Hypothalamo-pituitary-adrenal Research Articles

Effect of estrogen and stress on estrogen receptor 1 in the HPG axis of immature male Gallus gallus domesticus: Involvement of anti-oxidant system

Estrogen plays a key role in the regulation of reproductive behavior and control of the neuroendocrine system in both males and females. However, excessive quantity of exogenous estrogen produces a deleterious effect on the male reproductive system. To elucidate the mechanism by which estrogen modulates its receptor alpha (ESR1) in immature chicken during stress the study has been undertaken. The experiment investigated the physiological changes in the abundance of ESR1 in brain, pituitary and testes of immature male chickens after stress like water restriction. Twenty four immature male chickens were randomly assigned into four groups. The control group was provided with food and water ad libitum, second was water restricted 9 h each day for seven days (WR), third was treated with estradiol benzoate (EB) and fourth group was treated with EB followed by water restriction during last seven days of treatment (EB + WR). EB was administered at a dose of 0.5 mg/100 g/day for 12 days. EB administration as well as WR increases both the H2O2 and Malondialdehyde levels indicating oxidative stress in brain as well as in testis. Plasma corticosterone significantly increased in all groups while estradiol significantly decreased after water restriction. ESR1 protein was detected by immuno-fluorescence predominantly in the pre-optic area of the hypothalamus, pituitary and testes after EB administration. EB administration increases ESR1 proteins abundantly in the Sertoli cells, Leydig cells, spermatogonia and spermatids while WR decreases it. The decline in ESR1 proteins after EB administration during stress appears to be mediated by interaction of estrogen with hypothalamo-pituitary-adrenal (HPA) axis. Therefore, the findings substantiate the fact that WR and EB treatment increase the stress and alter the anti-oxidant enzymes via its receptor ESR1 in the brain, pituitary and testis of immature chicks. Moreover, these findings highlight the effect of estradiol in male chicks causing stress which is disrupting the normal physiological feedback mechanism in hormone release and the expression of receptor ESR1 along the hypothalamo-pituitary-gonadal (HPG) axis.

Expression of hypothalamic feeding-related peptide genes and neuroendocrine responses in an experimental allergic encephalomyelitis rat model

Experimental allergic encephalomyelitis (EAE) is considered to be a useful animal model of human multiple sclerosis (MS). However, among the various symptoms of MS, the mechanisms contributing to inflammatory anorexia remain unclear. In the present study, we used an EAE rat model to examine changes in expression levels of hypothalamic feeding-related peptide genes and neuroendocrine responses such as the hypothalamo-neurohypophysial system and the hypothalamo-pituitary-adrenal (HPA) axis. The weight gain and cumulative food intake in EAE rats in the early days after immunization was significantly lower than that of the control group. The expression of orexigenic peptide genes Npy and Agrp were significantly increased, whereas the levels of anorectic peptide genes (Pomc and Cart) were significantly decreased in the hypothalamus of EAE rats. There was also a significant increase in the mRNA and plasma oxytocin (OXT) but not of arginine vasopressin (AVP) in the supraoptic and paraventricular nuclei (PVN) of EAE rats at days 12 and 18 after immunization. The expression of corticotropin-releasing hormone (Crh) and Avp was downregulated and upregulated, respectively, in the parvocellular division of the PVN at day 12 after immunization. The expression level of Pomc in the anterior pituitary significantly increased, accompanied by increased plasma corticosterone levels, at days 6, 12, and 18 after immunization. These results suggest that inflammatory anorexia in rat EAE may be caused by activation of the OXT-ergic pathway and HPA axis via changes in the expression of hypothalamic feeding-related peptides, including Avp but not Crh.

Acute Mono-Arthritis Activates the Neurohypophysial System and Hypothalamo-Pituitary Adrenal Axis in Rats.

Various types of acute/chronic nociceptive stimuli cause neuroendocrine responses such as activation of the hypothalamo-neurohypophysial [oxytocin (OXT) and arginine vasopressin (AVP)] system and hypothalamo-pituitary adrenal (HPA) axis. Chronic multiple-arthritis activates the OXT/AVP system, but the effects of acute mono-arthritis on the OXT/AVP system in the same animals has not been simultaneously evaluated. Further, AVP, not corticotropin-releasing hormone (CRH), predominantly activates the HPA axis in chronic multiple-arthritis, but the participation of AVP in HPA axis activation in acute mono-arthritis remains unknown. Therefore, we aimed to simultaneously evaluate the effects of acute mono-arthritis on the activity of the OXT/AVP system and the HPA axis. In the present study, we used an acute mono-arthritic model induced by intra-articular injection of carrageenan in a single knee joint of adult male Wistar rats. Acute mono-arthritis was confirmed by a significant increase in knee diameter in the carrageenan-injected knee and a significant decrease in the mechanical nociceptive threshold in the ipsilateral hind paw. Immunohistochemical analysis revealed that the number of Fos-immunoreactive (ir) cells in the ipsilateral lamina I–II of the dorsal horn was significantly increased, and the percentage of OXT-ir and AVP-ir neurons expressing Fos-ir in both sides of the supraoptic (SON) and paraventricular nuclei (PVN) was increased in acute mono-arthritic rats. in situ hybridization histochemistry revealed that levels of OXT mRNA and AVP hnRNA in the SON and PVN, CRH mRNA in the PVN, and proopiomelanocortin mRNA in the anterior pituitary were also significantly increased in acute mono-arthritic rats. Further, plasma OXT, AVP, and corticosterone levels were significantly increased in acute mono-arthritic rats. These results suggest that acute mono-arthritis activates ipsilateral nociceptive afferent pathways at the spinal level and causes simultaneous and integrative activation of the OXT/AVP system. In addition, the HPA axis is activated by both AVP and CRH in acute mono-arthritis with a distinct pattern compared to that in chronic multiple-arthritis.

Remote CB1 receptor antagonist administration reveals multiple sites of tonic and phasic endocannabinoid neuroendocrine regulation

Endogenous cannabinoids (endocannabinoids, eCB) are expressed throughout the body and contribute to regulation of the hypothalamo-pituitary-adrenal (HPA) axis and general stress reactivity. This study assessed the contributions of CB1 receptors (CB1R) in the modulation of basal and stress-induced neural and HPA axis activities. Catheterized adult male rats were placed in chambers to acclimate overnight, with their catheters connected and exteriorized from the chambers for relatively stress-free remote injections. The next morning, the CB1R antagonist AM251 (1 or 2 mg/kg) or vehicle was administered, and 30 min later, rats were exposed to loud noise stress (30 min) or no noise (basal condition). Blood, brains, pituitary and adrenal glands were collected immediately after the procedures for analysis of c-fos and CB1R mRNAs, corticosterone (CORT) and adrenocorticotropin hormone (ACTH) plasma levels. Basally, CB1R antagonism induced c-fos mRNA in the basolateral amygdala (BLA) and auditory cortex (AUD) and elevated plasma CORT, indicating disruption of eCB-mediated constitutive inhibition of activity. CB1R blockade also potentiated stress-induced hormone levels and c-fos mRNA in several regions such as the bed nucleus of the stria terminalis (BST), lateral septum (LS), and basolateral amygdala (BLA) and the paraventricular nucleus of the hypothalamus (PVN). CB1R mRNA was detected in all central tissues investigated, and the adrenal cortex, but at very low levels in the anterior pituitary gland. Interestingly, CB1R mRNA was rapidly and bidirectionally regulated in response to stress and/or antagonist treatment in some regions. eCBs therefore modulate the HPA axis by regulating both constitutive and activity-dependent inhibition at multiple levels.

Sex, stress and steroids.

The hypothalamo-pituitary-adrenal (HPA) axis plays a key role in the neuroendocrine response to stress and in maintaining physiological homoeostasis. However, stress that is chronic in nature can lead to HPA axis dysfunction and increase the risk for developing affective disorders, particularly if the stress is experienced during vulnerable periods in life. Sex differences in how the HPA axis responds to stress are well established, with females typically displaying heightened responses. The underlying cause of these sex differences is important to understand, as many neuropsychiatric disorders disproportionately affect females. Much research has provided evidence for gonadal sex steroids in underpinning sex differences in HPA axis responsivity; however, we suggest that neuroactive metabolites of these steroids also play a key role in the brain in mediating sex differences in HPA axis responses to stress. The relationship between neuroactive steroids and stress is complex. Acute stress rapidly increases neuroactive steroid production, which can in turn modulate activity of the HPA axis. However, under chronic stress conditions, stress can impact the brain's capacity to generate steroids, and this in turn has corollary effects on HPA axis function that may increase the propensity for psychopathology, given both HPA axis dysfunction and deficits in neuroactive steroids are implicated in affective disorders. Hence, here we review the evidence from animal and human studies for sex differences in the interactions between neuroactive steroids and the stress axis at various stages of life, under physiological and pathophysiological stress conditions and consider the implications for health and disease.

Effect of long term inhaled corticosteroid therapy on adrenal suppression, growth and bone health in children with asthma

BackgroundInhaled corticosteroids (ICS) are the most effective treatment for children with persistent asthma. However adverse effects of ICS on Hypothalamo Pituitary Adrenal (HPA) axis, growth and bone metabolism are a concern. Hence the primary objective of this study was to describe the effects of long term inhaled corticosteroid therapy (ICS) on adrenal function, growth and bone health in children with asthma in comparison to an age and sex matched group of children with asthma who were not on long term ICS. Describing the association between the dose of ICS and duration of therapy on the above parameters were secondary objectives.MethodSeventy children with asthma on ICS and 70 controls were studied. Diagnosis of asthma in selected patients was reviewed according to the criteria laid down by GINA 2018 guidelines. The estimated adult heights were interpreted relative to their Mid Parental Height (MPH) range. Serum calcium, alkaline phosphatase and vitamin D levels were analyzed in both groups and cortisol value at 30 min following a low dose short synacthen test was obtained from the study group. The average daily dose of ICS (Beclamethasone) was categorized as low, medium and high (100–200, 200–400, > 400 μg /day) respectively according to published literature.ResultsHeights of all children were within the MPH range. There was no statistically significant difference in the bone profiles and vitamin D levels between the two groups (Ca: p = 0.554, vitamin D: p = 0.187) but vitamin D levels were insufficient (< 50 nmol/l) in 34% of cases and 41% of controls. Suppressed cortisol levels were seen in 24%. Doses of ICS were low, medium and high in 56, 32 and 12% of children respectively. The association between adrenal suppression with longer duration of therapy (p < 0.01) and with increasing dose of ICS (p < 0.001) were statistically significant.ConclusionICS had no impact on the growth and bone profiles but its dose and duration were significantly associated with adrenal suppression.

The effects of prenatal dexamethasone exposure and fructose challenge on pituitary-adrenocortical activity and anxiety-like behavior in female offspring

Prenatal glucocorticoid overexposure could largely influence pituitary-adrenal activity and anxiety-like behavior in offspring. Our aim was to study the possible potentiating effect of moderate dose of fructose – common ingredient of today’s diet – on prenatal glucocorticoid treatment-induced hypothalamo-pituitary-adrenal (HPA) axis changes. Pregnant female rats were treated with multiple dexamethasone (Dx) doses (3 x 0.5 mg/kg/b.m. Dx; 16th-18th gestational day). Half of female offspring from control and Dx treated dams were supplemented with 10% fructose solution, from weaning till adulthood. Immunohistochemistry, unbiased stereological evaluation and hormonal analysis are used to provide the morpho-functional state of pituitary and adrenal gland. Anxiety-like behavior was assessed using the light/dark box test and the elevated plus maze test. Prenatally Dx exposed females, with or without fructose consumption, had markedly reduced adrenocortical volume (p < 0.05) comparing to controls. Increased basal plasma ACTH level in these females (p < 0.05) maintained corticosterone concentration at control level produced by smaller adrenal glands. In parallel, anxiety-like behavior was shown by both tests used. In conclusion, prenatal Dx exposure cause negative psychophysiological outcome reflected in increased HPA axis activity and anxiety behavior in female offspring, while moderately increased fructose consumption failed to evoke any alteration or to potentiate effects of prenatal Dx exposure.

Fat tissue and adrenal function: mechanisms of mutual influence

The mechanisms of mutual influence of fat tissue and the hypothalamo-pituitary-adrenal (HPA) axis include the regulation of the metabolism of adipocytes by adrenal cortex hormones, on the one part, and the effect of adipocytes and adipocytokines on secretion, metabolism and action of steroid hormones in target cells - on the other part. Glucocorticoids contribute to the differentiation of preadipocytes into mature adipocytes; brown fat tissue transforms into white under the effect of GC. Mineralocorticoids are also involved in the process of adipocyte differentiation, regulate adipokine expression, and induce oxidative stress in fat tissue. There is evidence that suggest that circulating dehydroepiandrosterone sulfate (DHEAS), obesity, insulin sensitivity are associated with the presence of cardiovascular diseases. Orexigenic neuropeptides and inflammatory mediators, which trigger the synthesis of corticotropin-releasing hormone (CRH) in the hypothalamic paraventricular nuclei, are considered as possible mechanisms of (HPA) axis activation in obesity. Expression of 1ip-hydroxysteroid dehydrogenase type 1 (11P-HSD1) in fat tissue and the formation of cortisol from cortisone at the tissue level can be considered as one of the factors involved in development of insulin resistance. The autocrine and paracrine regulatory effect of these hormones on adipocyte function is the consequence of aldosterone production and aromatization of androgens by fat tissue.

92 Intra-nasal oxytocin treatment does not attenuate the hypothalamo-pituitary-adrenal axis in beef heifers subjected to isolation stress or restraint and isolation stress

Abstract Changes in the physiological, psychological, and behavioral manifestations of stress are observed in association with increases in circulating oxytocin. Providing oxytocin intra-nasally attenuates stressor-induced hypothalamo-pituitary-adrenal (HPA) axis activation in humans and rodents. The present study was conducted to investigate effects of intra-nasal oxytocin supplementation on stressor-induced activation of the HPA axis in beef cattle. We hypothesized that oxytocin would attenuate activation of the HPA axis, ultimately decreasing plasma cortisol. Bos taurus heifers (n = 28) were blocked by bodyweight and randomly allocated to one of four treatment groups, in a 2 × 2 factorial arrangement: 1) Saline, isolated, standing, and unrestrained (S-IS, 0.015mL/kg BW 0.9% isotonic saline, n = 7); 2) Saline, isolated, and restrained (S-RIS; 0.015 ml/kg BW 0.9% isotonic saline; n = 7); 3) Oxytocin, IS (OXT-IS, 0.3 IU/kg BW oxytocin; n = 7); and 4) Oxytocin and isolated and restrained (OXT-RIS, 0.3 IU/kg BW oxytocin; n = 7). Oxytocin and saline were administered intra-nasally. Appropriate stressors were applied 30 minutes following intra-nasal treatment. Blood samples were collected directly following imposing the stressor, and every 10 minutes thereafter, for 2 h. Cortisol concentrations increased over time in animals exposed to restraint and isolation stress (P &lt; 0.01) and decreased over time in animals exposed to isolation stress (P &lt; 0.01). In the present study, oxytocin did not affect measured indicators of HPA axis activation. Greater plasma oxytocin concentrations were observed in restrained animals administered saline, compared with their standing counterparts administered oxytocin (P &lt; 0.01), indicating some endogenous release of oxytocin in response to restraint stress. Overall, restraint stress increased cortisol and oxytocin in Bos taurus heifers compared with heifers subjected only to isolation. Finding a more intermediate stress model may allow for more precise detection of effects of oxytocin on the stress response.

Intranasal oxytocin treatment does not attenuate the hypothalamo-pituitary-adrenal axis in beef heifers subjected to isolation stress or restraint and isolation stress

Changes in the physiological, psychological, and behavioral manifestations of stress have been observed in association with increases in circulating oxytocin (OXT). Providing OXT intranasally has been shown to attenuate stressor-induced hypothalamo-pituitary-adrenal (HPA) axis activation in humans and rodents; however, anxiolytic effects may be context and species specific. The present study aimed to investigate the effect of intranasal OXT supplementation on stressor-induced activation of the HPA axis in beef cattle. We hypothesized that OXT would attenuate activation of the HPA axis, ultimately decreasing plasma cortisol and adrenocorticotropic hormone (ACTH). Twenty-eight Bos taurus heifers were blocked by bodyweight and randomly allocated to one of four treatment groups, in a 2 × 2 factorial arrangement: (1) saline, isolated, standing, and unrestrained (S-isolation stress [IS], 0.015 mL/kg BW 0.9% isotonic saline, n = 7); (2) saline, isolated, and restrained (S-restraint and isolation stress [RIS]; 0.015 mL/kg BW 0.9% isotonic saline; n = 7); (3) OXT, IS (OXT-IS, 0.3 IU/kg BW oxytocin; n = 7); and (4) OXT and RIS (OXT-RIS, 0.3 IU/kg BW oxytocin; n = 7). Oxytocin and saline were administered intranasally. Intranasal treatments were given followed by a waiting time of 30 min when each of the stress treatments was applied for 2 h. Blood samples were collected via jugular catheters directly after stressor application and every 10 min thereafter, for 2 h. Cortisol concentrations increased over time in animals exposed to RIS (P < 0.01) and decreased over time in animals exposed to IS (P < 0.01). Concentrations of ACTH decreased over time for the IS-treated heifers but remained elevated for the RIS-treated heifers (P < 0.01). Under the conditions of the present study, OXT treatment did not affect measured indicators of HPA axis activation. A treatment × time interaction (P < 0.01) was detected for OXT, such that OXT heifers exhibited greater initial OXT concentrations followed by a decline; saline-treated heifers had consistently stable oxytocin concentrations. The RIS-treated heifers increased their glucose (P < 0.01) and lactate (P < 0.01) concentrations throughout the application of the stressors compared with the IS-treated heifers. Overall, restraint stress increased cortisol and oxytocin in B taurus heifers compared with heifers subjected only to isolation. Finding a more intermediate stress model may better allow for detection of the effects of oxytocin on the stress response.

Recovery of the Hypothalamo-Pituitary-Adrenal Axis After Transsphenoidal Adenomectomy for Non-ACTH-Secreting Macroadenomas.

Secondary adrenal insufficiency is a potential complication of transsphenoidal adenomectomy (TSA). Most centers test recovery of the hypothalamo-pituitary-adrenal (HPA) axis after TSA, but, to our knowledge, there are no data predicting likelihood of recovery or the frequency of later recovery of HPA function. To assess timing and predictors of HPA axis recovery after TSA. Single-center, retrospective analysis of consecutive pituitary surgeries performed between February 2015 and September 2018. Patients (N = 109) with short Synacthen test (SST) data before and at sequential time points after TSA. Recovery of HPA axis function at 6 weeks, and 3, 6, and 9 to12 months after TSA. Preoperative SST indicated adrenal insufficiency in 21.1% Among these patients, 34.8% recovered by 6 weeks after TSA. Among the 65.2% (n = 15) remaining, 13.3% and 20% recovered at 3 months and 9 to 12 months, respectively. Of the 29% of patients with adrenal insufficiency at the 6-week SST, 16%, 12%, and 6% subsequently recovered at 3, 6, and 9 to 12 months, respectively. Preoperative SST 30-minute cortisol, postoperative day 8 cortisol, and 6-week postoperative SST baseline cortisol levels above or below 430 nmol/L [15.5 μg/dL; AUC ROC, 0.86]; 160 nmol/L (5.8 μg/dL; AUC ROC, 0.75); and 180 nmol/L (6.5 μg/dL; AUC ROC, 0.88), were identified as cutoffs for predicting 6-week HPA recovery. No patients with all three cutoffs below the threshold recovered within 12 months after TSA, whereas 92% with all cutoffs above the threshold recovered HPA function within 6 weeks (OR, 12.200; 95% CI, 5.268 to 28.255). HPA axis recovery can occur as late as 9 to 12 months after TSA, demonstrating the need for periodic reassessment of patients who initially have SST-determined adrenal insufficiency after TSA. Pre- and postoperative SST values can guide which patients are likely to recover function and potentially avoid unnecessary lifelong glucocorticoid replacement.

Serotonergically dependent antidepressant-like activity on behavior and stress axis responsivity of acacetin

Acacetin, a natural flavonoid, possesses broad spectrum of pharmacological and biochemical activities, such as neuroprotection, antinociception and inhibition of monoamine oxidase. The current work aimed to investigate the antidepressant-like activity of acacetin in mice and explore the underlying mechanism(s). Chronic, but not acute, acacetin treatment (5, 15 or 45 mg/kg, p.o., once per day for three weeks) exerted in mice dose-dependently antidepressant-like activity, assessed by forced swim test (FST) and tail suspension test (TST). Although acacetin-treated mice showed normal circadian hypothalamo-pituitary-adrenal (HPA) axis activity, their endocrine responsivity to both acute restraint stress and intracerebroventricular injection of corticotropin-releasing factor (CRF) was buffered. The acacetin-triggered antidepressant-like activities are serotonergically dependent, since its impacts on behavior and stress responsivity were totally abolished by chemical depletion of brain serotonin by PCPA. Consistently, acacetin-treated mice showed escalated levels of brain monoamines especially serotonin and depressed activity of monoamine oxidase. Moreover, the acacetin-evoked anti-depression was preferentially counteracted by co-administration of 5-HT1A receptor antagonist WAY-100635, but potentiated by 5-HT1A receptor agonist 8-OH-DPAT and sub-effective dose of serotonergic antidepressant fluoxetine, suggesting a pivotal engagement of 5-HT1A related serotonergic system. In vitro, acacetin (1–100 nM) increased the Emax of 8-OH-DPAT. Collectively, these findings confirm that chronic acatetin administration to mice engenders antidepressant-like efficacy on both behavior and stress axis responsivity, with serotonergic system that preferentially couples with 5-HT1A receptors being critically involved.

Acupuncture improves hippocampal apoptosis state by reducing expression of ROS and Cytochrome C and Caspase-3 in Chronic Restraint Stress Rats

The depressant-like effects of albiflorin (AF) were studied on stressed chronic restraint stress (CRS) rats. Experimental rats were subjected to immobilization stress for a daily 6 h-restraining in a plastic restrainer for continuous 21 d and were treated with 30 or 15 mg·kg−1 of AF for 21 d. Control rats were maintained in completely non stressed conditions. Behavioral tests and biochemical analysis were applied to investigating a regulatory mechanism of anti-stress of AF. Treatment with AF significantly restored the depressant-like behaviors. Besides, AF increased the levels of 5-hydroxytryptophan (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), noradrenaline (NE) and dopamine (DA) in the hippocampus and increased the level of brain-derived neurotrophic factor (BDNF) in serum and protein expression in hippocampus. In addition, AF decreased the levels of hypothalamo-pituitary-adrenal (HPA) cascade, reduced the level of NO and cGMP in serum and inhibited the overexpression of 5-HT2AR mRNA and protein expression. Taken together, AF can modulate the NO-mediated network pathway in the hippocampus against stress-induced depressive-like behaviors. These physiological and behavioral changes allow rats to avoid potential deleterious effects of stress that may result from chronically elevated levels of glucocorticosteroids over days.

Hypoglycemia-activated Hypothalamic Microglia Impairs Glucose Counterregulatory Responses

Glucose is a major fuel for the central nervous system and hypoglycemia is a significant homeostatic stressor, which elicits counterregulatory reactions. Hypothalamic metabolic- and stress-related neurons initiate these actions, however recruitment of glia in control such adaptive circuit remain unknown. Groups of fed- and fasted-, vehicle-injected, and fasted + insulin-injected male mice were compared in this study. Bolus insulin administration to fasted mice resulted in hypoglycemia, which increased hypothalamo-pituitary-adrenal (HPA) axis- and sympathetic activity, increased transcription of neuropeptide Y (Npy) and agouti-related peptide (Agrp) in the hypothalamic arcuate nucleus and activated IBA1+ microglia in the hypothalamus. Activated microglia were found in close apposition to hypoglycemia-responsive NPY neurons. Inhibition of microglia by minocycline increased counterregulatory sympathetic response to hypoglycemia. Fractalkine-CX3CR1 signaling plays a role in control of microglia during hypoglycemia, because density and solidity of IBA1-ir profiles was attenuated in fasted, insulin-treated, CX3CR1 KO mice, which was parallel with exaggerated neuropeptide responses and higher blood glucose levels following insulin administration. Hypoglycemia increased Il-1b expression in the arcuate nucleus, while IL-1a/b knockout mice display improved glycemic control to insulin administration. In conclusion, activated microglia in the arcuate nucleus interferes with central counterregulatory responses to hypoglycemia. These results underscore involvement of microglia in hypothalamic regulation of glucose homeostasis.

SUN-452 Predictive Factors of Recurrence in Cushing's Disease after Successful Transsphenoidal Surgery

Introduction: Successful long-term management in Cushing’s disease (CD) is challenging. Transsphenoidal surgery (TS) is the treatment of choice. Recurrence rates vary from 15–66% within 5-10 years of initially successful surgery. Objective: To evaluate the predictive factors for recurrence in patients with CD submitted to TS. Methods: Retrospective study of 44 patients with CD submitted to TS between 2005 and 2016 in a single tertiary center. Patients were divided into two groups, based on the outcome after TS (remission vs recurrence/persistence of disease), for comparison. Immediate postoperative remission (IPR) was defined as cortisol < 2ug/dL and ACTH <5 pg/mL within 7 days of tumor resection. Recurrence is defined by CD relapse after an initial remission after TS. Different variables were analyzed: age at diagnosis, gender, preoperative basal and dynamic hormonal tests and pituitary MRI, immediate postoperative hormonal tests, histological findings, postoperative hypopituitarism, time to recurrence, and time to recovery of hypothalamo-pituitary-adrenal (HPA) axis. Statistical analysis was performed with SPSS software, version 20. Statistical significance: p < 0.05. Results: From a total of 44 patients, 42 were eligible for the analysis and 2 were excluded due to unknown outcome after TS. The mean age was 40.6 ± 15 years and 90.5% were female. Based on immediate postoperative biochemical evaluation, performed in 35 individuals, only 18 (51,4%) would be considered in remission. Later clinical and biochemical evolution enabled considering 39 patients (92.9%) in remission. At a median follow-up of 6 years (1-21), 23 patients (59%) were still in remission whereas the remaining 41% relapsed; median time to recurrence – 3 years (0.25-17). Recurrence was significantly more frequent in: patients who needed glucocorticoid replacement therapy during less than 6 months after TS (19% vs 77.8%, p=0.004) and patients without histological evidence of adenoma/hyperplasia (75% vs 31%, p=0.04). There were no statistically significant differences between groups concerning the remaining variables studied. Conclusions: Absence of IPR criteria does not allow for conclusion of disease persistence. On the other hand, IPR is not a guarantee of life long remission. In this study, 41% of the patients who achieved surgical remission after TS recurred during long term follow-up making surveillance essential. Rapid recovery of HPA axis and negative histology were predictive factors of recurrence.

Sex Hormone Influence on Nesfatin‐1 Signaling in the Pituitary

The stress response is intimately connected to appetite regulation; indeed, many peptides that modulate feeding behavior play a role in stress‐related behaviors. Nesfatin‐1 is a potent anorectic peptide that participates in the hypothalamo‐pituitary‐adrenal (HPA) axis. While nesfatin‐1 signaling in the hypothalamus is well‐studied, nesfatin‐1 signaling in the pituitary has yet to be investigated. Furthermore, the receptor through which nesfatin‐1 acts is currently unknown, and identification of that receptor would be a vital step toward establishing the physiological relevance of nesfatin‐1. Experiments were conducted in dispersed rat pituitaries to identify a candidate receptor and downstream signaling events elicited by treatment with nesfatin‐1. Our preliminary data indicate that the action and expression of nesfatin‐1 is influenced by female sex hormones; therefore, downstream signaling was investigated in both male and cycled female dispersed pituitaries. These studies suggest that nesfatin‐1 signals through an orphan GPCR to physiologically induce activation of the HPA axis in a sex‐dependent manner. Gaining a fuller understanding of how sex hormones influence nesfatin‐1 signaling in the pituitary will provide key insight into sex differences in stress‐related disorders.Support or Funding InformationNational Institute of HealthThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Endocrine responses after a single bout of moderate aerobic exercise in healthy adult humans.

Exercise is a stress stimulus for the human organism affecting the homeostatic mechanisms of the body, depending on the type, duration, intensity and frequency of exercise. The aim of this study was to determine the effects of a moderate aerobic exercise bout on the Hypothalamo-Pituitary-Adrenal (HPA) axis acute hormonal responses in healthy adult humans. Twelve healthy male and female volunteers (age: 30.6 ± 4.4 years), performed a single bout of a 30-minute aerobic exercise at 70% of VO2max on a treadmill, following standard diet. Blood samples were collected before (t0), at the end of the exercise bout (t30), and 30 min after the completion of exercise (t60). Serum adrenocorticotropic hormone (ACTH), cortisol (COR), aldosterone (ALDO) and renin (REN) were measured. One-way ANOVA was used for statistics. ACTH and COR decreased after exercise, reaching significance (p < 0.01) 30 min after the completion of the exercise bout. ALDO increased at the end of exercise and remained elevated 30 min after its completion. REN significantly increased at the end of exercise (p < 0.05) and remained elevated. The exercise regimen used in this study had beneficial effects on the stress axis, suggesting that specific exercise protocols can be characterised by mild physiological stress-inducing effects hence be prescribed for special diseased populations.

Expression profile of Galp, alarin and their receptors in rat adrenal gland.

Galanin-like peptide (Galp) and alarin (Ala) are 2 new members of the galanin peptide family. Galanin (Gal), the "parental" peptide of the entire family, is known to regulate numerous physiological processes, including energy and osmotic homeostasis, reproduction, food intake, and secretion of adrenocortical hormones. Galp and Ala are known to regulate food intake. In the rat, Galp mRNA has been found in the brain, exclusively in the hypothalamic arcuate nucleus (ARC) and median eminence, which are involved in the regulation of energy homeostasis. Alarin-like immunoreactivity is present in the locus coeruleus (LC) and the ARC of rats and mice. The aim of the study was to investigate the expression of Ala, Galp and their receptors in the organs of the hypothalamo-pituitary-adrenal (HPA) axis of the rat. The expression of the examined genes was measured in different models of adrenal growth of the rat in vivo (postnatal ontogenesis, compensatory adrenal growth, adrenocortical regeneration, adrenocorticotropic hormone (ACTH) administration). The expression was evaluated using the Affymetrix® microarray system or quantitative polymerase chain reaction (qPCR). The expression of Ala gene was observed in each organ of the HPA axis (the hypothalamus, hypophysis and adrenal gland). The elevated level of expression of this gene was observed in the pituitary of 2-day rats, while very low levels of Ala mRNA were observed in the adrenals. Galp mRNA expression was observed only in the hypothalamus and the hypophysis during postnatal ontogenesis. The expression of Gal receptors was demonstrated in the hypothalamus, the hypophysis and the adrenal gland. In different compartments of the adrenal glands of adult, intact male and female rats, the expression of Ala, Galp and galanin receptor 1 (Galr1) genes was negligible, but the expression of galanin receptor 2 (Galr2), galanin receptor 3 (Galr3) and neurotrophic receptor tyrosine kinase 2 (Ntrk2) genes was noticeable. The examined genes showed different expression levels within the studied HPA axis; some of them were neither expressed in the hypothalamus or the pituitary gland, nor in the adrenal gland.

The relationship between acute stress and EEG repetition suppression in infants

Over activation of the hypothalamo–pituitary–adrenal (HPA) axis in stress situations is known to influence learning and memory. In adults, an inverted-U shape relationship between acute stress, and learning and memory has been demonstrated. Whether this model fits learning performances in infants is unknown. In this study, we used EEG repetition suppression as physiological measure of learning and salivary cortisol in response to a stressor to investigate the relationship between acute stress and learning in infants. We hypothesized that EEG repetition suppression would be modulated by acute stress following an inverted-U shape relationship. Saliva samples were collected during an EEG experiment before, during and after EEG net installation in 37 healthy infants (18 males) aged between 6 and 26 months. The effect of variation in stress hormones on repetition suppression were modeled using a linear mixed model, with cortisol, age and sex as predictors. Results indicated that in healthy infants, elevations in stress hormones within the normal range are associated with a higher repetition suppression response and an increased response to the first presentation of the stimulus. The later increase could be related to vigilance. Considering that early childhood is a critical period of development, future studies should keep investigating the influence of stress on learning processes in infants.

Impulsivity and Salivary Cortisol Level in Patients With Substance Dependence

Objectives: The aim of this work was to study the association between different dimensions of impulsive behavior from one side and addiction-related problems and diurnal salivary cortisol levels from the other side. Methods: A cross sectional case/control study with 50 subjects consisting 2 equal groups. Subjects were recruited consecutively from Kasr Al-Ainy Psychiatry and Addiction Hospital, Cairo University and were matched for age, sex, and socioeconomic status. Both groups were subjected to Structured Clinical Interview for DSM-IV Axis I disorders (SCID-I), Arabic version; UPPS Impulsive Behavior Scale. Patients with substance dependence completed the Addiction Severity Index, Arabic version. Diurnal salivary cortisol level was measured in both groups to reflect baseline activity of the hypothalamo-pituitary-adrenal (HPA) axis. Results: Patients with substance dependence had statistically significant higher scores on urgency (P=0.000), lack of premeditation (P=0.006), and lack of perseverance (P=0.018) subscales. About 76% had no problem, (20%) had mild problems and (4%) had severe alcohol use problems. Difference between the 2 groups in terms of salivary cortisol levels was not statistically significant (P=0.806). Conclusions: Substance-dependent subjects scored significantly higher than control subjects on lack of premeditation, urgency, and lack of perseverance traits. There was no relation between diurnal salivary cortisol levels and impulsivity.