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Division of Endocrinology and Metabolism, Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
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NIHR Health Protection Research Unit on Chemical Radiation Threats and Hazards, Imperial College London, London, UK
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NIHR Health Protection Research Unit on Chemical Radiation Threats and Hazards, Imperial College London, London, UK
National Institute for Health Research (NIHR) Health Protection Research Unit in Environmental Exposures and Health, Imperial College London, London, UK
Mohn Centre for Children’s Health and Wellbeing, Imperial College London, London, UK
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NIHR Health Protection Research Unit on Chemical Radiation Threats and Hazards, Imperial College London, London, UK
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NIHR Health Protection Research Unit on Chemical Radiation Threats and Hazards, Imperial College London, London, UK
National Institute for Health Research (NIHR) Health Protection Research Unit in Environmental Exposures and Health, Imperial College London, London, UK
Mohn Centre for Children’s Health and Wellbeing, Imperial College London, London, UK
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Context
Salivary androgens represent non-invasive biomarkers of puberty that may have utility in clinical and population studies.
Objective
To understand normal age-related variation in salivary sex steroids and demonstrate their correlation to pubertal development in young adolescents.
Design, setting and participants
School-based cohort study of 1495 adolescents at two time points for collecting saliva samples approximately 2 years apart.
Outcome measures
The saliva samples were analyzed for five androgens (testosterone, androstenedione (A4), 17-hydroxyprogesterone, 11-ketotestosterone and 11β-hydroxyandrostenedione) using liquid chromatography-mass spectrometry; in addition, salivary dehydroepiandrosterone (DHEA) and oestradiol (OE2) were analysed by ELISA. The pubertal staging was self-reported using the Pubertal Development Scale (PDS).
Results
In 1236 saliva samples from 903 boys aged between 11 and 16 years, salivary androgens except DHEA exhibited an increasing trend with an advancing age (ANOVA, P < 0.001), with salivary testosterone and A4 concentration showing the strongest correlation (r = 0.55, P < 0.001 and r = 0.48, P < 0.001, respectively). In a subgroup analysis of 155 and 63 saliva samples in boys and girls, respectively, morning salivary testosterone concentrations showed the highest correlation with composite PDS scores and voice-breaking category from PDS self-report in boys (r = 0.75, r = 0.67, respectively). In girls, salivary DHEA and OE2 had negligible correlations with age or composite PDS scores.
Conclusion
In boys aged 11–16 years, an increase in salivary testosterone and A4 is associated with self-reported pubertal progress and represents valid non-invasive biomarkers of puberty in boys.
University of Alcalá, Madrid, Spain
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Purpose
The aim of this study was to evaluate the prevalence of autonomous cortisol secretion (ACS) in patients with primary aldosteronism (PA) and its implications on cardiometabolic and surgical outcomes.
Methods
This is a retrospective multicenter study of PA patients who underwent 1 mg dexamethasone-suppression test (DST) during diagnostic workup in 21 Spanish tertiary hospitals. ACS was defined as a cortisol post-DST >1.8 µg/dL (confirmed ACS if >5 µg/dL and possible ACS if 1.8–5 µg/dL) in the absence of specific clinical features of hypercortisolism. The cardiometabolic profile was compared with a control group with ACS without PA (ACS group) matched for age and DST levels.
Results
The prevalence of ACS in the global cohort of patients with PA (n = 176) was 29% (ACS–PA; n = 51). Ten patients had confirmed ACS and 41 possible ACS. The cardiometabolic profile of ACS–PA and PA-only patients was similar, except for older age and larger tumor size of the adrenal lesion in the ACS–PA group. When comparing the ACS–PA group (n = 51) and the ACS group (n = 78), the prevalence of hypertension (OR 7.7 (2.64–22.32)) and cardiovascular events (OR 5.0 (2.29–11.07)) was higher in ACS–PA patients than in ACS patients. The coexistence of ACS in patients with PA did not affect the surgical outcomes, the proportion of biochemical cure and clinical cure being similar between ACS–PA and PA-only groups.
Conclusion
Co-secretion of cortisol and aldosterone affects almost one-third of patients with PA. Its occurrence is more frequent in patients with larger tumors and advanced age. However, the cardiometabolic and surgical outcomes of patients with ACS–PA and PA-only are similar.
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Primary aldosteronism (PA) is associated with urolithiasis as it causes hypercalciuria and hypocitraturia. However, the influence of different subtypes of PA on urinary stone formation remains unclear. This study aimed to evaluate the association between aldosterone-producing adenoma (APA) and the burden of urolithiasis in patients with PA. In the present study, we enrolled 312 patients with PA from a prospectively maintained database, of whom 179 had APA. Clinical, biochemical, and imaging data (including the presence, volume, and density of urinary stones on abdominal computed tomography) were compared between groups, with employment of propensity score matching (PSM) analysis to balance possible confounding factors. Kaplan–Meier analysis was used to estimate the acute renal colic event during follow-up. After PSM for age, sex, serum calcium, phosphate, blood urea nitrogen, creatinine, and uric acid, the APA and non-APA groups had 106 patients each. Patients with APA had higher serum intact parathyroid hormone (iPTH) (79.1 ± 45.0 vs 56.1 ± 30.3, P < 0.001) and a higher prevalence of urolithiasis (27.4% vs 12.3%, P = 0.006) than non-APA patients. During follow-up, a higher incidence of acute renal colic events was noted in the APA group than the non-APA group (P = 0.011); this association remained significant (P = 0.038) after adjustment for age and sex in Cox-regression analysis. Our data suggest that APA is associated with a heavier burden of urolithiasis and higher incidence of renal colic events compared to the non-APA subtype of PA.
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Purpose
To externally validate the performance of the S-GRAS score and a model from the Surveillance, Epidemiology, and End Results (SEER) database in a Chinese cohort of patients with adrenocortical carcinoma (ACC).
Methods
We first developed a model using data from the SEER database, after which we retrospectively reviewed 51 ACC patients hospitalized between 2013 and 2018, and we finally validated the model and S-GRAS score in this Chinese cohort.
Results
Patient age at diagnosis, tumor size, TNM stage, and radiotherapy were used to construct the model, and the Harrell’s C-index of the model in the training set was 0.725 (95% CI: 0.682–0.768). However, the 5-year area under the curve (AUC) of the model in the validation cohort was 0.598 (95% CI: 0.487–0.708). The 5-year AUC of the ENSAT stage was 0.640 (95% CI: 0.543–0.737), but the Kaplan–Meier curves of stages I and II overlapped in the validation cohort. The resection status (P = 0.066), age (P=0.68), Ki67 (P = 0.69), and symptoms (P = 0.66) did not have a significant impact on cancer-specific survival in the validation cohort. In contrast, the S-GRAS score group showed better discrimination (5-year AUC: 0.683, 95% CI: 0.602–0.764) than the SEER model or the ENSAT stage.
Conclusion
The SEER model showed favorable discrimination and calibration ability in the training set, but it failed to distinguish patients with various prognoses in our institution. In contrast, the S-GRAS score could effectively stratify patients with different outcomes.
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Faculty of Life Sciences and Medicine, King’s College London, London, UK
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Faculty of Life Sciences and Medicine, King’s College London, London, UK
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Objective
Succinate dehydrogenase subunit (SDHx) pathogenic variants predispose to phaeochromocytoma and paraganglioma (PPGL). Lifelong surveillance is recommended for all patients to enable prompt detection and treatment. There is currently limited evidence for optimal surveillance strategies in hereditary PPGL. We aim to detail the clinical presentation of PPGL in our cohort of non-index SDHB and SDHD pathogenic variant carriers.
Methods
Retrospective analysis of medical and genetic records from a single tertiary referral centre identified SDHB or SDHD pathogenic variants in 74 non-index cases (56 SDHB and 18 SDHD). Surveillance screening for asymptomatic relatives consisted of annual plasma metanephrine measurement and whole-body MRI with contrast at 3–5 yearly intervals.
Results
Twenty-three out of 74 non-index patients (10 SDHB and 13 SDHD) were diagnosed with PPGL, 17 patients through surveillance screening (24 tumours in total) and 6 diagnosed prior to commencement of cascade screening with symptomatic presentation. MRI with contrast identified PPGL in 22/24 screen-detected tumours and 5/24 tumours had elevated plasma metanephrine levels. Penetrance in non-index family members was 15.2 and 47.2% for SDHB carriers and 71.6 and 78.7% for SDHD carriers at age of 50 and 70 years, respectively.
Conclusion
Surveillance screening with combined biochemical testing and imaging enables early detection of PPGL in asymptomatic relatives with SDHx pathogenic variants. The presence of disease at first screen was significant in our cohort and hence further multi-centre long-term data are needed to inform counselling of family members undergoing lifelong surveillance.
National Institute of Endocrinology CI Parhon, Bucharest, Romania
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National Institute of Endocrinology CI Parhon, Bucharest, Romania
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National Institute of Endocrinology CI Parhon, Bucharest, Romania
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National Institute of Endocrinology CI Parhon, Bucharest, Romania
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Background
Pheochromocytomas (PHEOs) are rare catecholamine-secreting adrenal tumors. Approximately 60–90% of bilateral PHEOs are hereditary. We retrospectively analyzed the clinical characteristics of patients with bilateral PHEOs and the morbidity rate (malignancy, tumor recurrence and adrenal insufficiency (AI) rate) related to surgery technique and genetic status of the patients.
Results
Fourteen patients (12.5%, nine women, five men) had synchronous or metachronous bilateral PHEOs (out of 112 PHEO patients who underwent surgery between 1976 and 2021). The median age at diagnosis was 32 years (9–76) (three were children). Nine patients (64.2%) presented synchronous bilateral tumors, five (35.7%) contralateral metachronous tumors, 2–12 years after the first surgical intervention; three (21.4%) were metastatic. Median follow-up: 5 years (1–41), IQR 19 months. A total of 78.5% had a germline mutation (eight RET gene with MEN2A syndrome, three VHL syndrome, three not tested). Post-surgery recurrence was noted in 16.6% of patients (one with MEN2A syndrome and metastatic PHEOs, one with VHL syndrome), with similar rates after total adrenalectomy or cortical-sparing adrenal surgery. AI was avoided in 40% after cortical-sparing surgery.
Conclusion
Bilateral PHEOs are usually associated with genetic syndromes. The surgical technique for patients with hereditary bilateral PHEOs should be chosen based on a personalized approach, as they are at higher risk for developing new adrenal tumors requiring additional surgeries.
Centre for Endocrinology and Metabolism, Hudson Institute of Medical Research, Victoria, Australia
Department of Endocrinology and Metabolism, BSMMU, Dhaka, Bangladesh
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Centre for Endocrinology and Metabolism, Hudson Institute of Medical Research, Victoria, Australia
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Primary aldosteronism (PA) is the most common cause of endocrine hypertension and is often underdiagnosed. This condition is associated with increased cardiovascular morbidity and mortality in comparison to age and blood pressure matched individuals with essential hypertension (EH). The diagnostic pathway for PA consists of three phases: screening, confirmatory testing, and subtyping. The lack of specificity in the screening step, which relies on the aldosterone to renin ratio, necessitates confirmatory testing. The Endocrine Society’s clinical practice guideline suggests four confirmatory tests, including the fludrocortisone suppression test (FST), saline suppression test (SST), captopril challenge test (CCT), and oral sodium loading test (SLT). There is no universally accepted choice of confirmatory test, with practices varying among centers. The SST and FST are commonly used, but they can be resource-intensive, carry risks such as volume overload or hypokalemia, and are contraindicated in severe/uncontrolled HTN as well as in cardiac and renal impairment. In contrast, CCT is a safe and inexpensive alternative that can be performed in an outpatient setting and can be applied when other tests are contraindicated. Despite its simplicity and convenience, the variability in captopril dose, testing posture, and diagnostic threshold limit its widespread use. This narrative review evaluates the diagnostic accuracy of the CCT across different populations, addresses controversies in its usage, and proposes recommendations for its use in the diagnosis of PA. Furthermore, suggestions for future research aimed at promoting the wider utilization of the CCT as a simpler, safer, and more cost-effective diagnostic test are discussed.
Department of Endocrinology, Sahlgrenska University Hospital, Gothenburg, Sweden
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Department of Endocrinology, Sahlgrenska University Hospital, Gothenburg, Sweden
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Department of Endocrinology, Sahlgrenska University Hospital, Gothenburg, Sweden
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Department of Endocrinology, Sahlgrenska University Hospital, Gothenburg, Sweden
Wallenberg Center for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden
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Objective
It is unknown whether glucocorticoid (GC)-induced adrenal insufficiency may cause premature mortality in GC users. We conducted a retrospective cohort study to investigate if undiagnosed and undertreated GC-induced adrenal insufficiency is a contributor to premature death in GC users.
Methods
Information on dispensed prescriptions in West Sweden from 2007 to 2014 was obtained from the Swedish Prescribed Drug Register. Cause of death was collected from the Swedish Cause of Death Register. Of 223,211 patients who received oral GC prescriptions, 665 died from sepsis within 6 months of their last prescription. Three hundred of these patients who had died in hospital were randomly selected for further investigation. Medical records were initially reviewed by one investigator. Furthermore, two additional investigators reviewed the medical records of patients whose deaths were suspected to be caused by GC-induced adrenal insufficiency.
Results
Of 300 patients (121 females, 40%), 212 (75%) were prescribed GC treatment at admission. The mean age was 76 ± 11 years (range 30–99). Undiagnosed or undertreated GC-induced adrenal insufficiency was considered a probable contributor to death by at least two investigators in 11 (3.7%) patients. In five of these 11 cases, long-term GC therapy was abruptly discontinued during hospitalization. Undiagnosed or undertreated GC-induced adrenal insufficiency was considered a possible contributing factor to death in a further 36 (12%) patients.
Conclusion
GC-induced adrenal insufficiency is an important contributor to premature death in GC users. Awareness of the disorder during intercurrent illness and following cessation of GC treatment is essential.
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Objective
Primary adrenal insufficiency (PAI) is a rare disease with an increasing prevalence, which may be complicated by life-threatening adrenal crisis (AC). Good quality epidemiological data remain scarce. We performed a Belgian survey to describe the aetiology, clinical characteristics, treatment regimens, comorbidities and frequency of AC in PAI.
Methods
A nationwide multicentre study involving 10 major university hospitals in Belgium collected data from adult patients with known PAI.
Results
Two hundred patients were included in this survey. The median age at diagnosis was 38 years (IQR 25–48) with a higher female prevalence (F/M sex ratio = 1.53). The median disease duration was 13 years (IQR 7–25). Autoimmune disease was the most common aetiology (62.5%) followed by bilateral adrenalectomy (23.5%) and genetic variations (8.5%). The majority (96%) of patients were treated with hydrocortisone at a mean daily dose of 24.5 ± 7.0 mg, whereas 87.5% of patients also received fludrocortisone. About one-third of patients experienced one or more AC over the follow-up period, giving an incidence of 3.2 crises per 100 patient-years. There was no association between the incidence of AC and the maintenance dose of hydrocortisone. As high as 27.5% of patients were hypertensive, 17.5% had diabetes and 17.5% had a diagnosis of osteoporosis.
Conclusion
This study provides the first information on the management of PAI in large clinical centres in Belgium, showing an increased frequency of postsurgical PAI, a nearly normal prevalence of several comorbidities and an overall good quality of care with a low incidence of adrenal crises, compared with data from other registries.
IRCCS, Istituto Auxologico Italiano, Milan, Italy
Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
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Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
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Background
Cushing’s syndrome (CS) is a rare condition of chronically elevated cortisol levels resulting in diverse comorbidities, many of which endure beyond successful treatment affecting the quality of life. Few data are available concerning patients’ experiences of diagnosis, care and persistent comorbidities.
Objective
To assess CS patients’ perspectives on the diagnostic and care journey to identify unmet therapeutic needs.
Methods
A 12-item questionnaire was circulated in 2019 by the World Association for Pituitary Organisations. A parallel, 13-item questionnaire assessing physician perceptions on CS patient experiences was performed.
Results
Three hundred twenty CS patients from 30 countries completed the questionnaire; 54% were aged 35–54 and 88% were female; 41% were in disease remission. The most burdensome symptom was obesity/weight gain (75%). For 49% of patients, time to diagnosis was over 2 years. Following treatment, 88.4% of patients reported ongoing symptoms including, fatigue (66.3%), muscle weakness (48.8%) and obesity/weight gain (41.9%). Comparisons with delay in diagnosis were significant for weight gain (P = 0.008) and decreased libido (P = 0.03). Forty physicians completed the parallel questionnaire which showed that generally, physicians poorly estimated the prevalence of comorbidities, particularly initial and persistent cognitive impairment. Only a minority of persistent comorbidities (occurrence in 1.3–66.3%; specialist treatment in 1.3–29.4%) were managed by specialists other than endocrinologists. 63% of patients were satisfied with treatment.
Conclusion
This study confirms the delay in diagnosing CS. The high prevalence of persistent comorbidities following remission and differences in perceptions of health between patients and physicians highlight a probable deficiency in effective multidisciplinary management for CS comorbidities.