Multi-center comparison of corticotropin releasing hormone vs. desmopressin stimulation responses in inferior petrosal sinus sampling for Cushing's disease.

Long-term trajectories of cognitive function, fatigue, and quality of life in patients after pituitary adenoma surgery: A retrospective study.

Risk of Infection-Related Hospitalization Is More Than Doubled in Cushing's Syndrome vs Matched Controls.

PurposeThe association between persistent endogenous hypercortisolism and hepatic hemangioma (HH) remains unclear. This study compared the prevalence of HH between patients with Cushing’s disease (CD) and silent corticotroph adenomas (SCA) and explored factors associated with HH in CD patients.MethodsThis retrospective observational study included 96 CD patients and 219 SCA patients treated between May 2015 and December 2025. Demographic, laboratory, and imaging data were collected. Propensity score matching (PSM) balanced baseline characteristics. HH was diagnosed by contrast-enhanced abdominal CT. Multivariate analyses, including logistic regression, LASSO regression, and Firth-corrected likelihood regression, were performed. Model performance was assessed using receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA).ResultsAfter PSM, HH prevalence was higher in CD patients than in SCA patients (20.0% vs. 9.5%, P = 0.024). Among CD patients, elevated midnight cortisol (OR = 1.402, 95% CI: 1.078–2.031, P = 0.010) and increased 24-hour urinary free cortisol (OR = 1.013, 95% CI: 1.006–1.023, P < 0.001) were independently associated with HH. The predictive model demonstrated good discrimination (AUC = 0.982, 95% CI: 0.961–1.000) and acceptable calibration, with potential clinical utility supported by DCA.ConclusionHH was more prevalent in patients with Cushing’s disease than in those with silent corticotroph adenomas. Elevated cortisol levels may be an important factor associated with HH. This study offers a predictive tool to support early risk assessment and clinical management.Clinical trial numberNot applicable.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12902-026-02333-8.

Corticotroph adenomas include functioning tumors causing Cushing disease (CD) and silent corticotroph adenomas (SCA), which differ markedly in size, clinical presentation, and aggressiveness. The molecular basis for these differences remains incompletely understood. To characterize genomic and transcriptomic alterations underlying the divergent clinical behavior of CD and SCA. Thirty-eight tumors from 34 patients underwent whole-exome sequencing, copy-number variation (CNV) analysis, and mRNA sequencing. Molecular findings were integrated with clinical, radiological, and pathological data. USP8/USP48 mutations were present in 10 of 21 CD tumors (48%) and were associated with low CNV levels, minimal invasion, and favorable post-operative remission. In contrast, five of 13 SCAs harbored TP53/ATRX/DAXX mutations, all had markedly elevated CNV, and aggressive clinical features. Transcriptomic analysis identified an ATRX-FAM138A mRNA fusion, resulting in loss of ATRX expression in an aggressive tumor. Unsupervised transcriptome analyses defined four clusters. All USP8/USP48-mutant CD clustered together had low CNV and low recurrence rates. Cluster 2 consisted of a mixture of CD and SCA, with intermediate CNV and non-aggressive behavior. Cluster 3 included USP8-wildtype CD with heterogeneous yet generally non-aggressive courses. Cluster 4 represented high-CNV tumors enriched for TP53/ATRX/DAXX alterations, with the highest rates of radiological invasion, persistent disease, and recurrence or progression. Across the cohort, higher CNV was significantly associated with parameters of aggressiveness. Corticotroph adenomas comprise distinct molecular subtypes. USP8/USP48-mutant CD represents a low-CNV, low-risk group, whereas tumors harboring TP53/ATRX/DAXX mutations exhibit high CNV and aggressive clinical behavior. CNV and mutation profiling may assist in postoperative risk stratification.

Recurrent Cushing's disease is most commonly caused by residual or newly developed pituitary neuroendocrine tumor (PitNET) tissue within the sellar region. Extrasellar recurrence due to postoperative tumor cell seeding is exceedingly rare. We report the unique case of a 30-year-old woman who achieved endocrine remission after gross total resection of an ACTH-secreting PitNET but later developed biochemical and clinical recurrence without radiological evidence of a sellar lesion. Despite long-term medical therapy including cabergoline, metyrapone, and pasireotide, the hypercortisolism gradually progressed. Nearly 10 years after the initial surgery, a reoperation was performed to explore the occult tumor. Intraoperatively, a small soft tumor attached to the posterior surface of the anterior wall of the sphenoid sinus was discovered. Histopathological examination confirmed the presence of a recurrent corticotrophic PitNET. A retrospective review of CT, MRI, and octreotide scintigraphy revealed a subtle lesion that had previously been overlooked. Complete resection resulted in an immediate endocrine remission. This case demonstrates that recurrent Cushing's disease may, although rarely, arise from the implantation of tumor cells that drop into the sphenoid sinus during transsphenoidal surgery. Awareness of this mechanism is crucial for evaluating MRI-negative recurrences. Careful inspection of the sphenoid sinus and meticulous irrigation during surgery may help prevent iatrogenic seeding and improve long-term outcomes.

Modest sensitivity of 24 h urine free cortisol LC-MS/MS to detect Cushing's disease.

The purpose of our study was to develop and externally validate a multivariable diagnostic model to distinguish ectopic ACTH secretion (EAS) from Cushing's disease (CD) using routine clinical parameters. The model was derived from a Spanish multicenter retrospective cohort and externally validated in a Colombian cohort. Predictors were selected through a multivariable logistic regression model with penalized logistic regression (LASSO) using the Spanish cohort. Discriminative performance was assessed using the area under the ROC curve (AUC) and calibration using the slope, the origin, and the Brier score. The derivation cohort included 253 patients from Spain (199 with CD and 54 with EAS). The external validation cohort comprised 72 Colombian patients (53 with CD and 19 with EAS). In the derivation cohort, multivariable modeling identified four independent predictors: ACTH concentration, 24-h urinary free cortisol (UFC), serum potassium, and maximum pituitary tumor diameter. The final model demonstrated good discrimination in the derivation cohort (mean AUC of 0.987), with excellent calibration (calibration slope ranged from 0.998 to 5.22, intercept -0.2 to 0.99, Brier score 0.035). In external validation, model performance remained robust (AUC ranging from 0.9885 to 0.9890; Brier score 0.0381). The model achieved a sensitivity of 95.3%, specificity of 93.6%, positive predictive value of 82.3%, and negative predictive value of 98.7% for detecting EAS. Thus, the diagnostic model developed, based on routinely available clinical variables, shows high accuracy and calibration in differentiating between EAS and CD, supporting its potential use in diverse clinical settings and integration into diagnostic workflows.

Lower Cutoffs Improve the Diagnostic Performance of DDAVP-Stimulated Bilateral Inferior Petrosal Sinus Sampling for Cushing Disease: A Prospective Cohort Study.

Structure-based rational design of high-affinity JAZF1 variants peptides to target the testicular orphan nuclear receptor 4 and pro-opiomelanocortin axis in Cushing's disease.

Evaluate the effects of osilodrostat short- and long-term treatment on health-related quality of life (HRQoL) in Cushing's disease. LINC 3 and LINC 4 studies (pooled analysis). 185 patients (mean baseline total scores: Cushing's Quality of Life [CushingQoL], 44.0; Beck Depression Inventory II [BDI-II], 15.6; EuroQol Five Dimensions Five Levels [EQ--5D-5L], 0.7). Changes from baseline in CushingQoL, BDI--II and EQ-5D-5L scores. CushingQoL and EuroQol Five Dimensions Three Levels (EQ-5D-3L) scores were assessed in analyses of hypocortisolism-related adverse events (HAEs). Mean CushingQoL score improved (all p < 0.001) by +7.72 (Week [W]12), +11.45 (W26; achieving minimal clinically important difference [MCID]) and +15.32 (W72). Mean BDI-II score improved (all p < 0.001) by -19.0% (W12; achieving MCID) and -41.2% (W72). EQ-5D-5L utility score improved over W26-72 (p < 0.01), reaching the MCID range at W26. All items/domains in the HRQoL questionnaires significantly improved over time (p < 0.001; ordinal mixed-effects regression), except one BDI-II item (past failure) and one EQ-5D-5L domain (self-care). CushingQoL total score improved in patients with mild (mean urinary free cortisol [mUFC] ≤ 2x upper limit of normal [ULN]), moderate (mUFC > 2-5 × ULN) and severe (mUFC > 5 × ULN) hypercortisolism. BDI-II and EQ-5D-5L total scores improved in patients with moderate and severe hypercortisolism. Grade 3 HAEs temporarily reduced CushingQoL and EQ-5D-3L scores during event weeks. In the multivariable models, longer treatment duration was associated with CushingQoL improvements; higher mUFC, higher body mass index, and occurrence of HAEs were associated with lower CushingQoL scores. Osilodrostat improved HRQoL, with clinically meaningful, consistent improvements across HRQoL assessments.

Patients with Cushing's syndrome (CS) have a high prevalence of cardiovascular disease, and other recognized risk factors for atrial fibrillation/flutter (AF/AFL); however, the prevalence of AF/AFL has not been well characterized in this population. We conducted a retrospective matched-cohort study using the Clalit Health Services database, including patients with CS and 1:5 matched controls. We assessed the risk of new-onset AF/AFL overall and according to disease etiology and remission status. Pre-existing AF/AFL was defined as >30 days before CS, and new-onset as within 30 days or thereafter. The cohort included 609 patients with CS and 3018 controls. Pre-existing AF/AFL was more common among patients with CS than controls (3.6% vs. 2.1%; OR 1.70, 95% CI 1.04-2.78). During a mean follow-up of 15 years, patients with CS had a significantly higher risk of developing new-onset AF/AFL compared with controls (HR 1.55, 95% CI 1.19-2.03). This increased risk was observed in both Cushing's disease (CD) (HR 1.53, 95% CI 1.01-2.32) and adrenal CS (HR 1.70, 95% CI 1.06-2.74). AF/AFL risk did not significantly differ according to remission status, although a trend toward lower risk was observed. Multivariate analysis identified older age at diagnosis, male sex, hypertension, vascular disease, and higher BMI as predictors for new-onset AF/AFL. CS is associated with an increased risk of AF/AFL. This elevated risk is observed across both CD and adrenal CS and persists despite disease remission, underscoring the need for heightened awareness and close cardiovascular surveillance in this population. The increased risk of AF/AFL appears to be primarily driven by coexisting cardiovascular comorbidities rather than cortisol excess or other CS-specific features.

Pituitary adenomas are common intracranial neoplasms and represent a clinically relevant but frequently underrecognized cause of secondary osteoporosis and fragility fractures. Hormonal excess, coexisting pituitary deficiencies, and the iatrogenic burden of multimodal treatments act synergistically to impair bone remodeling, microarchitecture, and mechanical strength. Consequently, skeletal fragility may manifest at a relatively young age and is often inadequately predicted by dual-energy X-ray absorptiometry (DXA)-derived areal bone mineral density (aBMD) alone.This narrative review summarizes current evidence on skeletal involvement in functioning pituitary adenomas, including acromegaly, Cushing's disease (CD), prolactinomas, and thyrotropin [TSH]-secreting adenomas (TSHomas), with a specific focus on sex-related differences relevant to clinical practice. Although several pituitary adenomas are more prevalent in women, male patients frequently present with delayed diagnoses, harboring larger and more aggressive tumors. Consequently, men may be affected by a longer cumulative exposure to hormone excess and a higher prevalence and severity of panhypopituitarism, often exacerbated by the mass effect and multiline therapies. Across clinical cohorts, these interacting factors are consistently associated with an increased burden of fragility fractures, particularly in male patients.In pituitary disorders, fracture risk is commonly underestimated because DXA-derived aBMD does not adequately capture alterations in bone quality and structural integrity. Comprehensive skeletal evaluation, including systematic vertebral morphometry, trabecular bone score (TBS), and selected advanced imaging techniques, improves detection of occult fractures and refines fracture risk stratification. Moreover, the persistently low awareness, diagnosis, and treatment rates of osteoporosis in men represent a substantial and potentially modifiable gap in care, particularly in secondary forms related to endocrine diseases.This review highlights the need for a proactive, sex-aware clinical approach that integrates endocrine management with appropriate skeletal assessment and bone-directed therapy, with the aim of reducing fracture burden and improving long-term outcomes in patients with pituitary diseases.

Real-time PCR-based intraoperative molecular boundary diagnosis of corticotroph pituitary neuroendocrine tumors.

Reviewer Comment on Levitan et al. "Quality of Life Recovery in Cushing's Disease: A Cluster Analysis".

Cushing's disease (CD) is a rare endocrine disorder caused by the overproduction of adrenocorticotrophin hormone (ACTH) from a pituitary tumour, leading to excessive secretion of cortisol. The chronic exposure to cortisol leads to endocrine and cardiovascular complications that persist even after remission of hypercortisolism. CD is associated with a significant clinical burden characterised by insulin resistance, renal dysfunction and cardiovascular complications. In addition, patients frequently experience impaired health-related quality of life (HRQoL) and have an increased risk of mortality. There are currently no approved therapies targeting these complications. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are antihyperglycaemic agents that target SGLT2 transporters in the renal proximal convoluted tubules, thus leading to glycosuria and reduction of glycaemia. Initially approved as anti-diabetic agents, SGLT2i have subsequently revealed to exert a wide range of beneficial effects, namely cardiorenal protection; therefore having been recently approved as a first-line treatment for chronic kidney disease and heart failure, regardless of the presence of diabetes. While the clinical and metabolic efficacy of SGLT2i has been extensively documented in type 2 diabetes, heart failure and chronic kidney disease, their systemic effects may also be relevant in patients with CD, who exhibit cardiovascular, renal and metabolic alterations even after biochemical remission. The myriad benefits of SGLT2i align closely with the unmet clinical needs for new medical treatment for patients with CD, supporting their potential therapeutic relevance in this disease. Accordingly, we herein review the pathophysiology, clinical presentation and treatment of CD, and explore the potential therapeutic benefit of SGLT2i in this disorder.

Successful surgery for Cushing's disease (CD) leads to an abrupt change in cortisol levels, and patients often experience symptoms that can adversely affect their quality of life (QOL). The goal of this study was to provide a detailed characterization of the changes in QOL before and after successful surgery. The QOL-CD, a CD-specific questionnaire, was administered at routine clinical visits during active disease prior to surgery and during the early postoperative phase following successful surgery. Descriptive statistics and nonparametric tests characterized clinical, endocrinological, and ophthalmological attributes at both phases. Euclidean hierarchical clustering of the 34 patients who completed both pre- and postoperative questionnaires identified latent subgroups of QOL change. In the cohort as a whole, hypertension (OR = 0.31, p = .003), emotional health (p = .026) and physical health (p < .001) improved following treatment. Changes in emotional health were correlated with changes in mental status (r = 0.66, p < .001) and social well-being (r = 0.53, p = .001). The cluster analysis revealed five distinct patterns of pre- to postoperative changes in QOL domains, grouped into three categories based on severity. Group 1 (n = 5) patients showed worsening in most domains of QOL, Group 2 (n = 20) showed marginal changes in QOL and Group 3 (n = 9) demonstrated improvements across all QOL domains. Our results highlight the need to educate and support patients before and after surgery for CD. Long-term follow-up studies are needed to better understand the trajectory of QOL recovery and to identify predictors of treatment response.

Background: Cushing’s disease (CD) is a rare endocrine disorder associated with significant morbidity and increased mortality if left untreated. Endoscopic transsphenoidal surgery (ETSS) is the preferred first-line treatment; however, reported remission and recurrence rates vary widely due to differences in biochemical remission criteria and follow-up duration. This study aimed to evaluate surgical outcomes, remission rates using standard and strict biochemical criteria, recurrence, and postoperative complications following ETSS for CD at a tertiary referral center.Methods: This retrospective analysis included 82 patients with confirmed CD who underwent ETSS between January 2015 and July 2025. Diagnosis was established using standard biochemical tests, with inferior petrosal sinus sampling where clinically indicated. Postoperative remission was assessed using two criteria: (1) standard remission – early morning serum cortisol <138 nmol/L within 7 days of surgery and (2) strict remission – postoperative day-3 serum cortisol <50 nmol/L. Patients with persistent hypercortisolism were managed with early repeat ETSS, radiotherapy, or medical therapy. Postoperative complications, endocrine deficits, and recurrence were analyzed.Results: The cohort comprised 58 females and 24 males, with a median age of 33.6 years (range 14–71). Preoperative MRI identified microadenomas in 64 patients and macroadenomas in 18 patients. Using standard criteria, remission after initial ETSS was achieved in 70 of 82 patients (85.4%), increasing to 90.2% (74/82) after inclusion of early repeat ETSS. Using strict criteria, early biochemical remission was observed in 56 patients (68.3%) following initial surgery. Persistent hypercortisolism was noted in 12 patients (14.6%), of whom six underwent early repeat ETSS, achieving remission in 66% by standard criteria. Transient diabetes insipidus (DI) occurred in 26.8% and permanent DI in 9.8% of patients. No cases of cerebrospinal fluid leak, meningitis, vascular injury, or postoperative visual deterioration were observed. During short-term follow-up, recurrence was documented in two patients, both with macroadenomas. Median follow-up duration was 4 months.Conclusion: ETSS provides high remission rates with minimal surgical morbidity in patients with CD. Remission rates are significantly influenced by the biochemical criteria applied, with higher rates observed using standard Endocrine Society definitions compared to stricter postoperative cortisol thresholds. Microadenomas demonstrate superior surgical outcomes. While early biochemical remission rates were high, the relatively short median follow-up limits assessment of long-term recurrence and durability of remission, underscoring the need for extended surveillance.

Cushing's disease (CD) is a neuroendocrine disorder characterized by excessive adrenocorticotropic hormone (ACTH) secretion from pituitary adenomas, closely associated with ubiquitin-specific protease 8 (USP8) mutations. This study aimed to investigate whether USP8 mutations activate the Sonic Hedgehog (SHH) pathway by deubiquitinating its key component Smoothened (SMO), thereby promoting ACTH production in CD. mRNA expression profiles of USP8-mutated and wild-type CD patients (GEO dataset GSE132982) were analyzed for differentially expressed genes, followed by GO and KEGG pathway enrichment. USP8 mutant/wild-type plasmids were transfected into HeLa cells. Co-immunoprecipitation and Western blot evaluated USP8-SMO interaction and SMO ubiquitination. RT-qPCR, luciferase reporter assays, and nuclear translocation analysis assessed SHH pathway gene expression and GLI2 transcriptional activity. Immunohistochemistry detected SMO/SHH proteins in 9 USP8-mutated and 9 wild-type pituitary adenomas. Primary tumor cells were treated with the SMO inhibitor cyclopamine, and POMC mRNA/ACTH secretion were measured by RT-qPCR/ELISA. Chromatin immunoprecipitation (ChIP) verified GLI2 binding to the POMC promoter. SHH pathway genes were significantly dysregulated in USP8-mutated CD. Mutant USP8 enhanced SMO interaction, reduced SMO ubiquitination, and upregulated SHH target genes, promoting GLI2 nuclear translocation/activity. SMO-positive cells were more frequent in mutated tumors, with unchanged SHH expression. Cyclopamine suppressed POMC/ACTH specifically in mutated cells, and ChIP confirmed GLI2-POMC promoter binding. USP8 mutations activate the SHH pathway via SMO deubiquitination, driving GLI2-mediated POMC transcription and excessive ACTH secretion in CD. Targeting the SHH pathway may offer a novel therapeutic strategy for USP8-mutated Cushing's disease.

Transsphenoidal surgery (TSS) is the treatment of choice for Cushing's disease (CD). In experienced pituitary centers a high remission rate is reported. Nevertheless, endocrinologists and neurosurgeons face cases with persistent or recurrent CD. In addition to medical treatment, radiation therapy and bilateral adrenalectomy, repeat TSS must also be considered. This study evaluates outcomes and predictors of remission following repeat TSS in patients with CD. A retrospective single-center analysis was conducted including all patients who underwent re-TSS for persistent (n = 29) or recurrent (n = 42) CD between 2004 and 2024. Clinical, radiological, intraoperative, and biochemical data were analyzed for factors influencing remission and long-term outcome. Remission was achieved in 75.4% at first follow-up and 55.7% at long-term follow-up; early/long-term remission was 70.8%/50.0% after surgery for persistence and 78.4%/59.5% after surgery for recurrence. First reoperation yielded higher remission than those with ≥ 2 prior surgeries (81.6% vs. 50.0%, p = 0.030). Invasive tumor growth was strongly associated with reduced remission (p = 0.001). Selective adenomectomy or adenomectomy with rim excision achieved the highest early remission, whereas subtotal or purely explorative resections were less effective (p = 0.011), indicating that targeted resection of an identifiable lesion improves outcome. Postoperative complications occurred in 14.1% (10/71); major complications in 8.5% (6/71); there was no perioperative mortality. Repeat TSS is a safe and effective treatment for both persistent and recurrent CD in specialized pituitary centers. Surgical success depends on tumor invasiveness, prior operations, and surgical strategies. Reoperation should be considered an essential part of individualized, multidisciplinary management to achieve sustained remission.