Adrenocorticotropic Hormone Secretion Research Articles

8738 Unveiling Potential Therapeutic Candidates for ACTH-Silent Pituitary Neuroendocrine Tumors Through High Throughput Drug Screening

Abstract Disclosure: J.M. Marques: None. N.D. D' Alessandre: None. G.D. Guardia: None. F.L. Craveiro: None. C. Grutzmacher: None. G.O. Silva: None. B.B. Mendonca: None. L.R. Carvalho: None. F. Fattahi: None. P.A. Galante: None. R.L. Batista: None. Introduction: ACTH-silent pituitary neuroendocrine tumours (PitNETs) are a subtype of PitNETs that arise from corticotroph cells of the anterior pituitary gland. They can show positive immunoreactivity for adrenocorticotropic hormone (ACTH) but with no clinical or laboratory evidence of hypercortisolism. ACTH-silent PitNETs display notably more aggressive behavior and treatment resistance. Currently, there is no established pharmacological therapy for this specific tumor subtype. Aim: To use high throughput drug screening to identify compounds that modulate ACTH secretion and tumor progression in ACTH-silent PitNETs. Methods: WTC11 cells (GM25256) were differentiated into pituitary using E6 with SB431542 10µM, SHH 200ng/mL, FGF8 100ng/mL and FGF10 50ng/mL until day 30. Pituitary cells were passaged in 384 well plates and treated with FDA-approved compound library with 3113 drugs at 1μM for 72h (#L1300, Selleckchem). Cells were stained with ACTH and imaged on ImageXpress® HCS. ACTH intensity was normalized to total cell number, measured by DAPI, using MetaXpress Software and compounds z-score was calculated, considering -2.5 for analysis. Gene and pathway enrichment analysis were performed and PitNET RNAseq data, publicly available (GSE207937), was used to determine target drugs based on similar target pathways and gene expression. To validate hits, we collected tumor samples from a patient with an aggressive silent ACTH PitNET. PitNET was histologically confirmed and hypercortisolism was excluded clinically and laboratory. Samples were cultured on DMEN/F12 with 10% FBS and 1% antibiotic and pituitary hormones were measured at days 3, 6 and 8. Cells were treated with 1uM of Letrozole, Linsitinib and Raloxifene for 48h and sample for RNA and hormone dosage were collected. Results: We identified 8 drugs that decreased ACTH in induced pituitary cells and selected 3 of them for validation. PitNET was successfully cultured and treated with selected drugs and ACTH secretion was detected at all periods (972.1 pg/mL to 10490 pg/mL), gonadotropins were below the detected level. Letrozole significantly reduced ACTH in the PitNET culture at day 8 (600.9 ± 25.8pg/mL, p<0,001). ACTH was also decreased in Linsitinib treated cells (932 ± 12.7pg/mL, p<0.05), while Raloxifene did not change ACTH secretion (980 ± 95.1pg/mL, p=0.061). Microscopically, PitNET cells aggregate in spheres and this seems to be affected by letrozole treatment, not influencing cell viability. Conclusion: We performed a high throughput drug screen using induced pituitary cells that led to the discovery of 3 compounds that might be used as an alternative for PitNET treatment. Pathway and gene expression analysis from target drugs and PitNET RNAseq may help in the understanding of drug effect in the PitNET context and improve the understanding of tumorigenesis and pharmacological treatment. Presentation: 6/1/2024

7743 A Case Study of Ectopic Adrenocorticotropic Hormone Secretion from Pancreatic Neuroendocrine Tumor

Abstract Disclosure: K.S. Wei: None. J. Huang: None. Introduction: Pancreatic neuroendocrine tumors (PanNETs) are uncommon cancers that account for less than 2% of pancreatic malignancies. Even rarer are ACTH-producing NETs which may only become symptomatic until after metastasis. This case study examines the distinct presentation and diagnostic complexities associated with ectopic adrenocorticotropic hormone (ACTH) secretion from a PanNET. Clinical Case:A 42 year-old male with hypertension and type 2 diabetes initially presented to the hospital with increased abdominal girth for one month, bilateral lower extremity edema for two weeks, and generalized abdominal pain. He had unremarkable surgical, family, and social histories. Patient was afebrile, normotensive, saturating well on room air, with exam notable for a distended abdomen and 2+ bilateral pitting edema. Admission labs were notable for potassium of 2.4 (ref: 3.5-5.1 mmol/L). MRI abdomen showed hepatomegaly with numerous heterogeneously enhancing masses and an ill-defined pancreatic tail mass with involvement of the spleen. Liver biopsy showed well-differentiated neuroendocrine tumor, grade 2. He was started on octreotide 20mg q4weeks and capecitabine/temozolomide q4weeks. Two months later, the patient was readmitted after presenting with back pain for two days, found to have acute compression fractures of T9-L1 without spinal PET activity. At follow-up visit with endocrinology, he endorsed easy bruising and muscle weakness and had hypertension (161/96 mmHg) with hypokalemia. Random cortisol was 43.7 (ref: 2.5-11.9 mcg/dL). ACTH was 124 (ref: 6-50 pg/mL) despite receiving chemotherapy. 24-hour urine cortisol was 3,049 (ref: 4-50 mcg/24 hrs). He was diagnosed with ectopic Cushing’s disease from ACTH-producing PanNET leading to osteoporosis and fracture of the vertebral bodies. For the ectopic Cushing’s disease, he was started on ketoconazole 200mg BID with plan to start osilodrostat once approved. For the fracture, he is scheduled for Zometa infusion and IR kyphoplasty. Conclusion: This case offers several important clinical insights. In patients with PanNET with Cushingoid exam findings, ACTH-producing PanNET should be high on the differential. Most ACTH NETs are aggressive often with liver metastases, whereby metastatic disease will have already occurred by the time the Cushingoid features develop. The initial severe hypokalemia and hypertension should have prompted investigation for mineralocorticoid excess from hypercortisolism, which may have led to an earlier diagnosis of ectopic ACTH Cushing’s disease, thereby decreasing the possibility of developing vertebral fractures, uncontrolled diabetes and hypertension. Ketoconazole or osilodrostat may be used to treat Cushing’s disease from ACTH NETs. Presentation: 6/1/2024

12275 Effect Of Osilodrostat On Cardiovascular And Metabolic Manifestations Of Hypercortisolism In Patients With Non-Pituitary Cushing’s Syndrome: Findings From A Retrospective Observational Study (LINC 7)

Abstract Disclosure: N. Scheyer: Other; Self; Recordati Rare Diseases. J. Bertherat: Consulting Fee; Self; Novartis, HRA Pharma, Recordati Rare Diseases. B. Decoudier: Consulting Fee; Self; Recordati Rare Diseases. H. Lasolle: Speaker; Self; Recordati Rare Diseases. H. Lefebvre: Speaker; Self; Recordati Rare Diseases. D. Drui: None. C. Vaillant: None. J. Morera: None. F. Castinetti: Consulting Fee; Self; HRA Pharma Rare Diseases, Recordati Rare Diseases. Grant Recipient; Self; HRA Pharma Rare Diseases, Recordati Rare Diseases. J. Cristante: Grant Recipient; Self; HRA Pharma, Pfizer, Inc.. N. Chevalier: None. S. Fodil-Cherif: None. A. Antonellini: Employee; Self; Recordati Rare Diseases. W. Agbotounou: Employee; Self; Recordati Rare Diseases. A. Mueller: Employee; Self; Recordati Rare Diseases. A. Tabarin: Consulting Fee; Self; H Lundbeck A/S, Crinetics Pharmaceuticals, HRA Pharma, Recordati Rare Diseases. Introduction: Endogenous Cushing’s syndrome (CS) is associated with increased cardiovascular morbidity and mortality because of hypercortisolism. Osilodrostat, a potent oral 11β-hydroxylase inhibitor, is approved for patients (pts) with endogenous CS (EMA) and Cushing’s disease (CD; for whom pituitary surgery is not an option or has not been curative; FDA). The long-term safety and efficacy of osilodrostat has been demonstrated in Phase II (LINC 2, NCT01331239) and Phase III (LINC 3, NCT02180217; LINC 4, NCT02697734) studies of CD pts. Here, we investigated the effect of osilodrostat on clinical manifestations of hypercortisolism in a real-world, retrospective, observational study conducted in a heterogeneous patient population with non-pituitary CS (LINC 7; NCT05633953). Methods: Adult pts with non-pituitary CS who initiated osilodrostat prior to EU approval under the French Autorisation Temporaire d’Utilisation scheme and/or, once approved, in routine clinical practice were followed up retrospectively for up to 36 months. The primary endpoint was proportion of pts with mean urinary free cortisol (mUFC) ≤upper limit of normal (ULN) at week (W) 12, based on the modified intention-to-treat (mITT) population (pts with any cortisol measurement at W12 or not collected because of safety reasons). Secondary endpoints included cardiovascular and metabolic parameters, recorded every 4 or 12W, depending on clinical practice. No formal statistical hypothesis testing was performed; all analyses are descriptive. Results: 103 pts were enrolled (mean [SD] age: 59.3 years [15.5]; female 61.2% [n=63]; adrenal adenoma [16.5%, n=17/103; mITT: 9.6%, n=5/52], adrenocortical carcinoma [18.4%, n=19/103; mITT: 11.5%, n=6/52], macronodular adrenal hyperplasia [13.6%, n=14/103; mITT: 17.3%, n=9/52], ectopic adrenocorticotropic hormone secretion [51.5%, n=53/103; mITT: 61.5%, n=32/52]). Median (min-max) osilodrostat exposure and dose at baseline was 164.0 days (1-1178) and 5.0 mg/day (1-60), respectively. Median (min-max) osilodrostat dose at W12 and W36 was 6.0 mg/day (0-60) and 10.0 mg/day (0-120), respectively. 23/52 pts (44.2%; 95% CI 30.5-58.7) had mUFC ≤ULN at W12. Mean (95% CI) changes in cardiovascular and metabolic-related parameters from baseline to W12 and W36, respectively, were: systolic blood pressure (−5.7 [−17.9, −6.6] mmHg, n=29 and −6.3 [−19.0, −6.5] mmHg, n=11); diastolic blood pressure (−4.7 [−10.6, −1.1] mmHg, n=29 and −8.2 [−20.7, −4.3] mmHg, n=11); weight (−2.3 [−4.2, −0.4] kg, n=27 and −3.6 [−9.6, −2.5] kg, n=12); body mass index (−0.8 [−1.5, −0.2] kg/m2, n=27 and −1.2 [−3.2, −0.8] kg/m2, n=12). No new safety signals were identified. Conclusions: Findings from this real-world setting show that osilodrostat provides cortisol control alongside improvements in clinical manifestations of hypercortisolism in non-pituitary CS pts, alleviating the disease burden. Presentation: 6/1/2024

Reduced pineal gland volume in patients with obsessive-compulsive disorder.

Patients with obsessive-compulsive disorder (OCD) can have hyperactivity of the hypothalamic-pituitary-adrenal axis and may have increased secretion of adrenocorticotropic hormone and cortisol and reduced secretion of melatonin. Examination of pineal gland volumes in patients with OCD compared to healthy controls, thus, is an important consideration and the focus of this study. A total of 20 patients with OCD and 20 healthy controls were enrolled. Demographic and clinical characteristics of participants were assessed, and structural magnetic resonance imaging was performed. Patients with OCD had a statistically significant smaller pineal gland volumes compared to healthy controls. In this initial small study, patients with OCD exhibited smaller pineal gland volumes compared to healthy control subjects. While this finding suggests a potential link between the pineal gland and OCD pathophysiology, further research with larger sample sizes and measurement of hormonal changes are necessary.

An aggressive Cushing's syndrome originating from a rare thymic neuroendocrine tumor, controlled successfully with fluconazole and octreotide therapy before surgery.

Cushing's syndromes (CSs) due to the thymic neuroendocrine tumors are rarely seen. Here, a case of ectopic CS originating from an atypical neuroendocrine tumor has been presented. A 49-year-old woman was hospitalized with symptoms of fatigue, chest pressure, dyspnea, muscle weakness, and resistant hypertension. There was marked hyperpigmentation in the whole-body surface suggestive of adrenocorticotropic hormone (ACTH) excess and there were physical features of CS. There was deep hypokalemia. Basal hormone profile, dexamethasone suppression tests, midnight cortisol, and 24-hour urine cortisol levels were suggestive of ectopic CS. The pituitary magnetic resonance imaging revealed a 5 mm cystic lesion and the patient refused inferior petrosal sinus sampling. Thorax computerized tomography showed an anterior mediastinal mass. A fluorodeoxyglucose-positron emission tomography showed the same mediastinal lesion (suvmax: 11.4), and no other tumor focus was detected. There was an aggressive cortisol excess causing acute respiratory distress syndrome, making it difficult to perform the surgery. We immediately started fluconazole and octreotide therapy and were successful in lowering the cortisol level. Then a complete resection of the tumor had been able to be surgically performed and tumor cells showed strong cytoplasmic immunopositivity with ACTH. A definitive diagnosis of "ACTH secreting atypical thymic carcinoid tumor" was rendered based on the histopathological and immunohistochemical features. There was only surrounding vessel invasion, and no lymphoid or other organ metastases were detected. As there were surrounding vessel invasions, a two-cycle regimen cisplatin-etoposide chemotherapy and radiotherapy were employed. After surgical and medical therapy, the cortisol and ACTH levels turned to normal. The patient is in biochemical and clinical remission and has no tumor recurrence yet. Ectopic ACTH-producing thymic carcinoids are rare but life-threatening tumors because of the underlying malignancy and severe hypercortisolemia. It is important to consider this disease and perform appropriate treatment at the right time. Today, surgery is the standard therapeutic modality if it is possible to perform, but there is not a clear and constant recommendation for nonsurgical therapeutic modalities. Further studies are needed for the optimal treatment strategies.

PACS-1 Interacts with TRPC3 and ESyt1 to Mediate Protein Trafficking while Promoting SOCE and Cooperatively Regulating Hormone Secretion.

Corticotropic cells of the anterior pituitary gland release adrenocorticotropic hormone (ACTH) in a regulated manner to promote the production of cortisol and androgens. The process of ACTH secretion is partly mediated by the phosphofurin acidic cluster sorting protein 1 (PACS-1); however, the underlying mechanisms behind this regulation remain unclear. Herein, we demonstrated PACS-1 interactions with the short transient receptor potential channel 3 (TRPC3) calcium transporter and the extended synaptotagmin-1 (ESyt1) endoplasmic reticulum-plasma membrane tethering protein. Importantly, PACS-1 promoted interactions between TRPC3 and ESyt1 and regulated their plasma membrane localization. Lastly, we demonstrated that PACS-1 is required for a proper store-operated calcium entry (SOCE) response and that ESyt1 regulates ACTH secretion through an unknown mechanism regulated by PACS-1. Overall, our study provides new insights into the physiological role PACS-1 plays in modulating intracellular calcium levels and regulating ACTH secretion in corticotropic cells.

A quantitative modeling framework to understand the physiology of the hypothalamic-pituitary-adrenal axis and interaction with cortisol replacement therapy.

Congenital adrenal hyperplasia (CAH) is characterized by impaired adrenal cortisol production. Hydrocortisone (synthetic cortisol) is the drug-of-choice for cortisol replacement therapy, aiming to mimic physiological cortisol circadian rhythm. The hypothalamic-pituitary-adrenal (HPA) axis controls cortisol production through the pituitary adrenocorticotropic hormone (ACTH) and feedback mechanisms. The aim of this study was to quantify key mechanisms involved in the HPA axis activity regulation and their interaction with hydrocortisone therapy. Data from 30 healthy volunteers was leveraged: Endogenous ACTH and cortisol concentrations without any intervention as well as cortisol concentrations measured after dexamethasone suppression and single dose administration of (i) 0.5-10mg hydrocortisone as granules, (ii) 20mg hydrocortisone as granules and intravenous bolus. A stepwise model development workflow was used: A newly developed model for endogenous ACTH and cortisol was merged with a refined hydrocortisone pharmacokinetic model. The joint model was used to simulate ACTH and cortisol trajectories in CAH patients with varying degrees of enzyme deficiency, with or without hydrocortisone administration, and healthy individuals. Time-dependent ACTH-driven endogenous cortisol production and cortisol-mediated feedback inhibition of ACTH secretion processes were quantified and implemented in the model. Comparison of simulated ACTH and cortisol trajectories between CAH patients and healthy individuals showed the importance of administering hydrocortisone before morning ACTH secretion peak time to suppress ACTH overproduction observed in untreated CAH patients. The developed framework allowed to gain insights on the physiological mechanisms of the HPA axis regulation, its perturbations in CAH and interaction with hydrocortisone administration, paving the way towards cortisol replacement therapy optimization.

The Application of Pneumatic Arm in Neuroendoscopic Transsphenoidal Pituitary Adenoma Resection.

To summarize the application experience of the pneumatic arm in transnasal sphenoidal pituitary adenoma resection under neuroendoscope. A retrospective analysis was conducted on the clinical data of 52 patients with pituitary adenoma who underwent endoscopic transsphenoidal surgery with pneumatic arm fixation in the Neurosurgery Department of the First Affiliated Hospital of Anhui Medical University from July 2021 to March 2024. Among them, there were 5 cases of pituitary microadenoma, 35 cases of macroadenoma, and 12 cases of giant adenoma. Head CT and a full set of hormones were re-examined within 24 hours after surgery to evaluate the surgical effect. Follow-up was conducted by the outpatient department after surgery to assess the clinical symptoms, hormone level, and imaging of all patients. Among 52 patients, gross total resection was achieved in 48 cases (92.3%), subtotal resection in 3 cases (5.8%), and partial resection in 1 case (1.9%). Preoperatively, 43 patients had diminished vision, with 40 showing improvement postoperatively, 1 worsening, and 2 having no significant improvement. Thirty-eight patients had headaches preoperatively, and all showed varying degrees of improvement postoperatively. Routine hormone examination within 24 hours after surgery showed that all 20 prolactinoma patients had restored normal hormone levels, 10 of 12 growth hormone-secreting adenoma patients normalized, and 4 of 6 cases of adrenocorticotropic hormone-secreting adenoma immediately relieved after surgery. Postoperative complications included intracranial hematoma in 1 case, cerebrospinal fluid leakage in 2 cases, transient diabetes insipidus in 6 cases, intracranial infection in 1 case, and no death cases. The median follow-up time of 52 patients was 18.6 months (range: 1-32 mo). During the follow-up period, the initial clinical symptoms of all patients improved to varying degrees, and they were able to work and live normally. At the last follow-up, 1 patient had recurrent tumor and 1 patient had progression. Transnasal sphenoidal resection of pituitary adenoma using a pneumatic arm-fixed neuroendoscope allows the operator to perform the surgery with both hands, resulting in satisfactory overall tumor resection and fewer surgical complications. This technique has good clinical value for promotion.

Glucagon does not directly stimulate pituitary secretion of ACTH, GH or copeptin

Glucagon is best known for its contribution to glucose regulation through activation of the glucagon receptor (GCGR), primarily located in the liver. However, glucagon’s impact on other organs may also contribute to its potent effects in health and disease. Given that glucagon-based medicine is entering the arena of anti-obesity drugs, elucidating extrahepatic actions of glucagon are of increased importance. It has been reported that glucagon may stimulate secretion of arginine-vasopressin (AVP)/copeptin, growth hormone (GH) and adrenocorticotrophic hormone (ACTH) from the pituitary gland. Nevertheless, the mechanisms and whether GCGR is present in human pituitary are unknown. In this study we found that intravenous administration of 0.2 mg glucagon to 14 healthy subjects was not associated with increases in plasma concentrations of copeptin, GH, ACTH or cortisol over a 120-min period. GCGR immunoreactivity was present in the anterior pituitary but not in cells containing GH or ACTH. Collectively, glucagon may not directly stimulate secretion of GH, ACTH or AVP/copeptin in humans but may instead be involved in yet unidentified pituitary functions.

Emotional disorders in the structure of psychoorganic pathology in tumors of the diencephalon

IntroductionThe tumors of the diencephalon region (thalamic-hypothalamic-pituitary system) include a large group: pituitary adenomas, craniopharyngiomas, gliomas, and others. Tumors differ in the histological structure, and manifestations of the clinical symptoms; by hormonal data; by approaches and methods in treatment.Psychic symptoms are revealed in disease in addition to cerebral, neuroendocrine symptoms, neurological disorders. Psychoorganic syndrome is represented by emotional, motivational, personal, cognitive impairments, inversion of the sleep-wake cycle, seizures.Disorders of mental activity are detected in all tumors of this localization in varying degrees, according to the different authors from 20 to 100%; affective pathology varies from 2 to 80% by the literature.ObjectivesTo study the emotional disorders in the structure of psychoorganic pathology in tumors of diencephalon regionMethods290 patients (18-78 years old, mean age 38+2): pituitary adenomas (PA), as the most common – 170 (58,6%), craniopharyngiomas (CG), as with the most varied manifestation of mental symptoms – 120 (41,4%). Methods: psychopathological, data from endocrinological, neurological, neuroimaging methods.ResultsEmotional disorders were detected in patients from 30 to 68% of cases, depending on the histology of the tumours: PA with excessive secretion of growth hormone - emotional disorders are in 60%; PA with excessive secretion of adrenocorticotropic hormone - in 50%; PA with excessive secretion of prolactin - in 30%; with excessive secretion of thyroid-stimulating hormone - in 40%; non-functioning PA - in 16%; CG - in 68%.Emotional disorders were more often represented by changeable mood, depression, apathy, sleep disturbance, and visceral symptoms. Symptoms differed depending on the histology of the tumor (type and level of hormones), the volume of the lesion and direction of growth, and concomitant hypertensive-hydrocephalic symptoms. Emotional disturbances often include memory impairment, personality and behavior changes.ConclusionsEmotional disorders are detected in patients in 30-68% of cases in the structure of psychoorganic pathology with damage to the diencephalon region (in particular, with pituitary adenomas and craniopharyngiomas); are determined by the topography of the tumor and histology with the involvement of the corresponding structures and nuclei in the pathological process.Disclosure of InterestNone Declared

Identifying gray matter alterations in Cushing's disease using machine learning: An interpretable approach.

Cushing's Disease (CD) is a rare clinical syndrome characterized by excessive secretion of adrenocorticotrophic hormone, leading to significant functional and structural brain alterations as observed in Magnetic Resonance Imaging (MRI). While traditional statistical analysis has been widely employed to investigate these MRI changes in CD, it has lacked the ability to predict individual-level outcomes. To address this problem, this paper has proposed an interpretable machine learning (ML) framework, including model-level assessment, feature-level assessment, and biology-level assessment to ensure a comprehensive analysis based on structural MRI of CD. The ML framework has effectively identified the changes in brain regions in the stage of model-level assessment, verified the effectiveness of these altered brain regions to predict CD from normal controls in the stage of feature-level assessment, and carried out a correlation analysis between altered brain regions and clinical symptoms in the stage of biology-levelassessment. The experimental results of this study have demonstrated that the Insula, Fusiform gyrus, Superior frontal gyrus, Precuneus, and the opercular portion of the Inferior frontal gyrus of CD showed significant alterations in brain regions. Furthermore, our study has revealed significant correlations between clinical symptoms and the frontotemporal lobes, insulin, and olfactory cortex, which also have been confirmed by previousstudies. The ML framework proposed in this study exhibits exceptional potential in uncovering the intricate pathophysiological mechanisms underlying CD, with potential applicability in diagnosing otherdiseases.

Dietary tryptophan intervention counteracts stress-induced transcriptional changes in a teleost fish HPI axis during inflammation

Immune nutrition is currently used to enhance fish health by incorporating functional ingredients into aquafeeds. This study aimed to investigate the connections between tryptophan nutrition and the network that regulates the communication pathways between neuroendocrine and immune systems in European seabass (Dicentrarchus labrax). When tryptophan was supplemented in the diet of unstressed fish, it induced changes in the hypothalamic-pituitary-interrenal axis response to stress. Tryptophan-mediated effects were observed in the expression of anti-inflammatory cytokines and glucocorticoid receptors. Tryptophan supplementation decreased pro-opiomelanocortin b-like levels, that are related with adrenocorticotropic hormone and cortisol secretion. When stressed fish fed a tryptophan-supplemented diet were subjected to an inflammatory stimulus, plasma cortisol levels decreased and the expression of genes involved in the neuroendocrine response was altered. Modulatory effects of tryptophan dietary intervention on molecular patterns seem to be mediated by altered patterns in serotonergic activity.

Ectopic ACTH Syndrome: Possibilities of Modern Diagnostics

The ectopic ACTH syndrome (EAS) is a constellation of clinical signs and symptoms caused by chronic excess production of cortisol by the adrenal glands due to stimulation by adrenocorticotropic hormone (ACTH) of extrapituitary origin. EAS is a rare pathology, it accounts for approximately 20% of all cases of ACTH-dependent hypercortisolism and up to 10% of all causes of endogenous autonomic cortisol production, however, it is often associated with severe hypercortisolism and is a life-threatening condition. The sources of ectopic secretion of ACTH are neuroendocrine tumors (NET), which differ in histological type, malignant potential, clinical course, and also have different, often difficult to detect localization. Early identification of ACTH -producing NET reduces the risk of death of the patient both from severe hypercortisolism and the tumor itself. The paper describes the features of the course of EAS, the possibilities of its diagnosis, and presents an algorithm for EAS diagnosis, created on the basis of the latest achievements of Russian and world medicine.

Pituitary Adenoma Prevalence and Characteristics of Omani Patients: A Single Center Experience.

To estimate the incidence of pituitary adenomas (PA) in adult Omani patients and describe its epidemiological, clinical, and radiological characteristics. In this longitudinal, descriptive study, we reviewed the records of all PA patients from January 2015 to January 2020 who presented at the endocrinology facilities at Sultan Qaboos University Hospital, Muscat. The participants comprised of 112 Omani patients with PA. The incidence of PA among all adult patients at Sultan Qaboos University Hospital (inpatient and outpatient) over five years (2015-2020) was 0.23%. The cohort had a mean age of 41.0±15.0 years. Of the 112 patients included in this study, 79 (70.5%) were women. Nearly half (51; 45.5%) of adenomas were prolactinomas while 46 (41.1%) were non-functioning adenomas, and seven (6.3%) were growth hormone-secreting adenomas while six (5.4%) were adrenocorticotropic hormone secreting adenomas. Headache was present in 67 (59.8%) patients, followed by visual field defects (40; 35.7%), galactorrhea (26; 23.2%), and fatigue (19; 17.0%). The majority of women (45/79; 57.0%) presented with menstrual cycle abnormalities. Radiological appearances were nearly equally distributed between micro- and macroadenomas. Most cases (58/112; 52.0%) of PA were treated medically by cabergoline, octreotide, and replacement therapies such as hydrocortisone and thyroxin, 38 (33.9%) were treated surgically (mainly by trans-sphenoidal pituitary resection), and the remaining 10 (8.9%) cases were subjected to radiotherapy. Medical treatment combined with surgery was employed for 15 (13.4%) patients. In our investigation, PA was primarily prevalent among Omani female patients, and the most common subtype of pituitary tumors was prolactinomas. The most common presentation symptom was headaches; most female patients had menstrual irregularities. Medical treatment was the primary approach for the applicable types of PAs, while surgery and radiotherapy were found to be secondary and tertiary treatment options, respectively.

Diverse presentations of Cushing's syndrome during pregnancy - A case series.

Cushing's syndrome (CS) encompasses various causes of hypercortisolism including adrenocorticotropic hormone (ACTH) secreting pituitary adenoma with or without bilateral adrenal hyperplasia, an adrenal adenoma or carcinoma, ectopic ACTH or corticotrophin-releasing hormone (CRH) secretion by a neoplasm or exogenous corticosteroid therapy. The diagnosis of CS in pregnancy presents a challenge due to overlapping clinical features of pregnancy (weight gain, striae, acne). If untreated, CS in pregnancy is associated with increased risk of maternal and fetal complications. With fewer than 250 cases currently published, we aim to review the clinical presentations, diagnostic methods, management, and outcomes of patients with CS in pregnancy to help optimise our clinical practice. This is a single-centre, retrospective review of woman with documented hypercortisolism receiving antenatal care at a tertiary maternity hospital in Perth between 2006 to 2022. Data were collated from electronic and chart reviews. OMNI calculator was used for birthweight calculations. Local ethics and patient consent were obtained. Five women and seven pregnancies were identified. Four women had a pituitary source of ACTH-dependent CS as confirmed by brain magnetic resonance imaging. One woman had an ectopic source of ACTH. Two women were diagnosed during pregnancy. All pregnancies occurring prior to treatment of the Cushing's disease were complicated by secondary hypertension and diabetes. CS represents a rare and difficult to diagnose condition in pregnancy. When untreated, maternal and fetal outcomes are compromised. Close monitoring of the associated complications with involvement of a multidisciplinary team are recommended.

Bilateral giant adrenal myelolipoma associated with congenital adrenal hyperplasia

Adrenal myelolipomas are rare benign tumors, often non-functioning, located in the adrenal cortex, consisting mainly of mature adipose tissue and hematopoietic tissue. Although uncommon, the number of reported cases has increased due to the greater use of diagnostic imaging techniques. This tumor is usually unilateral and found as an adrenal incidentaloma, although there is a predominance of bilaterality in patients with congenital adrenal hyperplasia (CAH). In this study, we report the case of a 33-year-old male patient with CAH due to 21-hydroxylase deficiency, in non-regular use of the control medication, with bilateral giant adrenal myelolipoma and subsequent evolution of bilateral testicular adrenal rest tumors. He underwent bilateral adrenalectomy by video laparoscopy. The anatomopathological analysis, which confirmed myelolipomas’ diagnosis, revealed the right adrenal with 430 g and 12.5 x 9.3 cm and the left with 257 g and 11.5 x 10.4 cm. This tumor may be accompanied by adrenocortical adenoma and carcinoma, ganglioneuroma, pheochromocytoma, Addison’s disease, Cushing’s syndrome, or CAH.Among the hypotheses of its pathogenesis, we highlight an association between the development of adrenal myelolipoma and chronic hormonal stimulation by the adrenocorticotrophic hormone (ACTH), especially in CAH. The non-regular treatment of CAH with glucocorticoids may have contributed to the chronic and elevated secretion of ACTH and, consequently, to the development of bilateral giant adrenal myelolipoma.

Corticotropin-Releasing Hormone: A Novel Stimulator of Somatolactin in Teleost Pituitary Cells.

Corticotropin-releasing hormone (CRH) is known for its crucial role in the stress response system, which could induce pituitary adrenocorticotropic hormone (ACTH) secretion to promote glucocorticoid release in the adrenal gland. However, little is known about other pituitary actions of CRH in teleosts. Somatolactin is a fish-specific hormone released from the neurointermediate lobe (NIL) of the posterior pituitary. A previous study has reported that ACTH was also located in the pituitary NIL region. Interestingly, our present study found that CRH could significantly induce two somatolactin isoforms' (SLα and SLβ) secretion and synthesis in primary cultured grass carp pituitary cells. Pharmacological analysis further demonstrated that CRH-induced pituitary somatolactin expression was mediated by the AC/cAMP/PKA, PLC/IP3/PKC, and Ca2+/CaM/CaMK-II pathways. Finally, transcriptomic analysis showed that both SLα and SLβ should play an important role in the regulation of lipid metabolism in primary cultured hepatocytes. These results indicate that CRH is a novel stimulator of somatolactins in teleost pituitary cells, and somatolactins may participate in the stress response by regulating energy metabolism.

Uncommon presentation of small cell lung carcinoma with ectopic adrenocorticotropic hormone secretion and resistant hypokalemia: A case report

Paraneoplastic syndromes can serve as initial indicators of malignancy, with small cell lung cancer accounting for 13% of new lung cancer diagnoses. The most prevalent paraneoplastic syndrome associated with small cell lung cancer is inappropriate antidiuretic hormone syndrome, followed by ectopic adrenocorticotropic hormone-mediated Cushing’s syndrome. Cushing’s syndrome manifests as hypercortisolemia and presents with diverse symptoms, including central obesity, plethora, menstrual irregularities, hypertension/diabetes mellitus, ecchymoses, osteoporosis, muscle weakness, virilization/hirsutism, skin atrophy, decreased libido, and infertility. This case report details the uncommon presentation of small cell lung carcinoma manifesting with ectopic adrenocorticotropic hormone secretion (EAS), leading to resistant hypokalemia and rhabdomyolysis. This case emphasizes the importance of considering EAS in severe cases of Cushing's syndrome and highlights the diagnostic and therapeutic challenges associated with this condition.

The antianxiety effects of koumine and gelsemine, two main active components in the traditional Chinese herbal medicine Gelsemium: A comprehensive review

AbstractThe genus Gelsemium belongs to the family Loganiaceae, one of the traditional Chinese herbs. Gelsemium is traditionally used to treat rheumatoid and neuropathic pain. Its root extracts were found to protect against anxiety, especially the alkaloids koumine and gelsemine. Indeed, koumine and gelsemine can act as positive agonists of the glycine receptor (GlyR), which reduces neuronal excitability through chloride influx and can also increase neuroactive steroid content by enhancing 3alpha‐hydroxysteroid oxidoreductase (3α‐HSOR) expression. The latter can activate the excitation‐inhibitory response via the γ‐aminobutyric acid type A receptor (GABAAR), reduce the abnormal corticotropin‐releasing hormone (CRH) increase in the hypothalamus, inhibit adrenocorticotropic hormone (ACTH) secretion, and effectively inhibit the abnormal ACTH and corticosterone increases in the circulation. In addition, koumine and gelsemine inhibited the expression of the NLR family pyrin domain containing 3 (NLRP3) inflammasome, inhibiting the release of inflammatory factors and regulating anxiety‐related neural circuits. Gelsemine also inhibited the overexpression of brain‐derived neurotrophic factor (BDNF) and cAMP response element‐binding protein (CREB) in the hypothalamus to maintain the plasticity of brain neurons and protect neurogenesis to achieve anxiety regulation. In general, this article reviews the recent studies on Gelsemium in the anxiety field, discusses its possible antianxiety mechanism, and confirms the potential of Gelsemium as a therapeutic drug for anxiety‐related diseases.

Pathogenetic and clinical rationale for syntropic pathology based on metabolic syndrome, coronary heart disease and type 2 diabetes mellitus

Pathogenetic and clinical rationale for syntropic pathology based on metabolic syndrome, coronary heart disease and type 2 diabetes mellitus