Adrenal Activity Research Articles

Chronic Exposure to Cadmium Disrupts the Adrenal Gland Activity of the NewtTriturus carnifex(Amphibia, Urodela)

We intended to verify the safety of the freshwater values established for cadmium by the European Community and the Italian Ministry of Health in drinking water (5 μg/L) and sewage waters (20 μg/L). Therefore, we chronically exposed the newt Triturus carnifex to 5 μg/L and 20 μg/L doses of cadmium, respectively, during 3 and 9 months and verified the effects on the adrenal gland. We evaluated the serum concentrations of adrenocorticotropic hormone (ACTH), corticosterone, aldosterone, norepinephrine, and epinephrine. During the 3-month exposure, both doses of cadmium decreased ACTH and corticosterone serum levels and increased aldosterone and epinephrine serum levels. During the 9-month exposure, the 5 μg/L dose decreased ACTH and increased aldosterone and epinephrine serum levels; the 20 μg/L dose decreased norepinephrine and epinephrine serum levels, without affecting the other hormones. It was concluded that (1) chronic exposure to the safety values established for cadmium disrupted the adrenal gland activity and (2) the effects of cadmium were related both to the length of exposure and the dose administered. Moreover, our results suggest probable risks to human health, due to the use of water contaminated by cadmium.

Adrenocortical and renin-angiotensin systems in dynamics of experimental diabetes

Components of the adrenocortical system (adrenal and blood corticosteroid hormones and hepatic and renal 11beta-hydroxysteroid dehydrogenase activity) and also activity of the most important enzyme of the renin-angiotensin system, tissue and blood angiotensin converting enzyme (ACE) have been investigated in dynamics of alloxan diabetes. The study has shown that the initial period of diabetes is characterized by activation of synthesis and secretion of adrenocortical hormones into blood. High blood glucose and glucocorticoid honnones increase activity of the renin-angiotensin system in lungs and decrease ACE secretion into blood. This is accompanied by a decrease of activity of the renin-angiotensin system in kidneys. Subsequent progression of diabetes resulted in impairments of physiologically determined correlations between the components of these systems. Development of experimental diabetes for 30 days was accompanied by sign of a decrease of the adrenal glucocorticoid function regardless of stable impairments of carbohydrate metabolism. Under these conditions increased adrenal and hepatic 11beta-hydroxysteroid dehydrogenase activity may be responsible for maintenance of elevated levels of the main glucocorticoid in blood and tissues. Factor analysis revealed impairments in intersystem relationships between the adrenocortical and renin-angiotensin systems in experimental diabetes thus suggesting disintegration of regulatory systems.

Evaluation of Glucocorticoid Faecal Monitoring as a Non-Invasive Assessment of Stress in Captive Crab-Eating Fox (Cerdocyoun thous) After ACTH Stimulation

Blood sampling is a common method in biological research of domestic animals for studying hormone mechanisms. However, this approach can be stressful for wild species, and compromise research concerning animal welfare. The crab-eating fox (Cerdocyoun thous) is a medium-sized canid found in South America and a popular zoo species in that region. However, almost nothing is known of their biology or what factors impact captive welfare. Thus, a non-invasive method to measure adrenal activity and stress was developed for quantifying fecal glucocorticoids non-invasively in this species. The physiological relevance of the cortisol immunoassay was demonstrated by injection of exogenous ACTH into two males and one female, which led to a significant increase in fecal glucocorticoid metabolites within 24-48 h. From these findings we conclude that fecal samples can be used for the non-invasive assessment of adrenocortical status in crab-eating fox.

Commentary on Degenhardt et al. (2013): Specific effect of adolescent cannabis use on anxiety – tentative explanations

Commentary on Degenhardt <i>et al</i>. (2013): Specific effect of adolescent cannabis use on anxiety – tentative explanations

Salivary cortisol and interpersonal functioning: An event-contingent recording study in the offspring of parents with bipolar disorder

Despite a large body of research in non-human primates, the relationship between naturalistic patterns of social behaviour and basal cortisol levels has been understudied in humans. The present study examined the relationship between patterns of interpersonal functioning and cortisol levels in 23 offspring of parents with bipolar disorder (BD), at high risk for the development of an affective disorder, and 22 offspring of parents with no affective disorder (controls) in late adolescence and young adulthood. Using event-contingent recording, participants rated their dominance, submissiveness, quarrelsomeness, and agreeableness in naturally occurring social interactions over 14 consecutive days and provided salivary cortisol twice daily in the afternoon over the same period. In the full sample, multilevel modelling analyses revealed that dominance was a significant positive predictor of afternoon basal cortisol levels, t(35)=2.58, p<0.05. Moreover, risk group (having a parent with BD or parents with no affective disorder) significantly interacted with mean levels of quarrelsomeness to predict afternoon cortisol levels, t(29)=2.06, p<0.05. Offspring of parents with BD who reported more frequent quarrelsome behaviours exhibited lower levels of afternoon cortisol relative to high-risk offspring reporting few quarrelsome behaviours and control offspring. The results are consistent with evidence that dominance is associated with high cortisol levels in an unstable environment, and suggest that quarrelsomeness among high risk youth contributes to altered hypothalamic-pituitary-adrenal activity.

Hypothalamic–pituitary–adrenal (HPA) axis function in the California mouse (Peromyscus californicus): Changes in baseline activity, reactivity, and fecal excretion of glucocorticoids across the diurnal cycle

The California mouse, Peromyscus californicus, is an increasingly popular animal model in behavioral, neural, and endocrine studies, but little is known about its baseline hypothalamic–pituitary–adrenal (HPA) axis activity or HPA responses to stressors. We characterized plasma corticosterone (CORT) concentrations in P. californicus under baseline conditions across the diurnal cycle, in response to pharmacological manipulation of the HPA axis, and in response to a variety of stressors at different times of day. In addition, we explored the use of fecal samples to monitor adrenocortical activity non-invasively. California mice have very high baseline levels of circulating CORT that change markedly over 24h, but that do not differ between the sexes. This species may be somewhat glucocorticoid-resistant in comparison to other rodents as a relatively high dose of dexamethasone (5mg/kg, s.c.) was required to suppress plasma CORT for 8h post-injection. CORT responses to stressors and ACTH injection differed with time of day, as CORT concentrations were elevated more readily during the morning (inactive period) than in the evening (active period) when compared to time-matched control. Data from 3H-CORT injection studies show that the time course for excretion of fecal CORT, or glucocorticoid metabolites, differs with time of injection. Mice injected in the evening excreted the majority of fecal radioactivity 2–4h post-injection whereas mice injected during the morning did so at 14–16h post-injection. Unfortunately, the antibody we used does not adequately bind the most prevalent fecal glucocorticoid metabolites and therefore we could not validate its use for fecal assays.

Effects of Parental Depressive Symptoms on Child Adjustment Moderated by Hypothalamic Pituitary Adrenal Activity: Within‐ and Between‐Family Risk

Child hypothalamic pituitary adrenal (HPA) activity was investigated as a moderator of parental depressive symptom effects on child behavior in an adoption sample (n=210 families). Adoptive parents' depressive symptoms and child internalizing and externalizing were assessed at 18, 27, and 54months, and child morning and evening HPA activity measured through salivary cortisol at 54months. Children's daily cortisol levels and day-to-day variability were tested as moderators of longitudinal associations between parent and child symptoms at within- and between-family levels. Mothers' symptoms related directly to child internalizing, but child evening cortisol moderated effects of fathers' symptoms on internalizing, and of both parents' symptoms on externalizing. Different paths of within-family risk dynamics versus between-family risk synergy were found for internalizing versus externalizing outcomes.

A Substitution in the Ligand Binding Domain of the Porcine Glucocorticoid Receptor Affects Activity of the Adrenal Gland

Glucocorticoids produced in the adrenal cortex under the control of the hypothalamic-pituitary axis play a vital role in the maintenance of basal and stress-related homeostasis and influence health and well-being. To identify loci affecting regulation of the hypothalamic-pituitary-adrenal (HPA) axis in the pig we performed a genome-wide association study for two parameters of acute and long-term adrenal activity: plasma cortisol level and adrenal weight. We detected a major quantitative trait locus at the position of the glucocorticoid receptor gene (NR3C1) – a key regulator of HPA axis activity. To determine the causal variant(s), we resequenced the coding region of NR3C1 and found three missense single nucleotide polymorphisms (SNPs). SNP c.1829C>T, leading to a p.Ala610Val substitution in the ligand binding domain, showed large (about 0.6× and 1.2× phenotypic standard deviations for cortisol level and adrenal weight, respectively), and highly significant (2.1E-39≤log10(1/p)≤1.7E+0) negative effects on both traits. We were able to replicate the association in three commercial pig populations with different breed origins. We analyzed effects of the p.Ala610Val substitution on glucocorticoid-induced transcriptional activity of porcine glucocorticoid receptor (GR) in vitro and determined that the substitution introduced by SNP c.1829C>T increased sensitivity of GR by about two-fold. Finally, we found that non-coding polymorphisms in linkage disequilibrium with SNP c.1829C>T have only a minor effect on the expression of NR3C1 in tissues related to the HPA axis. Our findings provide compelling evidence that SNP c.1829C>T in porcine NR3C1 is a gain-of-function mutation with a major effect on the activity of the adrenal gland. Pigs carrying this SNP could provide a new animal model to study neurobiological and physiological consequences of genetically based GR hypersensitivity and adrenal hypofunction.

63. Long lasting effects of smoking: Breast cancer survivors’ inflammatory responses to acute stress differ by smoking history

Cigarette smoking continues to be the most preventable cause of illness and death. Current smokers have dysregulated hypothalamic–pituitary–adrenal (HPA) activity and elevated levels of inflammation compared to nonsmokers. To date, data in former smokers has been limited to observing persistent inflammation even years following cessation, yet there is little published on HPA function. This study examined cortisol and interleukin-6 (IL-6) responses to a laboratory stressor in breast cancer survivors who formerly smoked compared to their counterparts who had never smoked. Participants included 90 women (age = 51.4 ± 9.4 years) who had completed treatment for stage 0-IIIA breast cancer within the past three years and were at least two months post surgery, radiation or chemotherapy, whichever occurred last. Cortisol and IL-6 were evaluated in response to a standardized laboratory speech and mental arithmetic stressor. Former ( n = 25) and never ( n = 65) smokers did not differ by cancer stage, cancer treatment, comorbidities, time since treatment, depression, or stress. Despite having similar cortisol responses to the stressor, former smokers had exaggerated IL-6 responses two hours post-stressor compared to never smokers ( p

Inappropriately normal plasma ACTH and cortisol concentrations in the face of increased circulating interleukin-6 concentration in exercise in patients with sarcoidosis

Sarcoidosis is an autoimmune disease, and hypothalamic–pituitary–adrenal (HPA) axis activity is blunted in autoimmunity. Exercise stimulates the HPA axis, and we hypothesized that in sarcoidosis patients responses to treadmill exercise would be reduced. Hence, we studied 44 sarcoidosis patients [27 untreated (age, mean ± SD, 42 ± 2 years, 12 males, 15 females) and 17 dexamethasone treated (age, 46 ± 4 years, 7 males, 10 females)] and 20 healthy controls (40 ± 5 years old, 9 males, 11 females). Blood samples were drawn before, at peak (exhaustion), and 15 min after treadmill exercise for adrenocorticotropic hormone (ACTH), cortisol, tumor necrosis factor (TNF), interleukin-1β (IL-1β) and IL-6 measurements. At peak, plasma ACTH (pg/ml) was increased in untreated (mean ± SE, ΔACTH = 162.8 ± 29.9) and treated (ΔACTH = 123.3 ± 48.1) patients and controls (ΔACTH = 112.3 ± 41.7). Post-exercise, cortisol (ng/ml) was increased (p < 0.05) in untreated patients (Δcortisol = 48.4 ± 14.7) and controls (Δcortisol = 46.0 ± 15.9), but not significantly in treated patients (Δcortisol = 1.43 ± 2.56). At baseline, serum IL-6 (pg/ml) and TNF (pg/ml) were higher in untreated (3.02 ± 0.54 and 3.89 ± 0.72) and treated (1.75 ± 0.33 and 2.16 ± 1.00) patients, respectively, than in controls (0.80 ± 0.66 and 1.58 ± 0.32). At peak exercise, IL-6 was increased in untreated (ΔIL-6 = 0.96 ± 0.14) and treated (ΔIL-6 = 0.91 ± 0.47) patients and controls (ΔIL-6 = 0.96 ± 0.18); IL-1β was increased only in controls. Hence, the HPA axis of untreated sarcoidosis patients and controls responded similarly to treadmill exercise. In sarcoidosis patients, increased IL-6 was associated with HPA stimulation. Cortisol concentrations were similar between patients and controls, although IL-6 concentrations were higher in patients. Thus, in the face of chronically elevated IL-6 levels in sarcoidosis, there may be dysfunctional IL-6-induced HPA responses or HPA adaptation to high IL-6 concentrations.

Examining the role of endogenous orexins in hypothalamus–pituitary–adrenal axis endocrine function using transient dual orexin receptor antagonism in the rat

The orexin neuropeptide system regulates wakefulness and contributes to physiological and behavioral stress responses. Moreover, a role for orexins in modulating hypothalamus-pituitary-adrenal (HPA) axis activity has been proposed. Brain penetrating dual orexin receptor (OXR) antagonists such as almorexant decrease vigilance and have emerged as a novel therapeutic class for the treatment of insomnia. Almorexant was used here as a pharmacological tool to examine the role of endogenous orexin signaling in HPA axis endocrine function under natural conditions. After confirming the expression of prepro-orexin and OXR-1 and OXR-2 mRNA in hypothalamus, pituitary and adrenal glands, the effects of systemic almorexant were investigated on peripheral HPA axis hormone release in the rat under baseline, stress and pharmacological challenge conditions. Almorexant did not alter basal or stress-induced corticosterone release despite affecting wake and sleep stages (detected by radiotelemetric electroencephalography/electromyography) during the stress exposure. Moreover, almorexant did not affect the release of adrenocorticotropin (ACTH) and corticosterone at different time points along the diurnal rhythm, nor corticotrophin-releasing hormone (CRH)- and ACTH-stimulated neuroendocrine responses, measured in vivo under stress-free conditions. These results illustrate that dual OXR antagonists, despite modulating stress-induced wakefulness, do not interfere with endocrine HPA axis function in the rat. They converge to suggest that endogenous orexin signaling plays a minor role in stress hormone release under basal conditions and under challenge.

Adrenal activity in maned wolves is higher on farmlands and park boundaries than within protected areas

In this study we measured excreted fecal corticoid metabolites (FCM) in maned wolves (Chrysocyon brachyurus) living within a protected reserve, on farmlands or in a boundary zone between the two habitats, and determined the impacts of season and reproductive status on adrenal activity. Feces were collected within a national park (n=191 samples), a park boundary zone (n=39) and on nearby farmlands (n=27), processed and analyzed by enzyme immunoassay. FCM amounts from samples collected on farmlands were higher (P<0.05) than in those collected inside the reserve and from the boundary zone. In relation to seasonality, FCM were elevated (P<0.05) in spring (September–November) when wolf pairs were raising young. We then divided the samples collected during breeding season (March–August) into cycling females and male/non-cycling females based on fecal progesterone: fecal testosterone ratio. FCM concentrations of the former collected inside the park were higher than (P<0.05) than the latter group. However, there were no differences in FCM levels between the two groups for samples collected in the boundary zone and on farmlands. Furthermore, FCM concentrations of male/non-cycling females samples collected on farmlands were 2- to 5-fold higher (P<0.05) than in counterparts collected inside the park. The consistently high FCM concentrations in samples collected on farmlands indicate that, in addition to seasonality, gender and reproductive status, anthropogenic pressures also contribute to elevating adrenal steroid for individuals living in altered habitat.

Monitoring stress hormone metabolites as a useful, non-invasive tool for welfare assessment in farm animals

AbstractA multitude of endocrine mechanisms are involved in coping with challenges. Glucocorticoids, secreted by the adrenal glands, are in the front line of the battle to overcome stressful situations. They are usually measured in plasma samples as parameters of adrenal activity and thus of disturbance. Unfortunately, collecting blood samples itself can disturb an animal. Thus, non-invasive methods for the determination of glucocorticoids or their metabolites have become increasingly popular. The pros and cons of various non-invasive sample materials (saliva, excreta, milk, hair/feathers and eggs) for glucocorticoid determination are given. Above all, faecal samples offer the advantage that they can be collected easily. In faecal samples, circulating hormone levels are integrated over a certain period of time and represent the cumulative secretion of hormones. Thus, the levels are less affected by short fluctuations or the pulse-like nature of hormone secretion. However, using this technique to assess an animal's adrenocortical activity is not especially simple. Whether frequent sampling is necessary or single samples will suffice depends upon the study's aim (whether one is examining the impact of acute or chronic stressors). Background knowledge of the metabolism and excretion of cortisol/corticosterone metabolites is required and a careful validation for each species and sex investigated is obligatory. The present review also addresses analytical issues regarding sample storage, extraction procedures and immunoassays and includes a comprehensive list of published studies (up to 2011) describing the use of such methods in farmed animals. Applied properly, non-invasive techniques to monitor glucocorticoid metabolites in faecal samples of various species are a useful tool for welfare assessment, especially as they are easily applied at farm or group level.

Hypothalamus–pituitary–adrenal axis activity and the subsequent response to chronic stress differ depending upon life history stage

The hypothalamus–pituitary–adrenal (HPA) axis is modulated seasonally in many species, and chronic stress can alter HPA functioning. However, it is not known how these two factors interact – are there particular life history stages when animals are more or less vulnerable to chronic stress? We captured wild house sparrows (Passer domesticus) in Massachusetts during six different life history stages: early and late winter, pre-laying, breeding, late breeding, and molt. At each time point, we tested HPA function by measuring baseline and stress-induced corticosterone (CORT), negative feedback in response to an injection of dexamethasone, and maximum adrenal response through an injection of adrenocorticotropic hormone. We then brought birds into captivity as a model for chronic stress, and repeated the four tests 5days later. At capture, all HPA variables varied seasonally. Birds showed increased negative feedback during breeding and late winter compared to pre-laying. Furthermore, birds during the late breeding period had down-regulated their HPA axis, perhaps in preparation for molt. After 5days of captivity, house sparrows lost ∼11% of initial body mass, although birds lost more weight during molt and early winter. Overall, captive sparrows showed elevated baseline CORT and increased negative feedback, although negative feedback did not show a significant increase during any individual life history stage. During most of the year, adrenal sensitivity was unaffected by captivity. However, during late breeding and molt, adrenal sensitivity increased during captivity. Taken together, these data provide further support that HPA function naturally varies throughout the year, with the interesting consequence that molting birds may potentially be more vulnerable to a chronic stressor such as captivity.

Activation of NTS A1adenosine receptors inhibits regional sympathetic responses evoked by activation of cardiopulmonary chemoreflex

Previously we have shown that adenosine operating via the A(1) receptor subtype may inhibit glutamatergic transmission in the baroreflex arc within the nucleus of the solitary tract (NTS) and differentially increase renal (RSNA), preganglionic adrenal (pre-ASNA), and lumbar (LSNA) sympathetic nerve activity (ASNA>RSNA≥LSNA). Since the cardiopulmonary chemoreflex and the arterial baroreflex are mediated via similar medullary pathways, and glutamate is a primary transmitter in both pathways, it is likely that adenosine operating via A(1) receptors in the NTS may differentially inhibit regional sympathetic responses evoked by activation of cardiopulmonary chemoreceptors. Therefore, in urethane-chloralose-anesthetized rats (n = 37) we compared regional sympathoinhibition evoked by the cardiopulmonary chemoreflex (activated with right atrial injections of serotonin 5HT(3) receptor agonist phenylbiguanide, PBG, 1-8 μg/kg) before and after selective stimulation of NTS A(1) adenosine receptors [microinjections of N(6)-cyclopentyl adenosine (CPA), 0.033-330 pmol/50 nl]. Activation of cardiopulmonary chemoreceptors evoked differential, dose-dependent sympathoinhibition (RSNA>ASNA>LSNA), and decreases in arterial pressure and heart rate. These differential sympathetic responses were uniformly attenuated in dose-dependent manner by microinjections of CPA into the NTS. Volume control (n = 11) and blockade of adenosine receptor subtypes in the NTS via 8-(p-sulfophenyl)theophylline (8-SPT, 1 nmol in 100 nl) (n = 9) did not affect the reflex responses. We conclude that activation of NTS A(1) adenosine receptors uniformly inhibits neural and cardiovascular cardiopulmonary chemoreflex responses. A(1) adenosine receptors have no tonic modulatory effect on this reflex under normal conditions. However, when adenosine is released into the NTS (i.e., during stress or severe hypotension/ischemia), it may serve as negative feedback regulator for depressor and sympathoinhibitory reflexes integrated in the NTS.

Sympathetic activity and hypothalamo-pituitary–adrenal axis activity during sleep in post-traumatic stress disorder: A study assessing polysomnography with simultaneous blood sampling

Nightmares and insomnia in PTSD are hallmark symptoms, yet poorly understood in comparison to the advances toward a biological framework for the disorder. According to polysomnography (PSG), only minor changes in sleep architecture were described. This warrants alternative methods for assessing sleep regulation in PTSD. After screening for obstructive sleep apnea and period limb movement disorder, veterans with PTSD (n=13), trauma controls (TCs, n=17) and healthy controls (HCs, n=15) slept in our sleep laboratory on two consecutive nights with an IV catheter out of which blood was sampled every 20min from 22:00h to 08:00h. Nocturnal levels of plasma adrenocorticotropic hormone (ACTH), cortisol, melatonin were assessed in conjunction with PSG registration, as well as subjective sleep parameters. PTSD patients showed a significant increase in awakenings during sleep in comparison to both control groups. These awakenings were correlated with ACTH levels during the night, and with the subjective perception of sleep depth. Also, heart rate (HR) was significantly increased in PTSD patients as compared with both control groups. The diurnal regulation of ACTH, cortisol and melatonin appeared undisturbed. PTSD patients exhibited lower cortisol levels at borderline significance (p=0.056) during the first half of the night. ACTH levels and cortisol levels during the first half of the night were inversely related to slow wave sleep (SWS). This study suggests that hypothalamo-pituitary-adrenal (HPA) axis activity is related to sleep fragmentation in PTSD. Also, activity of the sympathetic nervous system (SNS) is increased during sleep in PTSD. Further research is necessary to explore the potential causal relationship between sleep problems and the activity of the HPA-axis and SNS in PTSD.

Synthetic peptide TPLVTLFK (octarphin) reduces the corticosterone production by rat adrenal cortex through nonopioid β‐endorphin receptor

The synthetic peptide octarphin (TPLVTLFK) corresponding to the sequence 12-19 of β-endorphin, a selective agonist of nonopioid β-endorphin receptor, was labeled with tritium to a specific activity of 29 Ci/mmol. [(3)H]Octarphin was found to bind to high-affinity naloxone-insensitive binding sites on membranes isolated from rat adrenal cortex (K(d) = 35.7 ± 2.3 nM, B(max) = 41.0 ± 3.6 pmol/mg protein). The binding specificity study revealed that these binding sites were insensitive not only to naloxone but to α-endorphin, γ-endorphin, [Met(5) ]enkephalin, and [Leu(5) ]enkephalin as well. At the same time, the [(3) H]octarphin-specific binding with adrenal cortex membranes was inhibited by unlabeled β-endorphin (K(i) = 32.9 ± 3.8 nM). Octarphin at concentrations of 10(-9) -10(-6) M was found to inhibit the adenylate cyclase activity in adrenocortical membranes, whereas intranasal injection of octarphin at doses of 5 and 20 µg/rat was found to reduce the secretion of corticosterone from the adrenals to the bloodstream. Thus, octarphin decreases the adrenal cortex functional activity through the high affinity binding to nonopioid receptor of β-endorphin.

Effects of birth date and natal dispersal on faecal glucocorticoid concentrations in juvenile Common hamsters

In seasonally breeding animals, timing of reproduction in females can influence offspring development and survival. Temporal and energetic constraints are often more pronounced in juveniles born late in the season, and could activate the stress axis. Common hamsters (Cricetus cricetus) are hibernating rodents, and adult females produce up to three litters during the active season. Birth dates range from May to September, and shortly after natal emergence pups are weaned and start to disperse. In this study, we used faecal cortisol metabolites (FCM) as a non-invasive measure of recent glucocorticoid exposure. We compared FCM levels between early- (June/July) and late- (August/September) born juvenile Common hamsters during their first weeks after natal emergence. We further compared FCM levels in juveniles born in the study area and individuals that immigrated either early or late in the season. Additionally, we investigated potential effects of human disturbances on cortisol secretion patterns. FCM levels in late-born juveniles increased during the first weeks post-emergence and were significantly higher than those in early-born individuals during the post-weaning period. Late-immigrating juveniles had significantly higher FCM levels than early immigrants and residents during the same time period. Individuals that inhabited areas frequently used by humans had higher FCM levels than those in low-impact areas. These results indicate that the seasonal timing of birth and dispersal affect cortisol secretion patterns in juvenile Common hamsters. As all juveniles immerged into their hibernacula during early October, we assume that late-born and late-immigrated individuals have less time to prepare for hibernation. This could elevate energetic demands and increase exposure to predators and/or humans during food caching. These factors might lead to increased adrenal activity and thus, elevated FCM concentrations in these individuals. Potential consequences of these time constraints and associated physiological effects could be reflected in the lower overwinter survival rates of juveniles born late in the season.

The mineralocorticoid receptor agonist, fludrocortisone, differentially inhibits pituitary–adrenal activity in humans with psychotic major depression

Hypothalamic-pituitary-adrenal (HPA) axis dysregulation has been linked with major depression, particularly psychotic major depression (PMD), with mineralocorticoid receptors (MRs) playing a role in HPA-axis regulation and the pathophysiology of depression. Herein we hypothesize that the MR agonist fludrocortisone differentially inhibits the HPA axis of psychotic major depression subjects (PMDs), non-psychotic major depression subjects (NPMDs), and healthy control subjects (HCs). Fourteen PMDs, 16 NPMDs, and 19 HCs were admitted to the Stanford University Hospital General Clinical Research Center. Serum cortisol levels were sampled at baseline and every hour from 18:00 to 23:00h, when greatest MR activity is expected, on two consecutive nights. On the second afternoon at 16:00h all subjects were given 0.5mg fludrocortisone. Mean cortisol levels pre- and post-fludrocortisone and percent change in cortisol levels were computed. There were no significant group differences for cortisol at baseline: F(2,47)=.19, p=.83. There were significant group differences for post-fludrocortisone cortisol: F(2,47)=5.13, p=.01, which were significantly higher in PMDs compared to HCs (p=.007), but not compared to NPMDs (p=.18). There were no differences between NPMD's and HC's (p=.61). Also, PMDs had a lower percent change from baseline in cortisol levels at 2200h than NPMDs (p=.01) or HCs (p=.009). Individuals with psychotic major depression compared to healthy control subjects have diminished feedback inhibition of the hypothalamic-pituitary-adrenal (HPA) axis in response to the mineralocorticoid receptor agonist fludrocortisone. To our knowledge, this is the first study to examine HPA axis response to MR stimulation in major depression (with and without psychosis), and only the third study to demonstrate that exogenously administered fludrocortisone can down-regulate the HPA axis in humans.

Biomarkers of hypothalamic–pituitary–adrenal axis activity in mice lacking 11β-HSD1 and H6PDH

Glucocorticoid concentrations are a balance between production under the negative feedback control and diurnal rhythm of the hypothalamic–pituitary–adrenal (HPA) axis and peripheral metabolism, for example by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which catalyses the reduction of inactive cortisone (11-dehydrocorticosterone (11-DHC) in mice) to cortisol (corticosterone in mice). Reductase activity is conferred upon 11β-HSD1 by hexose-6-phosphate dehydrogenase (H6PDH). 11β-HSD1 is implicated in the development of obesity, and selective 11β-HSD1 inhibitors are currently under development. We sought to address the concern regarding potential up-regulation of the HPA axis associated with inhibition of 11β-HSD1. We assessed biomarkers for allele combinations of 11β-HSD1 and H6PDH derived from double heterozygous mouse crosses. H6PDH knock out (KO) adrenals were 69% larger than WT while 11β-HSD1 KO and double KO (DKO) adrenals were ∼30% larger than WT – indicative of increased HPA axis drive in KO animals. ACTH-stimulated circulating corticosterone concentrations were 2·2-fold higher in H6PDH KO animals and ∼1·5-fold higher in 11β-HSD1 KO and DKO animals compared with WT, proportional to the observed adrenal hypertrophy. KO of H6PDH resulted in a substantial increase in urinary DHC metabolites in males (65%) and females (61%). KO of 11β-HSD1 alone or in combination with H6PDH led to significant increases (36 and 42% respectively) in urinary DHC metabolites in females only. Intermediate 11β-HSD1/H6PDH heterozygotes maintained a normal HPA axis. Urinary steroid metabolite profile by gas chromatography/mass spectrometry as a biomarker assay may be beneficial in assaying HPA axis status clinically in cases of congenital and acquired 11β-HSD1/H6PDH deficiency.