treatment of CS. Dopamine agonists (DAs), particularly cabergoline (CAB), are currently used as off-label treatment for CD, the most common form of CS, demonstrating efficacy in controlling hormone secretion and tumour growth in a relevant number of cases, with the improvement of clinical picture, and displaying good safety profile. Therefore, CAB may be considered a reasonable alternative treatment for persistent or recurrent CD after pituitary surgery failure, but occasionally also before pituitary surgery, as adjuvant treatment, or even instead of pituitary surgery as first-line treatment in case of surgery contraindications or refusal. A certain beneficial effect of CAB has been also reported in ectopic CS. However, the role of DAs in the clinical management of the different types of CS requires further evaluations.

Cushing's disease (CD) is a serious endocrine disorder characterized by chronic hypercortisolism, or Cushing's syndrome (CS), caused by a corticotroph pituitary tumor, which induces an excessive adrenocorticotropic hormone (ACTH) and consequently cortisol secretion. CD presents a severe clinical burden, with impairment of the quality of life and increase in mortality. Pituitary surgery represents the first-line therapy, but it is non-curative in one third of patients, requiring additional treatments. Among second-line treatments, medical therapy is gradually gaining importance, although the current medical treatments are unable to reach optimal efficacy and safety profile. Therefore, new drugs and new formulations of presently available drugs are currently under clinical investigation in international clinical trials, in order to assess their efficacy and safety in CD, or in the general population of CS. Among pituitary-directed agents, pasireotide, in the twice-daily subcutaneous formulation, has been demonstrated to be an effective treatment both in clinical trials and in real-world studies, and extension studies of the phase II and III clinical trials reported evidence of long-term efficacy with general good safety profile, although associated with frequent hyperglycemia, which requires monitoring of glucose metabolism. Moreover, the most recent once-monthly intramuscular formulation, pasireotide long-acting release (LAR), showed similar efficacy and safety, but associated with potential better compliance profile in CD. Roscovitine is an experimental drug currently under investigation. Among adrenal-directed agents, metyrapone is the only historical agent currently under investigation in a prospective, multicenter, international clinical trial, that would likely clarify its efficacy and safety in a large population of patients with CS. Osilodrostat, a novel agent with a mechanism of action similar to metyrapone, seems to offer a rapid, sustained, and effective disease control of CD, according to recently completed clinical trials, whereas levoketoconazole, a different chemical formulation of the historical agent ketoconazole, is still under investigation in clinical trials, with preliminary evidences showing an effective and safe control of CS. ATR-101 is an experimental drug currently under investigation. Among glucocorticoid receptor-directed drugs, mifepristone has been demonstrated to improve clinical syndrome and comorbidities, especially hypertension and impairment of glucose metabolism, but the occurrence of hypokalemia and in women uterine disorders, due to the concomitant action on progestin receptor, requires caution, whereas the preliminary evidence on relacorilant, characterized by high selectivity for glucocorticoid receptor, suggested good efficacy in the control of hypertension and impairment of glucose metabolism, as well as a good safety profile, in CS. Finally, a limited experience has demonstrated that combination therapy might be an interesting approach in the management of CD. The current review provides a summary of the available evidences from current and recent clinical trials on CD, with a specific focus on preliminary data.

Purposes Pasireotide is the first medical therapy officially approved for adult patients with Cushing’s disease (CD) experiencing failure of pituitary surgery or not candidates for surgery. The current study aimed at investigating pasireotide effects on clinical picture and metabolic profile in patients enrolled in the phase III CSOM230B2305 trial at Naples center. In addition, the current study focused on safety issues encountered during the study, detailing the management of the different adverse events associated with the treatment with pasireotide in Naples center. Methods Fourteen patients entered the study; eight patients, receiving pasireotide for at least 6 months, were considered for the efficacy analysis, whereas the entire cohort of 14 patients was considered for the safety analysis. Results Full or partial disease control was obtained in 85.7% of patients, according to a “per-protocol” methodology analysis, and in 42.9% of patients, according to an “intention-to-treat” methodology analysis, after 12 months of treatment. A relevant improvement in clinical signs and symptoms, mainly in facial rubor, supraclavicular fat pad, bruising, hirsutism, and muscle strength was observed; body weight, body mass index, and waist circumference significantly reduced, and a slight non-significant reduction was observed in the prevalence of visceral obesity, hypercholesterolemia, and hypertriglyceridemia. Deterioration of glucose metabolism represented the most common adverse event, occurring in 71.4% of patients, and requiring a dietary regimen as first step, metformin therapy and/or long-acting insulin as second step, and short-acting insulin, as third step; no patients discontinued treatment for hyperglycaemia. Additional adverse events of interest were nausea (21.4%), and vomiting (14.3%), spontaneously resolved in few weeks or some months, except in one patient unsuccessfully treated with metoclopramide and ondansetron, and diarrhoea (14.3%), improved with loperamide treatment. Millimetric gallstones and biliary sludge (7.1%) were managed with ursodeoxycholic acid, inducing lithiasis and biliary sludge resolution, whereas hypocortisolism-related adverse events (7.1%) were resolved with a reduction in the pasireotide dose. Conclusions The current study on a limited series of patients contributes to confirm that pasireotide may be considered a valid option for treatment of patients with CD, although it requires an appropriate management of adverse events, especially hyperglycaemia.

Primary or acquired resistant mechanisms prevent the employment of individualized therapy with target drugs like the mTOR inhibitor everolimus (EVE) in hepatocellular carcinoma (HCC). The current study evaluated the effect of 1,25(OH)2Vitamin D (VitD) treatment on EVE sensitivity in established models of HCC cell lines resistant to everolimus (EveR). DNA content and colony formation assays, which measure the proliferative index, revealed that VitD pre-treatment re-sensitizes EveR cells to EVE treatment. The evaluation of epithelial and mesenchymal markers by western blot and immunofluorescence showed that VitD restored an epithelial phenotype in EveR cells, in which prolonged EVE treatment induced transition to mesenchymal phenotype. Moreover, VitD treatment prompted hepatic miRNAs regulation, evaluated by liver miRNA finder qPCR array. In particular, miR-375 expression was up-regulated by VitD in EveR cells, in which miR-375 was down-regulated compared to parental cells, with consequent inhibition of oncogenes involved in drug resistance and epithelial-mesenchymal transition (EMT) such as MTDH, YAP-1 and c-MYC. In conclusion, the results of the current study demonstrated that VitD can re-sensitize HCC cells resistant to EVE treatment triggering miR-375 up-regulation and consequently down-regulating several oncogenes responsible of EMT and drug resistance.

ObjectiveDiabetes mellitus (DM) is one of the most frequent complications of Cushing's syndrome (CS). The aim of this study was to define the changes in insulin sensitivity and/or secretion in relation to glucose tolerance categories in newly diagnosed CS patients.DesignCross-sectional study on 140 patients with CS.MethodsA total of 113 women (80 with pituitary disease and 33 with adrenal disease, aged 41.7±15.7 years) and 27 men (19 with pituitary disease and eight with adrenal disease, aged 38.1±20.01 years) at diagnosis were divided according to glucose tolerance into normal glucose tolerance (CS/NGT), impaired fasting glucose and/or impaired glucose tolerance (CS/prediabetes), and diabetes (CS/DM) groups.ResultsSeventy-one patients had CS/NGT (49.3%), 26 (18.5%) had CS/prediabetes and 43 (30.8%) had CS/DM. Significant increasing trends in the prevalence of family history of diabetes (PPPP=0.043) and decreasing trends in HOMA-β (PPINS), Matsuda index of insulin sensitivity (ISI-Matsuda) and visceral adiposity index were detected.ConclusionsImpairment of glucose tolerance is characterized by the inability of β-cells to adequately compensate for insulin resistance through increased insulin secretion. Age, genetic predisposition and lifestyle, in combination with the duration and degree of hypercortisolism, strongly contribute to the impairment of glucose tolerance in patients with a natural history of CS. A careful phenotypic evaluation of glucose tolerance defects in patients with CS proves useful for the identification of those at a high risk of metabolic complications.

ObjectiveCabergoline (CAB) has been found to be associated with increased risk of cardiac valve regurgitation in Parkinson's disease, whereas several retrospective analyses failed to detect a similar relation in hyperprolactinemic patients. The current study aimed at investigating cardiac valve disease before and after 24 and 60 months of continuous treatment with CAB only in patients with hyperprolactinemia.Subjects and methodsForty patients (11 men and 29 women, aged 38.7±12.5 years) newly diagnosed with hyperprolactinemia entered the study. Cumulative CAB dose ranged from 12 to 588 mg (median 48 mg) at 24 months and 48–1260 mg (median 149 mg) at 60 months. All patients underwent a complete trans-thoracic echocardiographic examination. Valve regurgitation was assessed according to the American Society of Echocardiography.ResultsAt baseline, the prevalence of trace mitral, aortic, pulmonic, and tricuspid regurgitations was 20, 2.5, 10, and 40% respectively, with no patient showing clinically relevant valvulopathy. After 24 months, no change in the prevalence of trace mitral (P=0.78) and pulmonic (P=0.89) regurgitations and of mild aortic (P=0.89) and tricuspid (P=0.89) regurgitations was found when compared with baseline. After 60 months, the prevalence of trace tricuspid regurgitation was only slightly increased when compared with that after 24 months (37.5%; P=0.82), but none of the patients developed significant valvulopathy. No correlation was found between cumulative dose and prevalence or grade of valve regurgitation at both evaluations. Prolactin levels normalized in all patients but one.ConclusionCAB does not increase the risk of significant cardiac valve regurgitation in prolactinomas after the first 5 years of treatment.

Cushing syndrome (CS) is characterized by increased morbidity and mortality compared to the general population. However, there are patients who have more clinical aggressive forms than others. Aim of the study is to evaluate whether the degree of hypercortisolism, defined by the number of times urinary free cortisol (UFC) levels exceed the upper limit of the normal range (ULN), is related to the worsening of phenotypic features, as well as metabolic and cardiovascular parameters, in a cohort of CS patients. A cross-sectional study was conducted on 192 patients with active CS, consecutively presenting at the outpatients' clinic of the University Hospitals of Ancona, Naples, and Palermo. Patients were grouped into mild (UFC not exceeding twice the ULN), moderate (2-5 times the ULN), and severe (more than 5 times the ULN) hypercortisolism. Thirty-seven patients (19.3 %) had mild, 115 (59.8 %) moderate, and 40 (20.9 %) severe hypercortisolism. A significant trend of increase among the three groups was demonstrated for 8-, 16-, and 24-h serum cortisol levels (p