Neuroendocrine tumors (NETs) are rare neoplasms arising from the diffuse neuroendocrine system that can range from indolent to highly aggressive diseases. They usually clinically manifest when reaching a significant size or when hepatic metastases develop, leading to overproduction and impaired hepatic metabolism of vasoactive substances. The clinical course of NETs may be complicated by cardiac involvement, known as carcinoid heart disease (CHD), predominantly affecting the right side of the heart. CHD is characterized by specific echocardiographic features, including thickening, reduced excursion and retraction of valvular leaflets, resulting in valvular stenosis or regurgitation. Despite its clinical relevance, awareness of CHD as a complex hormonal sequela of NETs remains limited among cardiologists, and its echocardiographic findings are not universally recognized. This review aims to (a) provide cardiologists with the main principles for understanding CHD pathophysiology; (b) illustrate the main echocardiographic features of CHD, using a stepwise approach; and (c) refine a diagnostic algorithm for detecting cardiac involvement in NET populations and identifying patients at high risk of developing CHD.

A combination of morphological and functional imaging plays a crucial role for neuroendocrine tumors (NETs) management. Diffusion-weighted magnetic resonance imaging (DWI-MRI) is an emerging key imaging technique in the NET field. to evaluate the diagnostic and prognostic role of DWI-MRI in liver metastases (LMs) from NETs compared with multiparametric MRI and functional imaging with 68Ga-DOTA peptides positron emission tomography (PET)-computed tomography (CT). This is a monocentric, observational, both retrospective and prospective study including patients with histologically proven diagnosis of gastroenteropancreatic (GEP) NET with LM evaluated with MRI and 68Ga-DOTA peptides PET-CT, performed within 6 months apart at diagnosis or follow-up. We collected clinical, pathological, imaging data including lesions number detected on (a)MRI-gold standard, (b)DWI images, (c)68Ga-DOTA peptides PET-CT. Apparent diffusion coefficient (ADC) was calculated on target lesions. 426 LMs were analyzed from 17 patients (11 males, mean age 57.2 ± 12.6 years) meeting the inclusion criteria (11.8

Background/Objectives: The global incidence of neuroendocrine tumors (NETs) is steadily rising. While modifiable lifestyle factors impact oncological outcomes, the interplay between dietary habits, orthorexia nervosa (ON) tendencies, physical activity levels (PAL), and body image in NET survivors remains poorly understood. Methods: A cross-sectional study was conducted on a convenience sample of 61 patients with NETs. Validated evaluation tools included the PREDIMED questionnaire for Mediterranean Diet (MD) adherence, the GPAQ for PAL, and the ORTO-15 questionnaire for ON risk. Body image satisfaction and comprehensive clinical features were also assessed. Results: Most participants (75.4%) demonstrated moderate MD adherence. Body image dissatisfaction (32.8%) was significantly associated with a higher BMI (28.86 vs. 24.93 kg/m2, p < 0.01) and reduced PAL (660.0 vs. 1680.0 MET-min/week, p = 0.021, pFDR = 0.042). Notably, moderate MD adherence was linked to a higher orthorexic risk (corresponding to lower ORTO-15 scores) compared to low adherence (p = 0.032, pFDR = 0.078). Somatostatin analog therapy showed no detrimental impact on behavioral parameters (p > 0.05). Conclusions: These findings highlight specific vulnerabilities in NET patients: body image dissatisfaction correlates with higher BMI and lower physical activity, while moderate Mediterranean Diet adherence associates with orthorexic risk, which is localized and was not independent in multivariate analysis. Targeted nutritional and physical activity interventions should be integrated into multidisciplinary NET care.

BACKGROUND:Over the years, several observational studies and case reports have been published hypothesizing a potential association between the use of proton pump inhibitors (PPIs) and sexual dysfunctions in both male and female patients. OBJECTIVES:We aimed to investigate the potential association between PPI use and sexual dysfunction onset using VigiBase, the World Health Organization international pharmacovigilance database. METHODS:All individual case safety reports of sexual dysfunctions containing PPIs (i.e. omeprazole, lansoprazole, rabeprazole, pantoprazole and esomeprazole) as suspected or interacting drugs until 4 September, 2024 were selected from VigiBase using the Standardised MedDRA Query "Sexual dysfunction". A descriptive analysis of the selected individual case safety reports was carried out. Potentially new safety signals were identified through a disproportionality analysis and calculated as a reporting odds ratio (ROR) along with a 95% confidence interval (CI), which were adjusted via Bonferroni correction for multiple testing. To account for age-related effects on sexual functions, a subgroup analysis was carried out by restricting the study population only to patients aged from 18 to 64 years. RESULTS:A total of 420,598 individual case safety reports concerning PPIs were collected in VigiBase during the study period. Of these, 841 containing at least one Preferred Term included in the "Sexual dysfunction" Standardised MedDRA Query reporting information on sex were retrieved. Overall, disproportionate reporting for omeprazole concerning erectile dysfunction (adjusted ROR, 1.76; 95% CI 1.54-2.01) was observed, while two statistically significant adjusted RORs for esomeprazole, i.e. genital discomfort (ROR, 3.66; 95% CI 1.34-10.04) and oestrogen deficiency (ROR, 3.80; 95% CI 1.03-13.99) in female patients were found. The subgroup analysis confirmed the statistically significant disproportionate reporting of erectile dysfunction for omeprazole (adjusted ROR: 1.80; 95% CI 1.49-2.16), and generated new potential safety signals including an omeprazole-induced libido decrease (adjusted ROR, 1.49; 95% CI 1.05-2.12) and esomeprazole-induced hypogonadism (adjusted ROR, 5.22; 95% CI 1.22-22.34) in male individuals, and omeprazole-induced genital discomfort (adjusted ROR, 3.55; 95% CI 1.13-11.09) in female individuals. CONCLUSIONS:Findings of this study suggest the presence of safety signals of PPI-induced sexual dysfunctions, such as erectile dysfunction, genital discomfort and oestrogen deficiency. However, further observational studies are required to validate and further characterise these potential safety signals.

OBJECTIVE:Although GH and IGF-1 have long been proposed to play a role in immune-modulation, the circulating immune cell phenotype in acromegaly (ACRO) is poorly understood. DESIGN:This observational, prospective, single-site clinical trial (NCT05069324) analyzed peripheral blood mononuclear cell (PBMC) subpopulations in ACRO, investigating the role of disease control, pharmacological treatments, and metabolic profile. METHODS:Sixty consecutive patients with ACRO (34 males, mean age 54.7 ± 15) attending an outpatient visit between July 2020 and December 2024 were enrolled. Patients were compared with two populations: 40 healthy controls (CTRL) and 40 patients with type 2 diabetes (T2DM), with no significant differences in age or sex. An 8-week follow-up evaluation was performed and compared among patients according to the introduction or changes in their pharmacological treatment. RESULTS:Compared with CTRL, ACRO patients had lower total monocytes with a decreased percentage of classical and an increased proportion of non-classical subsets. There were fewer NK cells, with higher CD56dim and lower CD56bright subpopulations, and similar T and B lymphocytes. Compared with T2DM, ACRO showed lower total monocytes, with higher classical and lower non-classical subsets, as well as lower NK cells and B lymphocytes. In the short-term, treatment appeared unable to restore immune cell profile but partially affected the distributions of innate immune cells subpopulations. CONCLUSIONS:This is the first evidence of a distinct immunological pattern in ACRO that is independent of glucose metabolism. The immune signature may contribute to the persistence of cardio-metabolic and oncological risk observed in ACRO, even when the disease is adequately controlled by medical treatment.

BACKGROUND:Neuroendocrine neoplasms (NENs) may metastasize very rarely to the thyroid. The current paper aims at identifying peculiar thyroid nodule's features that could prompt their diagnosis and analyzing therapeutic approach and patient's outcome. MATERIALS AND METHODS:A case series of three patients have been collected from three Italian referral centers. Moreover, we performed a keyword based PUBMED search, using relevant keywords. RESULTS:We included in the review 27 papers and 33 cases have been identified. Patients' age ranged from 17 to 85 years (mean age: 55.8 ± 14.2 years), 14 males, 42.4%. The majority of cases (48.5%) originated from a thoracic NEN. Median time to diagnosis from the primary tumor was 48 months (range 1-252 months). At ultrasound, they were generally hypoechoic nodules with irregular margins. The diagnosis was made by fine-niddle aspiration in the majority of cases, followed by nuclear medicine imaging. At immunohistochemistry, chromogranin A and synaptophysin were expressed in almost all of them, with negative calcitonin and thyroid transcription factor-1. Surgery or systemic treatment were needed according to primary tumor, disease stage, and patients' general condition. Prognosis was variable, better if primary tumor origin was thoracic. CONCLUSIONS:Thyroid metastases from NENs should be considered in the diagnostic work-up of suspicious thyroid nodules in patients with a positive medical history of previous NEN, mainly of thoracic origin. Immunohistochemistry is the key diagnostic tool for their identification. A prompt and correct diagnosis is mandatory because of its crucial prognostic and therapeutic implications.

The incidence of differentiated thyroid carcinoma (DTC) is increasing, and environmental factors, including lifestyle and endocrine-disrupting chemicals (EDCs) exposure, have been advocated as having an etiologic role. To investigate the relationship between DTC, EDCs exposure, and lifestyle in a population from two Italian regions. A cross-sectional study evaluating chemical exposure, lifestyle, and DTC diagnosis in subjects with thyroid nodules, undergoing Fine Needle Aspiration Cytology from May 2019 to February 2021. 193 patients were split into groups based on cytological diagnosis: group A, benign or low-risk (TIR2-TIR3A); group B, high-risk (TIR3B-TIR4-TIR5). Age, sex, weight, height, body mass index (BMI), waist circumference (WC), thyroid hormone profile, lifestyle variables, and serum EDCs levels were compared. The percentage of male patients was significantly higher in group B (p = 0.033), as well as the prevalence of obesity (p = 0.001) and BMI (p = 0.013). Visceral obesity was higher in group B, without reaching statistical significance (70.4

We are grateful to the author of the letter for his interest in our recent paper, ‘Role of the calcium stimulation test in diagnosing medullary thyroid cancer: is it adequate to achieve a diagnosis in both sexes? An individual patient data meta-analysis’ in the European Thyroid Journal (2025), and for his comments on the methodological aspects of our IPD meta-analysis. We would like to clarify our methodological choices and address the concerns raised. Regarding the absence of PROSPERO registration, we recognize that registration would have improved transparency. We defined the analytic framework and objectives before conducting the analyses at the ‘NIKE’ (Neuroendocrine tumors Innovation Knowledge and Education) workshop held by Prof. Annamaria Colao, Prof. Antongiulio Faggiano, and Prof. Andrea M Isidori. The aim of the workshop was to boost the advancement of knowledge in various aspects of neuroendocrinology. However, we recognize the value of protocol registration to limit potential bias. This limitation was acknowledged in our paper, and we agree that future research should adopt protocol registration as a standard practice.

Background/Objectives: Male infertility is influenced by physiological factors like age, as well as lifestyle factors, including physical activity. However, the specific impact of sport activity on semen parameters, and thus on male fertility, remains unclear. Specifically, the aim of this systematic review is to evaluate how an intense regime of training may affect sperm parameters in professional and non-profession athletes. Methods: Studies reporting sperm parameters associated with high training load were included. In April 2024, three electronic databases and literature sources (PubMed, Scopus, and Web of Science) were searched. Quality appraisal was performed independently by three authors using the National Heart, Lung, and Blood Institute Quality Assessment Tools (NHLBI-QAT). Results: Four studies met the inclusion criteria, reporting a total of 156 participants. Sixteen weeks of intensive cycling training produced a significant decrease in seminal volume, sperm concentration, sperm motility, and morphology, with a return to their initial levels, except for sperm morphology and sperm concentration, after at least one week of rest. In addition, in athletes with varicocele, a 6-month stop from sports activity went a long way toward improving sperm concentration and sperm motility. However, DNA fragmentation, a greater presence of round cells, and high numbers of active macrophages were described. At least 30 days improve semen parameters in professional and non-professional athletes. Conclusions: Intensive training could worsen seminal parameters and, consequently, male fertility. However, certainty of evidence is very low, and the results should be interpreted with caution.

Background: Early diagnosis of medullary thyroid cancer (MTC) when basal calcitonin (CT) levels are <100 pg/mL remains a clinical challenge. The calcium stimulation test is a unique tool for stimulating CT. However, standardized and sex-specific cutoff values are lacking. Therefore, this study aimed to investigate whether the calcium stimulation test for CT is adequate for diagnosing MTC in both sexes and to identify sex-specific cutoff values. Methods: This was an individual patient data (IPD) meta-analysis. A literature search was performed using Scopus, PubMed, and Web of Science until September, 2024, to identify articles on the calcium stimulation test for diagnosing MTC. Results: A total of five studies involving 243 patients (148 females and 95 males) who underwent total thyroidectomy were included in this study. Before surgery, all patients underwent the calcium stimulation test with calcium gluconate (25 mg/kg) for CT assessed by chemiluminescence assay. In females, a global threshold of 162 pg/mL was identified, with a pooled sensitivity of 0.90 (95% confidence interval (95% CI): 0.79–0.97) and specificity of 0.66 (95% CI: 0.56–0.75). The pooled area under the curve (AUC) was 0.87 (95% CI: 0.76–0.97). In males, a global threshold of 562 pg/mL was identified, with a pooled sensitivity of 0.79 (95% CI: 0.60–0.92) and specificity of 0.89 (95% CI: 0.79–0.96). The pooled AUC was 0.94 (95% CI: 0.90–0.99). Conclusions: The calcium stimulation test for CT for the diagnosis of MTC showed better performance in males than in females, with a suggested cutoff value of 562 pg/mL in males. Significance statement: The management of indeterminate calcitonin (CT) values is still challenging in the early diagnosis of MTC, lacking general recommendations, which can help clinicians in these cases. This is the first IPD meta-analysis that underscores the sex-based disparity in the diagnostic accuracy of the calcium stimulation test for CT in suspected MTC cases, showing better performance in diagnosing MTC in male versus female patients, with a cutoff value of 562 pg/mL in male subjects. In the context of the limited literature, this paper provides added value for the clinical endocrine practitioner, suggesting the use of the calcium stimulation test in highly selected cases with indeterminate CT values (10–100 pg/mL) with a sex-oriented and personalized approach.

Purpose Cushing's syndrome (CS) is associated with severe cardiovascular (CV) morbidity and mortality. Cardiac magnetic resonance (CMR) is the non-invasive gold standard for assessing cardiac structure and function; however, few CMR studies explore cardiac remodeling in patients exposed to chronic glucocorticoid (GC) excess. We aimed to describe the CMR features directly attributable to previous GC exposure in patients with cured or treated endogenous CS. Methods This was a prospective, multicentre, case-control study enrolling consecutive patients with cured or treated CS and patients harboring non-functioning adrenal incidentalomas (NFAI), comparable in terms of sex, age, CV risk factors, and BMI. All patients were in stable condition and had a minimum 24-month follow-up. Results Sixteen patients with CS and 15 NFAI were enrolled. Indexed left ventricle (LV) end-systolic volume and LV mass were higher in patients with CS (p = 0.027; p = 0.013); similarly, indexed right ventricle (RV) end-diastolic and end-systolic volumes were higher in patients with CS compared to NFAI (p = 0.035; p = 0.006). Morphological alterations also affected cardiac function, as LV and RV ejection fractions decreased in patients with CS (p = 0.056; p = 0.044). CMR features were independent of metabolic status or other CV risk factors, with fasting glucose significantly lower in CS remission than NFAI (p < 0.001) and no differences in lipid levels or blood pressure. Conclusion CS is associated with biventricular cardiac structural and functional impairment at CMR, likely attributable to chronic exposure to cortisol excess independently of known traditional risk factors.

Background Glucocorticoids (GC) are potent entrainers of the circadian clock. However, their effects on biological rhythms in chronic human exposure have yet to be studied. Endogenous hypercortisolism (Cushing's Syndrome, CS) is a rare condition in which circadian disruption is sustained by a tumorous source of GC excess, offering the unique opportunity to investigate GC's chronic effects in vivo. Methods In a 12-month prospective case-control multicentre trial, the daily fl uctuations in the number of circulating peripheral blood mononuclear cells (PBMCs) and the time-specific expression of clock-related genes were analysed in a cohort of 68 subjects, 34 affected by CS and 34 matched controls. Cosinor mixed effects model, rhythmicity algorithms and machine learning techniques were applied to the multi-level dataset. Findings Multiple, 5-point daily sampling revealed profound changes in the levels, amplitude, and rhythmicity of several PBMC populations during active CS, only partially restored after remission. Clock gene analyses in isolated PBMCs showed a significant fl attening of circadian oscillation of CLOCK, PER1, PER2, PER3, and TIMELESS expression. In active CS, all methods confirmed a loss of rhythmicity of those genes which were circadian in the PBMCs of controls. Most, but not all, genes regained physiological oscillation after remission. Machine learning revealed that while combined time-course sets of clock genes were highly effective in separating patients from controls, immune profiling was efficient even as single time points. Interpretation In conclusion, the oscillation of circulating immune cells is profoundly altered in patients with CS, representing a convergence point of circadian rhythm disruption and metabolic and steroid hormone imbalances. Machine learning techniques proved the superiority of immune profiling over parameters such as cortisol, anthropometric and metabolic variables, and circadian gene expression analysis to identify CS activity. Funding The research leading to these results has received funding from the European Union in the context of the National Recovery and Resilience Plan, Investment PE8 - Project Age-It: " Ageing Well in an Ageing Society". This resource was co-financed by the Next Generation EU [DM 1557 11.10.2022], the PRecisiOn Medicine to Target Frailty of Endocrine-metabolic Origin (PROMETEO) project (NET-2018-12365454) by the Italian Ministry of Health, and through internal funding to Sapienza University of Rome.

CONTEXT:Pseudohypoparathyroidism (PHP) refers to a group of rare hereditary disorders associated with resistance to parathyroid hormone (PTH) and other hormones now termed inactivating PTH/PTHrP disorders (iPPSD). Hypercalcitoninemia has been seldom reported in small series. OBJECTIVE:Our aim was to investigate the characteristics of hypercalcitoninemia in pediatric and adult patients with PHP/iPPSD. METHODS:We retrospectively collected data from 2 cohorts from 2 European endocrinology tertiary centers: the pediatric cohort comprised 88 children with available calcitonin (CT) measurements; the adult cohort included 43 individuals with simultaneous CT and PTH measurements. RESULTS:In the pediatric cohort, 65.9% had hypercalcitoninemia (median CT 15 ng/L); in the adult cohort 53.5% (mean CT 21.6 ng/L). There was no difference between CT in pediatric and adult population; we observed stable CT levels over a median follow-up of 134.5 months in adults. Notably, no correlations were detected between CT and PTH levels. Other etiologies of hypercalcitoninemia were excluded; adult patients underwent regular thyroid ultrasound to screen for medullary thyroid cancer (MTC). We performed 20 calcium stimulation tests in adult patients. While there was a significant difference in basal and peak CT between our patients, healthy subjects, and subjects with MTC, there was no difference with patients with C-cell hyperplasia. CONCLUSION:This study underscores the common occurrence of hypercalcitoninemia in both pediatric and adult patients with PHP/iPPSD, in particular with subtypes iPPSD2 and iPPSD3. Furthermore, these patients show hyperresponsiveness to calcium stimulation tests falling between healthy subjects and patients with MTC. These findings contribute to the understanding of CT dynamics in the context of PHP/iPPSD.

Cardiac abnormalities are common in patients with acromegaly, contributing to the increased morbidity and mortality. Cardiac magnetic resonance (CMR) is the gold standard for measuring cardiac morpho-functional changes. This study aims to detect cardiac alterations in acromegaly through CMR, even when the disease is adequately controlled. In this, multicentre, case-control study, we compared consecutive patients with acromegaly, cured after surgery or requiring medical treatment, with matched controls recruited among patients harbouring non-functioning adrenal incidentalomas. We included 20 patients with acromegaly (7 females, mean age 50 years) and 17 controls. Indexed left ventricular-end-diastolic volume (LV-EDVi) and LV-end-systolic volume (LV-ESVi) were higher in patients than in controls (p < 0.001), as were left ventricular mass (LVMi) (p = 0.001) and LV-stroke volume (LV-SVi) (p = 0.028). Right ventricle (RV) EDVi and ESVi were higher, whereas RV-ejection fraction (RV-EF) was lower (p = 0.002) in patients than in controls (p < 0.001). No significant differences were observed in the prevalence of cardiometabolic comorbidities, including hypertension, glucose and lipid metabolism impairment, obstructive sleep apnoea syndrome, and obesity. IGF1 x upper limit of normal significantly predicted LVMi (b = 0.575; p = 0.008). Subgroup analysis showed higher LVMi (p = 0.025) and interventricular septum thickness (p = 0.003) in male than female patients, even after adjusting cardiac parameters for confounding factors. The CMR analysis reveals a cluster of biventricular structural and functional impairment in acromegaly, even when the biochemical control if achieved. These findings appear specifically triggered by the exposure to GH-IGF1 excess and show sex-related differences advocating a possible interaction with sex hormones in cardiac disease progression.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

OBJECTIVE:Fibromyalgia (FM) is a multifactorial disease characterized principally by chronic, widespread pain impairing a patient's quality of life. The management of FM requires a multidisciplinary approach that combines pharmacological and non-pharmacological strategies. Growing evidence suggests a potential beneficial role of micronutrients such as minerals and vitamins. Overall, the role of these supplements remains controversial, but clinical trials on vitamin D, vitamin B12, magnesium, and iron supplementation seem to provide promising results. The aim of this study was to investigate their role in an Italian female sample. SUBJECTS AND METHODS:An exploratory cross-sectional study was done to assess the association of selected micronutrients with symptoms of FM by using the Fibromyalgia Impact Questionnaire (FIQ) in twenty consecutive female patients with FM. A literature review was also conducted. RESULTS:FIQ results revealed that vitamin D and magnesium deficiency appear to play a role in FM symptoms, mainly in physical function and stiffness. From the literature review, only two studies investigating the role of micronutrients in FM were retrieved. CONCLUSIONS:Screening for micronutrient deficiencies in FM patients and supplementing them when levels are low might help counteract FM symptoms.

Dyslipidemia is a potential unfavorable prognostic factor in neuroendocrine tumors (NETs); conversely, statins proved to have antiproliferative effects in NET cell lines and could be a helpful therapeutic strategy for these patients. The main objective of this observational cohort retrospective study is to explore the associations between dyslipidemia and NET progression and evaluate the potential influence of statins in this context. 393 patients with histologically confirmed gastroenteropancreatic or bronchopulmonary NETs from six Italian centres didicated to NET diagnosis and therapy were included. The cohort included 123 patients with dyslipidemia, 81 of which were taking statins. Clinicopathological data, including patient demographics, tumor characteristics, and treatment details as well as the prevalence, timing of dyslipidemia and hypolipemic therapy were collected. The main outcome measure used is progression-free survival (PFS). Among the 393 patients, 123 (31.3%) had dyslipidemia. Statins were used by 81 (65.8%) dyslipidemic patients, mostly atorvastatin. Median PFS was 87 months overall, 124 months in non-dyslipidemic patients, and 72 months in dyslipidemic patients (p = .268). Dyslipidemic patients on statins had a significantly better median PFS (108 months) than those not on statins (26 months; p = .024). Recurrence-free survival (RFS) was also evaluated, but no significant differences were found. In conclusion, while PFS was lower in dyslipidemic patients compared to non-dyslipidemic patients, the difference was not statistically significant. Statin therapy was associated with improved PFS among dyslipidemic patients, suggesting a potential antiproliferative effect of statins in NETs. These findings warrant further investigation to substantiate the role of statins in the management of NETs.

The diagnosis of parathyroid diseases by imaging still has some intrinsic technical limitations due to the differential diagnosis of different structures of the neck that mimic the parathyroid glands. In this view, ultrasound (US) is an established, low-cost, and non-invasive imaging technique that still represents the first-line approach for evaluating patients with parathyroid disease. The objective of this article is to provide a comprehensive review of the applications of USs in clinical practice, discussing the histopathological and US characteristics of the parathyroid glands in normal and pathological conditions, the advantages of preoperative imaging, and novel updates on the most useful and currently available multiparameter US techniques.