Carla Scaroni

Objective: Cushing’s syndrome (CS) is associated with marked impairment in quality of life (QoL). This analysis aimed to comprehensively describe QoL impairment in participants of the PROMPT study using two validated instruments: the CushingQoL and the Tübingen Cushing’s Disease Quality of Life Inventory (CD-25). Methods: Cross-sectional analysis used baseline questionnaires from PROMPT (NCT02297945), a prospective study of metyrapone in 49 adults with confirmed endogenous CS. Item- and domain-level analyses were conducted for the CushingQoL (0-100; higher = better QoL) and CD-25 (0-100; higher = worse QoL). Subgroups: sex (15 males, 34 females) and biochemical UFC severity (31 moderate and 16 severe). Results: Patients reported substantial impairment in QoL. The mean CushingQoL score was 41.2 (95%CI 35.6-46.7), with greater physical (36.8) than psychosocial (45.5) burden. The CD-25 score was 39.8 (95%CI 32.7-46.9), with bodily restrictions (48.6) and eating behaviour (44.7) most severely affected. Worry about future health (75.5%) and physical appearance (73.5%) were the most prevalent individual concerns. The two instruments were strongly inversely correlated (r= −0.81, p<0.001). Females reported clinically worse psychosocial QoL compared with males (CushingQoL psychosocial: 41.7 vs 54.2, −12.2 points; CD-25 depression: 39.5 vs 26.9, + 12.6 points), despite similar biochemical severity. No meaningful differences in overall QoL scores were observed between patients with moderate versus severe hypercortisolism. Conclusions: Uncontrolled CS is associated with profound multidomain QoL impairment dominated by psychological distress, largely independent of biochemical disease severity. Women reported clinically meaningful worse psychosocial outcomes than men. Disease-specific, item-level QoL assessment may add information not captured by biochemical parameters in patients with active CS.

Background: The impact of environmental pollution on adrenocortical carcinoma (ACC) remains largely unexplored. Although a few studies have assessed the incidence of ACC in polluted areas, no data are available on clinical outcomes. Methods: We carried out a retrospective multicentre cohort study in adult patients with ACC diagnosed in 12 referral centres in Italy (1990-2018). We stratified patients for (1) residence in sites officially classified as contaminated (NPCSs [National Priority Contaminated Sites]) or in non-contaminated areas and (2) urbanization, as a contextual proxy for environmental exposure. Outcomes were recurrence-free survival (RFS) and overall survival (OS). Results: Among 336 patients, 250 had localized disease (stage I-III) and 86 metastatic disease (stage IV). Subgroups among patients with stage IV ACC were too small for a meaningful analysis. Among patients with localized ACC, 26 (10.4%) living in NPCSs had significantly shorter median RFS (13 vs 43 months; P = .011) and OS (67 vs 142 months; P = .016) compared to the 224 patients living in non-contaminated areas. At multivariable analysis, residence in NPCSs was independently associated with both recurrence (HR 1.89, 95% CI 1.13-3.16, P = .016) and death (HR 2.44, 95% CI 1.39-4.28, P = .002). No significant association was found between the level of urbanization and survival. Conclusions: This study provides the first evidence that environmental pollution is associated with worse clinical outcomes in patients with ACC. By linking contaminated-area residence with prognosis, these findings raise the possibility that environmental exposures may contribute to the disease behaviour, highlighting a new direction for integrated epidemiological and biological research.

Objective: This analysis describes the evolution of health-related quality of life (HRQoL) over 36 weeks of metyrapone treatment in the PROMPT study, identifying patterns of early, delayed improvement, or persistence using item-level resolution. Design and Methods: Longitudinal analysis of patient-reported outcomes from PROMPT (NCT02297945), a prospective, open-label, multicountry study of metyrapone in 49 evaluable adults with confirmed endogenous CS. HRQoL was assessed with the CushingQoL (0–100; higher = better QoL) and Tübingen CD-25 (0–100; higher = worse QoL) at weeks 4, 12, 24, and 36. Item-level analyses characterized the pattern and timing of improvement. Within-patient changes were assessed using the Wilcoxon signed-rank test. Results: Both questionnaires demonstrated significant overall improvement by week 36: CushingQoL increased by 10.4 points (P < .001; 44.7% with ≥10-point improvement), and Tübingen CD-25 decreased by −7.8 points (P = .01). Early responses (by week 12) involved eating behaviour and depression symptoms. Delayed improvements (consolidating at weeks 24-36) were observed in sexual activity, environment, and social domains. Bodily restrictions (−4.3 points, P = .203) and cognition (−6.8 points, P = .143) did not show improvement over the study period. Item-level analysis identified a cluster of symptoms, predominantly psychological health anxiety and physical appearance concerns, where burden remained elevated throughout the 36 weeks despite cortisol normalization. Conclusions: Metyrapone treatment is associated with meaningful, progressive HRQoL improvements across multiple symptom domains over 36 weeks, with a pattern consistent with rapid cortisol-mediated relief (eating, mood), delayed recovery in social and sexual domains, and persistent residual burden in symptom clusters likely driven by incomplete phenotypic reversal within the study timeframe.

Purpose: Polycystic ovary syndrome (PCOS) is a common and highly heterogeneous endocrine–metabolic disorder. The Rotterdam criteria identify four diagnostic phenotypes; however, it remains unclear whether these phenotypes or body mass index (BMI) better predict metabolic risk. The PCOSOUTCOME.net registry collects data from multiple Italian centers and provides an opportunity to compare the effectiveness of Rotterdam phenotypes versus BMI in characterizing the clinical, metabolic, and psychological heterogeneity of women with PCOS. Methods: We included 1,314 Caucasian women of reproductive age with PCOS. Participants were stratified according to Rotterdam phenotypes and BMI categories (normal weight, overweight, and obesity; and BMI < 27 kg/m² vs. ≥ 27 kg/m²). Clinical, hormonal, metabolic, gynecological, and psychological parameters were assessed and compared across subgroups. Results: No significant differences in BMI or in the prevalence of metabolic complications (dyslipidemia, glucose intolerance, hypertension, and metabolic syndrome) were observed among the four Rotterdam phenotypes, although anxiety scores were highest in phenotype A. In contrast, BMI-based stratification identified clear differences in metabolic markers: women with obesity or a BMI ≥ 27 kg/m² showed a higher prevalence of all metabolic complications, as well as higher free androgen index (FAI) and hirsutism scores. Conclusions: In this multicenter cohort, Rotterdam phenotypes failed to discriminate metabolic risk, whereas BMI-based stratification proved more informative in identifying cardiometabolic complications. Moreover, obesity in PCOS identifies a distinct hyperandrogenic phenotype. These findings underscore the need to integrate BMI into the classification of PCOS to better capture patient heterogeneity, with potential implications for metabolic assessment and risk stratification.

Context: Osilodrostat has demonstrated efficacy in clinical trials for Cushing's syndrome (CS). Real-world data remain limited. Objective: To assess the real-world effectiveness and safety of osilodrostat in a large cohort of CS patients. Design and setting: Multicenter, retrospective, phase IV study across 11 Italian endocrine referral centers. Patients: One hundred CS patients (74% pituitary, 16% adrenal, 10% ectopic). Main outcome measures: Primary endpoint was the percentage of patients with urinary free cortisol (UFC) ≤ upper limit of normal (ULN) at their last observation. Secondary endpoints included biochemical and hormonal control, clinical outcomes, quality of life (QoL), and adverse events (AEs). Results: Eighty-one percent of patients had normal UFC levels at last observation, 92% at least once within the 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. Conclusion: 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.

Introduction This Position Statement presents the recommendations of the Italian Society of Endocrinology (SIE) to identify patients with Cushing’s syndrome in specific clinical settings. We set two overarching research questions: 1. Which subjects should be screened (“who” should be screened)? 2. Which is the most appropriate first-line test (“how” to screen) for screening? All suggestions/recommendations are evidence-based and directed at endocrinologists and other physicians who deal with patients who have presumptive Cushing’s syndrome. Methods The recommendations, developed by a SIE committee, were formulated based on eight short-reviews commissioned to experts of the SIE Pituitary and Adrenal Clubs. These short reviews, published in a special issue of the Journal of Endocrinological Investigation, reported a comprehensive review of the literature, and each of them answered the two research questions (who and how to screen for hypercortisolism) in a specific population: (1) patients with type 2 diabetes mellitus or obesity; (2) patients with arterial hypertension; (3) children and adolescents; (4) women with hyperandrogenism and/or menstrual irregularities; (5) patients with osteoporosis and/or fractures; (6) patients with mood disorders; (7) patients with adrenal and pituitary incidentaloma; (8) patients with unusual infections or thrombotic events. Finally, 24 recommendations were formulated, based on the quality of available evidence. Conclusions The evidence-based Position Statement provides clear and pragmatic advice regarding “who” and “how” to screen for Cushing’s syndrome. The suggestions/recommendations are developed for all health care providers, not only endocrinologists, to raise awareness on the diagnosis of Cushing’s syndrome.

Background: Cushing’s syndrome (CS) is associated with increased metabolic and cardiovascular (CV) risk factors and morbidities. Evidence-based guidelines for the management of these issues in active or remitted CS are not available, so best practice is derived from guidelines developed for the general population. We aimed to evaluate the awareness and practice variation for CV comorbidities of CS across Reference Centres (RCs) of the European Reference Network on Rare Endocrine Conditions (Endo-ERN). Methods: A dedicated online survey was distributed from June 2022 to December 2022 to Endo-ERN RCs with recognized expertise in adrenal and/or pituitary diseases. Results: 19 centres provided complete responses to the survey, accounting for an estimated pool of around one thousand chronically cared CS patients across Europe. Most ERN experts consider patients with CS at high CV risk irrespectively of remission status. Preoperative cortisol-lowering treatment was a common practice, especially for severe cases, and deemed effective in reducing CV risk by many. Most comorbidities were regularly evaluated at diagnosis and during follow-up, although a lack of provocative testing to diagnose diabetes (used only in 26% of RCs) was evidenced. A strict glycaemic control was encouraged although its target differed. On the contrary, a less stringent approach to dyslipidaemia and overweight emerged. Preferred initial compounds for patients presenting comorbidities were angiotensin converting enzyme inhibitors, metformin and statins; lifestyle changes were preferred over drugs to control weight excess after cure. Screening for asymptomatic vascular disease was performed routinely and regularly repeated during follow-up by only half of the centres. Important heterogeneity in some responses emerged, especially regarding the effect of remission or medical treatment on comorbidities and CV risk. Discussion: Our survey highlights the awareness of ERN experts on management of metabolic and CV risk factors or disease in CS. Most of them use the current European guidelines and apply strategies for high CV risk patients, although not all these recommendations were fully followed. Since several CV risk factors seem to persist after disease remission, they should be adequately and promptly addressed. Population-specific studies are required to identify the optimal management of CV and metabolic comorbidities of CS patients.

Objective: We evaluated the safety and efficacy of metyrapone treatment for Cushing's syndrome (CS). Design: International, prospective, single-arm, open-label study. Methods: Fifty adults with endogenous CS (either unsuitable for or uncontrolled after surgery) and 3 urinary free cortisol (UFC) concentrations each ≥1.5-fold the upper limit of normal (ULN) were enrolled. After 12 weeks of metyrapone titration, participants with mean 24 h UFC (mUFC) ≤ 2-fold ULN could enter a 24-week extension phase. Safety was assessed, and doses adjusted at weeks 1-5, 8, 12, and 24. Pre-defined endpoints included normalization of mUFC at weeks 12 (primary), 24, and 36, and proportion of “responders” (normalization or ≥50% decrease of baseline mUFC), time to eucortisolemia, salivary cortisol day-curve, and quality of life (QoL). Results: Of the 49 evaluable participants, 47 completed the 12-week visit; 40 were evaluated at week 24 and 35 at week 36. The primary endpoint was met in 46.9% of participants (95% CI 32.5%-61.7%), with efficacy maintained at week 24 (52.5%; 95% CI 37.5%-67.1%) and week 36 (48.6%; 95% CI 33.0%-64.4%). The responder rates were 80.9%, 77.5%, and 71.4% at weeks 12, 24, and 36, respectively. Forty-seven participants (94%) developed mild-to-moderate adverse events (AEs), mostly during the first 12 weeks and most commonly nausea (38%), fatigue (26%), and headache (22%); 8 experienced severe AEs. Six participants developed reversible adrenal insufficiency during titration. Clinical features and QoL improved. Conclusion: Metyrapone is a safe and effective treatment for endogenous CS.

Background: The possibility of sustained disease remission in functioning pituitary adenomas after drug withdrawal is well-known for prolactinomas and it has also been described in a subset of acromegalic patients. Similarly, medical treatment for Cushing’s Disease (CD) is generally considered a life-long measure except for previously radio-treated patients. Sparse evidence of spontaneous remissions in CD has been reported, mainly related to a possible pituitary tumor apoplexy. To the best of our knowledge, none of these cases has included the use of a pituitary targeting agent. Case Presentation: Herein, we have reported the case of a radiotherapy-naïve patient with persistent CD after pituitary surgery who participated in the CSOMG230 trials, presenting sustained remission after Long-acting Release (LAR) pasireotide withdrawal. We have also briefly reviewed previous cases of sustained remission after somatostatin analogues withdrawal in other functioning pituitary adenomas. Under monthly pasireotide LAR 40 mg, the patient achieved urinary hormone control and clinical signs of cortisol excess normalization. After 8 years of treatment, the patient completed the study protocol and had to withdraw the drug as it was no longer available for CD in Italy. Before starting new therapies, we reassessed hormone levels that were surprisingly within normal ranges. At 24 months after the last dose of pasireotide, the patient was still in clinical and biochemical full remission. Conclusion: Far from the general rule, this case suggests that prolonged treatment with pasireotide LAR might induce a durable CD remission. A dose down-titration/suspension might be considered in patients well-controlled on long-term therapy and with negative pituitary imaging. However, close monitoring is recommended given the high rate of complications in untreated patients.

Background Pituitary adenomas (PAs) comprise a heterogeneous group of diseases: a scoring system to guide prognosis and therapy is still missing. Methods We assessed a retrospective single-center cohort of 401 patients with PAs followed over the last two decades using a newly developed Pituitary Society grading system, PANOMEN-3. Results A high initial grade of the adenoma predicted a worse long-term outcome despite multimodal treatments (grade 3, disease remission OR 0.49, 95%CI [0.27; 0.84], p = 0.01). The grade could predict tumor behavior following surgery: a higher grade at baseline predicted relapses after disease remission (grade 3 vs grade 1/2, p = 0.01) and a higher postoperative grade predicted the need for additional treatments in case of persisting disease (grade 2/3 vs grade 1, p = 0.02). A score downgrade obtained with primary medical predicted the reduction of additional interventions and long-term biochemical control. When considering CD patients, both a lower initial grade (grade 2 vs grade 3, p < 0.01) and preoperative eucortisolism (p = 0.04) reduced recurrence risk. Contrarily to the whole-cohort analysis, grade predicted the surgical outcome in non-functioning pituitary adenomas and in acromegaly. Conclusion Our data suggest for the first time that PANOMEN-3 grade system could be useful in everyday clinical practice, aiding physicians in both improving follow-up strategies for patients in remission and in the management of persisting disease for all pituitary adenomas. Especially for CD, a high initial grade could encourage clinicians to institute preoperative medical treatment and to adopt a closer follow-up schedule in cured cases.