European Journal of Endocrinology最新文献

Objective: Evaluate long-term efficacy, safety, and tolerability of once-weekly somapacitan, a long-acting growth hormone (GH) derivative, in children born small for gestational age (SGA) with short stature, including after switching from daily GH.

Design: REAL5 (NCT03878446) is a global, randomized, open-label, controlled phase 2 study comprising a 26-week main phase, 26-week extension I, and an ongoing 4-year extension II.

Methods: Sixty-two children born SGA with short stature were recruited at 38 clinics across 12 countries and randomized (1:1:1:1:1) to somapacitan (0.16, 0.20, or 0.24 mg/kg/week) or daily GH (0.035 or 0.067 mg/kg/day) until week 52 (inclusive main phase and extension I). Sixty participants entered extension II. Forty-eight participants switched to somapacitan 0.24 mg/kg/week from cohorts randomized to daily GH or lower somapacitan doses. Fifty-five children completed 208 weeks of treatment. Novel safety and efficacy results from week 52 to 208 are presented here.

Results: Across all treatment arms, continuous increases in height standard deviation scores were observed from week 52 to week 208, including after switch to somapacitan 0.24 mg/kg/week. The safety and tolerability profile for somapacitan 0.24 mg/kg/week was similar to the well-established safety and tolerability profile for daily GH in SGA. Patient preference questionnaire results indicate that most respondents (87%) prefer somapacitan over daily GH. Most respondents (80%) answered that they expect to be more adherent to treatment with somapacitan.

Conclusions: These results support long-term continuous efficacy, safety, and tolerability of GH therapy with somapacitan 0.24 mg/kg/week for up to 4 years in children born SGA, including after switching from daily GH.

Clinicaltrials.gov: NCT03878446.

Objective: Recent studies suggest a unique disease profile in elderly patients with primary aldosteronism (PA), who have a high prevalence of comorbidities and low clinical cure rate post-adrenalectomy. This study aims to investigate histopathology and genetic characteristics of PA in late adulthood.

Methods: Formalin-fixed, paraffin-embedded adrenal tissue sections from 114 patients with PA who underwent unilateral adrenalectomy at age 60 or older were used. Aldosterone synthase (CYP11B2) immunohistochemistry (IHC) was performed for histopathologic analysis. Somatic DNA variants were identified in aldosterone-producing tissue following CYP11B2 IHC-guided sequencing.

Results: Histopathologic analysis revealed that 56 adrenals contained an aldosterone-producing nodule (APN) (49%), 44 contained an aldosterone-producing adenoma (APA) (39%), 7 contained multiple APN (6%), and 7 contained only non-functioning adenomas [NFA, of which 6 had at least one aldosterone-producing micronodule (APM) in the adjacent tissue] (6%). NFAs were also identified alongside APN/APA in 24 cases. An APN was the most common histologic subtype in men (51/88, 58%), while APA was predominant in women (18/26, 69%). Of 67 APNs with successful sequencing, the majority had variants in CACNA1D (40/67, 60%). KCNJ5 variants were the most common alteration in APA (14/44, 32%).

Conclusions: Older individuals with lateralized PA exhibit distinct genetic and histologic causes of disease with sex differences in mutation prevalence and adrenal histopathology. In APN, the most frequently altered gene is CACNA1D, while KCNJ5 variants are most common in APA. Unlike young patients with PA, the presence of NFA is a frequent observation in late adulthood individuals with PA.

Objective: Endocrine and metabolic diseases are known to be common late effects in childhood cancer survivors (CCS). We assessed the prevalence of these diseases in a large German CCS cohort, and a matched comparison population, using health claims data.

Design: The cohort study was based on record linkage between the nationwide German Childhood Cancer Registry and claims data from 13 major German statutory health insurances.

Methods: The monitored insurance period covered the years 2017-2021. We assessed the frequencies of endocrine and metabolic diseases among 11 863 five-year CCS, diagnosed 1991-2021, with continuous insurance coverage and a matched comparison group of 35 589 insured persons without a history of childhood cancer. We present prevalence and prevalence ratios (PR) with corresponding 95% confidence intervals (95% CI).

Results: At least one endocrine or metabolic disease was recorded in 31.3% of survivors (n = 3716) and in 16.4% of the comparison group (n = 5819, PR = 1.9; 95% CI: 1.8-2.0). The frequency of diseases was higher among females than among males in both groups. The PR was 2.4 (95% CI: 2.3-2.5) for males and 1.6 (95% CI: 1.5-1.7) for females. The frequency of at least one disease increased with increasing attained age. The disease with the highest frequency among CCS was hypothyroidism (15.85%), and the highest PR was estimated for patients with primary thyroid cancer (43.5; 95% CI: 24.2-78.1).

Conclusions: Our study highlights the increased vulnerability of CCS to endocrine and metabolic diseases compared to the general population and underscores the need for risk-adapted surveillance during the whole survivorship trajectory.

Background: Premature pubarche (PP) is characterized by the early onset of pubic or axillary hair, body odor, or mild acne, most commonly reflected by elevated plasma dehydroepiandrosterone-sulfate (DHEA-S) concentrations. However, recent evidence suggests that 11-oxygenated adrenal androgens [11β-hydroxyandrostenedione (11OHA4), 11β-hydroxytestosterone (11OHT)] may better represent true androgenic activity.

Aim: This study aims to evaluate the predictive value of adrenal androgens in determining growth characteristics among girls with PP.

Subjects and methods: A prospective study was conducted to evaluate anthropometric and clinical features and to quantify plasma adrenal androgens-including DHEA, DHEA-S, androstenedione (A4), androsterone, 11OHA4, and 11OHT-using liquid chromatography-mass spectrometry in 53 girls with isolated PP at presentation and during follow-up. Thirty-six age-matched girls without PP served as the control group.

Results: The height, body mass index-standard deviation score (SDS), DHEA, DHEA-S, A4, androsterone, and 17OH-pregnenolone concentrations were higher (P < .0001), whereas no difference in 11OHA4 and 11OHT concentrations was observed in the PP group compared with controls. There was no correlation of adrenal androgen concentrations with height, corrected height, and growth velocity at baseline or during follow-up of 2.7 years. Corrected height SDS was positively correlated with baseline corrected height SDS (r = .63, P < .0001), baseline bone age (BA)/chronological age ratio (r = .31, P = .02), and baseline BA SDS (r = .32, P = .01) but not with hormone concentrations.

Conclusion: Isolated idiopathic PP appears to be a benign variant of normal development. In this setting, adrenal androgen concentrations are not associated with adverse linear growth outcomes and are unlikely to influence clinical management, supporting a conservative approach after exclusion of pathological causes.

Objective: To examine body image (BI) concerns in women with polycystic ovary syndrome (PCOS) by comparing perceptions with normative data, assessing links with psychological distress, clinical features, disordered eating, and quality of life (QoL), and identifying body image cut-offs that predict psychological risk.

Design: Mixed-methods observational study conducted in the United Kingdom (June 2023-October 2024).

Methods: Women with PCOS (n = 171) completed validated questionnaires assessing BI (Multidimensional Body-Self Relations Questionnaire-Appearance Scale), depression, anxiety, disordered eating, and QoL; 41 also participated in semi-structured interviews. Moderation by ethnicity and socioeconomic status (SES) was examined.

Results: Women with PCOS reported greater BI-distress than normative data, driven by elevated body mass index (BMI) and hirsutism. Poorer BI was linked to higher depression, anxiety, disordered eating, and reduced QoL. ROC-analyses identified self-classified weight scores (SW) ≥ 4.25 as the cut-off for depression and overweight preoccupation (OP) ≥ 2.88 for anxiety. In adjusted models, higher SW scores predicted nearly 5-fold greater depression risk, while elevated OP scores conferred a 4-fold higher anxiety risk and doubled disordered eating risk. Together with BMI, OP and SW predicted most PCOS-QoL domains, with the strongest effects in weight-related QoL. Socioeconomic deprivation amplified OP effects on disordered eating, while ethnicity showed minimal influence. Qualitative findings echoed these results, with weight gain, hirsutism, negative diagnostic experiences, and social withdrawal emerging as key distress drivers.

Conclusion: BI concerns are central to psychological morbidity and reduced QoL in PCOS. Establishing OP and SW cut-offs enables early risk stratification, while acknowledging that SES influences may support equitable, patient-centred care.

Background: The transition from paediatric to adult healthcare is a critical period for young individuals with endocrine conditions. Despite numerous published recommendations, Europe still lacks recent, comprehensive, evidence-based, and practically applicable guidelines for endocrine healthcare transition.

Objective: To develop European consensus guidance for transition from paediatric to adult care in endocrine conditions through a structured, evidence-based approach.

Methods: A systematic literature review identified 351 recommendations from 55 articles (2011-2023). Articles were included if they provided recommendations on transition from paediatric to adult care for patients with endocrine diseases or general (non-disease-specific) transition guidance. The guidance was developed by a core multidisciplinary group (n = 7) and refined through focus groups with 18 experts from 10 European countries, representing both paediatric and adult care settings. Patient representatives have reviewed and approved it.

Results: The guidance includes recommendations across 11 domains: structure of transition service, patient empowerment, patient-professional relationship, multidisciplinary team organization, healthcare provider education, timing and planning, care coordination, management of non-attendance, psychological support, parents/caregivers role, and readiness tools. Each recommendation was rated as either "recommend" (strong) or "suggest" (conditional) based on expert consensus and available evidence.

Conclusion: This ESE-ESPE guidance provides a comprehensive, practical framework for endocrine healthcare transition, applicable across different European healthcare settings. The recommendations emphasise structured programs, care coordination, and patient-centred approaches to optimize transition outcomes.

Objectives: To characterize whole-brain cortical thickness alteration in Kallmann syndrome (KS), assess its correlation with cognitive impairment, and explore the genetic association and extrapolated transcriptional underpinning.

Methods: We prospectively recruited 100 patients with KS and 100 age- and sex-matched healthy controls. All participants underwent high-resolution structural MRI and a comprehensive neuropsychological assessment targeting global cognition (Montreal Cognitive Assessment, MoCA), executive function and inhibitory control (Stroop Color and Word Test, SCWT), cognitive flexibility (Trail Making Test, TMT), working memory (Digit Span Test, DST), and visuospatial memory (Visual Reproduction task, VR). Cortical thickness and subcortical volumes were quantified using FreeSurfer. In the KS cohort, we examined brain-cognition correlations, performed exploratory genetic association analysis using whole-exome sequencing, and conducted extrapolated neuroimaging-transcription analysis using the Allen Human Brain Atlas (http://human.brain-map.org/) to identify underlying biological pathways.

Results: Compared to the healthy controls, patients with KS exhibited significant cognitive deficits, with 36% MoCA scoring below the clinical cutoff for cognitive impairment. Domain-specific analysis revealed impairments in SCWT-C, DST-Backward, TMT-B, and VR (all P-value < .05). Structurally, patients showed bilateral increased cortical thickness predominantly in the fronto-limbic circuit (orbitofrontal and subgenual cingulate cortices) and default mode network (voxel P-value < .001, cluster random field theory corrected P-value < .05), alongside bilateral hippocampal enlargement (P-FDR = .048). Crucially, the cortical thickness in these fronto-limbic regions was negatively correlated with SCWT-C and DST. Exploratory genetic analysis linked variants in genes such as OTUD4 and FGFR1 to cognitive variability (TMT-A and VR). Furthermore, the spatial pattern of cortical thickening was significantly associated with extrapolated gene expression profiles enriched for neurodevelopment, neuronal migration, and synaptic function.

Conclusions: This study identified cortical thickening involved in fronto-limbic and default mode network as key neuroanatomical signatures of the patients with KS, which was associated with cognitive impairment. Specific genetic variants may further modulate the structural alterations and cognitive functioning in patients with KS.

Circadian rhythms are a hallmark of life. They are present in numerous physiological functions, including behavioural patterns such as sleep-wake cycles or feeding-fasting behaviour, hormonal secretion, core body temperature, cardiovascular and brain activity, cell regeneration and metabolic processes. Most organisms have developed evolutionarily conserved biological clock mechanisms that effectively react to cyclic changes in the photic environment to synchronize behaviour and physiological processes accordingly. These "pacemaker" like clocks are present in almost every cell and are intrinsically generated to maintain internal rhythms with a cycle frequency of approximately 24 hours. Chronic disruption of circadian rhythms, as in the case of shift work, frequent jet lag or sleep disorders, is increasingly being recognized as an important contributor to adverse health conditions such as cardiovascular disease, neurodegeneration, cancer, bone loss and joint degeneration. The effects of chronic disruption of circadian rhythms on musculoskeletal health are multifactorial, but endogenous glucocorticoids are likely to be involved given their critical role in numerous physiological processes, including bone and mineral homeostasis, systemic metabolism, and the inflammatory response. Of particular interest are the actions of endogenous glucocorticoids in the regulation of intrinsic circadian rhythms. It is well established that glucocorticoids act as a potent internal time signal to synchronize cell-autonomous clocks in peripheral tissues (such as bone and cartilage) with the central master clock in the suprachiasmatic nucleus. Furthermore, disruption to physiological glucocorticoid rhythms can disturb normal rhythms in gene expression, with deleterious effects on bone health. Understanding how glucocorticoids regulate skeletal molecular clocks and bone remodelling during disruption of circadian rhythms may provide opportunities to mitigate the effects of shift work on skeletal homeostasis. This review will focus on the interactions between circadian rhythms and glucocorticoid actions in bone and cartilage and their role in skeletal pathology.

Objective: Bilateral macronodular adrenocortical disease (BMAD) is a rare disorder characterized by bilateral adrenocortical nodules and variable cortisol excess. ARMC5 is a well-established genetic driver of BMAD, but data in East Asian populations are limited. We investigated the prevalence of pathogenic variants and genotype-phenotype correlations in Korean patients with BMAD.

Methods: A total of 69 patients with BMAD were retrospectively enrolled at Seoul National University Hospital (2009-2023). Whole-exome sequencing was performed for 35 patients. Clinical, biochemical, and imaging data were analyzed. Serum steroid profiling was conducted using liquid chromatography-tandem mass spectrometry (LC-MS/MS) to quantify 18 adrenal-derived steroids.

Results: The mean age of the cohort was 66.4 years, and 58% were male. Most had mild autonomous cortisol secretion (79.7%), and 15.9% had overt Cushing syndrome. Among the 35 patients who underwent genetic testing, 22.9% harbored pathogenic/likely pathogenic (P/LP) variants in ARMC5. P/LP ARMC5 variant carriers had lower BMI (25.0 vs 27.4 kg/m2), larger maximal tumor diameter (4.1 vs 2.7 cm), and greater total adrenal volume (19.8 vs 15.3 cm3). LC-MS/MS profiling revealed that P/LP ARMC5 carriers had significantly higher cortisol (153.1 vs 100.6 ng/mL), corticosterone (16.5 vs 1.3 ng/mL), and 18-hydroxycortisol concentrations (1.66 vs .66 ng/mL) (P < .05).

Conclusion: This study in a Korean cohort with BMAD showed that P/LP ARMC5 variants were present in 22.9% of the genetically investigated patients and were associated with more severe radiological and steroidogenic features. These findings underscore the importance of closely monitoring patients with BMAD who carry ARMC5 P/LP variants.