Hypothalamic-pituitary-adrenocortical Axis Activity Research Articles

Examining the implications of contextual stress and maternal sensitivity for infants’ cortisol responses to the still face paradigm

Infants’ hypothalamic-pituitary-adrenocortical (HPA) axis responses to acute stressors are theorized to be shaped by parents’ sensitive responsiveness to infants’ cues. The strength and direction of the association between maternal sensitivity and infants’ HPA responses may depend on the context in which maternal sensitivity is observed and on broader environmental sources of stress and support. In this preregistered study, we used data from 105 mothers and their 7-month-old infants to examine whether two empirically identified forms of contextual stress—poor maternal psychosocial wellbeing and family socioeconomic hardship—moderate the association between maternal sensitivity and infants’ cortisol responses to the Still-Face Paradigm (SFP). Results indicated that maternal sensitivity during the free play and family socioeconomic hardship interacted to predict infants’ cortisol responses to the SFP. Specifically, maternal sensitivity during this non-distressing interaction was negatively associated with cortisol responses only among infants whose mothers were experiencing relatively high socioeconomic hardship. Exploratory analyses revealed that poor maternal psychosocial wellbeing was positively associated with overall infant cortisol production during the SFP. Altogether, these findings suggest that experiences within early parent-infant attachment relationships and sources of contextual stress work together to shape infant HPA axis activity.

Paeoniflorin Alleviates Anxiety and Visceral Hypersensitivity via HPA Axis and BDNF/TrkB/PLCγ1 Pathway in Maternal Separation-induced IBS-like Rats.

Irritable Bowel Syndrome (IBS) is a prevalent gastrointestinal disorder that significantly diminishes the quality of life for affected individuals. The pathophysiology of IBS remains poorly understood, and available therapeutic options for IBS are limited. The crucial roles of brain-gut interaction, which is mediated by the Hypothalamic-Pituitary-Adrenocortical (HPA) axis and the autonomic nervous system in IBS, have attracted increasing attention. The objective of this study was to examine the impact of paeoniflorin (PF) on anxiety and visceral hypersensitivity in maternal separation-induced IBS-like rats. The IBS-like rat model was established through the implementation of Maternal Separation (MS) and subsequently subjected to various doses of PF administered via oral gavage for 14 days. Anxiety-like behavior was evaluated using the Open Field Test (OFT) and Elevated Plus Maze (EPM) test. The assessment of visceral sensitivity involved the utilization of the Abdominal Withdrawal Reflex (AWR) score and electromyographic (EMG) responses of the external oblique muscle in response to colorectal distention. The levels of adrenocorticotropic hormone (ACTH), corticosterone (CORT), and corticotrophin-releasing hormone (CRH) were examined by ELISA. Quantitative real-time PCR (qRT-PCR) and immunofluorescence were employed to detect the expressions of CRH receptors 1 (CRHR1) and 2 (CRHR2). Glucocorticoid receptors (GR), mineralocorticoid receptor (MR), brain-derived neurotrophic factor (BDNF), tyrosine receptor kinase B (TrkB), and phospholipase C γ1 (PLCγ1) were examined by Western blot. The results showed that MS induced anxiety-like behavior and visceral hypersensitivity, while PF treatment attenuated these changes. Furthermore, the HPA axis hyperactivity in MS rats was attenuated by PF treatment, indicated by reduced serum ACTH, CORT, and CRH levels and recovered hippocampal CRHR1 and GR expressions. In addition, PF inhibited BDNF/TrkB signaling by downregulating the protein levels of BDNF, TrkB, and phospho-PLCγ1 in the colon. These findings suggest that PF alleviated anxiety and visceral hypersensitivity in MS-induced IBS-like rats, which may be the modulation of HPA axis activity and BDNF/TrkB/PLCγ1 signaling pathway.

FGF21 Induces Skeletal Muscle Atrophy and Increases Amino Acids in Female Mice: A Potential Role for Glucocorticoids.

Fibroblast growth factor-21 (FGF21) is an intercellular signaling molecule secreted by metabolic organs, including skeletal muscle, in response to intracellular stress. FGF21 crosses the blood-brain barrier and acts via the nervous system to coordinate aspects of the adaptive starvation response, including increased lipolysis, gluconeogenesis, fatty acid oxidation, and activation of the hypothalamic-pituitary-adrenocortical (HPA) axis. Given its beneficial effects for hepatic lipid metabolism, pharmaceutical FGF21 analogues are used in clinical trials treatment of fatty liver disease. We predicted pharmacologic treatment with FGF21 increases HPA axis activity and skeletal muscle glucocorticoid signaling and induces skeletal muscle atrophy in mice. Here we found a short course of systemic FGF21 treatment decreased muscle protein synthesis and reduced tibialis anterior weight; this was driven primarily by its effect in female mice. Similarly, intracerebroventricular FGF21 reduced tibialis anterior muscle fiber cross-sectional area; this was more apparent among female mice than male littermates. In agreement with the reduced muscle mass, the topmost enriched metabolic pathways in plasma collected from FGF21-treated females were related to amino acid metabolism, and the relative abundance of plasma proteinogenic amino acids was increased up to 3-fold. FGF21 treatment increased hypothalamic Crh mRNA, plasma corticosterone, and adrenal weight, and increased expression of glucocorticoid receptor target genes known to reduce muscle protein synthesis and/or promote degradation. Given the proposed use of FGF21 analogues for the treatment of metabolic disease, the study is both physiologically relevant and may have important clinical implications.

Evaluating Mixtures of Urinary Phthalate Metabolites and Serum Per-/Polyfluoroalkyl Substances in Relation to Adolescent Hair Cortisol: The HOME Study.

Results of toxicological studies indicate that phthalates and per-/polyfluoroalkyl substances (PFAS), 2 classes of endocrine-disrupting chemicals, may alter the functioning of the hypothalamic-pituitary-adrenocortical (HPA) axis. We evaluated the associations of urinary phthalate metabolites and serum PFAS during gestation and childhood with adolescent hair cortisol concentrations (pg/mg hair) at age 12 years, an integrative marker of HPA axis activity (n= 205 mother-child pairs; Cincinnati, Ohio; enrolled 2003-2006). We used quantile-based g-computation to estimate associations between mixtures of urinary phthalate metabolites or serum PFAS and hair cortisol. We also examined whether associations of individual phthalate metabolites or PFAS with cortisol varied by the timing of exposure. We found that a 1-quartile increase in all childhood phthalate metabolites was associated with 35% higher adolescent hair cortisol (phthalate mixture ψ= 0.13; 95% confidence interval: 0.03, 0.22); these associations were driven by monoethyl phthalate, monoisobutyl phthalate, and monobenzyl phthalate. We did not find evidence that phthalate metabolites during gestation or serum PFAS mixtures were related to adolescent hair cortisol concentrations. We found suggestive evidence that higher childhood concentrations of individual PFAS were related to higher and lower adolescent hair cortisol concentrations. Our results suggest that phthalate exposure during childhood may contribute to higher levels of chronic HPA axis activity.

Social isolation and breast cancer.

Although the role of life-stressors in breast cancer remains unclear, social isolation is consistently associated with increased breast cancer risk and mortality. Social isolation can be defined as loneliness or an absence of perceived social connections. In female mice and rats, social isolation is mimicked by housing animals one per cage. Social isolation causes many biological changes, of which an increase in inflammatory markers and disruptions in mitochondrial and cellular metabolism are commonly reported. It is not clear how the two traditional stress-induced pathways, i.e., hypothalamic-pituitary axis (HPA), resulting a release of glucocorticoids from the adrenal cortex, and autonomic nervous system (ANS), resulting a release of catecholamines from the adrenal medulla and post-ganglionic neurons, could explain the increased breast cancer risk in socially isolated individuals. For example, glucocorticoid receptor activation in estrogen receptor positive breast cancer cells inhibits their proliferation, and activation of β-adrenergic receptor (β-AR) in immature immune cells promotes their differentiation towards anti-tumorigenic T cells. However, activation of HPA and ANS pathways may cause a disruption in the brain-gut-microbiome axis, resulting gut dysbiosis. Gut dysbiosis, in turn, leads to an alteration in the production of bacterial metabolites, such as short chain fatty acids, causing a systemic low-grade inflammation and inducing dysfunction in mitochondrial and cellular metabolism. A possible causal link between social isolation -induced increased breast cancer risk and mortality and gut dysbiosis should be investigated, as it offers new tools to prevent breast cancer.

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

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

Ablation of NPFFR2 in Mice Reduces Response to Single Prolonged Stress Model

Mental stress is highly related to many clinical symptoms and disorders, as it activates the hypothalamic-pituitary-adrenocortical (HPA) axis to affect a wide variety of physiological functions. Furthermore, stress leads to the aberrations in HPA axis activity and disruptions of body homeostasis. It was previously shown that neuropeptide FF (NPFF) regulates the HPA axis through the activation of hypothalamus paraventricular nucleus (PVN), and genetic overexpression or pharmacological stimulation of NPFF receptor 2 (NPFFR2) triggers hyperactivity of HPA axis and suppresses behavioral correlates of emotion in mice. In this study, we further examined the role of NPFFR2 in stress response in mice by utilizing a single prolonged stress (SPS). SPS is considered a model of post-traumatic stress disorder (PTSD), and mice undergo physical restraint, forced swimming, and ether anesthesia within a day followed by social isolation for one week. NPFFR2 knockout B6 mice were generated by CRISPR/Cas9 technology and exposed to SPS. The NPFFR2 knockouts showed resistance to stress exposure-induced anxiety-like behaviors and HPA axis hyperactivity. Additionally, the hippocampal mRNA levels of glucocorticoid receptor and mineralocorticoid receptor were reduced in wild-type (WT) mice but not in NPFFR2 knockouts after stress exposure. Our data also suggested that NPFFR2 knockout mice have stronger negative feedback on the HPA axis after exposure to SPS. Mice with intra-PVN Npffr2 shRNA injection displayed trends toward resistance to SPS exposure in both behavioral and molecular assays. Together, our findings suggest that NPFFR2 may be a potential therapeutic target for disorders relating to stress/anxiety and HPA dysregulation.

Leptin’s hunger-suppressing effects are mediated by the hypothalamic–pituitary–adrenocortical axis in rodents

Leptin informs the brain about sufficiency of fuel stores. When insufficient, leptin levels fall, triggering compensatory increases in appetite. Falling leptin is first sensed by hypothalamic neurons, which then initiate adaptive responses. With regard to hunger, it is thought that leptin-sensing neurons work entirely via circuits within the central nervous system (CNS). Very unexpectedly, however, we now show this is not the case. Instead, stimulation of hunger requires an intervening endocrine step, namely activation of the hypothalamic-pituitary-adrenocortical (HPA) axis. Increased corticosterone then activates AgRP neurons to fully increase hunger. Importantly, this is true for 2 forms of low leptin-induced hunger, fasting and poorly controlled type 1 diabetes. Hypoglycemia, which also stimulates hunger by activating CNS neurons, albeit independently of leptin, similarly recruits and requires this pathway by which HPA axis activity stimulates AgRP neurons. Thus, HPA axis regulation of AgRP neurons is a previously underappreciated step in homeostatic regulation of hunger.

Effects of Intranasal Oxytocin on Pup Deprivation-Evoked Aberrant Maternal Behavior and Hypogalactia in Rat Dams and the Underlying Mechanisms

Oxytocin (OT), a hypothalamic neuropeptide, applied through nasal approach (IAO), could improve maternal health during lactation that is disrupted by mother–baby separation; however, the regulation of IAO effects on maternal behaviors and lactation as well as the underlying mechanisms remain unclear. Using lactating rats, we observed effects of intermittent pup deprivation (PD) with and without IAO on maternal behaviors and lactation as well as the activity of OT neurons in the supraoptic nucleus (SON) and the activity of hypothalamic pituitary-adrenal axis, key factors determining the milk-letdown reflex during lactation and maternal behaviors. The results showed that PD reduced maternal behaviors and lactation efficiency of rat dams as indicated by significantly longer latency to retrieve their pups and low litter’s body weight gains during the observation, respectively. In addition, PD caused early involution of the mammary glands. IAO partially improved these changes in rat dams, which was not as significant as IAO effects on control dams. In the SON, PD decreased c-Fos and increased glial fibrillary acidic protein (GFAP) filaments significantly; IAO made PD-evoked c-Fos reduction insignificant while reduced GFAP filament significantly in PD dams. IAO tended to increase the levels of phosphorylated extracellular signal-regulated kinases (pERK) 1/2 in PD dams. Moreover, PD+IAO significantly increased plasma levels of dam adrenocorticotropic hormone and corticosterone but not OT levels. Lastly, PD+IAO tended to increase the level of corticotropin-releasing hormone in the SON. These results indicate that PD disrupts maternal behaviors and lactation by suppressing the activity of hypothalamic OT-secreting system through expansion of astrocytic processes, which are partially reversed by IAO through removing astrocytic inhibition of OT neuronal activity. However, the improving effect of IAO on the maternal health could be compromised by simultaneous activation of hypothalamic pituitary-adrenocortical axis.

Endocannabinoid system, stress and HPA axis

The endocannabinoid system (ECS), which is composed of the cannabinoid receptors types 1 and 2 (CB1 and CB2) for marijuana's psychoactive ingredient ∆9-tetrahydrocannabinol (∆9-THC), the endogenous ligands (AEA and 2-AG) and the enzymatic systems involved in their biosynthesis and degradation, recently emerged as important modulator of emotional and non-emotional behaviors. In addition to its recreational actions, some of the earliest reports regarding the effects of Cannabis use on humans were related to endocrine system changes. Accordingly, the ∆9-THC and later on, the ECS signalling have long been known to regulate the hypothalamic-pituitary-adrenocortical (HPA) axis, which is the major neuroendocrine stress response system of mammals. However, how the ECS could modify the stress hormone secretion is not fully understood. Thus, the present article reviews current available knowledge on the role of the ECS signalling as important mediator of interaction between HPA axis activity and stressful conditions, which, in turn could be involved in the development of psychiatric disorders.

Attachment security buffers the HPA axis of toddlers growing up in poverty or near poverty: Assessment during pediatric well-child exams with inoculations

Poverty is associated with poor physical and emotional development. Activation of the hypothalamic-pituitary-adrenocortical (HPA) axis is argued to be one of the pathways through which poverty acts on these outcomes. While studies of school-aged children have found some evidence for this, there is little evidence for this hypothesis early in development. This may be, in part, because for very young children, the security of their attachment relationships with parents moderates the impact of poverty on HPA axis functioning. The current study investigated the relations between family income as a percentage of the federal poverty limit (FPL), salivary cortisol and attachment (Attachment Q-sort) during well-child checkups with inoculations in 177 toddlers between 12- and 22-months of age. Approximately half of the toddlers were in families living below 150% FPL, with 47% of these classified as securely attached, compared to 72% of toddlers in families living above 150% FPL. Cortisol levels increased in response to the inoculation and this did not differ by poverty or attachment security. Overall, however, beginning at clinic arrival toddlers in families living below 150% FPL who had an insecure attachment had significantly higher cortisol compared to toddlers living in poverty or near poverty with secure attachments. This finding held when we removed toddlers with high levels of negative life events in their families and primary caregivers who exceeded the screening cutoff for depressive symptoms. Thus, attachment was a significant moderator of the association between poverty and HPA axis activity, with significant implications for screening and referral of caregiving dyads at risk.

Free and bound cortisol in plasma and saliva during ACTH challenge in dairy cows and horses.

Cortisol levels reflect hypothalamic-pituitary-adrenocortical (HPA) axis activity. While most plasma cortisol is supposed to be bound to the soluble corticosteroid-binding globulin (CBG), only free cortisol (FC) actively regulates metabolic and immunological processes. We aimed to establish a multispecies suitable method to assess FC in cows and horses which in combination with total cortisol (TC) allows interpreting proportional changes of cortisol in saliva as well as in blood in response to a standardized HPA axis activation via ACTH. We further investigated if the ratios of cortisol fractions as obtained at basal levels in healthy horses (herbivorous and monogastric) and dairy cows (herbivorous and ruminant) change during HPA axis activation, and to which extent saliva cortisol (SC) is representative for alterations in plasma FC and adrenal cortex reactivity. However, it was not the objective of the present study to directly compare the two species. Dosages of ACTH applied in cows and horses were based on published data. Synthetic ACTH was intravenously administered to eight dairy cows (0.16 µg/kg BW) and five horses (1 µg/kg BW). Blood and saliva were collected every 30 min for 3 h from a jugular vein catheter, and analyzed for TC and SC, the ratio of free cortisol (rFC), and the concentration of FC (cFC) in plasma. During the entire sampling period of the ACTH test, plasma TC was paralleled by blood cFC, rFC, and SC in both cows and horses. All cortisol fractions increased within 30 min of ACTH administration compared to basal values (0 min, P < 0.05). Peak TC concentration reached 63.2 ± 9.6 ng/mL and 73.2 ± 11.8 ng/mL in bovine and equine plasma, respectively. Peak values of rFC averaged 17.9 ± 4.5% in cows and 19.2 ± 7.8% in horses. The ratio of SC to cFC in horses remained similar during the ACTH challenge suggesting that SC is recruited from plasma FC. However, SC increased less compared to plasma TC and FC during HPA axis activation in cows. In conclusion, the short-term activation of the HPA axis caused not only an elevation of TC, but also a similar increase of rFC in both species. SC closely reflected changes of FC in horses, but less accurately in cows. The concomitant evaluation of changes among cortisol fractions might give further indications on adaptation mechanisms in glucocorticoid regulation as well as differentiate cortisol-related health disorders.

Hypothalamic-Pituitary-Adrenocortical Axis Activity in Alcohol-Dependent Patients During Treatment with High-Dose Baclofen

Activity of the hypothalamic-pituitary-adrenocortical (HPA) axis has been reported to be affected in alcohol use disorder (AUD). It has been suggested that pharmacological relapse prevention in AUD might exert its effects partly by modulation of HPA axis activity. Here, we assessed the effects of high-dose treatment with baclofen on HPA axis activity in alcohol-dependent patients within a 24-week randomized, placebo-controlled trial (BACLAD study). Plasma levels of copeptin, adrenocorticotropic hormone (ACTH), and cortisol were measured at 3 timepoints in alcohol-dependent patients during the study. Corresponding plasma levels in healthy controls were assessed once. ACTH blood levels were significantly higher in the group of alcohol-dependent patients compared to controls. In patients receiving individually titrated high-dose baclofen, plasma cortisol levels decreased significantly, whereas no significant alterations were found in the placebo group. Our study underlines again the role of HPA axis alterations in AUD. Furthermore, a decrease in hormonal stress levels during treatment with high-dose baclofen might contribute to the relapse preventive effects of this compound.

Dietary Manipulations That Induce Ketosis Activate the HPA Axis in Male Rats and Mice: A Potential Role for Fibroblast Growth Factor-21

In response to an acute threat to homeostasis or well-being, the hypothalamic-pituitary-adrenocortical (HPA) axis is engaged. A major outcome of this HPA axis activation is the mobilization of stored energy, to fuel an appropriate behavioral and/or physiological response to the perceived threat. Importantly, the extent of HPA axis activity is thought to be modulated by an individual's nutritional environment. In this study, we report that nutritional manipulations signaling a relative depletion of dietary carbohydrates, thereby inducing nutritional ketosis, acutely and chronically activate the HPA axis. Male rats and mice maintained on a low-carbohydrate high-fat ketogenic diet (KD) exhibited canonical markers of chronic stress, including increased basal and stress-evoked plasma corticosterone, increased adrenal sensitivity to adrenocorticotropin hormone, increased stress-evoked c-Fos immunolabeling in the paraventricular nucleus of the hypothalamus, and thymic atrophy, an indicator of chronic glucocorticoid exposure. Moreover, acutely feeding medium-chain triglycerides (MCTs) to rapidly induce ketosis among chow-fed male rats and mice also acutely increased HPA axis activity. Lastly, and consistent with a growing literature that characterizes the hepatokine fibroblast growth factor-21 (FGF21) as both a marker of the ketotic state and as a key metabolic stress hormone, the HPA response to both KD and MCTs was significantly blunted among mice lacking FGF21. We conclude that dietary manipulations that induce ketosis lead to increased HPA axis tone, and that the hepatokine FGF21 may play an important role to facilitate this effect.

Dopamine D2-like receptors modulate freezing response, but not the activation of HPA axis, during the expression of conditioned fear.

Considering the complexity of aversive information processing and defensive response expression, a combined action of stress modulators may be required for an optimal performance during threatening situations. Dopamine is now recognized as one of the most active modulators underlying states of fear and anxiety. On the other hand, activation of hypothalamic-pituitary-adrenocortical (HPA) axis, which leads to the release of corticosterone in rodents, has been considered a key part of the stress response. The current study is an extension of prior work investigating modulatory effects of dopamine and corticosterone on conditioned fear expression. We have showed that corticosterone, acting through mineralocorticoid receptors in the ventral tegmental area (VTA), upregulates dopaminergic system in the basolateral amygdala (BLA), enabling the expression of conditioned freezing response. The novel question addressed here is whether VTA-BLA dopaminergic signaling is necessary for increases in corticosterone during conditioned fear expression. Using site-specific treatment with D2-like agonist quinpirole (VTA) and D2-like antagonist sulpiride (BLA), we evaluated freezing and plasma corticosterone in rats exposed to a light used as aversive conditioned stimulus (CS). Intra-VTA quinpirole and intra-BLA sulpiride significantly decreased freezing expression in the conditioned fear test, but this anxiolytic-like effect of the dopaminergic drugs was not associated with changes in plasma corticosterone concentrations. Altogether, data suggest that interferences with the ability of the CS to activate the dopaminergic VTA-BLA pathway reduce the expression of freezing, but activation of the HPA axis seems to occur upstream of the recruitment of dopaminergic mechanisms in conditioned fear states.

HPA Axis Interactions with Behavioral Systems.

Perhaps the most salient behaviors that individuals engage in involve the avoidance of aversive experiences and the pursuit of pleasurable experiences. Engagement in these behaviors is regulated to a significant extent by an individual's hormonal milieu. For example, glucocorticoid hormones are produced by the hypothalamic-pituitary-adrenocortical (HPA) axis, and influence most aspects of behavior. In turn, many behaviors can influence HPA axis activity. These bidirectional interactions not only coordinate an individual's physiological and behavioral states to each other, but can also tune them to environmental conditions thereby optimizing survival. The present review details the influence of the HPA axis on many types of behavior, including appetitively-motivated behaviors (e.g., food intake and drug use), aversively-motivated behaviors (e.g., anxiety-related and depressive-like) and cognitive behaviors (e.g., learning and memory). Conversely, the manuscript also describes how engaging in various behaviors influences HPA axis activity. Our current understanding of the neuronal and/or hormonal mechanisms that underlie these interactions is also summarized. © 2016 American Physiological Society. Compr Physiol 6:1897-1934, 2016.

Suitability of saliva cortisol as a biomarker for hypothalamic-pituitary-adrenal axis activation assessment, effects of feeding actions, and immunostimulatory challenges in dairy cows.

One of the most prominent physiological responses to stressors is the activation of the hypothalamic-pituitary-adrenocortical (HPA) axis, currently assessed by measuring cortisol concentration in blood plasma. To reduce animal discomfort during sampling, which negatively affects stress biomarkers, current research focuses on noninvasive sampling of media other than blood, for example, saliva. The aim of this study was to assess the suitability of saliva cortisol as a biomarker under different physiological and immunological states in dairy cows. Our objectives were to 1) evaluate the relationship between HPA axis activation and saliva cortisol concentration, 2) investigate effects of some feeding action (as influenced by feed and water consumption) on saliva cortisol concentration, and 3) evaluate the time lag between plasma and saliva cortisol during induced inflammatory conditions by intramammary lipopolysaccharide (LPS) and lipoteichoic acid (LTA) injection. During a specific activation of the HPA axis, a positive correlation ( = 0.75, < 0.0001) between saliva and blood cortisol concentrations was observed with increased ( < 0.01) plasma cortisol concentrations following ACTH administration. Saliva and blood samples were taken before, during, and after drinking, feeding, and ruminating. Only a low correlation between saliva and plasma cortisol concentrations ( = 0.03, = 0.83) but no significant effects of the different feeding actions on saliva cortisol were observed. When compared with basal concentrations, cortisol concentrations in plasma significantly increased during inflammatory responses following LPS and LTA injection. Compared with plasma cortisol, changes in saliva cortisol concentrations occurred at a much lower level within a narrow range and did not necessarily follow changes in plasma. In conclusion, the positive correlation between saliva and plasma cortisol concentration in response to ACTH and inflammation suggests the suitability of saliva cortisol measurement for the HPA axis activation assessment. However, changes in saliva cortisol concentration occur within a very narrow range. Furthermore, not only must variation among individual animals be considered but also variation within the same animal. Only with additional knowledge of the concomitant physiological status of the cow it is possible to correctly evaluate saliva and blood cortisol samples.

The influence of combined oral contraceptives containing drospirenone on hypothalamic-pituitary-adrenocortical axis activity and glucocorticoid receptor expression and function in women with polycystic ovary syndrome.

Most women with PCOS have increased adrenal androgen production, enhanced peripheral metabolism of cortisol and elevation in urinary excretion of its metabolites. Increased cortisol clearance in PCOS is followed by a compensatory overdrive of the hypothalamic-pituitary-adrenocortical (HPA) axis. We hypothesized that oral contraceptives containing ethinylestradiol and drospirenone (EE-DRSP) could modulate glucocorticoid receptor (GR) expression and function and thus affect HPA axis activity in PCOS patients. We analyzed 12 women with PCOS (age 24.17±4.88 years; body mass index 22.05±3.97 kg/m²) treated for 12 months with EE-DRSP and 20 BMI matched controls. In all subjects testosterone, dehydroepiandrosterone sulfate (DHEAS), sex hormone binding globulin (SHBG), cortisol (basal and after dexamethasone), concentrations of GR protein, phospo-GR211 protein, number of GR per cell (B(max) and its equilibrium dissociation constant (K(D)) were measured. Before treatment, increased concentrations of testosterone and DHEAS (p<0.001, respectively), unaltered basal cortisol and an increased sensitivity (p<0.05) of the HPA axis to dexamethasone were observed in PCOS women in comparison to controls. After treatment, testosterone (p<0.01), DHEAS (p<0.05) and cortisol suppression after dexamethasone (p<0.01) were decreased in PCOS women. There were no changes in GR protein concentration, GR phosphorylation nor in the receptor functional parameters B(max) and K(D) in women with PCOS before and after the therapy, and in comparison to controls. Prolonged treatment with EE-DRSP in PCOS women decreased serum androgens and increased cortisol in the presence of decreased sensitivity of the HPA axis and did not exert changes in GR expression and function.

GABAA receptor-acting neurosteroids: a role in the development and regulation of the stress response.

Regulation of hypothalamic-pituitary-adrenocortical (HPA) axis activity by stress is a fundamental survival mechanism and HPA-dysfunction is implicated in psychiatric disorders. Adverse early life experiences, e.g. poor maternal care, negatively influence brain development and programs an abnormal stress response by encoding long-lasting molecular changes, which may extend to the next generation. How HPA-dysfunction leads to the development of affective disorders is complex, but may involve GABAA receptors (GABAARs), as they curtail stress-induced HPA axis activation. Of particular interest are endogenous neurosteroids that potently modulate the function of GABAARs and exhibit stress-protective properties. Importantly, neurosteroid levels rise rapidly during acute stress, are perturbed in chronic stress and are implicated in the behavioural changes associated with early-life adversity. We will appraise how GABAAR-active neurosteroids may impact on HPA axis development and the orchestration of the stress-evoked response. The significance of these actions will be discussed in the context of stress-associated mood disorders.

Changes in salivary cortisol levels in pediatric patients with obstructive sleep apnea syndrome after adenotonsillectomy

ObjectiveObstructive sleep apnea syndrome (OSAS) activates the stress response system, including the hypothalamic–pituitary–adrenocortical (HPA) axis. The salivary cortisol, as an index of free circulating cortisol levels, may be used as a measure of HPA axis activity. We examined the change in the salivary cortisol level in pediatric OSAS patients before and after adenotonsillectomy (AT). MethodsForty-eight subjects from 80 subjects suspicious of having OSAS were diagnosed with OSAS by overnight PSG, 34 of 48 OSAS patients undergoing AT, and 13 of 34 OSAS patients were finally enrolled prospectively for this study. Before and three months after the AT, the saliva was collected at night before PSG (n-sCor) and in the early morning after PSG (m-sCor) for the measurements of the salivary cortisol level. ResultsChildren in the study population (n=13) were divided into mild (1⩽ AHI <5, n=5), moderate (5⩽ AHI <10, n=3), and severe (AHI ⩾10, n=5) OSAS groups. The mean preoperative AHI in the children was 14.7, and the mean postoperative AHI was 0.33. The percentage of children with AHI <1 after AT was 92.3%. Postoperative m-sCor, the difference of cortisol level (sub-sCor: m-sCor minus n-sCor), and the ratio of cortisol level (r-sCor: m-sCor/n-sCor) showed significant difference postoperatively. ConclusionsAT was associated with improvements in PSG and subjective symptoms in pediatric OSAS patients. In addition, these improvements were significantly related to normalization of salivary cortisol level after AT. Although further study on salivary cortisol levels needs to be done, the measurement of salivary cortisol level before and after AT may predict the outcome of AT as a treatment of OSAS.