Most of adrenocortical carcinomas (ACC) are characterized by IGF2 overexpression; therefore, several studies have focused on its two oncogenic effectors, the tyrosine-kinase receptors IGF1R and IR. However, the specific IGF2 receptor, IGF2R, due to its scavenging activity, was considered a tumour suppressor and has never been fully investigated in this context. Nevertheless, recent evidence from other tumours identified IGF2R as a pro-tumorigenic actor able to exert its function through the downstream activation of the pro-mitotic sphingosine kinases (SphK) enzymes responsible for sphingosine phosphorylation. Hence, the main aims of this study were to elucidate the role of IGF2R in ACC cells, investigate its action mechanism, and test IGF2R and SphK inhibitors as possible novel therapies for ACC. The present study was conducted in vitro in 4 different ACC cell lines and in 3 ACC primary cultures, to reflect the heterogeneity of ACC. Target protein and transcript expression were evaluated on normal and tumoral adrenal tissues and cell lines, while the effects of IGF2R downregulation and overexpression, along with IGF2R and SphK inhibition, were tested on cell viability, proliferation, and apoptosis as well as cortisol secretion. ACC tissue analysis demonstrated the IGF2R overexpression compared to normal adrenal cortex, which was also positively correlated with IGF2 and IGF1R expression in ACC. In vitro assays proved the pro-mitotic involvement of IGF2R and its role in the downstream activation of SphK. Finally, we observed the anti-tumoral efficacy of three different inhibitors of this pathway on ACC cell lines and primary cultures: a specific neutralizing anti-IGF2R antibody was tested for its anti-proliferative action, while two SphK inhibitors, safingol (SAF) and fingolimod (FTY), were able to decrease cell proliferation, viability, and cortisol secretion, while promoting cell apoptosis. Overall, this comprehensive in vitro evaluation of the role of IGF2R in ACC demonstrates its tumorigenic effect through SphK activation. Moreover, the three pharmacological strategies here employed successfully controlled in vitro ACC growth, suggesting IGF2R/SphK pathway represents a novel therapeutic target for ACC.

CONTEXT:Osilodrostat has demonstrated efficacy in clinical trials for Cushing's syndrome (CS). Real-world data remain limited. OBJECTIVE:To assess real-world effectiveness and safety of osilodrostat in a large cohort of CS patients. DESIGN&SETTING:Multicenter, retrospective, phase IV-study across 11 Italian endocrine referral centers. PATIENTS:100 CS patients [74% pituitary, 16% adrenal, 10% ectopic]. MAIN OUTCOME MEASURES:Primary endpoint was the percentage of patients with UFC≤ULN at their last observation. Secondary endpoints included biochemical and hormonal control, clinical outcomes, QoL, AEs. RESULTS:81% of patients had normal UFC levels at last observation, 92% at least once within study period. Excluding 12 patients with normal baseline UFC levels, 78.4% of patients had normal UFC levels at their last observation, whereas 90.9% at least once within the study period.The mean±SD (median,range) time to the first normalization of UFC levels, in the 80 patients who achieved normalization, was 92.1±86.3 (67.5,8-455) days, at a mean± SD (median,range) osilodrostat dose of 7.2±6.8 (5,1-40) mg/day.Significant reductions in late-night salivary cortisol and morning serum cortisol levels were observed. Improvements were noted in anthropometric parameters, blood pressure, glucose metabolism, clinical signs, and QoL. AEs occurred in 29% of patients, mostly mild-to-moderate; adrenal insufficiency was the most common AE reported in 20% of patients. Hormonal control and safety profiles were consistent across CS etiologies. CONCLUSIONS:Osilodrostat is effective, generally well tolerated in routine clinical practice, representing a valuable therapy for CS management, able to achieve rapid and sustained hormonal control, significant metabolic, cardiovascular, clinical and QoL improvements with a well-tolerated safety profile.

BACKGROUND:Clinical presentation of inactivating PTH/PTHrP signaling disorders (iPPSDs, historically pseudohypoparathyroidism (PHP)) exhibits pronounced age-dependence. Indeed, main features, including PTH resistance and brachydactyly, develop during late childhood, whilst other features (ectopic ossifications, obesity and hypothyroidism) are the most prevalent in toddlers. The latter are included among minor diagnostic criteria; therefore, a significant diagnostic delay has been reported. Aim of this work is to describe the early natural history of a large cohort of iPPSD/PHP patients, in order to improve the diagnosis, with the final goal of proposing new diagnostic criteria for early infancy and reducing the diagnostic delay. METHODS:We included 117 patients regularly followed up in two European Endocrinology tertiary centres and we retrospectively collected data on the age of onset of main clinical and hormonal features. RESULTS:In our cohort the median age at diagnosis was 5.9 years. Age of onset of PTH resistance and brachydactyly, major criteria for diagnosis, was significantly different from that of both TSH resistance and obesity (median age 6.1, 5.8, 1.85 and 2 years, respectively). Minor diagnostic criteria were more represented than major criteria in children before 2 years (p=0.002). Indeed, in 64% of patients before 2 years none of the major criteria were observed, conversely 71% had already developed at least one minor criterion; in particular, 20% had developed TSH resistance and obesity. CONCLUSION:Clinical picture of iPPSD/PHP in early infancy differs from that of mid-late infancy and adults, thus current diagnostic criteria may not be appropriate for children. We suggest that the combination of early onset obesity and elevated TSH should raise the suspicion and trigger genetic screening before 2 years of age.

OBJECTIVE:The aim of the study was to investigate bone comorbidities and their management in patients included in the European Register on Cushing's syndrome (ERCUSYN). DESIGN:A retrospective multicentric cohort study and on-line survey. METHODS:We analyzed the prevalence of osteoporosis (OP) and fractures among 1682 patients with Cushing's syndrome (CS), at initial evaluation and during follow-up. All the ERCUSYN partners received a survey addressing bone disease management in CS. RESULTS:Seven hundred and sixty-six patients (45%) had DXA examination at baseline, of whom 157 (21%) presented OP at spine and 103 (13%) at hip. Risk factors for OP were older age (P=0.038) and lower BMI (P=0.022). An X-ray was performed in 492 (29%) patients and fracture was detected in 87 (18%). Risk factors for fractures at baseline were male sex (P<0.001), muscle weakness (P=0.026) and bone mineral density (BMD) at hip indicating OP (P=0.026). During follow-up, spine BMD deterioration was more common in older patients (P=0.005) and in those with diabetes mellitus (P=0.024), while worsening of hip BMD was more frequent in patients with hypopituitarism (P=0.021), diabetes mellitus (P=0.034), on levothyroxine substitution (P=0.008) and those less often treated with anti-osteoporotic agents (P=0.022). The survey evidenced significant heterogeneity in terms of timing of bone evaluation and treatment initiation. CONCLUSIONS:A significant number of patients with CS experienced OP and fractures. Clinical factors may help to select patients at the highest risk. There are currently no standards of care for the management of bone complications in CS across Europe.

L’ossitocina, oltre al ruolo noto svolto durante il parto e l’allattamento, esercita numerose altre funzioni, tra cui modulazione di emozioni, comportamento sociale e metabolismo energetico. Una sua carenza può dunque contribuire all’insorgenza di disturbi psichici e metabolici, soprattutto in soggetti con patologia della regione ipotalamo-ipofisaria. Nonostante le difficoltà diagnostiche, cresce quindi l’interesse per un suo impiego terapeutico “oltre il parto”.

Background Psychological and cognitive disorders have been reported in acromegaly, yet with limited and heterogeneous data, especially concerning long-term cognitive functioning.Methods We conducted a cross-sectional study enrolling 44 acromegalic patients and 40 healthy controls. We systematically assessed anxiety and depressive symptoms through the State-trait Anxiety Inventory and the Beck Depression Inventory, respectively. We investigated their cognitive functioning thorough a wide battery of 16 tests addressing verbal and visuo-spatial memory, attention, verbal fluencies, executive functions and constructional praxis. Moreover, we performed a prospective evaluation in a 10-year time-span of a small subgroup of patients.Results Clinically significant depressive and anxiety symptoms were registered in 23 and 35% of patients respectively, mostly in the group with active disease at evaluation. Concerning cognition, patients scored worse than controls in all cognitive domains explored, with a significant difference registered in almost all tests administered. Moreover, hypopituitarism and IGF-1 levels seem to be related to a worse cognitive performance, especially in the group of tests exploring the memory domain. In the prospective group, with the limitation of a really small sample size, we observed a global improvement over time in all domains evaluated.Conclusion Acromegaly is characterized by higher levels of psychological distress and poorer neurocognitive functioning, with a possible association with activity of disease.

Male hypogonadism is associated with significant alterations in body composition, including reduced lean body mass (LBM), increased fat body mass (FBM), particularly visceral adiposity, and impaired muscle function, contributing to frailty and cardiometabolic risk. These changes reflect the disruption of a complex endocrine crosstalk among bone, muscle, and adipose tissue, mediated by cytokines such as osteokines, myokines, and adipokines. This dysregulation promotes the development of osteosarcopenic obesity, a condition characterized by the coexistence of low bone mass, sarcopenia, and excess adiposity. Testosterone (T) plays a central role in maintaining body composition by stimulating muscle protein synthesis, inhibiting adipogenesis, and preserving bone health. Its deficiency, irrespective of etiology, leads to rapid impairment of anabolic pathways, resulting in decreased lean mass and increased fat accumulation. Evidence from clinical and experimental models demonstrates that these alterations are partially reversible with T replacement therapy (TRT), although variability exists depending on the underlying cause of hypogonadism. Dual-energy X-ray absorptiometry (DXA) represents the gold standard for assessing bone mineral density (BMD) and a key tool for evaluating body composition through a three-compartment model. It allows precise quantification of fat and lean mass, as well as their regional distribution, with minimal radiation exposure. In this review, we provide a comprehensive and clinically oriented overview of body composition alterations in male hypogonadism, focusing on underlying pathophysiological mechanisms and the practical application of DXA across different clinical scenarios. We discuss evidence from conditions such as Klinefelter syndrome, Kallmann syndrome, androgen deprivation therapy, HIV infection, and transgender care, aiming to offer a pragmatic framework for integrating body composition assessment into routine practice and improving patient management.

Arginine infusion stimulates copeptin secretion, a surrogate marker of arginine vasopressin (AVP), thereby serving as a diagnostic test in the differential diagnosis of suspected AVP deficiency (AVP-D). Yet, the precise mechanism underlying the stimulatory effect of arginine on the vasopressinergic system remains elusive. Arginine plays a significant role in the urea cycle and increases the production of urea. An increase in plasma urea concentration raises blood osmolality, thereby possibly stimulating AVP release. We therefore hypothesized that the stimulatory effect of arginine on AVP may involve an increase in plasma urea levels. This analysis combined data from two prospective diagnostic studies. In total, 30 healthy adults (HA), 69 patients with AVP-D, and 89 patients with primary polydipsia (PP) underwent the arginine stimulation test. Infusion of arginine (L-­arginine­-hydrochloride 21

PURPOSE:Prognostication of surgical complexity is crucial for optimizing decision-making and patient counseling in pituitary surgery. This study aimed to develop a clinical score to predict gross-total resection (GTR) in non-functioning pituitary adenomas (NFPAs) using externally validated machine-learning (ML) models. METHODS:Clinical and radiological data were collected from two tertiary medical centers. Patients had pre- and postoperative structural T1-weighted MRI with gadolinium and T2-weighted preoperative scans. Three ML classifiers were trained on the National Hospital for Neurology and Neurosurgery dataset and tested on the Foundation IRCCS Ca' Granda Polyclinic of Milan dataset. Feature importance analyses and hierarchical-tree inspection identified predictors of surgical complexity, which were used to create the grading score. The prognostic performance of the proposed score was compared to that of the state-of-the art TRANSSPHER grade in the external dataset. Surgical morbidity was also analyzed. RESULTS:All ML models accurately predicted GTR, with the random forest classifier achieving the best performance (weighted-F1 score of 0.87; CIs: 0.71, 0.97). Key predictors-Knosp grade, tumor maximum diameter, consistency, and supra-sellar nodular extension-were included in the modified (m)-TRANSSPHER grade. The ROC analysis showed superior performance of the m-TRANSSPHER grade over the TRANSSPHER grade for predicting GTR in NFPAs (AUC 0.85 vs. 0.79). CONCLUSIONS:This international multi-center study used validated ML algorithms to refine predictors of surgical complexity in NFPAs, yielding the m-TRANSSPHER grade, which demonstrated enhanced prognostic accuracy for surgical complexity prediction compared to existing scales.

Symptoms and baseline laboratory results often fail to identify the underlying cause of polyuria–polydipsia syndrome (PPS). A copeptin-based approach has recently been proposed for the differential diagnosis in adults. Given the rarity and complexity of PPS, national endocrinology societies should provide guidance to minimize diagnostic delays and ensure patients receive the most accurate evaluation. The Hydro-Saline Club conducted a 22-question web-based survey targeting all endocrinologists registered with the Italian Society of Endocrinology in 2024. Data were collected from July 18 to September 22, 2024. A total of 120 endocrinologists from 75

The insulin-like growth factor 2 (IGF2) is overexpressed in 90% of adrenocortical carcinomas (ACC) and promotes cell proliferation via IGF1R and isoform A of insulin receptor (IRA). However, IGF2 role in ACC tumourigenesis has not been completely understood yet, and the contribution of IGF1R and IRA in mediating ACC cell growth has been poorly explored. This study aimed to investigate IGF1R and IR expression and localisation, including the expression of IR isoforms, in ACC and adrenocortical adenomas (ACA), and their role in IGF2-driven proliferation. Immunohistochemistry staining of IGF1R and IR was performed on 118 ACC and 22 ACA to evaluate their expression and cellular localisation and statistical analyses were carried out to assess correlations with clinicopathological data. The expression of IRA and IRB in ACC and ACA tissues, ACC cell lines and ACC and ACA primary cultures was determined by RT-qPCR. To appraise the specific role of IGF1R and IR in mediating IGF2 mitogenic pathway, single and double silencing of receptors and their inhibition in 2 ACC cell lines derived from primary tumours (H295R and JIL-2266) and 2 derived from metastatic tumours (MUC-1 and TVBF-7) as well as in ACC and ACA primary cultures were performed. We found a higher IGF1R plasma membrane localisation in ACC compared to ACA. In ACC this localisation was associated with higher Ki67 and Weiss score. IR was expressed in about half of ACC and in all ACA but, in ACC, it was associated with higher Ki67 and Weiss score. RT-qPCR revealed that the prevalent isoform of IR was IRA in ACC and ACA, but not in normal adrenals. In ACC cell lines, double IGF1R + IR silencing reduced cell proliferation in JIL-2266, MUC-1 and TVBF-7 but not in H295R. In ACC, but not ACA, primary cultures, cell proliferation was reduced after IR but not IGF1R knockdown. Overall, these data suggest that IGF1R localisation and IR expression represent new biomarkers predicting tumour aggressiveness, as well as possible molecular markers useful to patients' stratification for more individualized IGF1R-IR targeted therapies or for novel pharmacological approaches specifically targeting IRA isoform.

OBJECTIVE:Arginine vasopressin (AVP), synthesized in the hypothalamus and stored in the posterior pituitary, regulates osmotic balance and stress responses. During stress, AVP enhances corticotropin-releasing hormone-stimulated adrenocorticotropic hormone (ACTH) secretion, with cortisol and AVP providing negative feedback regulation. Disruption in AVP production might impair this feedback, leading to sustained cortisol elevations. The current analysis aims to investigate the effect of hypertonic saline (osmotic stress) and arginine infusion (non-osmotic stress) on the hypothalamic-pituitary-adrenal (HPA) axis response between patients with AVP-Deficiency and primary polydipsia (PP). DESIGN:Secondary sub-analysis of a prospective diagnostic study conducted at seven tertiary centers that utilized hypertonic saline and arginine infusion for diagnostic evaluation of patients with hypotonic polyuria-polydipsia syndrome. METHODS:ACTH and cortisol levels were measured at baseline and the expected peak for both stimulation tests and groups. A pooled linear mixed-effects model (without stimulation type as a variable) was used to compare hormone responses between groups, followed by stimulation test-specific linear regression models to assess differences between both tests. RESULTS:Twenty patients with AVP-Deficiency and 10 patients with PP were included. In the pooled analysis, patients with AVP-Deficiency showed a significantly greater increase in plasma ACTH [7.0 ng/L (95% CI, 0.8-13.3), P = .04] and plasma cortisol [106 nmol/L (95% CI, 24-188), P = .02] compared to patients with PP. Upon hypertonic saline, the changes in plasma ACTH [0.3 ng/L (95% CI, -10.0 to 11.0)] and plasma cortisol [78 nmol/L (95% CI, -32 to 188)] were similar. However, upon arginine infusion, plasma ACTH [9.2 ng/L (95% CI, 1.8-17)] and plasma cortisol [141 nmol/L (95% CI, 40-242)] increases were significantly greater in patients with AVP-Deficiency. CONCLUSION:An altered ACTH and cortisol response pattern to stress in patients with AVP-Deficiency was observed, indicating impaired regulation of the HPA axis. This alteration was primarily driven by differences observed for non-osmotic stress.

Somatostatin receptor ligands (SRLs) with high affinity for somatostatin receptors 2 and 5 (SSTR2 and SSTR5) are poorly efficacious in NF-PitNETs, expressing high levels of SSTR3. ITF2984 is a pan-SSTR ligand with high affinity for SSTR3, able to induce SSTR3 activation and to exert antitumoral activity in the MENX rat model. The aim of this study was to test ITF2984’s antiproliferative and proapoptotic effects in NF-PitNET primary cultured cells derived from surgically removed human tumors and to characterize their SSTR expression profile. We treated cells derived from 23 NF-PitNETs with ITF2984, and a subset of them with octreotide, pasireotide (SRLs with high affinity for SSTR2 or 5, respectively), or cabergoline (DRD2 agonist) and we measured cell proliferation and apoptosis. SSTR3, SSTR2, and SSTR5 expression in tumor tissues was analyzed by qRT-PCR and Western blot. We demonstrated that ITF2984 reduced cell proliferation (−40.8 (17.08)%, p < 0.001 vs. basal, n = 19 NF-PitNETs) and increased cell apoptosis (+41.4 (22.1)%, p < 0.001 vs. basal, n = 17 NF-PitNETs) in all tumors tested, whereas the other drugs were only effective in some tumors. In our model, SSTR3 expression levels did not correlate with ITF2984 antiproliferative nor proapoptotic effects. In conclusion, our data support a possible use of ITF2984 in the pharmacological treatment of NF-PitNET.