Hypothalamo-pituitary-adrenal Axis Research Articles

Yeast Extract Peptides Alleviate Depression in Chronic Restraint Stress Rats by Alleviating Hippocampal Neuronal Apoptosis and Dysbiosis of the Gut Microbiota.

Depression as a global neurological disorder, and hippocampal neuronal apoptosis and disorders of the gut microbiota are closely related to it. This study aims to expose the ameliorative effect of enzyme peptides (AP) from brewer's yeast on depressive behavior caused by chronic restraint stress (CRS) in rats. After 4 weeks of AP intervention, a significant alleviation of depressive behavior in the sucrose preference test (SPT), forced swim test (FST), and light-dark test (LDT) is observed in depressed rats. AP ameliorates neuronal damage with increased the expression of the key CREB/BDNF/TrkB/Akt signaling pathway, which increases the levels of the monoamine neurotransmitters 5-hydroxytryptamine (5-HT) and norepinephrine (NE) in the hippocampus, buffering hyperactivity of the hypothalamo-pituitary-adrenal axis (HPA), and decreasing the serum cortisol (CORT) and adrenocorticotropic hormone (ACTH) levels in rats. In addition, AP modulates the disruption of the rat gut microbiota by chronic restraint stress (CRS), and the changes in the abundance of Lactobacillus animalis and Lactobacillus johnsonii are probably the key for AP performing antidepressant benefits. A strong correlation is found between gut microbiota and biochemical markers of depression. AP, as a natural and safe active substance, has a positive effect in the treatment of depression.

Investigation of effect peripheral kisspeptin treatment on hypothalamo-pituitary-gonadal axis and hypothalamo-pituitary-adrenal axis in male rats.

Kisspeptin is an endogenous peptide hormone that is the most potent stimulator of the hypothalamo-pituitary-gonadal (HPG) axis. The HPG axis can be suppressed by the activation of the hypothalamo-pituitary-adrenal (HPA) axis. The physiological role of kisspeptin in the interaction of the HPG axis and the HPA axis is not fully understood yet. The purpose of the current study was to investigate the possible effects of peripheral injection (intraperitoneally) of kisspeptin on HPG axis and HPA axis activity as well. Adult male Wistar rats were randomly divided into seven groups as sham (control), kisspeptin(10nmol), p234 (10nmol), kisspeptin + p234, kisspeptin + antalarmin (10mg/kg), kisspeptin + astressin2b (100μg/kg), and kisspeptin + atosiban (0.250mg/kg) (n = 10 each group). At the end of the experiment, the hypothalamus, pituitary gland, and serum samples of the rats were collected. Serum follicle-stimulating hormone and luteinizing hormone levels of the kisspeptin, kisspeptin + antalarmin and kisspeptin + astressin2b groups were significantly higher than the control group. Serum testosterone levels were significantly higher in the kisspeptin, kisspeptin + antalarmin, kisspeptin + astressin2b, and kisspeptin + atosiban groups that compared to the control group. There was no a significant difference in corticotropic releasing hormone immunoreactivity in the paraventricular nucleus of the hypothalamus, serum adrenocorticotropic hormone and corticosterone concentrations among all groups. Moreover, no significant difference was found in the concentration of pituitary oxytocin. Our results suggest that peripheral kisspeptin injection induces an activation in the HPG axis, but not in the HPA axis in male rats.

The Interaction of Vasopressin with Hormones of the Hypothalamo-Pituitary-Adrenal Axis: The Significance for Therapeutic Strategies in Cardiovascular and Metabolic Diseases.

A large body of evidence indicates that vasopressin (AVP) and steroid hormones are frequently secreted together and closely cooperate in the regulation of blood pressure, metabolism, water-electrolyte balance, and behavior, thereby securing survival and the comfort of life. Vasopressin cooperates with hormones of the hypothalamo-pituitary-adrenal axis (HPA) at several levels through regulation of the release of corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and multiple steroid hormones, as well as through interactions with steroids in the target organs. These interactions are facilitated by positive and negative feedback between specific components of the HPA. Altogether, AVP and the HPA cooperate closely as a coordinated functional AVP-HPA system. It has been shown that cooperation between AVP and steroid hormones may be affected by cellular stress combined with hypoxia, and by metabolic, cardiovascular, and respiratory disorders; neurogenic stress; and inflammation. Growing evidence indicates that central and peripheral interactions between AVP and steroid hormones are reprogrammed in cardiovascular and metabolic diseases and that these rearrangements exert either beneficial or harmful effects. The present review highlights specific mechanisms of the interactions between AVP and steroids at cellular and systemic levels and analyses the consequences of the inappropriate cooperation of various components of the AVP-HPA system for the pathogenesis of cardiovascular and metabolic diseases.

Characterizing Adrenal Insuffciency in a Rat Model of Prader-Willi Syndrome: Insights into Hypothalamic-Pituitary-Adrenal Axis Dysregulation

Prader-Willi Syndrome (PWS) is a complex genetic disorder with distinct developmental stages. In the first stage, PWS manifests as failure to thrive, hypotonia and feeding diffculty in infants. This is followed by hyperphagia, hypogonadism, and behavioral challenges which characterize the later stage of this disease. Hypothalamic-pituitary dysregulation is believed to be responsible for many aspects of the PWS phenotype, potentially contributing to several of the hallmark characteristics of this disorder. Changes in the ability of the central nervous system to respond to stressors by integrating and responding to insults to the homeostatic state are well documented in PWS, and adrenal insuffciency may further complicate endocrine dysfunction in PWS. The inability of PWS patients to respond to stress may be due to alterations at any or all three levels of the hypothalamo-pituitary-adrenal (HPA) axis. In this study, we sought to investigate the hypothesis that adrenal insuffciency in Magel2-deficient rats, a model of PWS, is at least in part due to loss of pituitary secretory capacity, since disruption of Magel2 expression, as is observed in PWS patients, is known to affect vesicular traffcking and secretion. To address this hypothesis, anterior pituitaries collected from Magel2-deficient and wild type rats were dispersed and aliquoted. The following day, cells were treated with either 0.1, 1.0, 10, 100, or 1000 nM of corticotrophin-releasing hormone (CRH). Following a 60 minute incubation, media were collected for the assessment of adrenocorticotropin (ACTH) by radioimmunoassay. We also collected pituitary cells for measurement of intracellular content of ACTH. Our results showed that cells from Magel2-deficient rats had decreased basal ACTH secretion, but remained responsive to CRH stimulation, albeit to a lesser degree than cells isolated from wild type animals. This suggests a pituitary deficiency in the response to hypothalamic factors (e.g. CRH) that normally control ACTH release. It is also possible that the other two levels of the HPA axis are altered in PWS. We now are investigating potential alterations in CRH prohormone processing or release (i.e. hypothalmic deficiencies) and responsiveness of the adrenal gland itself to ACTH administration. Furthermore, we have investigated circulating levels of cortisol in stressed and non-stressed animals to determine if the Magel2 rat model recapitulates the the aberrant stress response observed in PWS patients. Through this investigation of Magel2’s potential contributions to adrenal insuffciency, we hope to advance the understanding of PWS pathophysiology and lay the groundwork for developing new treatment strategies. This work has been paid for through a grant from the Foundation for Prader-Willi Research. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Surface temperatures are influenced by handling stress independently of corticosterone levels in wild king penguins (Aptenodytes patagonicus)

Assessing the physiological stress responses of wild animals opens a window for understanding how organisms cope with environmental challenges. Since stress response is associated with changes in body temperature, the use of body surface temperature through thermal imaging could help to measure acute and chronic stress responses non-invasively. We used thermal imaging, acute handling-stress protocol and an experimental manipulation of corticosterone (the main glucocorticoid hormone in birds) levels in breeding king penguins (Aptenodytes patagonicus), to assess: 1. The potential contribution of the Hypothalamo-Pituitary-Adrenal (HPA) axis in mediating chronic and acute stress-induced changes in adult surface temperature, 2. The influence of HPA axis manipulation on parental investment through thermal imaging of eggs and brooded chicks, and 3. The impact of parental treatment on offspring thermal's response to acute handling.Maximum eye temperature (Teye) increased and minimum beak temperature (Tbeak) decreased in response to handling stress in adults, but neither basal nor stress-induced surface temperatures were significantly affected by corticosterone implant. While egg temperature was not significantly influenced by parental treatment, we found a surprising pattern for chicks: chicks brooded by the (non-implanted) partner of corticosterone-implanted individuals exhibited higher surface temperature (both Teye and Tbeak) than those brooded by glucocorticoid-implanted or control parents. Chick's response to handling in terms of surface temperature was characterized by a drop in both Teye and Tbeak independently of parental treatment.We conclude that the HPA axis seems unlikely to play a major role in determining chronic or acute changes in surface temperature in king penguins. Changes in surface temperature may primarily be mediated by the Sympathetic-Adrenal-Medullary (SAM) axis in response to stressful situations. Our experiment did not reveal a direct impact of parental HPA axis manipulation on parental investment (egg or chick temperature), but a potential influence on the partner's brooding behaviour.

Intracerebroventricular injection of kisspeptin in male rats activates hypothalamo-pituitary-gonadal axis, but not hypothalamo-pituitary-adrenal axis

Kisspeptin is an important hormone involved in the stimulation of the hypothalamo-pituitary gonadal (HPG) axis. The HPG axis can be suppressed in certain conditions such as stress, which gives rise to the activation of the hypothalamo-pituitary-adrenal (HPA) axis. However, the physiological role of kisspeptin in the interaction of HPG and HPA axis is not fully understood yet. This study was conducted to investigate the possible effects of central kisspeptin injection on HPG axis as well as HPA axis activity. Adult male Wistar rats were randomly divided into seven groups as followed: sham (control), kisspeptin (50 pmol), P234 (1 nmol), kisspeptin + p234, kisspeptin + antalarmin (0.1 μg), kisspeptin + astressin 2B (1 μg), and kisspeptin + atosiban (300 ng/rat) (n = 10 each group). At the end of the experiments, the hypothalamus, pituitary, and serum samples of the rats were collected. There was no significant difference in corticotropic-releasing hormone immunoreactivity in the paraventricular nucleus of the hypothalamus, serum adrenocorticotropic hormone, and corticosterone levels among all groups. Moreover, no significant difference was detected in pituitary oxytocin level. Serum follicle-stimulating hormone and luteinizing hormone levels of the kisspeptin, kisspeptin + antalarmin, and kisspeptin + astressin 2B groups were significantly higher than the control group. Serum testosterone levels were significantly higher in the kisspeptin kisspeptin + antalarmin, kisspeptin + astressin 2B, and kisspeptin + atosiban groups compared to the control group. Our findings suggest that central kisspeptin injection causes activation in the HPG axis, but not the HPA axis in male rats.

Multivariable Model to Predict an ACTH Stimulation Test to Diagnose Adrenal Insufficiency Using Previous Test Results.

The adrenocorticotropin hormone stimulation test (AST) is used to diagnose adrenal insufficiency, and is often repeated in patients when monitoring recovery of the hypothalamo-pituitary-adrenal axis. To develop and validate a prediction model that uses previous AST results with new baseline cortisol to predict the result of a new AST. This was a retrospective, longitudinal cohort study in patients who had undergone at least 2 ASTs, using polynomial regression with backwards variable selection, at a Tertiary UK adult endocrinology center. Model was developed from 258 paired ASTs over 5 years in 175 adults (mean age 52.4 years, SD 16.4), then validated on data from 111 patients over 1 year (51.8, 17.5) from the same center, data collected after model development. Candidate prediction variables included previous test baseline adrenocorticotropin hormone (ACTH), previous test baseline and 30-minute cortisol, days between tests, and new baseline ACTH and cortisol used with calculated cortisol/ACTH ratios to assess 8 candidate predictors. The main outcome measure was a new test cortisol measured 30 minutes after Synacthen administration. Using 258 sequential ASTs from 175 patients for model development and 111 patient tests for model validation, previous baseline cortisol, previous 30-minute cortisol and new baseline cortisol were superior at predicting new 30-minute cortisol (R2 = 0.71 [0.49-0.93], area under the curve [AUC] = 0.97 [0.94-1.0]) than new baseline cortisol alone (R2 = 0.53 [0.22-0.84], AUC = 0.88 [0.81-0.95]). Results of a previous AST can be objectively combined with new early-morning cortisol to predict the results of a new AST better than new early-morning cortisol alone. An online calculator is available at https://endocrinology.shinyapps.io/sheffield_sst_calculator/ for external validation.

Weathering the storm: Decreased activity and glucocorticoid levels in response to inclement weather in breeding Columbian ground squirrels

Inclement weather can rapidly modify the thermal conditions experienced by animals, inducing changes in their behavior, body condition, and stress physiology, and affecting their survival and breeding success. For animals living in variable environments, the extent to which they have adapted to cope with inclement weather is not established, especially for hibernating species with a short active season that are constrained temporally to breed and store energy for subsequent hibernation. We examined behavioral (foraging activity) and physiological (body mass and fecal cortisol metabolites) responses of Columbian ground squirrels (Urocitellus columbianus), small hibernating rodents inhabiting open meadows in Rocky Mountains, to 3 events of inclement weather (two snow storms in May 2021 and May 2022, one heavy rainfall in June 2022). We found that individuals adapted to inclement weather conditions by (1) reducing above-ground activity, including foraging, (2) decreasing the mobilization of stored resources as indicated by a decrease in the activity of the hypothalamo-pituitary-adrenal (HPA) axis and lower fecal cortisol metabolites in the hours/days following periods of inclement weather; and (3) compensating through increased foraging and more local activity when favorable conditions resumed. As a result, body mass and growth did not decrease following short periods of inclement weather. Columbian ground squirrels were well-adapted to short periods of inclement weather, coping via modifications of their behavior and the activity of the HPA axis.

Mapping of corticotropin-releasing factor, receptors, and binding protein mRNA in the chicken telencephalon throughout development.

Understanding the neural mechanisms that regulate the stress response is critical to know how animals adapt to a changing world and is one of the key factors to be considered for improving animal welfare. Corticotropin-releasing factor (CRF) is crucial for regulating physiological and endocrine responses, triggering the activation of the sympathetic nervous system and the hypothalamo-pituitary-adrenal axis (HPA) during stress. In mammals, several telencephalic areas, such as the amygdala and the hippocampus, regulate the autonomic system and the HPA responses. These centers include subpopulations of CRF containing neurons that, by way of CRF receptors, play modulatory roles in the emotional and cognitive aspects of stress. CRF binding protein also plays a role, buffering extracellular CRF and regulating its availability. CRF role in activation of the HPA is evolutionary conserved in vertebrates, highlighting the relevance of this system to help animals cope with adversity. However, knowledge on CRF systems in the avian telencephalon is very limited, and no information exists on detailed expression of CRF receptors and binding protein. Knowing that the stress response changes with age, with important variations during the first week posthatching, the aim of this study was to analyze mRNA expression of CRF, CRF receptors 1 and 2, and CRF binding protein in chicken telencephalon throughout embryonic and early posthatching development, using in situ hybridization. Our results demonstrate an early expression of CRF and its receptors in pallial areas regulating sensory processing, sensorimotor integration and cognition, and a late expression in subpallial areas regulating the stress response. However, CRF buffering system develops earlier in the subpallium than in the pallium. These results help to understand the mechanisms underlying the negative effects of noise and light during prehatching stages in chicken, and suggest that stress regulation becomes more sophisticated with age.

Activities of the hypothalamo-pituitary-adrenal axis and autonomic nervous system following a strong earthquake.

This study aimed to investigate the effects of post-traumatic stress, caused by a strong earthquake, on the hypothalamo-pituitary-adrenal axis (HPA) and autonomous nervous system activity (ANS). Activities of the HPA (as salivary cortisol) and ANS (as heart-rate variability [HRV]) were measured following the 2020 Elazig (Türkiye) earthquake (6.8 Richter Scale, classified as strong). A total of 227 participants (103 men (45%) and 124 women (%55)) provided saliva samples twice, namely, 1week and 6weeks after the earthquake. Of these participants, HRV was measured in 51 participants by 5min continuous electrocardiogram (ECG) recording. Frequency- and time-domain parameters of the HRV were calculated to assess the activity of ANS and low/high frequency (LF/HF) ratio was used as surrogate for sympathovagal balance. Salivary cortisol levels decreased from week 1 towards week 6 (17.40±1.48 and 15.32±1.37ng/mL, respectively, p<0.05). There were no gender differences (17.99±2.63 and 16.90±1.60ng/mL, respectively for females and males, p>0.05) for salivary cortisol levels. There were no differences in time- and frequency domain parameters of the HRV including LF/HF ratio (2.95±0.38 ms2 and 3.60±0.70 ms2 , respectively for week 1 and 6, p>0.05). The data show that HPA axis activity, but not that of the ANS, remains higher 1week after the earthquake but decreases afterwards towards the sixth week, suggesting that the HPA axis might be responsible for the long-term effects of a traumatic event like a strong earthquake.

Characterising approaches to steroid therapy in paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2.

We describe approaches to steroid therapy use in paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 (PIMS-TS) and examine the association between steroid therapy and key clinical markers of severity. We conducted a retrospective review of children (<18 years) admitted to a tertiary paediatric hospital in the UK with PIMS-TS. We collected data on if and why steroid therapy was used; the duration, type and dosing of steroids prescribed; and approaches to hypothalamo-pituitary-adrenal (HPA) axis monitoring, if performed. We examined associations between steroid exposure/total steroid dose (mg/m2 /day) and paediatric intensive care unit admission, mechanical ventilation and inotropic support. Steroid therapy was commenced in most children (84.9%, n = 104) with a median total daily steroid dose (hydrocortisone equivalent) of 271.0 mg/m2 /day (interquartile range 232.5-355.5) and treatment length of 26.0 days (interquartile range 19.0-32.0). Dosing regimens predominantly involved a short course of high-dose methylprednisolone followed by tapering oral prednisolone. Basal and/or dynamic testing of the HPA axis was conducted in a minority (11.8%, n = 15) and was normal. Duration of steroid therapy correlated positively with durations of paediatric intensive care unit admission (r = 0.407, P < 0.001) and mechanical ventilation (r = 0.797, P < 0.001). A greater proportion of children receiving steroid therapy also received inotropic support compared to those that did not receive steroid therapy (71.4% vs. 45.5%, P = 0.025). Prolonged, high-dose steroid therapy is often used in the management of severe PIMS-TS with the potential for HPA axis suppression and should be withdrawn carefully.

In early MS, the vasopressin peptide copeptin in serum is not a suitable surrogate for hypothalamo-pituitary-adrenal axis activity (P13-3.016)

<h3>Objective:</h3> To determine if a single measurement of copeptin, the C-terminal part of the AVP precursor (CT-proAVP), a stable and sensitive surrogate for AVP release, may serve as a more simply acquired substitute for the more cumbersome combined dexamethasone-corticotropin-releasing hormone test (DexCRH-test) to assess hypothalamo-pituitary-adrenal (HPA) axis activity in MS. <h3>Background:</h3> Activation of the HPA axis has been observed in MS by using the DexCRH-test, and may affect pathogenesis and clinical course. Vasopressin (AVP) costimulates ACTH secretion with CRH, but is not inhibited by dexamethasone. <h3>Design/Methods:</h3> Open, monocenter study, 44 HC, 55 patients with early relapsing-remitting MS (RRMS), 10 patients with clinically isolated syndrome (CIS). DexCRH-test (1.5 mg oral dexamethasone at 2300h the evening before; 100 μg i.v. synthetic hCRH at 1502h; serum ACTH and cortisol between 1500h and 1615h). Copeptin serum concentration before CRH application, and in a subset at 0900h before dexamethasone. Calculation of AUC for ACTH and cortisol output according to the trapezoidal rule. Independant samples t test, linear regression. <h3>Results:</h3> In HC (n=19) and MS (n=51), copeptin before and after dexamethasone correlated significantly, more stringently in HC (Pearson correlation, r²=0.627) than in MS (r²=0.301, both p&lt;0.001). No correlation was found between copeptin (before or after dexamethasone) and DexCRH test variables in either HC or MS (AUC of ACTH or cortisol secretion; p 0.13–0.35). Copeptin, AUC-ACTH and AUC-cortisol were not significantly different between HC and RRMS/CIS (p=0.35–0.42). <h3>Conclusions:</h3> In HC and MS, copeptin appears equally affected by dexamethasone. Our sample of early RRMS patients predominantly on DMT did not display significant activation of the HPA axis, and had a fairly homogeneous HPA axis activity. At least in this setting, a single measurement of copeptin did not appear suitable as a surrogate marker of HPA axis activity. A sample including more advanced stages and different courses of MS may be more informative. <b>Disclosure:</b> Maike Schlingmann has nothing to disclose. Muriel Stoppe has nothing to disclose. Klara Mayer has nothing to disclose. Christian Schinke has nothing to disclose. Ms. Haars has nothing to disclose. Elisa Schmidt has nothing to disclose. Dr. Then Bergh has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Then Bergh has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck. Dr. Then Bergh has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Dr. Then Bergh has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Horizon. Dr. Then Bergh has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for UCB. Dr. Then Bergh has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Actelion. Dr. Then Bergh has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Alexion. Dr. Then Bergh has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Biogen. Dr. Then Bergh has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Bayer. Dr. Then Bergh has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Genzyme. Dr. Then Bergh has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Roche. Dr. Then Bergh has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Fresenius. The institution of Dr. Then Bergh has received research support from Actelion. The institution of Dr. Then Bergh has received research support from Novartis. The institution of Dr. Then Bergh has received research support from DFG (German Science Fund). Dr. Then Bergh has received personal compensation in the range of $10,000-$49,999 for serving as a Member of the Institutional Ethics Board with University of Leipzig, Medical Faculty.

Hypothalamo-Pituitary-Adrenal Axis in Depressive Disorders and Treatment Resistance

Background: hypothalamo-pituitary-adrenal (HPA) axis plays an important role in the pathogenesis of depression. Patterns of HPA functioning depend on both biologic factors and psychological background, which, taken together, may increase the risk of depression later on. Objective: to analyze scientific publications on pathophysiology of depression, linked to HPA disruption, assess causal relationship between hypercorticism and depression, role of hypercorticism in clinical symptoms and course of depressive disorder.Material and methods: according to the key words “hypercortiсism”, “depression disorder”, “cortisol”, “treatment resistant depression”, “Cushing’s syndrome”, “Сushing’s disease”, a search was conducted for publications in databases Medline/ PubMed, Scopus, Web of Science, RSCI and other resources.Conclusion: there is a high comorbidity between depressive disorders and HPA axis abnormalities, including endocrine disorders with both increased and decreased cortisol secretion. Hypercorticism related to Сushing’s disease or Cushing’s syndrome is often associated with irreversible mental disorders, especially anxiety and depressive disorders, which persist after normalization of cortisol levels. Depressive patients are characterized by persistently elevated cortisol levels and their non-supression in the 1 mg dexamethasone suppression test (DST); however, sometimes they have reduced cortisol secretion. The possible pathophysiology mechanisms of hypercorticism are discussed. Beside hypercorticism, increased level of adrenocorticotropic hormone (ACTH) and decreased secretion of ACTH after CRH stimulation are demonstrated. It has been demonstrated that elevation of cortisol levels may precede the development of depression and as such can be used as marker of increased depression risk. Hypercorticism in patients with depression may promote its increased severity and transform ation of depressive symptoms. Persistent hypercorticism and non-supression of cortisol in DST are predictors of poor outcomes. HPA dysfunction seems to play an essential role in evolvement of treatment resistant depression. There is data on the efficacy of drugs modifying HPA activity for amelioration of affective disorders and psychotic symptoms in patients with depression. Further research into HPA functioning in patients with depression are needed to clarify pathogenetic mechanisms and development of newer treatment approaches to depression.

Circadian Rhythm, Hypothalamo-Pituitary Adrenal Axis, and Immunity: Physiological and Pathological Examples

All living organisms; from single-celled microorganisms to humans, they have to adapt to changing environmental conditions to maintain their survival processes. Circadian rhythm is one of the most important mechanism that associated with this adaptation processes. There are biological clocks in the body, which are related to the circadian rhythm and have a hierarchical organization. The master circadian clock is located in the suprachiasmatic nucleus (SCN) of hypothalamus. SCN maintain body rhythms in synchronous with the light-dark cycle in the external environment. There are also peripheral oscillators that work in coordination with SCN. Neurological, endocrinological, and immunological functions in the body are under the influence of circadian and seasonal rhythms. Melatonin and cortisol (corticosterone in animals) are among the most important hormones that show circadian rhythm in the body. The body adapts to daily and seasonal changes with biological rhythms regulated by biological clocks. It is well known that the immune system is affected by the external environment. Changes in endocrine system, hypothalaomo-pituitary adrenal (HPA) axis, and immune system are marked, especially depending on the seasonal changes. Therefore, the immune system has close relationship with the circadian rhythm. Understanding relationship between physiological regulation of the circadian rhythm, HPA axis and immune activity is important for to keep our body in healthy conditions and struggle with the diseases as well. In current review, the interaction and relationship of genes and proteins related to the circadian rhythm with HPA axis and immune system parameters are discussed with both physiological and pathological examples.

Chasing the Perplexing Purple Butterfly through Biopsychosocial Model-based Precision Medicine: the Enigma of Fibromyalgia Unraveled Biopsychosocial perspectives in fibromyalgia care

A purple butterfly symbolizes the heightened sensitivity to even a gentle touch in fibromyalgia (FM), which is a common syndrome with persistent widespread pain and tenderness. The biopsychosocial model is currently the main framework used to appreciate different factors contributing to chronic pain in FM. Widespread pain in fibromyalgia is effected by multiple biopsychosocial factors (cognitive ability, depression, somatization, psychological trauma, anxiety, and social deprivation/isolation), which interact and contribute to chronic persistent pain. Interaction of influences such as gender, neuroendocrine milieu, and the hypothalamo–pituitary–adrenal axis also affect FM susceptibility and its clinical expression. Multiple neuroanatomic and neurochemical systems with many autonomic, cognitive &amp; affective processes manifest as multisymptom illness in FM. While the etiology of FM is elusive, the associated symptoms indicate the role of autonomic dysfunction in its pathophysiology. Fatigue and widespread pain characterizing FM may be consequent to peripheral tissue ischemia caused by sympathetically mediated vasoconstriction. In light of some common denominators among FM patients, which include genetic variation, sympathetic hyper-activation, maladaptive thoughts, ineffective coping strategies, and nonrestorative sleep, an individualized care approach can help subgroup and phenotype these patients for specific diagnosis and management. A multidisciplinary approach involving person-centered approaches to biopsychosocial concepts in FM, incorporating relaxation therapy, physical activity, and psychotherapy targeting negative emotions that amplify pain, maladaptive coping strategies, and environmental stressors, can help manage FM's course, outcomes, and treatment.

GASTROINTESTINALTRACT: THE WORLD OF ‘SECOND BRAIN’

Mothers gift not just life but also a microbial profile to their babies, i.e., for vaginally delivered babies, these communities resemble the specific microbial communities found in the mother’s birth canal; for babies delivered by caesarean section, the communities resemble the skin communities of the mother. These gut microbiota, via a complex bidirectional communication system, interact with the Central Nervous System, the enteric nervous system, and the hypothalamo-pituitary-adrenal axis (HPA) (cognitive and emotional centers), referred to as the Gut-Brain axis. Though in contemporary societies microbes have a strong negative connotation and are viewed in a warlike context, not all are harmful but beneficial and indeed crucial for a normal healthy life. As many ongoing research studies link the pathogenesis of various diseases to altered gut microbiota, many studies on the other hand show dramatic recovery with faecal microbiota transplantation, confirming the earlier.

Prediabetes and mild hepatosteatosis are associated with blunted cortisol response to glucagon but not to growth hormone

BackgroundAlthough there is a close relationship between cortisol and growth hormone (GH) levels, glucose intolerance and hepatosteatosis, changes in GH and the hypothalamo-pituitary-adrenal (HPA) axis were not previously studied in prediabetes. The main purpose of the present study was to assess changes in GH and HPA axis and their relationship with hepatosteatosis in prediabetic patients. MethodsForty prediabetic patients, with body-mass index (BMI) 25–35kg/m2, and 23 healthy individuals, with normal glucose tolerance and similar age and BMI, were included. The 75g oral glucose tolerance test and glucagon stimulation test (GST) were used. ResultsNo significant differences were detected between prediabetic patients and healthy individuals in terms of insulin-like growth factor-1 (IGF-1), insulin-like growth factor-binding protein-3 (IGFBP-3), IGF-1/IGFBP3 ratio or adrenocorticotropic hormone (ACTH). GH responses to GST did not differ between groups. On the other hand, peak cortisol and area under the curve (AUC) (cortisol) response on GST were significantly lower in prediabetic patients. Both peak GH and AUC (GH) response on GST correlated negatively with waist circumference and body weight. The degree of hepatosteatosis correlated negatively with peak cortisol, GH, AUC (cortisol) and AUC (GH) response on GST. ConclusionCortisol response to GST is decreased in prediabetic patients, with relatively well conserved GH response. This suggests altered HPA axis responsiveness in prediabetes, as is known in diabetes. Thus, HPA axis changes in patients with diabetes probably start before the development of diabetes as such.

Abstract 92

Introduction: Coronavirus disease 2019 (COVID-19) mainly involves the lungs; it also affects the endocrine system including the hypothalamic-pituitary adrenal axis (HPA). Aims: To assess and compare the changes in the HPA axis in survivors of SARS CoV-2 infection 3 months after recovery. Methods: A cross-sectional, descriptive study was undertaken at JIPMER, including 69 patients ³18 years of age, after 3 months after the diagnosis of COVID-19. At baseline, a fasting sample was collected for basal cortisol, thyroid function, and biochemical investigations between 8.00-9.00 AM. A low dose Synacthen test (1 mg) was performed in all patient’s blood samples for serum cortisol collected after 30 and 60 minutes of intravenous administration. Results: The mean age (SD) was 49.74 ± 12.05 years, 24 (34.78%) were female and 45 (65.2%) were male patients. 20 (28.98%) patients had mild, 10 (14.4%) had moderate and 39 (56.52%) patients had severe COVID-19 infection. 62 (89.85%) patients had post covid symptoms. Out of the sixty-nine patients with COVID-19, nine patients (9/69, 13.04%) had peak serum cortisol &lt;18 mg/dL suggestive of secondary adrenal insufficiency. Peak serum cortisol did not differ according to disease severity [Mild, (13.03 ± 4.08 mg/dL) vs moderate, [(11.52 ± 2.40 mg/dL) vs severe, (13.70 ± 1.43 mg/dL), P = 0.67]. In addition, there was no difference in peak serum cortisol in patients with or without adrenal insufficiency [(12.99 ± 2.54 mg/dL) vs (22.44±5.52 mg/dL), P = 0.09 respectively. Conclusion: HPA axis is affected in 13.04% of patients 3 months after presentation with COVID-19. These findings have important implications for the clinical care and long-term follow-up of patients after COVID-19.

Interaction between the hypothalamo-pituitary-adrenal and thyroid axes during immobilization stress.

The location of corticotropin-releasing hormone receptor 2 (CRH-R2) on thyrotropes within the avian anterior pituitary (APit) and its activation by different stressors indicate a possible communication between hypothalamo-pituitary-adrenal (HPA) and thyroid (HPT) axes. Therefore, an experiment was designed to 1) compare the timing of major components of the HPT axis to those of the HPA axis; 2) address whether stressors activating the HPA axis may simultaneously upregulate components of the HPT axis. Blood, brain, and APit were sampled from chicks prior to stress (control) and 15, 30, 60, 90, and 120min following immobilization (IM) stress. The nucleus of the hippocampal commissure (NHpC) and paraventricular nucleus (PVN) were cryo-dissected from brains for RT-qPCR. Gene expression of thyrotropin-releasing hormone (TRH) and its receptors (TRH-R1 and TRH-R3), urocortin3 (UCN3), deiodinase 2 (D2), and the second type of corticotropin-releasing hormone (CRH2) within the NHpC and PVN was measured. Additionally, gene expression of TRH receptors, thyroid stimulating hormone subunit beta (TSHβ), and D2 was determined in the APit and corticosterone assayed in blood. In brains, a significant upregulation in examined genes occurred at different times of IM. Specifically, UCN3 and CRH2 which have a high affinity to CRH-R2 showed a rapid increase in their mRNA levels that were accompanied by an early upregulation of TRHR1 in the NHpC. In the APit, a significant increase in gene expression of TSHβ and TRH receptors was observed. Therefore, results supported concurrent activation of major brain and APit genes associated with the HPA and HPT axes following IM. The initial neural gene expression originating within the NHpC resulted in the increase of TSHβ mRNA in the APit. Specifically, the rapid upregulation of UCN3 in the NHpC appeared responsible for the early activation of TSHβ in the APit. While sustaining TSHβ activation appeared to be due to both CRH2 and TRH. Therefore, data indicate that CRH-producing neurons and corticotropes as well as CRH- and TRH-producing neurons and thyrotropes are activated to produce the necessary energy required to maintain homeostasis in birds undergoing stress. Overall, data support the inclusion of the NHpC in the classical avian HPA axis and for the first time show the concurrent activation of the HPA axis and components of the HPT axis following a psychogenic stressor.

Aerobic Exercise-induced Anabolic Responses After Inhibition/stimulation Of Hpa Axis In Healthy Adults

Exercise is a stress stimulus leading to endocrine changes in the human body. There are interactions between the Hypothalamo-Pituitary-Adrenal (HPA) axis components in response to exercise, depending on the characteristics of exercise (type, duration, intensity, and frequency). Anabolic responses after aerobic exercise are less predictable yet important to explore. PURPOSE: This study examined the anabolic factor insulin-like growth factor-1 (IGF-1) responses to a selected aerobic exercise protocol performed under inhibition or stimulation of the HPA axis in healthy volunteers. METHODS: Twelve healthy volunteers (8 males and 4 females, age: 30.6 ± 4.4 yrs, body mass: 77.3 ± 12.3 kg, height: 1.77 ± 0.07 m) performed a single bout of 30 min aerobic exercise at 70%VO2 max on a treadmill, on three different conditions [control (C), HPA axis inhibition (HPA-I, induced by glucocorticoid administration), HPA axis stimulation (HPA-S, induced by ACTH administration)], following standard diet. Blood samples were collected before (PRE) and at the end of the exercise bout (POST) and serum IGF-1 was measured with ELISA. Two-way ANOVA was used for statistics and data is presented as mean ± SE. RESULTS: In C condition, IGF-1 did not change post-exercise (189.4 ± 24.3; 191.6 ± 17,9 ng/mL; at PRE and POST, respectively). Under HPA-I condition, decreased levels of IGF-1 were observed at the end of exercise (212.6 ± 18.7; 155.2 ± 20.5; ng/mL; at PRE and POST, respectively), however this decrease failed to reach statistical significance (p > 0.05). Inversely, under HPA-S condition IGF-1 exhibited a trend to increase 30 min after exercise (p > 0.05) (141.8 ± 13.9; 156.1 ± 18.1 ng/mL; at PRE, and POST, respectively). Under HPA-S condition, IGF-1 levels were significantly lower compared to HPA-I condition at PRE (141.8 ± 13.9 vs 212.6 ± 18.7; p < 0.05). However, there were no significant differences in serum IGF-1 concentrations between the three conditions as a result of exercise, or between males and females. CONCLUSION: IGF-1 did not seem to change immediately after moderate aerobic exercise regardless of the inhibition or stimulation of the HPA axis. However, the modification of HPA axis found to affect IGF-1 levels at rest. Further studies are needed to characterize the IGF-1 responses during the recovery period after aerobic exercise.