ACTH

Biological and neurocognitive correlates of comorbid post-traumatic stress disorder and alcohol use disorder: a systematic review.

Ellen E Towers, Joel Hoffman, Eva E Louie +4 more

Background: Post-traumatic stress disorder (PTSD) and alcohol use disorder (AUD) frequently co-occur, leading to greater clinical burden than either disorder alone. Despite this, little is known about the biological pathways linking these two disorders.Objective: We conducted a systematic review to synthesize evidence on molecular, genetic, neural, and cognitive mechanisms contributing to comorbid PTSD & AUD.Method: Following PRISMA guidelines, we performed a comprehensive search of five databases using PTSD-related, AUD-related, biological, and neurocognitive terms. Participants had to meet diagnostic criteria for both PTSD and AUD, and studies were required to have a comparator including controls, PTSD only, or AUD only. A critical appraisal was completed for all studies.Results: From 3904 identified papers, 14 met the inclusion criteria. Four studies examined the same molecular marker, with three papers derived from the same cohort, investigating baseline and stress-induced cortisol and adrenocorticotropic hormone, and found no differences unique to PTSD & AUD. One study linked low brain-derived neurotrophic factor and hazardous drinking to PTSD onset over 2 years following hospital admission. Genetic studies showed considerable overlap (72%) between PTSD and AUD in female twins, whereby the DRD2 A1 allele and the absence of the APOE ϵ2 allele were strongly associated with PTSD and drinking. Studies also reported lower neurometabolites, white matter integrity, and hippocampal volume in PTSD & AUD. Critical appraisal of these studies highlighted prominent selection bias (predominantly male and veterans) and limited justification of sample size.Conclusions: These findings suggest that PTSD & AUD may be characterized by distinct neurobiological alterations and genetic vulnerabilities relative to comparator groups. However, as there are currently insufficient data to support or refute these findings, this highlights the need for further research.

Hidden in the Mediastinum: A Grade 1 Neuroendocrine Tumor Revealed by Refractory Hypokalemia and Ectopic Adrenocorticotropic Hormone (ACTH)-Dependent Cushing's Syndrome.

Sofía Paola Agüero-Pineda, Rodrigo Grimaldo-Rivera, José Abraham Camacho-Muñoz +8 more

Ectopic adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome (CS) is a rare, fulminant variant of endogenous hypercortisolism that demands rapid localization of the ACTH source to achieve a cure. A 51-year-old woman presented with progressive proximal muscle weakness, centripetal obesity, new-onset hypertension with a blood pressure of 150/90 mmHg at arrival, and persistent hypokalemia (2.2 mmol/L). Biochemical testing confirmed severe hypercortisolism that failed to suppress after an overnight 1-mg dexamethasone test. Plasma ACTH was markedly elevated (798 pg/mL), indicating ACTH-dependent disease. Pituitary MRI showed no adenoma, so an ectopic source was suspected. Contrast-enhanced thoracoabdominal CT revealed a 24 × 14-mm anterior mediastinal node, which was excised via video-assisted thoracoscopic surgery (VATS). Histopathology confirmed a grade 1 neuroendocrine tumor with diffuse positivity for synaptophysin, chromogranin A, and neuron-specific enolase. Twenty-four hours after surgery, serum cortisol decreased to 11.1 µg/dL and ACTH to 2.0 pg/mL; serum potassium normalized without supplementation. Octreotide receptor scintigraphy showed no residual or metastatic disease, and the patient remained normotensive and normokalemic at follow-up. Rapidly progressive hypercortisolism accompanied by refractory hypokalemia should prompt consideration of ectopic ACTH secretion. A stepwise diagnostic approach, including biochemical confirmation, exclusion of pituitary disease, and targeted thoracic localization, enabled early minimally invasive resection and biochemical cure in this case. Early recognition and surgery remain the cornerstones of management for ectopic ACTH-producing neuroendocrine tumors. Prompt identification and anatomical localization of the ectopic source are essential to prevent prolonged exposure to severe hypercortisolism and its associated metabolic and cardiovascular complications. Timely surgical resection allows rapid biochemical remission and improvement in short- and long-term outcomes.

Adrenocorticotropin hormone regulates sphingosine-1-phosphate synthesis via cortisol in bovine adrenocortical cells.

Zaire Belen Medina-Moctezuma, Adrian Guzmán-Sánchez, David González-Aretia +3 more

Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) stimulate the synthesis of sphingosine-1 phosphate (S1P) in Gs-coupled receptors dependent manner, enabling S1P to mediate specific bioactivities of FSH and LH. Because adrenocorticotropic hormone (ACTH) also acts via a Gs-coupled receptor to regulate adrenal cortex function, we hypothesized that ACTH could induce S1P secretion in adrenocortical cells, which could then mediate the steroidogenic and number of viable cells effects associated with ACTH. Primary bovine adrenocortical cell cultures were treated with ACTH, and number of viable cells, as well as S1P and cortisol concentrations in the culture media were measured. The effects of exogenous cortisol on number of viable cells, S1P and phosphorylated SPHK1 concentrations were also determined. Results show that the addition of 0.001 μM and 0.1 μM ACTH to the culture medium increased the number of viable adrenocortical cells, and the concentration of cortisol in culture media, respectively. However, ACTH addition did not increase S1P concentrations. Interestingly, a negative correlation between S1P and cortisol concentrations in the culture medium was observed. Moreover, while addition of 0.1 ng/mL cortisol increased S1P and phosphorylated SPHK1 concentrations, increasing cortisol from 1 to 10 ng/mL did not affect phosphorylated SPHK1 but reduced S1P concentration. Thus, while our data suggest that ACTH does not promote S1P synthesis; by stimulating cortisol synthesis, ACTH could be involved in regulation of S1P levels in bovine adrenocortical cells.

Measuring approach-avoidance behavior in patients with panic disorder using the human elevated plus maze in mixed reality.

Till Dobner, Jana Christina Müller, Daniel Biedermann +2 more

Avoidance behavior is a hallmark of panic disorder (PD), yet experimental evidence remains limited due to challenges in assessing unconditioned avoidance without specific threats. The human Elevated Plus Maze (EPM), implemented in mixed reality, provides an ecologically valid paradigm to measure approach-avoidance behavior under controlled conditions.

Cyclic Cushing syndrome as a clinical enigma and diagnostic dilemma in advanced endocrinology.

Yeva Ilkiv, Kateryna Potapova, Viktoriia Yerokhovych +1 more

Cyclic Cushing's syndrome (CCS), a rare and atypical form of endogenous hypercortisolism, remains a very relevant problem from a diagnostic point of view. To confirm this disease, it is necessary to record two episodes of hypercortisolism alternating with period of normocortisolism. Intercyclic phase is characterized not only by negative laboratory test results but also by the absence of pronounced symptoms, making the pathology hidden and, presumably, undiagnosed in certain cases. Some causes remain undetermined and require further investigation. The process of diagnosing and verifying CCS is often lengthy and requires repeated testing at certain intervals. However, none of the currently available methods are 100% accurate. Therefore, a step-by-step approach with confirmation by several highly sensitive tests is recommended for the differential diagnosis of ACTH-dependent and ACTH-independent cyclic hypercortisolism. The risk of false results cannot be ruled out even when the most reliable methods available today are used. Thus, the diagnostic algorithm for each individual case will be specific and will depend on the phase of the disease, the patient's condition, and concomitant pathology. Our review summarizes current data on the mechanisms of cyclic hypercortisolism known to date and provides a comparative and critical analysis of modern diagnostic methods that help identify this pathology and indicate its origin.

Adrenal axis integrity after IV methylprednisolone therapy for thyroid eye disease: a retrospective cohort study.

Grigoris Effraimidis, Athanasios Kasotas, Alexandra Bargiota

Only 5 prior studies, each involving 12 to 32 patients, have evaluated the impact of high-dose intravenous methylprednisolone (IVMP) on hypothalamic-pituitary-adrenal (HPA) axis function in patients with active moderate-to-severe thyroid eye disease (TED). Due to their small sample sizes and methodological limitations, uncertainty remains regarding the risk of adrenal suppression following this regimen.

Impact of mild autonomous cortisol secretion on metabolism & cardiac morphology in adrenal incidentaloma.

Yanan Li, Jiang Liu, Xin Zhao +1 more

Mild autonomous cortisol secretion (MACS) leads to the clustered manifestations of hypertension (HT), diabetes, and metabolic syndromes. However, whether the effect of MACS on myocardial remodeling and cardiac function is similar to that of Cushing's syndrome remains unclear. This study aimed to compare the metabolic risks and impact on cardiac structure and function between MACS and Cushing's syndrome.

Is it Possible to Have Coexisting Exogenous and Endogenous Cushing's Syndrome?

Sana Rafi, Nada El Idrissi Dfali, Ghizlane Elmghari +1 more

The coexistence of exogenous and endogenous Cushing's syndrome is exceptionally rare. Here, we report the case of a 40-year-old female patient who had been self-medicating with dexamethasone for three years and who presented with asthenia and abdominal pain ten days after discontinuing corticosteroid therapy. The initial clinical suspicion was adrenal insufficiency following corticosteroid withdrawal; however, the patient's 8 a.m. serum cortisol level was elevated at 46 µg/dL. The possibility of concomitant endogenous Cushing's syndrome was therefore considered. Hormonal investigations confirmed adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome, and magnetic resonance imaging of the pituitary region revealed a pituitary macroadenoma measuring 14 × 15 × 12 mm. The patient underwent transsphenoidal surgery with an uneventful postoperative course. Hormonal evaluation should be considered in patients receiving prolonged corticosteroid therapy when clinical manifestations persist after corticosteroid withdrawal, particularly in the presence of persistent hypercortisolism or absence of expected hypothalamic-pituitary-adrenal axis suppression.

Ectopic adrenocorticotropic hormone syndrome with Pneumocystis jirovecii pneumonia and pulmonary cryptococcosis: A case report and literature review.

Junlan Zhou, Chenyang Liu, Lingling Li +3 more

Ectopic adrenocorticotropic hormone syndrome is a distinct subtype of endogenous Cushing's syndrome characterized by excessive cortisol secretion, which increases susceptibility to opportunistic infections. Herein, we present the case of a male patient in his early 40s who was admitted with fatigue and bilateral lower-extremity edema. Laboratory tests revealed markedly elevated serum adrenocorticotropic hormone and cortisol levels. Ectopic adrenocorticotropic hormone syndrome was confirmed via dexamethasone suppression testing and somatostatin receptor-targeted positron emission tomography-computed tomography, which localized an ectopic adrenocorticotropic hormone-secreting right pulmonary carcinoid tumor (a neuroendocrine tumor). During hospitalization, the patient was diagnosed with concurrent Pneumocystis jirovecii pneumonia and pulmonary cryptococcosis, and he responded favorably to trimethoprim-sulfamethoxazole and fluconazole. This case, supported by a review of the relevant literature, highlights the importance of early infection diagnosis, prompt management, and appropriate prophylaxis in patients with ectopic adrenocorticotropic hormone syndrome to improve prognosis.

Central Adrenal Insufficiency Unmasked After Pneumonia-Associated Asthma Exacerbation Leading to the Diagnosis of Rathke's Cleft Cyst in an Elderly Woman: A Case Report.

Natsumi Yamamoto, Ryuichi Ohta, Akira Yamasaki +1 more

Rathke's cleft cyst (RCC) is a benign pituitary lesion that is often asymptomatic but can cause hypopituitarism, including central adrenal insufficiency, which may become clinically apparent under physiological stress. However, RCC presenting with adrenal insufficiency unmasked by acute respiratory illness is rare, particularly in elderly patients. We report a case of RCC diagnosed after adrenal insufficiency became evident following pneumonia-associated asthma exacerbation. An 89-year-old woman presented with fever, productive cough, and generalized fatigue and was diagnosed with pneumonia-triggered asthma exacerbation. Initial laboratory evaluation revealed hyponatremia (serum sodium 126 mEq/L). She was treated with bronchodilators, systemic corticosteroids, and antibiotics, resulting in prompt improvement of respiratory symptoms and normalization of serum sodium levels. After discontinuation of corticosteroids and discharge, she developed persistent fatigue, anorexia, and right eyelid ptosis. Brain magnetic resonance imaging revealed a 22-mm cystic lesion in the pituitary gland consistent with RCC. Endocrine evaluation demonstrated markedly reduced adrenocorticotropic hormone and cortisol levels, along with central hypothyroidism, hypogonadism, and growth hormone deficiency, confirming panhypopituitarism with central adrenal insufficiency. Hydrocortisone replacement therapy was initiated, leading to clinical stabilization. Surgical intervention was deferred due to advanced age and absence of visual field defects, and the patient was managed conservatively with hormone replacement and follow-up imaging. This case highlights that acute respiratory illness may precipitate overt adrenal insufficiency in patients with previously unrecognized RCC. Transient improvement with corticosteroids during acute treatment may mask the underlying endocrine disorder, delaying diagnosis. Persistent fatigue, hyponatremia, or neurological findings after resolution of respiratory illness should prompt evaluation for central adrenal insufficiency and pituitary pathology, as early recognition and hormone replacement are essential to prevent life-threatening complications.

Assay-Specific Diagnostic Thresholds for Adrenal Insufficiency: A Retrospective Comparison of Monoclonal Cortisol Measurements Using Roche Elecsys Cortisol II and Tosoh AIA-CL2400.

Shunsuke Kato, Hana Akanuma, Mitsuhiko Nara +4 more

Background The diagnosis of adrenal insufficiency traditionally relies on peak cortisol values during stimulation testing, with a cut-off of 18 µg/dL established using polyclonal antibody assays. However, newer monoclonal antibody-based assays show reduced cross-reactivity with other glucocorticoids. In April 2022, our hospital changed the cortisol measurement method from Roche Elecsys Cortisol II to Tosoh AIA-CL2400, both using monoclonal antibodies but with potentially different measurement characteristics. In addition to stimulation test results, physicians initiate hydrocortisone replacement based on the patient's clinical condition. Methods We retrospectively reviewed 226 patients who underwent adrenocorticotropic hormone (ACTH) or corticotropin-releasing hormone (CRH) stimulation testing for suspected adrenal insufficiency between March 2016 and September 2023. Patients with baseline cortisol ≥18 µg/dL or receiving steroid medications other than hydrocortisone were excluded. Assessment variables included baseline cortisol, baseline ACTH, peak cortisol, and the change in cortisol during stimulation tests. Clinical diagnosis of adrenal insufficiency was defined by initiation of hydrocortisone replacement therapy. Receiver operating characteristic (ROC) curve analysis was performed to determine optimal cut-off values. Background factors included gender, age, presence of adrenal insufficiency symptoms, and structural or functional abnormalities of the hypothalamus-pituitary-adrenal (HPA) axis. Simple and multiple logistic regression analyses were conducted with the diagnosis of adrenal insufficiency as the dependent variable. Results The mean age was 54 years, and 75 (33.2%) of the participants were male. Adrenal insufficiency symptoms were present in 118 (52.2%), while 135 (59.7%) had either structural or functional abnormalities of the HPA axis. When comparing values between the two assay periods, peak cortisol was significantly different (mean: 14.6 vs. 16.8 µg/dL for Elecsys Cortisol II vs. AIA-CL2400). The proportion of patients with cortisol peaks <18 µg/dL differed (128 (68.1%) vs. 18 (47.4%)), but hydrocortisone initiation remained similar (82 (43.6%) vs. 14 (36.8%)). Multiple logistic regression analysis identified peak cortisol, presence of symptoms, and structural or functional abnormalities of the HPA axis as significant factors associated with the clinical diagnosis. ROC curve analysis revealed that the optimal cut-off value increased from 14.5 µg/dL before the assay change to 17.0 µg/dL after the change. When stratified by symptom presence, cut-off values were 14.5 µg/dL (with symptoms) and 13.1 µg/dL (without symptoms) before the change, and 17.0 µg/dL (with symptoms) and 15.1 µg/dL (without symptoms) after the change. When stratified by structural or functional abnormalities of the HPA axis, cut-off values were 13.7 µg/dL (with abnormalities) and 14.5 µg/dL (without abnormalities) before the change, and 17.5 µg/dL (with abnormalities) and 16.4 µg/dL (without abnormalities) after the change. Conclusion Our study provides two key messages: First, differences in assay methodology can significantly alter cortisol values and appropriate diagnostic cut-offs, even when transitioning between monoclonal antibody-based assays. Second, both peak cortisol and symptom presence were crucial for clinical diagnosis of adrenal insufficiency, with potentially lower cut-off values being appropriate for asymptomatic cases.

Association Between Serum Cortisol Levels and Variant Angina.

Jeen Hwa Lee, Sung Rok Lee, Yeon Jung Lee +5 more

Variant angina (VA) is caused by coronary vasospasm, and psychological stress has been suggested as a potential trigger. However, the clinical association between cortisol, a key stress hormone, and VA is unclear. This study aimed to evaluate the relationship between serum cortisol levels and VA.

Cyclical ectopic Cushing's syndrome due to a mediastinal neuroendocrine tumor: a case-based review.

Carolina Peixe, Marta Vaz Lopes, Mariana de Griné Severino +2 more

Cyclical Cushing's syndrome (CCS) is an uncommon form of endogenous hypercortisolism characterized by alternating periods of cortisol excess and remission. Its intermittent nature delays diagnosis and localization of the adrenocorticotropic hormone (ACTH) source and complicates therapeutic decision-making.

Visualization of relative 11β-hydroxylase (CYP11B1) activity in human cortisol-producing adrenocortical adenoma (CPA) using mass spectrometry imaging-based enzyme histochemistry.

Erika Nagano, Masamichi Fujita, Hironobu Umakoshi +6 more

Enzymes play essential roles in numerous biochemical reactions, making it necessary to evaluate both their localization and activity. While conventional enzyme activity detection methods require specific antibodies and colorimetric reactions for each target compound, a recent method using mass spectrometry imaging enables the visualization of enzyme distribution and activity by applying substrates directly to tissue sections and detecting the resulting enzyme reaction products generated on these sections. Notably, the 11β-hydroxylase (CYP11B1, EC 1.14.15.4) reaction plays a key role in stress response, metabolism, and immune function regulation. Consequently, the regulation of CYP11B1 activity can significantly impact these physiological processes, enabling improved drug development. Therefore, controlling this enzyme activity will facilitate the development of new therapies for related diseases. This study investigated a method for visualizing the distribution and relative activity of CYP11B1 in cortisol-producing adrenocortical adenoma (CPA) tissue sections derived from patients with mild autonomous cortisol secretion (MACS). By optimizing key parameters such as the substrate and coenzyme concentrations, together with reaction times, the method successfully revealed the relative CYP11B1 activity in human MACS. Additionally, visualization was achieved in aldosterone-producing adrenocortical adenoma (APA) derived from patients with primary aldosteronism and in non-functioning adrenal adenoma (NFA) derived from patients with adrenal cortical adenoma. The relative CYP11B1 activities of CPA, APA, and NFA samples obtained in this study correlated with the clinical information and were consistent with the previously reported cortisol, adrenocorticotropic hormone, and dexamethasone suppression test profiles in blood and urine, thereby validating the proposed method.

Acupuncture plus wet cupping therapy for post stroke depression: a randomized controlled trial.

Dong Li, Hang Gao, Jin Li +4 more

To explore the preliminary clinical efficacy and safety of acupuncture plus wet cupping on post-stroke depression (PSD) and to investigate its potential associations with changes in the hypothalamic-pituitary-adrenal (HPA) axis and inflammatory factors.

The dynamic adrenal response of children to cardiac surgery and cardiac catheterisation.

Daniel Paul Fudulu, Isabella Marinelli, Daniel Galvis +22 more

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.

HPA axis function during adjunctive high-dose dexamethasone use in chemotherapy: a prospective pilot study.

Elżbieta Turska, Krzysztof Lewandowski, Igor Symonowicz +5 more

Glucocorticoid-induced adrenal insufficiency is a well-known adverse effect of glucocorticoid therapy, occurring not only with oral administration but also with intramuscular, inhaled, and other routes of administration. However, the impact of intermittent high-dose glucocorticoids used during chemotherapy on hypothalamic-pituitary-adrenal (HPA) axis function remains incompletely understood.

Mortality and clinical outcomes in patients with mild autonomous cortisol secretion: Adrenalectomy versus nonoperative management.

Niranjna Swaminathan, Zhixing Song, Peter Abraham +4 more

Mild autonomous cortisol secretion (MACS) is the most common hormonal abnormality in adrenal incidentalomas, but the benefits of adrenalectomy remain unclear.

Concurrent Assessment of Neurotrophic Factors and HPA-Axis Hormones in Early Childhood Autism Spectrum Disorder.

Hurşit Ferahkaya, Ayşegül Tuğba Hira Selen, Şeyma Tezer +4 more

Neurotrophic pathways and hypothalamic-pituitary-adrenal (HPA) axis regulation have been implicated in autism spectrum disorder (ASD), yet peripheral findings-particularly in early childhood-remain inconsistent. We examined peripheral neurotrophic factors and HPA-axis hormones in medication-naïve young children with ASD and evaluated their associations with clinical severity.

Diagnostic value of unilateral adrenal vein sampling with simple and biochemical/imaging correction: a study on early screening and typing for primary aldosteronism.

Yi Yan, Caie Li, Jianshu Chen +9 more

Adrenal vein sampling (AVS) is the gold standard for distinguishing subtypes for primary aldosteronism. However, its technical challenges and frequent intubation failures pose difficulties. Our study aimed to establish diagnostic models for unilateral primary aldosteronism (UPA) to guide appropriate treatment in early patients.

Prognostic significance of early ACTH levels on neurological recovery in patients with aneurysmal subarachnoid hemorrhage: a prospective cohort study.

Ghaith Saleh R Aljboor, Aoun Tulemat, Grace H E Tan +4 more

Aneurysmal subarachnoid hemorrhage (aSAH) triggers a marked systemic stress response and may be accompanied by hypothalamic-pituitary-adrenal (HPA) axis dysregulation. Adrenocorticotropic hormone (ACTH) may reflect the acute neuroendocrine response to injury and could be associated with early functional status. This study aimed to describe the frequency of acute-phase ACTH abnormalities and evaluate the association between early ACTH levels and functional outcomes at hospital discharge in patients with aSAH.

Case report and literature review: isolated ACTH deficiency induced by combined nivolumab and trastuzumab therapy in gastric adenocarcinoma.

Liwei Shi, Jinrong Wang, Xiaohong Xie +1 more

Isolated adrenocorticotropic hormone (ACTH) deficiency (IAD) is an uncommon endocrine disorder characterised by the selective reduction or absence of pituitary ACTH secretion, resulting in secondary adrenal insufficiency while other pituitary hormone axes remain functional. The clinical manifestations of this condition are frequently non-specific, and may include symptoms such as fatigue, decreased appetite, weight loss, hypotension, and hyponatremia. These symptoms can be easily confused with those of other diseases, resulting in either missed diagnoses or misdiagnoses. Glucocorticoid replacement therapy is generally considered to provide effective symptom relief and a favourable prognosis. In recent years, the widespread use of immune checkpoint inhibitors (ICIs) in cancer treatment has resulted in a significant increase in immune-related adverse events (irAEs). Isolated ACTH deficiency has been reported as a rare yet severe endocrine-type irAE, potentially arising from immune-mediated pituitary injury. In view of the nonspecific nature of its clinical presentation, early recognition and timely intervention are of critical importance.

Alterations of Growth Performance, Blood Parameters, and Antioxidant Function of Brown Adipose Tissue in Mice Exposed to Cold.

Xuekai Zhang, Xiao Jin, Zhipeng Han +2 more

Cold exposure is an unavoidable stressor in cold regions, leading to growth retardation, oxidative damage, and endocrine disruption. This study investigated changes in blood parameters and antioxidant function in the brown adipose tissue (BAT) of mice exposed to cold. Sixteen naturally mated female mice (aged 70 days) were selected and divided into a control group (CON, n = 8, 25 ± 1 °C) and a cold exposure group (CE, n = 8, 4 ± 1 °C). Each pregnant female gave birth to approximately 12 pups, and the litter (dams and pups co-housed) served as the independent experimental unit, with both euthanized for sampling when the pups reached 20 days of age. Results showed that cold exposure increased ADFI and ADG but decreased the feed conversion rate (FCR) in lactating mice. It also decreased platelet count (PLT) and mean corpuscular hemoglobin concentration (MCHC), elevated lactate dehydrogenase (LDH) activity, and decreased TG and non-esterified fatty acid (NEFA) levels. Hormonal changes included increased adrenocorticotropic hormone (ACTH), apelin 12 (AP12), INS, NE, decreased cortisol (COR), LEP, and thyroid-stimulating hormone (TSH). In pups, cold exposure inhibited growth, reduced PLT, plateletcrit (PCT), red blood cells (RBC), and hemoglobin (HGB), altered lipid profiles, and induced hormonal shifts. Notably, cold exposure enhanced the BAT antioxidant capacity in pups, increasing the total antioxidant capacity (T-AOC) and antioxidant enzyme activities, as supported by gene expression. These findings suggest that, despite growth suppression, mice maintain homeostasis by modulating blood parameters and enhancing BAT antioxidant function to mitigate cold-induced damage.

Neuroanatomical Investigation of Aggression in Pit Bulls.

Yasemin Üstündağ, Dilek Canlar Akar, Mehmet Kartal +3 more

Aggression is a complex social behaviour observed in many animal species, including dogs, and remains a major global concern due to its serious implications for public safety and animal welfare. This study focuses on Pit Bull dogs, a breed frequently associated with severe aggression episodes in many countries, making them an appropriate model for investigating the neuroanatomical factors underlying canine aggression. To better understand its underlying mechanisms, this study investigated neuroanatomical and biochemical factors associated with aggression in Pit bulls. 14 dogs were selected for MRI analysis based on their aggression scores obtained through a aggression assesment survey derived from Canine Behavioral Assessment and Research Questionnaire. The dogs underwent MRI scans and blood and urine sampling and were divided into control and aggressive groups. MRI analyses focused on the prefrontal cortex, amygdala, and hippocampus. Biochemical analyses included serum or plasma levels of serotonin, dopamine, vasopressin, adrenaline, noradrenaline, testosterone, cortisol, and adrenocorticotropic hormone, along with urinary concentrations of their metabolites; metanephrine, vanillylmandelic acid, homovanillic acid, and 5-hydroxyindoleacetic acid. Results showed significantly decreased prefrontal cortex volumes and increased amygdala volumes in aggressive dogs compared to controls. Testosterone and dopamine levels were also significantly higher in the aggressive group. These findings suggest that structural alterations in key brain regions, combined with hormonal and neurotransmitter imbalances, may contribute to a maladaptive neurocognitive profile. Reduced top-down control by the prefrontal cortex may fail to inhibit exaggerated threat perception and emotional reactivity mediated by the amygdala, leading to aggressive behaviour in Pit bulls.

Unmasking Adrenal Insufficiency in COVID-19: The Diagnostic Challenge of Concomitant Acute Kidney Injury and High Ileostomy Output.

Ioanna I Yglesias Dimadi, Afshan Hussain, Bronson Benno Joseph Raja

BACKGROUND The coronavirus disease 2019 (COVID-19) pandemic has elucidated various extrapulmonary manifestations of severe acute respiratory syndrome coronavirus 2, including endocrine complications that affect the hypothalamic-pituitary-adrenal axis. Efforts to diagnose adrenal insufficiency in critically ill patients are challenging due to overlapping symptoms such as hypotension and fatigue. This challenge is amplified in patients with renal comorbidities, among whom classic electrolyte derangements of adrenal insufficiency (eg, hyperkalemia) may be masked by acute kidney injury (AKI) and renal replacement therapy. CASE REPORT A 46-year-old man with chronic kidney disease and an ileostomy presented with fatigue, abdominal pain, high ileostomy output, and hypotension. Evaluation revealed COVID-19 with concomitant AKI, metabolic acidosis, and hyperkalemia. Initial management via hemodialysis and remdesivir corrected the acidosis and electrolyte abnormalities. However, after renal recovery and discontinuation of dialysis, the patient developed recurrent, refractory hypotension, hyperkalemia, and hypoglycemia, prompting assessment for adrenal dysfunction. Morning cortisol levels were critically low. A subsequent cosyntropin stimulation test showed a blunted cortisol response, confirming adrenal insufficiency. Hydrocortisone and fludrocortisone treatments resulted in hemodynamic stabilization and resolution of the electrolyte abnormalities. CONCLUSIONS This case highlights the "masking" effect of dialysis on the clinical presentation of adrenal insufficiency. Clinicians must maintain a high index of suspicion for adrenal insufficiency in patients with COVID-19 who display recurrent hypotension or hyperkalemia despite renal recovery. Furthermore, the presence of hyperkalemia in a patient with high ileostomy output is paradoxical and should prompt immediate evaluation for mineralocorticoid deficiency.

When hidden steroids cause harm: Secondary adrenal insufficiency from unrecognised exposure.

N A Absul, S C Thambiah, A D Masiman +2 more

Adrenal insufficiency is a life-threatening condition that often presents with non-specific symptoms, complicating diagnosis in elderly patients.

Peri-Arterial Neural Dissection During Adrenal Surgery Provides a Denervation-Like Benefit in Hypertension Control.

Liqi Yi, Yibang Cheng, Hai Huang +7 more

Peri-arterial neural tissue surrounding the renal artery contributes to sympathetic overactivity in hypertension. During adrenal surgery, surgical peri-arterial neural dissection may interrupt these fibers and exert a renal denervation-like effect. Whether this maneuver improves postoperative blood pressure control remains unclear.

Salivary responses to an experimental activation of the HPA axis in pigs: Effects of ACTH on analytes related to stress, immune system, inflammation, redox status and metabolism.

María Botía, José Joaquín Cerón, Silvia Martínez-Subiela +3 more

Non-invasive biomarkers are essential for assessing stress and welfare. Saliva is a suitable sample type because it can reflect endocrine, immune, inflammatory and redox responses without causing stress from handling. This study examined the impact of administering adrenocorticotropic hormone (ACTH) on a broad range of salivary analytes in pigs, to characterise the physiological response of saliva to the activation of the hypothalamic-pituitary-adrenal (HPA) axis. A total of twenty-two male Landrace x Large White pigs were randomly assigned to receive either ACTH (10 µg/kg; n = 11) or saline solution (n = 11). Saliva samples were collected before and after injection (at 20, 40, 60, 90 and 120 min, and after 24 h) and analysed for biomarkers of stress (cortisol, cortisone, chromogranin A, alpha-amylase, total esterase activity, butyrylcholinesterase and oxytocin), inflammation (haptoglobin, C-reactive protein and calprotectin), immunity (adenosine deaminase and total proteins), redox status (cupric reducing antioxidant capacity), and metabolism (urea and creatinine). ACTH administration induced significant increases in cortisol, cortisone, and total esterase activity, confirming HPA axis activation. However analytes related to sympathetic activation (chromogranin A and alpha-amylase) or positive welfare (oxytocin) remained unchanged. Regarding inflammatory markers, haptoglobin and calprotectin, but not C-reactive protein, increased. No significant changes were observed in redox and metabolism biomarkers. These data contribute to a better understanding of the physiological response of saliva components to ACTH administration, which is one of the major mechanisms involved in acute stress.

Congenital Adrenal Hyperplasia due to 11β-Hydroxylase Deficiency Presented With Leydig Cell Tumor and Testicular Adrenal Rest Tumors: A Case Report.

Shervin Mossavarali, Faezeh Sehatpour, Shahrzad Mohseni +1 more

Congenital adrenal hyperplasia (CAH) due to 11β-hydroxylase deficiency is an uncommon disorder characterized by impaired cortisol synthesis, hyperandrogenism, and mineralocorticoid excess. The coexistence of Leydig cell tumors (LCTs) and testicular adrenal rest tumors (TARTs) is rarely reported, highlighting the diagnostic and therapeutic challenges in such cases. A 35-year-old man with a history of hypertension and infertility presented with left testicular masses. His medical history was significant for a prior right orchiectomy, with pathology confirming LCT. Subsequent evaluations revealed azoospermia, elevated adrenal androgen levels, adrenocorticotropic hormone (ACTH) and 17-OH progesterone levels indicative of CAH due to 11β-hydroxylase deficiency. Imaging studies identified left testicular masses and bilateral adrenal myelolipomas. The patient was managed with oral dexamethasone and eplerenone, resulting in normalization of blood pressure and electrolytes. This case highlights the complexity of CAH presentations with overlapping testicular and adrenal pathologies. Patients with such conditions should be closely monitored and regularly checked for common complications to ensure timely intervention and optimal management.

Evaluation of thyroglobulin autoantibodies in dogs at the time of diagnosis of hypoadrenocorticism and during treatment.

Christin Emming, Sina Strey, Ina Leiter +4 more

Autoimmune thyroiditis (AIT) may occur more frequently in dogs with hypoadrenocorticism (HA) than previously recognised. The objective of this study was to determine the presence of thyroglobulin autoantibodies (TgAAs) in dogs with HA.

The 40th Minute Cortisol Measurement is the Key Time-Point in the Low-Dose Synacthen Stimulation Test: A Large, Assay-Specific Pediatric Validation Study.

Busra Gurpinar Tosun, Hazal Arikan Gacemer, Didem Helvacioglu +3 more

Low-dose synacthen stimulation test (LDSST) is widely used to assess central adrenal insufficiency (CAI). With the adoption of monoclonal antibody (mAb) cortisol immunoassays, lower basal and peak cortisol concentration thresholds require external validation under real-world clinical conditions.

Immune checkpoint blockade as an accelerator of adrenal aging: a testable model linking low-grade cortical inflammation to proteostasis failure, LDLR/SULT2A1 suppression, and reduced DHEA output.

Guanxiong Ding, Yangyang Xu, Ting Guo +1 more

Immune checkpoint blockade (ICB) unleashes antitumor immunity but frequently provokes enduring endocrine toxicities. We hypothesize that ICB accelerates adrenal aging by establishing chronic low-level inflammation within the adrenal cortex, with targeting vulnerability of the zona reticularis. Integrating a recently published human multiorgan aging proteome atlas and primate adrenal aging study with survivorship data after ICB therapy, we propose a testable signaling cascade: ICB-amplified interferon gamma (IFNγ)/ tumor necrosis factor (TNF)/ interleukin-1 signaling activates nuclear factor kappa B (NF-κB)/signal transducer and activator of transcription 1 (STAT1), suppressing sterol regulatory element-binding protein 2 (SREBP2)-low-density lipoprotein receptor (LDLR)-mediated cholesterol uptake; concurrent mitochondrial/endoplasmic reticulum stress drives proteome-transcriptome decoupling, loss of cytochrome b5 type A (CYB5A), and impaired cytochrome P450 family 17 subfamily A member 1 (CYP17A1) 17,20-lyase activity; inflammatory transcriptional repression of sulfotransferase family 2A member 1 (SULT2A1) with proteostasis decay reduces dehydroepiandrosterone (DHEA) sulfation. The net result is a persistent fall in DHEA/DHEA sulfate (DHEAS) with comparatively preserved cortisol-mirroring natural adrenal aging. We advocate prospective measurement of DHEAS, DHEA, adrenocorticotropic hormone (ACTH), and cortisol at baseline, during therapy, end of therapy, and 6-24 months post-therapy; if early DHEAS decline is confirmed, targeted interventions including DHEA replacement or glucocorticoid receptor antagonism warrant evaluation. This framework reframes certain endocrine immune-related adverse events as "accelerated organ aging," with implications for risk stratification, toxicity prevention, and survivorship care.

Complete glucocorticoid resistance: a lethal disorder in the neonatal period.

Natalie Segev, Sarah Swauger, K Nicole Weaver +3 more

Generalized glucocorticoid (GC) resistance (Chrousos syndrome) results from impaired GC receptor signaling due to variants in the NR3C1 gene. Severe neonatal presentations are extremely rare. We report an 8-week-old male infant born at 31-week gestation, with progressive respiratory failure, refractory hypotension, hypokalemic alkalosis, anasarca, jaundice, and multiorgan dysfunction. Laboratory evaluation demonstrated persistently elevated serum cortisol [>60 µg/dL (SI: >1655 nmol/L) (reference range 2.5-9.1 µg/dL, SI: 69.0-251.0 nmol/L)], adrenocorticotropic hormone [>2400 pg/mL (SI: >528 pmol/L) (reference range 7.2-63.3 pg/mL, SI: 1.6-13.9 pmol/L)], aldosterone [2036.0 ng/dL (SI: 56 nmol/L) (reference range 7.0-99.0 ng/dL, SI: 0.2-2.7 nmol/L)], and androgens despite treatment with escalating doses of dexamethasone (up to 12 mg, > 2000 mg/m2/day of hydrocortisone-equivalency). Whole-genome sequencing identified 2 NR3C1 variants: a maternally inherited variant of uncertain significance (c.2181+5 G>C) and a de novo likely pathogenic ∼7.9 kb deletion encompassing exon 8. In silico analyses suggested both variants could disrupt the GC receptor ligand-binding domain, potentially resulting in complete loss of GC receptor function. Autopsy demonstrated adrenomegaly with marked proliferation of zona fasciculata, cholestasis with bile duct paucity, and chronic neonatal lung disease. This case represents a rare and fatal manifestation of complete generalized GC resistance. It highlights the broad physiological role of GC in neonatal homeostasis.

Relative Adrenal Insufficiency is Associated With Worse Clinical Outcomes in Patients With Acute Decompensation of Cirrhosis and Hyponatremia.

Tanmay Jain, Kalyani Sridharan, Rohit Gupta +4 more

Relative adrenal insufficiency (RAI) and hyponatremia are both common in decompensated cirrhosis. The literature is scarce on the prevalence and clinical correlates of RAI in patients with acute decompensation (AD) of cirrhosis and hyponatremia.

Effect of glucose load on metabolism in patients with type 2 diabetes during elective surgery using remifentanil-induced anesthesia:a randomized controlled trial.

Asuka Kasai, Kohei Fukuta, Noriko Kambe +3 more

This study aimed to explore the effect of intraoperative glucose load on metabolism in patients with type 2 diabetes anesthetized with remifentanil. A total of 30 patients were enrolled and randomly allocated to one of two groups:no glucose or low-dose glucose (0.1 g/kg/h for 1 hour followed by 0.05 g/kg/h for 1 hour). Glucose, adrenocorticotropic hormone, 3-methylhistidine, insulin, cortisol, free fatty acid, ketone bodies, and creatinine were measured at several points before, during, and after general anesthesia. Glucose levels in the low-dose glucose group increased significantly at 1 and 2 hours after glucose infusion compared to their preanesthetic levels and to those in the no glucose group. Two patients in the low-dose glucose group had blood glucose levels exceeding 11.1 mmol/L. Free fatty acids, ketone bodies, and 3-methylhistidine/creatinine did not differ significantly between groups. Ketone body levels were significantly higher at 1 hour than preanesthetic levels in both groups;after 1 hour, however, they did not change in the no glucose group but significantly decreased in the low-dose glucose group. Intraoperative low-dose glucose load may suppress ketogenesis, but clinicians must consider the risk of causing hyperglycemia in patients with type 2 diabetes undergoing remifentanil-induced anesthesia. J. Med. Invest. 73 : 222-228, February, 2026.

Neuroendocrine signature of ME/CFS: Meta-analytic evidence for bioactive cortisol deficit and exaggerated feedback sensitivity.

Tae-Wook Woo, Yu-Jin Choi, Jun-Yeol Kim +2 more

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a major clinical challenge as a complex multisystemic disorder with no well-established pathophysiological mechanism, characterized by persistent fatigue and post-exertional malaise, along with unrefreshing sleep, cognitive impairment, and impaired stress recovery. Despite decades of investigation into the hypothalamic-pituitary-adrenal (HPA) axis, a definitive neuroendocrine hallmark has remained elusive due to inconsistent findings across various cortisol matrices. Therefore, this systematic review and meta-analysis aimed to provide an integrated understanding of HPA-axis regulation in ME/CFS. We identified 46 case-control studies (comprising 46 independent datasets, including 12 pharmacological challenge studies), involving 1388 ME/CFS patients (71.9% female; mean age 37.3 ± 6.2 years) and 1349 matched healthy controls. Meta-analyses showed lower salivary cortisol at awakening and in the morning. Reductions were also observed in 24-h urinary cortisol and hair cortisol. In pharmacological challenge tests, patients exhibited impaired cortisol release in response to adrenocorticotropic hormone (ACTH) stimulation and exaggerated suppression following glucocorticoid administration. Collectively, these alterations indicate reduced free cortisol availability and enhanced HPA-axis negative feedback sensitivity, consistent with a hyporeactive endocrine state in ME/CFS. This neuroendocrine hypo-reactivity may underlie hallmark clinical features such as unrefreshing sleep, post-exertional malaise, and severe fatigue, as well as cognitive slowing, emotional blunting, and diminished stress resilience frequently observed in ME/CFS and related functional disorders. Integrating neuroendocrine and psychological perspectives may help clarify mechanisms of chronic stress maladaptation and inform psychobiological interventions for fatigue syndromes.

[Clinical and genetic characteristics of 165 children with salt-wasting 21-hydroxylase deficiency in Henan Province].

Hai-Hua Yang, Ai Huang, Yuan Li +2 more

To explore the clinical and genetic characteristics of children with salt-wasting (SW) 21-hydroxylase deficiency (21-OHD) in Henan Province.

Blood Pressure and Adrenocortical Hormone Profiles in 84 Ill Dogs with Normal Post-ACTH Cortisol Concentrations.

Robert L J Runde, Sharon A Center, Ronald Lyman +1 more

Relationship between systolic blood pressure (SBP) and adrenocortical hormones in 10 normotensive (NT) control dogs and 84 ill dogs with clinical features of hypercortisolism but normal post-adrenocorticotropic hormone (ACTH) cortisol was studied. Doppler blood pressure classified dogs as NT (<140 mm Hg), prehypertensive (PHT; 140-159 mm Hg), or hypertensive (HT; ≥160 mm Hg). Serum cortisol, progesterone, 17-hydroxyprogesterone, androstenedione, and aldosterone were measured before and 1-hr after intramuscular (IM) ACTH (250 μg/dog). Ill dogs (40 NT, 29 PHT, and 15 HT) were significantly (P ≤ .04) older, smaller, and received higher ACTH dose/kg versus controls. ACTH dose/kg was not significantly associated with post-ACTH hormone concentrations. Compared to controls, baseline hormones were significantly (P ≤ .05) higher in ill dogs, except progesterone and 17-hydroxyprogesterone in HT and aldosterone in PHT dogs; significantly higher post-ACTH 17-hydroxyprogesterone and androstenedione (P ≤ .01) in NT and PHT dogs, and aldosterone (P = .03) in HT dogs occurred. No significant differences in baseline or post-ACTH hormones existed between SBP groups. Only 3/10 controls had all hormones within reference limits. Findings suggest risk for PHT and HT in ill dogs with increased noncortisol adrenocortical hormones, and show inexplicably increased adrenocortical sex hormones in NT healthy dogs.

The mechanism of Longdan Xiegan pills in chronic stress-induced hypertension:a study based on network pharmacology and experimentalvalidation.

Huizhuo Jia, Mingyao Lv, Ying Yang +7 more

This study integrated network pharmacology and experimental validation to elucidate the mechanism of Longdan Xiegan Pills (LDXG) in treating chronic stress-induced hypertension. Active components of LDXG were retrieved from the TCMSP database and screened based on oral bioavailability (OB) and drug-likeness (DL). Potential targets were predicted using SwissTargetPrediction. Disease targets related to hypertension were collected from OMIM and GeneCards. A compound-target network was constructed using Cytoscape, and protein-protein interaction (PPI) analysis was performed via the STRING database. Functional enrichment analysis (GO and KEGG) was conducted using DAVID. Molecular docking was performed with LeDock. In vivo, systolic and diastolic blood pressures were measured non-invasively, myocardial histopathology was evaluated by HE staining, the content of target protein in pvn and adrenal gland was measured by western blot, and serum inflammatory markers were quantified via ELISA. A total of 178 active components of LDXG were screened, Gentiana scabra Bunge (Gentian), Gardenia jasminoides Ellis (Gardeniae fructus), Scutellaria baicalensis Georgi (Huangcen), Bupleurum chinense DC (Bupleurum), and Glycyrrhiza uralensis Fisch (Licorice) were identified as the core components.The core targets included SRC, MAPK3, MAPK1, PIK3R1, RELA and STAT3. GO functional enrichment and KEGG pathway enrichment analyses indicated that LDXG primarily modulated protein kinase activity, ATP binding, protein serine/threonine kinase activity and protein kinase binding.These processes involved the PI3K-Akt, HIF-1, VEGF, ErbB and FoXO. Animal experiments demonstrated LDXG can significantly lowered blood pressure level in chronic stress-induced hypertension rats,reduced the contents of src and STAT3 in the PVN and MAPK1 in the adrenal gland and reduced serum levels of angiotensin II (Ang II), cortisol and adrenocorticotropic hormone(ACTH). LDXG can attenuate chronic stress hypertension by regulating JAK/STAT, Src/MAPK and other signaling pathways and reducing the expression of Ang II through a variety of active compounds.

Adrenal Biomarkers of Stress in Transgender and Gender-Diverse Adolescents.

Simone Coslovich, Stefania Tonetto, Giulia Bragato +7 more

Transgender and gender diverse (TGD) adolescents are frequently exposed to minority stress, which may influence the hypothalamic-pituitary-adrenal (HPA) axis during critical developmental windows. Altered cortisol dynamics have been described in populations facing chronic stress, yet evidence in TGD youth is limited. Understanding adrenal function in this context is essential for clarifying potential biological pathways linking social stressors to developmental and health outcomes. In the present study, identifying as TGD serves as an indirect proxy of exposure to minority stressors, which were not directly measured. We conducted a retrospective, case-control study at a tertiary pediatric center, including 48 TGD adolescents and 298 controls referred for evaluation of premature pubarche with nonclassical congenital adrenal hyperplasia excluded. All participants underwent a standard dose synacthen test (SDST; 250 µg tetracosactide iv, sampling at baseline and 60 min, 8:00 a.m.), which assesses adrenal responsiveness to pharmacological ACTH stimulation. Serum cortisol, DHEAS, ACTH, and 17-hydroxyprogesterone were assayed. Statistical analyses included nonparametric group comparisons, correlations, and multivariable regression adjusting for age and sex assigned at birth. TGD individuals demonstrated significantly higher baseline cortisol levels (293 vs. 214 nmol/L; p < 0.001) and a reduced cortisol response to SDST (Δcortisol: 354 vs. 446 nmol/L; p < 0.001). In the full sample, basal DHEAS levels were higher in TGD youth (231 vs. 142 nmol/L; p = 0.362), whereas the DHEAS-to-cortisol ratio did not differ significantly between groups. In an age-matched subsample (1:2 matching), the DHEAS-to-cortisol ratio was significantly lower in TGD adolescents (0.72 vs. 1.03; p = 0.004). Multivariate analysis confirmed an independent association between TGD status and higher basal cortisol, lower Δcortisol, and a reduced DHEAS-to-cortisol ratio after adjustment for covariates (all p < 0.001). Our findings provide preliminary evidence of altered adrenal responsiveness in TGD adolescents, potentially reflecting the biological embedding of minority stress during development. Although exploratory, these results highlight the need for prospective, longitudinal studies integrating psychosocial and neuroendocrine measures to clarify mechanisms linking stress, HPA axis function, and developmental outcomes in gender-diverse youth.

Glucose-dependent dynamics of glucagon, cortisol and adrenocorticotropic hormone before and after gastric bypass.

Vasileios Chronopoulos, Maria C Kjellsson, Martin H Lundqvist

Roux-en-Y gastric bypass (RYGB) improves glucose homeostasis beyond weight loss, but the underlying mechanisms remain incompletely understood. Counter-regulatory hormones such as glucagon, ACTH, and cortisol are key components of glucose regulation.

Autoimmune Polyglandular Syndrome Type II Presenting with Severe Hyponatraemia and Autoimmune Bicytopaenia.

Patrik Lecký, Martin Jozef Péč, Matej Turčan +4 more

Autoimmune polyglandular syndrome type II (APS II) is a rare, multifactorial disorder characterised by a combination of primary adrenal insufficiency with other autoimmune endocrinopathies, most commonly thyroid disease and type 1 diabetes mellitus. The clinical presentation is variable, and non-specific symptoms often lead to delayed diagnosis.

Cushing's Shadow: An Overlooked Diagnosis in Endocrinology.

Lala Soltanova, Serdar Sahin, Yucel Erbilgin +5 more

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.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.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. 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. 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.

Diagnostic Utility of ACTH, Cortisol, DHEAS, and Their Derived Ratios in Cushing's Syndrome Subtypes.

Ekin Yiğit Köroğlu, Abbas Ali Tam, Sevgül Faki +6 more

Background/Objectives: Differentiating Cushing's disease (CD) from adrenocorticotropic hormone (ACTH)-independent Cushing's syndrome (AICS) remains challenging in patients with equivocal ACTH levels. While dynamic testing is frequently required, baseline hormonal measurements may offer a simpler diagnostic approach. We aim to evaluate the diagnostic value of baseline plasma ACTH, cortisol, and dehydroepiandrosterone sulfate (DHEAS) levels and their derived ratios for differentiation between ACTH-dependent and ACTH-independent Cushing's syndrome, and to propose a diagnostic algorithm based on these parameters. Methods: This retrospective single-centre study included adult patients with endogenous Cushing's syndrome aged 18-75 years who were followed at our institution. Patients with ectopic/paraneoplastic Cushing's syndrome were excluded. The AICS group comprised overt adrenal CS and mild autonomous cortisol secretion cases. Morning baseline plasma ACTH (pg/mL), serum cortisol (µg/dL), and serum DHEAS (µg/dL) levels were measured and ratios calculated: cortisol-to-ACTH ratio (CAR), DHEAS-to-cortisol ratio (DCR), and CAR-to-DHEAS ratio (CAR/D). ROC analysis assessed diagnostic performance with age and sex adjustments. Results: A total of 100 patients were included, comprising 43 patients with CD and 57 with AICS. Plasma ACTH demonstrated high diagnostic accuracy for identifying CD with a cut-off of ≥14.65 pg/mL (sensitivity 100%, specificity 98.25%, AUC 0.998). Serum DHEAS showed strong discriminative power with a cut-off of ≥67.15 µg/dL (sensitivity 88.37%, specificity 91.23%, AUC 0.925), achieving high discriminative power after age-sex adjustment at ≥85.59 µg/dL (sensitivity 100%, specificity 100%, AUC 0.999). CAR showed good performance in identifying CD with a cut-off of ≤0.75 µg/dL per pg/mL (sensitivity 93.02%, specificity 98.25%, AUC 0.980). CAR/D demonstrated high diagnostic power with a cut-off of ≤1.54 (sensitivity 95.35%, specificity 98.25%, AUC 0.974), improving after age-sex adjustment to ≤2.36 (sensitivity 97.87%, specificity 96.23%, AUC 0.992). Conclusions: Baseline plasma ACTH, serum cortisol, and serum DHEAS measurements, along with derived ratios-especially CAR and CAR/D-provide highly accurate differentiation between ACTH-dependent and ACTH-independent Cushing's syndrome. These widely available measurements may reduce dependence on dynamic testing and improve diagnostic accuracy in patients with equivocal findings.

Effects of Fan Noise on Growth Performance, Blood Parameters, Feeding Behavior, and Slaughter Performance of Geese Aged 21-70 Days.

Qun Xie, Xiaofeng Huang, Zuolan Liu +10 more

We conducted this experiment with the aim of investigating the effects of different noise levels from ventilation fans on the growth and slaughter performance, meat quality, blood parameters, and feeding behavior of geese from 21 to 70 days of age. A total of 108 male geese (21-day-old) were randomly assigned to one of three conditions: a control group (no additional fan noise), low-noise treatment (65-75 dB), and high-noise treatment (85-95 dB). Each treatment included six replicates, with six geese per replicate. The results showed that neither ventilation fan noise level significantly affected growth performance, feeding behavior, slaughter performance, or major meat quality traits (p > 0.05). Compared with the control group, noise exposure significantly reduced circulating adrenocorticotropic hormone and corticosterone concentrations (p < 0.05), and the low-noise group exhibited significantly reduced cortisol concentrations (p < 0.05), while the high-noise group had increased cortisol concentrations. Under noise exposure conditions, no statistically significant effects were observed on superoxide dismutase, total antioxidant capacity, malondialdehyde concentration, catalase, and glutathione peroxidase activities compared with the control group (p > 0.05). Overall, prolonged noise stimulation (65-75 dB and 85-95 dB) alleviated stress responses in commercial geese aged 21-70 days, without negatively affecting their growth performance, slaughter performance, meat quality, or feeding behavior.

Delayed-onset central adrenal insufficiency following adjuvant pembrolizumab therapy for renal cell carcinoma.

Naseem Eisa

This report describes a woman in her early 70s who developed severe central adrenal insufficiency 11 months after completing 1 year of adjuvant pembrolizumab for resected clear cell renal cell carcinoma. She presented with debilitating fatigue, profound weakness, unintentional weight loss and hypotension. Because these symptoms were non-specific and emerged long after immunotherapy discontinuation, the diagnosis was delayed for several months. Laboratory testing showed a markedly suppressed morning cortisol with an inappropriately low adrenocorticotropic hormone (ACTH) level and no response to cosyntropin, confirming central adrenal insufficiency. Other pituitary hormone axes remained intact, consistent with isolated ACTH deficiency. Imaging demonstrated adrenal atrophy, supporting chronic central adrenal insufficiency. The patient improved rapidly after starting hydrocortisone replacement. This case highlights a prolonged interval between checkpoint inhibitor cessation and endocrine toxicity, emphasising the importance of continued surveillance for late-onset immune-related endocrinopathies even after therapy completion.

Challenging the known: unusual case report of acromegaly and subclinical Cushing's disease combination.

Xinlian He, Haiyan Li, Tingting Wu +3 more

Pituitary neuroendocrine tumors (PitNETs) are usually characterized by hormone secretion profiles that correspond to lineage-specific transcription factor expression. Growth hormone (GH) and prolactin (PRL) secretion is regulated by pituitary-specific transcription factor-1 (Pit-1), whereas adrenocorticotropic hormone (ACTH) production is classically dependent on T-box transcription factor 19 (T-pit). Accordingly, the concomitant secretion of GH and ACTH from a single pituitary adenoma is exceedingly rare.

A Practical Strategy for Primary Aldosteronism Subtyping: Leveraging the Unilateral Adrenal Vein Sampling Index When Bilateral Cannulation Fails.

Qing-Rong Deng, Xiang Cao, Jun Deng +9 more

Adrenal vein sampling (AVS) is the standard procedure for identifying unilateral primary aldosteronism (uPA) in surgical candidates. However, many patients undergo non-diagnostic or partially successful AVS, which may preclude them from curative surgery. This study aimed to evaluate the diagnostic utility of the unilateral AVS index for identifying uPA.

Racial and ethnic variations of metabolic indicators associated with childhood obesity: a comparative cross-sectional study.

Jing Wu, Zhenran Xu, Li Xi +3 more

Susceptibility to adult metabolic diseases varies significantly across ethnicities. Asian adults exhibit elevated risks associated with obesity at lower body mass index (BMI) levels; whether similar patterns occur in pediatric populations remains unclear. This study aimed to evaluate how metabolic indicators associated with childhood obesity vary across diverse racial/ethnic groups.

Ectopic ACTH-dependent Cushing syndrome due to mature ovarian teratoma.

Naseem Eisa

Ectopic adrenocorticotropic hormone (ACTH) secretion accounts for 10%-20% of ACTH-dependent Cushing syndrome, with ovarian teratomas being an exceptionally rare source. We present a female in her early 40s with severe Cushing syndrome due to ectopic ACTH secretion from a mature ovarian teratoma. She presented with progressive weight gain, moon facies, dorsocervical fat pad, proximal muscle weakness, hypertension and new-onset diabetes. Biochemical evaluation confirmed ACTH-dependent hypercortisolism with elevated cortisol, plasma ACTH, late-night salivary cortisol, urinary free cortisol and failure of dexamethasone suppression. Bilateral inferior petrosal sinus sampling (IPSS) confirmed an ectopic source. After negative pituitary and thoracoabdominal imaging, pelvic imaging identified a large right ovarian mass. Laparoscopic salpingo-oophorectomy was performed, and histopathology confirmed a mature cystic teratoma with ACTH-positive neuroendocrine cells. Postoperatively, the patient achieved complete clinical and biochemical remission with full hypothalamic-pituitary-adrenal axis recovery at 1 year follow-up. This case underscores the systematic diagnostic approach required for ectopic ACTH syndrome-including biochemical confirmation, IPSS to distinguish pituitary from ectopic sources and comprehensive imaging-as well as the importance of considering uncommon tumour sites, including ovarian teratomas, when standard thoracoabdominal imaging is unrevealing.

Absent nocturnal cortisol decline in Pheochromocytoma: A retrospective study.

Yahan Sun, Mitsuhiro Kometani, Ko Aiga +5 more

Pheochromocytoma is a catecholamine-producing tumor that may exhibit atypical hormonal profiles. Emerging evidence suggests an association with cortisol dysregulation in the absence of overt Cushing syndrome; however, systematic cortisol evaluation is not routinely performed. This study investigated the prevalence and clinical characteristics of absent nocturnal cortisol decline in pheochromocytoma. This retrospective study included 53 patients with histologically confirmed pheochromocytoma treated between 2011 and 2024. All eligible patients diagnosed during the study period were included. Among them, 22 had paired morning (8:00 AM) and midnight serum cortisol measurements for analysis of nocturnal cortisol decline. Adrenocorticotropic hormone (ACTH) and the 1-mg dexamethasone suppression test (DST) were assessed when available. Patients were stratified by midnight cortisol level (≥1.8 µg/dL vs < 1.8 µg/dL). Among the 22 patients, 18 (82%) had elevated midnight cortisol, indicating absent nocturnal decline (mean midnight, 5.1 µg/dL; mean morning, 13.7 µg/dL). The elevated group (n = 18) was older than the normal group (n = 4) (median, 64 vs 43 years). Metabolic comorbidities were more frequent in the elevated group, including diabetes (50% vs. 25%), dyslipidemia (61% vs. 25%), and cardiovascular disease (44% vs. 0%). DST was performed in 10 patients and showed adequate suppression in 7 of 8 patients with paired cortisol measurements, arguing against autonomous cortisol secretion. No patients had clinical features of overt Cushing syndrome. Absent nocturnal cortisol decline was common and may reflect a pseudo-Cushing state associated with catecholamine excess. These findings support further evaluation of cortisol regulation and its clinical implications.

Diagnostic challenges of Cushing's syndrome in pregnancy.

Fariha Tahir, Brendan Browne, Melina Kostoula +1 more

SummaryWe report a rare case of Cushing's syndrome in a pregnant woman carrying twins. Interestingly, the patient did exhibit many of the classic clinical features typically associated with hypercortisolism, including Cushingoid facies, violaceous striae, insulin-dependent diabetes, raised central adiposity, chronic hypertension and peripheral myopathy. Her case was less straightforward given her previous gastric sleeve bariatric surgery, which led to rapid weight loss prior to pregnancy. The occurrence of an atraumatic fracture of the femoral neck in a young woman with a medical history of type 2 diabetes mellitus, chronic hypertension and possible severe osteoporosis raised clinical suspicion of a unifying diagnosis, prompting further evaluation.Biochemical testing, including elevated cortisol and suppressed adrenocorticotropic hormone levels, alongside imaging studies, confirmed the diagnosis of adrenal Cushing's syndrome. This case prompted a deeper investigation into the physiological changes of the hypothalamic-pituitary-adrenal axis during normal pregnancy, as well as the unique challenges in diagnosing and managing Cushing's syndrome during pregnancy.This case highlights the need for a high index of suspicion and a multidisciplinary approach in diagnosing and managing complex presentations in pregnancy. Early recognition and treatment of Cushing's syndrome are critical to optimising maternal and fetal outcomes.Cushing's syndrome during pregnancy is a rare but serious hormonal syndrome characterised by elevated cortisol levels. This hypercortisolism may be a result of functional adrenal or pituitary tumours, or iatrogenic. Though uncommon, it poses a significant threat to both maternal and fetal health due to the high risk of complications. This case study aims to provide a current overview of the diagnosis and management of Cushing's syndrome in pregnancy, with an emphasis on minimising associated maternal and fetal morbidity. The case report highlights missed differential diagnoses of Cushing's syndrome in the pre-pregnancy period despite the presence of type 2 diabetes, hypertension and morbid obesity in a young patient. Bariatric surgery further complicated the differential diagnosis.

A Rare Case of Takotsubo Cardiomyopathy Responsive to Fludrocortisone in Secondary Adrenal Insufficiency.

Waqar Khalid, Muhammad Usman Khan, Maheen Khoso +3 more

We present a case of a middle-aged woman with a prolonged history of diarrhea, vomiting, and abdominal pain. Upon admission to the ICU, she exhibited hypotension and hypoglycemia. Based on presenting gastrointestinal complaints, she was initially treated for acute gastroenteritis; however, continuous refractory hypotension led to an echocardiographic assessment. A left ventricular ejection fraction (LVEF) of 30-35% with apical akinesis and distinct apical ballooning was visualized on a transthoracic echocardiogram, suggestive of takotsubo cardiomyopathy. An increasing inotropic demand raised concerns regarding alternative etiologies. Further evaluation revealed decreased adrenocorticotropic hormone and cortisol levels, leading to a diagnosis of secondary adrenal insufficiency. Treatment with fludrocortisone significantly improved her adrenal insufficiency and her cardiomyopathy. This case highlights secondary adrenal insufficiency as a rare but potential cause of takotsubo cardiomyopathy in Pakistan, with the use of fludrocortisone as a treatment option in a carefully selected patient.

Unruptured Giant Internal Carotid Artery Aneurysm Compressing the Pituitary Gland Leading to Panhypopituitarism.

Sapna Sharma, Madhav Acharya, Sara Bean +2 more

Internal carotid artery aneurysms are rare and can lead to hypopituitarism due to their mass effect. Hypopituitarism triggered by aneurysmal compression may persist, and postsurgical restoration of pituitary function is challenging, often necessitating long-term hormone replacement therapy. We herein report a case of hypopituitarism caused by intrasellar aneurysm.

Post-ACTH peak cortisol response is associated with genotype in children with nonclassic congenital adrenal hyperplasia.

Allie N Dayno, Marissa J Kilberg, Erin Gonter +4 more

Suboptimal cortisol levels after ACTH stimulation have been recently reported in approximately 30% of patients with nonclassic congenital adrenal hyperplasia (NCCAH). There is little information on the role of genotype on cortisol secretion in NCCAH. The aim of this study is to investigate the association between genotype (i.e compound heterozygote for one mild and one severe CYP21A2 variant vs. homozygous for two mild variants) and peak cortisol response after ACTH stimulation in a pediatric population with NCCAH.

Small-cell carcinoma of the cervix with acute-onset psychotic symptoms associated with clinically diagnosed ectopic ACTH production: a case report.

Kanako Ozaki, Junya Fujino, Kaoru Niimi +11 more

Small-cell carcinoma of the cervix (SCCC) is a rare and highly aggressive histological subtype of cervical cancer, associated with poor prognosis. SCCC is histologically classified as a neuroendocrine tumor and has the potential to produce ectopic hormones, leading to various paraneoplastic syndromes. This report is a rare case of recurrent SCCC presenting with psychiatric symptoms due to endogenous Cushing's syndrome caused by ectopic adrenocorticotropic hormone (ACTH) production. The patient initially developed mood and behavioral disturbances as the disease progressed, leading to hospitalization under the suspicion of a primary psychiatric disorder. However, further evaluation, prompted by the discovery of severe hypokalemia, revealed Cushing's syndrome associated with clinically diagnosed ectopic ACTH production in the setting of recurrent disease. Her psychiatric symptoms rapidly remitted following the administration of a cortisol synthesis inhibitor. This case highlights the importance of considering endocrine disorders as potential causes of psychiatric manifestations in patients with cancer, particularly those with neuroendocrine tumors such as SCCC. Acute and marked elevation of endogenous cortisol can induce distinct psychiatric symptoms, such as manic features and grandiose delusions, that often respond better to endocrine treatment aimed at normalizing cortisol levels rather than to antipsychotic therapy alone. Clinicians should be aware of this rare but important clinical presentation as timely diagnosis and management can improve patient outcomes.

Surgical resection of an adrenocorticotropic hormone-producing pulmonary typical carcinoid with mediastinal lymph node metastasis and high programmed death-ligand 1 expression.

Masakazu Matsuda, Fumihiko Kinoshita, Yukina Takeichi +9 more

The programmed death-ligand 1 positivity rate in typical carcinoid is generally low; however, cases with programmed death-ligand 1 expression are more frequently associated with lymph node metastasis and have a poorer prognosis. While immune checkpoint inhibitors were incorporated into adjuvant chemotherapy regimens for programmed death-ligand 1-positive non-small cell lung cancer, their efficacy in pulmonary carcinoids remains unclear. A 47-year-old woman presented to a local clinic with moon face. Laboratory testing revealed elevated levels of adrenocorticotropic hormone and cortisol and adrenocorticotropic hormone-dependent Cushing's syndrome was suspected. For further evaluation, the patient was referred to our hospital. Computed tomography revealed a nodule in the left lower lobe of the lung and enlargement of the left hilar lymph node, suggesting ectopic Cushing's syndrome. Left lung cancer (cT1bN1M0, cStage IIB) was suspected, and the patient underwent robot-assisted thoracoscopic left lower lobectomy with ND2a-2 lymph node dissection for diagnostic and therapeutic purposes. Pathological examination confirmed a diagnosis of typical carcinoid (pT1bN2M0, pStage IIIA) with high programmed death-ligand 1 expression. Considering the presence of mediastinal lymph node involvement and programmed death-ligand 1 expression, the patient received four courses of cisplatin and vinorelbine, followed by treatment with atezolizumab. Postoperatively, her adrenocorticotropic hormone levels normalized, and the patient has been alive 18 months postoperatively without recurrence. Programmed death-ligand 1-positive typical carcinoids are associated with a higher frequency of lymph node metastasis and poorer prognosis. Additional case investigations are required to assess the efficacy of immune checkpoint inhibitors in typical carcinoid.

Symptom management with osilodrostat in multiple endocrine neoplasia type 1 with a Cushing syndrome presentation.

Hasan Frookh Jamal

Multiple endocrine neoplasia type 1 (MEN1) syndrome is a rare autosomal dominant disorder characterized by predisposition to a multitude of endocrine neoplasms. Cushing syndrome (CS) within MEN1 presents complex diagnostic and therapeutic challenges. We report a case of a 36-year-old male with adrenocorticotropic hormone (ACTH)-dependent Cushing disease and MEN1 syndrome with thymic and pancreatic neuroendocrine tumors. The patient presented with weight gain, weakness and proximal myopathy. Biochemical testing confirmed ACTH-dependent hypercortisolism. Imaging revealed a pituitary microadenoma, a large anterior mediastinal mass, and pancreatic lesions. Genetic analysis confirmed a pathogenic heterozygous MEN1 frameshift variant. After thymectomy, he declined further surgery. Treatment with thymectomy and octreotide long-acting release (LAR) was ineffective. Initiation of osilodrostat (titrated to 5 mg twice daily) resulted in a 76% reduction in urinary cortisol levels and a 47 kg weight loss, with significant functional improvement. Pancreatic and pituitary lesions remained stable. This is the first reported case of successful symptom management of MEN1-associated Cushing disease with osilodrostat, establishing it as an effective therapeutic option for medically complex MEN1 cases where surgery is not feasible or is declined.

Endocrine Modulation of Inflammation: The Role of Adrenocorticotropic Hormone and Cortisol.

Maritza Vidal, Nancy E Lane

The melanocortin system, derived from pro-opiomelanocortin processing, represents a crucial neuroendocrine-immune interface that regulates inflammatory and metabolic pathways. Through its 5 melanocortin receptors (MCRs), MCR1 to MCR5, this system exerts widespread endocrine, paracrine, and autocrine functions across the central nervous system, skin, adipose tissue, bone, and immune cells. Activation of melanocortin signaling produces potent anti-inflammatory effects by modulating cytokine release, leukocyte trafficking, and transcriptional control of proinflammatory mediators. Adrenocorticotropic hormone (ACTH), via the hypothalamic-pituitary-adrenal axis and direct interaction with MCR2, stimulates both cortisol synthesis and mediates steroid-independent immunomodulation in extra-adrenal tissues. It should be taken into account that ACTH is the only ligand for MCR2 inducing steroidogenesis, cell proliferation and anti-inflammatory effects. Synthetic and natural ACTH formulations, such as repository corticotropin injection (Acthar® Gel) and Purified Cortrophin Gel, have demonstrated clinical benefit in refractory inflammatory diseases, as their efficacy may extend beyond classic glucocorticoid pathways. Recent preclinical studies of selective MCR agonists, including MCR1-targeted compounds like dersimelagon, highlight novel therapeutic possibilities for autoimmune and fibrotic disorders. Understanding the dual steroidogenic and nonsteroidogenic actions of melanocortins provides a framework for developing targeted therapies with improved safety profiles compared with conventional glucocorticoids.

Clinical characteristics, diagnosis, and treatment of Cushing's syndrome: analysis of a multicenter registry in Antioquia, Colombia.

Wilfredo Antonio Rivera-Martínez, María Johana Ramírez Castaño, Stefanía Cruz Calderón +9 more

Cushing's syndrome (CS) is a rare endocrine disorder caused by long-term exposure to excess cortisol and is linked to significant morbidity. Data from multiple centers in Latin America remains limited.

Discordant Cortisol Responses to Spontaneous Hypoglycaemia Versus Adrenocorticotropic Hormone Stimulation: A Diagnostic Challenge for Hypothalamic-Pituitary-Adrenal Axis Assessment.

Pushpa Machineni, Asha Ranjan, Adlyne R Asirvatham +1 more

The hypothalamic-pituitary-adrenal (HPA) axis is a critical regulator of cortisol secretion, assessed via dynamic tests such as the insulin tolerance test and adrenocorticotropic hormone (ACTH) stimulation test. Discordant cortisol responses in recurrent hypoglycaemia that is, blunted secretion during hypoglycaemia but preserved under ACTH stimulation, pose a diagnostic challenge in evaluating adrenal insufficiency (AI).

Uncommon tumor, uncertain course: functional oncocytic adrenocortical neoplasm with mild autonomous cortisol secretion.

Fatima Hallak, Kendra Frey, Maria Ortega Abad +3 more

Oncocytic adrenocortical neoplasms are rare adrenal tumors that are usually discovered incidentally. Although most are nonfunctional, about one-third secrete hormones, most often cortisol. We present the case of a 59-year-old man with a right adrenal mass and long-standing, difficult-to-control hypertension. Biochemical testing revealed a 1 mg dexamethasone suppression test (DST) of 2.8 μg/dL (77.25 nmol/L) (reference range: <1.8 μg/dL; <50 nmol/L), a repeated 1 mg DST of 2.3 μg/dL (63.44 nmol/L), a baseline adrenocorticotropic hormone of 6.5 pg/dL (1.4 pmol/L) (reference range: 7.2-63.3 pg/mL; 1.6-13.9 pmol/L), and a dehydroepiandrosterone of 66.5 μg/dL (1.80 μmol/L) (reference range: 51.7-295 μg/dL; 1.4-8.0 μmol/L); consistent with mild autonomous cortisol secretion. Adrenal computed tomography (CT) showed a stable 21 mm indeterminate adrenal nodule with an unenhanced CT attenuation of 22 Hounsfield units. The patient underwent laparoscopic adrenalectomy, and pathology confirmed an oncocytic adrenocortical neoplasm of uncertain malignant potential. Postoperatively, a 1 mg DST was within normal limits, confirming the resolution of mild autonomous cortisol secretion. He is currently under surveillance with annual CT imaging. This case underscores the need to consider oncocytic adrenocortical neoplasms in the differential diagnosis of adrenal incidentalomas and highlights the importance of further research into this rare entity.

Pulmonary neuroendocrine tumour-associated ectopic Cushing's syndrome: diagnostic challenges and multidisciplinary management.

Rubén D Carrasco B, Alba Juanes, Carmen Marrón +3 more

Ectopic adrenocorticotropic hormone (ACTH) secretion is a rare cause of Cushing's syndrome (CS), often associated with neuroendocrine tumours (NETs). Early diagnosis can be difficult due to variable clinical manifestations and psychiatric symptoms that may obscure the underlying endocrine disorder. We report a case of severe ectopic ACTH-dependent Cushing's syndrome secondary to a pulmonary NET, highlighting the importance of multidisciplinary management, advanced imaging with positron emission tomography/computed tomography with gallium-68-labelled DOTA-D-Phe-Tyr-octreotide (68Ga-DOTATOC PET-CT) and aggressive biochemical control to enable curative surgery and full clinical recovery.

Hypothalamic-pituitary-adrenal axis activity and neurotrophic factors in drug-naive children and adolescents with attention-deficit/hyperactivity disorder.

Hurşit Ferahkaya, Necati Uzun, Hasibe Ağır +5 more

Attention deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder with a complex and not fully understood etiology. Increasing evidence suggests that neurotrophic factors involved in neurodevelopment and synaptic plasticity, as well as hormones of the hypothalamic-pituitary-adrenal (HPA) axis that regulate the stress response, may contribute to the pathophysiology of ADHD.

Transient adrenocorticotropic hormone elevation with a disproportionate cortisol response prior to the onset of immune checkpoint inhibitor-related hypophysitis.

Hina Inui-Yasuda, Hironori Bando, Miki Watanabe +10 more

Central Hypothyroidism and Impaired Growth Hormone Secretion Due to Subclinical Cushing's Syndrome: A Case Report.

Masahito Katahira, Taku Tsunekawa, Akira Mizoguchi +4 more

A 34-year-old Chinese woman presenting with general fatigue was found to have central hypothyroidism and low-normal insulin-like growth factor 1 (IGF-1). Although she had no cushingoid features, her adrenocorticotropic hormone levels were suppressed, while her serum cortisol levels were normal. Cortisol secretion was not suppressed following a 1-mg dexamethasone suppression test, and computed tomography revealed a left adrenal tumor. After adrenalectomy, her thyroid function, growth hormone (GH) secretion, and IGF-1 levels were normalized. A histopathological examination confirmed adrenocortical adenoma. This case demonstrates that mild autonomous cortisol secretion can impair GH secretion and cause central hypothyroidism even in the absence of any overt cushingoid features.

Psychosocial and Biological Factors Associated with Non-Suicidal Self-Injury in Chinese Child and Adolescent Inpatients with Major Depressive Disorder.

Chao Liu, Xue-Yan Zhu, Yan-Ni Shi +8 more

This study assessed the prevalence and associated psychosocial and biological factors of non-suicidal self-injury (NSSI) in Chinese child and adolescent inpatients diagnosed with major depressive disorder (MDD) by DSM-5 criteria.

Clinical and Metabolic Outcomes of Adrenalectomy Versus Conservative Management in Mild Autonomous Cortisol Secretion.

Seda Karslı, Selin Çelik, Özge Şahin Kimyon +3 more

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.

Early hypocortisolism with persistent remission following osilodrostat in a patient with long-standing Cushing disease.

Liat Sasson, Ilan Shimon

Cushing syndrome is a disorder of endogenous hypercortisolism characterized by increased morbidity and mortality; when surgery is not curative or feasible, medical therapies targeting pituitary adrenocorticotropic hormone or adrenal cortisol production are essential. We report a case of early-onset hypocortisolism and sustained remission following a brief osilodrostat therapy in a 70-year-old woman with Cushing disease who had been treated for many years with pasireotide and metyrapone. Ten days after initiating osilodrostat, she developed clinical signs of adrenal insufficiency and a low morning serum cortisol of 2.8 µg/dL (SI: 76 nmol/L) (reference range 7-25 µg/dL [SI: 193-690 nmol/L]); osilodrostat was discontinued, and glucocorticoid replacement was initiated, remaining glucocorticoid-replacement dependent at low doses for 2 months. Over subsequent follow-up of over 20 months, her 24-hour urinary free cortisol normalized, and she maintained persistent biochemical and clinical eucortisolism off all Cushing therapy, with no relapse of hypercortisolism. She also experienced weight loss of 16.5 kg and marked improvement in diabetes control, enabling discontinuation of insulin and glucagon-like peptide-1 (GLP-1) receptor agonist therapy. This is among the earliest documented cases of osilodrostat-induced hypocortisolism with long sustained hormonal remission after treatment discontinuation, emphasizing the need for early monitoring and prolonged follow-up.

The potential role of aging on acute phase proteins and hypotalamus-pituitary-adrenal axis: A representative cohort study in pregnant mares.

Deborah La Fauci, Pietro Medica, Esterina Fazio +3 more

Pregnancy in mares triggers physiological adaptations involving changes in inflammatory biomarkers, particularly acute-phase proteins (APPs), and the activation of the hypothalamic-pituitary-adrenal (HPA) axis. However, the extent to which these responses are influenced by maternal age remains unclear. The hypothesis of this study was that both APP profile and HPA axis activity during gestation are modulated by the age of the mare. Accordingly, the objective was to evaluate these variables throughout pregnancy and assess the impact of age on their physiological regulation. A total of 41 Spanish Purebred mares were evaluated: n. 31 were pregnant (n. 15 of ≤10 years; n. 16 of >10 years old) and n. 10 were non-pregnant mares. Pregnant mares were monitored monthly throughout gestation, to assess temporal changes in APPs and HPA axis activity. Blood samples were collected to measure serum amyloid A (SAA), haptoglobin (Hp), C-reactive protein (CRP), adrenocorticotropic hormone (ACTH), and cortisol (CORT) concentrations. Statistical analysis included repeated measures ANOVA, and t-tests to assess biomarker differences by age and pregnancy status. Pregnant mares, particularly older individuals, showed elevated concentrations of inflammatory and endocrine markers compared to non-pregnant ones (p < 0.05). These findings demonstrate that pregnancy significantly alters inflammatory and endocrine biomarkers in mares; therefore, older pregnant individuals showed more pronounced and sustained increases compared to both younger pregnant and non-pregnant mares. This suggests that maternal age influences the physiological adaptation to pregnancy, particularly in the regulation of the HPA axis and acute-phase response.

Resting neuroendocrine markers in relation to acute mental stress-induced adrenergic reactivity profiles in adults: The SABPA study.

Dewald Naudé, Wayne Smith, Roland von Känel +1 more

Stress-induced hemodynamic reactivity was categorized as predominant alpha (α)- and beta (β)-adrenergic reactivity profiles. Within these profiles, we investigated resting neuroendocrine markers, their associations with hemodynamic reactivity, and odds of an α- or β-adrenergic reactivity profile. We included 375 teachers (20-65 years) and recorded one-minute beat-to-beat hemodynamic reactivity during Stroop-Color-Word-Conflict-test. We categorized α-responders [lowest-quartile ∆%CO, ∆%Cwk; n = 49], β-responders [highest-quartile ∆%CO, ∆%Cwk; n = 69], mixed-α/β-responders [remaining n = 257]. Baseline fasting serum adrenocorticotropic hormone (ACTH), cortisol, urinary norepinephrine-to-creatinine (u-NE/Cr), and epinephrine-to-creatinine (u-EPI/Cr) ratios were measured. Predominant α-responders were older with greater hypertension prevalence than other responders. In α-responders, u-NE/Cr inversely, and ACTH and cortisol positively associated with ∆%CO and ∆%Cwk (all p ≤ 0.044). In β-responders, u-NE/Cr positively associated with ∆%CO, u-EPI/Cr inversely with ∆%CO, and positively with ∆%Cwk (all p ≤ 0.045). Odds of an α-profile were higher with u-NE/Cr, ACTH, and cortisol in the highest-quartile (all p ≤ 0.004). Odds of a β-profile were higher with u-NE/Cr in the highest-quartile and ACTH and cortisol in the lowest-quartile (all p ≤ 0.006). Predominant α-responders exhibited higher u-NE/Cr, ACTH, and cortisol, suggesting vascular risk through peripheral vasoconstriction. Predominant β-responders showed higher u-NE/Cr only, suggesting adaptive cardiac performance via catecholaminergic drive. These findings reveal distinct neuroendocrine underpinnings with implications for personalized acute stress cardiovascular phenotyping.

[Modern capabilities of contrast-enhanced computed tomography in the diagnosis of adrenal adenomas].

N V Tarbaeva, A Chevais, A V Manaev +5 more

 Adrenal incidentalomas are common, with a detection rate of up to 7% in patients over 70 years of age. Of these, up to 25% are functionally active, leading to the development of severe clinical manifestations. Challenges of insufficient diagnosis and a lack of a personalized approach to the management of such patients persist. To overcome these challenges, the use of CT image analysis is proposed to develop criteria for non-invasive diagnosis, which is a pathway towards improving personalized patient management.

Effect of Normal Level Endocrine Hormones and Hypothalamic Neuropeptides on Obesity in Women of Childbearing Age.

Yingying Tang, Xiukun Zhang, Lei Fan +4 more

To explore the association of endocrine hormones and hypothalamic neuropeptides fluctuations within normal level with obesity in women of childbearing age.

Reversible Cardiomyopathy Induced by Adrenal Insufficiency: A Case Report.

Nehad M Makki, Amjad A Bugis, Amr E Waly +2 more

Adrenal insufficiency, though rare, can cause serious cardiovascular complications such as reversible cardiomyopathy. We present the case of a 56-year-old woman admitted to the intensive care unit with bradycardia, hypotension, and hypoglycemia, followed by hemodynamic instability and subsequent development of supraventricular tachycardia requiring stabilization. Endocrine assessment performed after stabilization demonstrated panhypopituitarism with radiological evidence of an empty sella, central hypothyroidism, and biochemical findings consistent with central adrenal insufficiency, confirmed by low morning cortisol with low adrenocorticotropic hormone levels. On admission, echocardiography showed biventricular dysfunction with a reduced ejection fraction and severe tricuspid regurgitation. Following initiation of intravenous hydrocortisone and supportive therapy, repeat echocardiography at one month demonstrated significant improvement, with recovery of systolic function and marked reduction in valvular regurgitation, consistent with reversible cardiomyopathy. This case highlights the importance of adrenal insufficiency as a potential cause of unexplained cardiomyopathy. The patient's cardiac function improved markedly following appropriate endocrine therapy, with normalization of ejection fraction and resolution of valvular abnormalities. These findings underscore the value of early endocrine evaluation and timely management in preventing irreversible cardiac damage and achieving complete functional recovery.

Incidentally Discovered Adrenal Mass With Mild Autonomous Cortisol Secretion and Pheochromocytoma.

Padala Ravi Kumar, Sai Madhav Reddy Duggempudi, Deepak K Dash +2 more

Adrenal incidentalomas are adrenal masses detected on imaging performed for conditions unrelated to suspected adrenal disease. While pheochromocytomas and adrenal cortical adenomas are well-recognized entities, their coexistence with autonomous cortisol secretion (ACS) within a single lesion is rare and presents diagnostic and therapeutic challenges. A 53-year-old woman was incidentally found to have a left adrenal mass during imaging performed for evaluation of obstructive jaundice. She had hypertension but no classic symptoms of pheochromocytoma or overt Cushing's syndrome. Adrenal-protocol non-contrast CT showed an attenuation of -13 Hounsfield units (HU), suggestive of a benign adrenal adenoma. Biochemical evaluation revealed non-suppressible cortisol on the overnight dexamethasone suppression test (ONDST) and low-dose dexamethasone suppression test (LDDST), along with suppressed adrenocorticotropic hormone (ACTH), consistent with mild autonomous cortisol secretion (MACS). Additionally, 24-hour urinary fractionated normetanephrine levels were elevated, with normal fractionated metanephrine levels, confirming catecholamine excess. Preoperatively, she was managed with alpha- and beta-blockade, followed by open left adrenalectomy. Intraoperatively, she developed hypertension requiring nitroprusside infusion, and postoperatively she experienced transient hypotension, which was managed with intravenous fluids and hydrocortisone. Histopathology revealed a collision tumor with features of adrenal cortical adenoma and pheochromocytoma. Postoperatively, her requirement for antihypertensive drugs decreased from three to one. Repeat 24-hour urinary fractionated normetanephrine levels were normal at four weeks after surgery. This case highlights the importance of comprehensive biochemical and imaging assessment in adrenal incidentalomas. The tumor's dual-secretory nature necessitated meticulous perioperative management to prevent complications, and recognition of such rare entities is crucial for optimizing surgical and medical outcomes.

Metachronous Bilateral Adrenal Adenomas Causing Adrenocorticotropic Hormone-Independent Cushing's Syndrome: A Case Report.

I-Ting Hsiao, Chieh-Hua Lu

Bilateral adrenal adenomas (BAAs) represent an uncommon etiology of adrenocorticotropic hormone (ACTH)-independent Cushing's syndrome (CS); however, metachronous BAAs, where the adenomas present years apart, are exceptionally rare, with only a few cases previously reported. We present the case of a 53-year-old woman who developed ACTH-independent CS from a left adrenal cortical adenoma 19 years ago, treated successfully with a left-sided adrenalectomy. Nineteen years after the first episode, she presented with classic hypercortisolism symptoms, including central obesity, striae, and osteoporosis. Workup confirmed recurrent ACTH-independent CS with a low baseline ACTH level and a failure of both low- and high-dose dexamethasone suppression tests to suppress cortisol. Laparoscopic-assisted right-sided adrenalectomy was performed after image confirmation. Adrenal cortical adenoma was diagnosed by histological examination. Following the adrenalectomy, the patient required permanent glucocorticoid and mineralocorticoid replacement therapy. Serial brain magnetic resonance imaging (MRI) scans were initiated for Nelson's syndrome (NS) surveillance. Over 38 months of follow-up, the patient's clinical symptoms improved, and no signs of NS were noted. This case represents the longest detailed reported case with an interval of 19 years between the diagnosis and surgical treatment of metachronous BAAs causing ACTH-independent CS. This rarity highlights the critical importance of long-term and regular follow-up for patients with unilateral adrenal adenoma to monitor for subsequent contralateral masses.

A rare case report of familial glucocorticoid deficiency type 4 (GCCD4) with dilated cardiomyopathy: a 3-year follow-up study.

Zeli Xun, Yan'an Du, Ting Zhao +1 more

Familial glucocorticoid deficiency type 4 (GCCD4), caused by nicotinamide nucleotide transhydrogenase (NNT) gene mutations, represents a rare multisystem disorder with poorly characterized cardiac manifestations.

The Association Between Suicidal Ideation, Personality Traits, and Stress Hormones in Final-Year Medical Students.

Feyza Nur Ozbahar, Hamit Sirri Keten, Seyithan Taysi

This study aims to investigate the relationship between suicide risk, personality traits, and stress-related hormone levels among final-year medical students.