Background Duodenal and pancreatic neuroendocrine tumors (DP-NETs) are the leading case of mortality in multiple endocrine neoplasia type 1 (MEN1), due to distant metastasis. Although surgery is the cornerstone of management, patients may require reintervention for disease progression or hormone-related morbidity. The clinical and genetic determinants of reintervention and long-term oncologic outcomes after index DP-PNET surgery in MEN1 remain unclear. Methods We retrospectively analyzed patients with genetically confirmed MEN1 and DP-NETs evaluated at our institution from 1985–2024. Reintervention was defined as any subsequent surgical or locoregional therapy. Kaplan–Meier methods and multivariable Cox proportional hazards models were used to evaluate predictors of reintervention-free survival and distant metastasis-free survival (DMFS), focusing on truncating versus non-truncating MEN1 variants. Results Among 153 MEN1 patients, 94 (61%) underwent surgical resection for DP-NETs at a median age of 40 years (IQR 28–49). After a median follow-up of 16.4 years, 25 patients (27%) required reintervention, with 45 total procedures performed. Truncating MEN1 variants were significantly more common among patients undergoing reintervention (88.0% vs 63.8%, P = .024). On multivariable analysis, truncating genotype was independently associated with reintervention (HR 3.82, 95% CI 1.25–16.68; P = .036). Among 84 patients without metastases at surgery, 24 (28.6%) developed distant metastases during follow-up; truncating genotype independently predicted shorter DMFS (HR 5.55, 95% CI 1.56–35.40; P =.024). Notably, 37.5% of patients who developed metastases had a largest resected tumor ≤2 cm. Conclusions Over a quarter of patients undergoing surgery for MEN1-associated DP-NETs require reintervention for progressive disease, and truncating MEN1 variants confer a nearly 4-fold higher risk of reintervention and >5-fold higher risk of distant metastatic progression during follow-up. Our findings underscore the limitations of size-based surgical algorithms and suggest that germline genotype may provide complementary prognostic information to refine postoperative risk stratification and surveillance strategies.

BACKGROUND:Benign adrenal tumours, found in 1-7% of adults, can be non-functioning (NFAT) or show mild autonomous cortisol secretion (MACS), i.e., biochemical cortisol excess without manifestations of Cushing's syndrome (CS). MACS occurs in 20-50% of cases and is linked to increased cardiometabolic burden. METHODS:In a cross-sectional study, we analysed the 24-h urinary steroid metabolome of 1305 prospectively recruited patients (649 NFAT, 591 MACS, 65 adrenal CS) by tandem mass spectrometry. A sub-group (104 NFAT, 140 MACS, 47 adrenal CS) underwent untargeted serum metabolome analysis by mass spectrometry. Data were analysed using linear regression and supervised machine learning. FINDINGS:Alongside the expected increase in glucocorticoid excretion from NFAT over MACS to adrenal CS, steroid analysis revealed decreased classic androgen metabolite excretion. By contrast, adrenal-derived 11-oxygenated androgen metabolites remained unchanged. Both glucocorticoid metabolites and the major 11-oxygenated androgen metabolite 11β-hydroxyandrosterone correlated with a higher risk of hypertension and type 2 diabetes. Untargeted metabolome analysis revealed gradual changes towards a lipotoxic phenotype from NFAT over MACS to adrenal CS, with perturbations in glycerophospholipids, lysoglycerophospholipids, triacylglycerides, ceramides, sphingolipids, and acylcarnitines. INTERPRETATION:MACS represents a metabolic continuum between NFAT and adrenal CS. Increased activity of the adrenal enzyme 11β-hydroxylase (CYP11B1), which catalyses key steps in cortisol and 11-oxygenated androgen biosynthesis, may contribute to steroid excess and cardiometabolic morbidity in MACS. These findings suggest that CYP11B1 may be a potential therapeutic target to ameliorate metabolic dysfunction in MACS. FUNDING:NIHR Birmingham Biomedical Research Centre; Diabetes UK; Wellcome Trust; European Commission; Medical Research Council.

BACKGROUND:Primary aldosteronism (PA) is a common and treatable cause of hypertension, yet data on the durability of medical treatment response beyond the first year are limited. Using the PA medical treatment outcomes framework, we evaluated long-term biochemical and clinical outcomes and factors associated with treatment response. METHODS:We conducted an international, multicenter, observational cohort study across 27 centers on 4 continents. Adults with PA treated with mineralocorticoid receptor antagonists and/or epithelial sodium channel blockers between 2016 and 2021 were included if follow-up data were available at ≥12 months. Biochemical and clinical responses were classified as complete, partial, or absent using PA medical treatment outcomes criteria. Ordinal logistic regression identified determinants of a favorable treatment response. RESULTS:The cohort included 1292 patients (47.5% women, mean age 52 years) with a median follow-up of 34 months (interquartile range, 21-51). At ≥12 months, 58.3% achieved a complete biochemical response, and 20.8% achieved a complete clinical response, with only 5% showing no response. Determinants of a favorable biochemical response included lower aldosterone and lateralization index, and higher renin and potassium levels at baseline. In those taking spironolactone, a higher daily dose was also associated with a favorable biochemical response. Determinants of a favorable clinical response included female sex, lower body mass index, shorter duration of hypertension, and absence of hypertension-mediated organ damage. CONCLUSIONS:Targeted medical therapy for PA can deliver sustained biochemical and clinical benefits. Early disease detection and adequate dose titration are highly actionable determinants of long-term treatment success.

Supplementary Tables Supplementary Table S1. Clinical and Tumoral Data from CCHD-PPGL patients. Supplementary Table S2. Selection inference in the PPGL (TCGA, non-CCHD) and CCHD-PPGL cohort. Supplementary Table S3. Cancer Cell Fraction of EPAS1 mutations in CCHD-PPGL and PPGL patients. Supplementary Table S4. Clonal Clustering of CCHD-PPGL tumor mutations, highlighting EPAS1 mutation, using Conipher. Supplementary Table S5. Clonal Clustering of PPGL tumor mutations (TCGA), highlighting EPAS1 mutation, using Conipher. Supplementary Table S6. Parallelism of EPAS1 genetic variant selection in high-altitude populations and human tumors. Supplementary Table S7. EPAS1 Frequencies of Denisovan AGGAA haplotype from 4,000 Han Chinese Population (https://www.biosino.org/pgghan2/index) compared with gnomAD cohort around the world. Supplementary Table S8. Genetic Instability Characteristics (MSI, CNA, TMB) from CCHD-PPGL and PPGL (TCGA) tumors. Supplementary Table S9. Data of 354 differentially expressed mitochondrial genes (from Human Mitocarta Database) between EPAS1MUT and EPAS1WT samples in patients with PPGL (TCGA). Supplementary Table S10. Gene expression profiling analysis from patients with hemoglobin disorders and 52 paragangliomas with various genotypes including 19 EPAS1 (including one tumor in duplicate), 6 SDHx, 2 SLC25A11, 6 VHL, 3 RET, 3 NF1, 1 MAX, 1 MAML3 and 11 unmutated paragangliomas (Mancini M et al. Br J Haematol, 2023). Supplementary Table S11. RNAseq Raw Counts from PC12 Cell line cultured under normoxia/hypoxia conditions. Supplementary Table S12. Tumor type and hypoxia onset in patients with CCHD-PPGL. Supplementary Table S13. O2 Saturation in CCHD patients with or without PPGL tumors. Supplementary Table S14. Heart surgery influence in tumor development in patients with CCHD-PPGL. Supplementary Table S15. Clinical features of tumors developed under hypoxia (CCHD-PPGL) and normoxia (non-CCHD-PPGL). Supplementary Table S16. Representation of clinical variables in patients with PPGL and CCHD-PPGL.

Supplementary Figure S1. Description of the CCHD-PPGL cohort of 27 individuals with CCHD who developed 38 PPGL tumors. Supplementary Figure S2. Summary of the clinical features of patients with CCHD-PPGL. Supplementary Figure S3. EPAS1 mutations are enriched in the hypoxic cohort of patients with CCHD-PPGL (88.8%) compared to the normoxic cohort of patients without CCHD-PPGL (4.5%). Supplementary Figure S4. EPAS1 clonality in PPGL tumor samples from TCGA(1–4) (patients without CCHD with PPGL in normoxic conditions). Supplementary Figure S5. No EPAS1 mutations were detected in carotid body PGL tumors. Supplementary Figure S6. Hierarchical cluster analysis of RNA sequencing data from EPAS1-mutated CCHD-PPGL tumors. Supplementary Figure S7. Convergent Evolution in Natural Populations and Human Tumors. Supplementary Figure S8. Evolutionary speed of EPAS1 selection in different cohorts. Supplementary Figure S9. Hematoxylin and eosin staining and immunohistochemistry for Chromogranin A (neuroendocrine tumors maker) and for mismatch repair (MMR) proteins in PPGL tumors. Supplementary Figure S10. Acquisition of EPAS1 mutation and subsequent selection in sympathetic PPGL tumors developed under systemic hypoxia. Supplementary Figure S11. Assessment of apoptosis marker in pheochromocytoma-derived cells upon expression of mutant EPAS1 genes or exposure to hypoxic conditions. Supplementary Figure S12. Increase levels of fumarate metabolite in EPAS1MUT PPGL tumors and increase levels of succinate metabolite in SDHxMUT PPGL tumors. Supplementary Figure S13. Decrease of fumarate hydratase/fumarase (FH) mRNA expression and increment of SDHB mRNA expression in EPAS1MUT/VHLMUT PPGL tumors when compared to EPAS1WT/VHLWT PPGL tumors, as well as to SDHxMUT PPGL tumors. Supplementary Figure S14. Decrease of FH mRNA expression in missense EPAS1-mutated tumors (n = 8) when compared to EPAS1-wild-type tumors (n = 170). Supplementary Figure S15. Elevated fumarate and succinate levels in EPAS1-Overexpressing PPGL cells. Supplementary Figure S16. Oxygen consumption and supply balance in the mitochondrial electron transport chain as an advantageous survival and proliferative mechanism. Supplementary Figure S17. Gene-level extremely positive selection on EPAS1 gene in systemic hypoxia. Supplementary Figure S18. Time-dependent effects of systemic hypoxia on oxygen-sensing tissues. Supplementary Figure S19. Specialization process of the HIF2α gene for adaptation to systemic hypoxia. Supplementary Figure S20. Proliferative advantage and increased sensitivity to HIF2α inhibition in HEK293T cells expressing the EPAS1 P405A/P531A double mutant. Supplementary Figure S21. Authentication of PPGL-derived PC12 cell line. Supplementary Figure S22. Full western blots shown in Fig. 3B. Supplementary Figure S23. Full western blots shown in Supplementary Fig S11.

CONTEXT:Evidence on the evolution of cardiometabolic comorbidities following surgical remission of hypercortisolism is scarce. OBJECTIVE:To determine the impact of surgical remission on cardiometabolic comorbidities in patients with endogenous hypercortisolism and to identify factors associated with cardiometabolic improvement. METHODS:Prospective single-center cohort study (2019-2025) of adults with Cushing syndrome (CS) or mild autonomous cortisol secretion (MACS) with surgical remission of hypercortisolism. Outcomes included (1) changes in severity of hypertension, diabetes mellitus (DM), hyperlipidemia, and obesity between baseline, 3, and 12 months postremission and (2) factors associated with improvement in comorbidities. RESULTS:Among 357 patients (49% MACS, 36% pituitary CS, 10% adrenal CS, 5% ectopic CS; median age 53 years [interquartile range 42-62]; 81% women), 336 (94%) had hypertension, 241 (68%) had obesity, and 122 (35%) had DM. At a median of 12 months postsurgery, improvement in hypertension occurred in 70% (90/128) of patients with CS and 51% (60/117) of patients with MACS, DM in 90% (46/51) patients with CS and 37% (13/35) patients with MACS, and obesity in 79% (77/97) patients with CS and 20% (14/71) patients with MACS. In a multivariable analysis, higher baseline biochemical severity scores were associated with improvement in hypertension [odds ratio (OR) 1.3, 95% confidence interval (CI) 1.1-1.5), DM (OR 2.5, 95% CI 1.7-4.1), and obesity (OR 1.5, 95% CI 1.2-1.8) at a median of 12 months postremission of hypercortisolism. CONCLUSION:Postsurgical improvement of cardiometabolic comorbidities was observed in both patients with CS and MACS. Higher baseline biochemical severity scores were associated with higher postremission improvement in comorbidities.

Objective Recent studies suggest a unique disease profile in elderly patients with primary aldosteronism (PA), who have a high prevalence of comorbidities and low clinical cure rate post-adrenalectomy. This study aims to investigate histopathology and genetic characteristics of PA in late adulthood.Methods Formalin-fixed, paraffin-embedded adrenal tissue sections from 114 patients with PA who underwent unilateral adrenalectomy at age 60 or older were used. Aldosterone synthase (CYP11B2) immunohistochemistry (IHC) was performed for histopathologic analysis. Somatic DNA variants were identified in aldosterone-producing tissue following CYP11B2 IHC-guided sequencing.Results Histopathologic analysis revealed that 56 adrenals contained an aldosterone-producing nodule (APN) (49%), 44 contained an aldosterone-producing adenoma (APA) (39%), 7 contained multiple APN (6%), and 7 contained only non-functioning adenomas [NFA, of which 6 had at least one aldosterone-producing micronodule (APM) in the adjacent tissue] (6%). NFAs were also identified alongside APN/APA in 24 cases. An APN was the most common histologic subtype in men (51/88, 58%), while APA was predominant in women (18/26, 69%). Of 67 APNs with successful sequencing, the majority had variants in CACNA1D (40/67, 60%). KCNJ5 variants were the most common alteration in APA (14/44, 32%).Conclusions Older individuals with lateralized PA exhibit distinct genetic and histologic causes of disease with sex differences in mutation prevalence and adrenal histopathology. In APN, the most frequently altered gene is CACNA1D, while KCNJ5 variants are most common in APA. Unlike young patients with PA, the presence of NFA is a frequent observation in late adulthood individuals with PA.

OBJECTIVE:Evidence on the duration of post-operative adrenal insufficiency (AI) in patients with endogenous hypercortisolism is scarce. We sought to determine the duration of post-operative AI and to identify factors associated with the duration of AI in patients undergoing surgery for endogenous hypercortisolism. METHODS:We conducted a single-center prospective cohort study, 2019-2025, of patients with endogenous hypercortisolism [Cushing syndrome (CS) or mild autonomous cortisol secretion (MACS)] treated with surgery. Associations of demographics, body mass index (BMI), clinical, and biochemical hypercortisolism severity, subtype of hypercortisolism, pre-surgical hypercortisolism duration, glucocorticoid type, and nadir cortisol in relation to duration of AI were investigated. RESULTS:The 242 patients [41% MACS, 46% pituitary CS, 12% adrenal CS, 1% ectopic CS, median age 50 years (IQR: 40-60), 85% women] who developed postsurgical AI were followed for a median duration of 13.7 months (IQR 7.2-26.3). The median time to recovery of AI was shorter in MACS vs. overt CS (3.9 months (95% CI: 3.3-6.2) vs. 13.5 months (95% CI 11.3-18.3), P value < .001). On multivariable analysis adjusting for age, sex, BMI, and glucocorticoid type, moderate to severe biochemical severity score (β = 11, P value < .001) and moderate to severe clinical severity score (β=8.7, P < .001), were associated with a longer duration of AI. CONCLUSIONS:Baseline clinical and biochemical hypercortisolism severity scores may inform individualized counseling on post-operative AI duration in patients treated for CS and MACS.

BACKGROUND:Biopsy of phaeochromocytomas and paragangliomas (PPGLs) is discouraged due to the perceived risk of catecholamine-related complications. However, a systematic review showed that this recommendation is primarily supported by case reports. We aimed to assess the safety of percutaneous biopsy in patients with PPGLs. METHODS:This international, multicentre, retrospective study included patients of any age with PPGLs referred to participating centres who had had percutaneous core-needle biopsy or fine-needle aspiration. Biopsies of head and neck paragangliomas were excluded. Participating centres completed standardised data-collection forms. The primary outcome was biopsy-related mortality rate for all patients who had biopsies performed at participating centres, given that biopsies done elsewhere that had fatal outcomes would be unlikely to be referred. Secondary outcomes included the incidence of serious catecholamine-related and non-catecholamine-related complications among all included patients. FINDINGS:Between Sep 1, 1993, and May 31, 2025, 222 patients (110 [50%] female, 112 [50%] male) underwent 234 biopsies in 19 hospitals across 11 countries. 139 (67%) of 207 patients had elevated epinephrine or norepinephrine (or metabolites) and 27 (12%) of 232 biopsies were preceded by the administration of α-adrenoceptor blockade. One (mortality rate 0·9% [95% CI 0·0-5·1]) of 106 biopsies led to death due to biopsy-related infection. Serious catecholamine-related complications occurred after four (1·7% [0·5-4·3]) of 233 biopsies and included tachyarrhythmia, hypertensive crisis, and cardiogenic shock. No serious catecholamine-related complications occurred in patients without catecholamine excess (n=59), receiving fine-needle aspiration (n=46), or after biopsy of metastatic lesions (n=114). Serious non-catecholamine-related complications occurred after ten (4·3% [2·1-7·8]) of 233 biopsies, mainly bleeding and infection. INTERPRETATION:Percutaneous biopsy of PPGLs was associated with a low mortality rate. Serious complication rates were also low, most of which were not catecholamine-related. These findings challenge current recommendations that biopsy should be avoided in suspected or confirmed PPGLs, and instead support a personalised, risk-benefit-based approach to the procedure. FUNDING:Cancerfonden. TRANSLATIONS:For the Chinese and French translations of the abstract see Supplementary Materials section.

Purpose: To evaluate the impact of corticosteroid premedication on the performance of adrenal vein sampling (AVS) in patients with primary aldosteronism (PA) and allergy to iodinated contrast media (ICM). Materials and Methods: Patients who underwent AVS for PA between September 1990 and October 2023, were retrospectively identified. Patients with ICM allergy who received corticosteroid premedication were matched 1:1 with patients without contrast media allergy. AVS was performed with continuous cosyntropin infusion (50 mu g/h beginning 30 minutes before AVS). Patient demographics, clinical characteristics, AVS results, and follow-up data were compared. Results: Of 1,243 patients, 35 (2.8%) received corticosteroid premedication (methylprednisolone, 32; dexamethasone, 3), with no breakthrough contrast media allergy reactions. Three patients with coexisting PA and hypercortisolism were excluded. Clinical presentation did not differ between the 2 groups. The absolute median cortisol levels (mu g/dL) from both the adrenal vein (AV) and inferior vena cava (IVC) were similar between groups (right AV, 706 vs 738 [P = .94]; left AV, 475.5 vs 406.5 [P = .15]; IVC, 23 vs 22 [P = .99]). Bilaterally successful cannulation (selectivity index, >= 5) rates were similar between groups (30 [93.8%] vs 30 [93.8%], P = 1). Identification of unilateral adrenal disease (lateralization index, >= 4) was also similar (18 [56.3%] vs 17 [53.1%], P > .99). Surgery was performed in 14 cases and 15 controls, with similar rates of suppressed aldosterone on postoperative Day 1 (13 [92.9%] vs 14 [93.3%], P > .99) suggesting surgical cure. Conclusions: AVS with continuous cosyntropin stimulation can be effectively performed in patients with ICM allergy and corticosteroid premedication with similar rates of disease subtyping and postoperative outcomes.

OBJECTIVE:Distinguishing between pituitary corticotropin (ACTH)-dependent Cushing disease (CD) and ectopic ACTH-dependent Cushing syndrome (EADCS) is diagnostically challenging. This study compared the diagnostic performance of bilateral inferior petrosal sinus sampling (BIPSS) and bilateral internal jugular vein sampling (BIJVS). METHODS:We retrospectively reviewed 109 patients at Mayo Clinic (1998-2018) who underwent simultaneous BIPSS and BIJVS. Eighty-four patients proceeded to pituitary surgery based on BIPSS results, and 81 ultimately received confirmed diagnoses: 74 with CD and 7 with EADCS. Sensitivity and specificity were calculated using pre- and post-corticotropin-releasing hormone (CRH) stimulation criteria. RESULTS:BIJVS was positive in 35/74 CD patients at baseline and 59/74 post-CRH, compared with 68/74 and 72/74, respectively, for BIPSS. Combined pre- and post-CRH criteria yielded 82% sensitivity and 86% specificity for BIJVS, compared with 100% sensitivity and specificity for BIPSS. CONCLUSION:BIPSS is superior to BIJVS for establishing the source of ACTH hypersecretion in ACTH-dependent Cushing syndrome. BIJVS demonstrates limited diagnostic utility in clinical practice.

SIGNIFICANCE:This study reveals a broad convergence in genetic adaptation to hypoxia between natural populations and tumors, suggesting that insights from natural populations could enhance our understanding of cancer biology and identify novel therapeutic targets. See related commentary by Lee, p. 875.

Disclosure: S.R. Chacko: None. C.A. Villavicencio Torres: None. K. Yu: None. S.G. Waguespack: None. L. Lu: None. Z. Belaya: None. T. Bandgar: None. A. Sada: None. O. Ragnarsson: None. B. Altieri: None. A. Newman: None. P. Vibhatavata: None. M. Tóth: None. E.V. Varlamov: None. C. Badiu: None. A. Paissan: None. M. St-Jean: None. H. Falhammar: None. N. Imamudeen: None. L. Haberbosch: None. M. Bobrowicz: None. A. Tabarin: None. R. Shah: None. M.R. Gadelha: None. A. Peersen: None. W.F. Young: None. J. Kaplan: None. J. Varghese: None. M.A. Habra: None. O. Golounina: None. G.A. Melnichenko: None. A.R. Lila: None. C. Yamichannaiah: None. I. Bancos: None. Context: Cushing syndrome (CS) due to ectopic ACTH secretion (EAS) is a rare condition, associated with severe hypercortisolism and consequent morbidity and mortality. Its varied and often emergent presentation make diagnosis and treatment challenging. Objectives: 1.Characterize clinical and biochemical presentation of EAS. 2.Describe the scope of hypercortisolism-related complications, overall and CS-specific mortality. 3.Identify factors associated with CS-specific mortality. Methods: We conducted a multicenter retrospective cohort study in patients with EAS at 37 centers. Outcomes were clinical/biochemical severity scores, complications, overall and CS-specific mortality. Results: In 1053 patients [median age at diagnosis 52 years (IQR 37-64), 57% women], metastatic disease was present at diagnosis in 585 (56%). The most common sources of EAS were bronchial neuroendocrine neoplasm (NEN) (304, 29%), pancreatic NEN (114, 11%) and small cell lung carcinoma (114, 11%), with the source of EAS being occult in 192 (18%). Clinical and biochemical severity scores were severe in 475 (45%) and 873 patients (92%) respectively. Hypokalemia was present in 819 patients (78%) in the year prior to diagnosis. Of 342 patients (32%) who had IPSS, 301 (88%) suggested an ectopic source, 7 (2%) a pituitary source, and 23 (7%) were non-diagnostic. Of 595 patients who had both functional and cross-sectional imaging, discordant findings were seen in 122 (21%), concordant lesion was seen on both in 326 (55%), and no lesion in 147 (25%). Of those with discordant results, cross-sectional imaging was accurate in 66 (54%) and functional imaging in 56 (46%).Management included medical therapy alone in 237 (23%), surgical excision of the source of EAS in 158 (15%), bilateral adrenalectomy in 77 (7%) and multimodal therapies in 498 patients (47%). Complications within 5 years after diagnosis included hospitalization related to CS or its therapy in 351 (33%), infection in 337 (32%), thromboembolic event in 102 (10%), cardiovascular event in 83 (8%) and cerebrovascular event in 27 (3%). During a median follow-up of 35 months (IQR 20-122) from CS diagnosis, death occurred in 462 patients (44%), with the cause of death related to CS in 149 (14%). CS-specific mortality was higher in metastatic compared with non-metastatic disease (19% vs. 7%, P<0.001). On multivariable analysis of age, sex, clinical and biochemical severity, older age (HR 1.03, 95% CI: 1.02-1.04) and lower clinical severity score (HR 0.97, 95% CI: 0.94-0.99), were associated with higher CS-specific mortality. Conclusion: Our interim analysis, the largest worldwide, found that most patients with EAS had severe hypercortisolism and hypokalemia. Metastatic disease was present in 56%, and the source of EAS was occult in 18%. CS-related death occurred in 14%, emphasizing the need for urgent management. Presentation: Monday, July 14, 2025

BACKGROUND:Primary aldosteronism (PA), a primary adrenal disorder leading to excessive aldosterone production by one or both adrenal glands, is a common cause of hypertension. It is associated with an increased risk of cardiovascular complications compared with primary hypertension. Despite effective methods for diagnosing and treating PA, it remains markedly underdiagnosed and undertreated. OBJECTIVE:To develop an updated guideline that provides a practical, clinical approach to identifying and managing PA to improve diagnosis rates and encourage targeted treatment. METHODS:The Guideline Development Panel (GDP), composed of a multidisciplinary panel of clinical experts and experts in systemic review methodology, used the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach to define 10 questions related to the diagnosis and treatment of PA. Systematic reviews were conducted for each question. The GDP used the GRADE Evidence to Decision (EtD) framework to consider contextual factors, such as stakeholder values and preferences, costs and required resources, cost-effectiveness, acceptability, feasibility, and the potential impact on health equity. RESULTS:We suggest that all individuals with hypertension be screened for PA by measuring aldosterone and renin and determining the aldosterone to renin ratio, and that subsequent clinical care be guided by the results. We suggest that individuals with PA receive PA-specific therapy, either medical or surgical. In individuals who screen positive for PA, we suggest (1) commencement of PA-specific medical therapy in individuals who do not desire or are not candidates for surgery and in situations where the probability of lateralizing PA (excess aldosterone produced by one adrenal) is low based on screening results; and (2) aldosterone suppression testing in situations when screening results indicate an intermediate probability for lateralizing PA and individualized decision making confirms a desire to pursue eligibility for surgical therapy. In those who test positive by aldosterone suppression testing, and in those in whom screening results show a high probability of lateralizing PA (obviating the need for aldosterone suppression testing), we suggest adrenal lateralization with computed tomography scanning and adrenal venous sampling prior to deciding the treatment approach (medical vs surgical). In all individuals with PA and an adrenal adenoma, we suggest performing a 1-mg overnight dexamethasone suppression test. We suggest the use of mineralocorticoid receptor antagonists (MRAs) over epithelial sodium-channel (ENaC) inhibitors in the medical treatment of PA. We suggest the use of spironolactone over other MRAs, given its lower cost and greater availability; however, all MRAs, when titrated to equivalent potencies, are anticipated to have similar efficacy in treating PA. Thus, MRAs with greater mineralocorticoid receptor specificity and fewer androgen/progesterone receptor-mediated side effects may be preferred in some situations. In individuals receiving MRA therapy, we suggest monitoring renin and, in those whose hypertension remains uncontrolled and renin is suppressed, titrating the MRA to increase renin. CONCLUSION:These recommendations provide a practical framework for the diagnosis and treatment of PA. They are based on currently available literature and take into consideration outcomes that are important to key stakeholders. The goal is to increase identification of individuals with PA and, by initiating PA-specific medical or surgical therapy, improve blood pressure control and reduce PA-associated adverse cardiovascular events. The guidelines also highlight important knowledge gaps in PA diagnosis and management.

OBJECTIVE:Glucocorticoid withdrawal syndrome (GWS) may develop in patients following successful surgery for endogenous hypercortisolism. Effective strategies to minimize GWS and improve quality of life (QoL) are currently lacking. We aimed to determine the impact of hydrocortisone vs prednisone therapy on GWS and QoL during the first 12 weeks postsurgery. METHODS:Single-center prospective cohort study (2019-2024) of adults with endogenous hypercortisolism who developed postoperative adrenal insufficiency and treated with either prednisone or hydrocortisone. Quality of life was assessed with Short Form-36 (SF-36) and Cushing QoL questionnaires at baseline and at 12 weeks postsurgery. GWS was assessed using weekly AddiQoL questionnaires for the first 12 weeks postsurgery. RESULTS:Of 165 patients, 101 (61%) were treated with hydrocortisone and 64 (39%) with prednisone. At baseline, no group differences were found in the hypercortisolism subtype, comorbidities, or QoL assessments. At follow-up, no group differences in final total daily hydrocortisone equivalent dose were seen.When adjusting for the baseline QoL assessment, patients treated with prednisone demonstrated a higher degree of improvement in their QoL, particularly in the SF-36 mental component score (estimate 0.33, 95% CI, 0.04-0.63), SF-36 role-emotional limitation (estimate 0.52, 95% CI, 0.2-0.84), and SF-36 body pain (estimate 0.31, 95% CI, 0.07-0.56) subcomponents. In the multivariable analysis of age, sex, body mass index, glucocorticoid type, baseline clinical severity score, and baseline QoL assessment, prednisone therapy was an independent predictor of better SF-36 mental component at 12 weeks postsurgery. CONCLUSIONS:Prednisone therapy was associated with better mental health QoL than hydrocortisone at 12 weeks postsurgery in patients with hypercortisolism.

Disclosure: S.R. Chacko: None. J. Saini: None. S. Sharma Sharma: None. S. Ahmadian: None. S.J. Achenbach: None. E. Atkinson: None. V. Fell: None. J.J. Van Gompel: None. W.F. Young, Jr.: None. I. Bancos: None. Context: Evidence on the duration of postoperative adrenal insufficiency (AI) in patients with endogenous hypercortisolism is scarce. Objective: To determine the duration of postoperative AI and to identify factors associated with the duration of AI in patients undergoing surgery for endogenous hypercortisolism.Methods: We conducted a single center prospective cohort study, 2019-2024, of patients with endogenous hypercortisolism [Cushing syndrome (CS) or mild autonomous cortisol secretion (MACS)] treated with surgery. Associations of demographics, BMI, clinical and biochemical hypercortisolism severity, subtype of hypercortisolism, presurgical hypercortisolism duration and glucocorticoid type in relation to duration of AI were investigated. Results: The 110 patients [36% MACS, 46% pituitary CS, 15% adrenal CS, 3% ectopic CS, median age 50 years (IQR: 40-60), 82% women] who developed postsurgical AI were followed for a median duration of 26 months (IQR: 15-38). By the end of follow up, 96 patients (87%) had recovery of AI. The median time to recovery of AI was shorter in MACS vs. Overt Cushing syndrome (3.0 months (95% CI: 2.5-6.2) vs. 12.3 months (95% CI 9.0-17.3), P =0.002). Biochemical severity score (r=0.32, P=0.002) and duration of preoperative hypercortisolism symptoms (r=0.29, P=0.005), but not age, sex, BMI, clinical severity, or glucocorticoid type were associated with the duration of AI. We found no differences in the duration of AI between patients with ACTH-dependent vs ACTH-independent CS (12.3 months (95% CI: 6.0-17.2) vs 13.9 months (95% CI: 9.0-25.5), P =0.7).Conclusion: In this interim analysis, we showed that after surgical remission of endogenous hypercortisolism, duration of postoperative AI was longer in CS compared to MACS. Additionally, higher biochemical hypercortisolism severity score and a longer duration of symptoms suggestive of hypercortisolism were associated with a longer duration of postoperative AI. Presentation: Sunday, July 13, 2025