Hypothalamo-pituitary-adrenal Research Articles

A Prefrontal→Periaqueductal Gray Pathway Differentially Engages Autonomic, Hormonal, and Behavioral Features of the Stress-Coping Response.

The activation of autonomic and hypothalamo-pituitary-adrenal (HPA) systems occurs interdependently with behavioral adjustments under varying environmental demands. Nevertheless, laboratory rodent studies examining the neural bases of stress responses have generally attributed increments in these systems to be monolithic, regardless of whether an active or passive coping strategy is employed. Using the shock probe defensive burying test (SPDB) to measure stress-coping features naturalistically in male and female rats, we identify a neural pathway whereby activity changes may promote distinctive response patterns of hemodynamic and HPA indices typifying active and passive coping phenotypes. Optogenetic excitation of the rostral medial prefrontal cortex (mPFC) input to the ventrolateral periaqueductal gray (vlPAG) decreased passive behavior (immobility), attenuated the glucocorticoid hormone response, but did not prevent arterial pressure and heart rate increases associated with rats' active behavioral (defensive burying) engagement during the SPDB. In contrast, inhibition of the same pathway increased behavioral immobility and attenuated hemodynamic output but did not affect glucocorticoid increases. Further analyses confirmed that hemodynamic increments occurred preferentially during active behaviors and decrements during immobility epochs, whereas pathway manipulations, regardless of the directionality of effect, weakened these correlational relationships. Finally, neuroanatomical evidence indicated that the influence of the rostral mPFC→vlPAG pathway on coping response patterns is mediated predominantly through GABAergic neurons within vlPAG. These data highlight the importance of this prefrontal→midbrain connection in organizing stress-coping responses and in coordinating bodily systems with behavioral output for adaptation to aversive experiences.

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.

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.

Stress Hormones Adreno Cortico Tropin, Cortisol, Catecholamines and Pregnancy Exercises for Childbirth

During pregnancy there are safe changes both physically and psychologically. Mothers who experience anxiety and stress, the signal travels through the Hypothalamo-Pituitary-Adrenal (HPA) which can cause the release of stress hormones including Adreno Cortico Tropin Hormone (ACTH), cortisol and catecholamines. The release of stress hormones in pregnant women results in systemic vasoconstriction, including placental vasa utero constriction which causes impaired blood flow in the uterus, so that oxygen transport into the myometrium is disrupted and results in weak uterine muscle contractions. This study aims to determine the effectiveness of pregnant gymnastics has a relationship with anxiety levels as a prenatal service in reducing anxiety facing first labour. The type of research used in this study is the Quasi Experiment method. The type of research used in this study is experimental research, which is a research procedure carried out by providing treatment / intervention on research subjects, with the aim of assessing the effect of a treatment on the independent variable on the dependent variable. The results of the study indicate that pregnant gymnastics as a prenatal service is effective in reducing anxiety facing the first childbirth, this can be seen from the results before and after the treatment and prenatal service of pregnant gymnastics.

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.

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.

A STUDY ON PROGNOSTIC VALUE OF SERUM CORTISOL IN STROKE AND ITS CORRELATION WITH NIHSS SCORE

Background: There are numerous clinical factors that have been identied as potential outcome predictors in patients with acute stroke, including symptom, severity, and advanced age. After an acute stroke, the hypothalamo-pituitary-adrenal (HPA) axis is activated as a result of the stress response. Abiomarker for predicting the outcome of an acute stroke is desperately needed. Aim and Objective:To assess the relationship of single serum cortisol level to the typeand severity of strokeand its correlation with NIHSS score. Methods: 100 new cases of stroke, within 72 hours of the onset, admitted in Alluri Sitarama Raju Academy of Medical Sciences from January 2021 to June 2022 were included in the study. CT Brain was taken to differentiate between ischemic and Haemorrhagic stroke. NIHSS (National Institute of Health Stroke Scale) score was assessed for severity. Serum cortisol levels were measured at admission. Correlation between serum cortisol levels and stroke scales were assessed. Results: Of the 100 cases,50 patients had ischemic(Group A), and 50 patients had hemorrhagic stroke(Group B). The Mean NIHSS score was signicantly higher in group B compared to group A(P&lt;0.001).There was a statistically signicant correlation with raised serum cortisol levels and the severity of stroke irrespective of type of stroke P&lt;0.001). Conclusion: In conclusion, serum cortisol is a prognostic indicator of severity of stroke. Serum cortisol level was found to have a signicant positive correlation with worse outcome of stroke

The Link Between Empty Sella Syndrome, Fibromyalgia, and Chronic Fatigue Syndrome: The Role of Increased Cerebrospinal Fluid Pressure.

The etiopathogenesis of fibromyalgia (FM) and chronic fatigue syndrome (CFS) is not yet elucidated. Hypothalamo-pituitary-adrenal (HPA) axis dysfunction is reflected in the hormonal disturbances found in FM and CFS. Some study groups have introduced a novel hypothesis that moderate or intermittent intracranial hypertension may be involved in the etiopathogenesis of FM and CFS. In these conditions, hormonal disturbances may be caused by the mechanical effect of increased cerebrospinal fluid pressure, which hampers blood flow in the pituitary gland. Severe intracranial pressure may compress the pituitary gland, resulting in primary empty sella (ES), potentially leading to pituitary hormone deficiencies. The aim of this narrative review was to explore whether similar hormonal changes and symptoms exist between primary ES and FM or CFS and to link them to cerebrospinal fluid pressure dysregulation. A thorough search of the PubMed and Web of Science databases and the reference lists of the included studies revealed that several clinical characteristics were more prevalent in primary ES, FM or CFS patients than in controls, including increased cerebrospinal fluid pressure, obesity, female sex, headaches and migraine, fatigue, visual disturbances (visual acuity and eye motility abnormalities), vestibulocochlear disturbances (vertigo and neurosensorial hearing loss), and bodily pain (radicular pain and small-fiber neuropathy). Furthermore, challenge tests of the pituitary gland showed similar abnormalities in all three conditions: blunted adrenocorticotropic hormone, cortisol, growth hormone, luteinizing hormone, and thyroid stimulating hormone responses and an increased prolactin response. The findings of this narrative review provide further support for the hypothesis that moderately or intermittently increased cerebrospinal fluid pressure is involved in the pathogenesis of FM and CFS and should stimulate further research into the etiopathogenesis of these conditions.

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.

Changes in DNA Methylation of Clock Genes in Obese Adolescents after a Short-Term Body Weight Reduction Program: A Possible Metabolic and Endocrine Chrono-Resynchronization

Circadian rhythms are generated by a series of genes, collectively named clock genes, which act as a self-sustained internal 24 h timing system in the body. Many physiological processes, including metabolism and the endocrine system, are regulated by clock genes in coordination with environmental cues. Loss of the circadian rhythms has been reported to contribute to widespread obesity, particularly in the pediatric population, which is increasingly exposed to chronodisruptors in industrialized society. The aim of the present study was to evaluate the DNA methylation status of seven clock genes, namely clock, arntl, per1-3 and cry1-2, in a cohort of chronobiologically characterized obese adolescents (n: 45: F/M: 28/17; age ± SD: 15.8 ± 1.4 yrs; BMI SDS: 2.94 [2.76; 3.12]) hospitalized for a 3-week multidisciplinary body weight reduction program (BWRP), as well as a series of cardiometabolic outcomes and markers of hypothalamo-pituitary-adrenal (HPA) function. At the end of the intervention, an improvement in body composition was observed (decreases in BMI SDS and fat mass), as well as glucometabolic homeostasis (decreases in glucose, insulin, HOMA-IR and Hb1Ac), lipid profiling (decreases in total cholesterol, LDL-C, triglycerides and NEFA) and cardiovascular function (decreases in systolic and diastolic blood pressures and heart rate). Moreover, the BWRP reduced systemic inflammatory status (i.e., decrease in C-reactive protein) and HPA activity (i.e., decreases in plasma ACTH/cortisol and 24 h urinary-free cortisol excretion). Post-BWRP changes in the methylation levels of clock, cry2 and per2 genes occurred in the entire population, together with hypermethylation of clock and per3 genes in males and in subjects with metabolic syndrome. In contrast to the pre-BWRP data, at the end of the intervention, cardiometabolic parameters, such as fat mass, systolic and diastolic blood pressures, triglycerides and HDL-C, were associated with the methylation status of some clock genes. Finally, BWRP induced changes in clock genes that were associated with markers of HPA function. In conclusion, when administered to a chronodisrupted pediatric obese population, a short-term BWRP is capable of producing beneficial cardiometabolic effects, as well as an epigenetic remodeling of specific clock genes, suggesting the occurrence of a post-BWRP metabolic and endocrine chronoresynchronization, which might represent a "biomolecular" predictor of successful antiobesity intervention.

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.

Exploring the Therapeutic Potential of Targeting Purinergic and Orexinergic Receptors in Alcoholic Neuropathy.

Alcoholic neuropathy emerges following the persistent alcohol imbibing, and triggers nerve damage through de-escalating the receptors situated in the central nervous system (CNS), which consecutively evolves into debilitating neuropathic state and further precipitates hyperalgesia, allodynia, dysesthesia, ataxia, numbness, immobility, and decline in certain body functions. Existing pharmacotherapy, such as anticonvulsants (gabapentin and topiramate), and antidepressant drugs (duloxetine, and venlafaxine) render short-lasting benefits; however, their continual use is not favoured nowadays because of their detrimental outcomes and habit-forming behaviour. Consequently, the research is being shifted towards exploring novel propitious targets which entirely assist in the cessation of the disease. This review discloses the multitudinous pathways implicated in the pathogenesis of alcoholic neuropathy, with special emphasis on purinergic and orexinergic receptors. Moreover, the review focuses on targeting purinergic (P2X3, P2X2/3, P2X4, P2X7, and P2Y12), and orexinergic (OX1 and OX2) receptors associated with the evolution of alcoholic neuropathy, and to incentivize further investigation to attain novel propitious strategy in alcoholic neuropathy treatment. The mechanisms implicated in the progression of alcoholic neuropathy comprises malnourishment (B vitamins scarcity), direct pernicious outcomes of alcohol, increased oxidative-nitrosative stress, protein kinase C epsilon (PKCε), and extracellular signal-regulated kinase (ERK)/mitogen activated protein kinase (MAPK) functioning, abnormalities in the axonal transport and cytoskeleton system, activation of nuclear factor-kappa B (NF-κB) and caspase pathway, stimulation of the sympathoadrenal and hypothalamo-pituitary-adrenal (HPA) axis, and microglial cells of spinal column. The purinergic receptor antagonists, orexins/orexinergic receptor antagonists eliminate/modulate hyperalgesia, allodynia, inflammatory pain, liberation of inflammatory mediators, NF-κB signalling pathway, ROS formation, nerve cell deterioration, and craving for alcohol consumption, thereby ceasing the evolution of alcoholic neuropathy. The authors focus to highlight the importance of this alternative strategy as a novel target in alcoholic neuropathy, and to incentivize researchers to scrutinize the possible benefits of purinergic and orexins/orexinergic receptors in the therapy of alcoholic neuropathy.

Investigation of pituitary functions after acute coronavirus disease 2019.

Although coronavirus disease 2019 (COVID-19) mainly involves the lungs, it also affects many systems. The hypothalamic/pituitary axis is vulnerable to hypoxia, hypercoagulation, endothelial dysfunction and autoimmune changes induced by COVID-19 infection. Given that there is no extensive investigation on this issue, we investigated the pituitary functions three to seven months after acute COVID-19 infection. Forty-three patients after diagnosis of COVID-19 infection and 11 healthy volunteers were included in the study. In addition to the basal pituitary hormone levels, growth hormone (GH) and hypothalamo-pituitary adrenal (HPA) axes were evaluated by glucagon stimulation test (GST) and low-dose adrenocorticotropic hormone (ACTH) stimulation test, respectively. The peak cortisol responses to low-dose ACTH test were insufficient in seven (16.2%) patients. Twenty (46.5%) and four (9.3%) patients had inadequate GH and cortisol responses to GST, respectively. Serum insulin-like growth factor-1 (IGF-1) values were also lower than age and sex-matched references in four (9.3%) patients. The peak GH responses to GST were lower in the patient group when compared to the control group. Other abnormalities were mild thyroid-stimulating hormone elevation in four (9.3%) patients, mild prolactin elevation in two (4.6%) patients and central hypogonadism in four (9.3%) patients. Mean total testosterone values were lower in male patients when compared to male controls; however, the difference was not significant. These findings suggest that COVID-19 infection may affect pituitary functions, particularly the HPA and GH axes. These insufficiencies should be kept in mind in post-COVID follow-up. Long-term data are needed to determine whether these deficiencies are permanent or not.

Stress system dysfunction revealed by integrating reactivity of stress pathways to psychological stress in lean and overweight/obese men.

Although the patterns of response within the sympathoadrenal medullary (SAM) system and hypothalamo-pituitary adrenal (HPA) axis are interesting and important in their own accord, the overall response to acute psychological stress involves reactivity of both pathways. We tested the hypothesis that consideration of the integrated response of these pathways may reveal dysregulation of the stress systems, which is not evident when considering either system alone. Age-matched lean and overweight/obese men were subjected to a Trier Social Stress Test and reactivity of the SAM system (salivary α-amylase, systolic blood pressure, diastolic blood pressure, and heart rate) and the HPA axis (salivary cortisol) were measured. Relative reactivity of SAM system and HPA axis was calculated as the ratio between the measures from each pathway. Although analysis of reactivity of individual stress pathways showed no evidence of dysfunction in overweight/obese compared with lean men, analysis of HPA/SAM reactivity revealed significantly lower cortisol over systolic blood pressure (CoSBP) and cortisol over diastolic blood pressure (CoDBP) reactivity in overweight/obese compared with lean men. Other measures of HPA/SAM reactivity and all measures of SAM/HPA reactivity were unaltered in overweight/obese compared with lean men. These findings suggest that the cortisol response per unit of blood pressure response is blunted in men with elevated adiposity. Furthermore, these findings support a notion of a coordinated overall approach to activation of the stress pathways with the degree of activation in one pathway being related to the degree of activation in the other.

COVID-19 and chronic fatigue syndrome: An endocrine perspective

Patients recovering from COVID-19 may have persistent debilitating symptoms requiring long term support through individually tailored cardiopulmonary and psychological rehabilitation programs. Clinicians need to be aware about the likely long-term complications and their diagnostic assessments to help identify any occult problems requiring additional help. Endocrinological evaluations should be considered as part of the armamentarium in the management of such individuals with diligent cognizance about the involvement of the hypothalamo-pituitary-adrenal (HPA) axis, adrenal and thyroid function. We here review the literature and potential pathophysiological mechanisms involved in and related to post COVID-19 symptoms with an emphasis on endocrine function.