Limumpornpetch P, Stewart PM, Pujades-Rodriguez M
… +4 more, Baxter PD, Tiganescu A, Nyaga VN, Morgan AW
J Clin Endocrinol Metab
· 2026 May · PMID 41873700
·
Full text
CONTEXT: Chronic oral glucocorticoids (GCs) are widely prescribed for multiple diseases. Although long-term GC exposure causes systemic toxicity, the magnitude, dose-response relationship, and causes of GC-associated mor...CONTEXT: Chronic oral glucocorticoids (GCs) are widely prescribed for multiple diseases. Although long-term GC exposure causes systemic toxicity, the magnitude, dose-response relationship, and causes of GC-associated mortality remain incompletely defined. OBJECTIVE: To quantify overall and cause-specific mortality associated with chronic oral GC exposure and evaluate dose-response relationships across underlying disease groups. METHODS: We conducted a systematic review and meta-analysis following PRISMA guidelines (PROSPERO CRD42017067530). PubMed/MEDLINE, EMBASE, Cochrane Library, Web of Science, and CINAHL were searched from 1945 to March 2019. Eligible studies reported standardized mortality ratios (SMRs) or absolute deaths among adults receiving chronic oral GCs. Random-effects meta-analysis and mixed-effects meta-regression were used to synthesize mortality and dose-response associations across GC exposure metrics, exposure duration, and disease subgroups. RESULTS: One-hundred and sixteen studies encompassing 128 cohorts and 51 380 patients were included. Chronic GC exposure was associated with excess mortality (pooled SMR 1.87; 95%CI 1.32-2.61; I2 74.0%). The pooled proportion of death was 12.0% (95%CI 10-14%). Mortality risk was highest in inflammatory diseases (30.0%) and the vasculitides (18.0%). Higher cumulative dose (≥5 g prednisolone-equivalent), average daily dose >5 mg/day, and higher initial dose were each independently associated with increased mortality. Cardiovascular disease was the leading causes of death (25.6%), followed by malignancy (15.7%) and infection (13.4%). CONCLUSION: Chronic oral GC exposure was associated with increased mortality across disease groups, with higher cumulative and early-treatment doses correlating with higher risk. However, causal attribution remains uncertain due to confounding by indication, limited disease-severity data, and exposure misclassification. These findings support GC stewardship and targeted cardiovascular and infection risk mitigation, rather than indiscriminate dose reduction.
CONTEXT: GLP-1 receptor agonists have revolutionized the treatment of obesity and type 2 diabetes but may cause excess muscle loss. Inhibitors of the myostatin-activin pathway can cause fat loss and skeletal muscle gain,...CONTEXT: GLP-1 receptor agonists have revolutionized the treatment of obesity and type 2 diabetes but may cause excess muscle loss. Inhibitors of the myostatin-activin pathway can cause fat loss and skeletal muscle gain, but the effect of chronic pathway inhibition on human cardiac muscle is not known. OBJECTIVE: Investigate the effects of extended inhibition of the myostatin-activin pathway on cardiovascular parameters in healthy older adults. DESIGN: Randomized, double-blind, placebo-controlled study with six months of treatment and up to six months of follow-up. SETTING: Single commercial study site. PARTICIPANTS: 68 healthy community-living men and women aged 60-86 years. INTERVENTIONS: Intravenous bimagrumab 10 mg/kg or placebo. MAIN OUTCOME MEASURES: Cardiac magnetic resonance assessment of changes in left ventricular mass index (LVMI) and left ventricular ejection fraction (LVEF). Changes in total lean body mass (LBM) and total body fat mass (FM) by dual energy X-ray absorptiometry (DXA). RESULTS: At 6 months, no clinically relevant change was observed in LVMI (least squares mean [90% confidence interval] 1.6 g/m2 [-0.2, 3.4], P=0.148) or LVEF (2.0% [-0.4, 4.4], P=0.176) between treatments. Total LBM (mean [standard deviation]) increased by 5.5% [3.6] and FM decreased by -14% [8.9] with bimagrumab vs placebo (both P<0.001). CONCLUSION: Six months of myostatin-activin pathway inhibition with bimagrumab had no effect on cardiac structure or function in healthy older adults compared to placebo. These results support consideration of bimagrumab as a skeletal muscle sparing intervention in adults undergoing weight loss with GLP-1 receptor agonists.
BACKGROUND: Lipodystrophy syndromes (LD) are a group of rare conditions characterised by the generalised or partial absence and/or dysfunction of adipocytes. Due to the lack of fat storage capacity, excess lipid accumula...BACKGROUND: Lipodystrophy syndromes (LD) are a group of rare conditions characterised by the generalised or partial absence and/or dysfunction of adipocytes. Due to the lack of fat storage capacity, excess lipid accumulates in other tissues, leading to severe insulin resistance. At present, effective therapeutic options remain limited, with metreleptin currently the only specific licensed treatment. To this end, we evaluated the therapeutic impact of tirzepatide in people with partial lipodystrophy (PLD). METHODS: This was a single-centre, retrospective, observational study, including all patients with PLD treated with tirzepatide between January 2022 and September 2025. RESULTS: 40 patients with PLD were included (FPLD1 like =26 (65%), FPLD2 =4 (10%), FPLD3 =7 (17.5%), FPLD7=1 (2.5%), APLD=1 (2.5%), Unclassified=1 (2.5%)). 87.5% (n=35) were female with a median age of 47 years (IQR 39 - 59) and a median BMI of 31.5 kg/m2 (IQR 27.3 - 35.5). After a median 9.5 month follow-up (IQR 7 - 11), marked reductions were seen in body weight from 91.0kg (IQR 75.0 - 106.0) to 82.8kg (IQR 69.0 - 93.4; p<0.0001), in HbA1c from 65 mmol/mol (IQR 54.5 - 85) to 52 mmol/mol (IQR 39 - 62; p<0.0001) and in serum triglycerides from 2.80 mmol/L (IQR 1.6 - 3.7) to 1.83 mmol/L (IQR 1.0 - 2.9; P=0.0005). Daily insulin requirements fell from 177.5 IU (IQR 101.3 - 213.8) to 58.0 IU (IQR 0 - 112.5; P=0.0028). CONCLUSION: In patients with partial lipodystrophy, tirzepatide use resulted in substantial statistically significant reductions in weight, glycaemic control, serum triglycerides and daily insulin requirement. We recommend further prospective studies to support these findings and to evaluate its impact earlier in the course of the disorder.
OBJECTIVE: This study compared in vivo changes in hepatic phosphate metabolites using phosphorus magnetic resonance spectroscopy (31P-MRS) in patients with vs. without MASLD after fructose consumption. METHODS: Thirty-se...OBJECTIVE: This study compared in vivo changes in hepatic phosphate metabolites using phosphorus magnetic resonance spectroscopy (31P-MRS) in patients with vs. without MASLD after fructose consumption. METHODS: Thirty-seven overweight or obese patients without diabetes underwent: a 2-hour oral glucose tolerance test, a fasting liver proton magnetic resonance spectroscopy (1H-MRS), and a 31P-MRS before and during 60 minutes after an oral 75-gram fructose challenge. RESULTS: Before fructose consumption, there were no differences in ATP, phosphomonoesters (PME) or phosphodiesters (PDE) between groups. After fructose, patients without MASLD had a rapid increase in PME (from 15.5±4.8 to 19.3±5.1 within 15 minutes, p=0.033). In these patients, inorganic phosphate decreased during the first 30 minutes but then increased leading to higher than basal levels (from 10.2±1.9 to 11.8±2.8, p=0.037). ATP significantly dropped in patients without MASLD within 15 minutes (from 21.8±3.4 to 19.9±4.0, p=0.018), with persistently lower levels after 60 minutes (19.1±4.1, p=0.006 vs. baseline). However, all these responses to oral fructose appeared blunted in patients with MASLD, with unchanged PME levels and only showing an inorganic phosphate increase 45 minutes after fructose consumption. ATP levels showed a non-significant drop in the first 15 minutes with recovery of baseline levels at minute 30. CONCLUSIONS: Following fructose consumption, patients with MASLD exhibited distinct patterns of change in phosphate metabolites, reflecting differences in hepatic metabolic responses. These findings suggest altered hepatic metabolic handling of fructose in MASLD, which may have implications for disease progression.
CONTEXT: BPA is a synthetic chemical used in consumer goods that has been linked to type 2 diabetes in observational studies. No human experimental studies have examined whether BPA reduces peripheral insulin sensitivity...CONTEXT: BPA is a synthetic chemical used in consumer goods that has been linked to type 2 diabetes in observational studies. No human experimental studies have examined whether BPA reduces peripheral insulin sensitivity. PURPOSE: To determine the effects of oral BPA administration on peripheral insulin sensitivity over 5 days. METHODS: Forty sedentary, but otherwise healthy adults (22 F, 18 M; 21.3 ± 2.1 yr; 22.1 ± 2.3 kg/m2; 85% Non-Hispanic White) completed a 2-day baseline energy-balanced diet low in BPA during which urine, blood, and peripheral insulin sensitivity via 120 min euglycemic hyperinsulinemic clamp technique (40 mU/m2/min; 90 mg/dL) were assessed. In a double-blind fashion, participants were randomly assigned to receive 5 days of oral BPA administration at 50 μg/kg body weight (BPA-50) or placebo (PL). All participants were fed the same energy-balanced diet. Outcomes were assessed using a two-way repeated-measures ANOVA adjusted for baseline sex, BMI, physical activity, and ethnicity. RESULTS: After treatment, urine BPA levels were significantly higher in BPA-50 compared to PL (+ 268,700 ± 63983 vs. PL: + 8893 ± 6786 pg/mL, P = 0.009). After treatment, body weight and fasting glucose were not statistically different between PL and BPA-50 (P > 0.05). However, BPA significantly decreased peripheral insulin sensitivity by 0.02 ± 0.01 mg/kg/min/uU/ml compared with an increase observed following PL by 0.02 ± 0.01 mg/kg/min/uU/ml (P = 0.01). CONCLUSION: BPA administration decreased peripheral insulin sensitivity after 5 days. These data provide the first experimental evidence in humans that BPA administration may reduce insulin sensitivity.
BACKGROUND: Complete 17α-hydroxylase/17,20-lyase deficiency (17-OHD) is a rare autosomal recessive form of congenital adrenal hyperplasia caused by CYP17A1 variants. Large-scale studies integrating clinical, genetic, and...BACKGROUND: Complete 17α-hydroxylase/17,20-lyase deficiency (17-OHD) is a rare autosomal recessive form of congenital adrenal hyperplasia caused by CYP17A1 variants. Large-scale studies integrating clinical, genetic, and functional data remain limited. METHODS: We recruited 113 genetically confirmed 17-OHD patients from 107 unrelated families. Comprehensive clinical manifestations, hormonal, and imaging examination data were collected. CYP17A1 variants were identified by Sanger sequencing, whole-exome sequencing or long-read sequencing. In vitro functional studies including enzyme activity assays and minigene splicing assays were performed to verify the pathogenicity of the variants. RESULTS: All patients presented as phenotypic females, with a median diagnostic age of 17 years. Hypertension (93.58%) and hypokalemia (74.31%) were the dominant clinical features, and 91.26% exhibited Tanner stage I breast development. We identified 50 pathogenic CYP17A1 variants, including 6 novel ones (c.286C>G, c.436+1G>T, c.1241C>T, c.1300C>T, c.1348C>T, c.1433G>T). The mutation spectrum was dominated by a founder hotspot, c.985_987delinsAA, accounting for 59.29% of alleles, with mutations clustering in exons 6 and 8. In vitro enzyme activity assays confirmed near-complete loss of both 17α-hydroxylase and 17,20-lyase activities in all variants except p.Val236Gly, which retained minimal residual activity. Notably, 5 variants (including 2 missense changes, c.1084C>T and c.1085G>A) were shown to disrupt normal pre-mRNA splicing in minigene assays, revealing a dual molecular mechanism of pathogenicity involving both protein dysfunction and aberrant RNA processing. CONCLUSION: This study defines the most comprehensive CYP17A1 variant spectrum for complete 17-OHD in China, identifies 6 novel pathogenic variants, and uncovers splicing disruption as an under-recognized mechanism in missense mutations. These findings expand the molecular and clinical understanding of 17-OHD, highlight the founder effect of c.985_987delinsAA in the Chinese population, and provide critical insights for genetic diagnosis and counseling.
CONTEXT: Follistatin inhibits TGF-β superfamily ligands, is involved in muscle atrophy, and is elevated in several endocrine disorders and in response to exercise or fasting. Follistatin is expressed in various tissues w...CONTEXT: Follistatin inhibits TGF-β superfamily ligands, is involved in muscle atrophy, and is elevated in several endocrine disorders and in response to exercise or fasting. Follistatin is expressed in various tissues with the liver as a major contributor to the circulating levels. Current evidence shows contradictory results on whether circulating levels of follistatin displays a circadian rhythm. OBJECTIVE: To characterize the 24-hour temporal pattern of plasma follistatin in healthy young men. DESIGN: Observational 24-hour study with blood sampling every three hours. Cosinor rhythmometry and one-way repeated measures ANOVA were used to analyze plasma follistatin. SETTING: Controlled research facility simulating normal daily life. PATIENTS OR OTHER PARTICIPANTS: Twenty-two healthy young men were included in this study. INTERVENTION(S): No interventions were applied. MAIN OUTCOME MEASURE(S): Plasma concentrations of follistatin. This was measured in order to investigate the temporal pattern of follistatin to gain insight into its physiological actions and regulation. RESULTS: Plasma follistatin showed a significant 24-hour rhythm (p<0.001) with a relative amplitude of 18% around a rhythm adjusted average (mesor±SD) of 873 ± 25 pg/mL, peaking at 11:50 h. ANOVA confirmed a significant effect of time, with morning and evening levels differing significantly. CONCLUSIONS: Plasma follistatin displayed a significant 24-hour rhythm in our cohort of 22 healthy young men. While meal intake, particularly protein, influences follistatin, it does not fully explain the observed rhythm. Further studies are needed to confirm this rhythm and clarify its clinical relevance.
CONTEXT: Transplacental transfer of Thyroid-Stimulating Hormone Receptor antibodies (TRAb) during pregnancy may cause fetal/neonatal thyroid dysfunction. Current guidelines recommend a universal TRAb titer threshold, irr...CONTEXT: Transplacental transfer of Thyroid-Stimulating Hormone Receptor antibodies (TRAb) during pregnancy may cause fetal/neonatal thyroid dysfunction. Current guidelines recommend a universal TRAb titer threshold, irrespective of gestational age or assay platform. However, evidence supporting trimester-specific and assay-specific thresholds is lacking. OBJECTIVE: 1) To determine whether trimester-specific TRAb levels predict fetal/neonatal thyroid dysfunction. 2) to establish assay-specific cutoff values for clinical risk stratification. DESIGN: Prospective multicenter observational cohort study (2010-2023), in which maternal TRAb titers were measured using the TRAK human assay on the BRAHMS Kryptor Compact Plus analyzer. SETTING: Tertiary and secondary care centers (n=44) across the Netherlands. PATIENTS: Women with a history of (n=500) or active (n=178) Graves' disease. MAIN OUTCOME MEASURE(S): Biochemically confirmed fetal/neonatal hyperthyroidism or hypothyroidism. RESULTS: Trimester-specific TRAb titer thresholds predicted risk with high accuracy. In women with a history of Graves' disease (n=500), trimester-specific cut-offs of 25-, 19-, and 6-fold the upper limit of normal (ULN) showed a negative predictive value of 100%. In women with active Graves (n=178), cut-offs of 10-, 12-, and 10-fold the ULN showed sensitivities of 89%, 86%, and 83%. Neonatal hyperthyroidism occurred despite low or declining maternal TRAb levels in mothers treated with antithyroid drugs. CONCLUSIONS: Trimester-specific TRAb thresholds were higher than the universal ULN multipliers commonly applied in clinical practice, and differed by gestational age and disease status. Application of a single ULN-based threshold titer across different TRAb assays may result in misclassification (i.e. overestimation of fetal and neonatal Graves' disease) and consequently in unnecessary and resource-intensive fetal surveillance. This indicates that TRAb thresholds are assay-specific and require platform-specific clinical validation, even when assays are calibrated against a common international standard.
PURPOSE: We assessed the prevalence of gestational diabetes (GDM) in South Africa, including early and late GDM, and investigated insulin sensitivity, 1st phase insulin secretion, and beta cell function to understand the...PURPOSE: We assessed the prevalence of gestational diabetes (GDM) in South Africa, including early and late GDM, and investigated insulin sensitivity, 1st phase insulin secretion, and beta cell function to understand the underlying pathophysiology of glucose metabolism in early and late pregnancy. We also examined the association between HIV and GDM. METHODS: We enrolled women with HIV (WWH) and HIV-seronegative women at <18 weeks' gestation. A 75g oral glucose tolerance test was administered at enrollment (early) and 32-36 weeks' gestation (late) to diagnose GDM using WHO criteria. Matsuda, Stumvoll, oral disposition index, and glucose sensitivity from Mari models were calculated. Logistic regression models were used to assess the association of HIV with GDM. RESULTS: Among 1573 (n=668 WWH) participants, median age was 28 years, gestation 13 weeks. Overall, 7.9% had GDM (6.7% WWH, 9.1% HIV-seronegative); of these, 65% had early GDM. Women with early GDM had the lowest Matsuda, Stumvoll, DIo, and glucose sensitivity at enrollment compared to those with late GDM and those without GDM. In adjusted analyses, WWH had lower odds of GDM than HIV-seronegative women [adjusted odds ratio: 0.57, 95% Confidence Interval: 0.38-0.85). CONCLUSION: GDM prevalence in South Africa is similar to North America/Europe. Early GDM was diagnosed in a large majority of women who also exhibited features of poorer insulin sensitivity and beta cell function than those diagnosed late in pregnancy or without GDM. WWH had lower GDM risk than HIV-seronegative women. Future studies to understand the implications of early GDM in African populations are warranted.
OBJECTIVE: In Osteogenesis Imperfecta (OI), phenotypic variability and the limited predictive value of genotype-phenotype correlations underscore the need for reliable predictive marker of disease severity. Periostin is...OBJECTIVE: In Osteogenesis Imperfecta (OI), phenotypic variability and the limited predictive value of genotype-phenotype correlations underscore the need for reliable predictive marker of disease severity. Periostin is a matricellular protein involved in bone formation, remodeling, and response to mechanical stress. It interacts with type I collagen and modulates osteoblast activity via Wnt/β-catenin and TGF-β signaling. Given its established role in other bone disorders, we hypothesized that circulating periostin may be a relevant biomarker in OI. METHODS: We performed a matched case-control analysis of serum periostin levels in 61 adult patients with OI and 61 age-, sex-, and BMI-matched controls. Periostin was measured by ELISA. Associations between periostin levels and clinical variables were assessed using t-tests, Pearson correlations, and multivariable linear regression models. RESULTS: Mean periostin levels were significantly higher in OI patients than in controls (796.5 ± 209 vs. 713.6 ± 167 pmol/L, p = 0.017). Among OI patients, higher periostin level was associated with female sex (p = 0.01), presence of scoliosis (p = 0.01), and Sillence type III (p = 0.05). Positive correlations were observed between periostin and markers of axial skeletal severity as height-wingspan discrepancy (r = 0.30, p = 0.023). In multivariable analysis, the number of severe fractures (defined as femur/pelvis/humerus/vertebral fractures) was independently associated with higher periostin level (β = 25.6, p = 0.041), while smoking was negatively associated (β = -269.8, p = 0.012). CONCLUSION: This study is the first to report the elevated circulating level of periostin in adults with OI and its association with disease severity.
BACKGROUND: Data on cognition in patients with primary aldosteronism (PA) are scarce. Mild autonomous cortisol secretion (MACS), defined based on post-dexamethasone cortisol >1.8 mcg/dL, is diagnosed in up to 30% of pati...BACKGROUND: Data on cognition in patients with primary aldosteronism (PA) are scarce. Mild autonomous cortisol secretion (MACS), defined based on post-dexamethasone cortisol >1.8 mcg/dL, is diagnosed in up to 30% of patients with PA. OBJECTIVES: 1) assess cognition in patients with PA versus referent subjects with hypertension, 2) determine differences in cognition between patients with PA and those with MACS. METHODS: A prospective, cross-sectional study, 2019-2023. Cognition was assessed by National Institute of Health Toolbox Cognition Battery and reported as T-scores corrected for age, sex, race, and education. Only subjects with hypertension were included. RESULTS: Cognitive assessment was performed in 52 patients with PA (including 11 patients with both PA and MACS, median age of 51.0 years, 30 (57.7%) women), 47 patients with MACS (median age of 57.0 years, 31 (66.0%) women), and 52 referent subjects (median age of 66.1 years, 30 (57.7%) women). When compared to referents, and after adjusting for age, smoking, systolic blood pressure and alcohol use, patients with PA had lower total cognition (β=-5.7, P=0.023), notably fluid cognition (β=-6.8, P=0.017), including attention and executive function (β=-5.6, P=0.012) and cognitive flexibility and executive function (β=-8.2, P=0.006). When compared to patients with MACS, patients with PA had a higher processing speed (β=9.0, P=0.003). No differences in cognition were found between patients with PA with and without MACS. CONCLUSION: Patients with PA demonstrated lower cognition compared with referents and processing speed compared with MACS. Future studies should characterize the impact of MACS on the cognition of patients with PA.
Hamidi O, St-Jean M, Lacroix A
… +1 more, Bancos I
J Clin Endocrinol Metab
· 2026 May · PMID 41830485
·
Full text
Endogenous Cushing syndrome (CS) is a rare disorder resulting from chronic exposure to excessive concentrations of cortisol. It is likely underdiagnosed because many clinical signs and symptoms are non-specific and overl...Endogenous Cushing syndrome (CS) is a rare disorder resulting from chronic exposure to excessive concentrations of cortisol. It is likely underdiagnosed because many clinical signs and symptoms are non-specific and overlap with those of common conditions. Furthermore, biochemical testing to diagnose CS can be complex and challenging, especially in milder cases. CS is characterized by excessive daily cortisol production, but it is also associated with a disrupted circadian rhythm of cortisol secretion. Traditional cortisol monitoring techniques rely on single-time-point measurements or a cumulation of measurements, which are unable to capture the complete daily rhythm of cortisol fluctuations. Currently, the utility of assessing individual patients' cortisol circadian rhythm during diagnosis and treatment of CS is not well characterized. In this review, we will discuss how cortisol is measured in clinical practice and the potential benefit of measurement and normalization of the cortisol circadian rhythm.
J Clin Endocrinol Metab
· 2026 Jun · PMID 41824769
·
Full text
CONTEXT: Excess growth hormone (GH) production leading to acromegaly most commonly emanates from an adenomatous pituitary somatotroph. Understanding the pathogenesis of these adenomas will elucidate how biologic behavior...CONTEXT: Excess growth hormone (GH) production leading to acromegaly most commonly emanates from an adenomatous pituitary somatotroph. Understanding the pathogenesis of these adenomas will elucidate how biologic behavior affects acromegaly treatment outcomes. EVIDENCE ACQUISITION: We searched PubMed for relevant English-language original research and review articles on signaling pathways and molecular drivers implicated in the pathogenesis of nonfamilial somatotroph adenomas in patients with acromegaly. EVIDENCE SYNTHESIS: Somatotroph cells express cognate G protein-coupled receptors for both hypothalamic stimulatory GH-releasing hormone (GHRH) and inhibitory somatostatin. Somatotroph GH transcription and secretion, as well as somatotroph cell lineage development, proliferation, and differentiation, are mediated by GHRH signaling through its cognate receptor (growth hormone-releasing hormone receptor [GHRHR]), driving increased intracellular cyclic adenosine monophosphate (cAMP) levels. Point mutations in GNAS and other genomic and nongenomic aberrations in the tightly regulated GHRH-GHRHR signaling pathway result in persistent cAMP signaling, inducing GH production and somatotroph proliferation, and potentially favoring the development of sporadic somatotroph adenomas. Enhanced cAMP signaling also increases DNA damage markers and activates DNA damage response pathways, leading to a senescent adenomatous phenotype tightly linked to GH overproduction. CONCLUSION: The cAMP pathway appears to be a dominant molecular driver of somatotroph adenoma pathogenesis. Elevated cAMP drives GH hypersecretion and somatotroph proliferation and also induces DNA damage, as evidenced by increased genomic instability and a senescent signature. Collectively, these findings elucidate a molecular framework for the biological behavior of these adenomas and their responsiveness to therapies targeting cAMP-dependent pathways, including somatostatin receptor ligands.
Araujo-Castro M, Bancos I, Detomas M
… +17 more, Reincke M, Mahdi S, Lu H, Altieri B, Kroiss M, Oettle M, Guerrero-Pérez F, Hanzu FA, García-Centeno R, Gónzalez-Fernandez L, Pasarón M, Gimeno PG, Valero LM, Luna AC, Echarri AI, Garcia-Agullo MDO, Martínez WAR
OBJECTIVE: To assess the efficacy and safety of osilodrostat in adrenal Cushing syndrome (CS). METHODS: International study of patients with adrenal CS: patients treated with osilodrostat at any time were enrolled in the...OBJECTIVE: To assess the efficacy and safety of osilodrostat in adrenal Cushing syndrome (CS). METHODS: International study of patients with adrenal CS: patients treated with osilodrostat at any time were enrolled in the safety evaluation and those treated for longer than 4 weeks, in the efficacy evaluation. Patients were classified as responders if they experienced a reduction in urinary free cortisol (UFC) > 50% (complete responders when UFC levels were below the upper limit of normal (ULN) and partial responders if there was a reduction >50% but not normalization). RESULTS: Twenty-eight patients with adrenal CS were enrolled: 16 with adrenocortical carcinoma and 12 with benign disease. Osilodrostat was used in monotherapy in 22 patients and in combination with metyrapone in 6 cases. In those patients treated for longer than 4 weeks (n = 21), 66.7% were classified as responders (28.6% with complete response and 38.1% with partial response) and for those treated for longer than 12 weeks, the rate of response increased to 87.5% The use of osilodrostat as a non-first-line therapy (Odds ratio [OR] 15.0, P = 0.010) was a predictor of response. Osilodrostat led to a significant decrease in systolic blood pressure and body weight (P < 0.05). Nine patients developed one or more adverse events and in 56% (n = 5) led to osilodrostat discontinuation. CONCLUSIONS: Osilodrostat controls hypercortisolism in 66.7% of patients with adrenal CS treated for longer than 4 weeks and in 87.5% of cases treated for longer than 12 weeks, with a positive impact on blood pressure and body weight. Patients who received osilodrostat after other previous steroidogenesis inhibitors have a higher probability of response.
Hyperthyroidism is a prevalent endocrine disorder that can lead to severe multisystem complications, including atrial fibrillation (AF), thyrotoxic periodic paralysis (TPP), and thyroid storm (TS). This review discusses...Hyperthyroidism is a prevalent endocrine disorder that can lead to severe multisystem complications, including atrial fibrillation (AF), thyrotoxic periodic paralysis (TPP), and thyroid storm (TS). This review discusses the pathophysiology, clinical presentation, and management challenges of these complications through illustrative clinical cases. AF is the most common cardiovascular manifestation, with restoration of euthyroidism and rate control being central to treatment. TPP presents with transient muscle weakness due to hypokalemia from intracellular potassium shift, requiring cautious potassium supplementation and hyperthyroidism control. TS is a life-threatening endocrine emergency characterized by multisystem decompensation, necessitating prompt multimodal therapy including antithyroid drugs, beta-blockers, corticosteroids, and supportive care. Thus, early recognition and tailored management remain the cornerstones of successful treatment for these severe complications of hyperthyroidism.
Nakamura-Utsunomiya A, Hasegawa K, Ono T
… +17 more, Kanno J, Shima H, Suzuki Y, Tanaka M, Ikegawa K, Amano N, Mogami Y, Yamada Y, Futagawa N, Higuchi Y, Sasaoka D, Nagamatsu F, Mori J, Kawai M, Moritake H, Nishi M, Matsuo M
CONTEXT: The early diagnosis of ROHHAD (-NET) syndrome is hard for pediatricians and endocrinologists because some symptoms, including rapid-onset obesity and autonomic dysfunction, are nonspecific and detected progressi...CONTEXT: The early diagnosis of ROHHAD (-NET) syndrome is hard for pediatricians and endocrinologists because some symptoms, including rapid-onset obesity and autonomic dysfunction, are nonspecific and detected progressively. An autoimmune mechanism involving ZSCAN1 antibody is proposed to contribute to the pathogenesis of the disease. However, the clinical significance of the anti-ZSCAN1 antibody titer remains unestablished. OBJECTIVES: To clarify the clinical features at onset or first visit to hospitals and the significance of anti-ZSCAN1 and anti-Nax antibody titers by ELISA in patients' serum. DESIGN: Observational cohort study of patients diagnosed clinically with ROHHAD (-NET) syndrome in Japan. RESULTS: Obesity was observed in 72.7% of cases, while autonomic dysregulation and central hypoventilation were observed in 18.2% and 36.2% of cases, respectively. Serum prolactin levels measured at the initial consultation were significantly elevated in all cases. Antibody analyses revealed positivity in 70% of 30 cases. The anti-ZSCAN1 antibody titer associated with neural crest tumors (NCT) was significantly higher than that without tumors. In a patient with NCT, the trend of anti-ZSCAN1 antibody titer tended to be decreased after tumor resection or immunosuppressive therapy. CONCLUSIONS: This study suggests that we need to evaluate clinically and in detail the autonomic dysregulation and hypoventilation in order to diagnose ROHHAD (-NET) syndrome in its early stages. Additionally, anti-ZSCAN1 antibody titers reflect the association of neural crest tumors (NCT) and may serve as a potential marker for the efficacy of tumor therapy. We also propose the anti-ZSCAN1 antibody titer as an indicator for the clinical management of ROHHAD (-NET) syndrome.
CONTEXT: Androgen abuse is an increasing public health concern, particularly among young men seeking muscular or image enhancement. Although most achieve biochemical recovery within 12 months of cessation, mood disturban...CONTEXT: Androgen abuse is an increasing public health concern, particularly among young men seeking muscular or image enhancement. Although most achieve biochemical recovery within 12 months of cessation, mood disturbances, sexual dysfunction, and fatigue is widely reported for years afterward. OBJECTIVE: To examine symptom severity the relationship to biochemical recovery during the first year after androgen abuse cessation. METHODS: We conducted a cross-sectional study of community-dwelling men grouped as non-users, current users, or past users who had ceased within the last 12 months. Participants completed questionnaires on androgen and substance use and four validated instruments assessing mood (BDI-II), anxiety (GAD-7), sexual function (IIEF-15), and quality-of-life (SF-36). Morning fasted serum hormonal analysis and screening to exclude undisclosed androgen use were performed. RESULTS: 247 men were included: 50 non-users, 125 current users, 72 past users. Self-reported psychiatric diagnoses were 2.5-fold higher among current and past users than non-users. Total testosterone was highest in current users (p<0.001) with no difference between past and non-users. Past users reported significantly worse mood, anxiety, sexual function, and quality of life versus non-users. Multivariable analyses showed psychiatric comorbidity was independently associated with depression (p=0.001), anxiety (p<0.001), and poorer quality-of-life (p<0.05). Older age and higher LH were associated with reduced sexual function (p<0.05), while lower testosterone showed only a modest association with depressive symptoms (p=0.03). CONCLUSION: Among men in the first year after stopping androgen abuse, psychological symptoms and reduced quality-of-life were most strongly associated with psychiatric comorbidity than biochemical recovery. These findings challenge the assumption that androgen withdrawal symptoms are predominantly driven by hypogonadism, and supports developing psychological and behavioural interventions, rather than pharmacological, to support androgen withdrawal in men.