Basal Adrenocorticotropic Hormone Levels Research Articles

Effects of mu, kappa, and delta opioid receptor agonists on the function of hypothalamic–pituitary–adrenal axis in monkeys

Opioids can modulate neuroendocrine function. Less is known about the involvement of opioid receptor subtypes in the stimulatory effects of opioids on the primate hypothalamic-pituitary-adrenal (HPA) axis. The aim of this study was to investigate the stimulatory effects of opioids selective for each receptor subtype on plasma adrenocorticotropic hormone (ACTH) and cortisol levels in both male and female monkeys. The blood collection procedure was conducted in home-caged and unanesthetized rhesus monkeys that showed low and stable basal ACTH and cortisol levels. Three opioid receptor agonists, fentanyl, U-50488H, and SNC80, were used in behaviorally active doses; they are highly selective for mu, kappa, and delta opioid receptors, respectively. Plasma samples were collected at multiple time points before and after IV administration of each compound and were quantified by radioimmunoassay. Neither fentanyl (0.0003-0.02mg/kg) nor SNC80 (0.03-0.3mg/kg) changed either ACTH or cortisol basal levels. In contrast, U-50488H (0.01-1mg/kg) dose-dependently stimulated ACTH and cortisol release in both male and female monkeys. Importantly, the stimulatory effects of U-50488H on the secretion of ACTH were blocked by a selective kappa opioid receptor antagonist, nor-Binaltorphimine. The antagonist effect of nor-binaltorphimine lasted up to 20 weeks. These results indicate that only synthetic kappa, but not mu or delta opioid receptor agonists stimulate HPA axis activity after acute administration in primates.

Temporal patterns of self-injurious behavior correlate with stress hormone levels in the developmentally disabled

While the origins and developmental course of self-injurious behavior (SIB) remain relatively unknown, recent studies suggest a biological imbalance may potentiate or provoke the contagious recurrence of SIB patterns in individuals with severe developmental disabilities (DD). Evidence from several laboratories indicates that functioning, relations, and processing of a stress-related molecule, proopiomelanocortin (POMC) may be perturbed among certain subgroups of individuals exhibiting SIB. The current investigation employed a unique time-pattern analysis program (THEME) to examine whether recurrent temporal patterns (T-patterns) of SIB were related to morning levels of two POMC-derived hormones: β-endorphin (βE) and adrenocorticotropic hormone (ACTH). THEME was used to quantify highly significant (non-random) T-patterns that included SIB within a dataset of in situ observational recordings spanning 8 days (∼ 40 h) in 25 subjects with DD. Pearson's product–moment analyses revealed highly significant correlations between the percentage of T-patterns containing SIB and basal levels of both βE and ACTH, which were not found with any other “control” T-patterns. These findings support the hypothesis that the recurrent temporal patterning of SIB represents a unique behavioral phenotype directly related to perturbed levels of POMC-derived stress hormones in certain individuals with severe DD.

Adrenocorticotropic Hormone/Cortisol Response to Physical Exercise in Abstinent Alcoholic Patients

Alterations in the hypothalamic-pituitary-adrenal (HPA) axis in alcoholic patients have been reported in various experimental conditions. To establish whether alcoholism affects the HPA axis activation during physical exercise, 10 recent abstinent alcoholic patients (age range: 33-45 years; duration of alcohol dependence: range 4-6 years) were tested by exercising on a bicycle ergometer. Ten age-matched healthy nonalcoholic men participated as controls. The workload was gradually increased at 3-minute intervals until exhaustion and lasted about 15 minutes for all subjects. Alcoholic patients were tested at 3 time points, at 4, 6, and 8 weeks after alcohol withdrawal, whereas controls were tested only once. Main outcome measurements were circulating levels of adrenocorticotropic hormone (ACTH) and cortisol and physiological variables during physical exercise [heart rate, blood pressure, ventilation, frequency of breathing, tidal volume, oxygen consumption (VO2), carbon oxide production (VCO2), and respiratory exchange ratio (R)]. Similar basal and exercise-induced changes in physiological variables were observed in controls and alcoholic patients in all tests. Basal levels of ACTH and cortisol were similar in all tests performed on alcoholic patients and on normal controls. In normal subjects, exercise induced a significant increase in plasma ACTH and serum cortisol levels, with peak levels at 20 minutes for ACTH (84% higher than baseline) and at 30 minutes for cortisol (70% higher than baseline). After 4 weeks of abstinence, slight but not significant ACTH/cortisol responses to physical exercise were observed in alcoholic patients (mean peaks were 10 and 18% higher than baseline, respectively, for ACTH and cortisol). By contrast, when the exercise test was repeated after 6 weeks abstinence, ACTH/cortisol levels rose significantly versus baseline (mean peak levels of ACTH and cortisol were 48 and 38% higher than baseline, respectively, for ACTH and cortisol). However, the hormonal responses were significantly lower than in the normal controls. At 8 weeks of abstinence, ACTH/cortisol responses were significantly higher than 2 weeks previously, and were not distinguishable from the increments observed in the normal controls (76 and 68% higher than baseline, respectively, for ACTH and cortisol). In concurrence with previous reports showing alterations of the HPA axis in the central nervous system in alcohol-dependent subjects, these data show a defect of the neuroendocrine mechanism(s) underlying the ACTH/cortisol response to physical exercise for at least a month after alcohol withdrawal, with reconstitution of a normal hormonal response at 8 weeks.

Effects of 3-Methyl-4-nitrophenol on the Suppression of Adrenocortical Function in Immature Male Rats

In previous studies, we found that 3-methyl-4-nitrophenol (4-nitro-m-cresol; PNMC) isolated from diesel exhaust particles, and also a degradation product of the insecticide fenitrothion, exhibited testicular toxicity in the male of both immature rat and adult Japanese quail. It is well established that a functional relationship exists between the gonads and adrenals. The present study investigates the effect of PNMC on the adrenocortical functions of immature male rats. We subcutaneously injected 28-d-old rats with PNMC (1, 10 or 100 mg/kg) daily for 5 d. The adrenal glands weights significantly decreased in rats treated with 10 or 100 mg/kg PNMC. Plasma concentrations of adrenocorticotropic hormone (ACTH) were significantly increased in animals treated with 100 mg/kg PNMC. In contrast, plasma concentrations of corticosterone were significantly decreased in all PNMC-treated groups, and plasma concentrations of progesterone were significantly decreased in rats treated with 10 or 100 mg/kg PNMC. To investigate the direct effects of PNMC on the secretion of ACTH from the anterior pituitary gland, and on the secretion of corticosterone from the adrenal, we exposed cultured primary anterior pituitary and adrenal cells to PNMC (10(-8), 10(-7), 10(-6), or 10(-5 m)) for 24 h. PNMC did not change basal levels of ACTH released from cultured anterior pituitary cells. However, PNMC significantly inhibited ACTH-stimulated production of corticosterone and progesterone from cultured adrenal cells. These results clearly show that PNMC has a direct effect on the adrenal gland to reduce corticosterone secretion, and the associated increase in plasma ACTH is probably due decreased negative feedback regulation by corticosterone.

The ACTH Response to Dexamethasone in Persian Gulf War Veterans

The basis of postdeployment health symptoms in Gulf War veterans remains poorly understood. Alterations in the feedback regulation of the hypothalamic-pituitary-adrenal (HPA) axis have been demonstrated in posttraumatic stress disorder (PTSD) and other bodily disorders related to stress. The objective of this article was to examine whether similar HPA axis alterations are related to Gulf War deployment, postdeployment health symptoms, or PTSD. Plasma adrenocorticotropic hormone (ACTH) was measured on consecutive mornings at 08:00 h before and after a low dose of oral dexamethasone (DEX) at 23:00 h in Gulf War veterans with PTSD (n = 14), Gulf War veterans without PTSD (n = 11), and healthy veterans never deployed to a war zone (n = 12). Both Gulf War veterans with PTSD and Gulf War veterans without PTSD had significantly lower post-DEX ACTH levels than the nonexposed veterans, in the absence of group differences in basal ACTH or DEX levels. Among Gulf War veterans, post-DEX ACTH levels were significantly associated with musculoskeletal symptoms. Gulf War deployment and postdeployment health symptoms appear to be associated with alterations in feedback regulation of the pituitary gland that suggests a possible common link between postdeployment health symptoms and other chronic stress-related conditions.

Altered Levels of Basal Cortisol in Healthy Subjects with a 118G Allele in Exon 1 of the Mu Opioid Receptor Gene

The mu opioid receptor is centrally involved in the development of the addictive diseases. It also modulates the stress responsive hypothalamic-pituitary-adrenal axis. Receptors encoded by the variant 118G polymorphism in exon 1 of the mu opioid receptor gene have a threefold increase in beta-endorphin binding and beta-endorphin is three times more potent in receptor-mediated activation of G protein-coupled inwardly rectifying potassium channels. Humans with this variant have increased stress response following opioid antagonism. Here, we study basal levels of adrenocorticotropic hormone and cortisol in subjects with this variant. In all, 59 healthy adults were genotyped and had morning levels of adrenocorticotropic hormone and cortisol measured following intravenous administration of saline placebo. Subjects with a 118G allele had significantly greater levels of cortisol than subjects with the prototype gene. Groups did not differ in levels of adrenocorticotropic hormone. A planned comparison revealed significantly greater cortisol in females with at least one copy of the 118G allele compared to females with the prototype gene. There was no significant effect of gender alone, nor was there a significant interaction between gender and genotype, on ACTH or cortisol. Subjects with at least one copy of the 118G allele have increased basal levels of cortisol, which may influence the susceptibility to and treatment of the stress responsive dyscrasia.

Experimentally-induced hyperthyroidism is associated with activation of the rat hypothalamic–pituitary–adrenal axis

Previous studies on the effects of altered thyroid function on the secretion and metabolism of adrenocortical hormones suggest a degree of adrenocortical hyperactivity in hyperthyroidism. We have previously shown that experimentally-induced hyperthyroidism is associated with significant alterations in pituitary-adrenal responsiveness to synthetic ovine corticotropin-releasing hormone (oCRH) that are contingent upon the duration of the altered thyroid function. The purpose of this study was to assess the time-dependent effects of hyperthyroidism on the functional integrity of the hypothalamic-pituitary-adrenal (HPA) axis by in vivo stimulation of the hypothalamic CRH neuron and adrenal cortex. The functional integrity of the HPA axis was examined in vivo in sham-thyroidectomized male Sprague-Dawley rats given placebo or in thyroidectomized rats given 50 mug of thyroxine every day for 7 or 60 days. Responses to insulin-induced hypoglycemia and IL-1alpha stimulation were used to assess the hypothalamic CRH neuron. Adrenocortical reserve was assessed in response to low-dose adrenocorticotropic hormone (ACTH), following suppression of the HPA axis with dexamethasone. Adrenal and thymus tissue weight, in addition to basal plasma ACTH, corticosterone and thyroid indices were also determined. Basal plasma corticosterone and corticosterone binding globulin (CBG) concentrations were significantly increased in short- and long-term hyperthyroid rats, and by 60 days, cerebrospinal fluid (CSF) corticosterone levels were significantly increased. Basal plasma ACTH levels were similar to controls. Although plasma ACTH responses to hypoglycemic stress and IL-1alpha administration in both short- and long-term hyperthyroidism were normal, corticosterone responses to the ACTH release during the administration of these stimuli were significantly increased. The adrenal reserve was significantly elevated in short-term hyperthyroidsim. Long-term hyperthyroidism, however, was associated with a significant reduction in adrenocortical reserve. A significant increase in adrenal weights and a decrease in thymus weights were observed in both short- and long-term hyperthyroidism. The available data confirms that hyperthyroidism is associated with hypercorticosteronemia, although the locus that is principally affected still remains unclear. Despite the sustained hyperactivity of the HPA axis, long-term experimentally-induced hyperthyroidism is associated with diminished adrenal functional reserve. The alterations in HPA function in states of disturbed thyroid function were found to be somewhat more pronounced as the duration of thyroid dysfunction increased.

Immobilization and cold stress affect sympatho–adrenomedullary system and pituitary–adrenocortical axis of rats exposed to long-term isolation and crowding

Changes in plasma levels of noradrenaline (NA), adrenaline (A), adrenocorticotropic hormone (ACTH) and corticosterone (CORT), as well as in cytosol glucocorticoid receptor (GR) and heat shock protein 70 (Hsp 70) in hippocampus of adult rat males exposed to two long-term types of psychosocial stress, both under basal conditions and in response to immobilization and cold as heterotypic additional stressor were studied. Long-term isolation produced a significant elevation of basal plasma ACTH and CORT levels, but did not affect that of NA and A, while long-term crowding conditions did not elevate the basal plasma levels of these hormones. Long-term isolation of rats exposed to 2 h of immobilization or cold led to a significant elevation of plasma NA, A and CORT in comparison with the controls. Long-term crowding conditions and exposure of animals to immobilization or cold also resulted in an increased plasma NA, A and CORT levels, but to a lesser extent in comparison with the long-term isolation. At the same time, plasma ACTH was significantly more elevated in long-term crowded than in long-term isolated rats. Both kinds of long-term psychosocial stresses (isolation and crowding) had similar but less pronounced effects on cytosol GR and Hsp 70 concentrations in hippocampus comparing to acute immobilization and cold stress. It seems that long-term psychosocial stresses attenuate the effects of an additional stress on hippocampal GR and Hsp 70 concentrations. These data suggest that individual housing of rats appear to act as a stronger stressor than crowding conditions. When the animals suffering a long-term isolation were exposed to either acute immobilization or cold, a stronger activation of the sympatho–adrenomedullary system (SAS) was recorded in comparison with that found in the long-term crowded group subjected to short-term immobilization or cold. No significant differences in the activity of hypotalamo–pituitary–adrenal (HPA) axis were observed between long-term isolated and long-term crowded rats.

Serum Total Prostate-Specific Antigen Assay in Women with Cushing’s Disease or Alcohol-Dependent Pseudo-Cushing’s State

Background: The distinction between Cushing’s disease (Cushing’s syndrome dependent on adrenocorticotropic hormone (ACTH)-secreting tumors of pituitary origin) and pseudo-Cushing’s states (Cushingoid features and hypercortisolism sometimes present in alcoholic, depressed or obese subjects) can present a diagnostic challenge in clinical endocrinology. Recently, the availability of a highly sensitive immunofluorometric assay for the measurement of total prostate-specific antigen (PSA) provided the possibility to measure serum PSA levels in women. Interestingly, PSA gene expression and protein production has been found to be upregulated by steroid hormones, such as androgens, glucocorticoids, mineral corticoids and progestins. In fact, serum total PSA concentrations appear to be higher in female patients with Cushing’s disease than in normal women. We wondered whether a similar phenomenon also occurs in pseudo-Cushing’s state. Methods: In order to answer this question, we compared the serum total PSA levels measured in 10 female subjects with alcohol-dependent pseudo-Cushing’s state with those observed in 8 female patients with Cushing’s disease and in 15 age-matched healthy women. Serum testosterone, ACTH and cortisol, and 24-hour urinary cortisol levels were measured; cortisol suppression after dexamethasone was also tested in all subjects. Results: The basal serum levels of ACTH and cortisol were significantly lower in normal subjects than in patients with Cushing’s disease or pseudo-Cushing’s state; these latter groups showed similar basal hormonal values. Dexamethasone administration was unable to suppress serum cortisol levels in 5 subjects with Cushing’s disease and 6 subjects with pseudo-Cushing’s state. Serum testosterone values in the group with Cushing’s disease were higher than in the other groups. No differences were observed between pseudo-Cushing’s and normal subjects. Serum total PSA levels were significantly higher in women with Cushing’s disease than in subjects with pseudo-Cushing’s state and normal controls; these latter groups showed similar PSA values. When serum total PSA and testosterone levels were considered together, a significant positive correlation was observed in the group with Cushing’s disease, but not in the other groups. Conclusions: These data indicate that the steroid milieu responsible for the elevation in serum PSA in women with Cushing’s disease is not present in subjects with alcohol-dependent pseudo-Cushing’s state, suggesting the possible use of PSA as a marker of differentiation between these pathological conditions in women.

Intermittent Food Deprivation Improves Cardiovascular and Neuroendocrine Responses to Stress in Rats

Stressful events may trigger disease processes in many different organ systems, with the cardiovascular system being particularly vulnerable. Five-mo-old male rats had ad libitum (AL) access to food or were deprived of food every other day [intermittent food deprivation (IF)] for 6 mo, during which time their heart rate (HR), blood pressure (BP), physical activity and body temperature were measured by radiotelemetry under nonstress and stress (immobilization or cold-water swim) conditions. IF rats had significantly lower basal HR and BP, and significantly lower increases in HR and BP after exposures to the immobilization and swim stressors. Basal levels of adrenocorticotropic hormone (ACTH) and corticosterone were greater in the IF rats. However, in contrast to large stress-induced increases in ACTH, corticosterone and epinephrine levels in AL rats, increases in these hormones in response to repeated immobilization stress sessions were reduced or absent in IF rats. Nevertheless, the IF rats exhibited robust hypothalamic/pituitary and sympathetic neuroendocrine responses to a different stress (swim). The IF treatment improved glucose metabolism, as indicated by lower basal levels of circulating glucose and insulin, but with maintenance of glucose and insulin responses to stress. We concluded that improvements in cardiovascular risk factors and cardiovascular and neuroendocrine stress adaptation occur in response to IF.

Dysfunction of the hypothalamic-pituitary-glandular axes and relation to Child???Pugh classification in male patients with alcoholic and virus-related cirrhosis

Objective To investigate anterior pituitary function (adrenal, somatotropic, thyroid and gonadal axes, and prolactin) in relation to the Child-Pugh score in male patients with alcoholic and virus-related liver cirrhosis. Method Anterior pituitary function was evaluated in 52 male cirrhotics (26 Child-Pugh class A (CPA), 16 Child-Pugh class B (CPB) and 10 Child-Pugh class C (CPC)) by a combined pituitary stimulation test, and was compared with 50 age-matched controls. Results A normal cortisol response to corticotropinreleasing hormone (CRH) stimulation was demonstrated in 57.6% of CPA patients, 31.1% of CPB patients and 20% of CPC patients, while basal levels of adrenocorticotropic hormone (ACTH) and cortisol in cirrhotics were comparable to those in controls. Levels of basal growth hormone (P < 0.001) and stimulated growth hormone (P < 0.01) were significantly higher in cirrhotics compared with controls, while levels of insulin-like growth factor 1 (IGF-1) were significantly lower (P < 0.001). Basal prolactin levels were elevated significantly in CPC patients (P < 0.01), while stimulated prolactin as well as basal and stimulated thyroid-stimulating hormone (TSH) levels were comparable. Basal luteinizing hormone levels were significantly higher in CPA (P < 0.001) and CPB (P < 0.001) patients, and stimulated luteinizing hormone levels were significantly lower in CPC patients than in controls (P < 0.005). Basal and stimulated follicle-stimulating hormone (FSH) levels were comparable in all groups. Child-Pugh score was correlated positively to prolactin and was correlated negatively to IGF-1, stimulated luteinizing hormone and free testosterone. Conclusions In cirrhotics, the hypothalamic-pituitaryadrenal and -gonadal axes and prolactin secretion are impaired. Growth hormone response to growth hormonereleasing hormone (GHRH) is accelerated in cirrhotics. Thus, elevated basal and stimulated levels of growth hormone probably reflect compensation for low levels of IGF-1, which are associated with deteriorating liver function. The aetiology of cirrhosis was found to have no influence on the degree of alteration of the hypothalamicpituitary-glandular axes.

Social suppression of cortisol in female marmoset monkeys: role of circulating ACTH levels and glucocorticoid negative feedback

Behaviorally subordinate female common marmoset monkeys ( Callithrix jacchus) exhibit pronounced, chronic reductions of circulating cortisol levels. Cortisol suppression in these animals is mediated in part by adrenocortical hyporesponsiveness to adrenocorticotropic hormone (ACTH). In addition, we hypothesized that social subordination may activate a central, neurally mediated mechanism to further inhibit hypothalamo-pituitary-adrenal function. In this study, therefore, we evaluated basal plasma cortisol and ACTH concentrations, as well as cortisol and ACTH responses to dexamethasone (DEX), in dominant and subordinate females to initially characterize such a mechanism. Morning plasma cortisol and ACTH levels were determined before, and 1, 2, and 3 days following administration of DEX (0.5, 1.0, or 5.0 mg/kg, IM) or saline. Baseline cortisol concentrations prior to DEX treatment were significantly lower in subordinate females than in dominants, as previously reported. However, ACTH concentrations in the same blood samples did not differ between the two groups. Furthermore, dominant and subordinate females showed similar cortisol and ACTH responses to DEX. These results indicate that reduced circulating cortisol levels in subordinate females are not associated with either altered circulating ACTH concentrations or enhanced responsiveness to glucocorticoid negative feedback. However, the finding that basal ACTH levels are not elevated in subordinate females as compared to dominants, in spite of low circulating cortisol concentrations, suggests that ACTH secretion in subordinate females is restrained by a steroid-independent inhibitory mechanism operating at the level of the brain or pituitary.

Low Basal Androstenedione Levels Plus Augmented 17α-Hydroxyprogesterone and Low Dehydroepiandrosterone Sulfate Responses to Adrenocorticotropic Hormone Stimulation in Patients with Adrenal Incidentaloma

To investigate the androstenedione, 17a-hydroxyprogesterone (17-OHP), and dehydroepiandrosterone sulfate (DHEAS) basal levels and responses to adrenocorticotropic hormone (ACTH) in patients with adrenal incidentalomas in order to determine which enzyme defects are present. In a study group of 23 patients (18 women and 5 men who ranged in age from 16 to 70 years) with incidentally discovered asymptomatic adrenal masses, ACTH stimulation was performed to evaluate the secretory responses of 17-OHP and DHEAS. The same test was performed in 15 age- and sex-matched control subjects. Of the 23 patients, 16 (70%) had a 17-OHP peak >30 nmol/L. The 17-OHP response to ACTH stimulation was significantly higher in patients with adrenal incidentalomas than in control subjects (P<0.001). Fourteen patients had basal DHEAS levels below the 3rd percentile of the control group (1.4 +/- 0.1 mmol/L). The mean stimulated DHEAS level was 1.7 +/- 0.2 mmol/L (range, 0.8 to 4.1) in patients with incidentalomas and 4.2 +/- 0.4 mmol/L (range, 1.8 to 5.6) in the control group (P<0.001). In 13 patients, stimulated DHEAS levels were low in association with high 17-OHP levels. Basal ACTH levels did not differ significantly between patients (8.14 +/- 1.2 pmol/L) and control subjects (8.73 +/- 0.7 pmol/L). Basal androstenedione levels were significantly lower in patients (1.9 +/- 0.3 nmol/L) than in control subjects (5.7 +/- 2.5 nmol/L) (P<0.001). No significant correlation was found between 17-OHP levels and tumor size. Enzyme defects may have an important role in adrenal incidentalomas. Two possible explanations for the observed abnormalities of steroid metabolism in patients with incidentalomas are that (1) the incidentalomas are true primary tumors that have aberrant steroid metabolic pathways or (2) such patients have underlying congenital adrenal hyperplasia that leads, over time, to development of pseudotumors. To assess these two possibilities, we need further studies such as genetic investigations, postoperative test results, and evidence relating the size of the adrenal mass to steroid-suppressible treatment.

Differential and age-dependent effects of maternal deprivation on the hypothalamic-pituitary-adrenal axis of brown norway rats from youth to senescence.

In this study, the hypothesis was tested that infants deprived from maternal care show persistent changes in hypothalamic-pituitary-adrenal activity. For this purpose, we studied the effect of maternal deprivation in one cohort of the healthy ageing Brown Norway rat strain showing still more than 80% survival rate at 32 months of age. Three-day-old male Brown Norway rats were either maternally deprived for 24 h or remained with the dam. In 3, 12 and 30-32 months (young, adult, senescent) deprived rats and their nondeprived littermates (controls), we determined basal resting and stress-induced plasma adrenocorticotropic hormone (ACTH) and corticosterone as well as corticotropin releasing hormone (CRH) mRNA expression in the paraventricular nucleus (PVN) of the hypothalamus. Mineralocorticoid (MR) and glucocorticoid receptors (GR) in hippocampus and PVN were also assessed using in vitro cytosol binding and in situ hybridization. The effect of ageing per se showed that in the control nondeprived Brown Norway rats, basal corticosterone and ACTH concentrations did not change during life. However, with age, the corticosterone response to novelty stress became progressively attenuated, but prolonged, while there was an age-related increase in the ACTH response. CRH mRNA expression in PVN decreased with age. Hippocampal MR binding and MR mRNA expression in the dentate gyrus were reduced at senescence, as were the GR binding capacities in hippocampus and hypothalamus. Maternal deprivation did not affect survival rate, body weight, nor adrenal weight of the ageing Brown Norway rats. Basal corticosterone and ACTH levels were not affected by deprivation, except for a rise in basal corticosterone concentrations at 3 months. At this age, the corticosterone output in response to novelty was attenuated in the deprived rats. In contrast, a striking surge in novelty stress-induced corticosterone output occurred at midlife while, at senescence, the corticosterone and ACTH responses were attenuated again in the deprived animals, particularly after the more severe restraint stressor. CRH mRNA expression was reduced only during adulthood in the deprived animals. After maternal deprivation, the MR mRNA in dentate gyrus showed a transient midlife rise. GR binding in hypothalamus and hippocampus GR binding was reduced in young rats while, in the senescent deprived animals, a reduced GRmRNA expression was observed in PVN and hippocampal CA1. In conclusion, in the Brown Norway rat, ageing causes a progressive decline in corticosterone output after stress, which is paralleled at senescence by decreased MR and GR mRNA expression in hippocampus and hypothalamus. The long-term effects of maternal deprivation become manifest differently at different ages and depend on test conditions. The deprivation effect culminates in a midlife corticosterone surge and results at senescence in a strongly reduced corticosterone output.

Hormonal Parameters in Gestational Diabetes mellitus during the Third Trimester: High Glucagon Levels

Hormonal parameters during the last trimester of pregnancy contribute to a natural increase of insulin resistance. It is not known whether any of these are further involved in the manifestation of gestational diabetes mellitus (GDM) in affected individuals. Basal levels of adrenocorticotropic hormone, cortisol, growth hormone, insulin-like growth factor-I, prolactin, glucagon, estradiol, progesterone, human placental lactogen and human chorionic gonadotropin were investigated in 15 nonobese women with GDM and 26 matched normal pregnant women (N). A linear discriminant analysis was performed to further compare the predictive value of the basal hormone levels. Plasma glucagon levels were significantly higher in the GDM group (p = 0.014); this difference was even higher (p = 0.007) when the number of women was increased (GDM = 33, N = 62). No significant differences were found in the levels of any of the other hormones. It is not clear whether elevated glucagon levels have any involvement in the pathogenesis of GDM or simply reflect the relative insulin deficiency of these women.

Increased adrenocorticotropin responses to acute stress in Otsuka Long–Evans Tokushima Fatty (type 2 diabetic) rats

The Otsuka Long–Evans Tokushima Fatty (OLETF) rat is a new diabetic strain of rats whose disease closely resembles human type 2 diabetes. We measured plasma adrenocorticotropic hormone (ACTH) and corticostrone levels, and iodine-125-labeled ovine corticotropin-releasing factor ([ 125 I ]oCRF) binding in the anterior pituitary after ether-laparotomy stress in OLETF rats to examine the alteration of the hypothalamic-pituitary-adrenal (HPA) axis. In addition, we examined ACTH secretion following CRF administration in vivo and in vitro to characterize the mechanisms regulating the HPA axis in OLETF rats. Body weight, plasma glucose and insulin levels in OLETF rats were significantly higher than that in Long–Evans Tokushima Otsuka (LETO) rats. Basal plasma ACTH levels tended to be higher in OLETF rats than in LETO but it did not reach statistical significance. Ether-laparotomy stress dramatically increased plasma ACTH levels at 2 h after the stress both in either OLETF and LETO rats; the peak plasma ACTH level in OLETF rats following the stress was significantly greater than in LETO rats. Plasma ACTH levels following CRF (2 μg/kg, i.v.) in OLETF and LETO rats showed statistically significant increases at 10 and 30 min after CRF administration compared to ACTH levels at 0 min, however, the peak plasma ACTH level in OLETF rats at 10 min after CRF administration was significantly greater than in LETO rats. In contrast to ACTH levels, no significant differences in corticosterone levels between OLETF and LETO were observed at any of the time points. CRF (10 ng/ml) significantly increased ACTH secretion in pituitary cultures from OLETF compared to LETO rats. These data reveal a complex regulation of the endocrine system in this diabetic condition and suggest that HPA axis may be more stimulated during acute stress in diabetes mellitus than in unaffected subjects.

Differences between Rainbow Trout and Brown Trout in the Regulation of the Pituitary–Interrenal Axis and Physiological Performance during Confinement

The responses of rainbow trout and brown trout to the same stressor were compared by measuring primary and secondary stress responses during and after a 5.5-h net confinement. Basal levels of adrenocorticotropic hormone (ACTH), α-melanocyte-stimulating hormone (α-MSH), and glucose were higher in brown trout than in rainbow trout. While confinement induced transient increases in plasma ACTH and cortisol levels in both species, the magnitude of these responses, but not the time course, was greater in brown trout. Brown trout, but not rainbow trout, showed a reduction in plasma α-MSH levels after 5.5 h confinement before returning to control values, and the glucose levels in the brown trout were elevated throughout the confinement and recovery periods. Confinement also resulted in increased hematocrit values and reduced plasma sodium and chloride levels in both species. Rainbow trout appeared to recover faster from the confinement, as glucose and hematocrit values in the brown trout remained elevated and ionoregulatory disturbances persisted even after 46 h. During recovery effects on the immune system were more pronounced in brown trout than in rainbow trout. Circulating white blood cell numbers were reduced in both species following 23 h recovery, but remained low in the brown trout. Elevated alternative complement activity and oxygen radical production were found after 23 h recovery, and reduced lysozyme activity was found after 46 h, in brown trout only. Results indicate that differences in the stress response of these closely related species, as illustrated by the intensity of the cortisol response, originate at the level of the pituitary and are also manifested through secondary stress responses.

Interrenal Stress Responsiveness of Tilapia (Oreochromis mossambicus) Is Impaired by Dietary Exposure to PCB 126

Activation of the hypothalamus–pituitary–interrenal (HPI) axis is characteristic of stress responses, which may result from a variety of environmental challenges. To investigate whether the stress response, and in particular the HPI axis, in tilapia (Oreochromis mossambicus) is compromised by short-term exposure to PCB 126, fish of both sexes were fed diets containing PCB 126 (50 μg/kg fish·day) for 5 days. In the first approach, which was performed twice, fish were acutely stressed for periods varying between 1 and 30 min at the end of the exposure period; in the second approach fish were sampled at the end of the exposure period either at rest or after 2 h of stress (confinement). After 5 days, the body weights in all experiments were significantly lower in PCB-fed fish than in control fish. There were no changes in basal plasma glucose levels, plasma ion concentrations, or branchial, renal, and intestinal Na,K-ATPase activity following PCB exposure. In the first experimental approach, in which fish experienced acute sampling stress, plasma cortisol levels reached lower levels in PCB-fed fish than in controls. This suggests an impaired ability to acutely activate interrenal steroidogenesis in PCB-treated tilapia. Adrenocorticotropic hormone (ACTH)- and cAMP-stimulatedin vitrocortisol release from superfused head kidneys was lower in tissues from tilapia exposed to PCB 126 than in tissues from control animals. This effect persisted after 24 hin vitro,which, together with the high PCB 126 concentrations measured in the head kidneys of PCB-fed fish, may indicate direct toxic effects on the interrenal cells. The second experimental approach demonstrated that basal plasma cortisol and ACTH levels were not influenced by PCB treatment, but that the basal ACTH content of the rostral pars distalis (RPD) of the pituitary gland of PCB-fed fish was lower than that of control fish. After 2 h confinement, plasma cortisol levels and ACTH content of the RPD rose to similar values in both groups, whereas plasma ACTH levels were higher in confined PCB-fed fish than in confined controls. PCB-fed fish showed a lower hyperglycemic response to confinement than control fish. Confinement resulted in similarly elevated renal and intestinal Na,K-ATPase activities in both PCB-fed and control fish; branchial enzyme activities were not affected. Since PCB did not affect Na,K-ATPase activities and plasma ion concentrations, it is concluded that the effects of PCB 126 on the HPI axis in tilapia are not secondary to ionoregulatory dysfunction.

Norepinephrine Depletion in the Amygdala Inhibits CRF-41, ACTH, and Corticosterone Responses Following Photic Simulation

The effects of amygdaloid norepinephrine depletion by 6-hydroxydopamine on changes in corticotropin releasing factor-41 (CRF-41) and serum adrenocorticotropic hormone (ACTH) and corticosterone levels, following neural stimuli were investigated. In intact animals, photic or acoustic stimulation caused CRF-41 depletion from the median eminence and a rise in serum ACTH and corticosterone levels. In rats with amygdalar norepinephrine depletion there were no changes in basal CRF-41, ACTH, or corticosterone levels. However, the above responses of the hypothalamo-pituitary adrenocortical axis were blocked following photic, but not acoustic, stimulation. These results indicate that the facilitatory role of the amygdala on the above responses following photic stimulation depends on the presence of norepinephrine in this region.

Norepinephrine depletion in the amygdala inhibits CRF-41, ACTH, and corticosterone responses following photic simulation

The effects of amygdaloid norepinephrine depletion by 6-hydroxydopamine on changes in corticotropin releasing factor-41 (CRF-41) and serum adrenocorticotropic hormone (ACTH) and corticosterone levels, following neural stimuli were investigated. In intact animals, photic or acoustic stimulation caused CRF-41 depletion from the median eminence and a rise in serum ACTH and corticosterone levels. In rats with amygdalar norepinephrine depletion there were no changes in basal CRF-41, ACTH, or corticosterone levels. However, the above responses of the hypothalamo-pituitary adrenocortical axis were blocked following photic, but not acoustic, stimulation. These results indicate that the facilitatory role of the amygdala on the above responses following photic stimulation depends on the presence of norepinephrine in this region.