Claudia Pivonello

Neuropsychiatric disorders in Cushing's syndrome

Endogenous Cushings syndrome (CS), a rare endocrine disorder characterized by cortisol hypersecretion, is associated with psychiatric and neurocognitive disorders. Major depression, mania, anxiety, and neurocognitive impairment are the most important clinical abnormalities. Moreover, patients most often complain of impairment in quality of life, interference with family life, social, and work performance. Surprisingly, after hypercortisolism resolution, despite the improvement of the overall prevalence of psychiatric and neurocognitive disorders, the brain volume loss at least partially persists and it should be noted that some patients may still display depression, anxiety, panic disorders, and neurocognitive impairment. This brief review aimed at describing the prevalence of psychiatric and neurocognitive disorders and their characterization both during the active and remission phases of CS. The last section of this review is dedicated to quality of life, impaired during active CS and only partially resolved after resolution of hypercortisolism.

Insulin-like growth factor-1 predicts cognitive functions at 2-year follow-up in early, drug-naïve Parkinson's disease

Cognitive impairment is common in Parkinsons disease (PD), even in the early stages. We aimed to assess the relationship between insulin‐like growth factor‐1 (IGF‐1) and cognitive functions in early, drug‐naïve patients with PD.

Effect of Cabergoline on Metabolism in Prolactinomas

Introduction: Hyperprolactinemia has been implicated in the pathogenesis of obesity and glucose intolerance and is reportedly associated with an impaired metabolic profile. The current study aimed at investigating the effects of 12- and 60-month treatment with cabergoline (CAB) on metabolic syndrome (MetS) in patients with prolactinomas. Patients and Methods: 61 patients with prolactinomas (13 men, 48 women, 41 with microadenoma, 20 with macroadenoma), aged 34.4 ± 10.3 years, entered the study. In all patients, prolactin (PRL) and metabolic parameters were assessed at diagnosis and after 12 and 60 months of continuous CAB treatment. MetS was diagnosed according to NCEP-ATP III criteria. Results: Compared to baseline, CAB induced a significant decrease in PRL with complete normalization in 93% of patients after the 60-month treatment. At baseline, MetS prevalence was significantly higher in patients with PRL above (34.5%) than in those with PRL lower (12.5%) than the median (129 μg/l, p = 0.03). MetS prevalence significantly decreased after 12 (11.5%, p = 0.039) and 60 (5.0%, p = 0.001) months compared to baseline (28.0%). At both evaluations the lipid profile significantly improved compared to baseline. Fasting insulin and homeostatic model assessment of insulin resistance significantly decreased after 1 year of CAB (p = 0.012 and p = 0.002, respectively) and further improved after 60 months (p = 0.000). The visceral adiposity index significantly decreased after the 60-month treatment (p = 0.000) compared to baseline. At the 5-year evaluation CAB dose was the best predictor of percent decrease in fasting insulin (t = 2.35, p = 0.022). Conclusions: CAB significantly reduces MetS prevalence and improves the adipose tissue dysfunction index. The improvement in PRL, insulin sensitivity and other metabolic parameters might reflect the direct effect of CAB.

Serum 25-Hydroxyvitamin D Levels, phosphoprotein enriched in diabetes gene product (PED/PEA-15) and leptin-to-adiponectin ratio in women with PCOS

BackgroundPolycystic ovary syndrome (PCOS) is frequently associated with hypovitaminosis D. Vitamin D is endowed with pleiotropic effects, including insulin resistance (IR) and apoptotic pathway. Disruption of the complex mechanism that regulated ovarian apoptosis has been reported in PCOS. Phosphoprotein enriched in diabetes gene product (PED/PEA-15), an anti-apoptotic protein involved in type 2 diabetes mellitus (T2DM), is overexpressed in PCOS women, independently of obesity. Leptin-to-adiponectin ratio (L/A) is a biomarker of IR and low-grade inflammation in PCOS. The aim of the study was to investigate the levels of 25-hydroxy vitamin D (25(OH)D), and L/A, in association with PED/PEA-15 protein abundance, in both lean and overweight/obese (o/o) women with PCOS.Patients and MethodsPED/PEA-15 protein abundance and circulating levels of 25(OH)D, L/A, sex hormone-binding globulin, and testosterone were evaluated in 90 untreated PCOS patients (25 ± 4 yrs; range 18-34) and 40 healthy controls age and BMI comparable, from the same geographical area. FAI (free androgen index) and the homeostasis model assessment of insulin resistance (HoMA-IR) index were calculated.ResultsIn o/o PCOS, 25(OH)D levels were significantly lower, and L/A values were significantly higher than in lean PCOS (p < 0.001), while there were no differences in PED/PEA-15 protein abundance. An inverse correlation was observed between 25(OH)D and BMI, PED/PEA-15 protein abundance, insulin, HoMA-IR, FAI (p < 0.001), and L/A (p < 0.05). At the multivariate analysis, in o/o PCOS L/A, insulin and 25(OH)D were the major determinant of PED/PEA-15 protein abundance (β = 0.45, β = 0.41, and β = -0.25, respectively).ConclusionsLower 25(OH)D and higher L/A were associated to PED/PEA-15 protein abundance in PCOS, suggesting their involvement in the ovarian imbalance between pro-and anti-apoptotic mechanisms, with high L/A and insulin and low 25(OH)D levels as the main determinants of PED/PEA-15 protein variability. Further studies, involving also different apoptotic pathways or inflammatory cytokines and granulosa cells are mandatory to better define the possible bidirectional relationships between 25(OH)D, PED/PEA-15 protein abundance, leptin and adiponectin in PCOS pathogenesis.

Curcumin AntiCancer Studies in Pancreatic Cancer

Pancreatic cancer (PC) is one of the deadliest cancers worldwide. Surgical resection remains the only curative therapeutic treatment for this disease, although only the minority of patients can be resected due to late diagnosis. Systemic gemcitabine-based chemotherapy plus nab-paclitaxel are used as the gold-standard therapy for patients with advanced PC; although this treatment is associated with a better overall survival compared to the old treatment, many side effects and poor results are still present. Therefore, new alternative therapies have been considered for treatment of advanced PC. Several preclinical studies have demonstrated that curcumin, a naturally occurring polyphenolic compound, has anticancer effects against different types of cancer, including PC, by modulating many molecular targets. Regarding PC, in vitro studies have shown potent cytotoxic effects of curcumin on different PC cell lines including MiaPaCa-2, Panc-1, AsPC-1, and BxPC-3. In addition, in vivo studies on PC models have shown that the anti-proliferative effects of curcumin are caused by the inhibition of oxidative stress and angiogenesis and are due to the induction of apoptosis. On the basis of these results, several researchers tested the anticancer effects of curcumin in clinical trials, trying to overcome the poor bioavailability of this agent by developing new bioavailable forms of curcumin. In this article, we review the results of pre-clinical and clinical studies on the effects of curcumin in the treatment of PC.

Multiple system atrophy is associated with changes in peripheral insulin‐like growth factor system

Insulin‐like growth factors (IGF‐I and IGF‐II) have been shown to have several neurotrophic actions and IGF system may be impaired in neurodegenerative disorders. The aim of this study was to investigate the IGF system in patients with MSA and to evaluate correlations between this endocrine system and clinical features of the disease. Serum levels of IGF‐I, IGF‐II, insulin, IGF‐binding protein 1 (BP1), and IGF‐binding protein 3 (BP3) were measured in 25 patients with probable MSA and 25 age, sex and BMI‐matched healthy controls. Clinical status of each patient was evaluated with the Unified Multiple System Atrophy Rating Scale (UMSARS) Part II and the Hoehn and Yahr rating scale. IGF‐I levels were significantly higher in MSA (164.1 + 66.2 μg/L) than in healthy controls (111.7 + 60.3 μg/L; p = 0.001). Insulin levels were significantly higher in MSA patients (21.9 ± 14.4 μU/mL) than in healthy controls (13.3 ± 5.1 μU/mL, p = 0.048). No significant difference was found in serum IGF‐II, IGF‐BP1, and IGF‐ BP3 levels between patients with MSA and healthy controls. There was a trend toward significantly higher IGF‐II levels in MSA patients with UMSARS score <26 (1026.3 ± 442.6 μg/L) than MSA patients with UMSARS score >26 (796.1 ± 234 μg/L, p = 0.055). The results of this study demonstrated that IGF system is altered in MSA. The degenerative process in MSA could lead to a compensatory increase in IGF‐I and insulin in an attempt to provide additional support to degenerating neurons.

The GH-IGF system in amyotrophic lateral sclerosis: correlations between pituitary GH secretion capacity, insulin-like growth factors and clinical features.

Background and purpose:  The growth hormone (GH) and insulin‐like growth factor (IGF) system may be involved in neurodegenerative processes, and some abnormalities have been reported in amyotrophic lateral sclerosis (ALS). Our aim was to investigate the GH–IGF axis in patients with ALS and evaluate correlations between this endocrine system and clinical features.

Influence of Bisphenol A on Type 2 Diabetes Mellitus

Bisphenol A (BPA) is an organic synthetic compound employed to produce plastics and epoxy resins. It is used as a structural component in polycarbonate beverage bottles and as coating for metal surface in food containers and packaging. The adverse effects of BPA on human health are widely disputed. BPA has been recently associated with a wide variety of medical disorders and, in particular, it was identified as potential endocrine-disrupting compound with diabetogenic action. Most of the clinical observational studies in humans reveal a positive link between BPA exposure, evaluated by the measurement of urinary BPA levels, and the risk of developing type 2 diabetes mellitus. Clinical studies on humans and preclinical studies on in vivo, ex vivo, and in vitro models indicate that BPA, mostly at low doses, may have a role in increasing type 2 diabetes mellitus developmental risk, directly acting on pancreatic cells, in which BPA induces the impairment of insulin and glucagon secretion, triggers inhibition of cell growth and apoptosis, and acts on muscle, hepatic, and adipose cell function, triggering an insulin-resistant state. The current review summarizes the available evidences regarding the association between BPA and type 2 diabetes mellitus, focusing on both clinical and preclinical studies.

The environment and male reproduction: The effect of cadmium exposure on reproductive function and its implication in fertility

Cadmium is an environmental pollutant known as endocrine disruptor. Testis is particularly susceptible to cadmium, and testis injury occurs at high but even low levels of exposure. Cadmium reproductive toxicity is mediated by multiple mechanisms, including structural damage to testis vasculature and blood-testis barrier, inflammation, cytotoxicity on Sertoli and Leydig cells, oxidative stress mainly by means of mimicry and interference with essential ions, apoptosis, interference with selected signaling pathways and epigenetic regulation of genes involved in the regulation of reproductive function, and disturbance of the hypothalamus-pituitary-gonadal axis. The current review outlines epidemiological observational findings from environmental and occupational exposure in humans, and reports experimental studies in humans and animals. Lastly, a focus on the pathogenetic mechanisms of cadmium toxicity and on the specific mechanisms of cadmium sensitivity and resistance, particularly assessed in animal models, is included. Despite convincing experimental findings in animals and supporting evidences in humans identifying cadmium as reproductive toxicant, observational findings are controversial, suffering from heterogeneity of study design and pattern of exposure, and from co-exposure to multiple pollutants.

Germline polymorphisms of the VEGF-pathway predict recurrence in non-advanced differentiated thyroid cancer

Context: Tumor angiogenesis is determined by host genetic background rather than environment. Germline single nucleotide polymorphisms (SNPs) of the vascular endothelial growth factor (VEGF) pathway have demonstrated prognostic value in different tumors. Objectives: Our main objective was to test the prognostic value of germline SNPs of the VEGF pathway in nonadvanced differentiated thyroid cancer (DTC). Secondarily, we sought to correlate analyzed SNPs with microvessel density (MVD). Design: Multicenter, retrospective, observational study. Setting: Four referral centers. Patients: Blood samples were obtained from consecutive DTC patients. Genotyping was performed according to the TaqMan protocol, including 4 VEGF-A (−2578C>A, −460T>C, +405G>C, and +936C>T) and 2 VEGFR-2 (+1192 C>T and +1719 T>A) SNPs. MVD was estimated by means of CD34 staining. Outcome Measures: Rate of recurrent structural disease/disease-free survival (DFS). Difference in MVD between tumors from patients with different genotype. Results: Two hundred four patients with stage I–II DTC (mean follow-up, 73 ± 64 months) and 240 patients with low- to intermediate-risk DTC (mean follow-up, 70 ± 60 months) were enrolled. Two “risk” genotypes were identified by combining VEGF-A SNPs −2578 C>A, −460 T>C, and +405 G>C. The ACG homozygous genotype was protective in both stage I–II (odds ratio [OR], 0.08; 95% confidence interval [CI], 0.01 to 1.43; P = 0.018) and low- to intermediate-risk (OR, 0.14; 95% CI, 0.01 to 1.13; P = 0.035) patients. The CTG homozygous genotype was significantly associated with recurrence in stage I–II (OR, 5.47; 95% CI, 1.15 to 26.04; P = 0.018) and was slightly deleterious in low- to intermediate-risk (OR, 3.39; 95% CI, 0.8 to 14.33; P = 0.079) patients. MVD of primary tumors from patients harboring a protective genotype was significantly lower (median MVD, 76.5 ± 12.7 and 86.7 ± 27.9, respectively; P = 0.024). Conclusions: Analysis of germline VEGF-A SNPs could empower a prognostic approach to DTC.