Effect Of Adrenocorticotropic Hormone Research Articles

Changes of Transcriptomic Activity in Rat Brain Cells under the Influence of Synthetic Adrenocorticotropic Hormone-Like Peptides.

Synthetic peptides have a wide range of clinical effects. Of particular interest are peptides based on adrenocorticotropic hormone (ACTH) both as already used and as potential drugs for preventing consequences of cerebral ischemia. However, it is necessary to study influence of the peptide on the brain cells under normal physiological conditions, including understanding the risks of their use. Here, we used high-throughput RNA sequencing (RNA-Seq) to identify differentially expressed genes (DEGs) in the brain frontal cortex of rat receiving intraperitoneal administration of ACTH-like peptides ACTH(4-7)PGP (Semax) and ACTH(6-9)PGP, or saline. Weidentified 258 and 228 DEGs, respectively, with the fold change >1.5 and Padj<0.05 at 22.5h after the first administration of Semax and ACTH(6-9)PGP. Metabolic pathways, characterizing both common and specific effects of the peptides on the transcriptome were identified. Both peptides predominantly caused decrease in expression of the genes associated with the immune system. At the same time, when comparing the effects of ACTH(6-9)PGP relative to Semax, DEGs were identified that characterized the main differences in the effects of the peptides. These genes were mostly downregulated and associated with neurosignaling systems and regulation of ion channels, thus characterizing differences in the effects of the peptides. Our data show how differences in the structure of ACTH derivatives are associated with the changes in the brain cell transcriptome following exposure to these related peptides. Furthermore, our results demonstrate that when studying influence of regulatory peptides on transcriptome under pathological conditions, it is necessary to take into account their actions under normal physiological conditions.

Adrenocorticotropic hormone therapy alters Q-albumin ratios in patients with infantile epileptic spasms syndrome of unknown etiology

PurposeInfantile epileptic spasms syndrome (IESS) with epileptic spasms as the main seizure type, is treated with adrenocorticotropic hormone (ACTH). This study, for the first time, examines the effects of epileptic spasms and ACTH on blood-brain barrier (BBB) permeability in patients with IESS of unknown etiology. MethodsWe prospectively evaluated the changes in BBB permeability in patients with IESS of unknown etiology at the Saitama Children's Medical Center between February 2012 and February 2024. We compared the levels of serum-albumin, cerebrospinal fluid (CSF)-albumin, Q-albumin, and CSF-neuron-specific enolase (NSE) before and after ACTH therapy. We also assessed the correlation between the frequency of epileptic spasms and these markers. ResultsOverall, 16 patients with IESS (8 males) were included in the study. The median age at IESS onset was 5 (range, 2–9) months. The median duration between the epileptic spasms onset and the serum and CSF sample examination before ACTH therapy was 26 (range, 1–154) days. After ACTH therapy, CSF-albumin and Q-albumin levels significantly decreased (CSF-albumin: 13.5 (9.0–32.0) mg/dL vs 11.0 (7.0–19.0) mg/dL, p = 0.001. Q-albumin: 3.7× 10−3 (2.2 × 10−3-7.3 × 10−3) vs 2.8× 10−3 (1.9 × 10−3-4.5 × 10−3), p = 0.003). No correlation was observed between the epileptic spasms frequency and levels of serum-albumin, CSF-albumin, Q-albumin, and CSF-NSE (Spearman's coefficient: r = 0.291, r = 0.141, r = 0.094, and r = −0.471, respectively). ConclusionACTH therapy is one of the factors that play a role in restoring BBB permeability in patients with IESS of unknown etiology. Our findings may be useful in elucidating the mechanism of ACTH action and IESS pathophysiology.

Electroacupuncture ameliorates cardiac dysfunction in myocardial ischemia model rats: a potential role of the hypothalamic-pituitary-adrenal axis.

To verify the hypothesis that electroacupuncture inhibits the hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis regulating the expression of glial fibrillary acidic protein (GFAP) in the hippocampus of acute myocardial ischemia (AMI) rats. Sixty-six healthy male Sprague-Dawley rats were randomly divided into five groups: Sham, AMI (Model), electroacupuncture at Shenmen (HT7)-Tongli (HT5) segment (EA), non-acupoint electroacupuncture (Control), and Model + corticosterone (Model + CORT). AMI was induced occlusion of the left anterior descending coronary artery, followed by 3 d of electroacupuncture at Shenmen (HT7)-Tongli (HT5) segment. In the Control group, electroacupuncture was applied at points lying 5 and 10 mm from the base of the tail. The AMI + CORT group was injected with CORT (20 mg/kg) in saline. Hemorheology, electrocardiography (ECG), hematoxylin and eosin staining, and expression of glycogen phosphorylase BB (GPBB) and heart-type fatty acid-binding protein (H-FABP) were used to assess cardiac function. The effects of adrenocorticotropic hormone (ACTH) and CORT were evaluated by enzyme-linked immunosorbent assay. Protein expression in the Sham and Model groups were screened by tandem mass tag-based quantitative proteomics analysis. Protein expression was evaluated by Western blotting (vimentin and GFAP) and immunofluorescence staining (GFAP). Compared with the Sham group, the hemorheology indicators, heart rate, ECG-ST segment elevation, and GPBB and H-FABP levels were higher in Model rats. The EA group showed reductions in these indicators compared with the Model group. Similarly, in Model rats, the expression of ACTH and CORT were significantly increased compared with the Sham group. The EA group also showed reduced expression of ACTH and CORT. Importantly, proteomics analysis showed that vimentin was differentially expressed in Model rats. Compared with the Sham group, vimentin and GFAP expression in the hippocampus was increased in the Model group but decreased in the AMI + EA group. Additionally, intraperitoneal injection of CORT aggravated the expression of GPBB, H-FABP and GFAP. Our results suggested that electroacupuncture may protect against cardiac injury induced by AMI through regulation of HPA axis hyperactivity, and that hippocampal GFAP may play an important role in the regulation.

Adrenocorticotropic hormone application lowered aldosterone/cortisol value on dominant side without superior surgical outcomes during adrenal venous sampling.

Adrenal venous sampling (AVS) is thought to be the gold standard for primary aldosteronism (PA) subtype discrimination, during which the application of adrenocorticotropic hormone (ACTH) arouses heated debate. We aimed to identify the effect of ACTH on AVS and surgical outcomes. After propensity score matching (PSM), a total of 220 patients diagnosed with PA and completed AVS were included (110 without ACTH stimulation and 110 with ACTH stimulation). According to AVS results, surgeries were conducted in appropriate patients. ACTH stimulation significantly increased almost all selectivity index (SI) in both left adrenal vein (LAV) and right adrenal vein (RAV). We discovered that aldosterone/cortisol (A/C) value on dominant side significantly reduced after ACTH stimulation, with a reduction in lateralization index (LI) observed. Finally, 39 patients in unstimulated group and 32 patients in stimulated group completed surgery and enough follow-up. The comparison between surgical outcomes with and without ACTH stimulation was analyzed and the difference was not significant (p=.464). In conclusion, ACTH application significantly lowered A/C value instead of the relative aldosterone secretion index (RASI) value on dominant side, which did not yield superior surgical outcomes and might render confusing AVS interpretation.

Severe Obesity Associated With Pituitary Corticotroph Hyperplasia and Neoplasia

ObjectiveTo investigate the incidence of corticotroph hyperplasia (CH) or lymphocyte infiltration in the pituitary of patients with obesity. MethodsThe pituitary and adrenal glands from 161 adult autopsies performed between 2010 and 2019 at our institution were reviewed. The clinical history, body mass index (BMI), and cause of death were recorded. Routine hematoxylin and eosin staining, reticulin staining, and immunohistochemical staining for adrenocorticotropic hormone, CD3, and CD20 were performed. The results were analyzed using the Fisher and chi-square statistics. Decedents were separated into 4 groups based on BMI (kg/m2): (1) lean (BMI, <25.0), (2) overweight (BMI, 25.0-29.9), (3) obesity class I (BMI, 30.0-34.9), and (4) obesity classes II to III (BMI, >34.9). ResultsCH/neoplasia was identified in 44 of 161 pituitary glands. Four (9.1%) of 53 lean patients had pituitary lesions, whereas 27.3% (12) of overweight, 22.7% (10) of obesity class I, and 40.9% (18) of obesity class II patients had hyperplasia (P < .0001). Small corticotroph tumors were identified in 15 patients; only 1 was a lean patient, and the tumor was associated with the Crooke hyaline change of nontumorous corticotrophs. The presence of CH and neoplasia was associated with adrenal cortical hyperplasia and lipid depletion. Microscopic foci of T and B lymphocytes were identified in the pituitaries of patients in each weight category; no independent association between BMI and lymphocyte inflammation was found. ConclusionOur data indicate an association between CH/neoplasia and obesity. It remains unclear whether obesity is the cause or effect of adrenocorticotropic hormone and cortisol excess.

Yeast hydrolysate attenuates lipopolysaccharide-induced inflammatory responses and intestinal barrier damage in weaned piglets

BackgroundIntestinal inflammation is the main risk factor causing intestinal barrier dysfunction and lipopolysaccharide (LPS) can trigger inflammatory responses in various eukaryotic species. Yeast hydrolysate (YH) possesses multi-biological effects and is received remarkable attention as a functional ingredient for improving growth performance and promoting health in animals. However, there is still inconclusive on the protective effects of dietary YH supplementation on intestinal barrier of piglets. This study was conducted to investigate the attenuate effects of YH supplementation on inflammatory responses and intestinal barrier injury in piglets challenged with LPS.MethodsTwenty-four piglets (with an average body weight of 7.42 ± 0.34 kg) weaned at 21 days of age were randomly assigned to one of two dietary treatments (12 replications with one pig per pen): a basal diet or a basal diet containing YH (5 g/kg). On the 22nd d, 6 piglets in each treatment were intraperitoneally injected with LPS at 150 μg/kg BW, and the others were injected with the same amount of sterile normal saline. Four hours later, blood samples of each piglet were collected and then piglets were euthanized.ResultsDietary YH supplementation increased average daily feed intake and average daily gain (P < 0.01), decreased the ratio of feed intake to gain of piglets (P = 0.048). Lipopolysaccharide (LPS) injection induced systemic inflammatory response, evidenced by the increase of serum concentrations of haptoglobin (HP), adrenocorticotropic hormone (ACTH), cortisol, and interleukin-1β (IL-1β). Furthermore, LPS challenge resulted in inflammatory intestinal damage, by up-regulation of the protein or mRNA abundances of tumor necrosis factor-α (TNF-α), IL-1β, toll-like receptors 4 (TLR4) and phosphor-nuclear factor-κB-p65 (p-NFκB-p65) (P < 0.01), and down-regulation of the jejunal villus height, the protein and mRNA abundances of zonula occludens-1 (ZO-1) and occludin (OCC; P < 0.05) in jejunal mucosa. Dietary YH supplementation decreased the impaired effects of ACTH, cortisol, HP, IL-1β and diamine oxidase in serum (P < 0.05). Moreover, YH supplementation also up-regulated the jejunal villus height, protein and mRNA abundances of ZO-1 and OCC (P < 0.05), down-regulated the mRNA expressions of TNF-α and IL-1β and the protein abundances of TNF-α, IL-1β, TLR4 and p-NFκB-p65 in jejunal mucosa in LPS-challenged pigs (P < 0.01).ConclusionYeast hydrolysate could attenuate inflammatory response and intestinal barrier injury in weaned piglets challenged with LPS, which was associated with the inhibition of TLR4/NF-κB signaling pathway activation.Graphical

Epileptik ensefalopatide kullanılan adrenokortikotropik hormonun kemik mineral metabolizması ve adrenal yolak üzerine kısa dönem etkilerinin değerlendirilmesi

Background: We aimed to investigate the short-term effects of adrenocorticotropic hormone (ACTH) treatment on the adrenal pathway and bone metabolism in patients with epileptic encephalopathy.&#x0D; Methods: Two groups with 16 patients and 16 controls were formed. Before the treatment, all patients and controls were tested for bone and adrenal metabolism. Twenty doses of ACTH therapy were given to the patient group over 3 months. The tests on the patient group were repeated 1 month after the end of the treatment.&#x0D; Results: In the patient group, serum calcium, phosphorus and parathyroid hormone levels increased significantly after treatment compared with before treatment. Comparing the bone metabolism of the patient and control groups, urinary calcium/creatinine ratio was higher before treatment; serum phosphorus level, bone-specific alkaline phosphatase level and the urinary calcium/creatinine ratio were higher after treatment in the patient group. In the evaluation of the adrenal pathway, no significant differences were found between fasting serum glucose, sodium, potassium, cortisol and ACTH levels before and after treatment and in the comparison of the patient and control groups.&#x0D; Conclusion: Our study investigated the short-term effect of ACTH on the adrenal pathway and bone metabolism. The results show that ACTH treatment did not have a negative effect on the adrenal pathway in the early period but, its effects on bone metabolism have not been adequately clarified.

Immunological markers of drug resistant epilepsy and its response to immunomodulatory therapy with ACTH in children.

Drug-resistant epilepsy in infancy and childhood is a devastating condition, frequently associated with neuropsychiatric comorbidities. West syndrome is one of the most severe epilepsy syndromes. Adrenocorticotropic hormone (ACTH) treatment is recommended in such cases, but its mechanism of action is still unknown. We prospectively observed levels of selected cytokines in order to identify biomarkers of response to ACTH and the potential mechanism of its antiseizure effect. Fifty-three infants and young children with pharmacoresistant epilepsy receiving ACTH 1-24 were included. There were 2 control groups - children with epilepsy responding to the first medication and children with no history of epilepsy. Blood concentrations of IL-1b, IL-1Ra, IL-6, IL-8, IL-10, TNF-a, IFN-g, MCP-1 and MIP-1a were analyzed at three time points: T0 (before ACTH), T1 (after intensive ACTH treatment) and at T2 (at the end of ACTH withdrawal). The results were correlated with the response to treatment, dose of ACTH and concomitant medications. We found statistically significantly higher concentrations of IL-1, IL-8 and MIP-1a at baseline (T0) in the study group compared to the control groups. ACTH significantly lowered levels of IL-6, IFN-g and MCP from time T0 to T1. This effect was short lasting and no significant changes in cytokine levels were found between T2 and T0. We did not find any differences in immunological markers between the responders and non-responders to ACTH. Our research did not allow us to identify any reliable immunological marker of response to ACTH treatment. We did not observe a positive effect of higher ACTH doses on the response rate in the patients. Our study showed significantly lower concentrations of IL-10 and IFN in the group of patients receiving levetiracetam. The concentration of TNF was higher and the concentration of MIP was lower in the group receiving valproic acid. Our study indicates that increased levels of IL-1, IL-8 and MIP-1a are associated with drug-resistant epilepsy in infants and young children and might be considered immunological markers. IL-6, IFN-g and MCP-1 take part in the effect of ACTH. Immunological mechanisms seem also to be involved in the mechanism of action of classical antiseizure drugs.

Exogenous ACTH stimulus during the preovulatory period alters patterns of leukocyte recruitment in the ovary of dairy cows

Before ovulation, the ovary exhibits signs of local inflammation. However, the effects of adrenocorticotropin (ACTH) on the complexity of this inflammatory response are not yet well described. Thus, the aim of this study was to evaluate the effects of ACTH administered to dairy cows during the preovulatory period on the local distribution of different subsets of leukocytes infiltrated in the ovary, along with the gene expression of relevant chemokines (C–C motif chemokine ligand-2 (CCL2), C-X-C motif chemokine ligand-8 (CXCL8), CCL25 and CXCL1) involved in leukocyte chemotaxis and blood perfusion on the follicular wall of dominant follicles. Also, the direct effect of ACTH on chemokine gene expression was addressed in cultured antral follicular walls. For this purpose, both an in vivo and an in vitro experiment were performed. For the in vivo experiment, exogenous ACTH (100 IU) was administered intramuscularly to Holstein cows (n = 12) during proestrus every 12 h for four days before ovulation, when ovariectomy was performed (day 18). Daily ovarian Doppler ultrasonography was used to evaluate the percentage of irrigated area, the pulsatility index and the resistance index in the dominant follicles. The distribution of monocytes-macrophages (CD14), T- (CD2) and B-lymphocytes (CD79a) and granulocytes (CH138A) in the ovary was analyzed by immunohistochemistry. In follicular wall samples, gene expression of CCL2, CXCL8, CXCL1 and CCL25 was evaluated, whereas IL-17A expression was analyzed by Western blot. The total number of CD14, CD79a and CD2 infiltrated cells was lower in the ACTH-treated group than in the control group (p < 0.05). Chemokine gene expression showed lower mRNA of CCL2, CCL25 and CXCL1 (p < 0.05) in the ACTH-treated group. Meanwhile, IL-17A protein expression and hemodynamic parameters were similar between groups (p > 0.05). In the in vitro assay, antral follicular walls were stimulated with ACTH to corroborate the gene expression profile of chemokines. mRNA expression of CCL2 tended to be lower in the stimulated follicular walls (p = 0.092). Our results suggest that exogenous ACTH stimulus during the preovulatory period reduces the number of infiltrated leukocytes in the bovine ovary and this could be due to a lower chemotaxis capacity of the ovary.

Natural Adrenocorticotropic Hormone (ACTH) Relieves Acute Inflammation in Gout Patients by Changing the Function of Macrophages.

Gout is a common arthritis caused by deposition of monosodium urate crystals. Macrophage is crucial in the process of monosodium urate (MSU)-induced inflammation. Although it has been reported that adrenocorticotropic hormone (ACTH) in nature can be used to cure urarthritis, the mechanism concerning macrophage is still not clear. However, gout patients manifest other complications, such as hypertension, diabetes, chronic kidney disease, and hormone intolerance, which limit efficacy of some of these first-line drugs. Therefore, this study aims to explore how natural ACTH can alleviate urarthritis through functional changes in macrophage. We analyzed the variations in VAS pain scores of five patients, knowing the time of action and detecting the level of cortisol and ACTH in patients 24 hours after the application of ACTH. The effect of natural ACTH on joint inflammation and the level of cortisol in blood in the mouse model was evaluated by studies in vivo. In vitro studies, we evaluated the effect of natural ACTH on macrophages and revealed different functions of ACTH and dexamethasone on macrophages in the transcriptional level. In patients with acute gout, natural ACTH can quickly alleviate pain and does not affect the level of cortisol and ACTH. Natural ACTH is able to ease the swelling and inflammatory cell infiltration caused by arthritis, without changing the level of cortisol. Besides, natural ACTH in vitro can alleviate acute gouty inflammation by regulating phagocytosis and polarization of macrophage, which also exerts different effects on the transcription of some related genes. Natural ACTH is able to alleviate acute gouty inflammation by regulating macrophage, and this effect differs from that of dexamethasone at the transcriptional level.

Effects of ACTH and Acute Heat Stress on Oxidative Stress in an Early Environmentally Enriched Broilers

Objective: In this study, the effects of early (≤21. d) environmental enrichment and acute heat stress on oxidative stress were investigated and the ability of broilers to cope with later heat stress and adrenocorticotropic hormone (ACTH) treatments were determined. Material and Methods: Six hundred day-old chicks were randomly assigned to 3 experimental groups as a control (C), environmental enrichment (EE) and environmental enrichment plus heat stress (EE+HS). At 21 d of age, broilers in EE+HS group were exposed to acute heat stress at 38±1 ˚C for 3 h. On the day 42nd, C and EE groups were divided into 2 subgroups as well Control, Control+ACTH, EE, EE+ACTH. While 50 IU ACTH/kg body weight was injected to Control+ACTH and EE+ACTH groups intramuscularly, broilers in C, EE and EE+HS groups were exposed to heat stress and oxidative stress responses of birds were evaluated. Results: Environmental enrichment did not affect blood corticosterone (CORT), malondialdehyde (MDA) and liver superoxide dismutase (SOD) levels of broilers at 21 d of age. ACTH treatment caused a significant decrease in CORT and MDA concentrations in EE broilers compared to the control group. Exposing birds to heat stress (42nd day) significantly increased CORT, MDA and decreased liver SOD levels in control as compared to EE and EE+HS groups. No significant differences were found in the SOD serum levels between groups. ACTH treatment caused more stress reactions than heat stress. Conclusion: The results obtained from this study show that exposure of broilers to acute heat stress or treatment of experimental adrenocorticotropic hormone causes preferable reactions in oxidative metabolism. It was concluded that rearing in an enrichment environment beginning from early ages can be recommended as a useful method for adaptation to stress.

MC2R/MRAP2 activation could affect bovine ovarian steroidogenesis potential after ACTH treatment

Stressors activate the hypothalamic–pituitary–adrenal (HPA) axis, reducing fertility by interfering with the mechanisms that regulate the timing of events within the follicular phase of the estrous cycle. In the HPA axis, melanocortin 2 receptor (MC2R) mediates responses to adrenocorticotropic hormone (ACTH) in concert with melanocortin receptor accessory protein 2 (MRAP2). The aims of the present study were: (1) to evaluate the effects of ACTH administered in cows in the preovulatory period on the expression of the MC2R/MRAP2 complex in the dominant follicle; and (2) to analyze the involvement of Extracellular signal Regulated Kinase 1 (ERK1) signaling in the activation of MC2R and the expression of key enzymes involved in the biosynthesis of glucocorticoids (GCs) in the dominant follicle. To this end, 100 IU ACTH was administered to Holstein cows from a local dairy farm during pro-estrus every 12 h for four days until ovariectomy, which was performed before ovulation. Protein immunostaining of MC2R was higher in the dominant follicles of ACTH-treated cows (p < 0.05). Also, Western blot analysis showed higher activation of the ERK1 signaling pathway in ACTH-treated cows (p < 0.05). Finally, immunohistochemistry performed in the dominant follicles of ACTH-treated cows detected higher expression of CYP17A1 and CYP21A2 (p < 0.05). These results suggest that the bovine ovary is able to respond locally to ACTH as a consequence of stress altering the expression of relevant steroidogenic enzymes. The results also confirm that the complete GC biosynthesis pathway is present in bovine dominant follicle and therefore GCs could be produced locally.

Medication selection, health services outcomes, and cost trajectories for Medicaid beneficiaries with infantile spasms

ObjectiveThere are three recommended first-line treatments for infantile spasms, adrenocorticotropic hormone (ACTH), oral corticosteroids, and vigabatrin, though non-standard treatments such as topiramate are sometimes selected. Is it uncertain how treatment selection influences health services outcomes. MethodsWe conducted a retrospective cohort study of Medicaid beneficiaries newly diagnosed with infantile spasms from 2009–2010. We included infants with a new diagnosis of infantile spasms between age 2–9 months who filled ACTH (reference), prednisolone, vigabatrin, or topiramate prescriptions. Multivariable Cox proportional hazards regression compared time to first emergency department (ED) visit or hospitalization across treatment groups during 2 years of follow-up. Monthly costs for each treatment were examined in 6-month intervals and compared in a multivariable generalized linear model. ResultsAmong 256 children with infantile spasms, 116 received ACTH, 62 prednisolone, 15 vigabatrin, and 63 topiramate. The rate of ED visit or hospitalization per person-year did not differ significantly for prednisolone (0.9 [95 % CI 0.7–1.2]; adjusted hazard ratio [aHR] 0.84, 95 % CI 0.57–1.24), vigabatrin (0.8 [95 % CI 0.4–1.5]; aHR 0.91, 95% CI 0.45–1.84), or topiramate (1.7 [95 % CI 1.3–2.3]; aHR 1.15, 95 % CI 0.80–1.65), when compared to ACTH (1.1 [95 % CI 0.9–1.3]). The median payment for ACTH was $96,406 (interquartile range 70,742–138,476) during the first 6 months. The adjusted mean total payment in the first 6 months was 73% lower for prednisolone (95% CI −82, −61), 69% lower for vigabatrin (95% CI −84, −40), and 73% lower for topiramate (95% CI −82, −59). However, in subsequent 6-month intervals, costs associated with ACTH were not significantly different compared to other treatments. SignificanceCompared to other treatments for infantile spasms, use of ACTH was associated with greater cost in the first 6 months of treatment, but not with reduced ED visits or hospitalizations. The cost effectiveness of ACTH depends on its relative clinical efficacy, and merits additional research.

Repository Corticotropin Injections Promote Clinical Remission and Regulatory T Cell Expansion in Membranous Nephropathy

Repository Corticotropin Injections Promote Clinical Remission and Regulatory T Cell Expansion in Membranous Nephropathy

Decisive evidence of direct effect of ACTH treatment in West syndrome: A case report

In patients with West syndrome, the administration of exogenous adrenocorticotropic hormone (ACTH) is considered a potent and effective treatment [1]. Exogenously administered ACTH hyperactivates the hypothalamic-pituitary-adrenal axis (Fig. 1A); however, the resulting hormonal changes cannot fully account for the therapeutic effect of ACTH. Indeed, the administration of corticosteroids to patients with West syndrome failed to provide an anti-epileptic effect comparable to that of ACTH [1]. Thus, the antiepileptic effect of ACTH in West syndrome has been postulated to involve a direct action of ACTH on the central nervous system (i.e., a “direct pathway”) that occurs independently of the hypothalamic-pituitary-adrenal axis (i.e., an “indirect pathway”).

Effect of intramuscular ACTH versus oral prednisolone on the developmental trajectories of children with West syndrome over 24 months: A randomised control study.

To assess the developmental progression and compare the developmental attainments of children treated with two hormonal therapies for infantile spasms (IS) over two years (seizure and EEG outcomes of this RCT published previously). Newly diagnosed infants with IS were randomised to receive adrenocorticotrophin (ACTH) or prednisolone for 14 days. All underwent Bayley III Infant and Toddler Assessments in cognitive (Cog), receptive (RC) and expressive (EC) communication, fine (FM) and gross (GM) motor developmental subsets at baseline (T0), one-year (T1) and two-years (T2). 95 infants randomised to prednisolone (n=48) and ACTH (n=47) groups were eligible for developmental assessments. Mean age at initial assessment was 8.75 months (SD=6.37, range 1.46-34.4 months). 48 children presented for all three assessments. Mean composite scores of each developmental domain improved across the three time points; but the progression was significant only in relation to motor development (p=0.04). When comparing the treatment outcomes at 2-years, mean composite scores of children treated with ACTH were significantly lower in motor domain (p=0.023). As for developmental delay, the ACTH group (n=32) showed significant delay in expressive communication (adjusted OR 5.46, 95% CI: 1.1, 28.57; p=0.04) and fine motor (adjusted OR 9.4, 95% CI: 1.1, 83.3; p=0.04) at T2 compared to the prednisolone (n=30) in a regression analysis. The number of children with delay at the 2 year follow up were significantly higher in two domains in the ACTH group compared to the prednisolone group. Overall results do not show a significant advantage of ACTH over prednisolone for developmental outcomes at two years, but further comparative studies over longer periods are required for more definitive conclusions.

RELATIONSHIP BETWEEN THE HYPOTHALMIC-PITUITARY-ADRENOCORTICAL AXIS ACTIVITY AND THE CHARACTERISTICS OF ALDOSTERONE-PRODUCING ADENOMAS

Objective: Aldosterone production can be regulated by adrenocorticotrophic hormone (ACTH) which normally controls cortisol secretion. Some cases of aldosterone-producing adenoma (APA) display features which may suggest increased sensitivity to the stimulatory effects of ACTH. The objective of this study is to investigate if there is any relationship between the hypothalamic-pituitary-adrenocortical (HPA) axis activity and the characteristics of APAs. Design and method: This is a retrospective review of the HPA axis activity of 41 histologically-confirmed APA cases which were characterised with regards to clinical, biochemical and somatic mutation status. HPA axis activity was assessed from morning plasma cortisol, ACTH and 1 mg overnight dexamethasone (DEX) suppression test. Correlation was analysed by Pearson's correlation coefficient, and the HPA axis activity between APAs with KCNJ5 mutation and those without was compared using Mann Whitney U-test. Results: Twelve out of 41 patients (29.3%) were women, median age was 49 years and 85.4% were overweight/obese. All except 2 had somatic mutations within APA. Fourteen (34.1%) were KCNJ5 mutation. Only one patient (APA not KCNJ5 mutated) had post-DEX cortisol &gt; 50 nmol/L. Upright morning plasma aldosterone concentration (PAC) correlated with tumour size (r = 0.347, P = 0.026), plasma cortisol (r = 0.425, P = 0.006) and plasma ACTH (r = 0.446; P = 0.056). Plasma ACTH and cortisol were positively correlated (r = 0.511, P = 0.025). Higher PAC, cortisol and ACTH concentrations were in turn associated with the need for higher defined-daily-dose (DDD) of anti-hypertensive medications (r = 0.466, P = 0.002 for PAC; r = 0.315, P = 0.045 for cortisol; r = 0.449, P = 0.054 for ACTH). Higher PAC was also predictive of higher BMI (r = 0.348, P = 0.026). Plasma cortisol, ACTH, post-DEX cortisol, BMI and DDD of anti-hypertensives were not significantly different between those with KCNJ5 mutation compared to those without. Conclusions: HPA axis activity correlated with clinico-biochemical characteristics in patients with APAs, but the prevalence of autonomous hypercortisolism was low. The findings suggest a potential role of ACTH in the pathophysiology of APAs. There was no significant difference in HPA axis activity between those with somatic KCNJ5 mutation compared to those without.

Novel function of adrenocorticotropic hormone in the stimulation of vascular endothelial growth factor release in healthy children and adolescents: a proof-of-concept study.

PurposeTo assess the effect of adrenocorticotropic hormone (ACTH) on plasma vascular endothelial growth factor (VEGF) levels in healthy children and adolescents and to inform future work on the effects of ACTH on VEGF in bone.MethodsAn Institutional Review Board-approved prospective study of 10 healthy subjects, ages 9–17, was conducted to assess the effect of ACTH on plasma VEGF levels. VEGF levels were collected at baseline and every 30 minutes for 3 hours. Cosyntropin (a synthetic ACTH analogue) was administered at a low-dose (1 μg) given at t=0 minutes and a high-dose (250 μg) given at t=60 minutes. A Friedman test was performed comparing baseline to peak VEGF levels after stimulation with low-dose and high-dose cosyntropin.ResultsPeak plasma VEGF levels significantly increased after high-dose cosyntropin compared with baseline (P=0.042). Peak plasma VEGF levels did not significantly increase after low-dose cosyntropin compared to baseline.ConclusionsTo our knowledge, this is the first study to demonstrate that ACTH administration causes a significant increase in plasma VEGF levels in humans. This finding may have important implications in the protective effects of ACTH on bone. Decreased bone mineral density and adrenal suppression are common side effects of glucocorticoid use in pediatrics. VEGF increases vascularity and may play a role in reducing glucocorticoid-induced bone disease. Animal studies have shown that ACTH stimulates release of VEGF in osteoblasts, though this effect has yet to be evaluated in humans.

Cost-effectiveness of adrenocorticotropic hormone versus oral steroids for infantile spasms.

To compare the effectiveness and cost-effectiveness of adrenocorticotropic hormone (ACTH) and oral steroids as first-line treatment for infantile spasm resolution, we performed a systematic review, meta-analysis, and cost-effectiveness study. A decision analysis model was populated with effectiveness data from a systematic review and meta-analysis of existing literature and cost data from publicly available prices. Effectiveness was defined as the probability of clinical spasm resolution 14days after treatment initiation. We included 21 studies with a total of 968 patients. The effectiveness of ACTH was not statistically significantly different from that of oral steroids (.70, 95% confidence interval [CI] = .60-.79 vs. .63, 95% CI = .56-.70; p=.28). Considering only the three available randomized trials with a total of 185 patients, the odds ratio of spasm resolution at 14days with ACTH compared to high-dose prednisolone (4-8mg/kg/day) was .92 (95% CI = .34-2.52, p=.87). Adjusting for potential publication bias, estimates became even more favorable to high-dose prednisolone. Using US prices, the more cost-effective treatment was high-dose prednisolone, with an incremental cost-effectiveness ratio (ICER) of $333 per case of spasms resolved, followed by ACTH, with an ICER of $1432200 per case of spasms resolved. These results were robust to multiple sensitivity analyses and different assumptions. Prednisolone at 4-8mg/kg/day was more cost-effective than ACTH under a wide range of assumptions. For infantile spasm resolution 2weeks after treatment initiation, current evidence does not support the preeminence of ACTH in terms of effectiveness and, especially, cost-effectiveness.

Non-Invasive Monitoring of Adrenocortical Activity in Three Sympatric Desert Gerbil Species.

Simple SummaryIn this era, characterized by remarkable anthropogenic impacts on wildlife, it is crucial to monitor the health of wild animal populations while minimizing the interference to them. To this end, for a better understanding of the eco-physiology of wild animals, the adrenocortical activity can be non-invasively evaluated by measuring glucocorticoid metabolites excreted in feces. However, to ensure that the endocrine information is reliable, the experimental assays should be first validated and the causes for the major variability among individuals should be considered. Here we validated an enzyme immunoassay for measuring fecal corticosterone metabolites (FCM) in three wild gerbil species and emphasized the differences among them. These are endangered species, which play a key role in psammophilic communities, and provide a model system for various aspects in ecology. Thus, this work constitutes the first step toward using the FCMs of these species as indicators for individual and community stress.The study of the endocrine status can be useful to understand wildlife responses to the changing environment. Here, we validated an enzyme immunoassay (EIA) to non-invasively monitor adrenocortical activity by measuring fecal corticosterone metabolites (FCM) in three sympatric gerbil species (Gerbillus andersoni, G. gerbillus and G. pyramidum) from the Northwestern Negev Desert’s sands (Israel). Animals included into treatment groups were injected with adrenocorticotropic hormone (ACTH) to stimulate adrenocortical activity, while control groups received a saline solution. Feces were collected at different intervals and FCM were quantified by an EIA. Basal FCM levels were similar in the three species. The ACTH effect was evidenced, but the time of FCM peak concentrations appearance differed between the species (6–24 h post-injection). Furthermore, FCM peak values were observed sooner in G. andersoni females than in males (6 h and 18 h post-injection, respectively). G. andersoni and G. gerbillus males in control groups also increased FCM levels (18 h and 48 h post-injection, respectively). Despite the small sample sizes, our results confirmed the EIA suitability for analyzing FCM in these species as a reliable indicator of the adrenocortical activity. This study also revealed that close species, and individuals within a species, can respond differently to the same stressor.