Daily Endocrinology Research Analysis
Analyzed 43 papers and selected 3 impactful papers.
Summary
Three endocrine-focused studies stand out today: a large multi-omics analysis refines pathophysiology and cardiometabolic risk in mild autonomous cortisol secretion, a systematic review/meta-analysis defines real-world outcomes of stereotactic radiosurgery for persistent/recurrent Cushing’s disease, and a randomized crossover trial links circadian-aligned, dairy-enriched diets to improved glycaemic control and clock gene expression in type 2 diabetes.
Research Themes
- Adrenal autonomous cortisol secretion and cardiometabolic risk
- Therapeutic outcomes of radiosurgery in Cushing’s disease
- Chrononutrition and macronutrient timing in type 2 diabetes
Selected Articles
1. Endocrine and metabolic determinants of cardiometabolic risk in mild autonomous cortisol secretion.
In a cross-sectional, multi-omics analysis of 1305 patients with adrenal incidentalomas, glucocorticoid metabolites increased from NFAT to MACS to adrenal Cushing’s, while classic androgen metabolites decreased and 11-oxygenated androgens remained unchanged. Glucocorticoid metabolites and 11β-hydroxyandrosterone correlated with hypertension and type 2 diabetes, and serum metabolomics showed a shift toward lipotoxic signatures. Increased adrenal CYP11B1 activity is implicated and proposed as a therapeutic target.
Impact: This large, prospectively recruited cohort uses comprehensive steroidomics and metabolomics to connect MACS biochemistry with cardiometabolic risk and nominates CYP11B1 as a target, refining risk stratification beyond traditional hormonal tests.
Clinical Implications: Clinicians should recognize MACS as a metabolic continuum with elevated cardiometabolic risk; urinary steroid profiling may aid risk stratification. Pharmacologic modulation of CYP11B1 warrants investigation to mitigate metabolic complications.
Key Findings
- Glucocorticoid metabolite excretion increases from NFAT to MACS to adrenal Cushing’s; classic androgen metabolites decrease, while 11-oxygenated androgens remain unchanged.
- Glucocorticoid metabolites and 11β-hydroxyandrosterone correlate with higher risk of hypertension and type 2 diabetes.
- Untargeted serum metabolomics shows progression toward a lipotoxic phenotype across NFAT→MACS→Cushing’s.
- Findings implicate increased adrenal CYP11B1 activity and support it as a potential therapeutic target in MACS.
Methodological Strengths
- Large prospectively recruited cohort with comprehensive 24-h urinary steroid metabolomics by tandem mass spectrometry.
- Integration of untargeted serum metabolomics and machine learning to link biochemical profiles with cardiometabolic risk.
Limitations
- Cross-sectional design limits causal inference and cannot establish temporal relationships.
- Serum metabolomics performed in a subset; residual confounding and selection bias possible across recruiting centers.
Future Directions: Prospective longitudinal studies to validate steroidomic risk markers, interventional trials testing CYP11B1 modulation, and external validation across diverse populations with standardized thresholds.
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.
2. Radiosurgery in recurrent and persistent Cushing's Disease: a Systematic Review and Meta-Analysis.
Across 9 studies (n=341), stereotactic radiosurgery achieved 97.4% tumor control and 67.1% biochemical remission at a mean 26.4 months, with 21% recurrence by ~39 months. New hypopituitarism occurred in 29.9%, while visual or other cranial nerve deficits were rare (~2%); no radionecrosis was reported.
Impact: Provides synthesized, quantitative outcomes for salvage therapy in Cushing’s disease, informing patient counseling on remission likelihood, time-to-response, and adverse effects.
Clinical Implications: SRS is a viable option for persistent/recurrent Cushing’s disease with high tumor control and moderate remission rates; clinicians should counsel regarding delayed biochemical remission and a substantial risk of hypopituitarism.
Key Findings
- Tumor control rate after SRS was 97.4% with 67.1% biochemical remission at a mean 26.4 months.
- Recurrence after remission occurred in 21% at a mean of 39 months.
- New-onset hypopituitarism occurred in 29.9%; visual and other cranial nerve deficits were ~2%; no radionecrosis reported.
Methodological Strengths
- PRISMA-guided systematic review and meta-analysis with multi-database search.
- Long mean follow-up (61.5 months) enabling assessment of remission durability and late toxicities.
Limitations
- Included studies were non-randomized with potential selection and reporting biases.
- Heterogeneity in SRS protocols, definitions of biochemical remission, and prior treatments limits comparability.
Future Directions: Prospective, standardized studies comparing SRS modalities and doses, head-to-head comparisons with fractionated radiotherapy or medical therapy, and predictive biomarkers for response and hypopituitarism.
Cushing's disease (CD) is a severe systemic metabolic disorder caused by elevated levels of cortisol sustained by a pituitary neuroendocrine tumor. Endoscopic trans-sphenoidal surgery (ETS) is the first-line treatment, but does not achieve disease remission in all patients. For patients with persistent or recurrent Cushing's disease, stereotactic radiosurgery (SRS) has been reported as an effective treatment option. This review and meta-analysis assesses the available evidence to systematically highlight the current strengths and limitations of SRS in the treatment of CD. In May 2025, following the PRISMA 2020 statement, a systematic review of Pubmed, Scopus, and Ovid was performed. Of 687 articles screened, 9 were considered eligible, describing a population of 341 patients. Most patients (90%) underwent a single dose of Gamma Knife SRS. The tumor control rate was 97.4% (95% CI: 95.2-99.6%). After a mean follow-up of 61.5 months after the latest SRS cycle, biochemical remission was achieved in 67.1% (95% CI: 58.5-75.7%) of cases in a mean time of 26.4 months. Recurrence post-SRS remission was documented in 21% of cases after a mean time of 39 months. New-onset hypopituitarism was observed in 29.9% of cases, visual impairment and other cranial nerve dysfunction in 1.8% (95% CI: 0.2-3.4%), and 1.9% (95% CI: 0.1-3.7%), respectively. No cases of radionecrosis were seen. After a single cycle of treatment, SRS effectively controls the disease in about half of patients affected by persistent or recurrent CD, with a low percentage of post-treatment complications. Based on the available literature, SRS emerges as a safe and effective treatment, and its implementation in common clinical practice may play a relevant role in the management of CD. Nevertheless, prospective and standardized studies are needed to thoroughly assess its real potential.
3. Glycaemic, appetite and circadian benefits of a dairy-enriched diet with high-protein breakfast and early daytime-restricted carbohydrate intake in type 2 diabetes: a randomised crossover trial.
In a randomized crossover trial (n=25 randomized; 19 completed), a dairy-enriched, time-structured diet upregulated BMAL1, REV-ERBα, CRY1, and PER1 expression. Fasting glucose decreased by ~1.7 mmol/L, glucose management indicator by 0.7%, time in range increased by 9%, and hunger/sweet cravings fell by 15–20% versus the non-dairy phase.
Impact: Connects dietary protein source and meal timing with circadian gene regulation and clinically meaningful glycaemic improvements in type 2 diabetes using a randomized crossover design.
Clinical Implications: Dietary prescriptions that prioritize high-protein dairy at breakfast and restrict carbohydrates to early daytime may complement standard T2D care by improving glycaemia and appetite; translation requires longer, pragmatic trials.
Key Findings
- Dairy-enriched, time-structured diet upregulated BMAL1 (+1.8x), REV-ERBα (+2.2x), CRY1 (+1.4x), with higher PER1 expression at 4 weeks.
- Improved glycaemic control: fasting glucose ~−1.7 mmol/L, GMI −0.7%, and TIR +9% versus baseline.
- Reduced appetite metrics: hunger and sweet craving decreased by 15–20%.
Methodological Strengths
- Randomized crossover design reduces inter-individual variability.
- Use of CGM-based outcomes and targeted assessment of clock gene expression adds mechanistic depth.
Limitations
- Small sample size with attrition (19 completed) and short intervention duration.
- Dietary interventions were not blinded; generalizability beyond study setting is uncertain.
Future Directions: Larger, longer-term, and pragmatic RCTs to confirm glycaemic and circadian benefits, head-to-head comparisons of dairy vs non-dairy protein sources, and evaluation of cardiometabolic outcomes.
AIMS/HYPOTHESIS: The circadian timing of food intake and the composition of dietary protein sources may jointly influence metabolic regulation. Our aim was to examine the effects of a dairy-enriched vs non-dairy isoenergetic diet with structured meal timing on circadian clock gene expression, glycaemic management and appetite regulation in individuals with type 2 diabetes. METHODS: In a randomised, crossover trial, 25 participants with type 2 diabetes and HbA RESULTS: Twenty-nine individuals were screened; 25 met eligibility criteria and were randomised to YesMilk or NoMilk dietary interventions in a crossover design. Thirteen participants began with the YesMilk dairy diet, all of whom completed both phases. Of the 12 who began with the NoMilk diet, six completed the study. Nineteen participants completed both intervention phases. Compared with the NoMilk phase, the YesMilk diet upregulated BMAL1 (+1.8-fold, p=0.0003), REV-ERBα (also known as NRD1D1) (+2.2-fold, p<0.001) and CRY1 (+1.4-fold, p=0.03), with higher PER1 expression (p=0.01 between diets at 4 weeks). Glycaemic variables improved under the YesMilk diet, with fasting glucose reduced by ~1.7 mmol/l, glucose management indicator reduced by 0.7%, and time in range increased by 9% compared with baseline (all p<0.05). Hunger and sweet craving scores decreased by 15-20% (p<0.05). CONCLUSIONS/INTERPRETATION: A dairy-enriched diet aligned with structured meal timing enhanced circadian clock gene expression and improved glycaemic and appetite-related variables in individuals with type 2 diabetes. These findings support a mechanistic link between dietary protein source, circadian regulation and metabolic health, warranting confirmation in larger, long-term studies. TRIAL REGISTRATION: ClincalTrials.gov NCT03772067 FUNDING: The Israeli Ministry of Health provided funding.