BACKGROUND:Rare bone diseases comprise a heterogeneous group of complex and disabling conditions. Evidence on age-specific hospitalization patterns and in-hospital outcomes across multiple rare bone diseases is limited. METHODS:Population-based cohort study using national hospitalization data (01/2012-12/2021). Among 11,092,151 hospitalizations, 2,875 admissions of children and adults with rare bone diseases were identified via ICD-10 codes (X-linked hypophosphatemia, osteogenesis imperfecta, fibrous dysplasia, achondroplasia, pseudohypoparathyroidism, fibrodysplasia ossificans progressiva) and compared with 14,375 age-, sex-, and patient-complexity-matched hospitalizations from the general population. RESULTS:Hospitalization patterns differed substantially by disease and age. Patients with X-linked hypophosphatemia had an increased risk of emergency admissions in late adulthood, whereas planned admissions were more frequent in early adulthood among patients with achondroplasia and fibrous dysplasia. Malignancies were diagnosed in 22.7% of patients with X-linked hypophosphatemia, and fractures were the leading cause of hospitalization among patients with osteogenesis imperfecta. Across the rare bone diseases, patients had higher all-cause in-hospital mortality compared with matched controls (RR, 2.26; 95% CI, 1.77 to 2.89), longer hospital stays (median difference, 6 days [IQR 3-13 days]), higher risk of ICU admission (RR, 3.08; 95% CI, 2.78 to 3.40), and higher readmission risk (RR, 1.31, 95% CI, 1.15 to 1.49). CONCLUSIONS:The studied rare bone diseases are associated with distinct, disease-specific hospitalization patterns and substantially worse in-hospital outcomes across the lifespan. This underscores the need for tailored preventive strategies and coordinated, long-term care models for patients with rare bone diseases.
BACKGROUND:The finding of autoantibodies against the angiotensin II type-1 receptor (AT1R) in human primary aldosteronism (PA) suggests a loss of immunological tolerance; however, whether autoreactive AT1R-specific T cells exist and if and how aldosterone or cortisol modulate their activity is unknown. METHODS:Peripheral blood mononuclear cells from patients with confirmed PA and healthy donors were stimulated with overlapping AT1R peptides to identify autoreactive T cells. The chronic and rapid aldosterone effects on CD4+ and CD8+ T cells and the receptors involved were evaluated using mineralocorticoid receptor (MR) and G-protein estrogen receptor (GPER) antagonists. Cortisol effects and 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) expression were also examined. Functional cytotoxicity of AT1R-specific CD8+ clones toward human endothelial cells was assessed. RESULTS:Compared to healthy donors, PA patients exhibited a marked expansion of AT1R-specific CD8+ T cells recognizing the AFHYESQ epitope of the second extracellular AT1R loop, which was not detected in CD4+ cells. Both T-cell subsets expressed MR and GPER but lacked 11βHSD2 expression. Chronic aldosterone exposure enhanced CD8+ proliferation and IFN-γ production through MR. Rapid aldosterone stimulation activated CD8+ cells via MR and GPER. In CD8+ cells cortisol also increased IFN-γ-production through MR. AT1R-specific CD8+ T-cell clones induced apoptosis of human endothelial cells expressing AT1R. CONCLUSIONS:PA patients harbor autoreactive AT1R-specific CD8+ T cells that respond to aldosterone and cortisol through MR and GPER. These findings identify an adaptive autoimmune mechanism in PA and provide insight into how steroid-driven T-cell activation may contribute to hypertension-mediated organ damage in aldosteronism and hypercortisolism.
OBJECTIVE:Data on hypothalamic-pituitary-adrenal axis (HPAA) recovery after adrenalectomy are limited by small samples, heterogeneous criteria, and no distinction between mild autonomous cortisol secretion (MACS) and adrenal Cushing syndrome (CS). We investigated HPAA recovery duration and associated factors separately in MACS and adrenal CS. DESIGN:Retrospective, multicenter cohort. METHODS:We analyzed 139 adults with MACS and 280 with adrenal CS who underwent unilateral adrenalectomy and required postoperative glucocorticoid replacement. HPAA recovery was defined as glucocorticoid discontinuation. Associated factors were evaluated using Cox proportional hazards models and restricted mean survival time (RMST) regression. RESULTS:The Kaplan-Meier-estimated median (95% confidence interval [CI]) time to recovery was 8.2 (6.5-9.7) months in MACS and 14.8 (13.2-16.3) months in adrenal CS. In MACS, older age (hazard ratio [HR]=0.72 per 10 years; +94 days for >61 years, τ=540 days) and cortisol after 1-mg overnight dexamethasone suppression test (post-ODST cortisol) >10.0 µg/dL (+113 days) were associated with delayed recovery, whereas higher dehydroepiandrosterone-sulphate (DHEA-S) ratio (HR=1.50 per log-unit; -91 days for >0.61) and adrenocorticotropic hormone (ACTH) (HR=1.61 per log-unit) were associated with faster recovery. In adrenal CS, older age (HR=0.74 per 10 years; +198 days for >36 years, τ=1,095 days), higher glycated hemoglobin (HbA1c) (HR=0.81 per 1%), and post-ODST cortisol >7.9 µg/dL (+364 days) were associated with delayed recovery, whereas higher ACTH (HR=1.27 per log-unit; -130 days for >5.1 pg/mL) was associated with faster recovery. CONCLUSION:Older age was consistently associated with delayed recovery, while biochemical markers contributed differentially by disease subtype.
Long-acting growth hormone (LAGH) preparations have moved from development to routine clinical use over the past decade. Several products are now approved for paediatric growth hormone deficiency (GHD), selected non-GHD short-stature indications, and, in some regions, for adult GHD. The Growth Hormone Research Society convened an international workshop in October 2025 to reappraise the evidence base and refine clinical recommendations. Currently, data are available for up to 7 years of LAGH treatment in over 8,000 individuals. This remains substantially shorter and smaller than for daily GH. Across preparations, short- to mid-term efficacy appears comparable to daily somatropin, provided dosing is individualised and monitored appropriately. Approvals and pivotal trials include both, treatment initiation and switching from daily GH, depending on product and regional label. No new major safety signals have been identified in trials and real-world reports, although data on BMI trajectories require further evaluation. Injection-site reactions remain the most frequent adverse event and vary by formulation. Anti-drug-antibodies have been observed, yet evidence suggests they have limited clinical impact. Effects on glucose metabolism resemble those of daily therapy, but metabolically high-risk groups are under-represented in studies. Among cancer survivors, data on tumour recurrence and second neoplasms with LAGH are not yet available. Recommendations and practice points emphasised careful patient selection and counselling, product-specific dosing, and insulin-like growth factor-I (IGF-I) monitoring. Urgent knowledge gaps include transition care, long-term efficacy, adherence and safety in cancer survivors. Well-resourced registries are essential for addressing these gaps and supporting safe, effective, and patient-centred use of LAGH.
OBJECTIVE:Graves' disease (GD) is the predominant cause of hyperthyroidism and a multifactorial autoimmune disorder in which genetic susceptibility interacts with environmental exposures. Although gut microbiota alterations have been reported in GD, the association between antibiotic exposure and GD risk remains unclear. DESIGN:This population-based retrospective cohort study used the Korean National Health Insurance Service database and included 311,911 adults aged ≥40 years who underwent health screening in 2005-2006. METHODS:Cumulative antibiotic prescriptions during the five years before the index date were categorized as none, 1-14, 15-60, and ≥61 days. The number of distinct antibiotic classes prescribed (0, 1, 2, 3, and ≥4) was also evaluated. Cox proportional hazards regression estimated adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) after adjustment for various covariates. RESULTS:Longer cumulative antibiotic exposure was associated with higher GD risk (P for trend <0.0001). Compared with non-users, aHRs (95% CIs) for 1-14, 15-60, and ≥61 days of antibiotic exposure were 1.23 (1.03-1.47), 1.43 (1.20-1.70), and 1.43 (1.18-1.73), respectively. Exposure to ≥4 antibiotic classes was also associated with higher GD risk (aHR, 1.50; 95% CI, 1.25-1.80; P for trend <0.0001). The incidence rate increased from 4.6 per 10,000 person-years among non-users to 6.3, 8.1, and 8.2 per 10,000 person-years for 1-14, 15-60, and ≥61 days, respectively. CONCLUSION:Prolonged antibiotic exposure and exposure to a greater number of antibiotic classes were associated with a modest relative increase in subsequent GD risk, although absolute differences were small. These observational findings do not establish causality and warrant confirmation.
OBJECTIVE:This analysis describes the evolution of 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, multi-country 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 characterised 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 < 0.001; 44.7% with ≥10-point improvement), and Tübingen CD-25 decreased by -7.8 points (p = 0.01). Early responses (by week 12) involved eating behaviour and depression symptoms. Delayed improvements (consolidating at week 24-36) were observed in sexual activity, environment, and social domains. Bodily restrictions (-4.3 points, p = 0.203) and cognition (-6.8 points, p = 0.143) did not show improvement over the study period. Item-level analysis identified a cluster of symptoms, predominantly psychological health anxiety, physical appearance concerns, where burden remained elevated throughout the 36 weeks despite cortisol normalisation. 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.
OBJECTIVE:Androgen excess in 21-hydroxylase deficiency (21OHD) remains difficult to manage in adolescent females. Combined oral contraceptive(s) (OC) containing ethinylestradiol and progestin modulate ovarian and adrenal steroidogenesis, but their specific impact on 21OHD has not been systematically evaluated. We therefore examined how combined OCs influence the steroid metabolome in young women with classic 21OHD. DESIGN:Prospective observational study. METHODS:Young women aged 11-24 years with classic 21OHD who planned to initiate combined OC were enrolled. The study comprised 3 visits and included blood sampling and 24-hour urine collection: Visit 1 before OC initiation, Visit 2 during the third OC cycle, and Visit 3 during the sixth OC cycle. Plasma steroids were quantified by liquid chromatography-mass spectrometry and urinary metabolites by gas chromatography-mass spectrometry. Differences in steroid and metabolite levels across visits were assessed using the Friedman test. RESULTS:Of the 20 participants recruited, 17 (median age 16.8 years, range 11-24) completed the study. Compared with baseline, plasma concentrations of 17α-hydroxyprogesterone, androstenedione, dehydroepiandrosterone, and testosterone decreased significantly (all P < .005), while cortisol increased (P < .001). Urinary 24-hour excretion of androgen metabolites, including 11-oxo-etiocholanolone, declined. Between visits 1 and 3, 8 participants (47%) reduced their hydrocortisone dose in response to biochemical changes. CONCLUSIONS:Combined OCs were observed to modify steroid metabolism and lower androgen levels in women with classic 21OHD. OC therapy may serve as a useful adjunct in the management of androgen excess in this population, particularly when conventional glucocorticoid therapy alone does not achieve satisfactory biochemical control.
OBJECTIVE:To evaluate liver morphology and clinical determinants in acromegaly. DESIGN:Retrospective single-center cohort study. METHODS:We analyzed 394 acromegaly patients followed at a single tertiary center over four decades for hepatic morphology and metabolic dysfunction-associated steatotic liver disease (MASLD). Patients were compared by hepatic cyst and MASLD status; multivariable logistic regression identified independent predictors, using outcome-specific primary hormonal exposures-the peri-imaging IGF1×ULN for MASLD and time-weighted-average IGF1×ULN (TWAvg) for hepatic cysts. Standardized prevalence ratios (SPR) against age- and sex-stratified references were also examined. RESULTS:Of 282 imaged patients, MASLD, hepatic cyst, hemangioma, and cholelithiasis prevalence was 31.0%, 15.6%, 4.3%, and 36.8%. Cyst prevalence matched population estimates, whereas imaging-detected MASLD was significantly lower than expected (SPR 0.56-0.78). Hepatic cyst was independently associated with renal cyst (OR 2.769) and inversely with MASLD (0.231), with older age borderline significant. MASLD was inversely associated with the peri-imaging IGF1×ULN (OR 0.74 per doubling), hepatic cyst (0.109), and longitudinal exposure (log2 TWAvg IGF1×ULN 0.61), and positively with cholelithiasis (3.158). CONCLUSIONS:Hepatic cyst prevalence matched population estimates, whereas imaging-detected MASLD was significantly lower. Cysts associated with older age, renal cysts, and absence of MASLD; MASLD associated inversely with the peri-imaging and longitudinal IGF1 exposure and positively with cholelithiasis. The inverse cyst-MASLD relationship is hypothesis-generating: MASLD tracked GH/IGF1 activity whereas cysts did not, suggesting distinct hepatic phenotypes of a shared, as-yet-unmeasured determinant rather than opposite readouts of one hormonal signal.
BACKGROUND:Type 2 diabetes mellitus (T2DM) is often the first condition on the pathway to patients developing multiple long-term conditions (MLTC). The impact of sodium-glucose cotransporter 2 inhibitors (SGLT-2i), a key T2DM treatment, on hospitalisation and MLTC progression remains uncertain. METHODS:In this comparative effectiveness study, we emulated a target trial using linked primary care, hospital, and mortality records in England (2012-2023). Adults aged ≥40 years with T2DM initiating SGLT-2i or dipeptidyl peptidase-4 inhibitors (DPP-4i) were included (n=364,522). Outcomes included all-cause mortality, first hospitalisation, number of hospitalisations, and incidence of 59 prespecified long-term conditions across 17 organ systems. Weighted Cox proportional hazards and negative binomial regression models were used to estimate adjusted hazard ratios (aHRs) or adjusted mean differences (aMDs), with 95% CIs and Benjamini-Yekutieli correction for multiple testing. FINDINGS:Compared with DPP-4i, SGLT-2i use was associated with lower risks of all-cause mortality (aHR 0.73, 95% CI 0.71-0.75), first hospitalisation (aHR 0.86, 95% CI 0.85-0.87), and number of hospitalisations (aMD -0.36, 95% CI -0.38 to -0.34; all p<0.001). SGLT-2i initiators had reduced risks for 28 conditions, including dementia, cancer, metabolic dysfunction-associated steatotic liver disease, diabetic foot ulcer, epilepsy, and rheumatoid arthritis. Increased risks were observed for four conditions, including candidiasis and diabetic ketoacidosis. INTERPRETATION:SGLT-2i use in T2DM was associated with significant reductions in mortality, hospitalisation, and MLTC burden. The broad protective effects across multiple organ systems highlight the potential of SGLT-2i to offer a holistic therapeutic strategy in the management of diabetes and its multisystem complications.
PURPOSE:The aims of this study were to evaluate sickness compensation before and after transsphenoidal surgery (TSS) for pituitary adenoma compared to the general population and to identify factors associated with return to work (RTW) after TSS. METHODS:This study included working-age patients who had undergone TSS for a pituitary adenoma at Sahlgrenska University Hospital and matched controls (1:5) from the general population in Sweden. Data for sickness compensation from 1 year before TSS (index) to up to 2 years after was obtained from national registers. Demographic factors, cognition, and fatigue were evaluated based on impact on number of days to RTW or by comparing the groups of patients with and without RTW 1-year post-surgery. RESULTS:Sixty-six patients and 329 matched controls were included. The proportion of patients with sickness compensation was approximately twice that of controls 1 year prior to TSS. The proportion of patients with sickness compensation continued to increase until TSS and decreased thereafter but did not return to the level observed 1 year prior to TSS. Prior sickness compensation and Cushing's disease, albeit this subgroup was small, were predictive of more days to RTW after TSS. Patients without RTW 1-year post-surgery reported more fatigue and more often had adrenal insufficiency compared to the group of patients with RTW. CONCLUSIONS:Sickness compensation for patients with pituitary adenoma is mainly limited to the surgical period and the months thereafter. Sustained higher levels 1-year post-surgery suggest that work disability remains a long-term issue for a subgroup of patients.
CONTEXT:Combined oral contraceptives (OCPs) and metformin are commonly used in patients with polycystic ovary syndrome (PCOS), who are at elevated risk of dyslipidemia and cardiovascular disease (CVD), but their effects on advanced lipid phenotyping remain unclear. OBJECTIVE:To examine the impact of OCPs and metformin on (1) lipoproteins, (2) apolipoproteins, and (3) cholesterol efflux capacity (CEC, marker of HDL function). DESIGN:Secondary analysis of the COMET-PCOS randomized clinical trial. SETTING:Two tertiary care reproductive endocrinology clinics. PATIENTS OR OTHER PARTICIPANTS:Patients with hyperandrogenic PCOS and elevated BMI with paired serum samples for lipoprotein/apolipoprotein analysis (n = 180) and cholesterol efflux capacity (n = 129). INTERVENTION(S):24 weeks of metformin, OCP, or OCP + metformin. MAIN OUTCOME MEASURE(S):Change in HDL particles (HDL-P), low-density lipoprotein particles (LDL-P), triglyceride-rich lipoprotein particles (TRL-P); apolipoproteins A-I, B, and C-III; and CEC. RESULTS:HDL-P concentration increased in the OCP and OCP + metformin arms, while atherogenic small LDL-P increased slightly. Metformin had a largely neutral effect on advanced lipid phenotyping. Cholesterol efflux capacity increased in the OCP arm, though this was attenuated when adjusting for change in ApoA-I (adjusted ratio of geometric means 1.08, 95% CI 0.99-1.17), which increased in all arms. CONCLUSIONS:In patients with PCOS and high metabolic risk, OCP use resulted in improved HDL-C function and a mixed effect on lipoproteins and apolipoproteins, with no clear benefit from metformin. These findings do not support or refute the cardiovascular risk-benefit of OCP use in PCOS and highlight the need for studies evaluating long-term clinical outcomes.
Postoperative hypocalcemia after parathyroidectomy may be challenging to manage. We report a 50-year-old man with severe primary hyperparathyroidism, very high parathyroid hormone levels, markedly elevated alkaline phosphatase and extensive skeletal disease, including a brown tumor with pathological fracture. Following parathyroidectomy, he developed persistent postoperative hypocalcemia with biochemical features suggestive of both transient postoperative hypoparathyroidism and hungry bone physiology. Despite high-dose calcium, calcitriol, and electrolyte replacement, hypocalcemia persisted, requiring intensive care unit admission and prolonged intravenous supplementation. Teriparatide was initiated on postoperative day 11 at a dose of 20 µg twice daily, subsequently reduced to 20 µg once daily. Thereafter, calcium levels progressively normalized, allowing discontinuation of intravenous supplementation and early hospital discharge. A short course was associated with sustained calcium-phosphate stabilization without recurrence of hypocalcemia during follow-up. This case highlights the potential role of short-term teriparatide as rescue therapy in selected patients with persistent postoperative hypocalcemia and hungry bone features.
OBJECTIVE:Acromegaly may impair balance and increase fall risk. We aimed to evaluate postural stability, fall risk, and vestibulo-ocular reflex function in patients with acromegaly and to assess the effects of a balance-oriented exercise program. DESIGN:Single-center, prospective case-control study with an exercise intervention. METHODS:Thirty-two patients with acromegaly (15 active, 17 inactive) and 32 age-, sex-, and body mass index-matched sedentary healthy controls were enrolled. Balance was assessed using computerized dynamic posturography along the anterior-posterior (AP) and medial-lateral (ML) axes. Vestibulo-ocular reflex function was evaluated with the video head impulse test. Clinical assessments included the Berg Balance Scale, International Falls Efficacy Scale, and Dizziness Handicap Inventory-Short Form. Fifteen patients with balance impairment completed an 8-week home-based exercise program, with outcomes reassessed afterward. RESULTS:Patients had lower preference AP, visual ML, vestibular ML, and global AP/ML scores than controls (P < .01). Berg Balance Scale scores were lower, whereas fall risk, fear-of-falling, and dizziness scores were higher in patients (P < .05). Fourier analysis demonstrated increased sway amplitudes with low-frequency dominance under static and dynamic conditions (P < .05). Global AP/ML scores were lower in active than inactive patients (P < .05). Vestibulo-ocular reflex gains were similar between groups (P > .05). Exercise significantly improved balance and clinical scale scores (P < .05). CONCLUSIONS:Balance impairment and increased fall risk may occur in acromegaly, likely due to deficits in central sensory integration. Balance-oriented rehabilitation may improve postural control and reduce fall risk in this population.
Adrenocortical carcinomas (ACC) are aggressive cancers with limited therapeutic options. Cyclin-dependent kinases (CDKs) 1/2/4 and polo-like kinase 1 (PLK1) are upregulated in ACC, suggesting their role as potential targets. This study investigated the anti-tumour efficacy of the pan-CDK inhibitors (CDKi) dinaciclib, AT7519, and SNS-032; the CDK1-cyclin B1 inhibitor cucurbitacin E (curE); the PLK1 inhibitors (PLK1i) poloxin and plogosertib; and selected combination strategies in four genetically heterogeneous ACC cell lines (NCI-H295R, JIL-2266, MUC-1, TVBF-7) and primary cultures. ACC cells showed marked CDK1/2/4 and PLK1 transcript and protein upregulation compared to normal adrenal gland. Dinaciclib reduced cell growth and induced apoptosis at low nanomolar doses. CurE induced weaker pro-apoptotic effects, whereas AT7519 and SNS-032 displayed activity only in JIL-2266 and MUC-1. Among PLK1i, plogosertib impaired proliferation and increased apoptosis in a nanomolar range. Dinaciclib-plogosertib combination produced the highest synergistic anti-proliferative effects in NCI-H295R and TVBF-7. In steroidogenic NCI-H295R cells, dinaciclib lowered cortisol secretion and downregulated CYP11A1, CYP17A1, CYP21A2, SF-1, and GR transcripts, as well as GR protein expression. In parallel, dinaciclib broadly suppressed CDK1/2 axis and their downstream signalling proteins, including cyclin E1, and p21Waf1/Cip1, consistent with G1/S blockade. Plogosertib increased p-CDK1(Tyr15), cyclin B1, and γ-H2AX levels, indicative of DNA damage and mitotic stress. These results identify dinaciclib and plogosertib as the most effective inhibitors across all ACC models tested. Their simultaneous action on multiple checkpoints, alongside with their synergistic effect in selected cell lines, suggest a potential benefit of their use in ACC that needs to be further investigated in vivo.
IMPORTANCE:Adrenal insufficiency (AI) diagnosis is challenging, particularly with indeterminate morning cortisol levels (5-11 µg/dL). This study aimed to develop and validate a sex- and age-adjusted dehydroepiandrosterone sulfate (DHEAS)-index to improve AI diagnosis and reduce the need for ACTH stimulation tests. DESIGN:A 2-phase study was conducted. First, a retrospective training cohort of 3.307 DHEAS and morning cortisol measurements from 1.720 adult patients was analyzed to develop sex- and age-specific DHEAS cutoffs. Subsequently, these cutoffs were used to calculate a DHEAS-Index, which was then validated in a prospective external cohort of 71 patients undergoing ACTH stimulation testing for suspected AI. RESULTS:In the training cohort, DHEAS levels were significantly lower in patients with morning cortisol <5 µg/dL (0.10 [0.10-0.22] µg/mL) compared to those with cortisol >5 µg/dL (P = .000). Linear regression showed higher morning cortisol, male sex, and younger age were independently associated with higher DHEAS, while older age predicted lower levels (all P = .000). Optimal DHEAS cutoffs, determined by ROC analysis, demonstrated high discriminatory capacity (AUC ranging from 75.2% to 90.5%) for AI across all age and sex subgroups, with men aged 18-29 showing the highest AUC (90.5%). In the validation cohort, the DHEAS-Index achieved a sensitivity of 93% and specificity of 79% for classifying AI (cortisol 60' < 18 µg/dL), with a negative predictive value of 98%. The DHEAS-Index also correlated with the delta increase of cortisol during the ACTH test (rho=0.571, P < .001). Among patients with cortisol values 5-11 µg/dL, a DHEAS-Index >1 was associated with a very low probability of AI (5%), whereas a DHEAS-Index <1 increased the likelihood of AI (40%). Finally, a universal DHEAS threshold of <0.2 µg/mL yielded 80% sensitivity and 89% specificity, with a 94% negative predictive value, demonstrating the superior performance of the DHEAS-Index. CONCLUSIONS AND RELEVANCE:Age- and sex-adjusted DHEAS thresholds improve screening for adrenal insufficiency diagnosis, reducing unnecessary ACTH testing and enhancing clinical decision-making, particularly in patients with borderline baseline cortisol.
OBJECTIVE:Body image dissatisfaction is common in women with polyendocrine metabolic ovarian syndrome (PMOS), yet optimal assessment tools remain unclear. This study compared the Body Image Concern Inventory (BICI) and the Multidimensional Body-Self Relations Questionnaire-Appearance Scales (MBSRQ-AS) in women with PMOS, evaluating agreement, reliability, and associations with clinical and demographic characteristics. DESIGN:This was a multicenter cross-sectional observational study. METHODS:A total of 163 women were recruited from specialist clinics and community settings in the United Kingdom between June 2023 and October 2024. Body image was assessed using the BICI and MBSRQ-AS, alongside clinical and sociodemographic variables. Internal consistency, correlations, and multivariable regression analyses were performed to evaluate associations and predictors of clinically significant body image concern. RESULTS:The BICI was significantly associated with body mass index and hirsutism scores. Higher body mass index was associated with worse scores across the MBSRQ-AS subscales. BICI scores correlated negatively with Appearance Evaluation and Body Areas Satisfaction and positively with Overweight Preoccupation and Appearance Orientation (all P < .001). Hierarchical regression analysis showed that MBSRQ-AS scores explained additional variance in the BICI scores beyond clinical features, indicating distinct contributions to body image assessment. CONCLUSION:Both tools capture distinct dimensions of body image in women with PMOS. The selection of assessment tools should be context-driven to optimally address body image concerns in this population.
OBJECTIVE:Osteoporosis is associated with reduced active vitamin D, but the molecular basis remains incompletely understood. This study investigated how active vitamin D preserves skeletal homeostasis and prevents bone loss. DESIGN:Experimental mechanistic study using genetically modified mouse models and bone marrow mesenchymal stem cells (BMSCs). METHODS:Mice with reduced active vitamin D production were examined for bone mass, skeletal aging, and osteogenic capacity. Mouse and human BMSCs were used to assess proliferation, osteogenic differentiation, and molecular signaling. Gene expression, protein turnover, and pathway analyses determined how active vitamin D regulates cell-cycle control in skeletal progenitors. Genetic deletion studies tested the functional contribution of P27 to bone loss. RESULTS:Active vitamin D protected against osteoporosis by activating a vitamin D receptor (VDR)-dependent pathway that increased cyclin-dependent kinase 2 (CDK2) expression and promoted P27 degradation in BMSCs. Loss of this signaling caused P27 accumulation, reduced stem-cell proliferation, impaired osteogenic differentiation, and enhanced skeletal senescence, leading to bone loss. Active vitamin D promoted P27 phosphorylation at threonine 187 and its degradation via the ubiquitin-proteasome pathway. Importantly, P27 deletion partially rescued the osteoporotic phenotype in mice with reduced active vitamin D production. CONCLUSIONS:Active vitamin D maintains bone integrity through a VDR-dependent mechanism that enhances CDK2 expression and promotes P27 degradation in BMSCs. These findings identify a previously unrecognized mechanism linking vitamin D signaling to skeletal aging and suggest that targeting P27 turnover may offer a therapeutic strategy, provided tissue-specific approaches mitigate the oncogenic risks of P27 manipulation.
OBJECTIVE:The CHIRACIC trail supported the beneficial effect of adrenalectomy on hypertension in patients with unilateral adrenal incidentalomas associated with mild autonomous cortisol secretion (MACS). Additional assessments evaluated the impact of adrenalectomy on body weight excess, metabolic abnormalities and quality of life. DESIGN:Multicenter superiority open-label randomized trial comparing adrenalectomy to conservative management. METHODS:Following a run-in phase to control hypertension, receive lifestyle advice and treatment for comorbidities, patients underwent a workup including measurement of BMI, visceral and total fat, fat mass, fasting blood glucose, HbA1c, oral glucose tolerance test, plasma lipids and quality of life (QoL). Following randomization, assessment of comorbidities and adaptation of their treatment were performed every 3 months for 13 months. Workup was repeated at the end of the study. RESULTS:Forty-eight patients were randomly assigned to adrenalectomy (n = 23) and conservative management (n = 25). 93%, 71% and 90% of patients were overweight/obese, prediabetics/diabetics and dyslipidemic, respectively. There was no statistically significant improvement in anthropometric and metabolic parameters after adrenalectomy as compared to conservative management: 21% and 4% of adrenalectomized and conservatively treated obese/overweight patients lost > 5% of body weight, respectively (difference 22%, 95%CI: -2% to 39%). Glycemic status improved in 44% and 33% of adrenalectomized and conservatively treated dysglycemic patients, respectively (difference 10%, 95%CI: -22% to 43%). Dyslipidemia improved in 20% of adrenalectomized and none of conservatively treated dyslipidemic patients. Changes in QoL were not different between groups. CONCLUSION:The beneficial effects of adrenalectomy on excess weight, metabolic disorders and QoL demonstrated in the CHIRACIC trial are more limited than those observed for hypertension. Additional randomized interventional studies involving a larger number of patients are needed to support the use of adrenalectomy in the treatment of these comorbidities.
CONTEXT:Acromegaly is a rare disease typically caused by a growth hormone (GH) secreting pituitary adenoma. Somatostatin receptor ligand (SRL) monotherapy does not provide optimal control of circulating insulin-like growth factor-1 (IGF-1) levels in all patients with acromegaly. ALXN2420, a 16-amino acid peptide GH receptor antagonist (GHRA), is being developed in combination therapy in patients with acromegaly insufficiently controlled with SRLs. OBJECTIVE:To evaluate the safety and tolerability (primary), pharmacokinetics and pharmacodynamics of ALXN2420 in healthy subjects. DESIGN:Phase 1, randomized, double-blind, placebo-controlled single- (SAD) and 2-week multiple ascending dose (MAD) studies. SETTING:Single center. PATIENTS:Overall, 101 eligible and evaluable healthy subjects. INTERVENTION:ALXN2420 or placebo. MAIN OUTCOME MEASUREMENTS:Safety assessments, pharmacokinetic parameters, serum IGF-1 levels. RESULTS:Subcutaneous injections of ALXN2420 up to 120 mg/day were well tolerated, with no safety concerns. Pharmacokinetic parameters increased dose proportionally. The terminal half-life was approximately 22 hours. ALXN2420 induced dose-related decreases in IGF-1 levels at doses ≥20 mg, with a more prolonged reduction at higher doses for up to 72 hours (SAD) and up to the end of treatment (MAD). Repeated daily ALXN2420 administration for 2 weeks suggested a cumulative effect compared to single administration. For ALXN2420 doses ≥40 mg, maximal mean changes from baseline versus placebo in IGF-1 levels ranged from approximately 20% to 30% (SAD) and 40% to 50% (MAD). CONCLUSION:ALXN2420 doses of up to 120 mg/day appeared to be safe and substantially decreased IGF-1 levels in healthy subjects, thereby supporting further testing in patients with acromegaly.
OBJECTIVE:To evaluate and compare the efficacy of anti-osteoporotic-medications (AOM) for the prevention and treatment of glucocorticoid-induced-osteoporosis (GIOP). DESIGN:Systematic review and network-meta-analysis conducted in accordance with PRISMA-NMA guidelines (ProsperoID: CRD42024502298). METHODS:MEDLINE, Embase, and Web of Science were searched from inception to December 2025 to identify randomized-controlled-trials and comparative-observational-studies evaluating AOM in adults receiving oral glucocorticoids (GC). Outcomes included percentage change in areal bone- mineral-density (aBMD) at the lumbar-spine (primary), femoral-neck, and total-hip. A random effects network-meta-analysis was performed, integrating direct and indirect comparisons across AOM. Certainty of evidence was assessed using the CINeMA framework. RESULTS:Thirty-one studies (28 randomized-controlled-trials and 3 observational-studies) involving 5260 participants (age-range: 29.6-70.6 years, 72.5% females) were included. All AOM were superior to placebo or calcium/vitaminD supplementation in increasing lumbar-spine aBMD. Teriparatide demonstrated the greatest efficacy compared with alendronate (effect-size: 3.8; 95% CI: 2.9-4.6), risedronate (4.0; 95% CI: 2.9-5.1), denosumab (1.5; 95% CI: 0.1-2.9), and zoledronate (2.4; 95% CI: 1.1-3.6), while no significant difference was observed with romosozumab (0.3; 95% CI: -2.1 to 1.4). Among antiresorptive-medications, zoledronate and denosumab showed greater efficacy than oral bisphosphonates, which demonstrated modest positive effects. In sensitivity analyses restricted to established GIOP, defined as GC users ≥3months, teriparatide and romosozumab remained superior to antiresorptive-medications. Evidence for total-hip and femoral-neck aBMD outcomes was limited by substantial network inconsistency (mostly missing data). Included studies were underpowered to assess difference in fracture outcomes. CONCLUSIONS:This network-meta-analysis demonstrates a clear gradient of efficacy among AOM in GIOP, with anabolic and potent antiresorptive-medications producing the largest gains in lumbar-spine aBMD supporting current ECTS recommendations advocating risk-stratified treatment selection.
