Daily Endocrinology Research Analysis
Three studies advance endocrine diagnostics and risk stratification: a prospective modification of the overnight dexamethasone suppression test using late-afternoon cortisol and ACTH improved diagnostic accuracy for Cushing syndrome; a large real-world analysis shows 24-hour urinary aldosterone retains strong performance for diagnosing primary aldosteronism even without antihypertensive washout; and a nationwide cohort links so-called non-functional adrenal tumors to substantially higher risks o
Summary
Three studies advance endocrine diagnostics and risk stratification: a prospective modification of the overnight dexamethasone suppression test using late-afternoon cortisol and ACTH improved diagnostic accuracy for Cushing syndrome; a large real-world analysis shows 24-hour urinary aldosterone retains strong performance for diagnosing primary aldosteronism even without antihypertensive washout; and a nationwide cohort links so-called non-functional adrenal tumors to substantially higher risks of psychiatric and sleep disorders.
Research Themes
- Endocrine diagnostic optimization
- Adrenal disorders and cardiometabolic risk
- Neuropsychiatric comorbidity in adrenal incidentalomas
Selected Articles
1. Overnight Dexamethasone Suppression Test: Enhanced Accuracy with Late-Afternoon Cortisol and Morning/Late-Afternoon ACTH.
In a prospective diagnostic study, adding late-afternoon cortisol and ACTH to the standard 1‑mg ODST improved specificity, particularly in COCP and CKD, without sacrificing sensitivity for ACTH-dependent Cushing syndrome. A 4‑PM cortisol and 8‑AM/4‑PM ACTH (10 pg/mL cut-off) achieved excellent discrimination, and 4‑PM cortisol differentiated remission from persistent Cushing disease with 98.1% accuracy.
Impact: Offers a practical, immediately applicable enhancement to a widely used endocrine test, addressing known specificity issues in challenging subgroups. Could standardize a refined ODST protocol.
Clinical Implications: Consider measuring 4‑PM cortisol and ACTH alongside standard ODST sampling, especially in COCP and CKD, to improve specificity and postoperative monitoring of Cushing disease.
Key Findings
- 4‑PM cortisol was significantly lower than 8‑AM in healthy, COCP, CKD, and CD remission groups, but not in untreated ACTH-dependent Cushing syndrome or persistent Cushing disease.
- Using a 10 pg/mL ACTH cut-off at 8‑AM and 4‑PM yielded high specificity in healthy (95–100%), COCP (100%), and CKD (96.6–100%) with 100% sensitivity for A‑CS.
- 4‑PM cortisol discriminated Cushing disease remission vs persistence with 98.1% accuracy, outperforming morning ACTH.
Methodological Strengths
- Prospective, protocolized sampling with multiple clinically relevant subgroups (COCP, CKD, remission/persistent CD).
- Use of prespecified cut-offs and comparison of morning vs late‑afternoon measures with clear performance metrics.
Limitations
- Single-center design with modest subgroup sizes; external validation is needed.
- Potential assay and laboratory variability may affect generalizability of exact cut-offs.
Future Directions: Multicenter validation of 4‑PM cortisol/ACTH thresholds and cost-effectiveness analyses; integration into diagnostic algorithms and postoperative surveillance protocols.
CONTEXT: Overnight dexamethasone suppression test (ODST) is precise and highly sensitive; however, its specificity ranges from 80-90%. OBJECTIVE: To assess whether late-afternoon ODS cortisol and morning/late-afternoon ODS ACTH measurements improve ODST accuracy. METHODS: Prospective, single-centre study included healthy adults (n=60), combined oral contraceptive pill users (COCP, n=29), chronic kidney disease (CKD, n=29), treatment-naïve ACTH-dependent Cushing syndrome (A-CS, n=33), post-treatment Cushing Disease in remission (CD-R, n=23) or persistence (CD-P, n=31). Participants underwent the standard 1-mg dexamethasone suppression test; blood samples were collected at 8-9 AM for cortisol, ACTH, dexamethasone; and at 3-4 PM for cortisol and ACTH. RESULTS: ODS 4-PM cortisol was significantly lower than 8-AM in healthy adults (p=0.003), COCP (p<0.001), CKD (p<0.001), and CD-R (p=0.001), while this difference was not significant in treatment-naïve A-CS and CD-P. ODS 8-AM and 4-PM cortisol (cut-off: 1.8 μg/dL) showed high specificity in healthy adults (95% and 100%), but its specificity was low in COCP (55% and 79%) and CKD (17% and 52%). ODS 8-AM and 4-PM ACTH (cut-off: 10 pg/mL) showed high specificity in healthy adults (95%, 100%), COCP (100%, 100%), and CKD (96.6%, 100%), with 100% sensitivity for diagnosing A-CS. The diagnostic accuracy of ODS 4-PM cortisol, ODS 8-AM ACTH and ODS 4-PM ACTH in differentiating CD-R from CD-P was 98.1%, 81.5% and 81.5%, respectively. CONCLUSION: Late-afternoon cortisol measurement is a novel modification which enhances ODST specificity. ACTH measurement was particularly useful in COCP and CKD. Before widespread integration in clinical practice, further validation is required.
2. Diagnostic performance of 24-hour urinary aldosterone for primary aldosteronism in patients with or without discontinuation of antihypertensive medications.
In 842 derivation patients plus 157 external validations, 24‑h urinary aldosterone discriminated PA from essential hypertension with similar AUCs whether antihypertensives were stopped or continued. Optimal cut-offs were 9.57 μg off medications and 8.41 μg on medications, supporting feasible diagnosis without washout if thresholds are adjusted.
Impact: Addresses a major practical barrier in PA diagnosis—medication washout—by demonstrating robust performance of 24‑h Uald under real-world conditions and providing adjusted cut-offs.
Clinical Implications: Clinicians can consider 24‑h Uald for PA screening/confirmation without drug washout, using lower thresholds when patients remain on antihypertensives; unilateral PA tends to show higher Uald.
Key Findings
- AUCs for diagnosing PA were similar off vs on medications (0.879 vs 0.851).
- Optimal 24‑h Uald cut-offs: 9.57 μg (off meds; sensitivity 79.4%, specificity 88.6%) and 8.41 μg (on meds; sensitivity 75.8%, specificity 79.4%).
- External validation accuracy reached 89.2%; combination antihypertensive therapy lowered Uald, requiring adjusted thresholds.
- Unilateral PA exhibited higher 24‑h Uald levels than bilateral PA.
Methodological Strengths
- Large derivation cohort with an external validation set.
- Stratified analyses by antihypertensive regimens and PA lateralization.
Limitations
- Retrospective design with heterogeneous medication exposures and non-standardized dietary sodium.
- Single-country setting may limit generalizability of exact thresholds.
Future Directions: Prospective, multiethnic validation of on‑medication cut-offs and integration with ARR/imaging to streamline PA pathways.
Primary aldosteronism (PA) is the most common form of secondary hypertension. However, its diagnosis is complicated by the need to withdraw interfering antihypertensive medications. Traditionally, 24-h urinary aldosterone (Uald) level measurement is employed as part of the oral sodium loading test to diagnose PA. However, the diagnostic efficacy of 24-h Uald for PA under a usual diet and without drug washout remains unclear. This retrospective study enrolled 583 patients with essential hypertension (EH) and 259 patients with PA, as well as an external validation cohort comprising 157 hypertensive patients. Patients with unilateral PA presented higher 24-h Uald levels than those with bilateral PA. Combination antihypertensive therapy reduced 24-h Uald levels in both EH and PA groups. Receiver operating characteristic curve analysis revealed similar areas under the curve for 24-h Uald diagnosing PA between the off-medication group (0.879, 95% CI = 0.834-0.925) and the on-medication group (0.851, 95% CI = 0.817-0.886). The optimal 24-h Uald cut-offs for PA diagnosis were 9.57 μg (sensitivity 79.4%, specificity 88.6%) in the off-medication group and 8.41 μg (sensitivity 75.8%, specificity 79.4%) in the on-medication group, with closely matched thresholds observed between patients receiving renin-increasing medications (8.52 μg) and those on combined renin-increasing and renin-suppressing therapy (8.39 μg). The diagnostic accuracy of 24-h Uald reached 89.2% in the external validation cohort. Our research indicates that the 24-h Uald test is clinically feasible for diagnosing PA without additional sodium supplementation or drug washout. However, the diagnostic threshold for 24-h Uald should be adjusted downward in patients on medications.
3. Psychiatric and Sleep disorders in Patients with Non-Functional Adrenal Tumors.
In a nationwide register-based cohort of 17,561 NFAT patients with 5.4 years median follow-up, both prior prevalence and incident risk of psychiatric and/or sleep disorders were nearly doubled compared with controls, consistent across secondary outcomes and sensitivity analyses.
Impact: Challenges the notion of ‘non-functional’ adrenal incidentalomas by documenting substantial neuropsychiatric and sleep morbidity, prompting reconsideration of evaluation and follow-up strategies.
Clinical Implications: NFAT patients may warrant proactive screening and management for psychiatric and sleep disorders, and reassessment for mild autonomous cortisol secretion in those with new-onset symptoms.
Key Findings
- Adjusted odds of prior psychiatric/sleep disorders were approximately doubled in NFAT vs controls (adjusted OR 2.06, 95% CI 1.98–2.14).
- Incident psychiatric/sleep disorders were higher in NFAT during follow-up (adjusted HR 1.92, 95% CI 1.82–2.01; median follow-up 5.4 years).
- Elevations were consistent across secondary outcomes (e.g., mood, anxiety/stress-related, psychotic, substance use disorders) and multiple sensitivity analyses.
Methodological Strengths
- Very large, nationwide cohort with extensive adjustment for demographics and socioeconomic factors.
- Multiple sensitivity analyses and consistent findings across secondary outcomes.
Limitations
- Retrospective registry data may be subject to residual confounding and diagnostic misclassification.
- Lack of biochemical cortisol profiling limits mechanistic inference regarding mild cortisol excess.
Future Directions: Prospective studies integrating biochemical cortisol assessment and interventional trials to test whether addressing MACS reduces neuropsychiatric burden.
CONTEXT: An increase of psychiatric and sleep-related disorders could be hypothesized due to mild abnormal cortisol secretion in patients with non-functional adrenal tumors (NFATs). OBJECTIVE: To investigate the risk of psychiatric and sleep disorders in individuals with NFATs. METHODS: A national retrospective register-based study was conducted on patients diagnosed with NFATs 2005-2019 and controls, followed-up until death or 2019. Individuals diagnosed with adrenal hormone excess or previous malignancies were excluded. Follow-up commenced after 90 days of cancer-free survival following the NFAT diagnosis. Sensitivity analyses were performed on patients with acute appendicitis and gallbladder/biliary tract/pancreas disorders, and 180- and 365-day cancer-free survival. The primary study outcomes were the prevalence and incidence of psychiatric and/or sleep disorders after adjusting for sex, age, and socioeconomic factors. Secondary outcomes were psychiatric, sleep, substance abuse, mood, anxiety and stress-related, and psychotic disorders. RESULTS: In total, 17,561 cases (60% women, median (IQR) age 65 (56-73) years) and 122,561 controls were included. Previous psychiatric and/or sleep disorders were more prevalent in patients diagnosed with NFATs compared to controls (odds ratio (OR) 2.11, 95%CI 2.03-2.19, adjusted OR 2.06, 95%CI 1.98-2.14). During the follow-up period (5.4 years (IQR 2.4-8.6)), the incidence of psychiatric and/or sleep disorders was higher in patients with NFATs than in controls (hazard ratio (HR) 1.92, 95%CI 1.83-2.02, adjusted HR 1.92, 95%CI 1.82-2.01). Similar increases were found in all secondary outcomes as well as in the same direction in all sensitivity analyses. CONCLUSION: NFAT was associated with an increased risk of psychiatric and sleep disorders.