Publications by authors named "Valentina Guarnotta"

54 Publications

Long-term outcomes of conventional and novel steroid replacement therapy on bone health in primary adrenal insufficiency.

Sci Rep 2022 Aug 2;12(1):13280. Epub 2022 Aug 2.

Dipartimento di Promozione della Salute, Materno - infantile, Medicina Interna e Specialistica di Eccellenza "G. D'Alessandro" (PROMISE), Sezione di Malattie Endocrine, del Ricambio e della Nutrizione, Università di Palermo, piazza delle cliniche 2, 90127, Palermo, Italy.

Steroids affect bone health causing osteoporosis and fractures. The study aims to compare dual-release hydrocortisone (DR-HC) and conventional steroids on bone metabolism in patients with primary adrenal insufficiency (PAI). Thirty-five patients with PAI on conventional steroids (group A) and 35 patients switched to DR-HC (group B), consecutively referred at our hospital, were evaluated at baseline and after 18, 36 and 60 months of treatment. After 60 months of follow-up, patients in group A had a significant increase in body mass index (p = 0.004) and waist circumference (WC) (p = 0.026) and a significant decrease in osteocalcin (p = 0.002), bone alkaline phosphatase (p = 0.029), lumbar spine bone mass density (BMD) T and Z scores (p < 0.001 and p = 0.001, respectively) and vertebral fractures rate (p = 0.021) than baseline. By contrast, patients in group B had a significant decrease in WC (p = 0.047) and increase in bone alkaline phosphatase (p = 0.019), lumbar spine BMD T score (p = 0.032), femoral neck BMD T and Z scores (p = 0.023 and p = 0.036, respectively) than baseline. Long-term conventional steroid replacement therapy is associated with a decrease in BMD, notably at lumbar spine, and increase in vertebral fractures rate. By contrast, DR-HC treatment is associated with improvement of BMD.
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http://dx.doi.org/10.1038/s41598-022-13506-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9345970PMC
August 2022

Myoinositol supplementation in the treatment of gestational diabetes mellitus: effects on glycaemic control and maternal-foetal outcomes.

BMC Pregnancy Childbirth 2022 Jun 26;22(1):516. Epub 2022 Jun 26.

Dipartimento di Promozione della Salute, Materno-Infantile, Medicina Interna e Specialistica di Eccellenza "G. D'Alessandro" (PROMISE), Sezione di Malattie Endocrine, del Ricambio e della Nutrizione, Università di Palermo, Piazza delle Cliniche 2, 90127, Palermo, Italy.

Background: Gestational diabetes mellitus (GDM) is defined as glucose intolerance with onset during pregnancy. It is characterized by high risk of adverse outcomes for the mother and the foetus, if not adequately controlled. The aim of the study was to evaluate the effects of 4000 mg of myoinositol supplementation in women with GDM on maternal-foetal outcomes, compared to controls.

Methods: A cohort of 330 women with GDM, 150 supplemented with myoinositol and 180 controls were enrolled. Clinical and metabolic parameters and the prevalence of maternal and foetal complications were assessed.

Results: The same number of women in the two groups started insulin as additional therapy. Women treated with myoinositol more frequently had a long-acting insulin scheme of treatment than those untreated (p<0.001), while women untreated with myoinositol more frequently had a basal-bolus insulin regimen (p<0.001) compared to women on myoinositol. Patients treated with myoinositol had significantly lower fasting plasma glucose (p=0.032), post-prandial dinner glucose (p=0.014), insulin requirement both in the 2nd and in the 3rd trimesters (p=0.001 and p<0.001, respectively), than those not treated with myoinositol. With regard to maternal/foetal outcomes, lower birth weight (p=0.043) and frequency of hypoglycaemic events (p=0.001) were observed in women treated with myoinositol compared to controls.

Conclusions: Women with GDM treated with myoinositol showed an improved glycaemic control in the 3 trimester of pregnancy and a lower insulin requirement, when insulin was added to the treatment, compared to controls. In addition, they showed lower preterm birth weight and neonatal hypoglycaemia, compared to women not supplemented with myoinositol.
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http://dx.doi.org/10.1186/s12884-022-04852-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9233779PMC
June 2022

Very Low-Calorie Ketogenic Diet: A Potential Application in the Treatment of Hypercortisolism Comorbidities.

Nutrients 2022 Jun 9;14(12). Epub 2022 Jun 9.

Dipartimento di Promozione della Salute, Materno-Infantile, Medicina Interna e Specialistica di Eccellenza "G. D'Alessandro" (PROMISE), Sezione di Malattie Endocrine, del Ricambio e della Nutrizione, Università di Palermo, 90127 Palermo, Italy.

A very low-calorie ketogenic diet (VLCKD) is characterized by low daily caloric intake (less than 800 kcal/day), low carbohydrate intake (<50 g/day) and normoproteic (1-1.5 g of protein/kg of ideal body weight) contents. It induces a significant weight loss and an improvement in lipid parameters, blood pressure, glycaemic indices and insulin sensitivity in patients with obesity and type 2 diabetes mellitus. Cushing's syndrome (CS) is characterized by an endogenous or exogenous excess of glucocorticoids and shows many comorbidities including cardiovascular disease, obesity, type 2 diabetes mellitus and lipid disorders. The aim of this speculative review is to provide an overview on nutrition in hypercortisolism and analyse the potential use of a VLCKD for the treatment of CS comorbidities, analysing the molecular mechanisms of ketogenesis.
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http://dx.doi.org/10.3390/nu14122388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9228456PMC
June 2022

Impact of Chemical Endocrine Disruptors and Hormone Modulators on the Endocrine System.

Int J Mol Sci 2022 May 20;23(10). Epub 2022 May 20.

Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties "G. D'Alessandro" (PROMISE), Section of Endocrinology, University of Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy.

There is growing concern regarding the health and safety issues of endocrine-disrupting chemicals (EDCs). Long-term exposure to EDCs has alarming adverse health effects through both hormone-direct and hormone-indirect pathways. Non-chemical agents, including physical agents such as artificial light, radiation, temperature, and stress exposure, are currently poorly investigated, even though they can seriously affect the endocrine system, by modulation of hormonal action. Several mechanisms have been suggested to explain the interference of EDCs with hormonal activity. However, difficulty in quantifying the exposure, low standardization of studies, and the presence of confounding factors do not allow the establishment of a causal relationship between endocrine disorders and exposure to specific toxic agents. In this review, we focus on recent findings on the effects of EDCs and hormone system modulators on the endocrine system, including the thyroid, parathyroid glands, adrenal steroidogenesis, beta-cell function, and male and female reproductive function.
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http://dx.doi.org/10.3390/ijms23105710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9145289PMC
May 2022

Incretin Response to Mixed Meal Challenge in Active Cushing's Disease and after Pasireotide Therapy.

Int J Mol Sci 2022 May 6;23(9). Epub 2022 May 6.

Endocrinology Unit, Department of Medicine DIMED, University-Hospital of Padova, Via Ospedale Civile 105, 35128 Padova, Italy.

Cushing's disease (CD) causes diabetes mellitus (DM) through different mechanisms in a significant proportion of patients. Glucose metabolism has rarely been assessed with appropriate testing in CD; we aimed to evaluate hormonal response to a mixed meal tolerance test (MMTT) in CD patients and analyzed the effect of pasireotide (PAS) on glucose homeostasis. To assess gastro-entero-pancreatic hormones response in diabetic (DM+) and non-diabetic (DM-) patients, 26 patients with CD underwent an MMTT. Ten patients were submitted to a second MMTT after two months of PAS 600 µg twice daily. The DM+ group had significantly higher BMI, waist circumference, glycemia, HbA1c, ACTH levels and insulin resistance indexes than DM- ( < 0.05). Moreover, DM+ patients exhibited increased C-peptide ( = 0.004) and glucose area under the curve (AUC) ( = 0.021) during MMTT, with a blunted insulinotropic peptide (GIP) response ( = 0.035). Glucagon levels were similar in both groups, showing a quick rise after meals. No difference in estimated insulin secretion and insulin:glucagon ratio was found. After two months, PAS induced an increase in both fasting glycemia and HbA1c compared to baseline ( < 0.05). However, this glucose trend after meal did not worsen despite the blunted insulin and C-peptide response to MMTT. After PAS treatment, patients exhibited reduced insulin secretion ( = 0.005) and resistance ( = 0.007) indexes. Conversely, glucagon did not change with a consequent impairment of insulin:glucagon ratio ( = 0.009). No significant differences were observed in incretins basal and meal-induced levels. Insulin resistance confirmed its pivotal role in glucocorticoid-induced DM. A blunted GIP response to MMTT in the DM+ group might suggest a potential inhibitory role of hypercortisolism on enteropancreatic axis. As expected, PAS reduced insulin secretion but also induced an improvement in insulin sensitivity as a result of cortisol reduction. No differences in incretin response to MMTT were recorded during PAS therapy. The discrepancy between insulin and glucagon trends while on PAS may be an important pathophysiological mechanism in this iatrogenic DM; hence restoring insulin:glucagon ratio by either enhancing insulin secretion or reducing glucagon tone can be a potential therapeutic target.
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http://dx.doi.org/10.3390/ijms23095217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9105040PMC
May 2022

Metabolic Profile in a Cohort of Young Sicilian Patients with Klinefelter's Syndrome: The Role of Irisin.

Int J Endocrinol 2022 6;2022:3780741. Epub 2022 Apr 6.

Department of Health Promotion, Maternal-Infantile, Internal and Specialist Medicine of Excellence "G. D' Alessandro" (PROMISE), Section of Endocrinology and Metabolism, University of Palermo, Palerm, Italy.

Klinefelter's syndrome (KS) is the main cause of hypogonadism and infertility in men and is often related to obesity, metabolic syndrome, and diabetes. The purpose of our real-life observational study was to investigate the metabolic and anthropometric parameters in a population of patients with Klinefelter syndrome compared to a group of healthy age-matched subjects. . In our study, 25 consecutive Caucasian adult outpatients (age range 21-52 years, mean age 32.9 ± 12.2) with KS in testosterone replacement therapy and 30 healthy men (age range 25-45 years, mean age 32.4 ± 7.62) were studied. In both groups of subjects, anthropometric indices, lipid profile, glucose metabolic parameters, HbA1c, the homeostasis model assessment estimate of HOMA-insulin resistance (IR), and the insulin sensitivity index (ISI) were evaluated. In addition, we assessed the complete hormonal gonadic status and irisin values in both groups of patients. . No significant differences were found in BMI and total blood testosterone levels between KS and control subjects. Patients with KS had significantly higher values of WC (=0.028), HbA1c (=0.018), HOMA-IR ( < 0.001), FSH ( < 0.001), LH ( < 0.001), estradiol (=0.001), and irisin (=0.029) and significantly lower HDL-cholesterol (=0.002), AMH ( < 0.001), inhibin B ( < 0.001), and ISI-Matsuda ( < 0.001) compared to healthy controls. Univariate analysis revealed an inverse correlation between irisin and ISI-Matsuda (r = -0.128; =0.010). These data were then confirmed in multivariate analysis. . KS is characterized by early development of metabolic syndrome and in particular by alterations of the glucose metabolism, independently of testosterone levels serum and BMI. Irisin blood levels of Klinefelter's patients are higher than in healthy subjects and positively correlate with the degree of insulin resistance.
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http://dx.doi.org/10.1155/2022/3780741DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9007659PMC
April 2022

Vitamin D Deficiency in Cushing's Disease: Before and After Its Supplementation.

Nutrients 2022 Feb 25;14(5). Epub 2022 Feb 25.

Department of Health Promotion, Maternal-Infantile Care, Excellence Internal and Specialist Medicine "G. D'Alessandro" [PROMISE], Section of Endocrine Disease and Nutrition, University of Palermo, 90127 Palermo, Italy.

Background: The primary objective of the study was to assess serum 25-hydroxyvitamin D [25(OH)D] values in patients with Cushing's disease (CD), compared to controls. The secondary objective was to assess the response to a load of 150,000 U of cholecalciferol.

Methods: In 50 patients with active CD and 48 controls, we evaluated the anthropometric and biochemical parameters, including insulin sensitivity estimation by the homeostatic model of insulin resistance, Matsuda Index and oral disposition index at baseline and in patients with CD also after 6 weeks of cholecalciferol supplementation.

Results: At baseline, patients with CD showed a higher frequency of hypovitaminosis deficiency ( = 0.001) and lower serum 25(OH)D ( < 0.001) than the controls. Six weeks after cholecalciferol treatment, patients with CD had increased serum calcium ( = 0.017), 25(OH)D ( < 0.001), ISI-Matsuda ( = 0.035), oral disposition index ( = 0.045) and decreased serum PTH ( = 0.004) and total cholesterol ( = 0.017) values than at baseline. Multivariate analysis showed that mean urinary free cortisol (mUFC) was independently negatively correlated with serum 25(OH)D in CD.

Conclusions: Serum 25(OH)D levels are lower in patients with CD compared to the controls. Vitamin D deficiency is correlated with mUFC and values of mUFC > 240 nmol/24 h are associated with hypovitaminosis D. Cholecalciferol supplementation had a positive impact on insulin sensitivity and lipids.
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http://dx.doi.org/10.3390/nu14050973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8912655PMC
February 2022

Prediction of diabetes mellitus induced by steroid overtreatment in adrenal insufficiency.

Sci Rep 2022 01 18;12(1):885. Epub 2022 Jan 18.

Dipartimento di Promozione della Salute, Materno-Infantile, Medicina Interna e Specialistica di Eccellenza "G. D'Alessandro" (PROMISE), Sezione di Malattie Endocrine, del Ricambio e della Nutrizione, Università di Palermo, Piazza delle Cliniche 2, 90127, Palermo, Italy.

To assess the differences between patients with normal glucose tolerance (NGT) and prediabetes/diabetes mellitus (DM) in secondary adrenal insufficiency (SAI). We cross-sectionally evaluated 102, out of a total of 140, patients with SAI, who were on hydrocortisone (HC) (n = 50) and cortisone acetate (n = 52) replacement therapy. Clinical, anthropometric, and metabolic parameters were compared in patients with NGT (n = 60) and DM (n = 42). Patients with prediabetes/DM have a more marked family history of DM (p = 0.002), BMI (p < 0.001), higher waist circumference (p < 0.001), total cholesterol (p = 0.012), LDL-cholesterol (p = 0.004), triglycerides (p = 0.031), fasting glucose (p = 0.002), fasting insulin (p = 0.035), glutamate pyruvate transaminase (p = 0.018), HOMA-IR (p = 0.039), area under curves of glucose (p = 0.001) and insulin (p = 0.002), HbA1c (p < 0.001), Visceral adiposity index (VAI) (p = 0.038) and lower ISI-Matsuda (p = 0.008) and oral disposition index (p < 0.001) than patients with NGT. Multivariate analysis showed that family history of DM and VAI are independent predictive factors for DM in patients with SAI. Family history of DM and VAI can be predictors of the development of DM in patients with SAI and need to be investigated during steroid replacement therapy. Interestingly, the type and the dose of replacement steroid do not impact on diabetes mellitus.
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http://dx.doi.org/10.1038/s41598-022-04904-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8766568PMC
January 2022

Diabetic foot ulcers: Retrospective comparative analysis from Sicily between two eras.

PLoS One 2021 7;16(12):e0259405. Epub 2021 Dec 7.

Sezione di Malattie Endocrine, del Ricambio e della Nutrizione, Dipartimento di Promozione della Salute, Materno-Infantile, Medicina Interna e Specialistica di Eccellenza "G. D'Alessandro" (PROMISE), Università di Palermo, Palermo, Italy.

Aim: The aim of this study was to analyze changes in the incidence, management and mortality of DFU in Sicilian Type 2 diabetic patients hospitalized between two eras, i.e. 2008-2013 and 2014-2019.

Methods: We compared the two eras, era1: 2008-13, era2: 2014-19. In era 1, n = 149, and in era 2, n = 181 patients were retrospectively enrolled.

Results: In the population hospitalized for DFU in 2008-2013, 59.1% of males and 40.9% of females died, whilst in 2014-2019 65.9% of males and 34.1% of females died. Moderate chronic kidney disease (CKD) was significantly higher in patients that had died than in ones that were alive (33% vs. 43%, p < 0.001), just as CKD was severe (14.5% vs. 4%, p < 0.001). Considering all together the risk factors associated with mortality, at Cox regression multivariate analysis only moderate-severe CKD (OR 1.61, 95% CI 1.07-2.42, p 0.021), age of onset greater than 69 years (OR 2.01, 95% CI 1.37-2.95, p <0.001) and eGFR less than 92 ml/min (OR 2.84, 95% CI 1.51-5.34, p 0.001) were independently associated with risk of death.

Conclusions: Patients with DFU have high mortality and reduced life expectancy. Age at onset of diabetic foot ulcer, eGFR values and CKD are the principal risk factors for mortality.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0259405PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8651101PMC
January 2022

Effects of GLP-1 receptor agonists on myokine levels and pro-inflammatory cytokines in patients with type 2 diabetes mellitus.

Nutr Metab Cardiovasc Dis 2021 10 24;31(11):3193-3201. Epub 2021 Jul 24.

Dipartimento di Promozione della Salute, Materno-Infantile, Medicina Interna e Specialistica di Eccellenza "G. D'Alessandro" (PROMISE), Sezione di Malattie Endocrine, del Ricambio e della Nutrizione, Università di Palermo, Italy. Electronic address:

Background And Aims: To evaluate the change in circulating serum irisin and interleukin-6 (IL-6), in patients with type 2 diabetes mellitus (T2DM) after 6 and 12 months of GLP-1 treatment.

Methods And Results: Eighty-five patients with T2DM inadequately controlled with insulin or other hypoglycaemic drugs were added to dulaglutide (N° = 44) and liraglutide (N° = 41) treatment. After 6 months of GLP-1 analogues a significant decrease in BMI (p < 0.001), waist circumference (WC) (p < 0.001), fasting blood glucose (p < 0.001), HbA1c (p < 0.001), total cholesterol (p < 0.001), LDL-cholesterol (p = 0.003), triglycerides (p = 0.017), IL-6 (p = 0.045) and a significant increase in serum irisin (p < 0.001) were observed compared to baseline. After 12 months of treatment no significant differences were found compared to the levels at 6 months. The change in irisin from baseline (Δ_irisin) was significantly related to the changes in total-cholesterol (Δ_total-cholesterol) (r = -0.293; p = 0.020), while the change in IL-6 (Δ_IL-6) was significantly related to the changes in WC (Δ_WC) (r = 0.347; p = 0.006).

Conclusions: Additive treatment with GLP1-analogues results in an increase in serum circulating irisin levels and a decrease in IL-6. The post-treatment change in irisin was correlated with a decrease in total cholesterol, while the change in IL-6 was correlated with a decrease in WC.
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http://dx.doi.org/10.1016/j.numecd.2021.07.015DOI Listing
October 2021

Metabolic comorbidities of adrenal insufficiency: Focus on steroid replacement therapy and chronopharmacology.

Curr Opin Pharmacol 2021 10 17;60:123-132. Epub 2021 Aug 17.

Dipartimento di Promozione della Salute Materno-Infantile, Medicina Interna e Specialistica di Eccellenza "G. D'Alessandro" (PROMISE), Sezione di Malattie Endocrine, del Ricambio e della Nutrizione, Università di Palermo, Piazza delle Cliniche 2, 90127, Palermo, Italy. Electronic address:

Adrenal insufficiency (AI) is characterized by higher mortality and morbidity compared with the general population. Conventional replacement steroid therapy, currently recommended for the treatment of AI, is associated with increased frequency of metabolic comorbidities due to daily overexposure. By contrast, dual-release hydrocortisone is associated with a decreased risk of metabolic comorbidities, providing an adequate release of hydrocortisone and mimicking the physiological profile of cortisol. These favorable effects are due to a reduced daily steroid exposure that does not affect the expression of the clock genes which are involved in metabolic pathways and are regulated by the normal physiological circadian rhythm of endogenous cortisol. This narrative review focuses on the possible metabolic comorbidities of AI due to steroid replacement therapy, which evaluates the effects of conventional and novel drugs with attention to chronopharmacology.
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http://dx.doi.org/10.1016/j.coph.2021.07.003DOI Listing
October 2021

Microbiota Gut-Brain Axis in Ischemic Stroke: A Narrative Review with a Focus about the Relationship with Inflammatory Bowel Disease.

Life (Basel) 2021 Jul 19;11(7). Epub 2021 Jul 19.

Digestive Endoscopy Unit, Division of Gastroenterology, Humanitas Research Hospital, 20089 Rozzano, Italy.

The gut microbiota is emerging as an important player in neurodevelopment and aging as well as in brain diseases including stroke, Alzheimer's disease, and Parkinson's disease. The complex interplay between gut microbiota and the brain, and vice versa, has recently become not only the focus of neuroscience, but also the starting point for research regarding many diseases such as inflammatory bowel diseases (IBD). The bi-directional interaction between gut microbiota and the brain is not completely understood. The aim of this review is to sum up the evidencesconcerningthe role of the gut-brain microbiota axis in ischemic stroke and to highlight the more recent evidences about the potential role of the gut-brain microbiota axis in the interaction between inflammatory bowel disease and ischemic stroke.
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http://dx.doi.org/10.3390/life11070715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8305026PMC
July 2021

Correction to: One Year of Dapaglifozin Add-On Therapy Ameliorates Surrogate Indexes of Insulin Resistance and Adiposity in Patients with Type 2 Diabetes Mellitus.

Diabetes Ther 2021 Sep;12(9):2625

Section of Endocrinology, Department of Health Promotion Sciences, Maternal-Infant Care, Internal Medicine and Specialties of Excellence ''G.D'Alessandro'' (PROMISE), University Hospital P. Giaccone, University of Palermo, Piazza Delle Cliniche 2, 90127, Palermo, Italy.

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http://dx.doi.org/10.1007/s13300-021-01119-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8385013PMC
September 2021

Predictive factors of polycystic ovary syndrome in girls with precocious pubarche.

Endocr Connect 2021 Jul 21;10(7):796-804. Epub 2021 Jul 21.

Dipartimento di Promozione della Salute, Materno-Infantile, Medicina Interna e Specialistica di Eccellenza 'G. D'Alessandro' (PROMISE), Sezione di Malattie Endocrine, del Ricambio e della Nutrizione, Università di Palermo, Palermo, Italy.

Objective: The aim of this study is to clarify, in girls with premature pubarche (PP), the influence of premature androgenization on the prevalence of polycystic ovary syndrome (PCOS).

Design And Patients: Ninety-nine PP girls, 63 who developed PCOS and 36 who did not develop PCOS, were retrospectively included. Clinical, anthropometric, and metabolic parameters were evaluated at the time of diagnosis of PP and after 10 years from menarche to find predictive factors of PCOS.

Results: Young females with PP showed a PCOS prevalence of 64% and showed a higher prevalence of familial history of diabetes (P = 0.004) and a lower prevalence of underweight (P = 0.025) than PP-NO-PCOS. In addition, girls with PP-PCOS showed higher BMI (P < 0.001), waist circumference (P < 0.001), total testosterone (P = 0.026), visceral adiposity index (VAI) (P = 0.013), total cholesterol (P < 0.001), LDL-cholesterol (P < 0.001), non-HDL cholesterol (P < 0.001) and lower age of menarche (P = 0.015), ISI-Matsuda (P < 0.001), DIo (P = 0.002), HDL cholesterol (P = 0.026) than PP-NO-PCOS. Multivariate analysis showed that WC (P = 0.049), ISI-Matsuda (P < 0.001), oral disposition index (DIo) (P < 0.001), VAI (P < 0.001), total testosterone (P < 0.001) and LDL-cholesterol (P < 0.001) are independent predictive factors for PCOS in girls with PP.

Conclusions: Our study established a strong association between multiple risk factors and development of PCOS in PP girls. These risk factors are predominantly related to the regulation of glucose, lipid, and androgen metabolism. Among these factors, WC, ISI-Matsuda, DIo, VAI, total testosterone, and LDL-cholesterol predict PCOS.
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http://dx.doi.org/10.1530/EC-21-0118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8346197PMC
July 2021

Case Report: Unmasking Hypercalcemia in Patients With Neuroendocrine Neoplasms. Experience From Six Italian Referral Centers.

Front Endocrinol (Lausanne) 2021 19;12:665698. Epub 2021 May 19.

Endocrinology Unit, Department of Clinical and Molecular Medicine, Sant'Andrea Hospital, Sapienza University of Rome, Rome, Italy.

Background: Hypercalcemia is a common paraneoplastic syndrome which can occur in up to 10% of patients with advanced neoplasms. Paraneoplastic parathyroid hormone-related protein (PTHrP) represents the most frequent cause of this syndrome. In neuroendocrine neoplasms (NENs) paraneoplastic hypercalcemia is rare.

Case Series: The present series includes all patients with NENs and paraneoplastic hypercalcemia from four Italian centres: A 40-year-old man was hospitalized for repeated episodes of falls, hyposthenia and drowsiness. Severe hypercalcemia was found. Metastatic pancreatic G2 NEN and PTHrP-related hypercalcemia were diagnosed. The patient started therapy with somatostatin analogs (SSA) and Denosumab. After disease progression peptide receptor radionuclide therapy (PRRT) was started with an objective response associated with PTHrP reduction and normocalcemia. A 45-year-old man was referred for pancreatic G2 NEN. SSA and subsequently everolimus were administered for metastases occurrence. Hypercalcemia occurred and PRRT and Denosumab were started for disease progression with the onset of bone metastases. Despite disease stability after four cycles of PRRT the patient's performance status worsened until death. A 49-year-old woman was hospitalized for psychic slowdown, confusional state, sensory dullness. A severe hypercalcemia, associated with a pancreatic G1 NEN was diagnosed and treated with haemodialysis, bisphosphonates injections and continuous infusion of calcitonin. 1,25-dihydroxyvitamin D was high, PTHrP was undetectable. After surgery serum calcium levels and 1,25-dihydroxyvitamin D were normalized. A 69-year-old man was hospitalized after the onset of shortness of breath and dyspnea, asthenia and weight loss. Computed Tomography (CT) and Ga DOTATOC Positron Emission Tomography (PET)-CT revealed a left pulmonary nodule. Hypercalcemia and markedly elevated PTHrP levels were detected. The histological examination revealed an atypical carcinoid. After surgery, calcium levels were normalized, PTHrP was significantly reduced with an improvement of general conditions.

Conclusion: In our series, paraneoplastic PTHrP-related hypercalcemia occurred in pancreatic NEN and in one bronchial carcinoid representing the third case in the literature. Our case associated with 1,25-dihydroxyvitamin D secretion represents the fourth case in the literature. PTHrP secretion should be considered in NENs' patients with hypercalcemia. Acute treatment should be focused on lowering calcium levels, and long-term control can be achieved by tumor cytoreduction inhibiting PTHrP release.
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http://dx.doi.org/10.3389/fendo.2021.665698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8170398PMC
December 2021

One Year of Dapaglifozin Add-On Therapy Ameliorates Surrogate Indexes of Insulin Resistance and Adiposity in Patients with Type 2 Diabetes Mellitus.

Diabetes Ther 2021 Jun 30;12(6):1677-1688. Epub 2021 Apr 30.

Section of Endocrinology, Department of Health Promotion Sciences, Maternal-Infant Care, Internal Medicine and Specialties of Excellence "G. D'Alessandro" (PROMISE), University Hospital P. Giaccone, University of Palermo, Piazza Delle Cliniche 2, 90127, Palermo, Italy.

Introduction: This study investigates the effects of dapagliflozin on the visceral adiposity index (VAI), lipid accumulation product (LAP), product of triglycerides and glucose (TyG) and triglycerides to HDL-cholesterol ratio (TG/HDL-C) in patients with type 2 diabetes mellitus (T2D).

Methods: In this real-life study, dapaglifozin was added to metformin alone (group 1, no. 42) or insulin plus metformin (group 2, no. 58) in 100 T2D patients.

Results: In group 1, after 6 months of dapaglifozin addition, a significant decrease in BMI (p < 0.001), waist circumference (WC) (p < 0.001), systolic blood pressure (SBP) (p = 0.009), diastolic blood pressure (DBP) (p = 0.012), mean fasting blood glucose (FBG), post-breakfast glucose (PBG), post-lunch glucose (PLG) and post-dinner glucose (PDG) (all p < 0.001), HbA1c (p < 0.001), VAI (p = 0.020), LAP (p = 0.028), Tyg (p < 0.001), TG/HDL-C (p = 0.020) and glutamate pyruvate transaminase (GPT) (p < 0.001) was observed compared to baseline. After 12 months a significant decrease in BMI (p < 0.001), WC (p = 0.006), SBP (p = 0.023), DBP (p = 0.005), mean FPG, PBG, PLG and PDG (all p < 0.001), HbA1c (p < 0.001), total cholesterol (p = 0.038), triglycerides (p = 0.026), VAI (p = 0.013), GPT (p < 0.001), LAP index (p = 0.024), Tyg index (p < 0.001) and TG/HDL-c ratio (p = 0.016) was observed compared to baseline. In group 2, after 6 months of dapaglifozin addition, a significant decrease in BMI (p < 0.001), WC (p < 0.001), SBP (p = 0.015), DBP (p = 0.007), mean FPG, PBG, PLG and PDG (all p < 0.001), HbA1c (p < 0.001), VAI (p = 0.040), LAP (p = 0.047), Tyg (p < 0.001), TG/HDL-C (p = 0.048) and GPT (p < 0.001) was observed compared to baseline. By contrast, after 12 months a significant decrease in BMI (p < 0.001), WC (p < 0.001), SBP (p = 0.001), DBP (p = 0.002), mean FPG, PBG, PLG and PDG (all p < 0.001), HbA1c (p < 0.001), GPT (p < 0.001) and Tyg index (p = 0.003) was observed compared to baseline.

Conclusions: Dapagliflozin treatment significantly reduced surrogate indexes of insulin resistance and adiposity in patients with T2D.
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http://dx.doi.org/10.1007/s13300-021-01056-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8179882PMC
June 2021

Maternal-foetal complications in pregnancy: a retrospective comparison between type 1 and type 2 diabetes mellitus.

BMC Pregnancy Childbirth 2021 Mar 22;21(1):243. Epub 2021 Mar 22.

Dipartimento di Promozione della Salute, Materno-Infantile, Medicina Interna e Specialistica di Eccellenza "G. D'Alessandro" (PROMISE), Sezione di Malattie Endocrine, del Ricambio e della Nutrizione, Università di Palermo, Piazza delle Cliniche 2, 90127, Palermo, Italy.

Background: The aim of the study was a retrospective comparison of the differences in maternal-foetal outcomes between women with type 1 and type 2 diabetes mellitus (T1DM and T2DM).

Methods: A cohort of 135 patients with pregestational diabetes, 73 with T1DM (mean age 29 ± 5 years) and 62 with T2DM (mean age 33 ± 6 years), in intensive insulin treatment throughout pregnancy were evaluated. Clinical and metabolic parameters and the prevalence of maternal and foetal complications were assessed.

Results: Women with T1DM showed lower pregestational BMI (p < 0.001), pregestational weight (p < 0.001), weight at delivery (p < 0.001), ∆_total_insulin requirement (IR) at the first, second and third trimesters (all p < 0.001) and higher weight gain during pregnancy (p < 0.001), pregestational HbA1c (p = 0.040), HbA1c in the first (p = 0.004), second (p = 0.020) and third (p = 0.010) trimesters compared to T2DM. Women with T1DM had a higher risk of macrosomia (p = 0.005) than T2DM, while women with T2DM showed higher prevalence of abortion (p = 0.037) than T1DM. At multivariate analysis, pregestational BMI and ∆_total_IR of the first trimester were independently associated with abortion in T2DM, while weight gain during pregnancy was independently associated with macrosomia in T1DM.

Conclusion: Women with T1DM have a higher risk of macrosomia than T2DM due to weight gain throughout pregnancy. By contrast, women with T2DM have a higher risk of spontaneous abortion than T1DM, due to pregestational BMI and ∆_total_IR in the first trimester.
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http://dx.doi.org/10.1186/s12884-021-03702-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986522PMC
March 2021

Are diabetes and its medications risk factors for the development of COVID-19? Data from a population-based study in Sicily.

Nutr Metab Cardiovasc Dis 2021 02 1;31(2):396-398. Epub 2020 Oct 1.

Experimental and Clinical Biomedical Sciences "Mario Serio" Department, University of Florence, Italy.

Background And Aims: Diabetes mellitus (DM) has been associated with higher incidence of severe cases of COVID-19 in hospitalized patients, but it is unknown whether DM is a risk factor for the overall COVID-19 incidence. The aim of present study was to investigate whether there is an association of DM with COVID-19 prevalence and case fatality, and between different DM medications and risk for COVID-19 infection and death.

Methods And Results: retrospective observational study on all SARS-CoV-2 positive (SARS-CoV-2) cases and deaths in Sicily up to 2020, May 14th. No difference in COVID-19 prevalence was found between people with and without DM (RR 0.92 [0.79-1.09]). Case fatality was significantly higher in SARS-CoV-2 with DM (RR 4.5 [3.55-5.71]). No diabetes medication was associated with differences in risk for SARS-Cov2 infection.

Conclusions: in Sicily, DM was not a risk factor for COVID-19 infection, whereas it was associated with a higher case fatality.
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http://dx.doi.org/10.1016/j.numecd.2020.09.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7528967PMC
February 2021

ENDOCRINE TUMOURS: Calcitonin in thyroid and extra-thyroid neuroendocrine neoplasms: the two-faced Janus.

Eur J Endocrinol 2020 Dec;183(6):R197-R215

Department of Experimental Medicine 'Sapienza' University of Rome, Rome, Italy.

An increased calcitonin serum level is suggestive of a medullary thyroid cancer (MTC), but is not pathognomonic. The possibility of false positives or other calcitonin-secreting neuroendocrine neoplasms (NENs) should be considered. Serum calcitonin levels are generally assessed by immunoradiometric and chemiluminescent assays with high sensitivity and specificity; however, slightly moderately elevated levels could be attributable to various confounding factors. Calcitonin values >100 pg/mL are strongly suspicious of malignancy, whereas in patients with moderately elevated values (10-100 pg/mL) a stimulation test may be applied to improve diagnostic accuracy. Although the standard protocol and the best gender-specific cut-offs for calcium-stimulated calcitonin are still controversial, the fold of the calcitonin increase after stimulation seems to be more reliable. Patients with MTC show stimulated calcitonin values at least three to four times higher than the basal values, whereas calcitonin-secreting NENs can be distinguished from a C-cell disease by the absence of or
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http://dx.doi.org/10.1530/EJE-20-0506DOI Listing
December 2020

Glucocorticoid excess and COVID-19 disease.

Rev Endocr Metab Disord 2021 12 6;22(4):703-714. Epub 2020 Oct 6.

Dipartimento di Promozione della Salute, Materno-Infantile, di Medicina Interna e Specialistica di Eccellenza "G. D'Alessandro", UOC di Malattie endocrine, del Ricambio e della Nutrizione, Università degli studi di Palermo, Piazza delle Cliniche 2, 90127, Palermo, Italy.

The pandemic of coronavirus disease (COVID-19), a disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is causing high and rapid morbidity and mortality. Immune system response plays a crucial role in controlling and resolving the viral infection. Exogenous or endogenous glucocorticoid excess is characterized by increased susceptibility to infections, due to impairment of the innate and adaptive immune system. In addition, diabetes, hypertension, obesity and thromboembolism are conditions overrepresented in patients with hypercortisolism. Thus patients with chronic glucocorticoid (GC) excess may be at high risk of developing COVID-19 infection with a severe clinical course. Care and control of all comorbidities should be one of the primary goals in patients with hypercortisolism requiring immediate and aggressive treatment. The European Society of Endocrinology (ESE), has recently commissioned an urgent clinical guidance document on management of Cushing's syndrome in a COVID-19 period. In this review, we aim to discuss and expand some clinical points related to GC excess that may have an impact on COVID-19 infection, in terms of both contagion risk and clinical outcome. This document is addressed to all specialists who approach patients with endogenous or exogenous GC excess and COVID-19 infection.
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http://dx.doi.org/10.1007/s11154-020-09598-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538187PMC
December 2021

From microbiota toward gastro-enteropancreatic neuroendocrine neoplasms: Are we on the highway to hell?

Rev Endocr Metab Disord 2021 09 15;22(3):511-525. Epub 2020 Sep 15.

Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy.

Gut microbiota is represented by different microorganisms that colonize the intestinal tract, mostly the large intestine, such as bacteria, fungi, archaea and viruses. The gut microbial balance has a key role in several functions. It modulates the host's metabolism, maintains the gut barrier integrity, participates in the xenobiotics and drug metabolism, and acts as protection against gastro-intestinal pathogens through the host's immune system modulation. The impaired gut microbiota, called dysbiosis, may be the result of an imbalance in this equilibrium and is linked with different diseases, including cancer. While most of the studies have focused on the association between microbiota and gastrointestinal adenocarcinomas, very little is known about gastroenteropancreatic (GEP) neuroendocrine neoplasms (NENs). In this review, we provide an overview concerning the complex interplay between gut microbiota and GEP NENs, focusing on the potential role in tumorigenesis and progression in these tumors.
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http://dx.doi.org/10.1007/s11154-020-09589-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8346435PMC
September 2021

Circulating Irisin Levels as a Marker of Osteosarcopenic-Obesity in Cushing's Disease.

Diabetes Metab Syndr Obes 2020 11;13:1565-1574. Epub 2020 May 11.

Dipartimento di Promozione Della Salute, Materno-Infantile, Medicina Interna e Specialistica di Eccellenza "G. D'Alessandro" (PROMISE), Sezione di Malattie Endocrine, del Ricambio e della Nutrizione, Università di Palermo, Palermo, Italy.

Purpose: To evaluate circulating irisin levels in patients with active and controlled Cushing's disease (CD).

Design: Forty-four patients with CD evaluated during the active phase and after 12 months of biochemical remission and 40 controls were recruited.

Methods: Phenotypic, anthropometric, hormonal and metabolic parameters, including insulin sensitivity estimation by homeostatic model of insulin resistance, Matsuda index and oral disposition index and circulating irisin levels were evaluated.

Results: Patients with active CD showed lower irisin levels compared to controls (p<0.001) and controlled CD (p<0.001). The independent variables significantly associated with irisin were waist circumference (WC) (p=0.025), body fat percentage (BF%) (p=0.009), PTH (p=0.007) and chair rising test (CRT) (p<0.001) in active CD and WC (p=0.013), BF% (p=0.014), PTH (p=0.038), CRT (p=0.029) and urinary-free cortisol (p<0.001) in controlled CD.

Conclusion: Circulating irisin levels tend to be lower in patients with active CD compared to those with controlled CD and controls. They are strongly associated with osteosarcopenia and central obesity in CD and therefore may be a possible marker of diagnosis.
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http://dx.doi.org/10.2147/DMSO.S249090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7227819PMC
May 2020

Tenapanor for the treatment of irritable bowel syndrome with constipation.

Expert Rev Clin Pharmacol 2020 May 1;13(5):473-479. Epub 2020 Jun 1.

Section of Gastroenterology, S.Elia - Raimondi Hospital , Caltanissetta, Italy.

Introduction: Irritable bowel syndrome with constipation is associated with higher rates of functional impairment, as compared to other subtypes of the syndrome. Conventional laxative-based pharmacologic therapy of IBS-C, which is mostly symptom-based, is often unsatisfactory. Tenapanor represents a first-in-class orally available inhibitor of NHE3, which is minimally absorbed in the GI tract, what constitutes a significant therapeutic benefit, as it may act on the drug target.

Areas Covered: Aim of this article is to sum up the evidences about pharmacodynamics and pharmacokinetics of tenapanor, focusing on animal models and in vitro studies, but also discuss clinical trials on tenapanor's safety and efficacy in view of its important potential role in IBS-C treatment.

Expert Opinion: In the challenging setting of irritable bowel syndrome with constipation, tenapanor represents a novel strategy in the pipeline of the therapies of IBS-C. Its pharmacokinetic and pharmacodynamic profile provides that it is minimally absorbed from the intestinal lumen and that its action is local, but not systemic action, therefore guaranteeing the reduction of drug-drug interactions, toxicity and severe adverse effects. Phase 2b and 3 trials showed an optimal satisfaction of primary and secondary endpoints.
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http://dx.doi.org/10.1080/17512433.2020.1762570DOI Listing
May 2020

Epidemiology of pancreatic neuroendocrine neoplasms: a gender perspective.

Endocrine 2020 08 28;69(2):441-450. Epub 2020 May 28.

Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.

Purpose: Pancreatic neuroendocrine neoplasms (PNENs) are a group of clinically rare and heterogeneous tumors of the pancreas. Currently there are no studies investigating the gender difference in PNEN susceptibility. Thus, the purpose of this study was aimed at examining how gender shapes risk factors, clinicopathological features, and comorbidities in PNENs.

Methods: The study design consisted of an Italian multicenter, retrospective study. The study included all consecutive patients with PNENs followed at the participating centers. Two hundred and twenty-nine patients (105 males,124 females, age 54 ± 0.98 years) with PNENs were enrolled at the participating centers. The clinicopathological features (age, gender, BMI, histology, tumor size, tumor grade, distant metastasis, hormonal function, and diagnostic circumstances), comorbidities (cardiovascular diseases (CVD), pancreatitis, type 2 diabetes (T2DM), and potential risk factors (smoking and drinking) were included in the analysis.

Results: Females were slightly prevalent (54.15%). PNENs were diagnosed at younger age in females compared to males (p = 0.04). The prevalence of CVD was significantly higher in males than in females (p = 0.006). In the female group, the presence of T2DM was significantly associated with higher tumor grade (p = 0.04) and metastatic disease (p = 0.02). The proportion of smokers and alcohol drinkers was significantly higher in the male group (p < 0.001). No significant gender differences were detected regarding the other parameters included in the analysis.

Conclusions: This study has identified gender differences of PNENs in terms of age at diagnosis, associated comorbidities, and potential risk factors. A gender-tailored approach could become a potential strategy to better understand the natural history of PNENs and improve the effectiveness of PNENs clinical management.
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http://dx.doi.org/10.1007/s12020-020-02331-3DOI Listing
August 2020

Anti-Inflammatory Action of Heterogeneous Nuclear Ribonucleoprotein A2/B1 in Patients with Autoimmune Endocrine Disorders.

J Clin Med 2019 Dec 19;9(1). Epub 2019 Dec 19.

Laboratory of Regenerative Medicine, Section of Endocrinology, Diabetology and Metabolism, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE), University of Palermo, 90127 Palermo, Italy.

Our previous studies documented that human fibroblast-limbal stem cells (f-LSCs) possess immunosuppressive capabilities, playing a role in regulating T-cell activity. This study highlights the molecular activities by which human f-LSCs can attenuate the inflammatory responses of self-reactive peripheral blood mononuclear cells (PBMCs) collected from patients with autoimmune endocrine diseases (AEDs). Anti-CD3 activated PBMCs from twenty healthy donors and fifty-two patients with AEDs were cocultured on f-LSC monolayer. 2D-DIGE proteomic experiments, mass spectrometry sequencing and functional in vitro assays were assessed in cocultured PBMCs. We identified the downmodulation of several human heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNP A2/B1) isoforms in healthy and AED activated PBMCs upon f-LSC interaction. The reduction of hnRNPA2/B1 protein expression largely affected the cycling ki67, CD25, PD-1 reactive cells and the double marked CD8/hnRNPA2B1 T cell subset. Anti-PD1 blocking experiments evoked hnRNPA2/B1 overexpression, attributing putative activation function to the protein. hnRNPA2/B2 transient silencing inverted immunopolarization of the self-reactive PBMCs from AEDs toward a M2/Th2-type background. Pharmacological inhibition and co-immunoprecipitation experiments demonstrated the involvement of NF-ĸB in hnRNPA2/B activity and turnover. Our data indicate cardinal involvement of hnRNP A2/B1 protein in peripheral mechanisms of tolerance restoration and attenuation of inflammation, identifying a novel immunoplayer potentially targetable in all AEDs.
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http://dx.doi.org/10.3390/jcm9010009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7019344PMC
December 2019

Clinical and hormonal characteristics in heterozygote carriers of congenital adrenal hyperplasia.

J Steroid Biochem Mol Biol 2020 04 2;198:105554. Epub 2019 Dec 2.

Dipartimento di Promozione Della Salute, Materno-Infantile, Medicina Interna e Specialistica Di Eccellenza "G. D'Alessandro" (PROMISE), Sezione Di Malattie Endocrine, del Ricambio e della Nutrizione, Università di Palermo, Italy. Electronic address:

Non-classical congenital adrenal hyperplasia (NC-CAH) includes a group of genetic disorders due to a broad class of CYP21A2 variants identifying a disease-causing 'C' genotype. The heterozygous carriers of CYP21 mutations are at increased risk of developing clinically evident hyperandrogenism, even though clinical and laboratory characteristics are still underestimated. With the aim of obtaining a more accurate delineation of the phenotype of heterozygous carrier of CAH, we analyzed clinical, biochemical and molecular characteristics in a cohort of Sicilian subjects. Fifty-seven females with biallelic and monoallelic CYP21A2 variants classifying NC-CAH (24) and heterozygous carriers of CAH (33), respectively were selected. Forty-four females age-matched healthy controls were also enrolled and genotyped for CYP21A2. Clinical, hormonal and genetic data were collected. CYP21A2 monoallelic mutations, defining the heterozygous carriers state, were identified in subjects with clinical features including hirsutism, oligomenorrhoea, overweight and a PCO-like phenotype, particularly occurring in the age of adolescence. Consistently, levels of 17OHP and cortisol were found to be significantly different from NC-CAH. Overall, some clinical and laboratory findings including oligomenorrhea and 17OHP/cortisol ratio were observed as independent markers associated with carriers of CAH. Here we report a high prevalence of late-onset signs of polycystic ovary syndrome (PCOS) and hyperandrogenism in heterozygous carriers. The 17OHP/cortisol ratio may be a predictive tool to identify the carriers of CAH, even though specific cut-off values have not yet been identified.
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http://dx.doi.org/10.1016/j.jsbmb.2019.105554DOI Listing
April 2020

Dual-release hydrocortisone improves hepatic steatosis in patients with secondary adrenal insufficiency: a real-life study.

Ther Adv Endocrinol Metab 2019 28;10:2042018819871169. Epub 2019 Aug 28.

Dipartimento di Promozione della Salute, Materno-Infantile, Medicina Interna e Specialistica di Eccellenza "G. D'Alessandro" (PROMISE), Sezione di Malattie Endocrine, del Ricambio e della Nutrizione, Università di Palermo, piazza delle cliniche 2, 90127, Palermo, Sicilia, Italy.

Background: Conventional glucocorticoid treatment has a significant impact on liver in patients with adrenal insufficiency. Dual-release hydrocortisone (DR-HC) provides physiological cortisol exposure, leading to an improvement in anthropometric and metabolic parameters. We aimed to evaluate the effects of 12-month DR-HC treatment on the hepatic steatosis index (HSI), a validated surrogate index of hepatic steatosis, in patients with secondary adrenal insufficiency (SAI).

Methods: A total of 45 patients with hypopituitarism, 22 with hypogonadism, hypothyroidism, ACTH, and GH deficiencies, and 23 with hypogonadism, hypothyroidism, and ACTH deficiency, on replacement therapy for all the pituitary deficiencies, were switched from conventional hydrocortisone to DR-HC. At baseline and after 12 months, glucose and insulin levels, surrogate estimates of insulin sensitivity, and hepatic steatosis were evaluated through ultrasonography and HSI.

Results: At diagnosis, ultrasonography documented steatosis in 31 patients (68.8%) while 33 (73.3%) showed high HSI. Hydrocortisone (HC) dose (β = 1.231,   0.010), insulin resistance index (HOMA-IR) (β = 1.431,  = 0.002), and insulin sensitivity index (ISI)-Matsuda (β = -1.389,  = 0.034) were predictors of HSI at baseline. After 12 months of DR-HC, a significant decrease in body mass index (BMI) ( = 0.008), waist circumference (WC) ( = 0.010), fasting insulin (  0.041), HOMA-IR ( = 0.047), HSI ( < 0.001) and number of patients with HSI ⩾36 ( = 0.003), and a significant increase in sodium ( < 0.001) and ISI-Matsuda ( = 0.031) were observed. HOMA-IR (β = 1.431,   0.002) and ISI-Matsuda (β = -9.489,  < 0.001) were identified as independent predictors of HSI at 12 months.

Conclusions: In adults with SAI, DR-HC is associated with an improvement in HSI, regardless of the dose used, mainly related to an improvement in insulin sensitivity.
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http://dx.doi.org/10.1177/2042018819871169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6713956PMC
August 2019

A rare rarity: Neuroendocrine tumor of the esophagus.

Crit Rev Oncol Hematol 2019 May 2;137:92-107. Epub 2019 Mar 2.

Thyroid and Parathyroid Surgery Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione G. Pascale", IRCCS, Naples, Italy.

Esophageal Neuroendocrine tumors (NETs) are rare, aggressive and lacking specific symptoms. This causes a diagnostic delay, worsening the prognosis. Numerous cases are reported in literature, without a consensus on the management. Our aim was to clarify epidemiology, clinical presentation, diagnostic, therapeutic management of esophageal NETs. Extensive literature search identified a total of 226 articles. One hundred twenty-five articles (n = 1676) met the inclusion criteria, showing that: the incidence of esophageal NET varies geographically; men (60-70 years) are more affected; smoking and alcohol abuse are the major risk factors; dysphagia, weight loss, appetite loss are the most common clinical features. The histotypes include high-grade small and large cell esophageal carcinomas and low-grade carcinoid tumors. Mixed neuroendocrine/non-neuroendocrine neoplasms are the most common. Often the diagnosis occurs randomly on endoscopic examination. Circulating markers, functional combined with conventional imaging contributes to the diagnosis and management. Treatment depends on type, grade and stage of the tumor.
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http://dx.doi.org/10.1016/j.critrevonc.2019.02.012DOI Listing
May 2019

The medical treatment with pasireotide in Cushing's disease: an Italian multicentre experience based on "real-world evidence".

Endocrine 2019 06 9;64(3):657-672. Epub 2019 Apr 9.

Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Naples, Italy.

A phase III study has demonstrated that 6-month pasireotide treatment induced disease control with good safety in 15-26% of patients with Cushing's disease (CD). The aim of the current study was to evaluate the 6-month efficacy and safety of pasireotide treatment according to the real-world evidence. Thirty-two CD patients started pasireotide at the dose of 600 µg twice a day (bid) and with the chance of up-titration to 900 µg bid, or down-titration to 450 or 300 µg bid, on the basis of urinary cortisol (UC) levels or safety. Hormonal, clinical and metabolic parameters were measured at baseline and at 3-month and 6-month follow-up, whereas tumour size was evaluated at baseline and at 6-month follow-up. At baseline, 31 patients had very mild to moderate disease and 1 patient had very severe disease. Five (15.6%) patients discontinued treatment for adverse events; the remaining 27 patients (26 with very mild to moderate disease and 1 with very severe disease), reached 6-month follow-up. Considering the group of patients with very mild to moderate disease, responsiveness, defined by the normalization (<1 the upper limit of normal range, ULN) or near normalization (>1 and ≤1.1 ULN) of UC levels, was registered in 21 patients (full control in 19 and near control in 2), corresponding to 67.7% and 80.8% according to an "intention-to-treat" or "per-protocol" methodological approach, respectively. Weight, body mass index, waist circumference, as well as total and LDL-cholesterol significantly decreased, whereas fasting plasma glucose and glycated haemoglobin significantly increased. Hyperglycaemia was documented in 81.2%, whereas gastrointestinal disturbances in 40.6% of patients. In conclusion, in the real-life clinical practice, pasireotide treatment normalizes or nearly normalizes UC in at least 68% of patients with very mild to moderate disease, with consequent improvement in weight, visceral adiposity and lipid profile, despite the occurrence or deterioration of diabetes in the majority of cases, confirming the usefulness of this treatment in patients with milder disease and without uncontrolled diabetes.
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http://dx.doi.org/10.1007/s12020-018-1818-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6551343PMC
June 2019

Therapeutic sequences in patients with grade 1-2 neuroendocrine tumors (NET): an observational multicenter study from the ELIOS group.

Endocrine 2019 11 14;66(2):417-424. Epub 2019 Mar 14.

Division of Endocrinology, Department of Clinical Medicine and Surgery, Federico II University of Naples, Naples, Italy.

Purpose: Many different treatments are suggested by guidelines to treat grade 1-2 (G1-G2) neuroendocrine tumors (NET). However, a precise therapeutic algorithm has not yet been established. This study aims at identifying and comparing the main therapeutic sequences in G1-G2 NET.

Methods: A retrospective observational Italian multicenter study was designed to collect data on therapeutic sequences in NET. Median progression-free survival (PFS) was compared between therapeutic sequences, as well as the number and grade of side effects and the rate of dose reduction/treatment discontinuation.

Results: Among 1182 patients with neuroendocrine neoplasia included in the ELIOS database, 131 G1-G2 gastroenteropancreatic, lung and unknown primary NET, unresectable or persistent/relapsing after surgery, treated with ≥2 systemic treatments, were included. Four main therapeutic sequences were identified in 99 patients: (A) somatostatin analogs (SSA) standard dose to SSA high dose (n = 36), (B) SSA to everolimus (n = 31), (C) SSA to chemotherapy (n = 17), (D) SSA to peptide receptor radionuclide therapy (PRRT) (n = 15). Median PFS of the second-line treatment was not reached in sequence A, 33 months in sequence B, 20 months in sequence C, 30 months in sequence D (p = 0.16). Both total number and severity of side effects were significantly higher in sequences B and C than A and D (p = 0.04), as well as the rate of dose reduction/discontinuation (p = 0.03).

Conclusions: SSA followed by SSA high dose, everolimus, chemotherapy or PRRT represent the main therapeutic sequences in G1-G2 NET. Median PFS was not significantly different between sequences. However, the sequences with SSA high dose or PRRT seem to be better tolerated than sequences with everolimus or chemotherapy.
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http://dx.doi.org/10.1007/s12020-019-01894-0DOI Listing
November 2019
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