Abstract The global rise in aging populations has been accompanied by increasing rates of obesity and type 2 diabetes, both of which pose significant public health and economic challenges. This review aims to investigate the pathophysiological link between obesity and diabetes and evaluate emerging therapeutic strategies that involve glucagon-like peptide-1 receptor and melanocortin-4 receptor agonists, including their dual and triple agonist developments. A comprehensive literature review was conducted focusing on the mechanisms of glucagon-like peptide-1 receptor and melanocortin-4 receptor agonists, their clinical efficacy, and the evolution of combination therapies. Emphasis was placed on recent clinical trials and the development of oral agonist formulations to improve patient compliance. Glucagon-like peptide-1 receptor agonists, such as semaglutide and liraglutide, promote insulin secretion, suppress appetite, and result in effective weight loss and glycemic control. Semaglutide is available in both injectable and oral forms, improving accessibility. Liraglutide also reduces cardiovascular risk. Melanocortin-4 receptor agonists act via the central nervous system to reduce appetite and increase energy expenditure, with setmelanotide showing efficacy in genetic obesity. Dual and triple agonists, such as tirzepatide, simultaneously target glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide, and glucagon receptors, leading to enhanced metabolic outcomes. Oral drugs like rybelsus improve long-term adherence. Glucagon-like peptide-1 receptor and melanocortin-4 receptor agonists, particularly when used as dual or triple agents, represent promising therapeutic innovations for obesity and type 2 diabetes. The development of oral formulations further enhances treatment convenience and adherence, paving the way for improved clinical outcomes.
Laparoscopic sleeve gastrectomy (LSG) is an effective surgical intervention for morbid obesity, yet early hormonal changes contributing to metabolic adaptation remain underexplored. The objective of this study was to evaluate the early postoperative changes in the energy-regulating hormones irisin and nesfatin-1 following LSG in obese female patients. These hormones were selected due to their established roles in metabolic regulation and appetite control. This preliminary study included 27 women with obesity (body mass index, BMI>40 kg/m² or>35 kg/m² with comorbidities) undergoing LSG. Serum irisin and nesfatin-1 levels, body composition, and standard metabolic parameters were assessed preoperatively and at 1 month postoperatively. ELISA assays were used for hormone quantification. Repeated measures ANOVA and Spearman's correlation analyses were applied. One month postoperatively, serum irisin levels showed a significant increase (p<0.001), whereas nesfatin-1 levels demonstrated a significant decrease (p<0.001). Interestingly, nesfatin-1 exhibited a significant positive correlation with fat mass in the preoperative period; however, this relationship shifted to a negative correlation following the surgery, suggesting a potential alteration in regulatory mechanisms post-intervention. Reductions in BMI, fat mass, and muscle mass and improvements in glycemic and lipid profiles were also observed. The findings of this study reveal significant early postoperative shifts in irisin and nesfatin-1 levels following LSG, underscoring the potential regulatory role of these hormones in the body's initial metabolic adaptation to surgical weight loss.
ABSTRACT:Hashimoto's thyroiditis causes cell death, hypothyroidism, and insulin resistance. Cholecystokinin, orexin-A, and cocaine and amphetamine-regulated transcript are essential regulators of various endocrine and autonomic processes, including food intake. We aimed to determine the cocaine and amphetamine-regulated transcript, orexin-A, and cholecystokinin levels in Hashimoto's thyroiditis patients and assess the relationships between the metabolic parameters and Hashimoto's thyroiditis. The present study was carried out in 45 Hashimoto's thyroiditis patients and 40 healthy control groups. Serum cocaine and amphetamine-regulated transcript levels (p<0.05), homeostatic model assessment for insulin resistance (p<0.05) and body mass index (p<0.05) were significantly higher in Hashimoto's thyroiditis patients compared to the controls. Serum orexin-A levels were lower in Hashimoto's thyroiditis patients than those in the controls (p<0.05). Serum cholecystokinin levels were similar between the two groups. A negative correlation was observed between orexin-A levels and cocaine and amphetamine-regulated transcript and cholecystokinin levels (r =-0.365, p<0.05; r=- 0.297, p<0.05, respectively). A positive correlation was observed between cocaine and amphetamine-regulated transcript levels and body mass index, insulin, and homeostatic model assessment for insulin resistance levels (r=0.448, p<0.01; r=0.489, p<0.01; r=0.492, p<0.01, respectively). Increased cocaine and amphetamine-regulated transcript and decreased orexin-A levels may be involved in the pathogenesis of Hashimoto's thyroiditis by controlling the thyroid-dependent immune system, insulin resistance, appetite, and body weight. We believe that our findings will lead to new developments in the diagnosis and treatment of this disease.
Abstract:This cross-sectional study aimed to explore the relationship between thyroid peroxidase antibody (TPOAb) and osteoporosis, and the moderating effect of visceral-to-subcutaneous fat area ratio (VSR). A total of 128 males aged over 60 years with normal thyroid function and positive TPOAb (>9 IU/ml) were included. Lumbar spine, femoral neck, and whole-body bone mineral density (BMD) were measured by dual-energy X-ray absorptiometry. Visceral fat area (VFA) and subcutaneous fat area (SFA) were measured by the Omron DUALSCAN device. The relationships between TPOAb, VSR, interaction term (VSR*TPOAb) and BMD were analyzed using multiple linear regression models. Further subgroup analyses were performed stratified by VSR tertiles. TPOAb showed a significant negative correlation with BMD in the unadjusted model (p<0.01). However, when adjusted for confounding covariates, the correlation between TPOAb and BMD was no longer statistically significant (p>0.05). Further analysis showed VSR and the interaction term (VSR*TPOAb) were significantly negative associated with BMD in fully adjusted model (p<0.01). Subgroup analysis, stratified by VSR tertiles, showed that TPOAb only in T3 group (VSR>0.67) was negatively associated with lumbar spine and whole-body BMD (p<0.05). Hence, the relationship between TPOAb and BMD in elderly males varies with VSR. The abnormal body fat distribution may be a key moderator of the TPOAb-BMD relationship, suggesting the necessity for personalized bone health monitoring. Specifically, for patients with VSR>0.67, TPOAb screening is of great significance for the early prevention of osteoporosis.
ABSTRACT:Pediatric growth hormone deficiency requires dynamic testing for accurate diagnosis because of the pulsatile secretion of growth hormone. The insulin tolerance test (ITT) is regarded as one of the most robust individual provocative tests for growth hormone deficiency, although the broader pediatric diagnostic standard requires a composite of auxological, clinical, and biochemical criteria together with an inadequate response to two independent stimulation tests, except in specific high-probability contexts; insulin-like growth factor-1 (IGF-1) alone has limited diagnostic accuracy. This study evaluated whether combining low IGF-1 levels with a single failed ITT could improve diagnostic efficiency for pediatric growth hormone deficiency. We conducted a retrospective cohort study of 214 children with short stature (aged 2-16 y) evaluated at King Chulalongkorn Memorial Hospital between August 2019 and January 2025. Growth hormone deficiency was confirmed in 63 patients using two growth hormone stimulation tests (peak growth hormone level: < 7 ng/mL). IGF-1 levels were expressed as standard deviation scores and analyzed at cutoff values of ≤ -1, -1.5, -2, and -2.5 in combination with failed ITT results. Diagnostic performance indices were calculated at each predefined cutoff/test combination, including sensitivity, specificity, positive predictive values, negative predictive values, area under the receiver operating characteristic curve, odds ratios, and accuracy. An IGF-1 standard deviation score of ≤ -2.5 combined with a single failed ITT showed a sensitivity of 38.6% and a specificity of 92.6%, with a positive predictive value and a negative predictive value of 73.9% and 73.5%, respectively (p<0.001). Because the reference standard for the growth hormone deficiency required failure of two stimulation tests, one of which was the ITT, we assessed this circularity directly: among 100 patients with both the ITT and clonidine results, findings were discordant in 37 (exact McNemar p=0.008), and IGF-1 standard deviation scores did not differ significantly across concordant and discordant subgroups (Kruskal-Wallis p=0.407). An IGF-1 standard deviation score cutoff of ≤ -2.5 combined with a single failed ITT identifies a subgroup of children at higher probability of growth hormone deficiency who may be prioritized for confirmatory evaluation. Given the modest sensitivity and positive predictive values of this criterion and the circularity inherent in a reference standard that itself incorporates the ITT, these findings should be regarded as hypothesis-generating rather than as a basis for changing current diagnostic practice, which continues to require two independent stimulation tests except in specific high-probability contexts; prospective, multicenter validation is required.
Abstract:This meta-analysis aimed to clarify the association between glucagon-like peptide-1 receptor agonists, used for weight management in obesity, and the risks of pancreatitis and pancreatic cancer. We systematically searched PubMed, Web of Science, Embase, the Cochrane Library, and Scopus through June 15, 2026, for clinical studies conducted in obese populations. Peto odds ratios with 95% confidence intervals were calculated. Heterogeneity was assessed using I² statistic, and random-effects models were applied when I² exceeded 60%. Subgroup analyses were conducted according to study design, follow-up duration, control type, glucagon-like peptide-1 receptor agonist agent type, and dose regimen. Leave-one-out sensitivity analyses were additionally performed. This meta-analysis included 52 studies. The pooled analysis demonstrated no significant association between glucagon-like peptide-1 receptor agonist use and pancreatic cancer (odds ratio=1.34; 95% confidence interval: 0.76-2.34; p=0.31) or pancreatitis (odds ratio=1.29; 95% confidence interval: 0.91-1.84; p>0.05). Additional subgroup analyses according to study design, follow-up duration, control type, and dose regimen yielded findings consistent with the primary analyses. Leave-one-out sensitivity analyses were performed to assess the robustness of the pooled estimates. Glucagon-like peptide-1 receptor agonists used for weight management in obesity were not associated with an increased risk of pancreatitis or pancreatic cancer. The consistency of findings across multiple subgroup and sensitivity analyses further supports the pancreatic safety profile of glucagon-like peptide-1 receptor agonists.
Abstract:In type 2 diabetes, hyperglycaemia usually clusters with atherogenic dyslipidaemia and low-grade inflammation; yet, these axes may dissociate in some patients. We aimed to estimate the prevalence of a normolipidemic dysglycemia phenotype in adults with type 2 diabetes and characterise its clinical-biochemical profile within an analytical window free of lipid-lowering and chronic anti-inflammatory/immunomodulatory therapy. In this retrospective, cross-sectional study, we analysed records of 1,046 adults aged 25-60 years with type 2 diabetes from a tertiary care hospital between 2020 and 2024. Individuals with other diabetes types, acute inflammatory conditions, malignancy, advanced organ failure and non-euthyroid status were excluded. Normolipidemic dysglycemia was defined as glycated hemoglobin≥64 mmol/mol with low-density lipoprotein cholesterol<100 mg/dL, triglycerides<150 mg/dL, high-density lipoprotein cholesterol≥40 mg/dL in men or≥50 mg/dL in women, and high-sensitivity C-reactive protein<5 mg/l in the absence of lipid-lowering or chronic anti-inflammatory/immunomodulatory therapy. Comparative analyses were restricted to a hyperglycaemic subpopulation free of lipid-lowering and chronic anti-inflammatory/immunomodulatory therapy (glycated hemoglobin≥64 mmol/mol; n=183), while glucose-lowering treatment status was recorded separately and evaluated as a potential confounder. Normolipidemic dysglycemia was identified in 47/1,046 individuals (prevalence: 4.49%; 95% confidence interval: 3.40-5.92) and 47/183 individuals (prevalence: 25.7%; 95% confidence interval: 19.9-32.5) within the analytical subpopulation. Compared with atherogenic dysglycemia, normolipidemic dysglycemia showed lower triglycerides, lower high-sensitivity C-reactive protein, higher high-density lipoprotein cholesterol, higher fasting plasma glucose and higher creatinine-based estimated glomerular filtration rates. In multivariable models, higher fasting plasma glucose, longer diabetes duration and higher creatinine-based estimated glomerular filtration rates remained associated with normolipidemic dysglycemia, whereas age, sex and body mass index were not independently associated with normolipidemic dysglycemia. These findings identify a clinically detectable subgroup in which marked hyperglycaemia coexists with relatively preserved lipid and inflammatory markers. The normolipidemic dysglycemia construct reflects metabolic heterogeneity rather than established prognostic distinction and requires prospective validation with cardiovascular and renal outcomes.
Abstract:Lipedema is a chronic disorder characterized by disproportionate subcutaneous fat accumulation and pain, with an incompletely understood inflammatory component. It remains unclear whether this inflammatory profile is disease-specific or primarily driven by coexisting adiposity. This study aimed to evaluate systemic inflammatory markers in women with lipedema compared with women with obesity and normal-weight controls. This retrospective study included 229 women aged 30-65 years: 78 with lipedema, 76 with obesity without lipedema, and 75 normal-weight controls. Demographic and laboratory data were obtained from medical records. Inflammatory indices, including the neutrophil-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, platelet-to-lymphocyte ratio, systemic immune-inflammation index, C-reactive protein-to-albumin ratio, and C-reactive protein-albumin-lymphocyte index, were calculated. Group comparisons were performed using one-way analysis of variance with appropriate post hoc tests. Age was similar across groups, whereas body mass index was significantly higher in the lipedema and obesity groups than in controls (p<0.001). The erythrocyte sedimentation rate, C-reactive protein level, and CAR were significantly higher in both the lipedema and obesity groups compared with controls, whereas no significant differences were observed between lipedema and obesity groups. The neutrophil-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, platelet-to-lymphocyte ratio, systemic immune-inflammation index, and C-reactive protein-albumin-lymphocyte index did not differ significantly among groups. Inflammatory indices were generally comparable across lipedema grades. These findings suggest that lipedema is associated with low-grade systemic inflammation; however, its inflammatory profile largely overlaps with obesity, indicating shared inflammatory mechanisms rather than a distinct systemic inflammatory phenotype. Among the evaluated markers, C-reactive protein-based parameters, particularly the C-reactive protein-to-albumin ratio, appeared to better reflect inflammatory burden than hematological composite indices.
Abstract:Understanding the determinants that influence parents' decisions to participate with their infants in primary prevention trials is essential for achieving representative study samples and ensuring the generalizability of outcomes. We analyzed quantitative and qualitative data collected from infants eligible for the Primary Oral Insulin Trial (N=2,750) or the Supplementation with B. INfantis for Mitigation of Type 1 Diabetes Autoimmunity Trial (N=3,309). Both trials were conducted within the Global Platform for the Prevention of Autoimmune Diabetes between 07/2017 and 04/2024. Among all eligible infants, a longer decision time (odds ratio: 1.01, 95% confidence interval: 1.00-1.01, and p=0.002), having a first-degree relative with type 1 diabetes (odds ratio: 2.18, 95% confidence interval: 1.95-2.43, and p<0.001), and a higher maternal age (odds ratio: 1.03, 95% confidence interval: 1.01-1.05, and p=0.003) were associated with a higher likelihood of participation, whereas infants born in fall (odds ratio: 0.85, 95% confidence interval: 0.73-0.98, and p=0.03) and families with longer travel distances to the study center (odds ratio: 0.97, 95% confidence interval: 0.95-0.99, and p=0.01) were less likely to participate. Participation was lower in the Supplementation with B. INfantis for Mitigation of Type 1 Diabetes Autoimmunity Trial than in the Primary Oral Insulin Trial (odds ratio: 0.86, 95% confidence interval: 0.78-0.96, and p=0.005), and stratified analyses indicated that some factors, such as recruitment during the COVID-19 pandemic, affected participation differently between studies. Analysis of qualitative data from 638 families identified additional factors, including the parental perception of the child's risk for type 1 diabetes and the burden of participation. In conclusion, this study identifies both general and study-specific determinants and reasons of participation and non-participation in infant primary prevention trials.
Abstract:Diabetes mellitus (DM) and hypercortisolemia are closely associated endocrine disorders that significantly affect glucose metabolism; however, their direct organ-specific interactions remain incompletely understood. This study aimed to comparatively evaluate the effects of experimental DM on the adrenal gland and glucocorticoid-induced hypercortisolemia on the pancreas. Thirty male Wistar albino rats were allocated into three groups: control, DM (streptozotocin, 20 mg/kg), and hypercortisolemia (prednisolone, 10 mg/kg/day) for 30 days. Postprandial glucose levels were measured. Pancreatic and adrenal tissues were examined using histopathological and immunohistochemical methods to assess insulin, glucagon, and insulin receptor expression. Both experimental conditions were associated with histopathological alterations in endocrine tissues. The DM group exhibited degenerative changes in pancreatic islets, while the hypercortisolemia group showed structural alterations in both pancreatic islets and adrenal cortex. Immunohistochemical analysis revealed reduced insulin and insulin receptor expression in both groups. Postprandial glucose levels were significantly elevated (p<0.001), including in the hypercortisolemia group, supporting the hyperglycemic effect of glucocorticoid exposure. These findings suggest that both DM and glucocorticoid excess are associated with structural and functional alterations in endocrine tissues. These findings suggest that both DM and glucocorticoid excess are associated with parallel structural and functional alterations in endocrine tissues, rather than indicating a direct bidirectional interaction. Further molecular studies are required to clarify the underlying mechanisms and causal relationships. These findings highlight that each condition induces structural alterations in the reciprocal endocrine organ, suggesting cross-organ vulnerability under metabolic stress.
Abstract:The potential association between mild autonomous cortisol secretion and psychopathological symptoms remains inadequately studied. This study aimed to investigate whether women with mild autonomous cortisol secretion exhibit greater psychological symptom severity and distress compared with patients with nonfunctional adrenal adenomas, as assessed by multidimensional self-report scales including the Beck Depression Inventory-II, Beck Anxiety Inventory, and Symptom Checklist‑90. A cross-sectional study was conducted at the endocrinology department of a tertiary-care hospital in Turkey between June 2022 and 2025. The study cohort included 91 women with adrenal adenomas, comprising 50 patients with mild autonomous cortisol secretion and 41 patients with nonfunctional adrenal adenoma. Questionnaire-derived scores from the 10 subscales and Global Severity Index of the Symptom Checklist-90, as well as the Beck Anxiety Inventory and Beck Depression Inventory-II, along with hormonal parameters, including morning cortisol, adrenocorticotropic hormone, dehydroepiandrosterone sulfate, 1-mg dexamethasone-suppressed cortisol, 24-hour urinary free cortisol, the dehydroepiandrosterone sulfate ratio, and the cortisol/dehydroepiandrosterone sulfate ratio, were compared between the groups. Women with mild autonomous cortisol secretion exhibited higher overall psychological distress, as measured by the Global Severity Index of the Symptom Checklist-90. Depressive (Beck Depression Inventory-II) and anxiety (Beck Anxiety Inventory) symptoms did not differ significantly between groups, although a non-significant pattern suggested that depressive symptom severity may increase with higher basal cortisol levels. No significant associations were found between hormonal parameters and psychological scores. These findings indicate that patients with mild autonomous cortisol secretion may experience increased general psychological distress, highlighting the importance of considering mental health in their clinical evaluation and warranting further research into the relationship between mild cortisol excess and specific psychiatric symptoms.
Abstract:We are seeing an exploding expansion of antisemitic attacks worldwide, raising concerns about their potential impact on biological stress regulation and health. Antisemitism is a historically persistent and structurally embedded form of social exclusion that may contribute to chronic psychosocial stress exposure. Building on research into intergenerational trauma, including neuroendocrine alterations in Holocaust survivors and their descendants, this commentary integrates psychometric, empirical, and conceptual approaches to propose a biologically grounded framework linking antisemitism to endocrine and cardiometabolic processes. Preliminary findings from a pilot study using a Checklist of Antisemitic Perception instrument, in combination with established psychometric measures, indicate an increased psychological burden associated with antisemitic experiences, with clinically relevant symptom levels observed across groups. Mechanistically, chronic stress is mediated by neuroendocrine pathways involving the hypothalamic-pituitary-adrenal axis, autonomic nervous system, and immune regulation, contributing to allostatic load and cardiometabolic risk. Emerging evidence suggests that stress responses are heterogeneous and influenced by individual coping styles, with distinct allostatic set-points and associated neurobiological adaptations, including alterations in striatal glutamatergic signaling. Institutional and discursive contexts may further modulate exposure to antisemitic stressors, as reflected in heterogeneous professional engagement and variations in thematic emphasis within medical discourse. Taken together, these observations support the conceptualization of antisemitism as a chronic stressor with potential biological consequences and highlight the importance of integrating psychometric and biological approaches in future research.
Abstract Severe acute respiratory syndrome coronavirus-2 infection is a systemic disease associated with metabolic and hormonal disturbances, including thyroid dysfunction such as primary hypothyroidism, subacute thyroiditis, and non-thyroidal illness syndrome. This study aimed to investigate the association between severe acute respiratory syndrome coronavirus-2 infection and changes in thyroid function during hospitalization and follow-up and evaluate whether these alterations are related to disease severity. We retrospectively analyzed a random cohort of 500 patients admitted to the Medicine Department of a central hospital between March 2020 and 2022. After excluding deaths, prior thyroid disease, and cases without thyroid evaluation, 218 patients were included. Serum thyroid-stimulating hormone, free triiodothyronine and free thyroxine values were measured at admission and after hospitalization. Patients were classified as having thyrotoxicosis, hypothyroidism, isolated hypothyroxinemia, and non-thyroidal illness syndrome. Thyroid dysfunction was defined by compatible biochemical findings with serological and/or imaging evidence of thyroid pathology and/or the need for therapy. COVID-19 cases were grouped by severity. Non-thyroidal illness syndrome was the most frequent abnormality, followed by isolated hypothyroxinemia and primary hypothyroidism. Non-thyroidal illness syndrome was more common in severe cases of COVID-19, although no statistically significant association was found between disease severity and type of thyroid abnormality. Most reassessed patients showed normalization of thyroid function during follow-up. The small sample size may have limited statistical power. Thyroid function alterations are common in severe acute respiratory syndrome coronavirus-2 infection, transient, and more frequent in severe disease. These findings suggest an adaptive response to systemic stress and inflammation. Larger prospective studies are needed to clarify evolution and clinical impact.
Abstract:Epidermal growth factor plays an important role in cervical maturation and tissue remodeling during pregnancy. This study aimed to investigate the association between maternal serum epidermal growth factor levels measured at 37 weeks of gestation and late-term delivery. This single-center case-control study was conducted at a tertiary maternity hospital. Low-risk pregnant women were enrolled, and high-risk pregnancies were excluded. Maternal blood samples were collected at 37 weeks of gestation prior to the onset of labor. Serum epidermal growth factor concentrations were measured using an enzyme-linked immunosorbent assay. Participants were classified according to the gestational age at delivery as late-term pregnancies or term controls. Demographic characteristics, obstetric outcomes, mode of delivery, neonatal outcomes, and serum epidermal growth factor levels were compared between groups. A total of 83 pregnant women were included, of whom 35 women delivered at the late term and 48 women delivered at term. The maternal age, body mass index, obstetric history, and Apgar scores did not differ significantly between groups. The gestational age at delivery and birth weight were significantly higher in the late-term group (p=0.001 and p=0.004, respectively). Cesarean delivery was more frequent among late-term pregnancies (70.8% vs 40%, p=0.005). Mean maternal serum epidermal growth factor levels were significantly lower in the late-term group compared with term controls (28.8±9.8 ng/L vs 56.7±27.3 ng/l, p=0.005). Maternal serum epidermal growth factor levels measured at 37 weeks of gestation were significantly lower in pregnancies resulting in late-term delivery. These findings suggest that altered epidermal growth factor regulation may be associated with prolonged gestation and delayed cervical maturation.
Abstract:Ambulatory hypercalcemia is a proxy for primary hyperparathyroidism. Reports of an increased incidence of hypercalcemia and undiagnosed primary hyperparathyroidism in several electronic medical record studies have prompted a population-based trend analysis of serum calcium. Data from the 2000-2020 U.S. National Health and Nutritional Examination Survey were used to study the trend of serum calcium and related factors. The NHANES has contemporary insight into the ambulatory state of health in the large and diverse U.S. population. Joinpoint regression estimated yearly changes of serum calcium and related factors using annual percentage changes. Serum calcium levels increased by an average of 0.65 mg/dL/y from 2000 to 2004 and then decreased on average by 0.12 mg/dL annually from 2004 to 2020. Among women, serum calcium levels increased by an average of 0.69 mg/dL/y from 2000 to 2004 but then decreased on average by 0.13 mg/dL annually from 2004 to 2020. Among men, serum calcium levels increased by an average of 0.61 mg/dL/y from 2000 to 2004 and then remained stable. Trends of body mass index increased by an average of 0.49/y from 2014 to 2020. Ambulatory hypercalcemia is a proxy for primary hyperparathyroidism. Over 20 years in the U.S. National Health and Nutritional Examination Survey (2000-2020), calcium levels have been decreasing slightly since 2004 after an increase while body mass index has been increasing since 2014. These data conflict with reported observations of the undiagnosed and increased incidence of primary hyperparathyroidism. These data may ultimately serve to refine primary hyperparathyroidism data phenotype for machine learning deployed within an electronic medical record.
Abstract:Adrenalectomy and conservative management are therapeutic approaches for mild autonomous cortisol secretion; however, their comparative clinical impact in routine practice remains uncertain. We aimed to evaluate real-world hormonal, clinical, and metabolic outcomes according to the treatment strategy in patients with mild autonomous cortisol secretion. This single-center retrospective observational study included consecutive patients with adrenal incidentaloma fulfilling guideline-based diagnostic criteria for mild autonomous cortisol secretion between January 2015 and December 2024. Sixty-five patients with complete hormonal evaluation and follow-up data were analyzed and classified into surgery (n=23) and conservative (n=42) groups. Demographic characteristics, adenoma features, comorbidities, hormonal parameters, and metabolic outcomes were assessed at baseline and at the final follow-up. The median follow-up duration was approximately 3 years and similar between groups (p>0.05). At baseline, the body mass index, adenoma size, and cortisol levels after the 1-mg dexamethasone suppression test were significantly higher, while adrenocorticotropic hormone levels were lower in the surgery group (p=0.02, p=0.02, p=0.036, and p<0.01, respectively). During the follow-up, adrenocorticotropic hormone levels increased and post-dexamethasone suppression test cortisol levels significantly decreased after adrenalectomy (p=0.001 and p=0.036, respectively), whereas metabolic parameters and comorbidity profiles remained largely unchanged. In the conservative group, total cholesterol increased modestly over time (p=0.048), with no significant changes in other clinical outcomes. No significant difference in comorbidity progression was observed between treatment strategies. In this real-world cohort, adrenalectomy resulted in clear hormonal improvement without parallel short-term metabolic or clinical benefits compared with conservative management. These findings highlight the heterogeneous clinical expression of mild autonomous cortisol secretion and underscore the importance of individualized patient selection for surgery.
Abstract:Hypoestrogenism causes an imbalance in bone homeostasis, which can affect bone microarchitecture and result in loss of tissue strength and increased risk of fractures. Physical training and melatonin can act on bone formation; however, in a state of hypoestrogenism, the potential effect of the combination of both interventions is not understood. The aim of this study was to investigate the effect of 12 weeks of swimming physical training associated with melatonin administration on the mineral content and biomechanical parameters in bone tissue under hypoestrogenism conditions. The animals (Wistar rats) performed an incremental swimming test to determine the individual anaerobic lactacidemic threshold and underwent bilateral ovariectomy. The interventions consisted of physical training (30 min, 5 d/wk, 90% of individual anaerobic lactacidemic threshold) and melatonin administration (10 mg/kg/d via gavage). After 12 weeks, the femur was collected for the analysis of calcium and phosphorus contents and the three-point flexion test to obtain biomechanical parameters. Data were expressed as mean±standard deviation, subjected to factorial analysis of variance and the Newman-Keuls post hoc test (a significance level of 5%). The association of endurance physical training with melatonin administration resulted in a significant increase in calcium and phosphorus contents, while presenting a significant increase in the capacity to support a greater maximum load and promote rigidity to bone tissue. Considering the detrimental impact of hypoestrogenism on bone tissue, both interventions, endurance physical training and melatonin administration, were able to generate beneficial results regarding the bone mineral content, influencing the improvement of biomechanical parameters that determine tissue strength, which can prevent bone fracture.
Abstract:Thyrotoxicosis is associated with heightened adrenergic activity, arrhythmogenic susceptibility, and procoagulant alterations; yet, its contribution to sudden death outside overt thyroid storm remains incompletely understood. We retrospectively screened 975 consecutive autopsies and identified 7 cases with biochemical evidence of thyroid hormone excess defined by elevated free T3 and/or free T4 levels. Clinical background, medication exposure, thyroid-related biomarkers, including thyroglobulin, thyroid autoantibodies, and interleukin-6, together with detailed histopathological examination of the thyroid gland and the cardiovascular system, were integrated to assess the potential contribution of thyroid hormone excess to the fatal outcome. Targeted genetic analysis was additionally performed in selected cases. Two cases fulfilled clinicopathological criteria for thyroid storm and showed markedly elevated IL-6 concentrations, suggesting severe systemic decompensation. In the remaining cases, death was attributed to structural cardiovascular or cerebrovascular pathology, including intracerebral hemorrhage, acute coronary thrombosis with plaque rupture, hydrocephalus, or presumed arrhythmic mechanisms. Biochemical thyrotoxicosis was observed even in the absence of thyroid-stimulating hormone suppression, and exogenous or treatment-associated thyrotoxicosis was sometimes accompanied by thyroid atrophy rather than hyperplasia. These findings indicate that thyroid hormone excess detected at autopsy represents a clinicopathological spectrum ranging from primary thyroid-driven death to contexts in which thyrotoxicosis functions as a physiological modifier that lowers the threshold for fatal cardiovascular events. Integrative interpretation of biochemical, pathological, and clinical findings may improve the understanding of thyroid hormone-mediated vulnerability in sudden death.
Purpose The purpose of this study was to describe a novel heterozygous missense variant in the nuclear receptor subfamily 3 group C member 1 ligand-binding domain causing primary generalized glucocorticoid resistance and highlight diagnostic pitfalls that can mimic Cushing's disease. Clinical case A 22-year-old woman was evaluated for suspected Cushing's disease after elevated cortisol levels and pituitary imaging findings. She underwent three transsphenoidal surgeries, but hypercortisolism and clinical symptoms including hirsutism, acne, menstrual irregularities, and weight gain persisted. The absence of classical Cushing's stigmata prompted genetic evaluation, which led to the diagnosis of primary generalized glucocorticoid resistance. Methods Whole-exome sequencing was performed in the index case. The identified variant was validated by Sanger sequencing and segregation analysis was carried out in her sister. Results A novel heterozygous, likely pathogenic missense variant (NM_000176.3:c.1940T>C, p.(Leu647Pro)) in the nuclear receptor subfamily 3 group C member 1 gene was detected in two siblings. Conclusions We describe a novel nuclear receptor subfamily 3 group C member 1 variant associated with primary generalized glucocorticoid resistance, expanding the mutational spectrum of glucocorticoid receptor defects. This case underscores the importance of considering primary generalized glucocorticoid resistance in patients with adrenocorticotropic hormone-dependent hypercortisolism lacking typical Cushing's features to prevent unnecessary invasive procedures and guide appropriate genetic counseling
This study in central precocious puberty girls receiving gonadotropin-releasing hormone analogues for 18 months aimed to compare leuprorelin biannual (6-mo subcutaneous leuprorelin, group 1, n=13) with the quarterly (3-mo intramuscular leuprorelin, group 2, n=10) on height, pubertal progression, and adverse events.Twenty-three girls aged 5.7-9.0 years with median bone age advancement (2.7 y and 2.3 y, respectively) underwent clinical visits every 3 months, including pelvis, breasts and injection site ultrasound and luteinizing hormone measurements 2 hours after and 1 week after gonadotropin-releasing hormone analogue administration. Bone age was determined every 6 months.Both protocols were able to stop height lost (stabilization of one age adjusted height standard deviation score: group 1=-1.1 to -1.1 and group 2=-0.2 to -0.1, respectively). The difference between bone age and chronological age was significantly reduced in group 1 (p=0.001) and showed a trend in group 2 (p=0.08). The body mass index-standard deviation score remained similar. A decreased breast diameter (p=0.04) and a reduction in uterine volume (p=0.02) were observed in patients from group 1. Local non-inflammatory nodules were identified in groups 1 and 2 (100% and 50%, respectively). Local nodules were larger in group 1 (1.3 vs. 0.1 cm; p=0.03). Luteinizing hormone levels were reduced in all groups, with random luteinizing hormone levels remaining below 0.6 IU/L. Luteinizing hormone values 2 hours after gonadotropin-releasing hormone analogue administration showed a more homogeneous suppressive effect in group 1. Mild to moderate pain was present in both groups, but higher in group 1. Scores for acceptance, easiness and satisfaction were similar between groups.Six month subcutaneous leuprorelin deaccelerated bone age, preserving the predicted final height in a manner similar to 3-month intramuscular leuprorelin. Only 6-month subcutaneous leuprorelin could reduce uterine and breast volumes. Pain was more prominent with six-month subcutaneous leuprorelin, and drug deposition in the subcutaneous tissue was identified more frequently, without an inflammatory process or a risk of therapeutic failure.
