Dynamic Tests in Pituitary Endocrinology: Pitfalls in Interpretation during Aging.

Aging and age-related diseases represent hot topics of current research. Progressive damage in morphology and function of cells and tissue characterizes the normal process of aging that is influenced by both genetic and environmental factors. The ability of each individual to adapt to these stressors defines the type of aging and the onset of age-related diseases (i.e., metabolic syndrome, inflammatory disorders, cancer, and neurodegenerative diseases). The endocrine system plays a critical role in this process because of its complex relationships with brain, immune system, and skeletal muscle; thus, alterations in hormonal networks occur during aging to maintain homeostasis, with consequent under- or overactivity of specific hypothalamic-pituitary-peripheral hormone axes. On the other hand, the increase in life expectancy has led to increasing incidence of age-related diseases, including endocrine disorders, which may prompt assessment of endocrine function in aging individuals. In this context, there is growing awareness that natural changes of endocrine physiology and physiopathology occurring with increasing age may necessitate age-driven diagnostic cutoffs requiring validation in the elderly. This review aims to analyze the available literature on the hormone response to the most important dynamic tests currently used in the clinical practice for the screening of anterior pituitary-related diseases to underline pitfalls in interpretation during aging.

Targeting microbiota in dietary obesity management: a systematic review on randomized control trials in adults.

Obesity is an alarming public health problem. Tailored nutritional therapy is advisable since emerging evidence on complex cross-talks among multifactorial agents. In this picture, the gut microbiota is highly individualized and intricately dependent on dietary patterns, with implications for obesity management. Most of the papers on the topic are observational and often conflicting. This review aimed to systematically organize the body of evidence on microbiota deriving from dietary trials in adult obesity giving the most certain phylogenetic, and metabolomic signatures in relation to both the host metabolism and phenotype changes published until now. We retrieved 18 randomized control trials on 1385 subjects with obesity who underwent several dietary interventions, including standard diet and healthy dietary regimens. Some phyla and species were more related to diets rich in fibers and others to healthy diets. Weight loss, metabolism improvements, inflammatory markers decrease were specifically related to different microorganisms or functions. The Prevotella/Bacteroides ratio was one of the most reported predictors. People with the burden of obesity comorbidities had the most significant taxonomic changes in parallel with a general improvement. These data emphasize the possibility of using symbiotic approaches involving tailored diets, microbiota characteristics, and maybe drugs to treat obesity and metabolic disorders. We encourage Authors to search for specific phylogenetic associations beyond a too generally reported Firmicutes/Bacteroides ratio.

Second-Day Morning Cortisol Levels after Transsphenoidal Surgery Are Accurate Predictors of Secondary Adrenal Insufficiency with Diagnostic Cut-Offs Similar to Those in Non-Stressed Conditions.

INTRODUCTION: Multiple studies tried to identify cortisol cut-offs after pituitary surgery that could accurately assess hypothalamic-pituitary-adrenal (HPA) axis function; however, there is no consensus nowadays. This study aimed to evaluate the accuracy of morning cortisol after transsphenoidal surgery in predicting long-term secondary adrenal insufficiency. METHODS: In our tertiary center, we prospectively determined first- and second-day cortisol after transsphenoidal surgery in 92 patients without preoperative adrenal -insufficiency and not treated with glucocorticoids perioperatively. Definitive diagnosis of secondary adrenal insufficiency was obtained with re-evaluation 3 months after trans-sphenoidal surgery and clinical follow-up of at least 1 year. RESULTS: Ten patients (10.8%) developed long-term postoperative secondary adrenal insufficiency. The ROC curves demonstrated that first-day cortisol had a moderate diagnostic accuracy, while a second-day cortisol ≤9.3 µg/dL (257 nmol/L) showed the best performance in predicting adrenal insufficiency (sensitivity [Se] 88.9%, specificity [Sp] 86.9%, AUC 0.921). Moreover, a second-day cortisol ≤3.2 µg/dL (89 nmol/L) was able to diagnose adrenal insufficiency in 100% of cases (Se 22.2%, Sp 100%) and >14 µg/dL (386 nmol/L) was able to exclude ACTH deficiency (Se 100%, Sp 57.4%). CONCLUSIONS: Adrenal function can be carefully studied on the second day after pituitary surgery, using cut-off values that international guidelines suggested for non-stressed conditions. In fact, second-day cortisol levels ≤3.2 µg/dL (89 nmol/L) and >14 µg/dL (386 nmol/L) are diagnostic of secondary adrenal insufficiency and normal function, respectively. We also suggest performing a definitive re-evaluation with an HPA axis stimulation test when second-day cortisol values are between 3.3 and 14 µg/dL (90-386 nmol/L).

Neuroinflammation and Hypothalamo-Pituitary Dysfunction: Focus of Traumatic Brain Injury.

The incidence of traumatic brain injury (TBI) has increased over the last years with an important impact on public health. Many preclinical and clinical studies identified multiple and heterogeneous TBI-related pathophysiological mechanisms that are responsible for functional, cognitive, and behavioral alterations. Recent evidence has suggested that post-TBI neuroinflammation is responsible for several long-term clinical consequences, including hypopituitarism. This review aims to summarize current evidence on TBI-induced neuroinflammation and its potential role in determining hypothalamic-pituitary dysfunctions.

Primary Pituitary Lymphoma As Rare Cause Of A Pituitary Mass And Hypopituitarism In Adulthood.

OBJECTIVE: Differential diagnosis of nonadenomatous sellar masses causing hypopituitarism is still a challenge. Among these masses, growing evidence has demonstrated that primary pituitary lymphoma is a specific and emerging entity. The aim of our study was to describe our experience with a case of primary pituitary lymphoma and to perform a review of the available literature. METHODS: We searched relevant databases up to March 2020, identifying 36 suitable articles basing on inclusion criteria (primary pituitary lymphoma in adult immunocompetent subjects). Overall, 43 cases were included in the review, adding a new case diagnosed and treated in our hospital. Epidemiologic data, clinical presentation, hormonal status, radiologic findings, pathology, treatment, and outcome were extracted. RESULTS: Mean age at diagnosis was 58.9 years, without gender difference. Symptoms related to mass were common (52.3%), in particular cranial nerve palsy (70.5%), headache (56.8%), and alteration in visual field (40.9%). Impaired hormonal status was detected in 89.7% of patients; of them, 58.9% presented with anterior pituitary failure (partial or total), while 25.6% presented with panhypopituitarism. Overall, diabetes insipidus was present in 30.8% and hyperprolactinemia in 41.0% of patients. The majority of patients presented a radiologically invasive mass in the suprasellar region and cavernous sinus (65.9% and 40.9%, respectively) and histologic diagnosis of diffuse B-cell lymphoma (54.5%). CONCLUSION: The differential diagnosis of sellar and parasellar masses causing hypopituitarism should include primary pituitary lymphoma, even in absence of systemic symptoms or posterior pituitary dysfunction. The disease has a heterogeneous pattern, so a collaboration between endocrinologists, neuroradiologists, neurosurgeons, and hematologists is desirable.

Clinical picture and the treatment of TBI-induced hypopituitarism.

Traumatic brain injury (TBI) is an important public health problem with an increasing incidence in the last years. Relatively few cases are fatal; most individuals will survive and, in the long-term, the sequalae of TBI will include neuroendocrine dysfunctions with a much higher frequency than previously suspected. Patients who develop hypopituitarism after TBI present manifestations due to the number of deficient hormones, severity of hormonal deficiency, and the duration of hypopituitarism without diagnosis and treatment. The clinical spectrum of hypopituitarism is very large and many signs and symptoms of TBI survivors such as fatigue, concentration difficulties, depressive symptoms are nonspecific and overlap with symptoms of post-traumatic stress disorder and variably severe hypopituitarism related to brain damage remaining undiagnosed. This can explain why the diagnosis of hypopituitarism is often missed or delayed after this condition with potentially serious and hazardous consequences for the affected patients. Moreover, clinical experience cumulatively suggests that TBI-associated hypopituitarism is associated with poor recovery and worse outcome, since post-traumatic hypopituitarism is independently associated with cognitive impairment, poor quality of life, abnormal body composition, and adverse metabolic profile. In the present review, the current data related to clinical consequences of pituitary dysfunction after TBI in adult patients and therapeutic approaches are reported.

VRT (verbal reasoning test): a new test for assessment of verbal reasoning. Test realization and Italian normative data from a multicentric study.

Verbal reasoning is a complex, multicomponent function, which involves activation of functional processes and neural circuits distributed in both brain hemispheres. Thus, this ability is often impaired after brain injury. The aim of the present study is to describe the construction of a new verbal reasoning test (VRT) for patients with brain injury and to provide normative values in a sample of healthy Italian participants. Three hundred and eighty healthy Italian subjects (193 women and 187 men) of different ages (range 16-75 years) and educational level (primary school to postgraduate degree) underwent the VRT. VRT is composed of seven subtests, investigating seven different domains. Multiple linear regression analysis revealed a significant effect of age and education on the participants' performance in terms of both VRT total score and all seven subtest scores. No gender effect was found. A correction grid for raw scores was built from the linear equation derived from the scores. Inferential cut-off scores were estimated using a non-parametric technique, and equivalent scores were computed. We also provided a grid for the correction of results by z scores.

Integrative analysis of systemic lupus erythematosus biomarkers: Role of fecal hsa-mir-223-3p and gut microbiota in transkingdom dynamics.

Systemic lupus erythematosus (SLE) involves a florid set of clinical manifestations whose autoreactive origin is characterized by an overactivation of the immune system and the production of a large number of autoantibodies. Because it is a complex pathology with an inflammatory component, its pathogenesis is not yet fully understood, assuming both genetic and environmental predisposing factors. Currently, it is known that the role of the human microbiome is crucial in maintaining the transkingdom balance between commensal microorganisms and the immune system. In the present work we study the intestinal microbiota of Argentine patients with different stages of SLE receiving or not different treatments. Microbiota composition and fecal miRNAs were assessed by 16 S sequencing and qPCR. hsa-miR-223-3p, a miRNA involved in several inflammation regulation pathways, was found underexpressed in SLE patients without immunosuppressive treatment. In terms of microbiota there were clear differences in population structure (Weighted and Unweighted Unifrac distances, p-value <0.05) and core microbiome between cases and controls. In addition, Collinsella, Bifidobacterium, Streptococcus genera and aromatics degradation metabolisms were overrepresented in the SLE group. Medical treatment was also determinant as several microbial metabolic pathways were influenced by immunosuppressive therapy. Particularly, allantoin degradation metabolism was differentially expressed in the group of patients receiving immunosuppressants. Finally, we performed a logistic regression model (LASSO: least absolute shrinkage and selection operator) considering the expression levels of the fecal hsa-miR223-3p; the core microbiota; the differentially abundant bacterial taxa and the differentially abundant metabolic pathways (p<0.05). The model predicted that SLE patients could be associated with greater relative abundance of the formaldehyde oxidation pathway (RUMP_PWY). On the contrary, the preponderance of the ketodeoxyoctonate (Kdo) biosynthesis and activation route (PWY_1269) and the genera Lachnospiraceae_UCG_004, Lachnospira, Victivallis and UCG_003 (genus belonging to the family Oscillospiraceae of the class Clostridia) were associated with a control phenotype. Overall, the present work could contribute to the development of integral diagnostic tools for the comprehensive phenotyping of patients with SLE. In this sense, studying the commensal microbial profile and possible pathobionts associated with SLE in our population proposes more effective and precise strategies to explore possible treatments based on the microbiota of SLE patients.

Glucose Alterations, Insulin Resistance, Arterial Hypertension, and Renin are Strictly Associated in Pediatric Obesity.

Context: Insulin resistance, glucose alterations, arterial hypertension (HTN), and the renin-angiotensin-aldosterone system (RAAS) are related in adult obesity. This crosstalk is still unexplored in childhood. Objective: Characterize the relationships of fasting and postload glucose and insulin levels with new American Academy of Pediatrics classification of HTN and RAAS in pediatric obesity. Methods: This was a retrospective observational study; 799 pediatric outpatients (11.4 ± 3.1 years) at a tertiary center who were overweight or obese and not yet on diet were included. The main outcome measures were mean and correlations among parameters of a complete clinical and metabolic screening (body mass index, blood pressure, and glucose and insulin levels during an oral glucose tolerance test, and renin and aldosterone levels and their ratio). Results: 774 subjects had all the parameters, of whom 87.6% had HTN (5% elevated blood pressure, 29.2% stage I HTN, and 53.4% stage II HTN). Eighty subjects had 1 or more glucose alterations, and more frequently presented HTN. Blood pressure levels were higher in subjects with glucose alterations than in those with normal glucose levels. Fasting and stimulated glucose and insulin levels were directly related to the HTN stages, and insulin sensitivity was lower in HTN than in normal blood pressure. Aldosterone, renin, and aldosterone-renin ratio (ARR) were similar in sexes, whereas aldosterone was higher in prepubertal individuals. Subjects with impaired glucose tolerance (IGT) had higher renin and lower ARR. Renin was positively correlated with postload glucose, and ARR was negatively correlated with the Homeostatic Model Assessment for Insulin Resistance index. Conclusion: A close relationship exists among insulin resistance, glucose alterations, HTN, and renin in childhood obesity. Specific categories of risk could provide indicators for strict clinical surveillance.

Discordant biochemical parameters of acromegaly remission do not influence the prevalence or aggressiveness of metabolic comorbidities: a single-center study.

Purpose: The discrepancy between the biomarkers of disease's activity in acromegalic patients (GH and IGF-1) is almost frequent representing a challenge for the development of comorbidities in the long term. The aim of this study was to evaluate the prevalence and severity of metabolic comorbidities (diabetes, hypertension, and dyslipidemia) in surgically treated acromegalic patients with disease control and discordant GH and/or IGF-1 levels compared with those with concordant values. Patients and methods: Retrospective monocentric observational study on acromegalic surgically treated patients with biochemical remission (group A) or mild discordant GH or IGF-1 levels (group B). Metabolic complications and medical therapy were assessed at diagnosis and at the last follow-up visit. Severity of the disease was set for drug titration or shift to another molecule or more than before. Results: There were 18 patients that met the inclusion criteria [group A: nine patients; group B: nine patients, follow-up 7 years (IQR 5.0;11.25)]. The prevalence of female patients was significantly higher in the remission group compared with the discordant group (p < 0.02). Considering metabolic complications, at the last follow-up, 61.1% was affected by hypertension, 33.3% by diabetes, and 61.1% by dyslipidemia, without differences between groups. Drug characteristics (dose, shift, number) during the follow-up did not differ significantly between groups. Conclusion: Metabolic complications, mainly dyslipidemia, are frequent in cured acromegalic patients, but GH/IGF-1 discrepancy does not seem to represent a risk factor for their presence or persistence. More extended studies are needed to confirm our results in a long-term period.

Copeptin adaptive response to SGLT2 inhibitors in patients with type 2 diabetes mellitus: The GliRACo study.

Introduction: In type 2 diabetes mellitus (T2DM), the antidiuretic system participates in the adaptation to osmotic diuresis further increasing urinary osmolality by reducing the electrolyte-free water clearance. Sodium glucose co-transporter type 2 inhibitors (SGLT2i) emphasize this mechanism, promoting persistent glycosuria and natriuresis, but also induce a greater reduction of interstitial fluids than traditional diuretics. The preservation of osmotic homeostasis is the main task of the antidiuretic system and, in turn, intracellular dehydration the main drive to vasopressin (AVP) secretion. Copeptin is a stable fragment of the AVP precursor co-secreted with AVP in an equimolar amount. Aim: To investigate the copeptin adaptive response to SGLT2i, as well as the induced changes in body fluid distribution in T2DM patients. Methods: The GliRACo study was a prospective, multicenter, observational research. Twenty-six consecutive adult patients with T2DM were recruited and randomly assigned to empagliflozin or dapagliflozin treatment. Copeptin, plasma renin activity, aldosterone and natriuretic peptides were evaluated at baseline (T0) and then 30 (T30) and 90 days (T90) after SGLT2i starting. Bioelectrical impedance vector analysis (BIVA) and ambulatory blood pressure monitoring were performed at T0 and T90. Results: Among endocrine biomarkers, only copeptin increased at T30, showing subsequent stability (7.5 pmol/L at T0, 9.8 pmol/L at T30, 9.5 pmol/L at T90; p = 0.001). BIVA recorded an overall tendency to dehydration at T90 with a stable proportion between extra- and intracellular fluid volumes. Twelve patients (46.1%) had a BIVA overhydration pattern at baseline and 7 of them (58.3%) resolved this condition at T90. Total body water content, extra and intracellular fluid changes were significantly affected by the underlying overhydration condition (p < 0.001), while copeptin did not. Conclusion: In patients with T2DM, SGLT2i promote the release of AVP, thus compensating for persistent osmotic diuresis. This mainly occurs because of a proportional dehydration process between intra and extracellular fluid (i.e., intracellular dehydration rather than extracellular dehydration). The extent of fluid reduction, but not the copeptin response, is affected by the patient's baseline volume conditions. Clinical trial registration: Clinicaltrials.gov, identifier NCT03917758.

Bone Response to Weight Loss Following Bariatric Surgery.

Obesity is a global health challenge that warrants effective treatments to avoid its multiple comorbidities. Bariatric surgery, a cornerstone treatment to control bodyweight excess and relieve the health-related burdens of obesity, can promote accelerated bone loss and affect skeletal strength, particularly after malabsorptive and mixed surgical procedures, and probably after restrictive surgeries. The increase in bone resorption markers occurs early and persist for up to 12 months or longer after bariatric surgery, while bone formation markers increase but to a lesser extent, suggesting a potential uncoupling process between resorption and formation. The skeletal response to bariatric surgery, as investigated by dual-energy X-ray absorptiometry (DXA), has shown significant loss in bone mineral density (BMD) at the hip with less consistent results for the lumbar spine. Supporting DXA studies, analyses by high-resolution peripheral quantitative computed tomography (HR-pQCT) showed lower cortical density and thickness, higher cortical porosity, and lower trabecular density and number for up to 5 years after bariatric surgery. These alterations translate into an increased risk of fall injury, which contributes to increase the fracture risk in patients who have been subjected to bariatric surgery procedures. As bone deterioration continues for years following bariatric surgery, the fracture risk does not seem to be dependent on acute weight loss but, rather, is a chronic condition with an increasing impact over time. Among the post-bariatric surgery mechanisms that have been claimed to act globally on bone health, there is evidence that micro- and macro-nutrient malabsorptive factors, mechanical unloading and changes in molecules partaking in the crosstalk between adipose tissue, bone and muscle may play a determining role. Given these circumstances, it is conceivable that bone health should be adequately investigated in candidates to bariatric surgery through bone-specific work-up and dedicated postsurgical follow-up. Specific protocols of nutrients supplementation, motor activity, structured rehabilitative programs and, when needed, targeted therapeutic strategies should be deemed as an integral part of post-bariatric surgery clinical support.

Calreticulin and PDIA3, two markers of endoplasmic reticulum stress, are associated with metabolic alterations and insulin resistance in pediatric obesity: A pilot study.

Our aim was to evaluate the markers of endoplasmic reticulum (ER) stress among children and adolescents with obesity in relation to metabolic alterations. Calreticulin (CALR) and PDIA3 circulating levels were assessed on 52 pediatric subjects-26 patients with obesity and 26 normal weight controls (4-18 years)-enrolled in a pilot study. Clinical and metabolic evaluations were performed (BMI-SDS, insulin, and glucose at fasting and during an oral glucose tolerance test, lipid profile, blood pressure), and metabolic syndrome was detected. PDIA3 was higher (p < 0.02) and CALR slightly higher in children with obesity than in controls. PDIA3 was related positively to the Tanner stages. Both PDIA3 and CALR were positively associated with insulin resistance, cholesterol, and triglycerides and the number of criteria identifying metabolic syndrome and negatively with fasting and post-challenge insulin sensitivity. Our preliminary findings suggest the existence of a link between ER stress and metabolic changes behind obesity complications even at the pediatric age. CALR and PDIA3 could be early markers of insulin resistance and dyslipidemia-related ER stress useful to stratify patients at high risk of further complications.

Beyond bariatric surgery and weight loss medicaments. A systematic review of the current practice in obesity rehabilitative inpatient programs in adults and pediatrics.

Background: Obesity treatment strategies mainly include outpatient lifestyle modification, drugs and bariatric surgery. Voluntary rehabilitative inpatient programs are gaining relevance as potential alternative settings of care that focus on weight loss and prevention of weight regain through a multidisciplinary approach, but their prevalence is still limited due to the high costs. Aim: Considering the lack of evidence in this area, the objective of this study is to systematically review the currently available literature on non-pharmacological and non-surgical inpatient programs aimed at weight loss, to clarify the efficacy and the characteristics of these interventions. Methods: Proper English language articles from 2000 to 2022 were searched on relevant databases. Quality assessment was performed by two different authors using ROB2 and robvis tools. Adult and pediatric studies were reviewed separately and their characteristics were systematically displayed. Results: 36 articles were included (20 on adults, 16 on children, and adolescents) for a total of 5,510 individuals. The multidisciplinary approach was mainly comprehensive of a low-calorie diet, scheduled physical activity, and psychological support based on behavioral treatment. Educational and cooking sessions were present at a lower rate. Globally, inpatient weight loss programs showed a consistent efficacy in reducing body weight and inducing beneficial effects on quality of life, psychological well-being, eating behavior, physical performance, and fatigue. Follow-up data were scarce, but with a high percentage of patients regaining weight after a short period. Conclusion: Weight loss inpatient rehabilitation is a promising area that has evidence of all-rounded success in the amelioration of several aspects related to obesity. Nevertheless, it appears to be quite inconsistent in preserving these benefits after the intervention. This might slow the innovation process in this area and preclude further investments from national healthcare. Personalized and enriched programs could show greater impact when focusing on the behavioral and educational aspects, which are crucial points, in particular in pediatrics, for setting up a long-lasting lifestyle modification. More studies are therefore necessary to evaluate long-term efficacy based on the different work-up models.

Adherence to the Mediterranean Diet Is Associated with Better Metabolic Features in Youths with Type 1 Diabetes.

Our aim was to evaluate adherence to the Mediterranean diet (MedDiet) among children and adolescents with type 1 diabetes (T1D) in relation to metabolic control. Adherence to the MedDiet was assessed with the Mediterranean Diet Quality Index (KIDMED) questionnaire and physical activity by the International Physical Activity Questionnaire for Adolescent (IPAQ-A) on 65 subjects (32 males, 9-18 years) with T1D. Clinical and metabolic evaluation was performed (standardized body mass index (BMI-SDS), hemoglobin A1C (HbA1c), continuous glucose monitoring metrics when present, blood pressure, lipid profile). Parental characteristics (age, body mass index (BMI), socio-economic status) were reported. The adherence to the MedDiet was poor in 12.3%, average in 58.6%, and high in 29.1% of the subjects. Furthermore, 23.4% of patients were overweight/obese. The most impacting factors on BMI-SDS were skipping breakfast and their father's BMI. HbA1c and time in range % were positively associated with sweets and fish intake, respectively. Additionally, the father's socio-economic status (SES) and mother's age were associated with glucose control. Blood pressure was associated with travelling to school in vehicles, extra-virgin olive oil intake and milk/dairy consumption at breakfast. The promotion of the MedDiet, mainly having a healthy breakfast, is a good strategy to include in the management of T1D to improve glucose and metabolic control. This research is valuable for parents to obtain the best results for their children with T1D.

From SGAP-Model to SGAP-Score: A Simplified Predictive Tool for Post-Surgical Recurrence of Pheochromocytoma.

A reliable prediction of the recurrence risk of pheochromocytoma after radical surgery would be a key element for the tailoring/personalization of post-surgical follow-up. Recently, our group developed a multivariable continuous model that quantifies this risk based on genetic, histopathological, and clinical data. The aim of the present study was to simplify this tool to a discrete score for easier clinical use. Data from our previous study were retrieved, which encompassed 177 radically operated pheochromocytoma patients; supervised regression and machine-learning techniques were used for score development. After Cox regression, the variables independently associated with recurrence were tumor size, positive genetic testing, age, and PASS. In order to derive a simpler scoring system, continuous variables were dichotomized, using > 50 mm for tumor size, ≤ 35 years for age, and ≥ 3 for PASS as cut-points. A novel prognostic score was created on an 8-point scale by assigning 1 point for tumor size > 50 mm, 3 points for positive genetic testing, 1 point for age ≤ 35 years, and 3 points for PASS ≥ 3; its predictive performance, as assessed using Somers' D, was equal to 0.577 and was significantly higher than the performance of any of the four dichotomized predictors alone. In conclusion, this simple scoring system may be of value as an easy-to-use tool to stratify recurrence risk and tailor post-surgical follow-up in radically operated pheochromocytoma patients.

Development and internal validation of a predictive model for the estimation of pheochromocytoma recurrence risk after radical surgery.

Objective: Various features have been identified as predictors of relapse after complete resection of pheochromocytoma, but a comprehensive multivariable model for recurrence risk prediction is lacking. The aim of this study was to develop and internally validate an integrated predictive model for post-surgical recurrence of pheochromocytoma. Methods: The present research retrospectively enrolled 177 patients affected by pheochromocytoma and submitted to radical surgery from 1990 to 2016, in nine referral centers for adrenal diseases. Cox regression analysis was adopted for model development, and a bootstrapping procedure was used for internal validation. Results: Variables independently associated with recurrence were tumor size (hazard ratio (HR): 1.01, 95% CI: 1.00-1.02), positive genetic testing (HR: 5.14, 95% CI: 2.10-12.55), age (HR: 0.97, 95% CI: 0.94-0.99), and Pheochromocytoma of the Adrenal Gland Scaled Score (PASS) (HR: 1.16, 95% CI: 1.04-1.29). The predictive performance of the overall model, evaluated by Somers' D, was equal to 0.594, and was significantly higher than the ones of any single predictor alone (P = 0.002 compared to tumor size; P = 0.004 compared to genetic testing; P = 0.048 compared to age; P = 0.006 compared to PASS). Internal validation by bootstrapping techniques estimated an optimistic bias of 6.3%, which reassured about a small tendency towards overfit. Conclusions: We proposed a multivariable model for the prediction of post-surgical recurrence of pheochromocytoma, derived by the integration of genetic, histopathological, and clinical data. This predictive tool may be of value for a comprehensive tailoring of post-surgical follow-up in radically operated pheochromocytoma patients.

Insights into non-classic and emerging causes of hypopituitarism.

Hypopituitarism is defined as one or more partial or complete pituitary hormone deficiencies, which are related to the anterior and/or posterior gland and can have an onset in childhood or adulthood. The most common aetiology is a sellar or suprasellar lesion, often an adenoma, which causes hypopituitarism due to tumour mass effects, or the effects of surgery and/or radiation therapy. However, other clinical conditions, such as traumatic brain injury, and autoimmune and inflammatory diseases, can result in hypopituitarism, and there are also genetic causes of hypopituitarism. Furthermore, the use of immune checkpoint inhibitors to treat cancer is increasing the risk of hypopituitarism, with a pattern of hormone defects that is different from the classic patterns and depends on mechanisms that are specific for each drug. Moreover, autoantibody production against the pituitary and hypothalamus has been demonstrated in studies investigating the development or worsening of some cases of hypopituitarism. Finally, evidence suggests that posterior pituitary damage can affect oxytocin secretion. The aim of this Review is to summarize current knowledge on non-classic and emerging causes of hypopituitarism, so as to help clinicians improve early identification, avoid life-threatening events and improve the clinical care and quality of life of patients at risk of hypopituitarism.

Regulation of GH and GH Signaling by Nutrients.

Growth hormone (GH) and insulin-like growth factor-1 (IGF-I) are pleiotropic hormones with important roles in lifespan. They promote growth, anabolic actions, and body maintenance, and in conditions of energy deprivation, favor catabolic feedback mechanisms switching from carbohydrate oxidation to lipolysis, with the aim to preserve protein storages and survival. IGF-I/insulin signaling was also the first one identified in the regulation of lifespan in relation to the nutrient-sensing. Indeed, nutrients are crucial modifiers of the GH/IGF-I axis, and these hormones also regulate the complex orchestration of utilization of nutrients in cell and tissues. The aim of this review is to summarize current knowledge on the reciprocal feedback among the GH/IGF-I axis, macro and micronutrients, and dietary regimens, including caloric restriction. Expanding the depth of information on this topic could open perspectives in nutrition management, prevention, and treatment of GH/IGF-I deficiency or excess during life.

Case Report: Liraglutide for Weight Management in Beckwith-Wiedemann Syndromic Obesity.

Genetic obesity, including syndromic and non-syndromic forms, represents a minority of cases compared to essential obesity but gene dysregulations lead to complex clinical conditions that make their management particularly difficult. Among them, Beckwith-Wiedemann syndrome (BWS) is a multisystem human genomic imprinting disorder characterized by overgrowth. We describe the first case of liraglutide treatment in an 18-year-old boy patient affected by BWS complicated by macroglossia, cryptorchidism, nephroblastoma, organomegaly, microscopic lymphocytic colitis, pharmacologically treated arterial hypertension, obesity, and obstructive sleep apnea syndrome. He presented a normal cognitive development. Body mass index at the time of first transition visit in the adult endocrinology department at the age of 18-years-old was 40.6 kg/m2 without glucose metabolism impairment. Lifestyle interventions failed because of poor compliance. During 20 months of 3.0 mg liraglutide treatment, a weight loss of 19 kg (-13.3%) and BMI reduction of 6.8 points were registered without side effects. To date, liraglutide treatment was effective on obesity in 7 subjects with Prader Willy Syndrome and 14 with melanocortin-4 receptor mutations. The efficacy of liraglutide in BWS could be related to a crosstalk among glucagon-like peptide (GLP)-1 system, mechanisms related to the cyclin-dependent kinase inhibitor 1C (CDKN1C), and dopamine mesolimbic circuit. Clinical trials aiming at a tailored medicine in genetic obesity are needed.