Exogenous Adrenocorticotropic Hormone Research Articles

Abstract 5642: Quantitative comparison of hydrocortisone and prednisone in the postoperative hormone therapy of hypercortisolism

Abstract Tumors and several types of malignancies including lung cancer, pancreatic cancer, pituitary tumor, and most often adrenal adenoma, may cause hypercortisolism, which requires glucorticoid (GC) replacement following adrenalectomy and/or surgical resection of the tumor. Based on our previous report of a simplified GC therapy scheme and the perioperative observation, we further investigated its efficacy and safety up to 6 months post-surgery in this retrospective cohort study. All patients received no GC before surgery. The i.v. doses of hydrocortisone (HC) were 100 mg during surgery, 100 mg bid on day 0 and day 1, followed by 100 mg qd on the morning of day 2 post-surgery. Patients were grouped by oral reception of either HC or prednisone since day 2. The doses and the withdrawal schedule are shown in Table. We found in adrenal adenoma patients, the adrenocorticotropic hormone (ACTH) levels were normal, and sufficient to stimulate the recovery of the dystrophic adrenal cortex, thus exogenous supplemental ACTH might not be necessary. By 6 months post-surgery, prednisone and HC exhibited similar efficacy in correcting hypertension, hyperglycemia, and hypokalemia (p>0.05). Most patients lost weight. Both groups reported significant improvement in a subjective evaluation questionnaire. HC showed advantages over prednisone in improving liver function (p=0.035), but also caused significant leg edema (p=0.034). Both groups developed adrenal insufficiency (AI) during GC withdrawal, with no significant difference regarding the incidence rate or severity. Most AI symptoms were relieved by resuming the prior oral doses, while the severe cases were treated in hospital. No particular variable was identified as risk factor for AI. The withdrawal process may last longer time for HC than prednisone. HC may be prioritized for patients with hyperglycemia or abnormal liver function, while prednisone may reduce the incidence of leg edema. hydrocortisoneprednisonepathology2220adrenal adenoma14/2216/20Cushing's Disease8/224/20oral glucorticoid schemedose on day 240 mg, tid10 mg, tidwithdrawal20 mg/week5 mg/weekaverage length (month)6.64.9correction of symptomshypertension10/1512/19hyperglycemia6/117/10hypokalemia12/1211/11abnormal liver panel7/82/7 *weight loss20/2217/20adrenal insufficiency10/227/20severe case1/101/7leg edema6/220/20 * Note: This abstract was not presented at the meeting. Citation Format: Kunlong Tang, Yuting Huang, Shangwen Dong, Peng Gao. Quantitative comparison of hydrocortisone and prednisone in the postoperative hormone therapy of hypercortisolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5642. doi:10.1158/1538-7445.AM2017-5642

Blubber transcriptome response to acute stress axis activation involves transient changes in adipogenesis and lipolysis in a fasting-adapted marine mammal

Stress can compromise an animal’s ability to conserve metabolic stores and participate in energy-demanding activities that are critical for fitness. Understanding how wild animals, especially those already experiencing physiological extremes (e.g. fasting), regulate stress responses is critical for evaluating the impacts of anthropogenic disturbance on physiology and fitness, key challenges for conservation. However, studies of stress in wildlife are often limited to baseline endocrine measurements and few have investigated stress effects in fasting-adapted species. We examined downstream molecular consequences of hypothalamic-pituitary-adrenal (HPA) axis activation by exogenous adrenocorticotropic hormone (ACTH) in blubber of northern elephant seals due to the ease of blubber sampling and its key role in metabolic regulation in marine mammals. We report the first phocid blubber transcriptome produced by RNAseq, containing over 140,000 annotated transcripts, including metabolic and adipocytokine genes of interest. The acute response of blubber to stress axis activation, measured 2 hours after ACTH administration, involved highly specific, transient (lasting <24 hours) induction of gene networks that promote lipolysis and adipogenesis in mammalian adipocytes. Differentially expressed genes included key adipogenesis factors which can be used as blubber-specific markers of acute stress in marine mammals of concern for which sampling of other tissues is not possible.

Sources of variation in plasma corticosterone and dehydroepiandrosterone in the male northern cardinal (Cardinalis cardinalis): I. Seasonal patterns and effects of stress and adrenocorticotropic hormone

The secretion of steroids from the adrenal gland is a classic endocrine response to perturbations that can affect homeostasis. During an acute stress response, glucocorticoids (GC), such as corticosterone (CORT), prepare the metabolic physiology and cognitive abilities of an animal in a manner that promotes survival during changing conditions. Although GC functions during stress are well established, much less is understood concerning how adrenal androgens, namely dehydroepiandrosterone (DHEA) are influenced by stress. I conducted three field studies (one experimental and two descriptive) aimed at identifying how both CORT and DHEA secretion in free-living male northern cardinals (Cardinalis cardinalis), vary during acute stress; across different circulations (brachial vs. jugular); in response to ACTH challenge; and during the annual cycle. As predicted, restraint stress increased plasma CORT, but unexpectedly DHEA levels decreased, but the latter effect was only seen for blood sampled from the jugular vein, and not the brachial. The difference in DHEA between circulations may result from increased neural uptake of DHEA during stress. Injection with exogenous adrenocorticotropic hormone (ACTH) increased CORT concentrations, but failed to alter DHEA levels, thus suggesting ACTH is not a direct regulator of DHEA. Monthly field sampling revealed distinct seasonal patterns to both initial and restraint stress CORT and DHEA levels with distinct differences in the steroid milieu between breeding and non-breeding seasons. These data suggest that the CORT response to stress remains relatively consistent, but DHEA secretion is largely independent of the response by CORT. Although CORT functions have been well-studied in wild animals, little research exists for the role of DHEA and their variable relationship sets the stage for future experimental research addressing steroid stress responses.

Diminished adrenal sensitivity to endogenous and exogenous adrenocorticotropic hormone in critical illness: a prospective cohort study.

IntroductionAdrenal dysfunction may represent critical illness-related corticosteroid insufficiency (CIRCI), as evidenced by a diminished cortisol response to exogenous adrenocorticotropic hormone (ACTH), but this concept and its clinical significance remain highly controversial. We studied the adrenal response to exogenous ACTH as a function of the endogenous cortisol-to-ACTH ratio, a measure of adrenal sensitivity, and of clinical variables, during critical illness and recovery from the acute phase.MethodsWe prospectively included 59 consecutive septic and nonseptic patients in the intensive care unit with treatment-insensitive hypotension in whom CIRCI was suspected; patients having received etomidate and prolonged corticosteroids were excluded. An ACTH test (250 μg) was performed, followed by a second test after ≥7 days in acute-phase survivors. Serum total and free cortisol, ACTH, and clinical variables were assessed. Patients were divided according to responses (delta, Δ) of cortisol to ACTH at the first and second tests.ResultsPatients with low (<250 nM) Δ cortisol (n = 14 to 17) had higher baseline cortisol and ACTH but lower cortisol/ACTH ratios than patients with a normal Δ cortisol (≥250 nM) in the course of time. A low Δ cortisol in time was associated with more-severe disease, culture-positive sepsis, and prolonged activated prothrombin time. Results for free cortisol were similar.ConclusionsEven though the pituitary-adrenal axis is activated after stress during critical illness, diminished adrenal sensitivity to endogenous ACTH predicts a low increase of cortisol to exogenous ACTH, suggesting adrenal dysfunction, irrespective of the stage of disease. The data further suggest a role of disease severity and culture-positive sepsis.

Heat stress and ACTH administration on cortisol and insulin-like growth factor I (IGF-I) levels in lactating Holstein cows

ABSTRACTPhysiological and productive responses were studied in five Holstein cows in thermal comfort (T1), stress by exogenous adrenocorticotropic hormone (ACTH) administration (T2) and heat stress (T3) to compare acute and punctual stress (ACTH) and prolonged stress (heat stress). During T1 and T2, cows were housed in a climatic-free stall barn. In T3, the animals were kept in a climatic room (air temperature of 37°C from 08:00 to 13:00 h, and of 26°C from 14:00 to 07:00 h) for 7 days. Milk yield, rectal temperature (RT), respiratory rate (RR) and blood samples were obtained before, during and after all treatments. In T1 at 08:00 h, RT and RR were below the upper critical limit. Simultaneously, cortisol and insulin growth-factor I (IGF-I) were within the normal limits. After ACTH administration (T2), cortisol significantly increased, reaching maximum levels at 60 min and returning to basal levels at 300 min. However, IGF-I was not affected. During T3, Holstein cows did not effectively dissipate their body temperature and RT, RR and cortisol significantly increased. There was a 26.6% reduction in milk production after heat stress (P < .05). Prolonged heat stress was more stressful and cows had higher levels of CORT in T3 than in T2 even before the increase in body temperature. Although the total amount of cortisol and IGF-I presented a negative and significant Pearson correlation (r = −0.79), IGF-I was not significantly influenced by heat stress or ACTH administration, and the relationship between IGF-I and heat stress remains controversial.

The central anorexigenic mechanism of adrenocorticotropic hormone involves the caudal hypothalamus in chicks

Adrenocorticotropic hormone (ACTH), consisting of 39 amino acids, is most well-known for its involvement in an organism's response to stress. It also participates in satiety, as exogenous ACTH causes decreased food intake in rats. However, its anorexigenic mechanism is not well understood in any species and its effect on appetite is not reported in the avian class. Thus, the present study was designed to evaluate central ACTH's effect on food intake and to elucidate the mechanism mediating this response using broiler chicks. Chicks that received intracerebroventricular (ICV) injection of 1, 2, or 4nmol of ACTH reduced food intake, under both ad libitum and 180min fasted conditions. Water intake was also reduced in ACTH-injected chicks under both feeding conditions, but when measured without access to feed it was not affected. Blood glucose was not affected in either feeding condition. Following ACTH injection, c-Fos immunoreactivity was quantified in key appetite-associated hypothalamic nuclei including the ventromedial hypothalamus (VMH), dorsomedial hypothalamus, lateral hypothalamus (LH), arcuate nucleus (ARC) and the parvo- and magno-cellular portions of the paraventricular nucleus. ACTH-injected chicks had increased c-Fos immunoreactivity in the VMH, LH, and ARC. Hypothalamus was collected at 1h post-injection, and real-time PCR performed to measure mRNA abundance of some appetite-associated factors. Neuropeptide Y, pro-opiomelanocortin, glutamate decarboxylase 1, melanocortin receptors 2–5, and urocortin 3 mRNA abundance was not affected by ACTH treatment. However, expression of corticotropin releasing factor (CRF), urotensin 2 (UT), agouti-related peptide (AgRP), and orexin (ORX), and melanocortin receptor 1 (MC1R) mRNA decreased in the hypothalamus of ACTH-injected chicks. In conclusion, ICV ACTH causes decreased food intake in chicks, and is associated with VMH, LH, and ARC activation, and a decrease in hypothalamic mRNA abundance of CRF, UT, AgRP, ORX and MC1R.

Endocrine and immunological responses to adrenocorticotrophic hormone (ACTH) administration in juvenile harbor seals (Phoca vitulina) during winter and summer

There is increasing interest in measuring endocrine and immune parameters in free-ranging seals and sea lions, but there is a lack of understanding in how an acute stress response, often associated with capture and handling, influences these parameters of interest. The main objective of this study was to assess the impact of a simulated stressor on both endocrine and immune parameters. During two seasons, exogenous adrenocorticotrophic hormone (ACTH) was administered to seven female juvenile harbor seals and the response of several hormones (cortisol, aldosterone, total and free thyroxine and total triiodothyronine) and immunological parameters (total and differential leukocyte counts and peripheral blood mononuclear cells (PBMC) proliferation) were assessed. Cortisol peaked at 165min (winter 203.1±84.7ng/ml; summer 205.3±65.7ng/ml) and remained significantly elevated 240min after ACTH infusion in both seasons. Aldosterone peaked at 90min (winter 359.3±249.3pg/ml; summer 294.1±83.7pg/ml) and remained elevated 240min after administration of ACTH in both seasons. An increase in circulating total white blood cells was driven primarily by the increase in neutrophils which occurred simultaneously with a decrease in lymphocytes leading to an overall increase in neutrophil to lymphocyte ratio. These findings demonstrate that a simulated stress response in juvenile harbor seals results in a predictable increase in both cortisol and aldosterone concentrations, and were associated with altered immunological parameters.

Muscle transcriptome response to ACTH administration in a free-ranging marine mammal.

While much of our understanding of stress physiology is derived from biomedical studies, little is known about the downstream molecular consequences of adaptive stress responses in free-living animals. We examined molecular effectors of the stress hormones cortisol and aldosterone in the northern elephant seal, a free-ranging study system in which extreme physiological challenges and cortisol fluctuations are a routine part of life history. We stimulated the neuroendocrine stress axis by administering exogenous adrenocorticotropic hormone (ACTH) and examined the resultant effects by measuring corticosteroid hormones, metabolites, and gene expression before, during, and following administration. ACTH induced an elevation in cortisol, aldosterone, glucose, and fatty acids within 2 h, with complete recovery observed within 24 h of administration. The global transcriptional response of elephant seal muscle tissue to ACTH was evaluated by transcriptomics and involved upregulation of a highly coordinated network of conserved glucocorticoid (GC) target genes predicted to promote metabolic substrate availability without causing deleterious effects seen in laboratory animals. Transcriptional recovery from ACTH was characterized by downregulation of GC target genes and restoration of cell proliferation, metabolism, and tissue maintenance pathways within 24 h. Differentially expressed genes included several adipokines not previously described in muscle, reflecting unique metabolic physiology in fasting-adapted animals. This study represents one of the first transcriptome analyses of cellular responses to hypothalamic-pituitary-adrenal axis stimulation in a free-living marine mammal and suggests that compensatory, tissue-sparing mechanisms may enable marine mammals to maintain cortisol and aldosterone sensitivity while avoiding deleterious long-term consequences of stress.

Validation and use of hair cortisol as a measure of chronic stress in eastern chipmunks (Tamias striatus).

Stress levels of individuals are documented using glucocorticoid concentrations (including cortisol) in blood, saliva, urine or faeces, which provide information about stress hormones during a short period of time (minutes to days). In mammals, use of hair cortisol analysis allows for the assessment of prolonged stress over weeks and months and provides information on chronic stress levels without bias associated with handling. Here, we validate hair cortisol analysis in wild rodents using exogenous adrenocorticotrophic hormone (ACTH challenge) and apply the technique to evaluate stress in eastern chipmunks inhabiting logged and natural sites. Chipmunks were subjected to a mark-recapture study and injected weekly with ACTH (Synacthen Depot) or saline, with hair being collected at the conclusion of the challenge. Subsequently, faecal and hair samples were collected from chipmunks occupying logged and natural sites to assess the utility of hair cortisol in comparison with faecal cortisol metabolites. Following extraction, cortisol concentrations were quantified in hair and faecal extracts by enzyme immunoassay. Hair cortisol concentrations were significantly elevated in samples from ACTH-injected chipmunks compared with saline-injected control animals (five times higher). Chipmunks inhabiting logged sites had increased faecal cortisol metabolite concentrations compared with those in natural sites, but no differences were observed in hair cortisol concentrations. Faecal cortisol metabolite levels were positively correlated with hair cortisol levels in chipmunks. Hair cortisol levels reflect changes in circulating cortisol levels and can be used to evaluate the adrenal stress response, and thus stress, in natural populations. Nonetheless, because of the differences in the temporal scale of stress that hair and faeces represent, we caution the use of hair cortisol for detecting differences in physiological stress when comparing individuals within populations and suggest that it is best suited to examining population-level differences.

Altered entrainment to the day/night cycle attenuates the daily rise in circulating corticosterone in the mouse.

The suprachiasmatic nucleus (SCN) is a circadian oscillator entrained to the day/night cycle via input from the retina. Serotonin (5-HT) afferents to the SCN modulate retinal signals via activation of 5-HT1B receptors, decreasing responsiveness to light. Consequently, 5-HT1B receptor knockout (KO) mice entrain to the day/night cycle with delayed activity onsets. Since circulating corticosterone levels exhibit a robust daily rhythm peaking around activity onset, we asked whether delayed entrainment of activity onsets affects rhythmic corticosterone secretion. Wheel-running activity and plasma corticosterone were monitored in mice housed under several different lighting regimens. Both duration of the light∶dark cycle (T cycle) and the duration of light within that cycle was altered. 5-HT1B KO mice that entrained to a 9.5L:13.5D (short day in a T = 23 h) cycle with activity onsets delayed more than 4 h after light offset exhibited a corticosterone rhythm in phase with activity rhythms but reduced 50% in amplitude compared to animals that initiated daily activity <4 h after light offset. Wild type mice in 8L:14D (short day in a T = 22 h) conditions with highly delayed activity onsets also exhibited a 50% reduction in peak plasma corticosterone levels. Exogenous adrenocorticotropin (ACTH) stimulation in animals exhibiting highly delayed entrainment suggested that the endogenous rhythm of adrenal responsiveness to ACTH remained aligned with SCN-driven behavioral activity. Circadian clock gene expression in the adrenal cortex of these same animals suggested that the adrenal circadian clock was also aligned with SCN-driven behavior. Under T cycles <24 h, altered circadian entrainment to short day (winter-like) conditions, manifest as long delays in activity onset after light offset, severely reduces the amplitude of the diurnal rhythm of plasma corticosterone. Such a pronounced reduction in the glucocorticoid rhythm may alter rhythmic gene expression in the central nervous system and in peripheral organs contributing to an array of potential pathophysiologies.

Hypothalamic-pituitary-adrenal axis in lethal canine Staphylococcus aureus pneumonia.

The clinical significance and even existence of critical illness-related corticosteroid insufficiency is controversial. Here, hypothalamic-pituitary-adrenal (HPA) function was characterized in severe canine Staphylococcus aureus pneumonia. Animals received antibiotics and titrated life-supportive measures. Treatment with dexamethasone, a glucocorticoid, but not desoxycorticosterone, a mineralocorticoid, improves outcome in this model. Total and free cortisol, adrenocorticotropic hormone (ACTH). and aldosterone levels, as well as responses to exogenous ACTH were measured serially. At 10 h after the onset of infection, the acute HPA axis stress response, as measured by cortisol levels, exceeded that seen with high-dose ACTH stimulation but was not predictive of outcome. In contrast to cortisol, aldosterone was largely autonomous from HPA axis control, elevated longer, and more closely associated with survival in early septic shock. Importantly, dexamethasone suppressed cortisol and ACTH levels and restored ACTH responsiveness in survivors. Differing strikingly, nonsurvivors, sepsis-induced hypercortisolemia, and high ACTH levels as well as ACTH hyporesponsiveness were not influenced by dexamethasone. During septic shock, only serial measurements and provocative testing over a well-defined timeline were able to demonstrate a strong relationship between HPA axis function and prognosis. HPA axis unresponsiveness and high aldosterone levels identify a septic shock subpopulation with poor outcomes that may have the greatest potential to benefit from new therapies.

Monitoring physiological stress in semi-free ranging populations of an endangered Australian marsupial, the Greater Bilby (Macrotis lagotis)

Rapid and reliable physiological evaluation of stress is necessary for understanding the potential impacts of environmental changes on managed populations of threatened mammals. In situ populations of Australia’s iconic marsupial, the greater bilby (Macrotis lagotis), are nearing extinction due to the impacts of competition and predation by feral animals and unpredictable climatic events (summer heat waves). In this study, we focussed our aim to identify a non-invasive method to measure adrenal activity in the species and also to identify potential factors that should be considered when comparing physiological stress in semi-free ranging populations of the species. We validated an enzyme immunoassay (EIA) for detecting fecal cortisol metabolites (FCM) from fresh fecal pellets taken from bilbies within four captive sites and two semi-free ranging populations around Queensland and New South Wales, Australia. Our FCM EIA successfully detected the ‘raise and fall’ pattern of FCM levels within 3 days of exogenous adrenocorticotropic hormone (ACTH) challenge. Mean FCM levels differed significantly between the captive sites and between sexes. All male bilbies grouped outdoor in captivity expressed the highest mean FCM level in comparison to all captive males that were housed individually or as groups indoors. Also, semi-free ranging bilbies expressed higher mean FCM levels than the captive bilbies. Overall, our study successfully validated a non-invasive tool for monitoring physiological stress in the greater bilby. In the future, it will be worthwhile to consider factors such as housing conditions, sex and location when comparing the adrenal sensitivity to environmental changes, to help evaluate the success of management interventions (such as predator free enclosures) and support the survival of the species.

Pubertal shifts in adrenal responsiveness to stress and adrenocorticotropic hormone in male rats

Studies have indicated significant pubertal-related differences in hormonal stress reactivity. We report here that prepubertal (30 days) male rats display a more protracted stress-induced corticosterone response than adults (70 days), despite showing relatively similar levels of adrenocorticotropic hormone (ACTH). Additionally, we show that adrenal expression of the ACTH receptor, melanocortin 2 receptor (Mc2r), is higher in prepubertal compared to adult animals, and that expression of melanocortin receptor accessory protein (Mrap), a molecule that chaperones MC2R to the cell surface, is greater in prepubertal males following stress. Given that these data suggest a pubertal shift in adrenal sensitivity to ACTH, we directly tested this possibility by injecting prepubertal and adult males with 6.25 or 9.375μg/kg of exogenous rat ACTH and measured their hormone levels 30 and 60min post-injection. As these doses resulted in different circulating levels of ACTH at these two ages, we performed regression analyses to assess the relationship between circulating ACTH and corticosterone concentrations. We found no difference between the ages in the correlation between ACTH and corticosterone levels at the 30min time point. However, 60min following the ACTH injection, we found prepubertal rats had significantly higher corticosterone concentrations at lower levels of ACTH compared to adults. These data suggest that prolonged exposure to ACTH leads to greater corticosterone responsiveness prior to puberty, and indicate that changes in adrenal sensitivity to ACTH may, in part, contribute to the protracted hormonal stress response in prepubertal rats.

Plasma cortisol activity in rats under conditions of chronic stress supplemented with resveratrol

Objective: Determine the activity of cortisol in rats treated with exogenous adrenocorticotropic hormone (ACTH) and a resveratrol supplement.Methods: Forty-eight adult male rats and 16 adult female rats (Rattus norvegicus) three months old with a body weight of 200 to 250 g and 300 to 350 g for both male and female were used and kept in controlled environmental conditions, temperature of 20±2° C and light-dark cycles of 14 and 10 hours. They were fed with balanced food and had free access to water. The rats were randomly divided into four groups: group 1, was treated with 5 μg/kg of ACTH i.p. every twelve hours; group 2, received the same treatment with ACTH plus a grape extract supplementation of 40 mg/kg; group 3, only received grape extract and group 4,served as control and only received saline solution (0.9%) i.p. The experimental was designed as a 2×2 factorial with two ACTH levels and two extract grape levels.Results: Significant differences were not found in cortisol concentrations for day, gender or treatment effects (0.75 μg/dL ± 0.11; p &lt;0.001).Conclusion: Results suggest that chronic stress and consume of resveratrol did not produce any effect in the activity of plasmatic cortisol, in stressed and unstressed rats stressed. In the same way, possibly, dose of ACTH did not produce stimulation of the suprarenal gland for these animals.

The effect of temperament and responsiveness towards humans on the behavior, physiology and milk production of multi-parous dairy cows in a familiar and novel milking environment

The objectives of this study were to investigate whether; 1) temperament or 2) behavioral responsiveness to humans, can affect the behavior, physiology and productivity of dairy cows being milked in a familiar and novel milking environment. Temperament of multi-parous cows was defined based on exit time from a restraint device, as High Responders (HR; n=10), Medium Responders (MR; n=10) or Low Responders (LR; n=10). The behavioral response of cows to humans was assessed using four tests: restraint, exit speed, avoidance distance test and a voluntary approach test. Cows were milked according to their established routines in a rotary (familiar) milking parlor and behavioral, physiological and production data were collected over five consecutive days, including heart rate, cortisol and oxytocin concentrations and milk yield. The following week, cows were milked in a novel environment (herringbone parlor within the same farm facility) over five consecutive days, and the data and sample collection program was repeated. Cows were then given an exogenous adrenocorticotropic hormone (ACTH) challenge to measure adrenal responsiveness. Exit time was negatively correlated with the behavioral responses of cows to restraint and human avoidance distance (HAD) in the paddock and arena. The behavioral response of cows to the milking process was greater in MR than LR and HR cows in the familiar and novel milking environments. Milk yields were greater in LR than HR cows in the novel but not the familiar milking parlor. Oxytocin concentrations increased during milking in the novel environment, regardless of cow temperament. In the familiar and novel environments, heart rates were higher in HR than LR cows before and during milking and rMSSD was lower in HR cows during milking in a novel environment. There was no difference in cortisol concentrations between LR and HR cows in response to an ACTH challenge, but HR cows had higher baseline cortisol levels than LR cows. The number of leg lifts cows performed when restrained in the crush was associated with several physiological and milk production measures. These results indicate that cows with different temperaments vary in their basal physiology as well as their behavioral and physiological responses to milking and stress associated with being milked in a novel environment.

Regulation of the HPA axis is related to song complexity and measures of phenotypic quality in song sparrows

Regulation of the hypothalamic–pituitary–adrenal (HPA) axis is a key component of the vertebrate stress response. Prior studies have found that variation in HPA responses were correlated to measures of fitness and physiological condition. In addition, sexually-selected traits have also been found to correlate to measures of condition. The proximate mechanisms responsible for such covariation between sexually selected traits and measures of quality are unclear, but could involve variation in HPA regulation. We investigated whether HPA activity is related to song complexity, body size/condition and leukocyte profiles in wild male song sparrows (Melospiza melodia). We characterized three aspects of HPA activity: 1) response to restraint stress; 2) negative feedback, assessed by the ability of exogenous dexamethasone to suppress corticosterone levels; and 3) adrenal sensitivity to exogenous adrenocorticotropic hormone (ACTH). Birds with lower responses to restraint stress had more complex song and more heterophils and higher heterophil to lymphocyte (H:L) ratios. Birds with more effective negative feedback were larger and had fewer heterophils and lower H:L ratios, suggesting lower levels of physiological stress or infection. We observed no relationship between adrenal sensitivity to exogenous ACTH and any of the factors. These findings illustrate important relationships between HPA activity, song complexity, and morphological and physiological traits. Song complexity may thus provide receivers with information about the ability of the singer to cope with stressors.

Hypothalamic–pituitary–adrenal axis function in pony foals after neonatal ACTH‐induced glucocorticoid overexposure

The effects of overexposure to glucocorticoids during early life of the foal on the subsequent HPA programming of the hypothalamic-pituitary-adrenal axis are unknown. To test the hypotheses that excess glucocorticoid exposure in early life subsequently increases both basal plasma concentrations of cortisol and the adrenocortical responsiveness to exogenous adrenocorticotropic hormone (ACTH). Foals received either saline (0.9% NaCl, n = 9) or long-acting ACTH (0.125 mg i.m. b.i.d., n = 6) for 5 days from Day 1 to increase endogenous cortisol concentrations. Long-term indwelling catheters were inserted under local anaesthesia into the jugular veins of foals aged 2 and 12 weeks. After recovery, short-acting ACTH1-24 was given as a single i.v. injection (2 microg/kg bwt) and blood samples were taken at 5-30 min intervals before and after ACTH administration to measure plasma cortisol concentrations. Basal plasma cortisol concentrations were higher in ACTH- than in saline-treated foals at age 3 weeks, but not at 13 weeks. There were no significant differences in either the time profile or the area under the cortisol curve in response to ACTH between the 2 groups. These data suggest that ACTH-induced overexposure to glucocorticoids during early post natal life of the foal does not have a programming effect on HPA axis function at 13 weeks. In foals, the effects of ACTH-induced overexposure to glucocorticoids, if any, may not become apparent until much later in life in a long-lived species such as the horse. These studies suggest that clinical and other stressful conditions that raise plasma cortisol concentrations during early life are unlikely to programme cardiovascular and metabolic function in horses in the short term.

Steroidogenesis in the adrenal dysfunction of critical illness: impact of etomidate

IntroductionThis study was aimed at characterizing basal and adrenocorticotropic hormone (ACTH)-induced steroidogenesis in sepsis and nonsepsis patients with a suspicion of critical illness-related corticosteroid insufficiency (CIRCI), taking the use of etomidate-inhibiting 11β-hydroxylase into account.MethodThis was a prospective study in a mixed surgical/medical intensive care unit (ICU) of a university hospital. The patients were 62 critically ill patients with a clinical suspicion of CIRCI. The patients underwent a 250-μg ACTH test (n = 67). ACTH, adrenal steroids, substrates, and precursors (modified tandem mass spectrometry) also were measured. Clinical characteristics including use of etomidate to facilitate intubation (n = 14 within 72 hours of ACTH testing) were recorded.ResultsAt the time of ACTH testing, patients had septic (n = 43) or nonseptic critical illness (n = 24). Baseline cortisol directly related to sepsis and endogenous ACTH, independent of etomidate use. Etomidate was associated with a lower baseline cortisol and cortisol/11β-deoxycortisol ratio as well as higher 11β-deoxycortisol, reflecting greater 11β-hydroxylase inhibition in nonsepsis than in sepsis. Cortisol increases < 250 mM in exogenous ACTH were associated with relatively low baseline (HDL-) cholesterol, and high endogenous ACTH with low cortisol/ACTH ratio, independent of etomidate. Although cortisol increases with exogenous ACTH, levels were lower in sepsis than in nonsepsis patients, and etomidate was associated with diminished increases in cortisol with exogenous ACTH, so that its use increased, albeit nonsignificantly, low cortisol increases to exogenous ACTH from 38% to 57%, in both conditions.ConclusionsA single dose of etomidate may attenuate stimulated more than basal cortisol synthesis. However, it may only partly contribute, particularly in the stressed sepsis patient, to the adrenal dysfunction of CIRCI, in addition to substrate deficiency.

Immunoglobulin changes in boars exposed to administration of levamisole and exogenous adrenocorticotropic hormone

The objective of this paper is to determine the effect of levamisole (LEV) immunoglobulin concentration in the serum of boars exposed to three-day stress induced by the adrenocorticotropic hormone (ACTH). Boars were assigned to four groups (n=7). The first group received LEV for three days (2.5 mg/kg BW), the second group received ACTH (10 g/kg BW) for three days and the third group received LEV for three consecutive days and ACTH on the three following days (2.5 mg/kg BW ; ACTH 10 g/kg BW). The control group received saline solution (1 mL) during the experiment (six days). Concentrations of total protein, globulin, albumin and immunoglobulin concentration (IgG, IgA and IgM) were determined during levamisole, ACTH and levamisole + ACTH combined treatment administration, and during the 16-day post- administration period. Total protein levels were significantly increased during the stress period and over the next sixteen days (p0.01 to p0.0001, respectively) in the ACTH group of boars. However, total protein levels were significantly elevated in the LEV+ACTH group on day 1 and 2 of ACTH injection (p0.05 and p0.001) and on day 5 and the last day of measurement (p0.001 and p0.01). However, the three-day administration of levamisole (LEV) stimulated a statistically significant increase of protein concentrations compared to control values after levamisole treatment, on days 2 and on days 11, 15 and 24 (p0.01, all). Levels of serum albumin were not affected with levamisole or ACTH treatment. According to determined total protein concentrations, globulin concentrations were significantly increased throughout and after the ACTH treatment in the second group (p0.01 to p0.0001, respectively). Also, globulin concentrations were significantly elevated in the LEV+ACTH group throughout the three-day ACTH treatment and in the 16-day post-administration period (p0.05 to p0.01, respectively). The three-day levamisole administration resulted in an increase of globuline concentrations (LEV). However, there were no statistically significant differences in comparison to control pigs. ACTH treatment significantly elevated serum IgG concentration during the stress period (p0.001 to p0.0001, respectively) and over the next 16 days (p0.01 to p0.0001, respectively). However, in the LEV+ACTH group of boars, IgG levels were significantly elevated on days 1 and 3 of ACTH injection (p0.05 and p0.01) and days 1 and 5 in the post-treatment period (p0.01 and p0.05). Administration of levamisole (LEV) had no significant impact on IgG levels compared to the control boar group. However, a statistically significant increase in IgA concentrations in boars treated with levamisole (LEV) was determined on day 2 (p0.02) and day 11 (p0.05) after administration of levamisole compared to animals of the LEV+ACTH group. Furthermore, boars receiving levamisole before stress induction (LEV+ACTH) on day 5 after stress induction had IgM concentrations statistically significantly higher (p0.05) than animals treated only with ACTH. These results show that levamisole may stimulate the immune system in swine and immunoglobulin in the serum of boars exposed to stress.

Maternal dexamethasone treatment in late gestation induces precocious fetal maturation and delivery in healthy Thoroughbred mares

The foal requires an active hypothalamo-pituitary-adrenal (HPA) axis for organ maturation and post natal survival. Prenatal administration of synthetic glucocorticoids may provide an effective method for inducing fetal maturation safely in the mare. To determine whether dexamethasone administered to late pregnant mares: 1) will induce fetal maturation and precocious delivery; 2) is safe to use and 3) to identify endocrine responses in the mare and foal. Pregnant Thoroughbred mares received either 100 mg dexamethasone i.m. (treated n = 5) or 50 ml saline i.m. (control n = 5) at 315, 316 and 317 days of gestation. Plasma progestagens, cortisol and prostaglandin F(2α) metabolite (PGFM) concentrations were measured before and after treatment. The foals were weighed, the crown-rump length (CRL) measured and an adrenal stimulation test performed on Day 1. Dexamethasone significantly (P<0.01) reduced gestation length in treated mares without apparent adverse effects. Plasma progestagens increased (P<0.05), and cortisol and PGFM (P<0.05) decreased, following dexamethasone treatment compared with control mares. Foals were clinically mature but those from dexamethasone treated mares had reduced (P<0.05) CRL, but not bodyweights, compared with controls. Their cortisol concentrations increased following exogenous adrenocorticotrophic hormone stimulation but 2 foals from dexamethasone treated mares showed evidence of adrenal suppression. Dexamethasone stimulates precocious fetal maturation and delivery in healthy late pregnant mares. However, fetal HPA activity may be suppressed. Dexamethasone treatment could be used to improve foal viability in mares at risk of preterm delivery. The endocrine effects of such a therapy must be evaluated before clinical intervention with glucocorticoids can be recommended.