Sodium-glucose cotransporter 2 (SGLT2) inhibitors block glucose reabsorption in the renal proximal tubules, thereby promoting urinary glucose excretion. Although originally developed as antidiabetic agents, large-scale c...Sodium-glucose cotransporter 2 (SGLT2) inhibitors block glucose reabsorption in the renal proximal tubules, thereby promoting urinary glucose excretion. Although originally developed as antidiabetic agents, large-scale clinical trials have demonstrated that SGLT2 inhibitors not only lower blood glucose levels but also significantly reduce cardiovascular and renal events in patients with diabetes. Subsequent studies further established that these agents confer cardio-renal protection in individuals with heart failure or chronic kidney disease, irrespective of diabetes status. Beyond these established clinical benefits, accumulating evidence suggests that SGLT2 inhibitors may exert anti-aging effects. Mechanistically, they induce metabolic adaptations that resemble caloric restriction and ketogenic states, attenuate systemic inflammation, improve mitochondrial function, and enhance cellular resilience against the burden of senescence. Supporting this concept, multiple preclinical studies have shown that SGLT2 inhibitors extend lifespan and ameliorate age-related functional decline in animal models. Notably, recent findings indicate that SGLT2 inhibitors can reduce senescent cell burden and modulate the senescence-associated secretory phenotype (SASP), raising the possibility that they possess senotherapeutic-or even senolytic-properties targeting a fundamental driver of aging. Collectively, these data suggest that SGLT2 inhibitors may influence core aging pathways beyond their glucose-lowering and cardio-renal protective effects. In this review, we summarize current insights into the molecular and physiological mechanisms by which SGLT2 inhibitors may modulate aging biology and discuss their emerging potential as therapeutic agents capable of extending health span and preventing age-related diseases.
CONTEXT: Impaired awareness of hypoglycemia (IAH) significantly impacts efforts to maintain optimal glycemia. IAH occurs when recurrent episodes of hypoglycemia (HG) occur within a short period of time, but the mechanism...CONTEXT: Impaired awareness of hypoglycemia (IAH) significantly impacts efforts to maintain optimal glycemia. IAH occurs when recurrent episodes of hypoglycemia (HG) occur within a short period of time, but the mechanisms are unknown. Upregulation of glucose transport may contribute to the development of IAH. OBJECTIVE: To determine if brain glucose transport is upregulated in response to recurrent HG in people with type 1 diabetes (T1D) and normal awareness of hypoglycemia. DESIGN: Forty-five subjects enrolled and 30 completed the entire 3-day protocol. Participants underwent magnetic resonance spectroscopy scans at 3 tesla during which they were clamped at 150, 225 or 300 mg/dL before and after exposure to three 2-hr HG (target = 50mg/dL) clamps over 2 days between December 2020 and June 2023. The primary metabolite of interest was glucose. Brain glucose transport kinetics were measured in the hypothalamus (HTL) and prefrontal cortex (PFC) during hyperglycemic clamps using reversible symmetric Michaelis-Menten model. SETTING: Academic medical center. PATIENTS OR OTHER PARTICIPANTS: Participants were recruited from a clinical registry. Inclusion criteria were diagnosis of T1D, 18-65 years, hemoglobin A1C <8.5%, and diabetes duration of 2-25 years. Exclusion criteria included IAH on the Clarke and Gold questionnaires. INTERVENTIONS: Three 2-hr HG clamps over 2 days. MAIN OUTCOME MEASURE: The ratio of maximal transport rate to cerebral metabolic rate of glucose (Vmaxt/CMRglc). RESULTS: Brain glucose transport kinetics measured during hyperglycemic clamps were not different before vs. after exposure to recurrent HG clamps. CONCLUSIONS: Short-term exposure to recurrent HG does not upregulate glucose transport kinetics in the setting of T1D.
Fudulu DP, Marinelli I, Galvis D
… +22 more, Zavala E, Walker-Smith T, Evans J, Papadopoulou F, Upton T, Ramesh A, Rapetto F, Kershaw Y, Fox J, Aramburo A, Stoica SC, Caputo M, Parry A, Macrae D, Michielon G, Hoschtitzky JA, Sheehan K, Van Faassen M, Kema I, Angelini GD, Lightman S, Gibbison B
CONTEXT: The hypothalamic-pituitary-adrenal (HPA) axis is the key homeostatic system regulating the response to surgical stress. Imbalances in HPA axis hormones increase morbidity and mortality in children after cardiac...CONTEXT: The hypothalamic-pituitary-adrenal (HPA) axis is the key homeostatic system regulating the response to surgical stress. Imbalances in HPA axis hormones increase morbidity and mortality in children after cardiac surgery. Despite this, the physiology of the HPA axis in children undergoing cardiac surgery is poorly understood, leading to controversies in clinical practice. OBJECTIVE: To characterise dynamic HPA axis responses in children undergoing cardiac surgery and to determine age- and procedure-related differences in cortisol and cortisone physiology. METHODS: We recruited children (0-18 years) undergoing cardiac surgery with cardiopulmonary bypass or cardiac catheterisation. Tissue-free cortisol and cortisone were sampled every 20 minutes for up to 24 hours via microdialysis, alongside serum adrenocorticotropic hormone (ACTH), cortisol, cortisol-binding globulin (CBG), and inflammatory markers. We developed dynamic markers to quantify age- and procedure-dependent differences in hormonal responses and built a mathematical model to explain them. RESULTS: Neonates undergoing surgery showed higher free cortisol and cortisone AUC and peak concentrations than catheterisation patients. Neonates had higher peaks of cortisol and cortisone than older children undergoing surgery. The much higher tissue cortisone levels observed in neonates can be explained by enzymatic interconversion between cortisol and cortisone, likely due to persistent foetal high 11-βHSD2 activity and reduced 11-βHSD1 activity.Low post-operative blood cortisol and CBG values in neonates resulted in high free cortisol peaks in interstitial fluid during and after surgery. CONCLUSION: Neonates differ physiologically, with higher free cortisol levels that more readily diffuse into interstitial tissues, with implications for perioperative management.
INTRODUCTION: Epiphyseal growth plate development is stimulated by GH and IGF-I. Serum IGF-I is applied as an efficacy and safety marker, monitoring growth in short GH-treated children. However, IGF-I offers poor guidanc...INTRODUCTION: Epiphyseal growth plate development is stimulated by GH and IGF-I. Serum IGF-I is applied as an efficacy and safety marker, monitoring growth in short GH-treated children. However, IGF-I offers poor guidance to clinicians, especially in children without GHD. Thus, novel biomarkers reflecting endogenous and GH-induced linear growth are needed. We evaluated the association between linear growth during pubertal transition and circulating levels of procollagen type I and II (PRO-C1, PRO-C2). METHODS: We included 1700 serum samples from 213 healthy children and adolescents (51% female), aged 5-16 years, from the prospective longitudinal Copenhagen Puberty study, followed between 2006--2014. We assessed peak height velocity (PHV), pubertal development, serum IGF-I, sex-steroids (LC-MS/MS), and PRO-C1, PRO-C2 (immunoassays). Additionally, PRO-C1 and PRO-C2 were determined in short children born small-for-gestational-age (SGA) before and after 12 months of GH-treatment. RESULTS: Age-, sex-, and puberty-related reference intervals for PRO-C1 and PRO-C2 concentrations were established. PRO-C1 and PRO-C2 increased significantly with age and pubertal development (Tanner B1 through B3, p<0.0001; G1 through G4, p<0.001). During growth spurt, PRO-C1 and PRO-C2 were associated with increased height standard deviation score (SDS) and height velocity, both reached peak concentrations at the time of PHV, earlier than IGF-I and sex-steroids, followed by a rapid decline. In GH-treated prepubertal children, PRO-C1 increased from 0.70 to 3.78 SDS (p<0.0001) and PRO-C2 from -2.07 to 0.69 SDS (p=0.0055). IN CONCLUSION: we present longitudinal changes in PRO-C1 and PRO-C2 in normal and disordered growth, suggesting PRO-C1 and PROC-2 as potential biomarkers of endogenous and GH-induced linear growth.
Primary Ovarian Insufficiency (POI) is a highly heterogeneous condition characterized by the cessation of ovarian function before age 40. While genetic factors play a substantial role, the contribution of structural vari...Primary Ovarian Insufficiency (POI) is a highly heterogeneous condition characterized by the cessation of ovarian function before age 40. While genetic factors play a substantial role, the contribution of structural variants remains incompletely mapped. We conducted a systematic review and in silico genomic re-analysis of published copy number variations (CNVs) in individuals with POI. Following PRISMA guidelines, we aggregated 382 CNVs from 25 studies, standardized genomic coordinates, and filtered variants against population databases. Pathogenicity was re-evaluated using ACMG/ClinGen guidelines, yielding 42 pathogenic/likely pathogenic variants and 25 large CNVs (>3.5 Mb). Consistent with previous findings, the X chromosome exhibited the highest CNV burden, emphasizing its central role in structural genomic instability and POI pathogenesis. Beyond canonical POI-associated genes, gene ontology and GTEx expression profiling identified several biologically plausible, highly ovary-expressed candidate genes within disrupted loci-notably ATF3, GAS5, PPP4R1, and PRKAA1. Despite their established roles in cellular stress responses, DNA repair, and meiotic progression, these genes remain absent from most commercial POI diagnostic panels. This comprehensive re-analysis highlights the complex structural genomic landscape of POI and suggests that expanding current clinical testing panels to include these under-recognized genes could improve diagnostic yields for genetically unexplained cases.
CONTEXT: Prior reports of plasma estradiol concentrations and their reference ranges in postmenopausal women identified marked variation, in part due to assay method and body mass index (BMI). OBJECTIVE: To develop an in...CONTEXT: Prior reports of plasma estradiol concentrations and their reference ranges in postmenopausal women identified marked variation, in part due to assay method and body mass index (BMI). OBJECTIVE: To develop an international reference range for plasma estradiol in postmenopausal women, to support accurate assessment of concentrations during systemic and local (e.g., vaginal) estradiol therapy, and to improve risk prediction for diseases, including osteoporosis, breast and endometrial cancers. METHODOLOGY: Estradiol concentrations were measured using primarily liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays in five international cohorts of community-dwelling, postmenopausal women of primarily European ancestry aged 38-100 years who were not using exogenous estrogens (n=7206). Measurements were harmonized to the Centers for Disease Control and Prevention (CDC) reference measurement procedure (RMP) by re-assaying a subset of samples for each cohort and generating recalibration equations. Reference intervals were determined for all women, non-obese women, and specific BMI categories. RESULTS: Estradiol concentrations from separate LC-MS/MS assays correlated closely with the CDC RMP, and harmonization minimized inter-assay variability. Estradiol concentrations correlated with BMI but not with chronological age. The reference range (2.5th-97.5th percentile) was 1.1-18.2 pg/mL (4.0 - 66.8 pmol/L) with median of 4.9 pg/mL (18.0 pmol/L) for all postmenopausal women and 1.1-12.5 pg/mL (4.0 - 45.9 pmol/L) with median of 4.1 pg/mL (15.1 pmol/L) for non-obese women (BMI<30). Reference ranges increased progressively with higher BMI categories. CONCLUSION: Cross-calibration of estradiol measurements with the CDC RP enabled the development of harmonized plasma estradiol reference ranges for postmenopausal women who were not using exogenous estrogens, suitable for future studies to establish clinical utility. Increasing obesity in postmenopausal women was associated with increasing estradiol concentration and BMI category-specific reference ranges.
CONTEXT: The clinical relevance of etiologic concordance and temporal presentation in bilateral adrenal masses remains poorly defined, creating uncertainty in diagnostic evaluation and management. OBJECTIVE: To character...CONTEXT: The clinical relevance of etiologic concordance and temporal presentation in bilateral adrenal masses remains poorly defined, creating uncertainty in diagnostic evaluation and management. OBJECTIVE: To characterize the etiologic spectrum of bilateral adrenal masses, evaluate patterns by concordance and synchronicity, and identify predictors of discordance and malignant or pheochromocytoma contralateral lesions. DESIGN: Retrospective cohort study (2010-2025). SETTING: Tertiary referral center. PARTICIPANTS: Adults with bilateral adrenal masses. MAIN OUTCOME MEASURES: Etiology, concordance, synchronicity, interval to contralateral lesion, and factors associated with discordance and malignant or pheochromocytoma contralateral lesions. RESULTS: Among 1,035 patients (median age 59.6 years; 51% women), 85% had concordant and 15% discordant etiologies. Concordant cases were predominantly bilateral benign cortical lesions (76%), whereas discordant cases were heterogeneous (benign 35%, malignant 31%, indeterminate 34%). Presentation was synchronous in 84% and asynchronous in 16%, with a median interval of 45 months (IQR 15-87). Asynchronous disease was associated with higher discordance (23% vs 13%, P=0.001) and greater prevalence of malignant lesions (bilateral malignant: 17% vs 7%; discordant malignant: 8% vs 4%; overall P<0.001). Among asynchronous cases, shorter interval to contralateral lesion (<2 vs ≥5 years) was independently associated with malignant or pheochromocytoma etiology (adjusted OR 2.63, 95% CI 1.01-6.85), as was larger tumor size (adjusted OR 1.06 per mm, 95% CI 1.02-1.09). CONCLUSIONS: Most bilateral adrenal masses are benign and concordant; however, discordant or asynchronous disease identifies a higher-risk subgroup enriched for malignancy. Early contralateral lesion development and larger tumor size are key risk factors.
The hypothalamus integrates signals from the body and the environment and coordinates homeostatic responses in multiple physiologic processes including: water balance, stress response, temperature regulation, energy bala...The hypothalamus integrates signals from the body and the environment and coordinates homeostatic responses in multiple physiologic processes including: water balance, stress response, temperature regulation, energy balance, feeding behavior, sleep-wake cycles, and reproduction. Endocrinologists care for individuals for whom hypothalamic injury, whether from tumors, their treatment, or other causes, impairs pituitary hormone production and secretion. The extent of other symptoms in affected individuals is also influenced the extent of hypothalamic injury. "Acquired hypothalamic syndrome" refers to this broader collection of problems attributable to hypothalamic injury, variably including not only pituitary hormone deficiencies, but also hypothalamic obesity (or rarely, diencephalic syndrome), sleep and circadian disruption, temperature dysregulation, and behavioral issues (including memory problems and impulse control). Our goal is to present a pragmatic guide to the multidisciplinary, collaborative evaluation and management of hypothalamic syndrome.
Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders affecting women of reproductive age. Its diagnosis during adolescence is particularly challenging, as physiological pubertal changes overlap...Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders affecting women of reproductive age. Its diagnosis during adolescence is particularly challenging, as physiological pubertal changes overlap with key features of PCOS; nevertheless, this developmental stage often represents the earliest window for clinical manifestation. Accordingly, a definitive diagnosis should be established only in the presence of clear and persistent evidence of both hyperandrogenism and menstrual irregularity. Adolescents presenting with a single feature should be considered at increased risk for PCOS and followed longitudinally, in order to minimize both underdiagnosis and overdiagnosis. Careful exclusion of alternative diagnoses is essential, as several conditions may mimic PCOS. Importantly, PCOS extends beyond reproductive dysfunction and constitutes a chronic condition associated with long-term metabolic risk and adverse mental health outcomes. This broader disease spectrum underscores adolescence as a critical period for early risk stratification and preventive interventions. Management should prioritize lifestyle modification as the foundation of therapy, with pharmacological treatment individualized according to clinical presentation, metabolic profile, contraindications, and patient preferences. Combined oral contraceptive pills remain the first-line therapy for menstrual irregularity and hyperandrogenism and provide an important opportunity for counseling on sexual and reproductive health, including pregnancy prevention and protection against sexually transmitted infections. Metformin is recommended as first-line therapy for metabolic comorbidities, mirroring its established role in adult populations. All these considerations highlight adolescence as an important stage for accurate diagnosis, comprehensive risk assessment, and timely intervention in PCOS, with potential implications for long-term reproductive, metabolic, and psychosocial health.
INTRODUCTION: The binary sex classification protects elite female athletes from the male physical advantages arising from puberty; however, mutations causing XY Disorders of Sex Development (DSD) challenge the binary sex...INTRODUCTION: The binary sex classification protects elite female athletes from the male physical advantages arising from puberty; however, mutations causing XY Disorders of Sex Development (DSD) challenge the binary sex classification. Hormonal features of the most frequent XY DSDs in sports, androgen insensitivity syndrome [AIS] and 5α-reductase type 2 deficiency [5ARD] are not well described. AIMS: To define serum androgen profiles in elite Athletics (Track and Field) events. METHODS: Serum samples from elite athletes (n=1689; male 889, female 800; n=5516 samples, median 3 per person) were analysed by LCMS for serum testosterone [T], dihydrotestosterone [DHT] and androstenedione in 19 WADA-accredited laboratories. Serum steroids and ratios were analyzed by linear mixed model for repeated measures with adjustment for multiple comparisons and imputation for left-censored (DHT) data. Among females, XY DSD identified by adult male serum T concentrations, had clinical diagnosis of 5ARD, AIS or unclassified (UNCL]. RESULTS: XY DSD comprised 12 with 5ARD with two with AIS (1 complete). Excluding pregnancy or androgen doping samples, men had higher serum T (n=2671, 19.7 ± 0.1 nmol/L) and T/DHT ratio (n=1903, 14.4 ± 0.2) than women (n=2793, 1.1 ± 0.1 nmol/L; n=1809, 3.7 ± 0.12, respectively) with XY DSD featuring male-like results (n=52, 28.9 ± 0.8 nmol/L; n=39; 32.0 ± 1.3). CONCLUSIONS: The prevalence of XY DSD in elite female athletes greatly exceeds that of the community with a high proportion androgen sensitive 5ARD. Serum T/DHT ratio by LCMS to characterize 5ARD can be extended to elite athletes.
CONTEXT: Adrenal vein sampling (AVS) is the standard of care for guiding surgery in primary aldosteronism (PA). Because of its technical complexity and limited availability, however, many centers still use cross-sectiona...CONTEXT: Adrenal vein sampling (AVS) is the standard of care for guiding surgery in primary aldosteronism (PA). Because of its technical complexity and limited availability, however, many centers still use cross-sectional imaging for surgical guidance. DESIGN: Single referral-center retrospective cohort study of patients with PA who underwent unilateral adrenalectomy between 2012-2024. Blinded cross-sectional imaging interpretation was corroborated with CYP11B2 immunohistochemistry (IHC) of formalin-fixed paraffin-embedded adrenal tissue. RESULTS: Of 173 patients, age 52.6±11.8 years, 119 (68.8%) were men, 134 (77.5%) White, 30 (17.3%) Black, and 9 (5.2%) other races. CYP11B2 IHC identified a single aldosterone-producing adenoma (APA) or nodule (APN) in 87 (50.3%) and 38 (22.0%) patients, respectively; multiple CYP11B2-positive foci in 45 (26.0%) patients, and no CYP11B2-positive lesions in 3 patients. A single corresponding APA or APN on both IHC and imaging was found in only 53/173 (31%) patients, and an additional 38/173 (22%) patients also had adrenal thickening. Discrepant IHC-imaging findings were observed in 82 (47.4%) patients, including: 1) additional nodule(s) on imaging (ipsilateral non-functional adenoma, n=21; bilateral nodules, n=29; or contralateral nodule(s), n=6); 2) normal adrenals (n=2) or unilateral adrenal hyperplasia (n=4), but discrete CYP11B2-positive foci on IHC; and 3) corresponding APA/APN on imaging-IHC with additional CYP11B2-positive area(s) (n=20). Patients with IHC-imaging concordance had the highest proportion of women and KCNJ5 mutations, while CACNA1D mutations were most frequent in the discordant group. CONCLUSIONS: Even in patients with lateralized PA, IHC mapping of aldosterone sources corresponded with imaging findings in approximately half of the cases. These data caution against targeted therapy guided by cross-sectional imaging.
CONTEXT: New and emerging non-glucocorticoid (GC) therapies for classic congenital adrenal hyperplasia (CAH) can reduce ACTH-mediated androgen production, allowing for GC dose reductions. With the approval of crinecerfon...CONTEXT: New and emerging non-glucocorticoid (GC) therapies for classic congenital adrenal hyperplasia (CAH) can reduce ACTH-mediated androgen production, allowing for GC dose reductions. With the approval of crinecerfont as an adjunctive treatment to GC replacement for classic CAH for patients 4 years of age and older, expert recommendations were developed to provide guidance for GC reduction in pediatric patients after starting crinecerfont. EVIDENCE ACQUISITION: In December 2024, 11 expert endocrinologists participated in a panel to provide input on strategies and considerations when reducing GC doses after introducing crinecerfont. A smaller panel reconvened in January 2025 to review previous discussions and develop recommendations for GC dose reduction after starting crinecerfont in pediatric patients with classic CAH (4-17 years). EVIDENCE SYNTHESIS: Approaches to GC reduction should be tailored to individual clinical goals, cortisol needs, and lifestyle. In pediatric patients, GC dose reductions should be guided by androgen concentrations, with the general goal of maintaining androgens near normal range to achieve normal growth and normalize bone age maturation while also minimizing complications from long-term GC exposure. GC doses should be reduced gradually with frequent monitoring and should not be decreased below the dose needed for physiologic cortisol replacement. CONCLUSIONS: The approval of crinecerfont has initiated a shift in the treatment approach for classic CAH, in which GCs are used at lower doses predominantly for cortisol replacement. These recommendations will become increasingly relevant as treatment for these patients continues to shift toward a new paradigm of physiologic GC replacement with adjunctive control of androgens.
CONTEXT: Differentiating ectopic ACTH secretion (EAS) from Cushing's disease (CD) remains one of the most challenging steps in the diagnostic workup of ACTH-dependent Cushing's syndrome (CS). Urinary free cortisol (UFC)...CONTEXT: Differentiating ectopic ACTH secretion (EAS) from Cushing's disease (CD) remains one of the most challenging steps in the diagnostic workup of ACTH-dependent Cushing's syndrome (CS). Urinary free cortisol (UFC) expressed as times above the upper limit of normal (ULN) has been proposed as a simple, noninvasive discriminator, but external validation in independent populations is lacking. OBJECTIVE: To validate the diagnostic performance of UFC×ULN for distinguishing EAS from CD and to explore complementary biochemical markers, including late-night salivary cortisol (LNSC×ULN) and hypokalemia. DESIGN, SETTING, AND PARTICIPANTS: Multicenter retrospective study from the Spanish Cushing Registry including 269 patients with ACTH-dependent Cushing's syndrome (208 CD, 61 EAS) diagnosed and managed in tertiary referral centers. MAIN OUTCOME MEASURES: Diagnostic accuracy of UFC×ULN and LNSC×ULN for discriminating EAS from CD, expressed as area under the ROC curve (AUC), sensitivity, specificity, and predictive value. RESULTS: EAS patients were older (median 59.0 vs 44.9 years; P<0.001) and showed higher UFC×ULN (16.6 vs 3.6; P<0.001) and LNSC×ULN (9.3 vs 1.5; P<0.001). UFC×ULN and LNSC×ULN achieved excellent discriminative performance (AUC 0.90 and 0.92). No EAS occurred with UFC×ULN < 3×ULN, while 40.5% of patients with UFC ≥ 10×ULN had EAS. The combination of severe hypercortisolism (UFC ≥ 10×ULN and LNSC ≥ 9×ULN) plus hypokalemia identified 75% of EAS with 98% specificity. CONCLUSIONS: UFC×ULN thresholds reliably stratify the probability of EAS versus CD. Severe hypercortisolism and hypokalemia strongly predict EAS, supporting a pragmatic diagnostic approach that prioritizes whole-body imaging in high-risk patients and pituitary-centered evaluation in mild cases.
van der Vliet BF, Camilleri E, Paes T
… +17 more, Treep M, Dolezal N, Cordfunke RA, Drijfhout JW, Biermasz NR, Bos MHA, Cannegieter SC, Rosendaal FR, van Hylckama Vlieg A, Dekkers OM, Meijer OC, Pereira AM, Hofland LJ, Ruhaak LR, Klok FA, van Vlijmen BJM, Feelders RA
OBJECTIVE: Cortisol excess in Cushing's disease (CD) induces widespread plasma protein alterations, affecting various pathways including coagulation and lipid metabolism. The extent to which these abnormalities normalize...OBJECTIVE: Cortisol excess in Cushing's disease (CD) induces widespread plasma protein alterations, affecting various pathways including coagulation and lipid metabolism. The extent to which these abnormalities normalize during long-term remission remains unclear. DESIGN: Cohort study investigating plasma protein profiles in CD patients before, and during long-term remission. METHODS: EDTA plasma samples of 26 CD patients were collected during active disease and during long-term remission (median 4.4 years, interquartile range 3.3-5.1). Plasma protein profiles were generated using quantitative protein mass spectrometry for 159 proteins, including 21 coagulation-related proteins, 18 complement proteins, 15 transport proteins, and 14 apolipoproteins. Protein levels before and after remission were compared with 80 controls (false discovery rate-adjusted t-test) with similar age and sex distribution. RESULTS: During active CD, 78 out of 159 proteins differed from controls, including 11 coagulation proteins, 10 transport proteins, and 3 apolipoproteins. Gelsolin and extracellular matrix protein-1 were most significantly changed. Following remission, 69 proteins changed significantly relative to active disease, but normalization was incomplete. Of the 78 proteins initially altered, 56 were similar to controls upon remission. After remission, 31 proteins remained different from controls, including coagulation proteins factor IX and factor XIII A chain, apolipoprotein A-II, several complement factors and extracellular matrix protein-1. CONCLUSION: Active CD is associated with profound alterations in plasma protein profiles across various functional domains. Long-term remission is accompanied by substantial, but incomplete normalization of plasma proteins. Sustained plasma protein abnormalities may contribute to persistent morbidities and ongoing adverse health risks after remission of CD.
J Clin Endocrinol Metab
· 2026 Jun · PMID 42056759
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The clinical presentation of acromegaly reflects systemic effects of chronic growth hormone (GH) and insulin-like growth factor 1 (IGF-I) excess. Diagnostic delay frequently ranges from 6 to 10 years. While classical man...The clinical presentation of acromegaly reflects systemic effects of chronic growth hormone (GH) and insulin-like growth factor 1 (IGF-I) excess. Diagnostic delay frequently ranges from 6 to 10 years. While classical manifestations such as acral enlargement and facial coarsening are diagnostically important, many patients initially develop nonspecific symptoms, including sleep apnea, carpal tunnel syndrome, arthralgia, and metabolic disturbances. The lack of symptom/comorbidity specificity highlights the need for improved screening strategies, particularly for patients without overt acral changes. Comorbidity cluster analyses, potentially supported by artificial intelligence, may facilitate earlier identification, prompting biochemical confirmation of the diagnosis. Biochemical evaluation has benefited from advances in hormone assay harmonization and the establishment of robust age-adjusted reference ranges. Serum IGF-I is the preferred initial screening test due to its stability and reflection of integrated GH secretion. However, interpretation of assay values should consider age, sex, assay variability, and confounding conditions such as diabetes, liver or renal disease, obesity, pregnancy, and estrogen exposure. For discordant biochemical and clinical findings, it is recommended to repeat IGF-I and to measure GH during an oral glucose tolerance test (OGTT). Although random GH levels are often elevated and correlate with somatotroph adenoma size, GH suppression during OGTT is the gold-standard confirmatory test, especially in patients with borderline results. The use of ultrasensitive GH assays has lowered the recommended nadir GH cut-off threshold to ∼0.4 µg/L, with assay-specific considerations. Advances in high-resolution MRI and PET/MRI, alongside AI-driven facial recognition, electronic medical record analysis, and radiomics, offer promising avenues for earlier and more accurate diagnosis of acromegaly.
Graf KE, Adam P, Megerle F
… +18 more, Machlah YM, Soll D, Berr CM, Budde I, Pfob CH, Käsmann L, Fuß CT, Küppers S, Corradini S, Mai K, Schott M, Sandner B, Führer D, Spitzweg C, Fassnacht M, Brandenburg T, Koehler VF, Kroiss M
CONTEXT: Prognosis of anaplastic thyroid cancer (ATC) remains poor. In the absence of immediately actionable molecular alterations, guidelines recommend multimodal therapy including radiotherapy and cytotoxic chemotherap...CONTEXT: Prognosis of anaplastic thyroid cancer (ATC) remains poor. In the absence of immediately actionable molecular alterations, guidelines recommend multimodal therapy including radiotherapy and cytotoxic chemotherapy but optimal regimens are not established. Many centers in Germany have adopted carboplatin-paclitaxel (CP), with or without radiotherapy, as a preferred first-line approach. OBJECTIVE: This study aims to compare the outcome of patients treated first-line with CP±radiotherapy versus other cytotoxic chemotherapy regimens in ATC. DESIGN: Retrospective multicenter registry study in Germany. SETTING AND PATIENTS: 158 adults with histologically confirmed ATC treated with first-line cytotoxic chemotherapy at seven German tertiary centers (2000-2024). MAIN OUTCOME MEASURES: Progression-free survival (PFS) and overall survival (OS) were compared with Kaplan-Meier and log-rank test; Cox proportional hazard model was used to identify risk factors. RESULTS: 97 patients received first-line CP and 61 received other chemotherapy. PFS (102 vs 89 days; log-rank p=0.23) and OS (278 vs 295 days; p=0.50) did not differ between CP and other regimens. Complete response occurred in 13% with CP and 8% with other chemotherapy (p=0.46). In multivariable analyses, age ≥65 years, lymph node metastasis, and distant metastasis were associated with higher mortality risk. Surgery was associated with lower mortality risk. CP was not associated with improved OS. Outcome of second line treatment was not different for chemotherapy vs. kinase inhibition±immunotherapy. CONCLUSION: In this registry study, CP showed no survival benefit in ATC; outcomes depended on disease burden and resectability, underscoring the need for rapid molecular diagnostics. Chemotherapy may serve as a bridging strategy.