ACTH Research Articles

Flibanserin conquers murine depressive pseudodementia by amending HPA axis, maladaptive inflammation and AKT/GSK/STAT/BDNF trajectory: Center-staging of the serotonergic/adrenergic circuitry

Depressive pseudodementia (DPD) is a debilitating cognitive dysfunction that accompanies major and/or frequent depressive attacks. DPD has gained significant research attention owing to its negative effects on the patients' quality of life and productivity. This study tested the procognitive potential of Flibanserin (FBN), the serotonin (5HT) receptor modulator, against propranolol (PRP), as β/5HT1A receptors blocker. Serving this purpose, female Wistar Albino rats were subjected to chronic unpredictable stress (CUS) and subsequently treated with FBN only (3 mg/kg/day, p.o), PRP only (10 mg/kg/day, p.o), or PRP followed by FBN, using the same doses. FBN ameliorated the behavioral/cognitive alterations and calmed the hypothalamic-pituitary-adrenal (HPA) axis storm by reducing the levels of stress-related hormones, viz, corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), corticosterone (CORT) parallel to epinephrine (EPI) hyperstimulation. The maladaptive inflammatory response, comprising of interleukin (IL)-1β/6, and tumor necrosis factor (TNF)-α, was consequently blunted. This was contemporaneous to the partial restoration of the protein kinase-B (AKT)/glycogen synthase kinase (GSK)3β/signal transducer and activator of transcription (STAT)-3 survival trajectory and the reinstatement of the levels of brain derived neurotrophic factor (BDNF). Microscopically, FBN repaired the hippocampal architecture and lessened CD68/GFAP immunoreactivity. Pre-administration of PRP partially abolished FBN effect along the estimated parameters, except for 5HT2A receptor expression and epinephrine level, to prove 5HT1A receptor as a fulcrum initiator of the investigated pathway, while its sole administration worsened the underlying condition. Ultimately, these findings highlight the immense procognitive potential of FBN, offering a new paradigm for halting DPD advancement via synchronizing adrenergic/serotonergic circuitry.

Stability of adrenocorticotropic hormone in whole blood samples: effects of storage conditions.

Adrenocorticotropic hormone (ACTH) is a peptide secreted by pituitary gland that plays an important role in regulating cortisol secretion. Its determination is difficult because of instability in whole blood. Several factors that influence ACTH stability in blood before analysis have been identified: temperature, hemolysis, time to centrifugation and presence of protease inhibitors. Published results on ACTH whole blood stability seem contradictory. We performed a stability study in 10 healthy volunteers. Three different conditions were tested: ethylenediaminetetraacetic acid (EDTA) at 4 °C, EDTA + aprotinin at 4 °C, EDTA + aprotinin at room temperature. Stability was evaluated for 8 hours. Adrenocorticotropic hormone measurements and hemolysis index were performed respectively on Cobas e602 and c701 (Roche Diagnostics, Mannheim, Germany). We compared percentage deviations with total change limit using a threshold of 7.5%. We showed that ACTH is stable 8 hours with EDTA at 4 °C, 4 hours with EDTA + aprotinin at 4 °C and 2 hours with EDTA + aprotinin at 22 °C. Aprotinin does not appear to give ACTH greater stability but can be used without exceeding 4 hours at 4 °C. Refrigerated pouch transport also seems to be more appropriate for ACTH in whole blood.

Effect of crowding stress on liver health, gut permeability and gut microbiota of genetically improved farmed tilapia (GIFT, Oreochromis niloticus)

This study investigated the effects of crowding stress on liver and gut health in genetically improved farmed tilapia (GIFT, Oreochromis niloticus). Fish averaging 18.90 ± 0.01 g were reared at low (LD, 5 g/L) or high densities (HD, 100 g/L) for 14 days. The analysis revealed that the HD group significantly increased serum cortisol, glucose and adrenocorticotropic hormone (ACTH) levels in GIFT (P < 0.05). Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were elevated in the HD group (P < 0.05). TUNEL staining of liver tissues revealed that the fluorescence intensity indicating apoptosis was significantly higher in the HD group (P < 0.05). Additionally, the HD group exhibited increased expression of p53 and Caspase3 in the liver (P < 0.05). In comparison to the LD group, the HD group showed a significant increase in gut superoxide dismutase (SOD) and catalase (CAT) activities, as well as malondialdehyde (MDA) content (P < 0.05). The expressions of inflammatory-related genes (tnfα, il-1β, il-8, and il-6) and pro-apoptotic genes (p53 and Caspase7) were significantly upregulated in the gut of the HD group (P < 0.05). Serum contents of D-lactate and diamine oxidase (DAO) were significantly elevated in HD group as comparison to LD group (P < 0.05), and significantly higher serum FITC-CM-dextran was observed in HD group versus LD group following oral gavage (P < 0.05). Furthermore, the HD group down-regulated the expressions of gut tight junction proteins (tjp2a, hif-1a, and zo-1) (P < 0.05), and significantly up-regulated the protein expression of phosphorylated myosin light chain 2 (P-MLC2) (P < 0.05). The 16S rDNA gene sequencing results indicated that the relative abundance of Cetobacterium was significantly lower (P < 0.05), and Enterovibrio and Weissella were significantly higher in the HD group (P < 0.05). Overall, crowding stress negatively affects GIFT liver and gut health, which is caused by inducing hepatic and intestinal apoptosis, impairing intestinal barrier function, and disrupting the gut microbiota.

Neuroendocrinology of bone.

The past decade has witnessed significant advances in our understanding of skeletal homeostasis and the mechanisms that mediate the loss of bone in primary and secondary osteoporosis. Recent breakthroughs have primarily emerged from identifying disease-causing mutations and phenocopying human bone disease in rodents. Notably, using genetically-modified rodent models, disrupting the reciprocal relationship with tropic pituitary hormone and effector hormones, we have learned that pituitary hormones have independent roles in skeletal physiology, beyond their effects exerted through target endocrine glands. The rise of follicle-stimulating hormone (FSH) in the late perimenopause may account, at least in part, for the rapid bone loss when estrogen is normal, while low thyroid-stimulating hormone (TSH) levels may contribute to the bone loss in thyrotoxicosis. Admittedly speculative, suppressed levels of adrenocorticotropic hormone (ACTH) may directly exacerbate bone loss in the setting of glucocorticoid-induced osteoporosis. Furthermore, beyond their established roles in reproduction and lactation, oxytocin and prolactin may affect intergenerational calcium transfer and therefore fetal skeletal mineralization, whereas elevated vasopressin levels in chronic hyponatremic states may increase the risk of bone loss.. Here, we discuss the interaction of each pituitary hormone in relation to its role in bone physiology and pathophysiology.

Beyond symptomatology: A comparative analysis of unilateral and bilateral macronodular mild autonomous cortisol secretion.

To investigate the clinical, laboratory findingsand signal intensity index (SII) on magnetic resonance imaging (MRI) of patients with bilateral and unilateral macronodular mild autonomous cortisol secretion (MACS). Clinical and laboratory findings of 81patients with MACS were examined from retrospective records. SII of adenomas and internodular areas were evaluated by MRI. The unilateral group included patients with an adrenal macronodule (≥1 cm) in a single adrenal gland, while the bilateral group included patients with at least one macronodule in both adrenal glands. In total, 46 patients were in the unilateral (57%), while 35 (43%) patients were in the bilateral groups. The dehydroepiandrosterone sulphate(DHEA-S) level was lower in the unilateral than in the bilateral group (p < .001). The presence of type 2 diabetes mellitus (T2DM), glycosylated haemoglobin (HbA1c) and low-density lipoprotein(LDL) concentrations were higher in the bilateral group (p < .05). However, no significant difference was detected in terms of adrenocorticotropic hormone(ACTH) and overnight 1 mgdexamethasone suppression test (DST) between the two groups (p > .05). There was no difference in SII between adenomas within the same patient, as well as between the unilateral and bilateral groups (p > .05). Logistic regression analysis based on the differentiation between unilateral and bilateral macronodular MACS demonstrated that DHEA-S, HbA1cand LDL concentrations were associated factors. DHEA-S levels may not be as suppressed in patients with bilateral macronodular MACS as compared to those with unilateral adenoma. T2DM and hypercholesterolaemia have a higher frequency in bilateral patients. However, ACTH, overnight 1 mgDSTand SII may not provide additional information for differentiation of bilaterality and unilaterality.

Calculated Right Adrenal Vein Aldosterone Levels in Patients Undergoing Adrenal Vein Sampling: The Potential to Lateralize Despite Unsuccessful Selection of the Right Adrenal Vein

PurposeThe aim of this study was to use calculated aldosterone level in the right adrenal vein (RAV) (cAldoRAV) rather than measured level for identifying the dominant side of aldosterone secretion in patients with primary aldosteronism undergoing adrenocorticotropic hormone–stimulated adrenal venous sampling (AVS). Materials and MethodsPatients with primary aldosteronism who had successful AVS (selectivity index, >3) were studied. Based on the assumption that cortisol production from both adrenal glands is equal, aldosterone level in the RAV was calculated using the data from the left adrenal vein and inferior vena cava. The aldosterone level in the left adrenal vein (AldoLAV) compared with the cAldoRAV (AldoLAV:cAldoRAV ratio) was then used to determine the dominant side of aldosterone secretion compared with standard AVS interpretation using lateralization index (LI). LI ≥4 indicated unilateral disease, and LI ≤3 indicated bilateral disease. The LI between 3 and 4 was diagnosed as indeterminate. ResultsSixty-eight patients with concordant results between AVS and adrenal imaging study (32 were left-sided, 22 were right-sided, and 14 were bilateral) were selected for studying diagnostic performance. The AldoLAV:cAldoRAV ratio with the cutoff values of ≥3 and ≤0.33 could identify unilateral diseases (left-sided and right-sided disease, respectively) with 92.6% sensitivity and 100% specificity. ConclusionsThe calculated AldoLAV:cAldoRAV ratio can determine the dominant side of aldosterone secretion with high sensitivity and specificity when compared with standard AVS interpretation of measured levels. It provides an option for identification of unilateral and bilateral disease in select patients in whom right adrenal vein selection is unsuccessful.

Differentiating lung neuroendocrine neoplasms from tumor-like infection using CT in patients with ectopic ACTH syndrome

ObjectivesPulmonary neuroendocrine neoplasms (NENs) are the most frequent cause of ectopic adrenocorticotropic hormone syndrome (EAS); lung infection is common in EAS. An imaging finding of infection in EAS patients can mimic NENs. This retrospective study investigated EAS-associated pulmonary imaging indicators.MethodsForty-five pulmonary NENs and 27 tumor-like infections from 59 EAS patients (45 NEN and 14 infection patients) were included. Clinical manifestations, CT features, 18F-FDG, or 68Ga-DOTATATE-PET/CT images and pathological results were collected.ResultsHigh-sensitivity C-reactive protein (p < 0.001) and expectoration occurrence (p = 0.04) were higher, and finger oxygen saturation (p = 0.01) was lower in the infection group than the NENs group. Higher-grade NENs were underrepresented in our cohort. Pulmonary NENs were solitary primary tumors, 80% of which were peripheral tumors. Overlying vessel sign and airway involvement were more frequent in the NENs group (p < 0.001). Multifocal (p = 0.001) and peripheral (p = 0.02) lesions, cavity (p < 0.001), spiculation (p = 0.01), pleural retraction (p < 0.001), connection to pulmonary veins (p = 0.02), and distal atelectasis or inflammatory exudation (p = 0.001) were more frequent in the infection group. The median CT value increment between the non-contrast and arterial phases was significantly higher in NENs lesions (p < 0.001). Receiver operating characteristic curve analysis indicated a moderate predictive ability at 48.3 HU of delta CT value (sensitivity, 95.0%; specificity, 54.1%).ConclusionChest CT scans are valuable for localizing and characterizing pulmonary lesions in rare EAS, thereby enabling prompt differential diagnosis and treatment.Critical relevance statementThin-slice CT images are valuable for the localization and identification of pulmonary ectopic adrenocorticotropic hormone syndrome lesions, leading to prompt differential diagnosis and effective treatment.Key PointsLung tumor-like infections can mimic neuroendocrine neoplasms (NENs) in ectopic adrenocorticotropic hormone syndrome (EAS) patients.NENs are solitary lesions, whereas infections are multiple peripheral pseudotumors each with identifying imaging findings.Typical CT signs aid in localization and creating an appropriate differential diagnosis.Graphical

Severe hypoglycemia in a diabetic patient with pituitary apoplexy: a case report

IntroductionHypoglycemia is a common occurrence in diabetic patients. But unlike non diabetic patients, its causes are frequently related to drugs they are receiving to control blood glucose. But this may not always be the case. Here we report a type 2 diabetic patient with severe hypoglycemia owing to acute hypopituitarism secondary to pituitary apoplexy.Case presentationA 45 year old male diabetic patient from Ethiopia taking 2 mg of oral glimepiride daily who presented with change in mentation of 30 minutes and blood glucose recording of 38 mg/dl upon arrival to the emergency room. Brain magnetic resonance imaging showed pituitary macroadenoma with hemorrhage suggestive of pituitary apoplexy. Blood work up showed low adrenocorticotropic hormone, cortisol, and serum sodium levels. Subsequently transsphenoidal hypophysectomy was done.ConclusionThe occurrence of hypoglycemia in a diabetic patient taking sulphonylurea monotherapy is common. But when it is severe enough to cause altered mentation, patients should be approached differently. In the presence of clinical clues suggesting cortisol deficiency, hypopituitarism can be a possible cause.

Cushing Disease in a Patient with Double Pituitary Adenomas Complicated with Diabetes Insipidus

Managing a patient with both pituitary hypersecretory and hyposecretory manifestations may be perplexing. We report a 14-year-old female who presented with weight gain, polyuria and polydipsia. Biochemical results were consistent with Cushing disease with central diabetes insipidus. Pituitary magnetic resonance imaging showed right adenoma with stalk thickening. The immunohistochemistry staining of both adenomas was positive for adrenocorticotropic hormone, thyroid stimulating hormone, growth hormone and luteinizing hormone. Postoperatively, the patient developed panhypopituitarism with persistent diabetes insipidus. The coexistence of double adenomas can pose diagnostic and management challenges and is a common cause of surgical failure. Intraoperative evaluation is important in the identification of double or multiple pituitary adenomas in a patient presenting with multiple secretory manifestations.

Before Low Serum Cortisol Can Be Attributed to SARS-Cov-2 Infection, Alternative Causes Must Be Ruled Out

We read with interest Banu et al.,’s article about a cross-sectional study of adrenal function using blood levels of cortisol and adrenocorticotropic hormone (ACTH) in 91 patients with acute SARS-CoV-2 infection. It was found that 27% of patients with severe COVID-19, 26% with mild COVID-19 and 4% with moderate COVID-19 had adrenal insufficiency. Decreased cortisol reserve was found in 6.6% of all patients. It was concluded that the adrenocortical response was impaired in a significant number of non-critically ill COVID-19 patients, with the percentage being highest in patients with severe COVID-19 disease.1 The study is impressive, but some points should be discussed. The major limitation of the study is that imaging of the pituitary gland and hypothalamus was not performed. To rule out pituitary adenoma, hypophysitis, pituitary apoplexy, pituitary abscess, sellar tuberculoma, or hypothalamic stroke or bleeding, magnetic resonance imaging (MRI) of the pituitary gland and the hypothalamus with contrast agent must be performed. Like any other infection, SARS-CoV-2 infection can trigger the appearance of symptoms of a pituitary pathology.2 A second limitation is that imaging of the suprarenal glands was not performed. To assess whether there was adrenal atrophy, adenoma, ischemia, bleeding, or carcinoma, adrenal imaging is mandatory. 3 A third limitation is that current medication was not reported. Several medications are known to affect serum cortisol levels, making it imperative to know all medications regularly taken by the included patients. Ketoconazole, isilodrostat, vitamin D and omega-3 fatty acids in particular are known to be able to reduce cortisol levels in the blood.4 A fourth limitation is that no ACTH stimulation test was performed to determine whether primary or secondary suprarenal insufficiency was present. Determining cortisol levels alone without ACTH stimulation testing is not reliable with regard to cortical adrenal function. A fifth limitation is that serum dehydroepiandrosterone (DHEA) levels were not measured. Since DHEA is the antagonist of cortisol and decreases with age, it is conceivable that high levels of DHEA promoted the reduction of serum cortisol.5 Since low thyroxine levels may be associated with low cortisol levels,6 it would also be desirable to know whether thyroid function was normal or abnormal in the included patients. In summary, the excellent study has limitations that should be addressed before drawing final conclusions. Clarifying the weaknesses would strengthen the conclusions and could improve the study. Serum cortisol levels may be low not only due to SARS-CoV-2 infection but also due to several other causes. Before adrenal insufficiency can be attributed solely to inadequate cortical cortisol production, the entire hypothalamic-pituitary-adrenal axis must be thoroughly examined.

The diverging role of O-GlcNAc transferase in corticotroph and somatotroph adenomas.

Molecular mechanisms involved in the pathogenesis and tumor progression of pituitary adenomas (PA) remain incompletely understood. Corticotroph and somatotroph PA are associated with a high clinical burden, and despite improved surgical outcomes and medical treatment options, they sometimes require multiple surgeries and radiation. Preliminary data suggested a role for O-GlcNAc Transferase (OGT), the enzyme responsible for the O-GlcNAcylation of proteins. O-GlcNAcylation and OGT have been found elevated in other types of tumors. We evaluated 60 functioning and nonfunctioning PA (NFPA) from operated patients and postmortem normal and tumoral pituitary tissue by immunohistochemistry. We performed transcriptomic analyses to explore the relevance of the O-GlcNAc Transferase (OGT) in PAs. We detected OGT in immunobiological analysis and define its level in PA tissue in patients. OGT was strongly associated with PA hormone secretory capacity in functioning PA and with tumor growth in NFPAs. In NFPAs, OGT was positively associated with tumor size but not with cavernous sinus invasion (Knosp grading). In GH-secreting PA, OGT expression was negatively correlated with circulating Insulin-like Growth Factor 1 level. In adrenocorticotropic hormone (ACTH)-secreting PA, OGT expression was positively associated with circulating ACTH levels. OGT did not correlate with tumor size in secreting PAs. OGT levels were higher in gonadotroph PA compared to normal glands. O-GlcNAcylation can be downregulated in non-cancerous tumors such as GH-secreting adenomas. Future studies are warranted to elucidate the role of OGT in the pathogenesis of PAs.

Examining aldosterone plasma concentration alterations post-ACTH stimulation in healthy subjects: a systematic literature review and meta-analysis on ACTH's role in aldosterone secretion.

Adrenocorticotropic hormone (ACTH), in addition to the renin-angiotensin-aldosterone axis, is a potent aldosterone stimulator, suggesting a potential contribution to conditions associated with increased ACTH concentrations. This study aims to systematically review and synthesize the scientific evidence of alterations of plasma aldosterone concentrations in response to ACTH stimulation during the cosyntropin (Synacthen) test and define the range of aldosterone response. A systematic search of PubMed, Medline, and Google Scholar databases according to PRISMA guidelines was performed. Only studies that assessed the alterations in plasma aldosterone concentrations following ACTH stimulation in healthy individuals were included. We incorporated studies that utilized the doses of 1μg, 250μg, 0.125μg/m2, or 0.5μg/m2 of ACTH. Out of 1599 initially assessed articles, 17 were deemed relevant to our research. The selected articles were assessed by two independent investigators based on the predetermined inclusion and exclusion criteria. Finally, eight full-text articles were included. The analyzed studies revealed a significant increase in plasma aldosterone concentrations in healthy subjects after ACTH stimulation, irrespective of the ACTH dose. The peak aldosterone concentration after the 250μg dose occurred at 30min, whereas smaller doses exhibited an earlier peak, at around 15min. On average, plasma aldosterone concentration increased by 125.5% after the 1μg and 0.5μg/m2 doses, and by 189.6% after 250μg. The presented evidence strongly supports the contribution of ACTH to aldosterone secretion regulation beyond the renin-angiotensin-aldosterone axis. Establishing a normal aldosterone response threshold following standardized ACTH stimulation could aid in identifying individuals with ACTH-dependent aldosterone hypersecretion and guide personalized and effective treatment strategies.

Effects of Premortem Stress on Protein Expression, Steak Color, Oxidation, and Myofibrillar Fragmentation Index in the Longissimus Lumborum.

Forty castrated Holstein calves underwent an adrenocorticotropic hormone (ACTH) challenge to assess the effects of premortem stress on the longissimus lumborum (LL) following harvest. LL biopsies were collected before the challenge, at different harvest times (2, 12, 24, and 48 h; n = 10), and after 14 d aging. The expression of small heat shock proteins (SHSPs), deglycase 1 (DJ-1), and troponin were analyzed. Blood was analyzed throughout the ACTH challenge and at harvest for cortisol, oxidative stress, and complete blood count (CBC). Color and myofibrillar fragmentation index (MFI) were measured in aged samples. Unexpectedly, calves from different harvest times differed (p = 0.05) in cortisol response. Calves were divided into two different cortisol response groups (high or low; n = 20). Statistical analysis assessed the effects of cortisol response (n = 20), harvest time (n = 10), and their interaction. Harvest time altered SHSPs (p = 0.03), DJ-1 (p = 0.002), and troponin (p = 0.02) expression. Harvest time and cortisol response impacted steak color (p < 0.05), and harvest time altered steak pH (p < 0.0001). Additionally, various CBCs were changed (p < 0.05) by harvest time. Harvest time changed (p = 0.02) MFI. These data demonstrate that the protein expression, color, and MFI of the LL may be influenced by premortem stress.

What Are the Key Factors for the Detection of Peptides Using Mass Spectrometry on Boron-Doped Diamond Surfaces?

We investigated the use of boron-doped diamond (BDD) with different surface morphologies for the enhanced detection of nine different peptides by matrix-assisted laser desorption/ionisation mass spectrometry (MALDI-MS). For the first time, we compared three different nanostructured BDD film morphologies (Continuous, Nanograss, and Nanotips) with differently terminated surfaces (-H, -O, and -F) to commercially available Ground Steel plates. All these surfaces were evaluated for their effectiveness in detecting the nine different peptides by MALDI-MS. Our results demonstrated that certain nanostructured BDD surfaces exhibited superior performance for the detection of especially hydrophobic peptides (e.g., bradykinin 1-7, substance P, and the renin substrate), with a limit of detection of down to 2.3 pM. Further investigation showed that hydrophobic peptides (e.g., bradykinin 1-7, substance P, and the renin substrate) were effectively detected on hydrogen-terminated BDD surfaces. On the other hand, the highly acidic negatively charged peptide adrenocorticotropic hormone fragment 18-39 was effectively identified on oxygen-/fluorine-terminated BDD surfaces. Furthermore, BDD surfaces reduced sodium adduct contamination significantly.

Autoimmune Thyroiditis Mitigates the Effect of Metformin on Plasma Prolactin Concentration in Men with Drug-Induced Hyperprolactinemia.

Metformin inhibits the secretory function of overactive anterior pituitary cells, including lactotropes. In women of childbearing age, this effect was absent if they had coexisting autoimmune (Hashimoto) thyroiditis. The current study was aimed at investigating whether autoimmune thyroiditis modulates the impact of metformin on the plasma prolactin concentration in men. This prospective cohort study included two groups of middle-aged or elderly men with drug-induced hyperprolactinemia, namely subjects with concomitant Hashimoto thyroiditis (group A) and subjects with normal thyroid function (group B), who were matched for baseline prolactin concentration and insulin sensitivity. Titers of thyroid peroxidase and thyroglobulin antibodies, levels of C-reactive protein, markers of glucose homeostasis, concentrations of pituitary hormones (prolactin, thyrotropin, gonadotropins, and adrenocorticotropic hormone), free thyroxine, free triiodothyronine, testosterone, and insulin growth factor-1 were measured before and six months after treatment with metformin. Both study groups differed in titers of both antibodies and concentrations of C-reactive protein. The drug reduced the total and monomeric prolactin concentration only in group B, and the impact on prolactin correlated with the improvement in insulin sensitivity and systemic inflammation. There were no differences between the follow-up and baseline levels of the remaining hormones. The results allow us to conclude that autoimmune thyroiditis mitigates the impact of metformin on prolactin secretion in men.

Reversible central adrenal insufficiency in survivors of COVID-19: results from a 24-month longitudinal study.

We studied the temporal course of hypothalamic-pituitary-adrenal (HPA) dysfunction in patients with coronavirus disease 2019 (COVID-19). Three hundred and two patients (median age 54 years (interquartile range (IQR) 42-64), 76% males) were recruited. The HPA axis was evaluated by morning cortisol and adrenocorticotrophic hormone (ACTH) at admission (n = 232). Adrenal insufficiency (AI) during acute illness was defined using a morning cortisol <83 nmol/L. AI at 12 months follow-up was defined using a peak cortisol <406 nmol/L in the ACTH stimulation test (APST) (n = 90). Those with AI at 12 months were further assessed by APST every 6 months for recovery of hypoadrenalism. The median morning cortisol and ACTH levels during COVID-19 were 295 (IQR 133-460) nmol/L and 3.9 (0.8-6.9) pmol/L, respectively. AI was present in 33 (14%) patients; ACTH was elevated in three and low or inappropriately normal in the rest 30 patients. At 12 months, AI was seen in 13% (12/90) patients, with all cases being hypothalamic-pituitary in origin; five (42%) of them had not met the diagnostic criteria for AI during COVID-19. AI diagnosed at admission persisted at 12 months in seven patients and recovered in seven; the remaining 19 patients were lost to follow-up. The presence of AI at 12 months was independent of severity and steroid use during COVID-19. A morning cortisol <138 nmol/L during COVID-19 predicted the presence of AI at 12 months. All patients showed recovery of the HPA axis in the ensuing 12 months. Central AI was common during acute COVID-19 and at 12 months of follow-up. AI can be late onset, developing after recovery from COVID-19, and was transient in nature.

Genotypic variation in the promoter region of the CRH-248 gene interacts with early rearing experiences to disrupt the development of the HPA axis in infant rhesus macaques (Macaca mulatta)

Aberrant functioning of the hypothalamic-pituitary-adrenal (HPA) axis is a hallmark of conditions such as depression, anxiety disorders, and post-traumatic stress disorder. Early-life adversity and genetic variation can interaction to disrupt HPA axis regulation, potentially contributing to certain forms of psychopathology. This study employs a rhesus macaque model to investigate how early parental neglect interacts with a single nucleotide polymorphism within the promoter region of the corticotropin-releasing hormone (CRH-248) gene, impacting the development of the HPA axis. For the initial six months of life, 307 rhesus monkey infants (n = 146 females, n = 161 males) were either reared with their mothers (MR) in conditions emulating the natural environment (control group) or raised without maternal care in groups with constant or 3-hours daily access to same-aged peers (NR). Blood samples collected on days 30, 60, 90, and 120 of life under stressful conditions were assayed for plasma cortisol and adrenocorticotropic hormone (ACTH) concentrations. Findings revealed that NR subjects exhibited a significant blunting of both ACTH and cortisol concentrations. Notably, there was a gene-by-environment interaction observed for ACTH and cortisol levels, with NR subjects with the polymorphism displaying higher ACTH concentrations and lower cortisol concentrations. To the extent that these results generalize to humans, they suggest that early parental neglect may render individuals vulnerable to HPA axis dysfunction, a susceptibility that is modulated by CRH-248 genotype—a gene-by-environment interaction that leaves a lasting developmental signature.

THSD7A-associated membranous nephropathy involves both complement-mediated and autonomous podocyte injury.

Membranous nephropathy (MN) continues to be a leading cause of nephrotic syndrome in non-diabetic adults. As a unique subtype in the serology-based classification of MN, thrombospondin type 1 domain containing 7A (THSD7A)-associated MN has attracted increasing interest, because, unlike other autoantigens, THSD7A is also expressed in preclinical species, facilitating the study of its role in MN. A heterologous mouse model of THSD7A-associated MN was previously established using a proprietary in-house antibody that was unfortunately not available to the research community. Here, we developed a mouse model of THSD7A-associated MN by administering a commercially available antibody targeting the most N-terminal part of THSD7A. Our model was characterized by heavy proteinuria and pathological features of human MN without sex differences. Complement depletion with cobra venom factor only partially attenuated proteinuria and glomerular injury in this model, entailing that complement-independent pathomechanisms also contribute. Consistently, in vitro in primary podocytes, exposure to the anti-THSD7A antibody caused evident podocytopathic changes, including disruption of actin cytoskeleton integrity, podocyte hypermobility, oxidative stress, and apoptotic cell death. These signs of podocytopathy were preserved, albeit to a lesser extent, after complement inactivation, indicating autonomous podocyte injury. Furthermore, as the first FDA-approved treatment for primary MN, adrenocorticotropic hormone therapy with repository corticotropin injection (Purified Cortrophin Gel®) appeared to be beneficial and significantly attenuated proteinuria and glomerular injury, suggesting that this model may be useful for developing novel treatments or understanding the pathogenesis of MN. Collectively, our model, based on the use of a commercially available anti-THSD7A antibody, will be an important tool for MN research.

Sex-differential testosterone response to long-term weight loss

ObjectivesObesity-associated gonadal dysfunction is a common comorbidity in patients seeking weight loss interventions. We examined the incremental effect of weight loss on gonadal axes in men and women over 3 years. Changes in sex hormones were compared between dietary intervention (Diet) and bariatric procedures: Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (SG) and laparoscopic adjustable gastric banding (LAGB). Additional analysis assessed changes in corticotropic, somatotropic and thyroid axes after weight loss interventions.MethodsThis prospective, observational study included 61 adults with Body Mass Index >30 kg/m2, mean age 51 (SD = 11) years. Endocrine parameters were measured at baseline and at 6 timepoints over 36-months.ResultsFor each 1 kg of weight lost, between baseline and 36 months, total testosterone increased by 0.6% (95% CI: 0.2%, 1.0%, p = 0.002) in males and decreased by 0.8% (95% CI: −1.4%, −0.3%, p = 0.003) in females. These changes remained statistically significant when controlled for age and for menopausal status in females. At 36 months, in comparison with Diet, RYGB women had lower total testosterone by 54% (95% CI: −90%, −17%, p = 0.004), reduced free androgen index (FAI) by 65% (95% CI; −114%, −17%, p = 0.009) while SG had reduced FAI by 39% (95% CI; −77%, 0%, p = 0.05). No such differences between groups were noted for male subjects. Adrenocorticotropic hormone declined by 0.3% (95% CI: 0.0, −0.5%, p = 0.05), insulin-like growth factor-1 increased by 0.4% (95% CI; 0.2%, 0.7%, p = 0.005), without such thyrotrophin change for each 1 kg of weight loss, for entire cohort, over 36 months.ConclusionsThe testosterone changes observed in this study were proportional to the amount of weight loss. In females, reduction in androgens was independent of age and menopausal status and more pronounced after bariatric procedures. This study finding warrants further clinical research to explore an impact of androgen reduction on functional and cognitive status in postmenopausal women. The observed changes in pituitary hormones may contribute to the metabolic benefits of bariatric surgery.

Application of peripheral blood cytokine and immunoglobulin detection in ACTH therapy for the treatment of infantile spasms.

This research aims to investigate the levels of lymphocytes, immunoglobulins, and cytokines in children with infantile spasms (IS) before and after adrenocorticotropic hormone (ACTH) therapy and to explore the application of these markers in evaluating the therapeutic effects of ACTH on infantile spasms. From May to November 2022, 35 children initially diagnosed with IS and treated at our hospital were regarded as the observation group, and 35 healthy children who underwent physical examination at our hospital during the same period were regarded as the control group. Children in the observation group received intramuscular injections of ACTH for 2 weeks. Fasting venous blood was collected from the control group and the observation group before and after ACTH therapy. Serum levels of immunoglobulins IgG, IgA, and IgM in serum were detected by immunoturbidimetry. T-cell subsets (CD3+, CD3+CD4+, and CD3+CD8+) and B-cell subsets [CD3-CD19+ and CD3-CD16+CD56+ natural killer (NK) cells] were detected by flow cytometry, and the ratio of CD3+CD4+/CD3+CD8+ was calculated. Serum levels of interleukin-1β (IL-1β), interleukin-2R (IL-2R), and interleukin-6 (IL-6) cytokines were detected by the enzyme-linked immunosorbent assay, and changes in serum cytokine and immunoglobulin levels in the two groups were compared before therapy, whereas in observation group one, these comparisons were made both before and after ACTH therapy. Compared to the control group, the observation group showed significantly increased serum levels of immunoglobulins IgG and IgM before therapy, while the level of IgA was significantly decreased (p < 0.05). Also, the percentage of CD3-CD19+ B cells was significantly increased, while the percentages of CD3+ T cells and CD3+CD4+ T cells were significantly decreased (p < 0.05). The percentages of CD3+CD8+ T cells, CD3-CD16+CD56+ NK cells, and CD3+CD4+/CD3+CD8+ cells did not change significantly (p > 0.05); the levels of cytokines IL-1 β, IL-2R, and IL-6 were significantly increased (p < 0.05). Compared to levels before treatment, the serum level of immunoglobulin IgG in the observation group after ACTH therapy was significantly reduced (p < 0.05), while the IgA and IgM levels did not change significantly (p > 0.05). The percentages of CD3+ T cells and CD3+CD4+ T cells were significantly increased, while the percentages of CD3-CD16+CD56+ NK cells and CD3-CD19+ B cells were significantly decreased (p < 0.05); however, the percentages of CD3+CD8+ T cells and the CD3+CD4+/CD3+CD8+ ratio did not change significantly (p > 0.05). Furthermore, the levels of cytokines IL-1 β, IL-2R, and IL-6 were significantly reduced (p < 0.05). Children with IS exhibit immune dysfunction, and the changes in serological immune indices after ACTH treatment indicate that ACTH may control seizures in IS children by regulating and improving immune dysfunction. Therefore, the therapeutic effects of ACTH on IS can be evaluated by detecting the levels of cytokines and immunoglobulins.