Increase In Adrenocorticotropic Hormone Research Articles

Physiological and Psychological Stress Reactivity in Narcolepsy Type 1.

Narcolepsy type 1 (NT1) is a chronic sleep-wake disorder, characterized by a loss of hypocretin production. Unexpectedly, in post-mortem tissue of people with NT1 there is a loss of corticotrophin-releasing hormone (CRH) in the paraventricular nucleus. CRH is known as activator of the hypothalamic-pituitary-adrenal (HPA) axis in response to stress. This activation results in the release of the stress hormones adrenocorticotropic hormone (ACTH) and cortisol. We hypothesize an altered physiological and psychological stress response in NT1. Participants were people with NT1 (n=14) and matched healthy controls (n=12). The Trier Social Stress Test for Groups (TSST-G), a validated socially evaluated stress test in controlled settings, induced acute stress. We measured ACTH and cortisol levels in blood before and at three timepoints after the TSST-G. We also measured subjective stress and heart rate levels. In both groups, acute stress led to increases in ACTH (p=0.006), cortisol (p<0.001), heart rate (p<0.001) and subjective stress (p<0.001). Subjectively, people with NT1 experienced more stress than controls (p<0.001). No differences were found in heart rate, cortisol, and ACTH between people with NT1 and controls at any timepoint. Secondary analyses showed that men with NT1 had lower cortisol levels immediately after stress induction than men in the control group (p=0.002). People with NT1 show an increased subjective stress response, but no changes in their endocrine or cardiovascular stress reactivity. Further research is required to determine the impact of reduced CRH production and gender in NT1.

7372 Anti-Corticotropin-Releasing Hormone (CRH) Monoclonal Antibody HBM9013 For The Treatment Of Congenital Adrenal Hyperplasia (CAH) And Polycystic Ovarian Syndrome (PCOS)

Abstract Disclosure: H. Pan: None. L.L. Liu: None. Q. Lv: None. F.G. Grosveld: None. D. Drabek: None. R.V. Haperen: None. X. Wang: None. Y. He: None. Y. Wang: None. J. Huang: None. J. Lee: None. G. Zhang: None. J.J. Rong: None. H.V. Chen: None. J.A. Majzoub: Advisory Board Member; Self; Chair of SAB of Harbour BioMed Alpha Therapeutics, which owns the rights of HBM9013.. Stock Owner; Self; Equity Owner of Harbour BioMed Alpha Therapeutics, which owns the rights of HBM9013.. J.J. Zhao: None. Anti-Corticotropin-Releasing Hormone (CRH) Monoclonal Antibody HBM9013 for the Treatment of Congenital Adrenal Hyperplasia (CAH) and Polycystic Ovarian Syndrome (PCOS). Abstract Congenital Adrenal Hyperplasia (CAH) is a rare autosomal recessive genetic disease due to mutation of CYP21A2 which leads to deficiency of 21-Hydroxylase enzymatic activity. Classical CAH patients are born with life-threatening deficiency of glucocorticoid (GC) and mineralocorticoid. Due to this enzymatic block and the lack of negative feedback on the hypothalamic-pituitary-adrenal (HPA) axis by GC, the adrenal gland produces excessive amounts of androgen which result in masculinized genitalia and virilization. The current standard care is supraphysiological doses of GC, which are difficult to balance between excess GC exposure and excess androgen secretion. Too little GC does not suppress production of androgen sufficiently and too much GC leads to Cushing Syndrome (CS). Previous work found that corticotropin-releasing hormone (CRH) is absolutely required for activation of the HPA axis during loss of GC negative feedback, via adrenocorticotropic hormone (ACTH) (1), which is necessary for production of adrenal androgens (2). We report here the development of Anti-CRH humanized monoclonal antibody HBM9013 (PR302334-24) for the treatment of CAH. HBM9013 binds to CRH with high affinity and neutralizes its signaling through both CRH Receptor 1 (CRHR1) and CRH Receptor 2 (CRHR2) in vitro. HBM9013 shows in vivo activities in two preclinical models. It blocks restraint stress-induced increases in plasma ACTH and corticosterone in mouse and rat. Mouse ACTH and Corticosterone were reduced from 210 ± 63 pg/ml to 27 ± 8 pg/ml (Mean ± SD, p = 5.2*10-6; IgG1 Control Group = 6 mice; HBM9013 Group = 8 mice) and from 303 ± 28 ng/ml to 57 ± 15 ng/ml (Mean ± SD, p = 6.2*10-[1][1]; IgG1 Control Group = 6 mice; HBM9013 Group = 8 mice), respectively. It also markedly reduces the constitutive, extremely elevated plasma ACTH levels in Mrap-knockout mice from 3847 ± 240 pg/mL to 1080 ± 302 pg/mL (Mean ± SD, n = 5 independent experiments, p = 2.3*10-7). HBM9013 has excellent CMC characteristics with ∼5 g/L titer and ∼80% yield. HBM9013 also has an excellent safety profile with no-observed-adverse-effect-level (NOAEL) of 150 mg/kg in weekly dosing for five doses in both rat and cynomolgus dose-ranging-finding (DRF) toxicology studies. HBM9013 is formulated up to 150 mg/ml as a weekly to monthly subcutaneous injection for ease of administration and compliance for CAH patient. HBM9013 could be a next generation therapy for CAH, in combination with a low physiological dose of GC that would avoid CS. Since ∼50% of Polycystic Ovarian Syndrome (PCOS) androgens may be of adrenal origin, we believe that HBM9013 could also be indicated for PCOS. References(1)Muglia LJ et al. J Clin Invest. 2000. 105:1269-77.(2)Weber A et al. Clin Endocrinol. 1997. 46:431-7. Presentation: 6/1/2024

ClassIIb histone deacetylase participates in perioperative neurocognitive disorders in elderly mice via HSP90/GR signaling pathway.

Multiple factors contribute to the development of perioperative neurocognitive disorders (PND). This study was designed to investigate whether Histone Deacetylase 6 (HDAC6) was involved in the formation of postoperative cognitive dysfunction in elderly mice by regulating the degree of acetylation of heat shock protein (HSP90) and related protein functions and quantities. C57BL/6J male mice were randomly divided into six groups: control naive (group Control), anesthesia (group Anesthesia), splenectomy surgery (group Surgery), splenectomy surgery plus dissolvent (group Vehicles), splenectomy surgery plus the inhibitor ACY-1215 (group Ricolinostat), and splenectomy surgery plus the inhibitor RU-486(group Mifepristone). After the mice were trained for Morris Water Maze (MWM) test for five days, anesthesia and operational surgery were carried out the following day. Cognitive function was assessed on the 1st, 3rd and 7th days post-surgery. The hippocampi were harvested on days 1, 3, and 7 post-surgeries for Western blots and ELISA assays. Mice with the splenectomy surgery displayed the activation of the hypothalamic-pituitary-adrenal axis (HPA-axis), marked an increase in adrenocorticotropic hormone (ACTH), glucocorticoid, mineralocorticoid at the molecular level and impaired spatial memory in the MWM test. The hippocampus of surgical groups showed a decrease in acetylated HSP90, a rise in glucocorticoid receptor (GR)-HSP90 association, and an increase in GR phosphorylation and translocation. HDAC6 was increased after the surgical treated. Using two specific inhibitors, HDAC6 inhibitor Ricolinostat (ACY-1215) and GR inhibitor Mifepristone (RU-486), can partially mitigate the effects caused by surgical operation. Abdominal surgery may impair hippocampal spatial memory, possibly through the HDAC6-triggered increase in the function of HSP90, consequently strengthening the negative role of steroids in cognitive function. Targeting HDAC6- HSP90/GR signaling may provide a potential avenue for the treatment of the impairment of cognitive function after surgery.

Increased Adrenocorticotropic Hormone Levels Predict Recovery of Consciousness in Patients With Disorders of Consciousness.

The potential influence of pituitary-related hormones (including both pituitary gland and target gland hormones) on functional recovery after traumatic brain injury has been observed. However, the relationship between these hormones and the recovery of consciousness in patients with disorders of consciousness (DOC) remains unclear. In this retrospective and observational study, 208 patients with DOC were recruited. According to the Glasgow Outcome Scale (GOS) scores after 6 months, patients with DOC were categorized into two subgroups: a favorable prognosis subgroup (n = 38) comprising those who regained consciousness (GOS score ≥3), and a poor prognosis subgroup (n = 156) comprising those who remained in DOC (GOS score <3). Comparative analyses of pituitary-related hormone levels between the two subgroups were conducted. Further, a binary logistic regression analysis was conducted to assess the predictive value of pituitary-related hormones for the patients' prognosis. The favorable prognosis subgroup showed a significant increase in adrenocorticotropic hormone (ACTH) levels (p = 0.036). Moreover, higher ACTH levels and shorter days since injury were significantly associated with a better prognosis, with odds ratios (ORs) of 0.928 (95% confidence interval [CI] = 0.873-0.985, p = 0.014) and 1.015 (95% CI = 1.005-1.026, p = 0.005), respectively. A subsequent receiver operating characteristic (ROC) analysis demonstrated the potential to predict patients' prognosis with an area under the curve value of 0.78, an overall accuracy of 75.5%, a sensitivity of 77.5%, and a specificity of 66.7%. Our findings indicate that ACTH levels could serve as a clinically valuable and convenient predictor for patients' prognosis.

TMIC-67. GLIOBLASTOMA AUGMENTS SYSTEMIC IMMUNUNOSUPPRESSION UPON LOSS OF TESTOSTERONE VIA ALTERATION OF GLUCOCORTICOIDS PRODUCTION

Abstract While sex differences in incidence, genetics, and immune changes are established in glioblastoma (GBM), the specific contribution of sex hormones to these differences has not been fully explored. Testosterone has been shown to have a pro-tumorigenic effect on human and mouse GBM tumor cells. However, the systemic effect of testosterone in an immune competent model has not been tested. To test this, we performed castration or sham surgery on C57BL/6 male mice, followed by intracranial implantation of syngeneic glioma cells. Surprisingly, castrated mice exhibited more aggressive tumor growth compared to sham surgery controls, and this castration-induced aggressiveness could be reversed by administering exogenous testosterone. This finding was further confirmed by chemically blocking androgen receptor signaling using enzalutamide. We observed a significant increase in adrenocorticotropic hormone (ACTH) levels in the serum from castrated mice compared to the sham group after tumor implantation. Additionally, mass spectrometry analysis detected elevated levels of circulating glucocorticoids in castrated mice, and pharmacological blockade of glucocorticoid receptor using mifepristone reversed the shorted survival in castrated mice, but not in sham control. Flow analysis revealed decreased production of anti-tumor cytokines such as IFN-γ and TNF-α in CD4+ and CD8+ T cells from tumors and lymph nodes in castrated mice, suggesting systemic immunosuppression in these animals. Indeed, castration of immune-compromised mice, specifically NSG and RAG1KO strains, did not result in reduced survival. Moreover, when GBM cells were subcutaneously implanted into the flank, tumor growth in castrated mice was decelerated compared to sham controls. We also observed significantly lower ACTH levels in the flank tumor model compared to the brain tumor model, indicating a brain-specific effect of steroid hormones on tumor control. Taken together, these findings demonstrate that testosterone regulates T cell function through glucocorticoids, ultimately affecting GBM growth in a site-specific manner.

Acute stress response on Atlantic salmon: a time-course study of the effects on plasma metabolites, mucus cortisol levels, and head kidney transcriptome profile

Farmed Atlantic salmon (Salmo salar) welfare and performance can be strongly influenced by stress episodes caused by handling during farming practices. To better understand the changes occurring after an acute stress response, we exposed a group of Atlantic salmon parr to an acute stressor, which involved netting and transferring fish to several new holding tanks. We describe a time-course response to stress by sampling parr in groups before (T0) and 10, 20, 30, 45, 60, 120, 240, 300, and 330 min post-stress. A subgroup of fish was also subjected to the same stressor for a second time to assess their capacity to respond to the same challenge again within a short timeframe (ReStressed). Fish plasma was assessed for adrenocorticotropic hormone (ACTH), cortisol, and ions levels. Mucus cortisol levels were analyzed and compared with the plasma cortisol levels. At 5 selected time points (T0, 60, 90, 120, 240, and ReStressed), we compared the head kidney transcriptome profile of 10 fish per time point. The considerably delayed increase of ACTH in the plasma (60 min post-stress), and the earlier rise of cortisol levels (10 min post-stress), suggests that cortisol release could be triggered by more rapidly responding factors, such as the sympathetic system. This hypothesis may be supported by a high upregulation of several genes involved in synaptic triggering, observed both during the first and the second stress episodes. Furthermore, while the transcriptome profile showed few changes at 60 min post-stress, expression of genes in several immune-related pathways increased markedly with each successive time point, demonstrating the role of the immune system in fish coping capacity. Although many of the genes discussed in this paper are still poorly characterized, this study provides new insights regarding the mechanisms occurring during the stress response of salmon parr and may form the basis for a useful guideline on timing of sampling protocols.

Clinical characteristics of patients with unexplainable hypothalamic disorder diagnosed by the corticotropin-releasing hormone challenge test: a retrospective study

The corticotropin-releasing hormone (CRH) challenge test can distinguish the disorders of the hypothalamus from those of the pituitary. However, the pathophysiology of hypothalamic disorder (HD) has not been fully understood. This study aimed to elucidate the clinical characteristics of patients with unexplainable HD, diagnosed by the CRH challenge test. We retrospectively reviewed patients who underwent the CRH challenge test. Patients were categorized into four groups as follows: patients with peak serum cortisol ≥18 μg/dL were assigned to the normal response (NR) group (n = 18), among patients with peak serum cortisol < 18 μg/dL and peak adrenocorticotropic hormone (ACTH) increase ≥two-fold, patients without obvious background pathology were assigned to the unexplainable-HD group (n = 18), whereas patients with obvious background pathology were assigned to the explainable-HD group (n = 38), and patients with peak serum cortisol < 18 μg/dL and peak ACTH increase <two-fold were assigned to the pituitary disorder (PD) group (n = 15). Inter-group comparisons were performed based on clinical characteristics. In the CRH challenge test, the peak plasma ACTH levels were significantly lower in the unexplainable-HD group than in the NR group, despite more than two-fold increase compared to basal levels. The increase in serum cortisol was significantly higher in the unexplainable-HD group than in the explainable-HD and PD groups. Although patients in the unexplainable-HD group showed a clear ACTH response in the insulin tolerance test, some patients had peak serum cortisol levels of < 18 μg/dL. Furthermore, attenuated diurnal variations and low normal levels of urinary free cortisol were observed. Most patients in the unexplainable-HD group were young women with chronic fatigue. However, supplementation with oral hydrocortisone at physiological doses reduced fatigue only in some patients. Patients with unexplainable HD diagnosed by the CRH challenge test had hypothalamic-pituitary-adrenal (HPA) axis dysfunction and some patients had mild central adrenal insufficiency. Hydrocortisone supplementation reduced fatigue only in some patients, suggesting that HPA axis dysfunction may be a physiological adaptation. Further investigation of these patients may help elucidate the pathophysiology of myalgic encephalitis/chronic fatigue syndrome.

Addison’s disease triggered by infection with mycobacterium abscessus, but not by adrenal tuberculosis or MAC pulmonary disease, in a subject with type 2 diabetes mellitus: case report

BackgroundAddison’s disease is primary adrenal dysfunction and is characterized by decrease of cortisol level and increase of adrenocorticotropic hormone (ACTH) level. It is known that infection is one of main causes of Addison’s disease. Among various infections, tuberculous infection accounts for the majority of them. Recently the number of subjects with non-tuberculous mycobacterial infection has been increased, and the infection can also bring about Addison’s disease. Mycobacterium avium complex (MAC) pulmonary disease accounts for the majority of non-tuberculous mycobacterial infection.Case presentationAn 83-year-old female was suspected of having adrenal failure in our outpatient care and hospitalized in our institution. There was pigmentation in her face, hands and legs, especially in auricle and nail beds in her hands and legs. In rapid ACTH load test (0.25 mg of 1–24 ACTH), cortisol level was not increased at all. An abdominal computed tomography (CT) showed swelling of both adrenal glands accompanied by calcification. QuantiFERON test was negative and mycobacterium tuberculosis complex was negative in PCR test using bronchial lung lavage fluid. These data ruled out the possibility of adrenal tuberculosis. It is known that MAC pulmonary disease accounts for the majority of non-tuberculous mycobacterial infection. In this subject, however, anti-MAC antibody was negative and MAC-related bacteria were not detected in PCR test using bronchial lung lavage fluid. These data ruled out the possibility of MAC pulmonary disease. Mycobacterium abscessus (Mab) was positive in bronchial lung lavage fluid culture. Based on these data, we diagnosed this subject with Addison’s disease triggered by infection with mycobacterium abscessus, but not by adrenal tuberculous or MAC pulmonary disease. Decreased sodium level and increased eosinophil number were normalized and appetite loss was markedly mitigated after starting hydrocortisone therapy. A chest CT which was taken about 6 months later showed drastic reduction of consolidation in the upper lobe of the left lung although calcification in the adrenal gland was still observed.ConclusionsWe should bear in mind the possibility of Addison’s disease triggered by another type of infection rather than adrenal tuberculosis or MAC pulmonary disease.

Antidepressant effects of cherry leaf decoction on a chronic unpredictable mild stress rat model based on the Glu/GABA-Gln metabolic loop.

Cherry leaves (Prunus pseudocerasus Lindl. [Rosaceae]), a traditional Chinese herbal medicine, can regulate the factors closely related to depression including inflammatory cytokines, oxidative stress and blood glucose level. However, the antidepressant effects of cherry leaves and underlying neuromodulatory mechanisms remain relatively have not been elucidated explicitly. The present study investigated the antidepressant effects of cherry leaf decoction (CLD). The underlying neuromodulatory mechanism was explored by examining the glutamate (Glu)/γ-aminobutyric acid (GABA)-glutamine (Gln) metabolic loop. The chronic unpredictable mild stress (CUMS) rodent model was used in this study. The main flavonoids components of CLD were identified using high-performance liquid chromatography (HPLC). The antidepressant effects of CLD were assessed throughout behavioural tests including the bodyweight, sucrose preference test (SPT), forced swimming test (FPT) and tail suspension test (TST). Moreover, The baseline levels of serum adrenocorticotropic hormone (ACTH) and corticosterone (CORT) were quantified. The expression of proteins integrally involved in the Glu/GABA-Gln metabolic loop were observed and quantified by Western blotting, reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry. This study found that CLD ameliorated depressive-like behaviours induced by CUMS. The increase of serum ACTH and CORT baseline levels induced by CUMS was also reversed after CLD intervention. Furthermore, CUMS reduced the expression of GAD65, GAD67, GLT-1, GS and GABAA and increased NMDAR1 levels in the rat hippocampus, which was normalized by CLD treatment. The findings demonstrated that CLD could ameliorate the depression-like behaviours induced by CUMS, potentially through the inhibition of hypothalamic-pituitary-adrenal (HPA) axis hyperactivity and the regulation of Glu/GABA-Gln metabolic loop.

Investigation of combined effects of propyl paraben and methyl paraben on the hypothalamic-pituitary-adrenal axis in male rats.

The aim of this study was to investigate the endocrine-disrupting effects of methyl paraben (MeP) and propyl paraben (PrP) mixture on the hypothalamic-pituitary-adrenal axis (HPA). In this study, six experimental groups were designated. These groups included three control groups (control, corn oil control, and positive control (50mg/kg/day BPA)) and three dose groups (10, 100, and 500mg/kg/day MeP+PrP). MeP with PrP were mixed in a 1:1 ratio and administered to the 42-day-old male rats by oral gavage for 30days. At the end of the experiment, adrenocorticotropic hormone (ACTH), corticosterone and aldosterone hormones were analyzed in serum. Effects of MeP+PrP on the adrenal glands were investigated by immunohistochemical staining of 11ß hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) enzymes involved in the synthesis steps of corticosterone and aldosterone. Also, pituitary and adrenal glands were examined histopathologically. In the histopathological findings, cortical nodule, congestion, and edema were found in the tissues. In the pituitary gland, cytokeratin rings were detected in all MeP+PrP dose groups, supporting the increase of corticosterone and ACTH. Serum corticosterone, aldosterone, and ACTH hormone levels were increased in the 100 mg/kg/day MeP+PrP and BPA groups. Results obtained from immunohistochemical staining showed that increased staining parallelled increased corticosterone and aldosterone hormone levels. In summary, the results showed that exposure to the MeP+PrP mixture caused a significant increase in ACTH and corticosterone. Also, the MeP+PrP mixture caused a significant increase of CYP11B1 and CYP11B2. MeP+PrP exposure disrupts the normal HPA axis.

The effect of month and breed on plasma adrenocorticotropic hormone concentrations in equids

Use of plasma adrenocorticotropic hormone (ACTH) concentrations for the diagnosis of PPID in equids requires awareness of other factors that might influence ACTH concentrations, including breed and time of year. This study was designed to investigate effects of breed on plasma ACTH concentrations and potential interactions between breed and time of year. Ten breeds were selected from a laboratory database containing data on plasma ACTH concentrations. Breeds represented were Arabians, Cobs, Connemara ponies, donkeys, Irish Sports horses, New Forest ponies, Shetland ponies, Thoroughbreds, Warmbloods and Welsh breeds. Multivariable analysis was used to determine the effects of month and breed on plasma ACTH concentrations.A circannual pattern of ACTH concentration was documented, with a nadir in April and a peak in September. Arabian horses and donkeys had significantly higher ACTH concentrations than some other breeds, primarily from May to November, whereas in Shetland ponies and Welsh breeds, relatively higher ACTH concentrations only occurred from July to November. The annual increase in plasma ACTH appeared to commence in late April/early May in response to increasing daylight and decreased again promptly after the late September equinox as daylength fell below 12 h per day. Inter-breed differences in plasma ACTH were substantial and indicated that breed and time of year should be considered when interpreting plasma ACTH concentrations in equids suspected for PPID.

Sciatic nerve injury rebalances the hypothalamic-pituitary-adrenal axis in rats with persistent changes to their social behaviours.

Increased glucocorticoids characterise acute pain responses, but not the chronic pain state, suggesting specific modifications to the hypothalamic–pituitary–adrenal (HPA)‐axis preventing the persistent nature of chronic pain from elevating basal glucocorticoid levels. Individuals with chronic pain mount normal HPA‐axis responses to acute stressors, indicating a rebalancing of the circuits underpinning these responses. Preclinical models of chronic neuropathic pain generally recapitulate these clinical observations, but few studies have considered that the underlying neuroendocrine circuitry may be altered. Additionally, individual differences in the behavioural outcomes of these pain models, which are strikingly similar to the range of behavioural subpopulations that manifest in response to stress, threat and motivational cues, may also be reflected in divergent patterns of HPA‐axis activity, which characterises these other behavioural subpopulations. We investigated the effects of sciatic nerve chronic constriction injury (CCI) on adrenocortical and hypothalamic markers of HPA‐axis activity in the subpopulation of rats showing persistent changes in social interactions after CCI (Persistent Effect) and compared them with rats that do not show these changes (No Effect). Basal plasma corticosterone did not change after CCI and did not differ between groups. However, adrenocortical sensitivity to adrenocorticotropic hormone (ACTH) diverged between these groups. No Effect rats showed large increases in basal plasma ACTH with no change in adrenocortical melanocortin 2 receptor (MC2R) expression, whereas Persistent Effect rats showed modest decreases in plasma ACTH and large increases in MC2R expression. In the paraventricular nucleus of the hypothalamus of Persistent Effect rats, single labelling revealed significantly increased numbers of corticotropin releasing factor (CRF) +ve and glucocorticoid receptor (GR) +ve neurons. Double‐labelling revealed fewer GR +ve CRF +ve neurons, suggesting a decreased hypothalamic sensitivity of CRF neurons to circulating corticosterone in Persistent Effect rats. We suggest that in addition to rebalancing the HPA‐axis, the increased CRF expression in Persistent Effect rats contributes to changes in complex behaviours, and in particular social interactions.

Histopathological and immunohistochemical evaluation for detecting changes in blood hormone levels caused by endocrine disruptors in a 28-day repeated-dose study in rats.

Although measurements of blood hormone levels in rodent toxicological studies can provide important information on the mechanisms of toxicity and extrapolation to humans, there are several difficulties such as large individual differences and limited sample volume. To develop a more simplified method that does not depend solely on blood samples, we examined the possible application of immunohistochemistry for detecting endocrine disruptors in short-term studies. Aminotriazole (AMT), propylthiouracil (PTU), phenobarbital, aminoglutethimide (AGT), estradiol, and vitamin D3 were administered orally to 6-week-old male and female SD rats (five/group) for 28 days. Measurements of serum hormone levels revealed decreases in triiodothyronine (T3) and thyroxine (T4) in the AMT and PTU groups, an increase in thyroid stimulating hormone (TSH) in the AMT, PTU, and AGT groups, and an increase in adrenocorticotrophic hormone in the AGT group. Increased thyroid, pituitary, and adrenal gland weights; histopathological lesions, including follicular hypertrophy/hyperplasia, hypertrophy/vacuolation of anterior pituitary cells, and increased adrenocortical vacuolation were observed in association with the hormone level changes. Immunohistochemical analysis revealed a decreased T4 level in the thyroid gland of the AMT and PTU groups and an increased area of TSH positive immunostaining in the pituitary gland of the AMT, PTU, and AGT groups, consistent with the changes in serum T4 and TSH levels, respectively. These results suggest that histopathological analysis and immunohistochemistry for T4 and TSH might be useful and sensitive methods of detecting thyroid dysfunction, and that combining organ weight measurements is a reliable parameter of detecting endocrine disruptors.

Whole-Body Cryotherapy Enhances the Expression of Heat Shock Protein 70 and Related Hormones

BACKGROUND: Whole-body cryotherapy (WBC) is used as a conditioning method for athletes. However, the scientific evidence for its effects is still insufficient. OBJECTIVE: To elucidate the effects of transient WBC on the expression of heat shock protein (HSP) 70 and the secretion of related hormones in humans. MATERIALS AND METHODS: The participants in this study were six healthy adult men. WBC was performed for 3 min in a booth at a temperature in the range of -150 to -120°C, and measurements were taken immediately before (Pre), immediately after (Post), and 60 min after WBC (Post60). For measurement of core body temperature (gastrointestinal temperature), participants ingested a capsule-type wireless temperature sensor. The body surface temperature was measured using a noncontact thermometer, and measurements were taken at four sites on the body surface (chest, abdomen, front of the thigh, and front of the lower thigh). Leukocyte count, lactate dehydrogenase, creatine kinase, hemoglobin, hematocrit, adrenaline, noradrenaline, cortisol, adrenocorticotropic hormone (ACTH), erythropoietin, and HSP70 in the collected blood were measured. RESULTS: The results showed a decrease in body surface temperature and an increase in noradrenaline and ACTH immediately after WBC. In addition, the core body temperature decreased 60 min after WBC, accompanied by an increase in HSP70 expression. CONCLUSION: WBC may increase HSP70 expression via noradrenaline and ACTH. The results of this study suggest the usefulness of WBC in triggering protein synthesis and the maintenance of immune function after training.

Long-term morbidity in congenital adrenal hyperplasia

Congenital adrenal hyperplasia (CAH) is one of the most common autosomal recessive disorders and is characterized by cortisol deficiency. The most common cause of CAH is amutation in the CYP21A2 gene, resulting in 21-hydroxylase deficiency in the adrenal cortex. The lack of cortisol causes an increase in adrenocorticotropic hormone (ACTH), which in turn results in an excess of adrenal androgens. Aldosterone synthesis may also be impaired. The clinical manifestation of CAH depends on the residual activity of 21-hydroxylase and the subsequent lack of cortisol and adrenal androgen excess. While classic CAH is apotentially life-threatening condition, non-classic CAH is mild to asymptomatic. Therapy of classic CAH consists of glucocorticoid and mineralocorticoid substitution. Despite optimization of therapy, CAH still leads to increased morbidity and mortality in patients. The clinical consequences of androgen excess in affected women range from intrauterine virilisation of external genitalia in classic CAH patients to mild symptoms of hyperandrogenism in non-classic forms. Increased demand for cortisol during illness or physical and psychological stress situations can trigger life-threatening adrenal crises. As current glucocorticoid therapy cannot mimic the physiological circadian rhythm and is usually supraphysiological in dose to control androgen excess, therapy-associated long-term consequences such as decreased bone health and an increased cardiometabolic risk profile are common. The burden of the disease may also lead to impaired quality of life and mental health. For this reason, regular screening and follow-up of patients with CAH should be performed in specialized centers to detect and treat possible comorbidities at an early stage.

Effect of iodine-bromine baths on stress-systems indicators in children with autism spectrum disorders

To evaluate the effect of iodine-bromine baths on stress-system indicators in children with ASD. The study involved 74 children with ASD (F84) aged 3 to 14 years (mean age 6.23±0.37 years) included in the main group (MG). The control group (CG) consisted of 25 healthy children.The examination included detailed history taking, examination by specialists, assessment of disease severity using CARS scale, evaluation of β-endorphin, adrenocorticotropic hormone (ACTH), and cortisol levels in blood serum by ELISA. Thirty-four (45.9%) children had a moderate autism level (total score 30-37), and 40 (54.1%) children had severe autism (total score 37-60). In the MG, there were 27 (36.5%) children with mild symptoms of hyperactivity (subgroup A) and 47 (63.5%) children with severe aggression, tantrums, and increased hyperactivity (subgroup B). All MG patients were assigned into two subgroups by randomization: Subgroup 1: 30 children with ASD received health resort treatment (HRT) without iodine-bromine baths (IB); Subgroup 2: 44 children with ASD received similar HRT and IB. Statistically significant increase of β-endorphin, ACTH and cortisol levels (p<0.01, p<0.05, p<0.01, respectively) in children with ASD (compared to those in CG children) was identified. In children without hyperactivity, a moderate increase of these parameters was noted; significantly higher values were observed in children with severe hyperactivity, impulsiveness, and aggression (p<0.05, p<0.001, respectively). After treatment, there was a statistically significant increase in β-endorphin level in subgroup 1 children who received HRT without IB, while in children of subgroups A and B (p<0.05, p<0.05, p<0.01, respectively), there was a decrease in ACTH level (p<0.05, p<0.01, p<0.001 respectively) and a trend towards a cortisol level decrease. Inclusion of IB in HRT course associated with a significant decrease of β-endorphin level in children of subgroups A and B (p<0.001), a decrease of ACTH level (p<0.001) and cortisol (p<0.001, p<0.01, p<0.001, respectively), which resulted in vicious circle breaking and normalization of relations between stress-limiting and stress-releasing parts of pathogenesis. Most children with autism spectrum disorders showed significant increases in β-endorphin, adrenocorticotropic hormone, and cortisol levels, indicating dysfunction between the stress-limiting and stress-releasing systems, as well as between the central and peripheral parts of the stress-releasing chain. The tonic effect of resort treatment was noted, limiting its use in children with autism spectrum disorders, increased hyperactivity, and aggression. The inclusion of iodine-bromine baths in resort treatment has a calming non-medicinal effect and can be recommended for use in children with symptoms of severe hyperactivity.

Hypercortisolism in patients with cholestasis is associated with disease severity

BackgroundCholestasis might lead to an impairment of adrenal function as suggested by in vitro and in vivo data as well as by clinical findings. Bile acid and adrenal steroid metabolism not only share the receptors farnesoid X receptor (FXR) and the G protein-coupled bile acid receptor 1 (TGR5), but supraphysiological bile acid levels were found to stimulate steroidogenesis independent of FXR and TGR5. Our previous experimental findings revealed that mice fed bile acids or subjected to common bile duct ligation develop hypercortisolemia. We thus aimed to assess adrenal gland function in patients with cholestasis.MethodsAdrenal gland function was assessed in 36 patients with cholestasis and in 32 patients without cholestasis by measuring total serum cortisol, adrenocorticotropic hormone (ACTH), as well as the increase of cortisol 20 and 30 min after administration of 1 µg of ACTH. Bile acid levels and bile acid pool composition were determined by high-resolution mass spectrometry.ResultsPatients with cholestasis per definition had markedly elevated levels of alkaline phosphatase (AP), bilirubin and serum bile acids. Baseline cortisol and maximum cortisol after ACTH stimulation were significantly higher in patients with cholestasis compared to controls. Increase of cortisol after ACTH stimulation and ACTH did not differ. In the cholestasis group, baseline cortisol correlated with bilirubin but not with AP, total serum bile acids and levels of conjugated and unconjugated bile acid species. Patients with duration of cholestasis < 6 months (n = 30) had significantly higher baseline cortisol levels than those with long standing cholestasis (> 6 months), together with higher bilirubin levels.ConclusionsWe find no evidence of adrenal insufficiency in non-cirrhotic patients with cholestasis. In contrast, patients with cholestasis show hypercortisolism associated with disease severity as mirrored by levels of bilirubin. Lack of ACTH increase in cholestasis suggests a direct effect of cholestasis on adrenals and not on the pituitary gland. Further studies are needed to elucidate the mechanism of cortisol elevation in patients with cholestasis and its clinical significance.

Особенности клинических проявлений и лечения синдрома Шмидта

Актуальность. Наиболее часто встречается аутоиммунный полигландулярный синдром 2-го типа. Представляет интерес развитие и течение синдрома Шмидта, что требует всесторонней диагностики ввиду сочетания нескольких аутоиммунных эндокринопатий и рациональной терапии. Цель: проанализировать особенности клинических проявлений и лечения аутоиммунного полигландулярного синдрома 2-го типа на конкретном примере. Материалы и методы. Для рассмотрения представлен наблюдаемый нами клинический случай синдрома Шмидта у пациентки 36 лет. Имели место первичная надпочечниковая недостаточность с аутоиммунным процессом к 21-гидроксилазе и наличие аутоиммунного тиреоидита с развитием гипотиреоза. Результаты. В клинических проявлениях заболевания доминировали синдромы гипотензии, общей и мышечной слабости, гиперпигментации, потери массы тела, диспептических расстройств, усугубившиеся в результате присоединения вирусной инфекции, на фоне отечного синдрома. Дополнительное обследование выявило значительное повышение адренокортикотропного гормона, ренина, гиперкалиемию, гиперхолестеринемию, повышение 17-гидроксипрогестерона, тиреотропного гормона, гипотироксинемию, повышение антител к 21-гидроксилазе и к тиреоидной пероксидазе при уменьшении объема щитовидной железы с наличием множественных линейных включений, повышением эхогенности. Анализ выявленных гормональных, метаболических и патоморфологических изменений позволил установить наличие в данном клиническом случае синдрома Шмидта. Проводимое лечение глюкокортикоидами сопровождалось побочными реакциями, что привело к неоднократной замене препаратов. Выбор был сделан в пользу кортефа, доза тщательно оттитрована под контролем кортизолурии. Назначение левотироксина сопровождалось достижением эутиреоза. Выводы. Манифестация синдрома Шмидта при одновременном проявлении первичной надпочечниковой недостаточности аутоиммунного генеза и аутоиммунного тиреоидита с развитием гипотиреоза отличалась взаимно отягощающим течением. Имелись значительные трудности в лечении данного полигландулярного синдрома, связанные с коррекцией гипокортицизма, вследствие плохой переносимости глюкокортикоидов, что требовало постоянного наблюдения, неоднократного контроля за состоянием гормонального и метаболического статусов.

Impact of blue light therapy on plasma adrenocorticotropic hormone (ACTH) and hypertrichosis in horses with pituitary pars intermedia dysfunction

Blue light therapy can be used in horses to alter the natural photoperiod and inhibit winter hair coat growth. Seasonal increases in ACTH occur in the fall season but are exaggerated in horses with pituitary pars intermedia dysfunction (PPID). Additionally, PPID horses frequently present with hypertrichosis. Thus, blue light therapy was proposed as a potential management tool for hypertrichosis and for investigating the impact of photoperiod manipulation on ACTH. Eighteen PPID horses, aged 18 to 31 yr, from a university-owned research herd were selected and assigned to either the control group (n = 10) or the treatment (blue light therapy) group (n = 8) based on age and clinical history, which included the results of multiple endocrine tests. Consistent daylength of approximately 14.5 h was maintained for the treated horses from July 15 through approximately late October via the extension of natural daylength using wearable masks that provided short wavelength blue light (465 nm) to 1 eye. The control group was exposed to only the natural photoperiod during this time. All horses were housed on the same farm and remained on pasture for the duration of the study. On Day 0, thyrotropin-releasing hormone (TRH) stimulation tests were performed to confirm PPID status; there were no differences between the 2 groups in resting plasma ACTH or plasma ACTH at 10 min after TRH administration. To determine an effect of treatment on ACTH, blood was collected via jugular venipuncture for measurement of ACTH at sequential timepoints over a 16-h period in mid-October. Hair weights were also assessed throughout the study. No differences in resting plasma ACTH were observed between the 2 groups across the seasonal analysis (July and October) or during the 16-h testing. The PPID horses receiving blue light therapy had lighter hair weights compared to the PPID control horses. These results suggest that blue light therapy does not alter ACTH concentrations but could potentially be used as an additional management tool for hypertrichosis in PPID horses. Manipulation of the photoperiod using blue light therapy did not affect seasonal changes in ACTH in this study.

Effects of red ginseng on gut, microbiota, and brain in a mouse model of post-infectious irritable bowel syndrome

BackgroundIrritable bowel syndrome (IBS), the most common functional gastrointestinal disorder, is characterized by chronic abdominal pain and bowel habit changes. Although diverse complicated etiologies are involved in its pathogenesis, a dysregulated gut–brain axis may be an important factor. Red ginseng (RG), a traditional herbal medicine, is proven to have anti-inflammatory effects and improve brain function; however, these effects have not been investigated in IBS. MethodsThree-day intracolonic zymosan injections were used to induce post-infectious human IBS-like symptoms in mice. The animals were randomized to receive either phosphate-buffered saline (CG) or RG (30/100/300 mg/kg) for 10 days. Amitriptyline and sulfasalazine were used as positive controls. Macroscopic scoring was performed on day 4. Visceral pain and anxiety-like behaviors were assessed by colorectal distension and elevated plus maze and open field tests, respectively, on day 10. Next-generation sequencing of gut microbiota was performed, and biomarkers involved in gut–brain axis responses were analyzed. ResultsCompared to CG, RG significantly decreased the macroscopic score, frequency of visceral pain, and anxiety-like behavior in the IBS mice. These effects were comparable to those after sulfasalazine and amitriptyline treatments. Moreover, RG significantly increased the proliferation of beneficial microbes, including Lactobacillus johnsonii, Lactobacillus reuteri, and Parabacteroides goldsteinii. RG significantly suppressed expression of IL-1β and c-fos in the gut and prefrontal cortex, respectively. Further, it restored the plasma levels of corticosterone to within the normal range, accompanied by an increase in adrenocorticotropic hormone. ConclusionRG may be a potential therapeutic option for the management of human IBS.