Science.gov

Sample records for pituitary gut adrenal

  1. Brain serotonin and pituitary-adrenal functions

    NASA Technical Reports Server (NTRS)

    Vernikos-Danellis, J.; Berger, P.; Barchas, J. D.

    1973-01-01

    It had been concluded by Scapagnini et al. (1971) that brain serotonin (5-HT) was involved in the regulation of the diurnal rhythm of the pituitary-adrenal system but not in the stress response. A study was conducted to investigate these findings further by evaluating the effects of altering brain 5-HT levels on the daily fluctuation of plasma corticosterone and on the response of the pituitary-adrenal system to a stressful or noxious stimulus in the rat. In a number of experiments brain 5-HT synthesis was inhibited with parachlorophenylalanine. In other tests it was tried to raise the level of brain 5-HT with precursors.

  2. Brain serotonin and pituitary-adrenal functions

    NASA Technical Reports Server (NTRS)

    Vernikos-Danellis, J.; Berger, P.; Barchas, J. D.

    1973-01-01

    It had been concluded by Scapagnini et al. (1971) that brain serotonin (5-HT) was involved in the regulation of the diurnal rhythm of the pituitary-adrenal system but not in the stress response. A study was conducted to investigate these findings further by evaluating the effects of altering brain 5-HT levels on the daily fluctuation of plasma corticosterone and on the response of the pituitary-adrenal system to a stressful or noxious stimulus in the rat. In a number of experiments brain 5-HT synthesis was inhibited with parachlorophenylalanine. In other tests it was tried to raise the level of brain 5-HT with precursors.

  3. Serotonin involvement in pituitary-adrenal function

    NASA Technical Reports Server (NTRS)

    Vernikos-Danellis, J.; Kellar, K. J.; Kent, D.; Gonzales, C.; Berger, P. A.; Barchas, J. D.

    1977-01-01

    Experiments clarifying the effects of serotonin (5-HT) in the regulation of the hypothalamic-pituitary-adrenocortical system are surveyed. Lesion experiments which seek to determine functional maps of serotonergic input to areas involved in regulation are reported. Investigations of the effects of 5-HT levels on the plasma ACTH response to stress and the diurnal variation in basal plasma corticosterone are summarized, and the question of whether serotonergic transmission is involved in the regulation of all aspects of pituitary-adrenal function is considered with attention to the stimulatory and inhibitory action of 5-HT.

  4. The hypothalamic-pituitary-adrenal axis.

    PubMed

    Feek, C M; Marante, D J; Edwards, C R

    1983-11-01

    Anterior pituitary corticotrophin cells secrete ACTH as part of a larger precursor molecule, pro-opiomelanocortin. Post-translational cleavage of this precursor yields three major peptides: ACTH, beta-LPH and N-POMC. Experiments both in vivo and in vitro suggest that N-POMC may act as a prohormone amplifier for ACTH-induced adrenal steroidogenesis and as regulator of adrenocortical cell growth. The secretion of POMC is under the control of CRF. These findings are discussed in relation to the pathophysiology of corticotrophinoma. The primary defect in this condition appears to reside at the level of the anterior pituitary cell and is readily amenable to treatment by trans-sphenoidal microsurgery. The estimation of plasma ACTH concentrations is proving useful in the monitoring of various clinical conditions including Addison's disease and congenital adrenal hyperplasia.

  5. Serotonin and pituitary-adrenal function. [in rat under stress

    NASA Technical Reports Server (NTRS)

    Berger, P. A.; Barchas, J. D.; Vernikos-Danellis, J.

    1974-01-01

    An investigation is conducted to evaluate the response of the pituitary-adrenal system to a stress stimulus in the rat. In the investigation brain serotonin synthesis was inhibited with p-chlorophenylalanine. In other tests the concentration of serotonin was enhanced with precursors such as tryptophan or 5-hydroxytryptophan. On the basis of the results obtained in the study it is speculated that in some disease states there is a defect in serotonergic neuronal processes which impairs pituitary-adrenal feedback mechanisms.

  6. Modulating the pituitary-adrenal response to stress

    NASA Technical Reports Server (NTRS)

    Vernikos-Danellis, J.

    1975-01-01

    Serotonin is believed to be a transmitter or regulator of neuronal function. A possible relationship between the pituitary-adrenal secretion of steroids and brain serotonin in the rat was investigated by evaluating the effects of altering brain 5-hydroxy tryptamine (HT) levels on the daily fluctuation of plasma corticosterone and on the response of the pituitary-adrenal system to a stressful or noxious stimulus in the rat. The approach was either to inhibit brain 5-HT synthesis with para-chlorophenyl alanine or to raise its level with precursors such as tryptophan or 5-hydroxy tryptophan.

  7. Modulating the pituitary-adrenal response to stress

    NASA Technical Reports Server (NTRS)

    Vernikos-Danellis, J.

    1975-01-01

    Serotonin is believed to be a transmitter or regulator of neuronal function. A possible relationship between the pituitary-adrenal secretion of steroids and brain serotonin in the rat was investigated by evaluating the effects of altering brain 5-hydroxy tryptamine (HT) levels on the daily fluctuation of plasma corticosterone and on the response of the pituitary-adrenal system to a stressful or noxious stimulus in the rat. The approach was either to inhibit brain 5-HT synthesis with para-chlorophenyl alanine or to raise its level with precursors such as tryptophan or 5-hydroxy tryptophan.

  8. Influence of chronic and repeated stress on the pituitary-adrenal system and behavior

    NASA Technical Reports Server (NTRS)

    Levine, S.

    1975-01-01

    The role of adrenal glucocorticoids and ACTH in behavior, and the influence of various behavioral situations on the neuroendocrine regulation of the pituitary-adrenal system were investigated. Results are presented and discussed.

  9. Hypothalamic-pituitary-adrenal axis function during perinatal depression.

    PubMed

    Gelman, Phillipe Leff; Flores-Ramos, Mónica; López-Martínez, Margarita; Fuentes, Carlos Cruz; Grajeda, Juan Pablo Reyes

    2015-06-01

    Abnormal function of the hypothalamic-pituitary-adrenal (HPA) axis is an important pathological finding in pregnant women exhibiting major depressive disorder. They show high levels of cortisol pro-inflammatory cytokines, hypothalamic-pituitary peptide hormones and catecholamines, along with low dehydroepiandrosterone levels in plasma. During pregnancy, the TH2 balance together with the immune system and placental factors play crucial roles in the development of the fetal allograft to full term. These factors, when altered, may generate a persistent dysfunction of the HPA axis that may lead to an overt transfer of cortisol and toxicity to the fetus at the expense of reduced activity of placental 11β-hydroxysteroid dehydrogenase type 2. Epigenetic modifications also may contribute to the dysregulation of the HPA axis. Affective disorders in pregnant women should be taken seriously, and therapies focused on preventing the deleterious effects of stressors should be implemented to promote the welfare of both mother and baby.

  10. Methamphetamine and the hypothalamic-pituitary-adrenal axis

    PubMed Central

    Zuloaga, Damian G.; Jacobskind, Jason S.; Raber, Jacob

    2015-01-01

    Psychostimulants such as methamphetamine (MA) induce significant alterations in the function of the hypothalamic-pituitary-adrenal (HPA) axis. These changes in HPA axis function are associated with altered stress-related behaviors and might contribute to addictive processes such as relapse. In this mini-review we discuss acute and chronic effects of MA (adult and developmental exposure) on the HPA axis, including effects on HPA axis associated genes/proteins, brain regions, and behaviors such as anxiety and depression. A better understanding of the mechanisms through which MA affects the HPA axis may lead to more effective treatment strategies for MA addiction. PMID:26074755

  11. Childhood maltreatment and adult psychopathology: pathways to hypothalamic-pituitary-adrenal axis dysfunction

    PubMed Central

    Mello, Marcelo F.; Faria, Alvaro A.; Mello, Andrea F.; Carpenter, Linda L.; Tyrka, Audrey R.; Price, Lawrence H.

    2015-01-01

    Objective The aim of this paper was to examine the relationship between childhood maltreatment and adult psychopathology, as reflected in hypothalamic-pituitary-adrenal axis dysfunction. Method A selective review of the relevant literature was undertaken in order to identify key and illustrative research findings. Results There is now a substantial body of preclinical and clinical evidence derived from a variety of experimental paradigms showing how early-life stress is related to hypothalamic-pituitary-adrenal axis function and psychological state in adulthood, and how that relationship can be modulated by other factors. Discussion The risk for adult psychopathology and hypothalamic-pituitary-adrenal axis dysfunction is related to a complex interaction among multiple experiential factors, as well as to susceptibility genes that interact with those factors. Although acute hypothalamic-pituitary-adrenal axis responses to stress are generally adaptive, excessive responses can lead to deleterious effects. Early-life stress alters hypothalamic-pituitary-adrenal axis function and behavior, but the pattern of hypothalamic-pituitary-adrenal dysfunction and psychological outcome in adulthood reflect both the characteristics of the stressor and other modifying factors. Conclusion Research to date has identified multiple determinants of the hypothalamic-pituitary-adrenal axis dysfunction seen in adults with a history of childhood maltreatment or other early-life stress. Further work is needed to establish whether hypothalamic-pituitary-adrenal axis abnormalities in this context can be used to develop risk endophenotypes for psychiatric and physical illnesses. PMID:19967199

  12. Fetal Hypothalamus-Pituitary-Adrenal Responses to Estradiol Sulfate

    PubMed Central

    2011-01-01

    Estradiol (E2) is an important modifier of the activity of the fetal hypothalamus-pituitary-adrenal axis. We have reported that estradiol-3-sulfate (E2SO4) circulates in fetal blood in far higher concentrations than E2 and that the fetal brain expresses steroid sulfatase, required for local deconjugation of E2SO4. We performed the present study to test the hypothesis that chronic infusion of E2SO4 chronically increases ACTH and cortisol secretion and that it shortens gestation. Chronically catheterized fetal sheep were treated with E2SO4 intracerebroventricular (n = 5), E2SO4 iv (n = 4), or no steroid infusion (control group, n = 5). Fetuses were subjected to arterial blood sampling every other day until spontaneous birth for plasma hormone analysis. Treatment with E2SO4 attenuated preparturient increases in ACTH secretion near term without affecting the ontogenetic rise in plasma cortisol. Infusion of E2SO4 intracerebroventricularly significantly increased plasma E2, plasma E2SO4, and plasma progesterone and shortened gestation compared with all other groups. These results are consistent with the conclusion that E2SO4: 1) interacts with the hypothalamus-pituitary-adrenal axis primarily by stimulating cortisol secretion and inhibiting ACTH and pro-ACTH secretion by negative feedback; and 2) stimulates the secretion of E2 and E2SO4. We conclude that the endocrine response to E2SO4 in the fetus is not identical with the response to E2. PMID:21952234

  13. [Hypoplasia adrenal congenita of anencephalic type: two cases with pituitary abnormalities and review of literature].

    PubMed

    Folligan, K; Roume, J; Razavi, F; Sepaniak, S; Bouvier, R; Morel, Y; Trouillas, J

    2011-03-01

    Hypoplasia adrenal congenita is an extremely uncommon disease of early onset. This condition can be lethal in the absence of treatment. Some forms are due to the congenital adrenal hypoplasia of anencephalic type whose origin is even unknown. Here, we present two cases of congenital adrenal hypoplasia of anencephalic type with pituitary abnormalities. The two male newborns died because adrenal insufficiency in the neonatal period. The adrenal glands were hypoplastic with a histological structure of anencephalic type Immunocytochemical study of the pituitary revealed an absence of the gonadotrophs. No mutation of DAX 1 and SF-1 was found.

  14. An acute adrenal insufficiency revealing pituitary metastases of lung cancer in an elderly patient

    PubMed Central

    Marmouch, Hela; Arfa, Sondes; Mohamed, Saoussen Cheikh; Slim, Tensim; Khochtali, Ines

    2016-01-01

    Metastases of solid tumors to the pituitary gland are often asymptomatic or appereas as with diabetes insipid us. Pituitary metastases more commonly affect the posterior lobe and the infundibulum than the anterior lobe. The presentation with an acute adrenal insufficiency is a rare event. A 69-year-old men presented with vomiting, low blood pressure and hypoglycemia. Hormonal exploration confirmed a hypopituitarism. Appropriate therapy was initiated urgently. The hypothalamic-pituitary MRI showed a pituitary hypertrophy, a nodular thickening of the pituitary stalk. The chest X Rays revealed pulmonary opacity. Computed tomography scan of the chest showed a multiples tumors with mediastinal lymphadenopathy. Bronchoscopy and biopsy demonstrated a pulmonary adenocarcinoma. Hence we concluded to a lung cancer with multiple pituitary and adrenal gland metastases. This case emphasizes the need for an etiological investigation of acute adrenal insufficiency after treatment of acute phase. PMID:27200139

  15. Pituitary-adrenal response to naloxone in non-ulcer dyspepsia: preliminary evidence for a reduction in central opioid tone.

    PubMed

    Scott, Lucinda V; Rathore, Omar; Dinan, Timothy G; Keeling, P W N

    2002-01-01

    Non-ulcer dyspepsia (NUD) is one of the core functional bowel disorders. There has been recent emphasis on possible abnormal brain-gut interactions as being central to its pathophysiology. In this preliminary study, we examined central opioid tone in Helicobacter pylori-negative NUD patients using naloxone, an opioid antagonist, which stimulates pituitary-adrenal activity. The opioid system is known to govern nociceptive processing and to play a role in gut motor activity. Eight subjects with NUD and 8 age- and sex-matched healthy subjects were examined. Naloxone, 0.125 mg/kg, was administered at time 0. Adrenocorticotropin (ACTH) and cortisol responses were measured over a 120-min period. Maximum pituitary-adrenal responses in the 2 groups were compared. The ACTH response was significantly attenuated in the NUD group (p < 0.05). The cortisol response did not differ between the 2 groups (p = 0.7). Central opioid tone may be reduced in subjects with NUD. Our preliminary findings suggest that altered opioidergic activity may contribute to NUD pathophysiology, influencing the symptom profile through altered gut motor activity or possibly by influencing visceral sensitivity. Copyright 2002 S. Karger AG, Basel

  16. Hypothalamic-pituitary-adrenal axis, neuroendocrine factors and stress.

    PubMed

    Tsigos, Constantine; Chrousos, George P

    2002-10-01

    The stress system coordinates the adaptive responses of the organism to stressors of any kind.(1). The main components of the stress system are the corticotropin-releasing hormone (CRH) and locus ceruleus-norepinephrine (LC/NE)-autonomic systems and their peripheral effectors, the pituitary-adrenal axis, and the limbs of the autonomic system. Activation of the stress system leads to behavioral and peripheral changes that improve the ability of the organism to adjust homeostasis and increase its chances for survival. The CRH and LC/NE systems stimulate arousal and attention, as well as the mesocorticolimbic dopaminergic system, which is involved in anticipatory and reward phenomena, and the hypothalamic beta-endorphin system, which suppresses pain sensation and, hence, increases analgesia. CRH inhibits appetite and activates thermogenesis via the catecholaminergic system. Also, reciprocal interactions exist between the amygdala and the hippocampus and the stress system, which stimulates these elements and is regulated by them. CRH plays an important role in inhibiting GnRH secretion during stress, while, via somatostatin, it also inhibits GH, TRH and TSH secretion, suppressing, thus, the reproductive, growth and thyroid functions. Interestingly, all three of these functions receive and depend on positive catecholaminergic input. The end-hormones of the hypothalamic-pituitary-adrenal (HPA) axis, glucocorticoids, on the other hand, have multiple roles. They simultaneously inhibit the CRH, LC/NE and beta-endorphin systems and stimulate the mesocorticolimbic dopaminergic system and the CRH peptidergic central nucleus of the amygdala. In addition, they directly inhibit pituitary gonadotropin, GH and TSH secretion, render the target tissues of sex steroids and growth factors resistant to these substances and suppress the 5' deiodinase, which converts the relatively inactive tetraiodothyronine (T(4)) to triiodothyronine (T(3)), contributing further to the suppression of

  17. Endomorphins and activation of the hypothalamo-pituitary-adrenal axis.

    PubMed

    Coventry, T L; Jessop, D S; Finn, D P; Crabb, M D; Kinoshita, H; Harbuz, M S

    2001-04-01

    Endomorphin (EM)-1 and EM-2 are opioid tetrapeptides recently located in the central nervous system and immune tissues with high selectivity and affinity for the mu-opioid receptor. Intracerebroventricular (i.c.v.) administration of morphine stimulates the hypothalamo-pituitary-adrenal (HPA) axis. The present study investigated the effect of centrally administered EM-1 and EM-2 on HPA axis activation. Rats received a single i.c.v. injection of either EM-1 (0.1, 1.0, 10 microg), EM-2 (10 microg), morphine (10 microg), or vehicle (0.9% saline). Blood samples for plasma corticosterone determinations were taken immediately prior to i.c.v. administration and at various time points up to 4 h post-injection. Trunk blood, brains and pituitaries were collected at 4 h. Intracerebroventricular morphine increased plasma corticosterone levels within 30 min, whereas EM-1 and EM-2 were without effect. In addition, pre-treatment of i.c.v. EM-1 did not block the rise in corticosterone after morphine. Corticotrophin-releasing factor (CRF) mRNA and arginine vasopressin (AVP) mRNA in the paraventricular nucleus (PVN) and POMC mRNA in the anterior pituitary were found to be unaffected by either morphine or endomorphins. Since release of other opioids are elevated in response to acute stress, we exposed rats to a range of stressors to determine whether plasma EM-1 and EM-2 can be stimulated by HPA axis activation. Plasma corticosterone, ACTH and beta-endorphin were elevated following acute restraint stress, but concentrations of plasma EM-1-immunoreactivity (ir) and EM-2-ir did not change significantly. Corticosterone, ACTH and beta-endorphin were further elevated in adjuvant-induced arthritis (AA) rats by a single injection of lipopolysaccharide (LPS), but not by restraint stress. In conclusion, neither EM-1 or EM-2 appear to influence the regulation of the HPA axis. These data suggest that endomorphins may be acting on a different subset of the mu-opioid receptor than morphine. The

  18. Childhood Parental Loss and Adult Hypothalamic-Pituitary-Adrenal Function

    PubMed Central

    Tyrka, Audrey R.; Wier, Lauren; Price, Lawrence H.; Ross, Nicole; Anderson, George M.; Wilkinson, Charles W.; Carpenter, Linda L.

    2009-01-01

    Background Several decades of research link childhood parental loss with risk for major depression and other forms of psychopathology. A large body of preclinical work on maternal separation and some recent studies of humans with childhood parental loss have demonstrated alterations of hypothalamic-pituitary-adrenal (HPA) axis function which could predispose to the development of psychiatric disorders. Methods Eighty-eight healthy adults with no current Axis I psychiatric disorder participated in this study. Forty-four participants experienced parental loss during childhood, including 19 with a history of parental death and 25 with a history of prolonged parental separation. The loss group was compared to a matched group of individuals who reported no history of childhood parental separation or childhood maltreatment. Participants completed diagnostic interviews and questionnaires and the dexamethasone/corticotropin-releasing hormone (Dex/CRH) test. Repeated measures general linear models were used to test the effects of parental loss, a measure of parental care, sex, and age on the hormone responses to the Dex/CRH test. Results Parental loss was associated with increased cortisol responses to the test, particularly in males. The effect of loss was moderated by levels of parental care; participants with parental desertion and very low levels of care had attenuated cortisol responses. ACTH responses to the Dex/CRH test did not differ significantly as a function of parental loss. Conclusions These findings are consistent with the hypothesis that early parental loss induces enduring changes in neuroendocrine function. PMID:18339361

  19. Frustrative nonreward and pituitary-adrenal activity in squirrel monkeys.

    PubMed

    Lyons, D M; Fong, K D; Schrieken, N; Levine, S

    2000-12-01

    Little is known about frustration-induced changes in stress physiology in humans and nonhuman primates. Here we assess in two experiments with squirrel monkeys plasma levels of pituitary-adrenal stress hormones in conditions designed to provoke frustrative nonreward. In the first experiment 18 prepubertal monkeys were trained to feed from one of eight sites, and then tested without food at any of the sites. These monkeys responded with significant increases in cortisol and adrenocorticotropic hormone (ACTH). In the second experiment 18 adult monkeys were trained to feed from one of eight sites, and then tested after food was moved to a different foraging site. Nine monkeys found food at the relocated site, discontinued foraging at the previously baited site, and responded with decreases in cortisol. The other nine monkeys failed to find the relocated site, initially increased their visits to the previously baited site, and responded with elevations in cortisol and ACTH. In keeping with comparable findings in rats, our observations indicate that frustrative nonreward elicits ACTH-stimulated secretion of cortisol in primates.

  20. Suppression of the Hypothalamic-Pituitary-Adrenal Axis after Oral Hydrocortisone Succinate Ingestion in Rats

    PubMed Central

    Mims, Robert B.

    1978-01-01

    Groups of Holtzman female rats were fed 10 mg/day of hydrocortisone succinate orally to study the responsiveness of the hypothalamic-pituitary-adrenal axis to acute stress. Pituitary ACTH content, plasma ACTH, adrenal venous corticosterone, and adrenal weights were studied simultaneously in experimental and control rats before, during, and up to two weeks after oral hydrocortisone administration. There was a significant decrease in pituitary ACTH content (p=<0.001), suppression of plasma ACTH and corticosterone in response to acute stress (p=<0.001), and adrenal atrophy during and following oral hydrocortisone administration. After discontinuing the hydrocortisone it required three to five days for the rats to respond adequately to acute stress. However, it was seven to ten days post-hydrocortisone before plasma ACTH and corticosterone responses to acute stress had returned to basal values, but decreased pituitary ACTH content and partial adrenal atrophy continued throughout the ten-day post-hydrocortisone study interval. Recovering from the suppressive effects of oral hydrocortisone was more rapid than following parenteral hydrocortisone. However, oral hydrocortisone causes identical but less sustained suppression of the hypothalamic-pituitary-adrenal axis as observed in animals treated with parenteral glucocorticoid preparations. PMID:212574

  1. Osteoporosis is more prevalent in adrenal than in pituitary Cushing's syndrome.

    PubMed

    Ohmori, Nariko; Nomura, Kaoru; Ohmori, Kazue; Kato, Yoshiharu; Itoh, Tatsuo; Takano, Kazue

    2003-02-01

    Osteoporosis is the most common complication of Cushing's syndrome. We retrospectively examined the prevalence and risk factors for osteoporosis in 42 female patients with Cushing's syndrome. Osteoporosis and atraumatic fractures were assessed by bone mineral density of the lumbar vertebral spine (L2-L4) using dual energy X-ray absorptiometry (DXA) and X-ray examination. The prevalence of osteoporosis and fracture were 54.8% and 21.4%, respectively. The prevalence of osteoporosis (69.6% vs. 37.8%) and atraumatic bone fracture (26.1% vs. 15.8%) were significantly higher in patients with adrenal Cushing's than in those with pituitary Cushing's. AP and lateral BMD was significantly higher in patients with pituitary origin than in those with adrenal origin. Among several variables examined by multiple logistic regression, the etiology of Cushing's syndrome (adrenal vs. pituitary origin) was a significant factor affecting the prevalence of osteoporosis. Neither age, body mass index, duration of amenorrhea, nor extent of hypercortisolism were significant factors in this analysis. Plasma DHEA-S and urinary 17-KS excretion were significantly higher in pituitary Cushing's than in adrenal Cushing's. The present study shows that the prevalence of osteoporosis in patients with Cushing's syndrome is influenced by its etiology. A factor associated with pituitary Cushing's syndrome, such as adrenal androgen, may protect these patients from glucocorticoid-induced osteoporosis.

  2. Hypothalamic-pituitary-adrenal axis function in ankylosing spondylitis

    PubMed Central

    Imrich, R; Rovensky, J; Zlnay, M; Radikova, Z; Macho, L; Vigas, M; Koska, J

    2004-01-01

    Objective: To assess basal function and responsiveness of the hypothalamic-pituitary-adrenal (HPA) axis in patients with ankylosing spondylitis during dynamic testing. Methods: Insulin induced hypoglycaemia (IIH) (Actrapid HM 0.1 IU/kg, as intravenous bolus) was induced in 17 patients and 11 healthy controls matched for age, sex, and body mass index. Concentrations of glucose, adrenocorticotrophic hormone (ACTH), cortisol, insulin, dehydroepiandrosterone sulphate (DHEAS), 17α-hydroxyprogesterone, interleukin 6 (IL-6), and tumour necrosis factor α (TNFα) were determined in plasma. Results: Comparable basal cortisol levels were found in the two groups, with a trend to be lower in ankylosing spondylitis. In the ankylosing spondylitis group, there were higher concentrations of IL-6 (mean (SEM): 16.6 (2.8) pg/ml v 1.41 (0.66) pg/ml in controls; p<0.001) and TNFα (8.5 (1.74) pg/ml v 4.08 (0.42) pg/ml in controls; p<0.01). Glucose, insulin, ACTH, DHEAS, and 17α-hydroxyprogesterone did not differ significantly from control. The IIH test was carried out successfully in 11 of the 17 patients with ankylosing spondylitis, and the ACTH and cortisol responses were comparable with control. General linear modelling showed a different course of glycaemia (p = 0.041) in the ankylosing spondylitis patients who met the criteria for a successful IIH test compared with the controls. Conclusions: The results suggest there is no difference in basal HPA axis activity and completely preserved responsiveness of the HPA axis in patients with ankylosing spondylitis. The interpretation of the different course of glycaemia during IIH in ankylosing spondylitis requires further investigation. PMID:15140773

  3. [Effect of prenatal stress on the pituitary-adrenal axis in blue foxes].

    PubMed

    Osadchuk, L V; Braastad, B; Bakken, M

    2004-01-01

    Handling is a source of stress for farm bred blue foxes. The influence of handling during the late gestation period on the pituitary--adrenal axis was studied in 10-day old male and female blue foxes. Cortisol and progesterone were measured by radioimmunoassay in the plasma, adrenal homogenates, and in vitro incubates from animals of both sexes. Adrenals were incubated in vitro in the absence or presence of ACTH. In addition, the adrenal weight and plasma concentration of ACTH were assessed. In cubs of both sexes, the adrenal weight was decreased after prenatal stress. The plasma concentration of progesterone and the adrenal cortisol in vitro production were elevated in the prenatally stressed female cubs, as compared to the control, along with the adrenal progesterone in vitro production in prenatally stressed male cubs. The adrenal cortisol and progesterone content and plasma ACTH and cortisol concentrations were not affected by prenatal stress. In conclusion, the results of this study suggest that the prenatal stress induced by handling pregnant vixens can affect the pituitary--adrenal axis in neonatal offspring, this effect being more pronounced in female cubs.

  4. Chronic ethanol consumption depresses hypothalamic-pituitary-adrenal function in aged rats

    SciTech Connect

    Nolan, C.J.; Bestervelt, L.L.; Mousigian, C.A.; Maimansomsuk, P.; Yong Cai; Piper, W.N. )

    1991-01-01

    In separate experiments, nine (n=20) and fifteen (n=12) month old rats were treated with either 6% ethanol or 12% sucrose in the drinking water to examine the effect of chronic ethanol consumption on the hypothalamic-pituitary-adrenal axis of aged rats. Blood was collected and plasma concentrations of adrenocorticotropin (ACTH) and corticosterone were determined by radioimmunoassay. Adrenal glands were cleaned, quartered and used to test in vitro responsiveness to ACTH. Anterior pituitary glands from all 15 month old rats and one half of the nine month old rats were collected, frozen and extracted for measurement of tissue ACTH concentration. The remaining anterior pituitary glands from the nine month old rats were challenged with corticotropin releasing hormone (CRH) to test in vitro responsiveness. In nine month old rats, chronic ethanol consumption decreased plasma ACTH and corticosterone. Pituitary ACTH concentrations were unchanged in treated nine month old rats, but the amount of pituitary ACTH released in response to CRH was decreased in rats consuming ethanol. In vitro responsiveness of the adrenal gland to ACTH in nine month old rats consuming ethanol was unchanged. Plasma ACTH and corticosterone concentrations were also decreased in 15 month old rats chronically consuming ethanol. No differences were noted in responsiveness of the adrenal gland or in the amount of pituitary ACTH due to ethanol consumptions in 15 month old rats.

  5. Contrast-enhanced ultrasonographic evaluation of adrenal glands in dogs with pituitary-dependent hyperadrenocorticism.

    PubMed

    Pey, Pascalline; Daminet, Sylvie; Smets, Pascale Marcel Yvonne; Duchateau, Luc; De Fornel-Thibaud, Pauline; Rosenberg, Dan; Saunders, Jimmy C H

    2013-03-01

    To assess vascular changes induced by hyperadrenocorticism of hyperplastic adrenal glands in dogs via contrast-enhanced ultrasonography. 12 dogs with pituitary-dependent hyperadrenocorticism (PDH) and 7 healthy control dogs ≥ 7 years old. Dogs were assigned to the PDH and control groups and to small-breed (n = 6), medium-breed (4), and large-breed (9) subgroups. Contrast-enhanced ultrasonography of both adrenal glands in each dog was performed with IV injections of contrast agent. Time-intensity curves for the adrenal cortex, adrenal medulla, and ipsilateral renal artery of both adrenal glands were generated. Perfusion variables (time to peak [TTP], upslope of wash-in phase, and downslope of washout phase) were calculated. Contrast-enhanced ultrasonography revealed no qualitative difference between PDH and control groups. Quantitatively, TTPs were longer in the adrenal cortex and adrenal medulla of the PDH group, compared with values for the control group, particularly in the adrenal cortex and adrenal medulla of the small-breed subgroup. Washout downslopes were lower for the renal artery, adrenal cortex, and adrenal medulla of the small-breed subgroup between the PDH and control groups. No other perfusion variables differed between groups. Contrast-enhanced ultrasonography of the adrenal glands in dogs with PDH revealed a delayed TTP in the adrenal cortex and adrenal medulla, compared with values for control dogs. Contrast-enhanced ultrasonography was able to detect vascular changes induced by hyperadrenocorticism. Further studies are needed to evaluate whether reference ranges for clinically normal dogs and dogs with PDH can be determined and applied in clinical settings.

  6. Hypothalamic Pituitary Adrenal Axis Functioning in Reactive and Proactive Aggression in Children

    ERIC Educational Resources Information Center

    Lopez-Duran, Nestor L.; Olson, Sheryl L.; Hajal, Nastassia J.; Felt, Barbara T.; Vazquez, Delia M.

    2009-01-01

    The purpose of this study was to examine the association between hypothalamic-pituitary-adrenal axis (HPA-axis) reactivity and proactive and reactive aggression in pre-pubertal children. After a 30-min controlled base line period, 73 7-year-old children (40 males and 33 females) were randomly assigned to one of two experimental tasks designed to…

  7. Mindful Parenting Predicts Mothers' and Infants' Hypothalamic-Pituitary-Adrenal Activity during a Dyadic Stressor

    ERIC Educational Resources Information Center

    Laurent, Heidemarie K.; Duncan, Larissa G.; Lightcap, April; Khan, Faaiza

    2017-01-01

    Mindfulness in the parenting relationship has been proposed to help both parents and children better regulate stress, though this has not yet been shown at the physiological level. In this study, we tested relations between maternal mindfulness in parenting and both mothers' and their infants' hypothalamic-pituitary-adrenal (HPA) axis activity…

  8. Adolescent Survivors of Hurricane Katrina: A Pilot Study of Hypothalamic-Pituitary-Adrenal Axis Functioning

    ERIC Educational Resources Information Center

    Pfefferbaum, Betty; Tucker, Phebe; Nitiéma, Pascal

    2015-01-01

    Background: The hypothalamic-pituitary-adrenal (HPA) axis constitutes an important biological component of the stress response commonly studied through the measurement of cortisol. Limited research has examined HPA axis dysregulation in youth exposed to disasters. Objective: This study examined HPA axis activation in adolescent Hurricane Katrina…

  9. Hypothalamic Pituitary Adrenal Axis Functioning in Reactive and Proactive Aggression in Children

    ERIC Educational Resources Information Center

    Lopez-Duran, Nestor L.; Olson, Sheryl L.; Hajal, Nastassia J.; Felt, Barbara T.; Vazquez, Delia M.

    2009-01-01

    The purpose of this study was to examine the association between hypothalamic-pituitary-adrenal axis (HPA-axis) reactivity and proactive and reactive aggression in pre-pubertal children. After a 30-min controlled base line period, 73 7-year-old children (40 males and 33 females) were randomly assigned to one of two experimental tasks designed to…

  10. Adolescent Survivors of Hurricane Katrina: A Pilot Study of Hypothalamic-Pituitary-Adrenal Axis Functioning

    ERIC Educational Resources Information Center

    Pfefferbaum, Betty; Tucker, Phebe; Nitiéma, Pascal

    2015-01-01

    Background: The hypothalamic-pituitary-adrenal (HPA) axis constitutes an important biological component of the stress response commonly studied through the measurement of cortisol. Limited research has examined HPA axis dysregulation in youth exposed to disasters. Objective: This study examined HPA axis activation in adolescent Hurricane Katrina…

  11. Fetal hypothalamus-pituitary-adrenal axis on the road to parturition.

    PubMed

    Schwartz, J; McMillen, I C

    2001-01-01

    1. Activity of the fetal hypothalamus-pituitary-adrenal (HPA) axis waxes and wanes as a function of gestational age. 2. In a number of species, including sheep, at the end of gestation there is an increase in HPA activity, as characterized by an increase in fetal plasma glucocorticoids. 3. To a certain degree, the hypothalamus, pituitary and adrenal all act autonomously and, therefore, may be thought of as contributing to the initiation of the signal that results in the increase in steroidogenesis before birth. 4. Because it integrates sensory information from beyond as well as within the HPA axis and likely triggers developmental changes within the pituitary, the hypothalamus may be a 'first among equals' in being the ultimate source of triggering information for the HPA axis.

  12. Effects of cytokines on pituitary beta-endorphin and adrenal corticosterone release in vitro.

    PubMed

    van der Meer, M J; Hermus, A R; Pesman, G J; Sweep, C G

    1996-03-01

    We investigated the effects of recombinant human IL-1 alpha, -1 beta, -2, -6 and TNF on the in vitro secretion of beta-endorphin-immunoreactivity (beta E-IR) by the rat anterior and neurointermediate lobes (AL and NIL, respectively) and of B by the rat adrenal gland. Isolated AL and NIL cells were incubated for 2 h with cytokines (1 pg/m1(-1) mu g/ml), CRH (5.10(-10) M) or with cytokines in combination with CRH (AL cells), isolated adrenal cells were incubated for 2 h with cytokines, ACTH (25 pg/ml) or with cytokines in combination with ACTH. Furthermore, AL, NIL and adrenal tissue fragments were superfused for 30 or 60 min with cytokines (10 and/or 100 ng/ml). Incubation of AL, NIL and adrenal cells and superfusion of these tissues with cytokines had no significant effect on beta E-IR and B release. However, there are some exceptions: incubation of AL cells with IL-2 increased CRH-induced beta E-IR release, incubation of NIL cells with IL-2 induced an increase of basal beta E-IR release, ACTH-induced B secretion was reduced after co-incubation of adrenal cells with TNF and after prolonged (6 h) superfusion of adrenal tissue with TNF, and finally, prolonged (6 h) superfusion of adrenal fragments with IL-1 beta increased basal B release. Taken together, these data suggest that the acute activation of the pituitary-adrenal axis of rats by administration of cytokines (at least IL-1, IL-6 and TNF) in vivo is not mediated by a direct action of these cytokines at the level of the pituitary and/or adrenal gland.

  13. Suppression of the Hypothalamic-pituitary-adrenal Axis by Maximum Androgen Blockade in a Patient with Prostate Cancer

    PubMed Central

    Kondo, Takeshi; Endo, Itsuro; Ooguro, Yukari; Morimoto, Kana; Kurahashi, Kiyoe; Yoshida, Sumiko; Kuroda, Akio; Aihara, Ken-ichi; Matsuhisa, Munehide; Abe, Masahiro; Fukumoto, Seiji

    2016-01-01

    A 78-year-old Japanese man showed suppression of the hypothalamic-pituitary-adrenal axis during maximum androgen blockade (MAB) therapy including chlormadinone acetate (CMA) for prostate cancer. After stopping the MAB therapy, both the basal ACTH level and the response to CRH recovered. While no reports have indicated that CMA suppresses the hypothalamic-pituitary-adrenal axis in patients with prostate cancer, CMA has been shown to inhibit this axis in animals. These observations suggest that we must monitor the hypothalamic-pituitary-adrenal axis in patients treated with CMA, especially under stressful conditions. PMID:27980263

  14. Suppression of the Hypothalamic-Pituitary-Adrenal Axis after Subcutaneous Cortisone Acetate Administration in Rats

    PubMed Central

    Mims, Robert B.

    1977-01-01

    Groups of female rats were injected daily for 14 days with 10 mg of cortisone acetate subcutaneously, to study the mechanisms of glucocorticoid suppression on the hypothalamic-pituitary-adrenal axis. Pituitary adrenocorticotropic hormone (ACTH) content, plasma ACTH, adrenal venous corticosterone, adrenal weights, and the catabolic effects on body weight were studied simultaneously (under stressful and non-stressful conditions) before, during, and up to six weeks after cortisone. This study confirmed the results of other investigators that cortisone acetate caused catabolic weight loss and adrenal atrophy, but it was noted to persist up to six weeks after the injections. Glucocorticoid acetate was more effective in causing ACTH-axis suppression than succinate or phosphate preparations, and the effects were dose and time related. Significant depletion of pituitary ACTH content, suppression of plasma ACTH, and corticosterone secretion occurred five to seven days after beginning cortisone acetate (p=<0.001); it was continuous throughout the injection schedule (p=<0.001); it remained for two to four weeks after the cortisone was discontinued (p=<0.001). The animals showed minimum plasma ACTH responsiveness to severe acute stress during this two to four-week suppression phase, but rapid recovery occurred thereafter. Plasma ACTH was undetectable up to six weeks post-cortisone when the animals were not under stress. This may be related to residual cortisone acetate found at the injection sites, or to an altered or different ACTH-axis control mechanism. The sequence of events during recovery from cortisone suppression appeared to be (1) repletion of corticotrophin-releasing hormone (by inference), (2) repletion of pituitary ACTH content, (3) secretion of plasma ACTH, (4) reversal of adrenal atrophy, and (5) subsequent secretion of corticosterone. PMID:224195

  15. [A test for evaluation of pituitary-adrenal axis disregulation].

    PubMed

    Rybnikova, E A; Mironova, V I; Pivina, S G

    2010-01-01

    In rat models, a modification of the fast feedback paradigm for the pituitary adrenocortical system applied to detect posttraumatic stress disorder (PTSD) was developed. Both standard and modified methods were used. In contrast to the standard method (injection of exogenous cortisol), the new modification suggested measuring blood corticosterone, rather than adrenocorticotropic hormone, at the early stages of development of the stress reaction (3, 10, 30, and 60 min of the exposure to stress factors). With the suggested modification, the fast feedback phenomenon was studied in reliable rat models of PTSD (stress-restress) and depression (learned helplessness). Fast pathological inhibition of the pituitary adrenocortical system by the fast feedback mechanism was revealed only during the simulated PTSD but not in the depressive-like state, which supported the specificity and validity of the developed modification of the test. Thus, the proposed methodological modification is a valid tool for diagnostics of the PTSD-specific fast feedback inhibition of the pituitary adrenocortical system in the animal models of this psychopathology.

  16. Patient With Severe Hyponatremia Caused by Adrenal Insufficiency Due to Ectopic Posterior Pituitary Lobe and Miscommunication Between Hypothalamus and Pituitary

    PubMed Central

    Grammatiki, Maria; Rapti, Eleni; Mousiolis, Athanasios C.; Yavropoulou, Maria; Karras, Spyridon; Tsona, Afroditi; Daniilidis, Michalis; Yovos, John; Kotsa, Kalliopi

    2016-01-01

    Abstract Hyponatremia may be one of the clinical manifestations of adrenal insufficiency (AI) and during the diagnostic workup of hyponatremic patients investigation of AI should be included. We report the case of an 82-year-old patient who was admitted to our hospital with clinical symptoms and laboratory findings of hyponatremia. Following the diagnostic algorithm of hyponatremia we reached the diagnosis of AI. Clinician's attention must focus on the underlying cause of AI which in this case was hidden in a miscommunication between hypothalamus and pituitary due to an ectopic posterior pituitary lobe and became apparent by a pituitary magnetic resonance imaging (MRI) scan. Treatment with oral hydrocortisone resulted in full clinical recovery and electrolyte balance, which was maintained after 7 months of follow-up. Secondary AI is related with hyponatremia through increased ADH secretion. Although a hyponatremic episode may be the first presentation of AI, clinical suspicion is of high importance in order to place the right diagnosis. Disruption of communication between hypothalamus and pituitary is a rare but considerable cause of AI. PMID:26962783

  17. [Immune outcomes of sleep disorders: the hypothalamic-pituitary-adrenal axis as a modulatory factor].

    PubMed

    Palma, Beatriz Duarte; Tiba, Paula Ayako; Machado, Ricardo Borges; Tufik, Sergio; Suchecki, Deborah

    2007-05-01

    To review the literature on the interaction between sleep and the immune system. A search on Web of Science and Pubmed database including the keywords sleep, sleep deprivation, stress, hypothalamic-pituitary-adrenal axis, immune system, and autoimmune diseases. On Web of Science, 588 publications were retrieved; 61 references, more significant and closer to our objective, were used, including original articles and review papers. Sleep deprivation and immune system exert a bidirectional influence on each other. Since sleep deprivation is considered a stressor, inasmuch as it induces elevation of cortisol or corticosterone levels in humans and rodents, respectively, and given the well-known immunosuppressive effect of glucocorticoids, we propose that increased activation of the hypothalamic-pituitary-adrenal axis is a major mediator of the immune alterations observed in patients with insomnia or in sleep deprived subjects.

  18. Increased rate of response of the pituitary-adrenal system in rats adapted to chronic stress

    NASA Technical Reports Server (NTRS)

    Sakellaris, P. C.; Vernikos-Danellis, J.

    1975-01-01

    The response and adaptation of the pituitary-adrenal system to chronic stresses was investigated. These included individual caging, confinement, and exposure to cold for varying periods of time. Studies were carried out demonstrating that during the period of adaptation when plasma corticosterone concentrations returned toward their prestress level despite continued exposure to the stressor, the animals responded to additional stimuli of ether for 1 min, a saline injection, or release from confinement with a faster increase (within 2.5 min) in plasma corticosterone than controls (10 min). It is concluded that during adaptation to a chronic stress the pituitary-adrenal system is not inhibited by the circulating steroid level but is actually hypersensitive to additional stimuli.

  19. Increased rate of response of the pituitary-adrenal system in rats adapted to chronic stress

    NASA Technical Reports Server (NTRS)

    Sakellaris, P. C.; Vernikos-Danellis, J.

    1975-01-01

    The response and adaptation of the pituitary-adrenal system to chronic stresses was investigated. These included individual caging, confinement, and exposure to cold for varying periods of time. Studies were carried out demonstrating that during the period of adaptation when plasma corticosterone concentrations returned toward their prestress level despite continued exposure to the stressor, the animals responded to additional stimuli of ether for 1 min, a saline injection, or release from confinement with a faster increase (within 2.5 min) in plasma corticosterone than controls (10 min). It is concluded that during adaptation to a chronic stress the pituitary-adrenal system is not inhibited by the circulating steroid level but is actually hypersensitive to additional stimuli.

  20. Autoimmune diseases of the adrenal glands, parathyroid glands, gonads, and hypothalamic-pituitary axis.

    PubMed

    Muir, A; Maclaren, N K

    1991-09-01

    Autoimmunity directed against the adrenal glands, parathyroid glands, gonads, and hypothalamic-pituitary axis can arise in isolation or as part of a polyglandular autoimmune syndrome. Affected patients can be asymptomatic, but they may also suffer significant morbidity or even mortality. Currently, treatment is restricted largely to hormone replacement when end-organ destruction is almost complete. As our understanding of the pathogenesis of autoimmune endocrinopathies improves, it is probable that early patient detection will become practical and trials of protective immunotherapies entertained.

  1. Is suppression of hypothalamic-pituitary-adrenal axis significant during clinical treatment of phimosis?

    PubMed

    Pileggi, F O; Martinelli, C E; Tazima, M F G S; Daneluzzi, J C; Vicente, Y A M V A

    2010-06-01

    Corticoids have been an option for phimosis treatment since 1993. However, long-term use or repeated cycles pose a concern regarding drug absorption and consequent systemic effects. The aim of this study was to investigate the effect of topical corticoids used in treating phimosis on the hypothalamus-pituitary-adrenal axis in children. A total of 31 children were included in the study. Cortisol secretion was evaluated by the measurement of salivary cortisol in saliva samples collected at 9:00 a.m. before starting treatment and after 8 weeks of topical treatment with 0.05% clobetasol propionate. Salivary cortisol was determined by radioimmunoassay. To confirm that use of clobetasol propionate was not detected by the assay, the presence of cortisol circadian rhythm was checked by an extra saliva sample obtained at 11:00 p.m. from 10 children, and was observed to be maintained in all of them. No significant difference in salivary cortisol levels was observed between samples obtained at 9:00 a.m. before starting treatment and after completing treatment when the entire group was analyzed. However, in 2 children the salivary cortisol levels after treatment were lower than the cutoff value (358 ng/dl) assumed to be suggestive of hypothalamus-pituitary-adrenal axis suppression. Topical clobetasol propionate used twice daily for clinical treatment of phimosis does not affect the hypothalamus-pituitary-adrenal axis in most patients. However, salivary cortisol level should be considered as a laboratory marker in long-term treatment or during repeated cycles to detect possible hypothalamus-pituitary-adrenal axis suppression. Copyright 2010 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

  2. Effect of intracerebroventricular injection of histamine on blood sugar level and hypothalamo-pituitary adrenal axis of rats.

    PubMed

    Trivedi, C P; Modi, N T; Balothia, R K

    1976-01-01

    Intraventricular injection of histamine and normal saline in rats caused a marked fall in adrenal ascorbic acid indicating a stimulatory effect of both on pituitary adrenal axis. Intraventricularly injected histamine caused significant hypoglycaemia also in rats as compared to control series.

  3. [Correlations between the hypothalamo-pituitary-adrenal axis and the metabolic syndrome].

    PubMed

    Góth, Miklós; Hubina, Erika; Korbonits, Márta

    2005-01-09

    The metabolic syndrome has several similarities with Cushing's syndrome (impaired glucose tolerance, hypertension, dyslipidemia, central obesity) suggesting that abnormalities in the regulation of the hypothalamic-pituitary-adrenal axis may have a link with the metabolic syndrome. Several studies suggested an association between the clinical signs of the metabolic syndrome and the increased hypothalamic-pituitary-adrenal axis activity based on increased cortisol concentration at 09.00 a.m. and increased cortisol response to corticotropin. According to the Barker hypothesis the fetal malnutrition could determine adult cardiovascular diseases (coronary heart disease, hypertension), some endocrine and metabolic disorders (obesity, type 2 diabetes and hyperlipidemia). The suggested mechanism of the phenomenon is that the suboptimal fetal nutrition results in glucocorticoid overproduction. The 11beta-hydroxysteroid dehydrogenase (converts biological inactive cortisone to cortisol and vice versa) is an important enzyme in cortisol metabolism. The increased expression of 11beta-hydroxysteroid dehydrogenase type 1 in fat tissue could lead to central obesity and impaired glucose tolerance. The hypothesis that increased corticotropin-releasing hormone production drives the overactive hypothalamo-pituitary-adrenal axis was not proven. Further investigations are needed to identify additional pathogenetic factors and to find new therapeutic possibilities.

  4. Genistein stimulates the hypothalamo-pituitary-adrenal axis in adult rats: morphological and hormonal study.

    PubMed

    Trifunović, Svetlana; Manojlović-Stojanoski, Milica; Ajdzanović, Vladimir; Nestorović, Nataša; Ristić, Nataša; Medigović, Ivana; Milošević, Verica

    2012-05-01

    Genistein, the soy isoflavone structurally similar to estradiol, is widely consumed for putative beneficial health effects. However, there is a lack of data about the genisteins' effects in adult males, especially its effects on the hipothalamo-pituitary-adrenal (HPA) axis. Therefore, the present study was carried out to investigate the effects of genistein on the HPA axis in orchidectomized adult rats, and to create a parallel with those of estradiol. Changes in the hypothalamic corticotrophin-releasing hormone (CRH) neurons and pituitary corticotrophs (ACTH cells) were evaluated stereologically, while corticosterone and ACTH levels were determined biochemically. Orchidectomy (Orx) provoked the enlargement (p<0.05) of: hypothalamic paraventricular nucleus volume (60%), percentage of CRH neurons (23%), percentage of activated CRH neurons (45%); pituitary weight (15%) and ACTH level (57%). In comparison with Orx, estradiol treatment provoked the enlargement (p<0.05) of: percentage of CRH neurons (28%), percentage of activated CRH neurons (2.7-fold), pituitary weight (131%) and volume (82%), ACTH level (69%), the serum (103%) and adrenal tissue (4.8 fold) level of corticosterone. Clearly, Orx has induced the increase in HPA axis activity, which even augments after estradiol treatment. Also, compared to Orx, genistein treatment provoked the enhancement (p<0.05) of: percentage of activated CRH neurons (2.3-fold), pituitary weight (28%) and volume (21%), total number of ACTH cells (22%) ACTH level (45%), the serum (2.6-fold) and adrenal tissue (2.8 fold) level of corticosterone. It can be concluded that an identical tendency, concerning the HPA axis parameters, follows estradiol and genistein administration to the orchidectomized adult rats.

  5. Angiotensin converting enzyme in the brain, testis, epididymis, pituitary gland and adrenal gland

    SciTech Connect

    Strittmatter, S.M.

    1986-01-01

    (/sup 3/H)Captopril binds to angiotensin converting enzyme (ACE) in rat tissue homogenates. The pharmacology, regional distribution and copurification of (/sup 3/H)captopril binding with enzymatic activity demonstrate the selectivity of (/sup 3/H)captopril labeling of ACE. (/sup 3/H)Captopril binding to purified ACE reveals differences in cationic dependence and anionic regulation between substrate catalysis and inhibitor recognition. (/sup 3/H)Captopril association with ACE is entropically driven. The selectivity of (/sup 3/H)captopril binding permits autoradiographic localization of the ACE in the brain, male reproductive system, pituitary gland and adrenal gland. In the brain, ACE is visualized in a striatonigral neuronal pathway which develops between 1 and 7 d after birth. In the male reproductive system, (/sup 3/H)captopril associated silver grains are found over spermatid heads and in the lumen of seminiferous tubules in stages I-VIII and XII-XIV. In the pituitary gland, ACE is localized to the posterior lobe and patches of the anterior lobe. The adrenal medulla contains moderate ACE levels while low levels are found in the adrenal cortex. Adrenal medullary ACE is increased after hypophysectomy and after reserpine treatment. The general of ligand binding techniques for the study of enzymes is demonstrated by the specific labeling of another enzyme, enkephaline convertase, in crude tissue homogenates by the inhibitor (/sup 3/H)GEMSA.

  6. Corticotropin-releasing hormone links pituitary adrenocorticotropin gene expression and release during adrenal insufficiency.

    PubMed

    Muglia, L J; Jacobson, L; Luedke, C; Vogt, S K; Schaefer, M L; Dikkes, P; Fukuda, S; Sakai, Y; Suda, T; Majzoub, J A

    2000-05-01

    Corticotropin-releasing hormone (CRH)-deficient (KO) mice provide a unique system to define the role of CRH in regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Despite several manifestations of chronic glucocorticoid insufficiency, basal pituitary proopiomelanocortin (POMC) mRNA, adrenocorticotrophic hormone (ACTH) peptide content within the pituitary, and plasma ACTH concentrations are not elevated in CRH KO mice. The normal POMC mRNA content in KO mice is dependent upon residual glucocorticoid secretion, as it increases in both KO and WT mice after adrenalectomy; this increase is reversed by glucocorticoid, but not aldosterone, replacement. However, the normal plasma levels of ACTH in CRH KO mice are not dependent upon residual glucocorticoid secretion, because, after adrenalectomy, these levels do not undergo the normal increase seen in KO mice despite the increase in POMC mRNA content. Administration of CRH restores ACTH secretion to its expected high level in adrenalectomized CRH KO mice. Thus, in adrenal insufficiency, loss of glucocorticoid feedback by itself can increase POMC gene expression in the pituitary; but CRH action is essential for this to result in increased secretion of ACTH. This may explain why, after withdrawal of chronic glucocorticoid treatment, reactivation of CRH secretion is a necessary prerequisite for recovery from suppression of the HPA axis.

  7. How should we interrogate the hypothalamic-pituitary-adrenal axis in patients with suspected hypopituitarism?

    PubMed

    Garrahy, Aoife; Agha, Amar

    2016-06-17

    Hypopituitarism is deficiency of one or more pituitary hormones, of which adrenocorticotrophic hormone (ACTH) deficiency is the most serious and potentially life-threatening. It may occur in isolation or, more commonly as part of more widespread pituitary failure. Diagnosis requires demonstration of subnormal cortisol rise in response to stimulation with hypoglycemia, glucagon, ACTH(1-24) or in the setting of acute illness. The choice of diagnostic test should be individualised for the patient and clinical scenario. A random cortisol and ACTH level may be adequate in making a diagnosis in an acutely ill patient with a suspected adrenal crisis e.g. pituitary apoplexy. Often however, dynamic assessment of cortisol reserve is needed. The cortisol response is both stimulus and assay- dependent and normative values should be derived locally. Results must be interpreted within clinical context and with understanding of potential pitfalls of the test used.

  8. Stability analysis of a hypothalamic-pituitary-adrenal axis model with inclusion of glucocorticoid receptor and memory

    NASA Astrophysics Data System (ADS)

    Kaslik, Eva; Navolan, Dan Bogdan; Neamţu, Mihaela

    2017-01-01

    This paper analyzes a four-dimensional model of the hypothalamic-pituitary-adrenal (HPA) axis that includes the influence of the glucocorticoid receptor in the pituitary. Due to the spatial separation between the hypothalamus, pituitary and adrenal glands, distributed time delays are introduced in the mathematical model. The existence of the positive equilibrium point is proved and a local stability and bifurcation analysis is provided, considering several types of delay kernels. The fractional-order model with discrete time delays is also taken into account. Numerical simulations are provided to illustrate the effectiveness of the theoretical findings.

  9. Contrast-enhanced ultrasonographic characteristics of adrenal glands in dogs with pituitary-dependent hyperadrenocorticism.

    PubMed

    Bargellini, Paolo; Orlandi, Riccardo; Paloni, Chiara; Rubini, Giuseppe; Fonti, Paolo; Peterson, Mark E; Boiti, Cristiano

    2013-01-01

    A noninvasive method for quantifying adrenal gland vascular patterns could be helpful for improving detection of adrenal gland disease in dogs. The purpose of this retrospective study was to compare the contrast-enhanced ultrasound (CEUS) characteristics of adrenal glands in 18 dogs with pituitary-dependent hyperadrenocorticism (PDH) vs. four clinically healthy dogs. Each dog received a bolus of the contrast agent (SonoVue®, 0.03 ml/kg of body weight) into the cephalic vein, immediately followed by a 5 ml saline flush. Dynamic contrast enhancement was analyzed using time-intensity curves in two regions of interest drawn manually in the caudal part of the adrenal cortex and medulla, respectively. In healthy dogs, contrast enhancement distribution was homogeneous and exhibited increased intensity from the medulla to the cortex. In the washout phase, there was a gradual and homogeneous decrease of enhancement of the adrenal gland. For all dogs with PDH, there was rapid, chaotic, and simultaneous contrast enhancement in both the medulla and cortex. Three distinct perfusion patterns were observed. Peak perfusion intensity was approximately twice as high (P < 0.05) in dogs with PDH compared with that of healthy dogs (28.90 ± 10.36 vs. 48.47 ± 15.28, respectively). In dogs with PDH, adrenal blood flow and blood volume values were approximately two- to fourfold (P < 0.05) greater than those of controls. Findings from the present study support the use of CEUS as a clinical tool for characterizing canine adrenal gland disease based on changes in vascular patterns. © 2013 Veterinary Radiology & Ultrasound.

  10. Alprazolam blocks the naloxone-stimulated hypothalamo-pituitary-adrenal axis in man.

    PubMed

    Torpy, D J; Grice, J E; Hockings, G I; Walters, M M; Crosbie, G V; Jackson, R V

    1993-02-01

    Alprazolam (APZ) is a benzodiazepine with unique antidepressant activity for a drug of its class. There is some evidence of inhibition of the unstimulated hypothalamo-pituitary-adrenal axis by APZ which may be important in its therapeutic action, and could be detrimental in APZ-treated subjects who encounter stressful stimuli. To assess the effect of APZ on stimulated ACTH and cortisol secretion, we studied 14 normal subjects in a randomized, double-blind, placebo-controlled design. APZ or placebo capsule was administered orally in doses of 0.5 mg and 2 mg, 90 min before either naloxone, 125 micrograms/kg body weight i.v. bolus dose, a known stimulator of ACTH and cortisol release, or placebo. After naloxone stimulation, the area under the plasma ACTH/time curves was significantly reduced by APZ, in both the 2 mg (P < 0.0005) and 0.5 mg (P < 0.005) doses, compared to their respective placebo studies; similar reductions in area under the plasma cortisol/time curves occurred after 2 mg (P < 0.00002) and 0.5 mg (P < 0.0005) APZ doses. We conclude that APZ is a potent inhibitor of naloxone-stimulated ACTH and cortisol release in humans. Since APZ has been shown to inhibit CRH release in vitro, and naloxone-induced ACTH secretion is likely to be caused through CRH release, this suggests that APZ inhibition of naloxone action is via the parvocellular CRH neurons of the paraventricular nucleus and/or central neurotransmitter pathways impinging directly or indirectly on these CRH neurons. Thus APZ may exert at least some of its clinical effects through inhibition of central CRH release. APZ treatment could lead to a relative hyporesponse of the pituitary-adrenal axis during stress. APZ may be an important tool for manipulation of hypothalamic CRH release in studies of pituitary-adrenal function.

  11. Adrenal and gonadal steroids and pituitary response to LHRH in girls. II. Precocious puberty.

    PubMed

    Pintor, C; Genazzani, A R; Ibba, P; Pecciarini-Snickars, L; Corda, R

    1978-04-01

    Three baby girls between 22 and 30 months of age, presenting with isosexual idiopathic precocious puberty apparently not due to any organic cause, were studied. Basal levels of plasma steroids of adrenal and gonadal origin, circadian rhythm of plasma cortisol, and pituitary response to 25 microgram of LHRH were evaluated. All cases were characterized by high levels of plasma gonadotropins and by a marked response to exogenous LHRH. Normal cortisol circadia rhythm was found in all cases, one of which characterized by slightly raised plasma values. The other adrenal steroids were all higher than those expected for the chronological age, corresponding to those of 5-6 years old girls. On the other hand, steroids of both adrenal and ovarian (A, T) or mainly ovarian origin (E2) and DHT were all found to be higher than those normally reported in girls at stage 2 of sexual development. These data indicate a hypersecretion of gonadotropins in idiopathic isosexual precocious puberty, with a marked gonadal steroidogenetic response. The secretion of adrenal androgens does not appear to have an important role in the etiology of this condition.

  12. Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function.

    PubMed

    Anacker, Christoph; O'Donnell, Kieran J; Meaney, Michael J

    2014-09-01

    We review studies with human and nonhuman species that examine the hypothesis that epigenetic mechanisms, particularly those affecting the expression of genes implicated in stress responses, mediate the association between early childhood adversity and later risk of depression. The resulting studies provide evidence consistent with the idea that social adversity, particularly that involving parent-offspring interactions, alters the epigenetic state and expression of a wide range of genes, the products of which regulate hypothalamic-pituitary-adrenal function. We also address the challenges for future studies, including that of the translation of epigenetic studies towards improvements in treatments.

  13. Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function

    PubMed Central

    Anacker, Christoph; O'Donnell, Kieran J.; Meaney, Michael J.

    2014-01-01

    We review studies with human and nonhuman species that examine the hypothesis that epigenetic mechanisms, particularly those affecting the expression of genes implicated in stress responses, mediate the association between early childhood adversity and later risk of depression. The resulting studies provide evidence consistent with the idea that social adversity, particularly that involving parent-offspring interactions, alters the epigenetic state and expression of a wide range of genes, the products of which regulate hypothalamic-pituitary-adrenal function. We also address the challenges for future studies, including that of the translation of epigenetic studies towards improvements in treatments. PMID:25364283

  14. Inhibition of the pituitary-adrenal response to stress during deprivation-induced feeding

    NASA Technical Reports Server (NTRS)

    Heybach, J. P.; Vernikos-Danellis, J.

    1979-01-01

    Plasma corticosterone and plasma and pituitary ACTH concentrations were determined during feeding and after application of an acute stress at various times after food and water presentation to male rats maintained on a restricted feeding and watering schedule. Both plasma corticosterone and ACTH concentrations fell after the presentation of food and water, and this fall was accompanied by increased levels of ACTH in the pituitary gland. In addition, a rise in plasma levels of ACTH was inhibited in response to an acute stress applied at 0-5 min after presentation of food and water, but ACTH synthesis was not. This inhibition of ACTH and corticosterone secretion in response to stress was transient and dissipated as a relatively linear function of the interval between food presentation and application of the stress. The results suggest that this feeding-induced, corticosteroid-independent inhibition of pituitary-adrenal activity involves active inhibitory mechanisms operating initially on ACTH secretory processes of the pituitary and later on the synthesis of ACTH or on the secretion of hypothalamic corticotropin-releasing factor.

  15. Improvement of kidney yang syndrome by icariin through regulating hypothalamus-pituitary-adrenal axis.

    PubMed

    An, Rui; Li, Bo; You, Li-sha; Wang, Xin-hong

    2015-10-01

    To investigate whether Epimedium brevicornu Maxim (EB) and icariin could exert their protective effects on hydrocortisone induced (HCI) rats by regulating the hypothalamus-pituitary-adrenal (HPA) axis and endocrine system and the possible mechanism. Male 10-week-old Sprague Dawley (SD) rats were allotted to 6 groups (A-F) with 12 each, group A was injected normal saline (NS) 3 mL/kg day intraperitoneally, group A and B were given NS 6 mL/kg day by gastrogavage, group B-F were injected hydrocortisone 15 mg/kg intraperitoneally, group C and D were given EB 8 or 5 g/(kg day) by gastrogavage, group E and F were given icariin 25 or 50 mg/(kg day) by gastrogavage. Gene expressions of hypothalamus corticotropin releasing hormone (CRH) and pituitary proopiomelanocortin (POMC) were detected by reverse transcription-polymerase chain reaction (RT-PCR), and protein of pituitary POMC by Western-blot. The serum T4, testosterone, cortisol and POMC mRNA expression were increased after treatment with EB or icariin in HCI rats, the serum CRH and the hypothalamus CRH mRNA expression released from hypothalamus corticotropin decreased compared with group B (P<0.05).The treatment with only icariin increased serum adrenocorticotropic hormone (ACTH) compared with group B (P<0.05). EB and icariin might be therapeutically beneficial in the treatment of HCI rats through attuning the HPA axis and endocrine system which was involved in the release of CRH in hypothalamic, and the production of POMC-derived peptide ACTH in anterior pituitary, the secretion of corticosteroids in adrenal cortex.

  16. Activational effects of gonadal steroids on hypothalamo-pituitary-adrenal regulation in the rat disclosed by response to dexamethasone suppression.

    PubMed

    Almeida, O F; Canoine, V; Ali, S; Holsboer, F; Patchev, V K

    1997-02-01

    Previous studies demonstrated that gonadal steroids secreted during perinatal life permanently 'organize' the mechanisms governing hypothalamo-pituitary-adrenal (HPA) function, leading to sexually differentiated patterns of pituitary-adrenal activity under basal and stress conditions. In this paper, we show that gonadal steroids can also exert 'activational' effects upon the HPA system. Examination of the ability of different doses of dexamethasone to suppress the nocturnal increase in corticosterone secretion and to attenuate the gene expression of CRH in the hypothalamic paraventricular nucleus of intact and gonadectomized male and female rats revealed that ovarian steroids make an important contribution to the higher sensitivity of the pituitary-adrenal axis in females to glucocorticoid suppression, whereas testicular steroids may be causal to the male's moderate responsiveness to glucocorticoid feedback. These findings may be implicated in a number of psychiatric and neurological disease states commonly associated with impaired HPA regulation, but which may be primarily rooted in altered gonadal steroid secretion.

  17. Depression and alterations in hypothalamic-pituitary-adrenal and hypothalamic-pituitary-thyroid axis function in male abstinent methamphetamine abusers.

    PubMed

    Li, Su-Xia; Yan, Shi-Yan; Bao, Yan-Ping; Lian, Zhi; Qu, Zhi; Wu, Ya-Ping; Liu, Zhi-Min

    2013-09-01

    The present study was to investigate depression and alterations in the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-thyroid (HPT) axis function in methamphetamine (METH) abusers after abstinence. Depression was assessed using the 13-item Beck Depression Inventory (BDI-13) scale; blood samples from in-patients who were METH abusers and age-matched and sex-matched healthy controls were collected. The demographic characteristics and history of METH abuse also was assessed. We found that serum levels of adrenocorticotropic hormone (ACTH) and thyroxine were increased; and serum levels of cortisol, triiodothyronine, and thyroid-stimulating hormone were decreased; and the BDI score was higher in METH abusers compared with control. In addition, there was no correlation between the BDI-13 score and any of hormones of HPA and HPT axis was found. Particularly, we found abnormally higher ACTH level and mismatched with lower cortisol level in abstinent METH abusers. These results indicate that METH abusers and that their HPA and HPT functions are all altered after abstinence. Chronically using METH may destroy the regulatory function of the HPA axis, especially the feedback regulation of cortisol to ACTH. Copyright © 2013 John Wiley & Sons, Ltd.

  18. Hypopituitarism in the elderly: a narrative review on clinical management of hypothalamic-pituitary-gonadal, hypothalamic-pituitary-thyroid and hypothalamic-pituitary-adrenal axes dysfunction.

    PubMed

    Curtò, L; Trimarchi, F

    2016-10-01

    Hypopituitarism is an uncommon and under-investigated endocrine disorder in old age since signs and symptoms are unspecific and, at least in part, can be attributed to the physiological effects of aging and related co-morbidities. Clinical presentation is often insidious being characterized by non-specific manifestations, such as weight gain, fatigue, low muscle strength, bradipsychism, hypotension or intolerance to cold. In these circumstances, hypopituitarism is a rarely life-threatening condition, but evolution may be more dramatic as a result of pituitary apoplexy, or when a serious condition of adrenal insufficiency suddenly occurs. Clinical presentation depends on the effects that each pituitary deficit can cause, and on their mutual relationship, but also, inevitably, it depends on the severity and duration of the deficit itself, as well as on the general condition of the patient. Indeed, indications and methods of hormone replacement therapy must include the need to normalize the endocrine profile without contributing to the worsening of intercurrent diseases, such as those of glucose and bone metabolism, and the cardiovascular system, or to the increasing cancer risk. Hormonal requirements of elderly patients are reduced compared to young adults, but a prompt diagnosis and appropriate treatment of pituitary deficiencies are strongly recommended, also in this age range.

  19. Early life adversity and serotonin transporter gene variation interact at the level of the adrenal gland to affect the adult hypothalamo-pituitary-adrenal axis.

    PubMed

    van der Doelen, R H A; Deschamps, W; D'Annibale, C; Peeters, D; Wevers, R A; Zelena, D; Homberg, J R; Kozicz, T

    2014-07-08

    The short allelic variant of the serotonin transporter (5-HTT) promoter-linked polymorphic region (5-HTTLPR) has been associated with the etiology of major depression by interaction with early life stress (ELS). Furthermore, 5-HTTLPR has been associated with abnormal functioning of the stress-responsive hypothalamo-pituitary-adrenal (HPA) axis. Here, we examined if, and at what level, the HPA-axis is affected in an animal model for ELS × 5-HTTLPR interactions. Heterozygous and homozygous 5-HTT knockout rats and their wild-type littermates were exposed daily at postnatal days 2-14 to 3 h of maternal separation. When grown to adulthood, plasma levels of adrenocorticotropic hormone (ACTH), and the major rat glucocorticoid, corticosterone (CORT), were measured. Furthermore, the gene expression of key HPA-axis players at the level of the hypothalamus, pituitary and adrenal glands was assessed. No 5-HTT genotype × ELS interaction effects on gene expression were observed at the level of the hypothalamus or pituitary. However, we found significant 5-HTT genotype × ELS interaction effects for plasma CORT levels and adrenal mRNA levels of the ACTH receptor, such that 5-HTT deficiency was associated under control conditions with increased, but after ELS with decreased basal HPA-axis activity. With the use of an in vitro adrenal assay, naïve 5-HTT knockout rats were furthermore shown to display increased adrenal ACTH sensitivity. Therefore, we conclude that basal HPA-axis activity is affected by the interaction of 5-HTT genotype and ELS, and is programmed, within the axis itself, predominantly at the level of the adrenal gland. This study therefore emphasizes the importance of the adrenal gland for HPA-related psychiatric disorders.

  20. Ultrasonographic adrenal gland measurements in clinically normal small breed dogs and comparison with pituitary-dependent hyperadrenocorticism.

    PubMed

    Choi, Jihye; Kim, Hyunwook; Yoon, Junghee

    2011-08-01

    Ultrasonography is a sensitive and specific screening method for assessing the adrenal glands. The upper limit of the normal adrenal gland width is used as 7.5 mm. It is not known if adrenal gland width remains consistent with body weight. A reliable criterion of adrenal gland width in small breed dogs should be established. Small breed dogs with body weights of less than 10 kg were divided into two groups: 189 normal dogs and 22 dogs with pituitary-dependent hyperadrenocorticism (PDH). A retrospective study was conducted on dogs seen between January 1, 2006, and February 10, 2008. One hundred eighty-nine dogs of 14 different small breeds were enrolled in the normal adrenal gland group; the median gland width was 4.20 mm. Twenty-two dogs were in the PDH group; the median gland width was 6.30 mm. The cut-off value between normal adrenal glands and PDH was 6.0 mm. This figure gave a sensitivity and specificity of 75 and 94%, respectively, for detecting PDH. The adrenal gland appeared as a peanut shape with homogeneous hypoechoic parenchyma in normal dogs and in most dogs with PDH as well. This study was performed in a large population of small breed dogs and suggests that the normal adrenal gland size in small breed dogs is smaller than previously reported. We believe that a cut-off of 6.0 mm may be used as the criterion for differentiating a normal adrenal gland from adrenal hyperplasia.

  1. Hypothalamic-pituitary-adrenal axis function in Sjögren's syndrome: mechanisms of neuroendocrine and immune system homeostasis.

    PubMed

    Johnson, Elizabeth O; Kostandi, Maria; Moutsopoulos, Haralampos M

    2006-11-01

    To date, evidence suggests that rheumatic diseases are associated with hypofunctioning of the hypothalamic-pituitary-adrenal (HPA) axis. Sjögren's syndrome (SS), the second most common autoimmune disorder, is characterized by diminished lacrimal and salivary gland secretion. To examine HPA axis activity in SS patients, the adrenocorticotropin (ACTH) response to ovine corticotropin-releasing factor (oCRH) was used as a direct measure of corticotrophic function, and the plasma cortisol response to the ACTH released during oCRH stimulation as an indirect measure of adrenal function. Significantly lower basal ACTH and cortisol levels were found in patients with SS and were associated with a blunted pituitary and adrenal response to oCRH compared to normal controls. Fibromyalgia (FM) patients demonstrated elevated evening basal ACTH and cortisol levels and a somewhat exaggerated peak, delta, and net integrated ACTH response to oCRH. A subgroup of SS patients also met the diagnostic criteria for FM and demonstrated a pituitary-adrenal response that was intermediate to SS and FM. These findings suggest not only adrenal axis hypoactivity in SS and FM patients, but also that varying patterns of adrenal and thyroid axes dysfunction may exist in patients with different rheumatic diseases.

  2. Hypothalamic-pituitary-adrenal axis function following intravitreal triamcinolone acetonide injection.

    PubMed

    Amiran, Maoz D; Yeung, Sonia N; Lang, Yaron; Sartani, Gil; Ishay, Avraham; Luboshitzky, Rafael

    2013-04-01

    To evaluate the pituitary-adrenal axis function by means of the adrenocorticotropic hormone (ACTH) stimulation test following a single intravitreal injection of triamcinolone acetonide (IVTA). Prospective comparative clinical interventional study. Twenty-eight patients (28 eyes) received a single IVTA (4 mg in 0.1 ml) for macular edema. The basal cortisol level and the response to 1 μg adrenocorticotropic hormone stimulation were determined on the morning before IVTA injection and at 1 day and 1, 2, and 4 weeks after IVTA injection. Results were compared with those obtained from a control group of 50 healthy subjects. All patients in the study had normal basal cortisol and normal response to ACTH challenge before receiving IVTA. 1 day following IVTA, basal cortisol was suppressed in one patient in the study group. Fasting serum cortisol levels at 1, 2, and 4 weeks after IVTA injection were normal in all patients in the study group. 1 day following IVTA, the peak response to ACTH at 30 min was blunted in four patients (14.3 % of the study group, p = 0.05) and the cortisol response at 60 min was suppressed (p = 0.009). 1 week following IVTA, the response to ACTH challenge was blunted in only one patient. A single IVTA injection may be associated with impaired hypothalamic-pituitary-adrenal function in some patients during the first 24 h following IVTA.

  3. The principle of homeostasis in the hypothalamus-pituitary-adrenal system: new insight from positive feedback.

    PubMed

    Peters, A; Conrad, M; Hubold, C; Schweiger, U; Fischer, B; Fehm, H L

    2007-07-01

    Feedback control, both negative and positive, is a fundamental feature of biological systems. Some of these systems strive to achieve a state of equilibrium or "homeostasis". The major endocrine systems are regulated by negative feedback, a process believed to maintain hormonal levels within a relatively narrow range. Positive feedback is often thought to have a destabilizing effect. Here, we present a "principle of homeostasis," which makes use of both positive and negative feedback loops. To test the hypothesis that this homeostatic concept is valid for the regulation of cortisol, we assessed experimental data in humans with different conditions (gender, obesity, endocrine disorders, medication) and analyzed these data by a novel computational approach. We showed that all obtained data sets were in agreement with the presented concept of homeostasis in the hypothalamus-pituitary-adrenal axis. According to this concept, a homeostatic system can stabilize itself with the help of a positive feedback loop. The brain mineralocorticoid and glucocorticoid receptors-with their known characteristics-fulfill the key functions in the homeostatic concept: binding cortisol with high and low affinities, acting in opposing manners, and mediating feedback effects on cortisol. This study supports the interaction between positive and negative feedback loops in the hypothalamus-pituitary-adrenal system and in this way sheds new light on the function of dual receptor regulation. Current knowledge suggests that this principle of homeostasis could also apply to other biological systems.

  4. Functional cross-talk between the hypothalamic-pituitary-gonadal and -adrenal axes.

    PubMed

    Viau, V

    2002-06-01

    Under normal conditions, the adrenal glucocorticoids, the endproduct of the hypothalamic-pituitary-adrenal (HPA) axis, provide a frontline of defence against threats to homeostasis (i.e. stress). On the other hand, chronic HPA drive and glucocorticoid hypersecretion have been implicated in the pathogenesis of several forms of systemic, neurodegenerative and affective disorders. The HPA axis is subject to gonadal influence, indicated by sex differences in basal and stress HPA function and neuropathologies associated with HPA dysfunction. Functional cross-talk between the gonadal and adrenal axes is due in large part to the interactive effects of sex steroids and glucocorticoids, explaining perhaps why several disease states linked to stress are sex-dependent. Realizing the interactive nature by which the hypothalamic-pituitary-gonadal and HPA systems operate, however, has made it difficult to model how these hormones act in the brain. Manipulation of one endocrine system is not without effects on the other. Simultaneous manipulation and assessment of both endocrine systems can overcome this problem. This dual approach in the male rat reveals that testosterone can act and interact on different aspects of basal and stress HPA function. Basal adrenocorticotropic hormone (ACTH) release is regulated by testosterone-dependent effects on arginine vasopressin synthesis, and corticosterone-dependent effects on corticotropin-releasing hormone (CRH) synthesis in the paraventricular nucleus (PVN) of the hypothalamus. In contrast, testosterone and corticosterone interact on stress-induced ACTH release and drive to the PVN motor neurones. Candidate structures mediating this interaction include several testosterone-sensitive afferents to the HPA axis, including the medial preoptic area, central and medial amygdala and bed nuclei of the stria terminalis. All of these relay homeostatic information and integrate reproductive and social behaviour. Because these modalities are affected

  5. Switching from systemic steroids to ciclesonide restores the hypothalamic pituitary-adrenal axis

    PubMed Central

    Ciebiada, Maciej; Górski, Paweł

    2014-01-01

    Introduction Treatment of difficult asthma with oral corticosteroids (OCS) may suppress the hypothalamic-pituitary-adrenal axis. Aim In this study we have checked if the substitution of OCS with very high doses of ciclesonide may restore the adrenal function without losing the control of the disease. Material and methods In 5 patients with difficult, uncontrolled asthma despite treatment with OCS, inhaled and systemic glucocorticosteroids were replaced with very high doses of ciclesonide (1600–2400 µg/day). The symptoms of asthma and the lung function were assessed at baseline and on the 28th, 56th and 70th day of treatment, whereas the levels of cortisol and adrenocorticotropic hormone (ACTH) in the morning were measured at baseline and on the 28th and the 56th day of treatment. Results In all patients, the control of asthma symptoms, measured with Asthma Control Test questionnaire, improved from the mean score of 9.4 to 19.8 in 70 days. In 4 subjects force expiratory volume in 1 s improved gradually through the entire study reaching a mean improvement of 585 ml in 70 days. The ACTH levels were normalized in 3 patients after 28 days of observation and in all patients after 56 days. The cortisol level was normalized in 4 patients after 28 days and in another subject after 56 days of treatment with ciclesonide. Conclusions Switching from prednisone to very high doses of ciclesonide normalized the hypothalamic-pituitary adrenal axis function and also improved the disease control and the lung function in these 5 patients with difficult asthma. PMID:25097469

  6. Prenatal xenobiotic exposure and intrauterine hypothalamus-pituitary-adrenal axis programming alteration.

    PubMed

    Zhang, Chong; Xu, Dan; Luo, Hanwen; Lu, Juan; Liu, Lian; Ping, Jie; Wang, Hui

    2014-11-05

    The hypothalamic-pituitary-adrenal (HPA) axis is one of the most important neuroendocrine axes and plays an important role in stress defense responses before and after birth. Prenatal exposure to xenobiotics, including environmental toxins (such as smoke, sulfur dioxide and carbon monoxide), drugs (such as synthetic glucocorticoids), and foods and beverage categories (such as ethanol and caffeine), affects fetal development indirectly by changing the maternal status or damaging the placenta. Certain xenobiotics (such as caffeine, ethanol and dexamethasone) may also affect the fetus directly by crossing the placenta into the fetus due to their lipophilic properties and lower molecular weights. All of these factors probably result in intrauterine programming alteration of the HPA axis, which showed a low basal activity but hypersensitivity to chronic stress. These alterations will, therefore, increase the susceptibility to adult neuropsychiatric (such as depression and schizophrenia) and metabolic diseases (such as hypertension, diabetes and non-alcoholic fatty liver disease). The "over-exposure of fetuses to maternal glucocorticoids" may be the main initiation factor by which the fetal HPA axis programming is altered. Meantime, xenobiotics can directly induce abnormal epigenetic modifications and expression on the important fetal genes (such as hippocampal glucocorticoid receptor, adrenal steroidogenic acute regulatory protein, et al) or damage by in situ oxidative metabolism of fetal adrenals, which may also be contributed to the programming alteration of fetal HPA axis.

  7. Comparison of miRNA expression profiles in pituitary-adrenal axis between Beagle and Chinese Field dogs after chronic stress exposure.

    PubMed

    Luo, Wei; Fang, Meixia; Xu, Haiping; Xing, Huijie; Fu, Jiangnan; Nie, Qinghua

    2016-01-01

    MicoRNAs (miRNAs), usually as gene regulators, participate in various biological processes, including stress responses. The hypothalamus-pituitary-adrenal axis (HPA axis) is an important pathway in regulating stress response. Although the mechanism that HPA axis regulates stress response has been basically revealed, the knowledge that miRNAs regulate stress response within HPA axis, still remains poor. The object of this study was to investigate the miRNAs in the pituitary and adrenal cortex that regulate chronic stress response with high-throughput sequencing. The pituitary and adrenal cortex of beagles and Chinese Field dogs (CFD) from a stress exposure group (including beagle pituitary 1 (BP1), CFD pituitary 1 (CFDP1), beagle adrenal cortex 1 (BAC1), CFD adrenal cortex 1 (CFDAC1)) and a control group (including beagle pituitary 2 (BP2), CFD pituitary 2 (CFDP2), beagle adrenal cortex 2 (BAC2), CFD adrenal cortex 2 (CFDAC2)), were selected for miRNA-seq comparisons. Comparisons, that were made in pituitary (including BP1 vs. BP2, CFDP1 vs. CFDP2, BP1 vs. CFDP1 and BP2 vs. CFDP2) and adrenal cortex (including BAC1 vs. BAC2, CFDAC1 vs. CFDAC2, BAC1 vs. CFDAC1 and BAC2 vs. CFDAC2), showed that a total of 39 and 18 common differentially expressed miRNAs (DE-miRNAs) (Total read counts > 1,000, Fold change > 2 & p-value < 0.001), that shared in at least two pituitary comparisons and at least two adrenal cortex comparisons, were detected separately. These identified DE-miRNAs were predicted for target genes, thus resulting in 3,959 and 4,010 target genes in pituitary and adrenal cortex, respectively. Further, 105 and 10 differentially expressed genes (DEGs) (Fold change > 2 & p-value < 0.05) from those target genes in pituitary and adrenal cortex were obtained separately, in combination with our previous corresponding transcriptome study. Meanwhile, in line with that miRNAs usually negatively regulated their target genes and the dual luciferase reporter assay, we finally

  8. Hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes: sex differences in regulation of stress responsivity.

    PubMed

    Oyola, Mario G; Handa, Robert J

    2017-08-31

    Gonadal hormones play a key role in the establishment, activation, and regulation of the hypothalamic-pituitary-adrenal (HPA) axis. By influencing the response and sensitivity to releasing factors, neurotransmitters, and hormones, gonadal steroids help orchestrate the gain of the HPA axis to fine-tune the levels of stress hormones in the general circulation. From early life to adulthood, gonadal steroids can differentially affect the HPA axis, resulting in sex differences in the responsivity of this axis. The HPA axis influences many physiological functions making an organism's response to changes in the environment appropriate for its reproductive status. Although the acute HPA response to stressors is a beneficial response, constant activation of this circuitry by chronic or traumatic stressful episodes may lead to a dysregulation of the HPA axis and cause pathology. Compared to males, female mice and rats show a more robust HPA axis response, as a result of circulating estradiol levels which elevate stress hormone levels during non-threatening situations, and during and after stressors. Fluctuating levels of gonadal steroids in females across the estrous cycle are a major factor contributing to sex differences in the robustness of HPA activity in females compared to males. Moreover, gonadal steroids may also contribute to epigenetic and organizational influences on the HPA axis even before puberty. Correspondingly, crosstalk between the hypothalamic-pituitary-gonadal (HPG) and HPA axes could lead to abnormalities of stress responses. In humans, a dysregulated stress response is one of the most common symptoms seen across many neuropsychiatric disorders, and as a result, such interactions may exacerbate peripheral pathologies. In this review, we discuss the HPA and HPG axes and review how gonadal steroids interact with the HPA axis to regulate the stress circuitry during all stages in life.

  9. Effects of Parental Depressive Symptoms on Child Adjustment Moderated by Hypothalamic Pituitary Adrenal Activity: Within- and between-Family Risk

    ERIC Educational Resources Information Center

    Laurent, Heidemarie K.; Leve, Leslie D.; Neiderhiser, Jenae M.; Natsuaki, Misaki N.; Shaw, Daniel S.; Fisher, Philip A.; Marceau, Kristine; Harold, Gordon T.; Reiss, David

    2013-01-01

    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 54 months, and child morning and evening HPA…

  10. Effects of Parental Depressive Symptoms on Child Adjustment Moderated by Hypothalamic Pituitary Adrenal Activity: Within- and between-Family Risk

    ERIC Educational Resources Information Center

    Laurent, Heidemarie K.; Leve, Leslie D.; Neiderhiser, Jenae M.; Natsuaki, Misaki N.; Shaw, Daniel S.; Fisher, Philip A.; Marceau, Kristine; Harold, Gordon T.; Reiss, David

    2013-01-01

    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 54 months, and child morning and evening HPA…

  11. Charcterization of the Hypothalamic-Pituitary-Adrenal Axis Response to Atrazine and Metabolites in the Female Rat

    EPA Science Inventory

    Atrazine (ATR) has recently been shown to activate the hypothalamic-pituitary-adrenal (HPA) axis in rodents. The current study investigated the effect of ATR and two of its chlorinated metabolites, desisopropylatrazine (DIA) and diamino-s-chlorotriazine (DACT), on the HPA axis in...

  12. Charcterization of the Hypothalamic-Pituitary-Adrenal Axis Response to Atrazine and Metabolites in the Female Rat

    EPA Science Inventory

    Atrazine (ATR) has recently been shown to activate the hypothalamic-pituitary-adrenal (HPA) axis in rodents. The current study investigated the effect of ATR and two of its chlorinated metabolites, desisopropylatrazine (DIA) and diamino-s-chlorotriazine (DACT), on the HPA axis in...

  13. [Evaluation of hypothalamic-pituitary-adrenal axis recovery after corticotherapy by using basal cortisol secretion].

    PubMed

    Silva, Ivani N; Cunha, Cristiane F; Finch, Francisca L; Colosimo, Enrico A

    2006-02-01

    The glucocorticoid-induced inhibition that occurs after discontinuation of treatment is the most frequent cause of adrenal insufficiency. There are yet some doubts about the best way of evaluating the hypothalamic-pituitary-adrenal (HPA) axis in those patients. The main objective of this study was to evaluate the utility of basal cortisol in diagnosing adrenal insufficiency. Thirty-five children with acute lymphoid leukemia (ALL) receiving glucocorticoid therapy (median age of 6.9 years) were evaluated. A stimulus test with corticotropin releasing hormone (CRH-1 mcg/kg) was performed before the introduction of dexamethasone (6 mg/m2/day, for 28 days), in the 8th and the 28th days of glucocorticoid therapy, and 48 hours and one month after discontinuation of therapy. Suppression of the basal secretion as well as the maximum concentration of cortisol (post-CRH) occurred during glucocorticoid therapy, which persisted for 48 hours after the steroid was removed from treatment (p< 0.01 and p< 0.0001, respectively, for the three tests). One month after ceasing the administration of the glucocorticoid, the basal secretion, as well as the maximum concentration of cortisol, were similar to that before glucocorticoid therapy. There was a positive and statistically significant correlation between basal secretion and maximum concentration of cortisol in all tests. We observed 95% of specificity for the diagnosis of adrenal insufficiency when the inferior limit of basal cortisol was 8.5 mcg/dl. According to these results we concluded that basal secretion of cortisol is a good marker of supra-renal function in evaluating children after discontinuation of glucocorticoid therapy.

  14. Transgenerational Effects of Prenatal Synthetic Glucocorticoids on Hypothalamic-Pituitary-Adrenal Function

    PubMed Central

    Iqbal, Majid; Moisiadis, Vasilis G.; Kostaki, Alisa

    2012-01-01

    Approximately 10% of pregnant women are at risk of preterm delivery and receive synthetic glucocorticoids (sGC) to promote fetal lung development. Studies have indicated that prenatal sGC therapy modifies hypothalamic-pituitary-adrenal (HPA) function in first-generation (F1) offspring. The objective of this study was to determine whether differences in HPA function and behavior are evident in the subsequent (F2) generation. Pregnant guinea pigs (F0) received betamethasone (BETA; 1 mg/kg) or saline on gestational d 40/41, 50/51, and 60/61. F1 females were mated with control males to create F2 offspring. HPA function was assessed in juvenile and adult F2 offspring. Locomotor activity was assessed in juvenile offspring. Analysis of HPA-related gene expression was undertaken in adult hippocampi, hypothalami, and pituitaries. Locomotor activity was reduced in F2 BETA males (P < 0.05). F2 BETA offspring displayed blunted cortisol response to swim stress (P < 0.05). After dexamethasone challenge, F2 BETA males and females displayed increased and decreased negative feedback, respectively. F2 BETA females had reduced pituitary levels of proopiomelanocortin (and adrenocorticotropic hormone), and corticotropin-releasing hormone receptor mRNA and protein (P < 0.05). F2 BETA males displayed increased hippocampal glucocorticoid receptor (P < 0.001), whereas in BETA females, hippocampal glucocorticoid receptor and mineralocorticoid receptor mRNA were decreased (P < 0.05). In conclusion, prenatal BETA treatment affects HPA function and behavior in F2 offspring. In F2 BETA females, pituitary function appears to be primarily affected, whereas hippocampal glucocorticoid feedback systems appear altered in both F2 BETA males and females. These data have clinical implication given the widespread use of repeat course glucocorticoid therapy in the management of preterm labour. PMID:22564976

  15. Diagnostic Accuracy of Perioperative Measurement of Basal Anterior Pituitary and Target Gland Hormones in Predicting Adrenal Insufficiency After Pituitary Surgery

    PubMed Central

    Cerina, Vatroslav; Kruljac, Ivan; Radosevic, Jelena Marinkovic; Kirigin, Lora Stanka; Stipic, Darko; Pecina, Hrvoje Ivan; Vrkljan, Milan

    2016-01-01

    Abstract The insulin tolerance test (ITT) is the gold standard for diagnosing adrenal insufficiency (AI) after pituitary surgery. The ITT is unpleasant for patients, requires close medical supervision and is contraindicated in several comorbidities. The aim of this study was to analyze whether tumor size, remission rate, preoperative, and early postoperative baseline hormone concentrations could serve as predictors of AI in order to increase the diagnostic accuracy of morning serum cortisol. This prospective study enrolled 70 consecutive patients with newly diagnosed pituitary adenomas. Thirty-seven patients had nonfunctioning pituitary adenomas (NPA), 28 had prolactinomas and 5 had somatotropinomas. Thyroxin (T4), thyrotropin (TSH), prolactin, follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, and insulin-like growth factor 1 (IGF-I) were measured preoperatively and on the sixth postoperative day. Serum morning cortisol was measured on the third postoperative day (CORT3) as well as the sixth postoperative day (CORT6). Tumor mass was measured preoperatively and remission was assessed 3 months after surgery. An ITT was performed 3 to 6 months postoperatively. Remission was achieved in 48% of patients and AI occurred in 51%. Remission rates and tumor type were not associated with AI. CORT3 had the best predictive value for AI (area under the curve (AUC) 0.868, sensitivity 82.4%, specificity 83.3%). Tumor size, preoperative T4, postoperative T4, and TSH were also associated with AI in a multivariate regression model. A combination of all preoperative and postoperative variables (excluding serum cortisol) had a sensitivity of 75.0% and specificity of 77.8%. The predictive power of CORT3 substantially improved by adding those variables into the model (AUC 0.921, sensitivity 94.1%, specificity 78.3%, PPV 81.9%, NPV of 92.7%). In a subgroup analysis that included only female patients with NPA, LH had exactly the same predictive value as CORT3. The

  16. Diagnostic Accuracy of Perioperative Measurement of Basal Anterior Pituitary and Target Gland Hormones in Predicting Adrenal Insufficiency After Pituitary Surgery.

    PubMed

    Cerina, Vatroslav; Kruljac, Ivan; Radosevic, Jelena Marinkovic; Kirigin, Lora Stanka; Stipic, Darko; Pecina, Hrvoje Ivan; Vrkljan, Milan

    2016-03-01

    The insulin tolerance test (ITT) is the gold standard for diagnosing adrenal insufficiency (AI) after pituitary surgery. The ITT is unpleasant for patients, requires close medical supervision and is contraindicated in several comorbidities. The aim of this study was to analyze whether tumor size, remission rate, preoperative, and early postoperative baseline hormone concentrations could serve as predictors of AI in order to increase the diagnostic accuracy of morning serum cortisol. This prospective study enrolled 70 consecutive patients with newly diagnosed pituitary adenomas. Thirty-seven patients had nonfunctioning pituitary adenomas (NPA), 28 had prolactinomas and 5 had somatotropinomas. Thyroxin (T4), thyrotropin (TSH), prolactin, follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, and insulin-like growth factor 1 (IGF-I) were measured preoperatively and on the sixth postoperative day. Serum morning cortisol was measured on the third postoperative day (CORT3) as well as the sixth postoperative day (CORT6). Tumor mass was measured preoperatively and remission was assessed 3 months after surgery. An ITT was performed 3 to 6 months postoperatively. Remission was achieved in 48% of patients and AI occurred in 51%. Remission rates and tumor type were not associated with AI. CORT3 had the best predictive value for AI (area under the curve (AUC) 0.868, sensitivity 82.4%, specificity 83.3%). Tumor size, preoperative T4, postoperative T4, and TSH were also associated with AI in a multivariate regression model. A combination of all preoperative and postoperative variables (excluding serum cortisol) had a sensitivity of 75.0% and specificity of 77.8%. The predictive power of CORT3 substantially improved by adding those variables into the model (AUC 0.921, sensitivity 94.1%, specificity 78.3%, PPV 81.9%, NPV of 92.7%). In a subgroup analysis that included only female patients with NPA, LH had exactly the same predictive value as CORT3. The addition

  17. Ontogenetic studies of tolerance development: effects of chronic morphine on the hypothalamic-pituitary-adrenal axis.

    PubMed

    Little, P J; Kuhn, C M

    1995-11-01

    Endogenous opiates are important regulators of the hypothalamic-pituitary-adrenal (HPA) axis in rats. Tolerance clearly develops to morphine-induced stimulation of the HPA axis in adult rats (Ignar and Kuhn 1990). The goal of the present study was to determine whether tolerance to morphine-induced stimulation of the HPA axis developed in neonatal and weanling rats treated chronically with morphine. Rats were injected with morphine or saline between days 4-8 postnatal (pups) or days 21-25 (weanlings) and tolerance assessed by determining dose-response curves for ACTH and corticosterone secretion following an acute morphine challenge. Weanlings displayed marked tolerance to the stimulation of ACTH and corticosterone secretion by morphine. Tolerance was also observed in pups to morphine-stimulated ACTH and corticosterone release. These findings suggest that the relative adaptability of the HPA axis to chronic morphine in neonatal and weanling rats is similar.

  18. Changes in hypothalamic-pituitary-adrenal stress responsiveness before and after puberty in rats.

    PubMed

    Klein, Zoe A; Romeo, Russell D

    2013-07-01

    This article is part of a Special Issue "Puberty and Adolescence". Many endocrine changes are associated with pubertal and adolescent development. One such change is the responsiveness of the hypothalamic-pituitary-adrenal (HPA) axis to physical and/or psychological stressors. Recent human and non-human animal studies have shown that hormonal stress reactivity increases significantly throughout puberty and adolescence. Specifically, exposure to various stressors results in greater adrenocorticotropic hormone (ACTH) and glucocorticoid responses in peripubertal compared to adult animals. This review will focus on how stress reactivity changes throughout puberty and adolescence, as well as potential mechanisms that mediate these changes in stress responsiveness. Though the implications of these pubertal shifts in stress responsiveness are not fully understood, the significant increase in stress-related mental and physical dysfunctions during this stage of development highlights the importance of studying pubertal and adolescent maturation of HPA function and its reactivity to stress.

  19. The influence of pituitary, adrenal, and parathyroid hormones on hemostasis and thrombosis.

    PubMed

    Squizzato, Alessandro; Van Zaane, Bregje; Gerdes, Victor E A; Büller, Harry R

    2011-02-01

    Endocrine disorders can influence the hemostatic balance. Abnormal coagulation test results have been observed in patients with abnormal hormone levels. The present review updates the available evidence on the influence of pituitary, adrenal, and parathyroid hormones on the coagulation and the fibrinolytic system, and their possible clinical implications. The literature supports a possible relevant clinical effect of the imbalance between coagulation and fibrinolysis on thrombotic events in endogenous Cushing's syndrome. An effect on markers of coagulation and fibrinolysis has been shown for hyperprolactinemia, growth hormone excess or deficiency, exogenous hypercortisolism, pheochromocytoma, primary hyperaldosteronism, and hyperparathyroidism. However, the clinical relevance is still unproven. Until definitive evidence is available, clinicians should be aware of the possibility that endocrine disorders may be risk factors for thrombotic events.

  20. Role of the Hypothalamic-Pituitary-Adrenal Axis in Developmental Programming of Health and Disease

    PubMed Central

    Xiong, Fuxia; Zhang, Lubo

    2012-01-01

    Adverse environments during the fetal and neonatal development period may permanently program physiology and metabolism, and lead to increased risk of diseases in later life. Programming of the hypothalamic-pituitary-adrenal (HPA) axis is one of the key mechanisms that contribute to altered metabolism and response to stress. Programming of the HPA axis often involves epigenetic modification of the glucocorticoid receptor (GR) gene promoter, which influences tissue-specific GR expression patterns and response to stimuli. This review summarizes the current state of research on the HPA axis and programming of health and disease in the adult, focusing on the epigenetic regulation of GR gene expression patterns in response to fetal and neonatal stress. Aberrant GR gene expression patterns in the developing brain may have a significant negative impact on protection of the immature brain against hypoxic-ischemic encephalopathy in the critical period of development during and immediately after birth. PMID:23200813

  1. Alteration of pituitary-adrenal dynamics induced by a water deprivation regimen

    NASA Technical Reports Server (NTRS)

    Sakellaris, P. C.; Vernikos-Danellis, J.

    1974-01-01

    Experiments are described which were designed to assess the degree of adaptation that occurs in rats chronically exposed to the stress of a water-deprivation regimen and to determine if that adaptation represents a normalization of the hypothalamic-pituitary-adrenal axis. There were no significant differences in mean corticosterone concentrations among control nondeprived rats 1, 4, and 8 weeks after the start of the experiment. The water-deprived rats, however, had significantly elevated plasma steroids 1 and 4 weeks after the onset of deprivation as compared to controls, but not after 8 weeks. Thus, there was a significant decrease in mean plasma corticosterone levels during water deprivation from 1 week to 8 weeks.

  2. Correcting hypothalamic-pituitary-adrenal axis dysfunction using observer-based explicit nonlinear model predictive control.

    PubMed

    Chakrabarty, Ankush; Buzzard, Gregery T; Corless, Martin J; Zak, Stanislaw H; Rundell, Ann E

    2014-01-01

    The hypothalamic-pituitary-adrenal (HPA) axis is critical in maintaining homeostasis under physical and psychological stress by modulating cortisol levels in the body. Dysregulation of cortisol levels is linked to numerous stress-related disorders. In this paper, an automated treatment methodology is proposed, employing a variant of nonlinear model predictive control (NMPC), called explicit MPC (EMPC). The controller is informed by an unknown input observer (UIO), which estimates various hormonal levels in the HPA axis system in conjunction with the magnitude of the stress applied on the body, based on measured concentrations of adreno-corticotropic hormones (ACTH). The proposed closed-loop control strategy is tested on multiple in silico patients and the effectiveness of the controller performance is demonstrated.

  3. Alteration of pituitary-adrenal dynamics induced by a water deprivation regimen

    NASA Technical Reports Server (NTRS)

    Sakellaris, P. C.; Vernikos-Danellis, J.

    1974-01-01

    Experiments are described which were designed to assess the degree of adaptation that occurs in rats chronically exposed to the stress of a water-deprivation regimen and to determine if that adaptation represents a normalization of the hypothalamic-pituitary-adrenal axis. There were no significant differences in mean corticosterone concentrations among control nondeprived rats 1, 4, and 8 weeks after the start of the experiment. The water-deprived rats, however, had significantly elevated plasma steroids 1 and 4 weeks after the onset of deprivation as compared to controls, but not after 8 weeks. Thus, there was a significant decrease in mean plasma corticosterone levels during water deprivation from 1 week to 8 weeks.

  4. Sympathetic and hypothalamic-pituitary-adrenal asymmetry in generalized anxiety disorder.

    PubMed

    Reeves, Jonathan W; Fisher, Aaron J; Newman, Michelle G; Granger, Douglas A

    2016-06-01

    Physiologic investigations of generalized anxiety disorder (GAD) have skewed toward assessment of the autonomic nervous system, largely neglecting hypothalamic-pituitary-adrenal (HPA) axis variables. Although these systems coordinate-suggesting a degree of symmetry-to promote adaptive functioning, most studies opt to monitor either one system or the other. Using a ratio of salivary alpha-amylase (sAA) over salivary cortisol, the present study examined symmetry between the sympathetic nervous system (SNS) and HPA axis in individuals with GAD (n = 71) and healthy controls (n = 37). Compared to healthy controls, individuals with GAD exhibited greater baseline ratios of sAA/cortisol and smaller ratios of sAA/cortisol following a mental arithmetic challenge. We propose that the present study provides evidence for SNS-HPA asymmetry in GAD. Further, these results suggest that increased SNS suppression in GAD may be partially mediated by cortisol activity.

  5. Differential flatness properties and adaptive control of the hypothalamic-pituitary-adrenal axis model

    NASA Astrophysics Data System (ADS)

    Rigatos, Gerasimos

    2016-12-01

    It is shown that the model of the hypothalamic-pituitary-adrenal gland axis is a differentially flat one and this permits to transform it to the so-called linear canonical form. For the new description of the system's dynamics the transformed control inputs contain unknown terms which depend on the system's parameters. To identify these terms an adaptive fuzzy approximator is used in the control loop. Thus an adaptive fuzzy control scheme is implemented in which the unknown or unmodeled system dynamics is approximated by neurofuzzy networks and next this information is used by a feedback controller that makes the state variables (CRH - corticotropin releasing hormone, adenocortocotropic hormone - ACTH, cortisol) of the hypothalamic-pituitary-adrenal gland axis model converge to the desirable levels (setpoints). This adaptive control scheme is exclusively implemented with the use of output feedback, while the state vector elements which are not directly measured are estimated with the use of a state observer that operates in the control loop. The learning rate of the adaptive fuzzy system is suitably computed from Lyapunov analysis, so as to assure that both the learning procedure for the unknown system's parameters, the dynamics of the observer and the dynamics of the control loop will remain stable. The performed Lyapunov stability analysis depends on two Riccati equations, one associated with the feedback controller and one associated with the state observer. Finally, it is proven that for the control scheme that comprises the feedback controller, the state observer and the neurofuzzy approximator, an H-infinity tracking performance can be succeeded.

  6. Novel aspects of hypothalamic-pituitary-adrenal axis regulation and glucocorticoid actions

    PubMed Central

    Uchoa, Ernane Torres; Aguilera, Greti; Herman, James P.; Fiedler, Jenny L.; Deak, Terrence; Cordeiro de Sousa, Maria Bernardete

    2014-01-01

    Normal hypothalamic-pituitary-adrenal (HPA) axis activity leading to rhythmic and episodic release of adrenal glucocorticoids is essential for body homeostasis and survival during stress. Acting through specific intracellular receptors in the brain and periphery, glucocorticoids regulate behavior, metabolic, cardiovascular, immune, and neuroendocrine activities. In contrast to chronic elevated levels, circadian and acute stress-induced increases in glucocorticoids are necessary for hippocampal neuronal survival and memory acquisition and consolidation, through inhibiting apoptosis, facilitating glutamate transmission and inducing immediate early genes and spine formation. In addition to its metabolic actions leading to increasing energy availability, glucocorticoids have profound effects on feeding behavior, mainly through modulation of orexigenic and anorixegenic neuropeptides. Evidence is also emerging that in addition to the recognized immune suppressive actions of glucocorticoids by counteracting adrenergic proinflammatory actions, circadian elevations have priming effects in the immune system, potentiating acute defensive responses. In addition, negative feedback by glucocorticoids involves multiple mechanisms leading to limiting HPA axis activation and preventing deleterious effects of excessive glucocorticoid production. Adequate glucocorticoid secretion to meet body demands is tightly regulated by a complex neural circuitry controlling hypothalamic corticotrophin releasing hormone (CRH) and vasopressin secretion, the main regulators of pituitary adrenocorticotrophic hormone (ACTH). Rapid feedback mechanisms, likely involving non-genomic actions of glucocorticoids, mediate immediate inhibition of hypothalamic CRH and ACTH secretion, while intermediate and delayed mechanisms mediated by genomic actions involve modulation of limbic circuitry and peripheral metabolic messengers. Consistent with their key adaptive roles, HPA axis components are evolutionarily

  7. Hypothalamo-pituitary-adrenal axis, glucose metabolism and TNF-α in narcolepsy.

    PubMed

    Maurovich-Horvat, Eszter; Keckeis, Marietta; Lattová, Zuzana; Kemlink, David; Wetter, Thomas-Christian; Schuld, Andreas; Sonka, Karel; Pollmächer, Thomas

    2014-08-01

    Narcolepsy with cataplexy is caused by a deficiency in the production of hypocretin/orexin, which regulates sleep and wakefulness, and also influences appetite, neuroendocrine functions and metabolism. In this case-control study, 11 patients with narcolepsy with cataplexy and 11 healthy adults underwent an oral glucose tolerance test, and dexamethasone suppression/corticotropin-releasing hormone stimulation test. The average age of patients and controls was 35.1 ± 13.2 and 41.0 ± 2.9 years, respectively, body mass index was 28.1 ± 6.6 and 25.5 ± 4.7 kg m(-2) . We did not find evidence of a significantly increased prevalence of disturbed glucose tolerance in patients with narcolepsy. After hypothalamo-pituitary-adrenal axis suppression, the number of non-suppressors did not differ between the groups, indicating normal negative feedback sensitivity. The level of cortisol after dexamethasone suppression was significantly lower in patients with narcolepsy, suggesting a slight basal downregulation and/or a slightly increased negative feedback sensitivity of the major endocrine stress system in narcolepsy. Following corticotropin-releasing hormone stimulation, there were no significant differences in levels of adrenocorticotropic hormone or cortisol, and in adrenocortical responsivity to adrenocorticotropic hormone. Finally, patients with narcolepsy displayed significantly higher plasma levels of tumour necrosis factor alpha, soluble tumour necrosis factor receptor p55, soluble tumour necrosis factor receptor p75 and interleukin 6 after adjustment for body mass index. The present study confirms that narcolepsy by itself is not associated with disturbances of glucose metabolism, but goes along with a subtle dysregulation of inflammatory cytokine production. We also found that dynamic hypothalamo-pituitary-adrenal system response is not altered, whereas negative feedback to dexamethasone might be slightly enhanced.

  8. [Changes in the activity of sympathetic-adrenal medullary system and hypothalamic-pituitary-adrenal system in humans exposed to psychogenic stressors and their effects on immunoreactivity].

    PubMed

    Simić, Natasa

    2010-10-01

    This paper gives an account of the functioning of the two systems in different stress induced situations. The activation of the sympathetic-adrenal medullary system is accompanied by the release of catecholamines, while the increased activity of the hypothalamic-pituitary-adrenal system results in the increased release of corticosteroids, especially cortisol. The role of the sympathetic-adrenal medullary system was investigated in immunologic changes induced by laboratory stressors. In the real, as in laboratory conditions, the effects of different stressors on the level of cortisol were studied, as it is the final product of the hypothalamic-pituitary-adrenal system activity. Additional (negative) effects on the functioning of these systems could induce some variables, as an increased consumption of alcohol, smoking, and sleeping disorder. Furthermore, the methodological shortcomings and the selection of subjects in previous studies are discussed. Previous results are also discussed, such as the immunosuppressive effects of cortisol, as well as the mediator and moderator variables in relation to stress and immunoreactivity.

  9. Overfeeding during a critical postnatal period exacerbates hypothalamic-pituitary-adrenal axis responses to immune challenge: a role for adrenal melanocortin 2 receptors

    PubMed Central

    Cai, Guohui; Ziko, Ilvana; Barwood, Joanne; Soch, Alita; Sominsky, Luba; Molero, Juan C.; Spencer, Sarah J.

    2016-01-01

    Early life diet can critically program hypothalamic-pituitary-adrenal (HPA) axis function. We have previously shown rats that are overfed as neonates have exacerbated pro-inflammatory responses to immune challenge with lipopolysaccharide (LPS), in part by altering HPA axis responses, but how this occurs is unknown. Here we examined neonatal overfeeding-induced changes in gene expression in each step of the HPA axis. We saw no differences in glucocorticoid or mineralocorticoid receptor expression in key regions responsible for glucocorticoid negative feedback to the brain and no differences in expression of key HPA axis regulatory genes in the paraventricular nucleus of the hypothalamus or pituitary. On the other hand, expression of the adrenal melanocortin 2 receptor (MC2R) is elevated after LPS in control rats, but significantly less so in the neonatally overfed. The in vitro adrenal response to ACTH is also dampened in these rats, while the in vivo response to ACTH does not resolve as efficiently as it does in controls. These data suggest neonatal diet affects the efficiency of the adrenally-mediated response to LPS, potentially influencing how neonatally overfed rats combat bacterial infection. PMID:26868281

  10. Overfeeding during a critical postnatal period exacerbates hypothalamic-pituitary-adrenal axis responses to immune challenge: a role for adrenal melanocortin 2 receptors.

    PubMed

    Cai, Guohui; Ziko, Ilvana; Barwood, Joanne; Soch, Alita; Sominsky, Luba; Molero, Juan C; Spencer, Sarah J

    2016-02-12

    Early life diet can critically program hypothalamic-pituitary-adrenal (HPA) axis function. We have previously shown rats that are overfed as neonates have exacerbated pro-inflammatory responses to immune challenge with lipopolysaccharide (LPS), in part by altering HPA axis responses, but how this occurs is unknown. Here we examined neonatal overfeeding-induced changes in gene expression in each step of the HPA axis. We saw no differences in glucocorticoid or mineralocorticoid receptor expression in key regions responsible for glucocorticoid negative feedback to the brain and no differences in expression of key HPA axis regulatory genes in the paraventricular nucleus of the hypothalamus or pituitary. On the other hand, expression of the adrenal melanocortin 2 receptor (MC2R) is elevated after LPS in control rats, but significantly less so in the neonatally overfed. The in vitro adrenal response to ACTH is also dampened in these rats, while the in vivo response to ACTH does not resolve as efficiently as it does in controls. These data suggest neonatal diet affects the efficiency of the adrenally-mediated response to LPS, potentially influencing how neonatally overfed rats combat bacterial infection.

  11. Attenuated hypothalamic-pituitary-adrenal axis functioning predicts accelerated pubertal development in girls 1 year later.

    PubMed

    Saxbe, Darby E; Negriff, Sonya; Susman, Elizabeth J; Trickett, Penelope K

    2015-08-01

    Accelerated pubertal development has been linked to adverse early environments and may heighten subsequent mental and physical health risks. Hypothalamic-pituitary-adrenal axis functioning has been posited as a mechanism whereby stress may affect pubertal development, but the literature lacks prospective tests of this mechanism. The current study assessed 277 youth (M = 10.84 years, SD = 1.14), 138 boys and 139 girls, who reported on their pubertal development and underwent the Trier Social Stress Test for Children at baseline and returned to the laboratory approximately 1 year later (M = 1.12 years, range = 0.59-1.98 years). For girls, lower cortisol area under the curve (with respect to ground) at Time 1 predicted more advanced pubertal development at Time 2, controlling for Time 1 pubertal development. This association persisted after additional covariates including age, body mass index, race, and maltreatment history were introduced, and was driven by adrenal rather than gonadal development. Cortisol was not linked to boys' subsequent pubertal development, and no interaction by gender or by maltreatment appeared. These results suggest that attenuated cortisol, reported in other studies of children exposed to early adversity, may contribute to accelerated pubertal tempo in girls.

  12. The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress

    PubMed Central

    Smith, Sean M.; Vale, Wylie W.

    2006-01-01

    Animals respond to stress by activating a wide array of behavioral and physiological responses that are collectively referred to as the stress response. Corticotropin-releasing factor (CRF) plays a central role in the stress response by regulating the hypothalamic-pituitary-adrenal (HPA) axis. In response to stress, CRF initiates a cascade of events that culminate in the release of glucocorticoids from the adrenal cortex. As a result of the great number of physiological and behavioral effects exerted by glucocorticoids, several mechanisms have evolved to control HPA axis activation and integrate the stress response. Glucocorticoid feedback inhibition plays a prominent role in regulating the magnitude and duration of glucocorticoid release. In addition to glucocorticoid feedback, the HPA axis is regulated at the level of the hypothalamus by a diverse group of afferent projections from limbic, mid-brain, and brain stem nuclei. The stress response is also mediated in part by brain stem noradrenergic neurons, sympathetic andrenornedullary circuits, and parasympathetic systems. In summary, the aim of this review is to discuss the role of the HPA axis in the integration of adaptive responses to stress. We also identify and briefly describe the major neuronal and endocrine systems that contribute to the regulation of the HPA axis and the maintenance of homeostasis in the face of aversive stimuli. PMID:17290797

  13. Atrial natriuretic factor: radioimmunoassay and effects on adrenal and pituitary glands

    SciTech Connect

    Gutkowska, J.; Horky, K.; Schiffrin, E.L.; Thibault, G.; Garcia, R.; De Lean, A.; Hamet, P.; Tremblay, J.; Anand-Srivastava, M.B.; Januszewicz, P.

    1986-06-01

    A simple and sensitive radioimmunoassay was developed for measurement of immunoreactive atrial natriuretic factor (IR-ANF) in rat and human plasma and in rat atria. The two atria contain about 20 ..mu..g ANF per rat. The right atrium contained 2.5 times more ANF than did the left. Ether anesthesia and morphine markedly increased IR-ANF in rat plasma. The concentration of IR-ANF in plasma of clinically normal human subjects was 65.3 +/- 2.5 pg/ml. Paroxysmal tachycardia and rapid atrial pacing significantly increased IR-ANF in human plasma. Two- to seven-fold higher concentrations were found in coronary sinus blood than in the peripheral circulation. In the plasma of rats and humans, circulating ANF is probably a small-molecular-weight peptide. ANF acts on the adrenal and the pituitary. ANF inhibits aldosterone secretion from rat zona glomerulosa and steroid secretion by bovine adrenal zona glomerulosa and fasciculata. ANF stimulated the basal secretion of arginine vasopressin (AVP) in vitro and inhibited KCl-stimulated release of AVP.

  14. Hypothalamic-pituitary, ovarian and adrenal contributions to polycystic ovary syndrome.

    PubMed

    Baskind, N Ellissa; Balen, Adam H

    2016-11-01

    Polycystic ovary syndrome (PCOS) is a prevalent heterogeneous disorder linked with disturbances of reproductive, endocrine and metabolic function. The definition and aetiological hypotheses of PCOS are continually developing to incorporate evolving evidence of the syndrome, which appears to be both multifactorial and polygenic. The pathophysiology of PCOS encompasses inherent ovarian dysfunction that is strongly influenced by external factors including the hypothalamic-pituitary axis and hyperinsulinaemia. Neuroendocrine abnormalities including increased gonadotrophin-releasing hormone (GnRH) pulse frequency with consequent hypersecretion of luteinising hormone (LH) affects ovarian androgen synthesis, folliculogenesis and oocyte development. Disturbed ovarian-pituitary and hypothalamic feedback accentuates the gonadotrophin abnormalities, and there is emerging evidence putatively implicating dysfunction of the Kiss 1 system. Within the follicle subunit itself, there are intra-ovarian paracrine modulators, cytokines and growth factors, which appear to play a role. Adrenally derived androgens may also contribute to the pathogenesis of PCOS, but their role is less defined. Copyright © 2016. Published by Elsevier Ltd.

  15. Immunology, signal transduction, and behavior in hypothalamic-pituitary-adrenal axis-related genetic mouse models.

    PubMed

    Silberstein, Susana; Vogl, Annette M; Bonfiglio, Juán José; Wurst, Wolfgang; Holsboer, Florian; Arzt, Eduardo; Deussing, Jan M; Refojo, Damián

    2009-02-01

    A classical view of the neuroendocrine-immune network assumes bidirectional interactions where pro-inflammatory cytokines influence hypothalamic-pituitary-adrenal (HPA) axis-derived hormones that subsequently affect cytokines in a permanently servo-controlled circle. Nevertheless, this picture has been continuously evolving over the last years as a result of the discovery of redundant expression and extended functions of many of the molecules implicated. Thus, cytokines are not only expressed in cells of the immune system but also in the central nervous system, and many hormones present at hypothalamic-pituitary level are also functionally expressed in the brain as well as in other peripheral organs, including immune cells. Because of this intermingled network of molecules redundantly expressed, the elucidation of the unique roles of HPA axis-related molecules at every level of complexity is one of the major challenges in the field. Genetic engineering in the mouse offers the most convincing method for dissecting in vivo the specific roles of distinct molecules acting in complex networks. Thus, various immunological, behavioral, and signal transduction studies performed with different HPA axis-related mutant mouse lines to delineate the roles of beta-endorphin, the type 1 receptor of corticotropin-releasing hormone (CRHR1), and its ligand CRH will be discussed here.

  16. Effect of pituitary graft-induced hyperprolactinemia on adrenal circadian rhythmicity.

    PubMed

    Villanúa, M A; Tresguerres, J A; Esquifino, A I

    1988-01-01

    Prolactin is involved in the regulation of several endocrine functions. In this study, the possible influence of hyperprolactinemia on circadian corticosterone secretion has been investigated. Pituitary grafted male and female rats exhibited increased plasma PRL levels at 1000 when compared to sham-operated controls. This increase was only maintained over the 24 h period in grafted female rats but not in males, thus suggesting a different sex dependent modification of the regulatory mechanisms of prolactin. The corticosterone secretion pattern in sham operated male and female rats was similar to those described earlier but was altered by hyperprolactinemia according to the sex of the animal. There was a significant decrease in the total amount of corticosterone secreted in a 24 h period in grafted males as compared to control animals, whereas no significant differences were observed in grafted female rats as compared to controls. Grafted females showed a 4 h delay in the 24 h secretion rhythm as compared to control animals. These data suggest that pituitary transplant induced hyperprolactinemia, directly or through modifications in catecholamine turnover, is able to modify adrenal rhythmicity.

  17. Characterization of the Hypothalamic-Pituitary-Adrenal-Axis in Familial Longevity under Resting Conditions

    PubMed Central

    Jansen, Steffy W.; Roelfsema, Ferdinand; Akintola, Abimbola A.; Oei, Nicole Y.; Cobbaert, Christa M.; Ballieux, Bart E.; van der Grond, Jeroen; Westendorp, Rudi G.; Pijl, Hanno; van Heemst, Diana

    2015-01-01

    Objective The hypothalamic-pituitary-adrenal (HPA)-axis is the most important neuro-endocrine stress response system of our body which is of critical importance for survival. Disturbances in HPA-axis activity have been associated with adverse metabolic and cognitive changes. Humans enriched for longevity have less metabolic and cognitive disturbances and therefore diminished activity of the HPA axis may be a potential candidate mechanism underlying healthy familial longevity. Here, we compared 24-h plasma ACTH and serum cortisol concentration profiles and different aspects of the regulation of the HPA-axis in offspring from long-lived siblings, who are enriched for familial longevity and age-matched controls. Design Case-control study within the Leiden Longevity study cohort consisting of 20 middle-aged offspring of nonagenarian siblings (offspring) together with 18 partners (controls). Methods During 24 h, venous blood was sampled every 10 minutes for determination of circulatory ACTH and cortisol concentrations. Deconvolution analysis, cross approximate entropy analysis and ACTH-cortisol-dose response modeling were used to assess, respectively, ACTH and cortisol secretion parameters, feedforward and feedback synchrony and adrenal gland ACTH responsivity. Results Mean (95% Confidence Interval) basal ACTH secretion was higher in male offspring compared to male controls (645 (324-1286) ngl/L/24 h versus 240 (120-477) ng/L/24 h, P = 0.05). Other ACTH and cortisol secretion parameters did not differ between offspring and controls. In addition, no significant differences in feedforward and feedback synchrony and adrenal gland ACTH responsivity were observed between groups. Conclusions These results suggest that familial longevity is not associated with major differences in HPA-axis activity under resting conditions, although modest, sex-specific differences may exist between groups that might be clinically relevant. PMID:26193655

  18. The Environmental Pollutant Tributyltin Chloride Disrupts the Hypothalamic-Pituitary-Adrenal Axis at Different Levels in Female Rats.

    PubMed

    Merlo, Eduardo; Podratz, Priscila L; Sena, Gabriela C; de Araújo, Julia F P; Lima, Leandro C F; Alves, Izabela S S; Gama-de-Souza, Letícia N; Pelição, Renan; Rodrigues, Lívia C M; Brandão, Poliane A A; Carneiro, Maria T W D; Pires, Rita G W; Martins-Silva, Cristina; Alarcon, Tamara A; Miranda-Alves, Leandro; Silva, Ian V; Graceli, Jones B

    2016-08-01

    Tributyltin chloride (TBT) is an environmental contaminant that is used as a biocide in antifouling paints. TBT has been shown to induce endocrine-disrupting effects. However, studies evaluating the effects of TBT on the hypothalamus-pituitary-adrenal (HPA) axis are especially rare. The current study demonstrates that exposure to TBT is critically responsible for the improper function of the mammalian HPA axis as well as the development of abnormal morphophysiology in the pituitary and adrenal glands. Female rats were treated with TBT, and their HPA axis morphophysiology was assessed. High CRH and low ACTH expression and high plasma corticosterone levels were detected in TBT rats. In addition, TBT leads to an increased in the inducible nitric oxide synthase protein expression in the hypothalamus of TBT rats. Morphophysiological abnormalities, including increases in inflammation, a disrupted cellular redox balance, apoptosis, and collagen deposition in the pituitary and adrenal glands, were observed in TBT rats. Increases in adiposity and peroxisome proliferator-activated receptor-γ protein expression in the adrenal gland were observed in TBT rats. Together, these data provide in vivo evidence that TBT leads to functional dissociation between CRH, ACTH, and costicosterone, which could be associated an inflammation and increased of inducible nitric oxide synthase expression in hypothalamus. Thus, TBT exerts toxic effects at different levels on the HPA axis function.

  19. Takotsubo cardiomyopathy in a patient with pituitary adenoma and secondary adrenal insufficiency

    PubMed Central

    Singh, Georgene; Manickam, Ari; Sethuraman, Manikandan; Rathod, Ramesh Chandra

    2015-01-01

    We describe a case of Takotsubo cardiomyopathy in a case of pituitary macroadenoma in acute adrenal crisis. A 48-year-old man presented with acute onset altered sensorium, vomiting, and gasping. On admission, he was unresponsive and hemodynamically unstable. He was intubated and ventilated and resuscitated with fluids and inotropes. The biochemical evaluation revealed hyponatremia, hyperkalemia, and hypocortisolism. Hyponatremia was corrected with 3% hypertonic saline. Contrast enhanced computed tomography (CT) scan of the brain revealed a sellar-suprasellar mass with hypothalamic extension with no evidence of pituitary apoplexy. A diagnosis of invasive pituitary adenoma with the Addisonian crisis was made and steroid replacement was initiated. Despite volume resuscitation, he had persistent refractory hypotension, recurrent ventricular tachycardia, and metabolic acidosis. Electrocardiogram (ECG) showed ST elevation and T-wave inversion in lateral leads; cardiac-enzymes were increased suggestive of acute coronary syndrome. Transthoracic echocardiography showed severe regional wall motion abnormalities (RWMAs) involving left anterior descending territory and low ejection fraction (EF). Coronary angiogram revealed normal coronaries, apical ballooning, and severe left ventricular dysfunction, consistent with a diagnosis of Takotsubo's cardiomyopathy. Patient was managed with angiotensin-converting enzyme inhibitors and B-blockers. He improved over few days and recovered completely. At discharge, ECG changes and RWMA resolved and EF normalized to 56%. In patients with Addisonian Crisis with persistent hypotension refractory to optimal resuscitation, possibility of Takotsubo's cardiomyopathy should be considered. Early recognition of association of Takotsubos cardiomyopathy in neurological conditions, prompt resuscitation, and supportive care are essential to ensure favorable outcomes in this potentially lethal condition. PMID:26816449

  20. Hormonal status modifies renin-angiotensin system-regulating aminopeptidases and vasopressin-degrading activity in the hypothalamus-pituitary-adrenal axis of male mice.

    PubMed

    García, María Jesús; Martínez-Martos, José Manuel; Mayas, María Dolores; Carrera, María Pilar; Ramírez-Expósito, María Jesús

    2003-06-20

    Local renin-angiotensin systems (RAS) have been postulated in brain, pituitary and adrenal glands. These local RAS have been implicated, respectively, in the central regulation of the cardiovascular system and body water balance, the secretion of pituitary hormones and the secretion of aldosterone by adrenal glands. By other hand, it is known that the hypothalamus-pituitary-adrenal (HPA) axis is involved in blood pressure regulation, and is affected by sex hormones. The aim of the present work is to analyze the influence of testosterone on RAS-regulating aminopeptidase A, B and M activities and vasopressin-degrading activity in the HPA axis, measuring these activities in their soluble and membrane-bound forms in the hypothalamus, pituitary and adrenal glands of orchidectomized males and orchidectomized males treated subcutaneously with several doses of testosterone. The present data suggest that in male mice, testosterone influences the RAS- and vasopressin-degrading activities at all levels of the HPA axis.

  1. The effect of epidural methylprednisolone acetate injection on the hypothalamic-pituitary-adrenal axis.

    PubMed

    Habib, George; Jabbour, Adel; Salman, Jameel; Hakim, Geries; Haddad, Henry

    2013-12-01

    To evaluate the effect of an epidural corticosteroid injection of 80 mg and 40 mg of methylprednisolone acetate on the hypothalamic-pituitary-adrenal axis and on back pain. Randomized, single-blinded prospective study. Operating room of a university-affiliated hospital. 42 patients with low back pain due to radiculopathy. Group 1 received an epidural corticosteroid injection of 80 mg of methylprednisolone acetate, and Group 2 received an epidural corticosteroid injection of 40 mg of methylprednisolone acetate. All study patients underwent a stimulation test of one μg of adrenocorticotropin hormone (ACTH), and their pain levels were graded just prior to and following the epidural corticosteroid injection on weeks one, 3, and 4. Serum cortisol of the ACTH stimulation tests and back pain levels were rated using a visual analog scale (VAS). Serum cortisol levels lower than 18 ng/mL 30 minutes following the ACTH stimulation test were considered to be secondary adrenal insufficiency. 21 patients were enrolled in each group. The rate of secondary adrenal insufficiency in Group 1 was ~86%, ~ 22%, and ~17% of patients versus ~53% (P = 0.024), 15% (P = 0.874), and ~12% (P = 0.715) of Group 2 patients at weeks one, 3, and 4, respectively. About 62%, 56%, and 39% of Group 1 patients had a favorable clinical response as opposed to ~47% (P = 0362), 35% (P = 0.21), and ~6% (P = 0.049) of Group 2 patients at weeks one, 3, and 4, respectively. Epidural corticosteroid injection of methylprednisolone acetate in both groups was associated with very high rates of secondary adrenal insufficiency, but significantly more so in Group 1 at week one. This suppression was transient, with recovery of the gland in most patients noted over the ensuing weeks. An epidural corticosteroid injection of 80 mg had higher rates of favorable clinical response than a 40 mg injection, but significantly more so at week 4 only. This favorable response waned over a few weeks in both groups. © 2013 Elsevier

  2. Leptin plasma concentrations, leptin gene expression, and protein localization in the hypothalamic-pituitary-gonadal and hypothalamic-pituitary-adrenal axes of the European beaver (Castor fiber).

    PubMed

    Chojnowska, Katarzyna; Czerwinska, Joanna; Kaminski, Tadeusz; Kaminska, Barbara; Kurzynska, Aleksandra; Bogacka, Iwona

    2017-01-01

    The European beaver (Castor fiber) is the largest seasonal free-living rodent in Eurasia. Since the physiology and endocrine system of this species remains unknown, the present study aimed to determine plasma leptin concentrations and the expression of the leptin gene and protein in the hypothalamic-pituitary-gonadal and hypothalamic-pituitary-adrenal (HPG and HPA) axes of beavers during breeding (April), postbreeding (July), and prebreeding (November) seasons. Leptin plasma concentrations did not change in females, whereas in males, leptin plasma concentrations were higher in July than those in April. The presence of leptin mRNA and protein was found in all examined tissues. In females, leptin mRNA expression in the hypothalamus, pituitary, ovaries, and myometrium was markedly higher in July than that in April. In males, leptin mRNA levels varied across the examined tissues of the HPG and HPA. Leptin synthesis increased in the hypothalamus during breeding and postbreeding seasons, but seasonal changes were not observed in the pituitary. In turn, testicular leptin levels were higher during breeding and prebreeding stages. Seasonal differences in the concentrations of leptin mRNA were also observed in the adrenal cortex. In males, leptin mRNA levels were higher in November than those in April or July. In females, leptin synthesis increased in the adrenal cortex during pregnancy relative to other seasons. This is the first ever study to demonstrate seasonal differences in leptin expression in beaver tissues, and our results could suggest that leptin is involved in the regulation of the HPG and HPA axes during various stages of the reproductive cycle in beavers. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. Dysfunction of the hypothalamic-pituitary-adrenal axis in opioid dependent subjects: effects of acute and protracted abstinence.

    PubMed

    Zhang, Guo-Fu; Ren, Yan-Ping; Sheng, Li-Xia; Chi, Yong; Du, Wan-Jun; Guo, Song; Jiang, Zuo-Ning; Xiao, Le; Luo, Xiao-Nian; Tang, Yi-Lang; Smith, Alicia K; Liu, Zhen-Qi; Zhang, Hong-Xi

    2008-01-01

    The function of the Hypothalamic-Pituitary-Adrenal (HPA) axis during opioid dependence has been inconsistent. We compared HPA axis measures between subjects during methadone stabilization and drug-free detoxification with healthy controls. Sixty heroin dependent patients received either non-opiate treatment (NOT) with benzodiazepines and clonidine (n = 30) or methadone stabilization treatment (MT, n = 30), and their serum levels of corticotropin releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and cortisol (COR) were measured and compared to those of healthy, nondependent controls. Compared with healthy controls, CRH was significantly lower (p < .001) while COR was higher (p < .001) during acute withdrawal in the NOT group. CRH and COR was lower (p < .001), while ACTH was normal in the MT group compared to healthy controls. Our findings suggest that chronic opioid dependence may cause reduced function of the HPA axis, while opioid withdrawal may decrease the response of the pituitary to CRH and increase the adrenal response to ACTH.

  4. Functional-morphological parallels of the hypothalamo-pituitary-adrenal system response reaction to long-term hypokinesia

    NASA Technical Reports Server (NTRS)

    Tsvetov, Y. P.; Razin, S. I.; Rychko, A. V.

    1980-01-01

    The effect of 2 and 4 week hypokinesia regimens on the hypothalamo-pituitary-adrenal system (HPAS) was investigated in 110 inbred mice. Progressive exhaustion and pathological reorganization of the HPAS morphofunctional structures was revealed. On the basis of established facts of interlineary and interspecies differences in the HPAS response, it is suggested that the animal body response reaction to the long term effects of hypokinesia depends largely on its HPAS resistance and the values of this system's defensive adaptation potential.

  5. Hypothalamic-pituitary-adrenal axis suppression related to topical glucocorticoid therapy in a child with psoriatic exfoliative erythroderma.

    PubMed

    Campbell, Lauren S; Chevalier, Michelle; Levy, Richard A; Rhodes, Arthur

    2012-01-01

    Exfoliative erythroderma is a rare presentation of psoriasis in children and adults. We report a 9-year-old girl with exfoliative erythroderma secondary to plaque-type psoriasis who developed hypothalamic-pituitary-adrenal axis suppression resulting from topical treatment with a medium-potency glucocorticoid. This case emphasizes the need for awareness of this potentially life-threatening complication of topical glucocorticoid use, particularly in patients who have significant compromise of barrier function secondary to widespread skin disease.

  6. Restoration of the Hypothalamic-pituitary-adrenal Response to Hypoglycemia in Type 2 Diabetes by Avoiding Chronic Hypoglycemia

    PubMed Central

    Tsuda, Shin-ichi; Konishi, Kazunori; Otoda, Toshiki; Nagai, Takako; Takeda-Watanabe, Ai; Kanasaki, Megumi; Kitada, Munehiro; Nakagawa, Atsushi; Nishizawa, Makoto; Kanasaki, Keizo; Koya, Daisuke

    2016-01-01

    An impaired ability to sense and respond to drug-induced hypoglycemia is a common and serious complication in diabetic patients. The hypothalamic-pituitary-adrenal (HPA) axis activity plays a critical role in the counterregulatory response to hypoglycemia. We herein report a case that experienced restoration of a blunted HPA axis by avoiding hypoglycemia with the use of the DPP-4 inhibitor sitagliptin. PMID:27904111

  7. The Recovery of Hypothalamic-Pituitary-Adrenal Axis Is Rapid in Subclinical Cushing Syndrome

    PubMed Central

    2016-01-01

    Background In subclinical Cushing syndrome (SC), it is assumed that glucocorticoid production is insufficient to cause a clinically recognizable syndrome. Differences in hormonal levels or recovery time of the hypothalamic-pituitary-adrenocortical (HPA) axis after adrenalectomy between patients with overt Cushing syndrome (OC) and SC remain unknown. Methods Thirty-six patients (10 with OC and 26 with SC) with adrenal Cushing syndrome who underwent adrenalectomy from 2004 to 2014 were reviewed retrospectively. Patients were treated with glucocorticoid after adrenalectomy and were reevaluated every 1 to 6 months using a rapid adrenocorticotropic hormone (ACTH) stimulation test. Results Levels of basal 24-hour urine free cortisol (UFC), serum cortisol after an overnight dexamethasone suppression test (DST), and serum cortisol and 24-hour UFC after low-dose DST and high-dose DST were all significantly lower in patients with SC compared with OC. Basal ACTH levels showed significantly higher in patients with SC compared with OC. The probability of recovering adrenal function during follow-up differed significantly between patients with OC and SC (P=0.001), with significant correlations with the degree of preoperative cortisol excess. Patients with OC required a longer duration of glucocorticoid replacement to recover a normal ACTH stimulation test compared with patients with SC (median 17.0 months vs. 4.0 months, P<0.001). Conclusion The HPA axis recovery time after adrenalectomy in patients with SC is rapid and is dependent on the degree of cortisol excess. More precise definition of SC is necessary to achieve a better management of patients and to avoid the risk of under- or over-treatment of SC patients. PMID:28029028

  8. Itraconazole and inhaled fluticasone causing hypothalamic-pituitary-adrenal axis suppression in adults with cystic fibrosis.

    PubMed

    Gilchrist, Francis J; Cox, Katrina J; Rowe, Rachel; Horsley, Alex; Webb, A Kevin; Jones, Andrew M; Bright-Thomas, Rowland J

    2013-07-01

    Although there have been case reports of hypothalamic-pituitary-adrenal (HPA) axis suppression in patients with cystic fibrosis (CF) caused by the combination of oral itraconazole and inhaled fluticasone, to date no study has assessed the incidence of this potentially serious side effect. Synacthen tests were conducted on all patients with CF receiving itraconazole and inhaled fluticasone and an equal number of patients with CF receiving inhaled fluticasone but not itraconazole. Itraconazole levels were measured in patients receiving the therapy. Twelve patients receiving itraconazole and fluticasone underwent synacthen tests. All 12 had abnormal synacthen test results and 10/12 (83%) had HPA axis suppression. Two patients had severe HPA axis suppression with a peak cortisol <75 nmol/L and further 3 patients had moderately severe suppression with a peak cortisol <250 nmol/L. In contrast, only 2/12 on fluticasone alone had HPA axis suppression (both mild). The median (range) basal cortisol levels were significantly lower in those patients receiving itraconazole and inhaled fluticasone compared to those on fluticasone alone (219(22-508)nmol/L v 348(41-738)nnmol/L, p=0.02), similar results were seen for peak cortisol levels (404(59-706)nmol/L v 672(432-1178)nmol/L, p<0.001) and cortisol rise (179(37-240)nmol/L v 368(210-539)nmol/L, p<0.001). The median (range) itraconazole level was 5.5(1.7-14.7)mg/L. Neither itraconazole levels nor fluticasone dose correlated with the degree of adrenal suppression. In this study, all patients receiving itraconazole and inhaled fluticasone had abnormal synacthen test results. The incidence of HPA axis suppression with this treatment combination appears to be higher than that previously reported with itraconazole and inhaled budesonide. Copyright © 2012 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

  9. Estrogen receptors ERα and ERβ participation in hypothalamus-pituitary-adrenal axis activation by hemorrhagic stress.

    PubMed

    Silva-Alves, Luana Maria; Barcelos Filho, Procópio Cleber Gama de; Franci, Celso Rodrigues

    2017-05-04

    The sympato-adrenal-system and hypothalamus-pituitary-adrenal (HPA) axis are anatomically and functionally connected with participation of several brain areas that express estrogen receptors (ERα and ERβ). We assessed the neuronal activity of these areas for FOS expression and the action of PPT (ERα agonist) or DPN (ERβ agonist) in HPA axis activity during hemorrhagic stress. Ovariectomized Wistar rats treated with vehicle (DMSO) or ER agonists were catheterized for blood collection. Animals received (control) or not (hemorrhagic) immediate reposition with the same volume of saline. Immunohistochemistry was performed for FOS, tyrosine hydroxylase (TH) and corticotropin releasing hormone (CRH) in the brain areas. In vehicle-treated animals, hemorrhage enhanced: plasma corticosterone (CORT), oxytocin (OT) and vasopressin (AVP) measured by radioimmunoassay; the expression of TH-FOS co-localized neurons in ventrolateral medulla (A1C1) and FOS expression in medial parvocellular paraventricular nucleus (mpPVN). In controls, PPT decreased: plasma CORT; FOS expression at locus coeruleus (LC); FOS and CRH-FOS at mpPVN, compared to vehicle. After hemorrhage, PPT decreased: plasma CORT; FOS expression at LC and mpPVN; TH-FOS at LC, solitary tract nucleus (NTS), A1C1; CRH-FOS at mpPVN, compared to vehicle. After hemorrhage DPN decreased: plasma CORT; FOS expression at LC and mpPVN; TH-FOS at LC, A1C1; CRH-FOS at mpPVN, compared to vehicle. PPT blocked the increase of OT secretion and increased AVP secretion, after hemorrhage. DPN reduced OT and increased AVP levels, regardless hemorrhage. In hemorrhagic stress, ERα and ERβ reduced the HPA axis activation and neuronal activity in brain areas involved in the HPA axis control.

  10. The Recovery of Hypothalamic-Pituitary-Adrenal Axis Is Rapid in Subclinical Cushing Syndrome.

    PubMed

    Kim, Hee Kyung; Yoon, Jee Hee; Jeong, Yun Ah; Kang, Ho Cheol

    2016-12-01

    In subclinical Cushing syndrome (SC), it is assumed that glucocorticoid production is insufficient to cause a clinically recognizable syndrome. Differences in hormonal levels or recovery time of the hypothalamic-pituitary-adrenocortical (HPA) axis after adrenalectomy between patients with overt Cushing syndrome (OC) and SC remain unknown. Thirty-six patients (10 with OC and 26 with SC) with adrenal Cushing syndrome who underwent adrenalectomy from 2004 to 2014 were reviewed retrospectively. Patients were treated with glucocorticoid after adrenalectomy and were reevaluated every 1 to 6 months using a rapid adrenocorticotropic hormone (ACTH) stimulation test. Levels of basal 24-hour urine free cortisol (UFC), serum cortisol after an overnight dexamethasone suppression test (DST), and serum cortisol and 24-hour UFC after low-dose DST and high-dose DST were all significantly lower in patients with SC compared with OC. Basal ACTH levels showed significantly higher in patients with SC compared with OC. The probability of recovering adrenal function during follow-up differed significantly between patients with OC and SC (P=0.001), with significant correlations with the degree of preoperative cortisol excess. Patients with OC required a longer duration of glucocorticoid replacement to recover a normal ACTH stimulation test compared with patients with SC (median 17.0 months vs. 4.0 months, P<0.001). The HPA axis recovery time after adrenalectomy in patients with SC is rapid and is dependent on the degree of cortisol excess. More precise definition of SC is necessary to achieve a better management of patients and to avoid the risk of under- or over-treatment of SC patients.

  11. Renin-Angiotensin-aldosterone system and hypothalamic-pituitary-adrenal axis in hospitalized newborn foals.

    PubMed

    Dembek, K A; Onasch, K; Hurcombe, S D A; MacGillivray, K C; Slovis, N M; Barr, B S; Reed, S M; Toribio, R E

    2013-01-01

    The renin-angiotensin-aldosterone system (RAAS) and hypothalamic-pituitary-adrenal axis (HPAA) and their interactions during illness and hypoperfusion are important to maintain organ function. HPAA dysfunction and relative adrenal insufficiency (RAI) are common in septic foals. Information is lacking on the RAAS and mineralocorticoid response in the context of RAI in newborn sick foals. To investigate the RAAS, as well as HPAA factors that interact with the RAAS, in hospitalized foals, and to determine their association with clinical findings. We hypothesized that critical illness in newborn foals results in RAAS activation, and that inappropriately low aldosterone concentrations are part of the RAI syndrome of critically ill foals. A total of 167 foals ≤3 days of age: 133 hospitalized (74 septic, 59 sick nonseptic) and 34 healthy foals. Prospective, multicenter, cross-sectional study. Blood samples were collected on admission. Plasma renin activity (PRA) and angiotensin-II (ANG-II), aldosterone, ACTH, and cortisol concentrations were measured in all foals. ANG-II, aldosterone, ACTH, and cortisol concentrations as well as ACTH/aldosterone and ACTH/cortisol ratios were higher in septic foals compared with healthy foals (P < .05). No difference in PRA between groups was found. High serum potassium and low serum chloride concentrations were associated with hyperaldosteronemia in septic foals. RAAS activation in critically ill foals is characterized by increased ANG-II and aldosterone concentrations. Inappropriately low cortisol and aldosterone concentrations defined as high ACTH/cortisol and ACTH/aldosterone ratios in septic foals suggest that RAI is not restricted to the zona fasciculata in critically ill newborn foals. Copyright © 2013 by the American College of Veterinary Internal Medicine.

  12. Acupoint specificity on acupuncture regulation of hypothalamic- pituitary-adrenal cortex axis function.

    PubMed

    Wang, Shao-jun; Zhang, Jiao-jiao; Yang, Hao-yan; Wang, Fang; Li, Si-ting

    2015-03-27

    The hypothalamus is an essential part of the brain that responds to a variety of signaling including stressful stimulations and acupuncture signals. It is also the key element of the hypothalamic-pituitary-adrenal cortex axis(HPAA). The effect of acupuncture is transmitted into the brain from the distance sensory receptor around the acupoints via peripheral nerves and body fluid. In vivo recording the activities of stress reaction neurons (SRNs, CRH-like neurons) in hypothalamic paraventricular nucleus (PVN) in response to the stimulations from different acupoints could therefore objectively reflect the acupuncture afferent effect. In this study, the electrophysiological method was adopted to record synchronously the activities of 43 CRH-like neurons after acupuncture stimulations at 33 acupoints located at the different regions. The acupoints that specifically activate certain CRH-like neurons (specificity acupoints) were selected. Furthermore, we investigated in a rat model of unpredictable chronic mild stress (UCMS) whether these specificity acupoints regulate HPAA function. The endpoints of measurement include corticosterone (CORT) level in peripheral blood, the expressions of corticotrophin releasing hormone (CRH) and glucocorticoid receptor (GR) protein in PVN and the animal behavioral performance. Our results reveal that Shenshu (BL23), Ganshu (BL18), Qimen (LR14), Jingmen (GB25), Riyue (GB24), Zangmen (LR13), Dazui (DU14) and auricular concha region (ACR) are the specificity acupoints; and Gallbladder, Liver and Du Channels were the specificity Channels. The acupoints on Gallbladder Channel and the acupoints innervated by the same spinal cord segments as the adrenal gland demonstrated dramatic effects. This study provides a new platform to further explore acupoints specificity in the regulation of HPAA activities.

  13. Immunohistochemical analysis of the hypothalamic-pituitary-adrenal axis in dogs: Sex-linked and seasonal variation.

    PubMed

    Gallelli, M F; Lombardo, D; Vissio, P; Quiroga, A; Caggiano, N; Soler, E; Meikle, A; Castillo, V A

    2016-02-01

    This study evaluated sexual dimorphism and seasonal variations in corticotrophs and adrenal zona fasciculata in dogs, as well as the expression of oestrogen receptor alpha (ERα). An immunohistochemical analysis was conducted in pituitaries for ACTH and in adrenal glands for ERα and for the melanocortin-2-receptor (MC2R) in winter and summer. Double immunofluorescence was performed to identify ERα in corticotrophs. Females had a greater proportion of corticotrophs per field (p<0.01), with a greater cellular area and optical density (p<0.001) than males. Optical density of corticotrophs was greater in winter for both sexes (p<0.001). In zona fasciculata, ERα and MC2R expression was greater in females (p<0.001) and was greater in winter (p<0.001). ERα was identified in corticotrophs. This study is the first to demonstrate ERα expression in corticotrophs and the adrenal cortex in dogs, providing evidence for sexual dimorphism and seasonal variations.

  14. Eszopiclone stimulates the hypothalamo-pituitary-adrenal axis in the rat.

    PubMed

    Pechnick, Robert N; Lacayo, Liliana M; Manalo, Charlene M; Bholat, Yasmin; Spivak, Inna

    2011-07-01

    Eszopiclone (Lunesta®) is used for the treatment of insomnia. It is the S (+)-enantiomer of racemic zopiclone, a cyclopyrrolone with no structural similarity to the hypnotic drugs zolpidem and zaleplon or to the benzodiazepines and barbiturates. Although eszopiclone interacts with the gamma-aminobutyric acid A-type (GABA(A)) receptor complex, it has a different binding profile than other sedative/hypnotic agents and modulates the receptor complex in a unique manner. Thus, eszopiclone might produce different pharmacological effects compared to other sedative/hypnotic agents. Beside their behavioral properties, sedative/hypnotic drugs affect the hypothalamo-pituitary-adrenal (HPA) axis. In general, low doses of benzodiazepine-type drugs decrease, whereas high doses increase the activity of the HPA axis. Furthermore, benzodiazepines reduce stress-induced increases in HPA axis activity. The goal of the present study was to characterize the effects of eszopiclone on the HPA axis in the rat. Male rats were injected with saline or eszopiclone and trunk blood was collected for the measurement of plasma levels of adrenocorticotropin (ACTH) and corticosterone by radioimmunoassay. The acute administration of eszopiclone produced dose-dependent increases in plasma levels of ACTH and corticosterone, and tolerance developed to these effects after repeated drug administration. Pretreatment with eszopiclone did not affect stress-induced stimulation of the HPA axis. These results show that eszopiclone and the benzodiazepine-type drugs differentially affect the HPA axis.

  15. Increased Hair Cortisol Concentrations and BMI in Patients With Pituitary-Adrenal Disease on Hydrocortisone Replacement.

    PubMed

    Staufenbiel, Sabine M; Andela, Cornelie D; Manenschijn, Laura; Pereira, Alberto M; van Rossum, Elisabeth F C; Biermasz, Nienke R

    2015-06-01

    Intrinsic imperfections and lack of reliable biomarkers preclude optimal individual dosing of hydrocortisone replacement in adrenal insufficiency (AI). However, the clinical relevance of optimal dosing is exemplified by frequently occurring side effects of overreplacement and the dangers of underreplacement. Cortisol in scalp hair has been identified as a retrospective biomarker for long-term cortisol exposure. We compared hair cortisol concentrations (CORT(hair)) of patients with primary or secondary AI on replacement therapy with those of patient controls with a pituitary disease without AI (PCs) and of healthy controls (HCs). In this cross-sectional study, hair samples and anthropometric data were collected in 132 AI patients (52 males), 42 PCs (11 males), and 195 HCs (90 males). The proximal 3 cm of hair were used. CORT(hair) were measured using an ELISA. CORT(hair) were higher in AI patients than in HCs and PCs (P < .001), and hydrocortisone dose correlated with CORT(hair) (P = .04). Male AI patients demonstrated higher CORT(hair) than female patients (P < .001). AI patients had higher body mass index (BMI) than HCs (P < .001), and BMI correlated with CORT(hair) in the whole sample (P < .001). Physiological hydrocortisone replacement is associated with increased CORT(hair). The association between CORT(hair) and BMI could suggest a mild overtreatment that may lead to adverse anthropomorphic side effects, especially in males. CORT(hair) measurements may be a promising additional tool to monitor cumulative hydrocortisone replacement in AI.

  16. Sexually dimorphic response of the hypothalamo-pituitary-adrenal axis to chronic alcohol consumption and withdrawal.

    PubMed

    Silva, Susana M; Santos-Marques, M João; Madeira, M Dulce

    2009-12-15

    In males, long-term alcohol consumption provokes neurochemical changes in the medial parvocellular division of the PVN (PVNmp) that are partially reversed by withdrawal. Because gonadal steroids modulate the activity of the hypothalamo-pituitary-adrenal axis, we analyzed the possibility that the repercussions of chronic alcohol consumption and withdrawal on the anatomy and neurochemistry of the PVNmp might differ between the sexes. Male and female Wistar rats were examined after ingesting a 20% alcohol solution for 6 months or after 2 months of withdrawal from 6 months of alcohol consumption. The levels of gonadal steroids and the basal concentrations of corticosterone were also evaluated. Chronic alcohol consumption and withdrawal did not alter the global cytoarchitectonic features of the PVNmp in rats of both sexes. However, alcohol consumption was associated with a decrease in the number of vasopressin (VP) neurons only in females and of corticotropin releasing hormone (CRH) neurons in males and females. Further, the response to withdrawal was sexually dimorphic because in males there was a partial recovery of the number of CRH neurons whereas in females there was a further loss of VP and CRH neurons. Corticosterone levels were unchanged by alcohol consumption, but they were decreased by withdrawal in females. Alcohol consumption and withdrawal did not alter estrogen and progesterone concentrations in females, but decreased testosterone levels in males. These findings show that the response of CRH and VP neurons to excess alcohol is gender-specific, with females being more vulnerable during alcohol consumption and, most notably, after withdrawal.

  17. Hypothalamic-Pituitary-Adrenal Axis Programming after Recurrent Hypoglycemia during Development.

    PubMed

    Rao, Raghavendra

    2015-08-28

    Permanent brain injury is a complication of recurrent hypoglycemia during development. Recurrent hypoglycemia also has adverse consequences on the neuroendocrine system. Hypoglycemia-associated autonomic failure, characterized by ineffective glucose counterregulation during hypoglycemia, is well described in children and adults on insulin therapy for diabetes mellitus. Whether recurrent hypoglycemia also has a programming effect on the hypothalamus-pituitary-adrenal cortex (HPA) axis has not been well studied. Hypoglycemia is a potent stress that leads to increased glucocorticoid secretion in all age groups, including the perinatal period. Other conditions associated with exposure to excess glucocorticoid in the perinatal period have a programming effect on the HPA axis activity. Limited animal data suggest the possibility of similar programming effect after recurrent hypoglycemia in the postnatal period. The age at exposure to hypoglycemia likely determines the HPA axis response in adulthood. Recurrent hypoglycemia in the early postnatal period likely leads to a hyperresponsive HPA axis, whereas recurrent hypoglycemia in the late postnatal period lead to a hyporesponsive HPA axis in adulthood. The age-specific programming effects may determine the neuroendocrine response during hypoglycemia and other stressful events in individuals with history of recurrent hypoglycemia during development.

  18. Hypothalamic-pituitary-adrenal axis responses of horses to therapeutic riding program: effects of different riders.

    PubMed

    Fazio, Esterina; Medica, Pietro; Cravana, Cristina; Ferlazzo, Adriana

    2013-06-13

    In order to determine whether therapeutic riding could result in higher levels of stress than recreational riding, hypothalamic-pituitary-adrenal (HPA) axis response was evaluated in six horses by monitoring circulating β-endorphin, ACTH and cortisol concentrations. Horses were already accustomed to be trained both for therapy and riding school activity since 2004. Intervention consisted of 60-minute therapeutic sessions, two times per week for 6weeks with different riders: disabled and recreational riders (session A and B respectively). The therapeutic riders' group (A) consisted of six children with psychomotor disabilities; the recreational riders' group (B) consisted of six healthy children without any previous horse riding experience. Horses were asked to perform the same gaits and exercises at all sessions, both with disabled and healthy users. The statistical analysis showed that during both sessions the mean basal β-endorphin and ACTH levels of horses did not show any significant changes, while the one way RM-ANOVA showed significant effects of sessions A on the cortisol (F=11.50; P<0.01) levels. Horses submitted to sessions A showed lower cortisol levels both at 5min (P<0.001) and at 30min (P<0.005) after therapeutic sessions than those after session B. Results suggest that in tested horses and for the variables settled, HPA axis was less responsive to disabled than healthy, recreational riders. Among the endocrine responses, cortisol was one of the indicators of HPA axis stress response.

  19. Amygdala volume and hypothalamic-pituitary-adrenal axis reactivity to social stress.

    PubMed

    Barry, Tom J; Murray, Lynne; Fearon, Pasco; Moutsiana, Christina; Johnstone, Tom; Halligan, Sarah L

    2017-11-01

    The amygdala plays a central role in emotional processing and has an activating influence on the hypothalamic-pituitary-adrenal (HPA) axis. Structural changes in the amygdala have been associated with early adversity and, in principle, may contribute to the later emergence of emotional pathologies by influencing the way that the brain responds to stress provocation. The present study examined the relationship between amygdala volumes and cortisol secretion in response to a social stressor among young adults who were or were not exposed to maternal postnatal depression (PND) early in development (referred to as PND offspring and controls, respectively). Hierarchical Linear Modelling (HLM) revealed that, on a sample-wide level, there was no evidence of a relationship between total amygdala volume, or the volume of the right or left hemisphere amygdala taken separately, and cortisol reactivity. Unexpectedly, for PND offspring, larger right hemisphere amygdala volume was associated with lower cortisol reactivity in response to stress, an effect that was not apparent in control offspring. We conclude that the relationship between amygdala volumes and stress reactivity may not be as clear as previous models suggested. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  20. Predictive modeling of the hypothalamic-pituitary-adrenal (HPA) axis response to acute and chronic stress.

    PubMed

    Marković, Vladimir M; Čupić, Željko; Vukojević, Vladana; Kolar-Anić, Ljiljana

    2011-01-01

    Detailed dynamics of the hypothalamic-pituitary-adrenal (HPA) axis is complex, depending on the individual metabolic load of an organism, its current status (healthy/ill, circadian phase (day/night), ultradian phase) and environmental impact. Therefore, it is difficult to compare the HPA axis activity between different individuals or draw unequivocal conclusions about the overall status of the HPA axis in an individual using single time-point measurements of cortisol levels. The aim of this study is to identify parameters that enable us to compare different dynamic states of the HPA axis and use them to investigate self-regulation mechanisms in the HPA axis under acute and chronic stress. In this regard, a four-dimensional stoichiometric model of the HPA axis was used. Acute stress was modeled by inducing an abrupt change in cortisol level during the course of numerical integration, whereas chronic stress was modeled by changing the mean stationary state concentrations of CRH. Effects of acute stress intensity, duration and time of onset with respect to the ultradian amplitude, ultradian phase and the circadian phase of the perturbed oscillation were studied in detail. Bifurcation analysis was used to predict the response of the HPA axis to chronic stress. Model predictions were compared with experimental findings reported in the literature and relevance for pharmacotherapy with glucocorticoids was discussed.

  1. Asparagus racemosus modulates the hypothalamic-pituitary-adrenal axis and brain monoaminergic systems in rats.

    PubMed

    Krishnamurthy, Sairam; Garabadu, Debapriya; Reddy, Nagannathahalli Ranga

    2013-11-01

    Asparagus racemosus (AR) is classified as an adaptogen, an important medicinal plant and food. Even though AR is widely used as food and nutraceutical, it has only been evaluated in the context of experimental disorders. Hence, the present study was designed to evaluate the effect of standardized methanolic extract of AR (MAR) on experimentally un-manipulated animals to observe the per se effects on stress pathways. MAR (50, 100, and 200 mg/kg, per oral) was administered for 7 days. Lorazepam (0.5 mg/kg, intraperitoneal) was used as a positive control. On the seventh day, plasma was collected for the estimation of corticosterone (CORT) and norepinephrine (NE), and brain was microdissected into hippocampus, hypothalamus (HYP), pre-frontal cortex, amygdala, and nucleus accumbens to estimate tissue level of monoamines (serotonin, dopamine, and NE), their metabolites, and turnover. MAR dose-dependently decreased the plasma CORT and NE levels, indicating its effects on the hypothalamic-pituitary-adrenal cortex axis and the sympathetic-noradrenergic system, respectively. MAR increased the levels of all monoamines in the HYP. However, MAR showed region-specific changes in monoamines and their metabolites, and turnover in other brain regions. MAR showed a physiological modulation of the stress pathways. Interestingly, in most brain regions the change in monoaminergic systems was limited by a ceiling effect at a dose of 100 mg/kg. These observations could explain the traditional use of AR as an adaptogen and a functional food.

  2. Fetal endocrine and metabolic adaptations to hypoxia: the role of the hypothalamic-pituitary-adrenal axis.

    PubMed

    Newby, Elizabeth A; Myers, Dean A; Ducsay, Charles A

    2015-09-01

    In utero, hypoxia is a significant yet common stress that perturbs homeostasis and can occur due to preeclampsia, preterm labor, maternal smoking, heart or lung disease, obesity, and high altitude. The fetus has the extraordinary capacity to respond to stress during development. This is mediated in part by the hypothalamic-pituitary-adrenal (HPA) axis and more recently explored changes in perirenal adipose tissue (PAT) in response to hypoxia. Obvious ethical considerations limit studies of the human fetus, and fetal studies in the rodent model are limited due to size considerations and major differences in developmental landmarks. The sheep is a common model that has been used extensively to study the effects of both acute and chronic hypoxia on fetal development. In response to high-altitude-induced, moderate long-term hypoxia (LTH), both the HPA axis and PAT adapt to preserve normal fetal growth and development while allowing for responses to acute stress. Although these adaptations appear beneficial during fetal development, they may become deleterious postnatally and into adulthood. The goal of this review is to examine the role of the HPA axis in the convergence of endocrine and metabolic adaptive responses to hypoxia in the fetus.

  3. Resilience and hypothalamic-pituitary-adrenal axis reactivity under acute stress in young men.

    PubMed

    Mikolajczak, Moïra; Roy, Emmanuel; Luminet, Olivier; de Timary, Philippe

    2008-11-01

    The present study examined the relationship between resilience (measured using the Resilience Scale for Adults) and hypothalamic-pituitary-adrenal (HPA) axis reactivity. We examined the subjective and cortisol responses of 28 healthy young men to an acute stressor (public speech task). Eight saliva samples were collected in order to obtain the response curve (anticipation, reactivity, recuperation) for each subject. ANOVA indicated that highly resilient individuals tended to display less mood deterioration than less resilient individuals (marginal p(time x group interaction) = 0.075). They also revealed that the former tended to secrete less cortisol overall than the latter during the experiment (marginal p(main group effect) = 0.087) but this effect was not uniform across time (p(time x group interaction) = 0.029). Additional analyses performed to identify the source of this interaction revealed that resilience moderates cortisol secretion in anticipation of the stressor (i.e. highly resilient individuals secreted less cortisol than less resilient ones, p = 0.05) but that it is not conductive to lower HPA reactivity amidst stress (i.e. there was no difference between groups in the increase in cortisol secretion from baseline to peak). The recovery slopes were likewise not statistically different. The implications of these findings regarding health are discussed.

  4. The critical importance of the fetal hypothalamus-pituitary-adrenal axis

    PubMed Central

    Wood, Charles E.; Keller-Wood, Maureen

    2016-01-01

    The fetal hypothalamus-pituitary-adrenal (HPA) axis is at the center of mechanisms controlling fetal readiness for birth, survival after birth and, in several species, determination of the timing of birth. Stereotypical increases in fetal HPA axis activity at the end of gestation are critical for preparing the fetus for successful transition to postnatal life. The fundamental importance in fetal development of the endogenous activation of this endocrine axis at the end of gestation has led to the use of glucocorticoids for reducing neonatal morbidity in premature infants. However, the choice of dose and repetition of treatments has been controversial, raising the possibility that excess glucocorticoid might program an increased incidence of adult disease (e.g., coronary artery disease and diabetes). We make the argument that because of the critical importance of the fetal HPA axis and its interaction with the maternal HPA axis, dysregulation of cortisol plasma concentrations or inappropriate manipulation pharmacologically can have negative consequences at the beginning of extrauterine life and for decades thereafter. PMID:26918188

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

    PubMed Central

    Hicks, Caitlin W.; Sun, Junfeng; Solomon, Steven B.; Eichacker, Peter Q.; Sweeney, Daniel A.; Nieman, Lynnette K.; Whitley, Elizabeth M.; Behrend, Ellen N.; Natanson, Charles; Danner, Robert L.

    2014-01-01

    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. PMID:25294215

  6. Fetal endocrine and metabolic adaptations to hypoxia: the role of the hypothalamic-pituitary-adrenal axis

    PubMed Central

    Newby, Elizabeth A.; Myers, Dean A.

    2015-01-01

    In utero, hypoxia is a significant yet common stress that perturbs homeostasis and can occur due to preeclampsia, preterm labor, maternal smoking, heart or lung disease, obesity, and high altitude. The fetus has the extraordinary capacity to respond to stress during development. This is mediated in part by the hypothalamic-pituitary-adrenal (HPA) axis and more recently explored changes in perirenal adipose tissue (PAT) in response to hypoxia. Obvious ethical considerations limit studies of the human fetus, and fetal studies in the rodent model are limited due to size considerations and major differences in developmental landmarks. The sheep is a common model that has been used extensively to study the effects of both acute and chronic hypoxia on fetal development. In response to high-altitude-induced, moderate long-term hypoxia (LTH), both the HPA axis and PAT adapt to preserve normal fetal growth and development while allowing for responses to acute stress. Although these adaptations appear beneficial during fetal development, they may become deleterious postnatally and into adulthood. The goal of this review is to examine the role of the HPA axis in the convergence of endocrine and metabolic adaptive responses to hypoxia in the fetus. PMID:26173460

  7. Mindful parenting predicts mothers' and infants' hypothalamic-pituitary-adrenal activity during a dyadic stressor.

    PubMed

    Laurent, Heidemarie K; Duncan, Larissa G; Lightcap, April; Khan, Faaiza

    2017-03-01

    Mindfulness in the parenting relationship has been proposed to help both parents and children better regulate stress, though this has not yet been shown at the physiological level. In this study, we tested relations between maternal mindfulness in parenting and both mothers' and their infants' hypothalamic-pituitary-adrenal (HPA) axis activity during a dyadic stressor 3 months later. Participants were 73 mother-infant dyads from a larger longitudinal study. At 3 months postpartum, mothers completed self-report measures of general dispositional mindfulness and parenting-specific mindfulness, as well as stressful life events. At 6 months postpartum, mother-infant dyads completed the Still Face task. Four saliva samples were collected from each dyad member for cortisol assay to index the HPA axis response. Hierarchical linear modeling of cortisol trajectories revealed a main effect of maternal parenting-specific mindfulness (mindful parenting), but not general dispositional mindfulness, on mothers' cortisol; mothers with higher mindful parenting showed steeper cortisol recovery slopes. In addition, maternal mindful parenting moderated the effect of life stress on later mother and infant cortisol. In the context of high life stress, maternal mindful parenting predicted lower infant cortisol levels, but more extended maternal cortisol elevations. Implications for a biobehavioral model of mindful parenting are discussed. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

  8. Stress and obesity: the role of the hypothalamic-pituitary-adrenal axis in metabolic disease.

    PubMed

    Bose, Mousumi; Oliván, Blanca; Laferrère, Blandine

    2009-10-01

    Chronic stress, combined with positive energy balance, may be a contributor to the increased risk for obesity, especially upper body obesity, and other metabolic diseases. This association may be mediated by alterations in the hypothalamic-pituitary-adrenal (HPA) axis. In this review, we summarize the major research that has been conducted on the role of the HPA axis in obesity and metabolic disease. Dysregulation in the HPA axis has been associated with upper body obesity, but data are inconsistent, possibly due to methodological differences across studies. In addition to systemic effects, changes in local cortisol metabolism in adipose tissue may also influence the risk for obesity. HPA axis dysregulation may be the causal link between conditions such as maternal malnutrition and sleep deprivation with metabolic disease. The present review provides evidence for the relationship between chronic stress, alterations in HPA activity, and obesity. Understanding these associations and its interactions with other factors will be important in developing effective treatments for obesity and related metabolic diseases.

  9. Does aerobic exercise affect the hypothalamic-pituitary-adrenal hormonal response in patients with fibromyalgia syndrome?

    PubMed Central

    Genc, Aysun; Tur, Birkan Sonel; Aytur, Yesim Kurtais; Oztuna, Derya; Erdogan, Murat Faik

    2015-01-01

    [Purpose] The hypothalamic-pituitary-adrenal (HPA) axis in the etiopathogenesis of fibromyalgia is not clear. This study aimed to analyze the effects of a 6-week aerobic exercise program on the HPA axis in patients with fibromyalgia and to investigate the effects of this program on the disease symptoms, patients’ fitness, disability, and quality of life. [Subjects and Methods] Fifty fibromyalgia patients were randomized to Group 1 (stretching and flexibility exercises at home for 6 weeks) and Group 2 (aerobic exercise three times a week and the same at-home exercises as Group 1 for 6 weeks). Serum levels of cortisol, adrenocorticotropic hormone, insulin-like growth factor-1, and growth hormone were analyzed at baseline and at the end of, and 1 hr after an exercise stress test. [Results] Group 2 showed better improvement in morning stiffness duration and pain. Growth hormone levels significantly increased after intervention and cortisol levels significantly decreased at time-time interaction in both groups. No significant differences in adrenocorticotropic hormone and insulin-like growth factor-1 were found. [Conclusion] The results of this study seem to support the hypothesis that there is a dysregulation of the HPA axis in patients with FM, and that a six-week exercise program can influence symptoms and affect the HPA axis hormones. PMID:26311959

  10. Hypothalamic-pituitary-adrenal axis function and the metabolic syndrome X of obesity.

    PubMed

    Gohil, B C; Rosenblum, L A; Coplan, J D; Kral, J G

    2001-07-01

    Obesity has negative health consequences related to fat distribution, particularly the central or visceral accumulation of fat. The major complications associated with visceral obesity, termed the "Metabolic Syndrome of Obesity," or "Syndrome X," are type II diabetes, hypertension, and dyslipidemia. As with certain mood disorders, the syndrome may be a consequence of neuroendocrine perturbations typically associated with chronic stress. Our work with bonnet macaque monkeys provides an animal model for the relationship between early stress, behavioral and hypothalamic-pituitary-adrenal (HPA) axis dysregulation, and Syndrome X. During their infant's first half-year, mothers face a variable foraging demand (VFD), in which ample food varies unpredictably in the difficulty of its acquisition, and the offspring show persistent abnormalities in systems known to modulate stress and affective regulation. Early work on the bonnet macaque noted the emergence of a sample of spontaneously obese subjects as they matured. Using the VFD model, the current study showed that there was a clear relationship between early cerebrospinal fluid corticotropin-releasing factor levels and subsequently measured body mass index, supporting the hypotheses regarding the interactive roles of early experience and HPA axis dysregulation in the ontogeny of both metabolic and mood disorders.

  11. A novel prednisolone suppression test for the hypothalamic-pituitary-adrenal axis.

    PubMed

    Pariante, Carmine M; Papadopoulos, Andrew S; Poon, Lucia; Checkley, Stuart A; English, Judie; Kerwin, Robert W; Lightman, Stafford

    2002-06-01

    We have developed a suppressive test for the hypothalamic-pituitary-adrenal (HPA) axis using prednisolone, which is similar to endogenous glucocorticoids. We used a single-blind, repeated-measure design in healthy volunteers. In the first phase of the study, we compared placebo or prednisolone 2.5 mg, 5 mg, or 10 mg; in the second phase of the study, we compared placebo or prednisolone 5 mg or dexamethasone.5 mg. On the following day, we collected plasma and salivary cortisol levels from 9 AM to 5 PM. Maximal average prednisolone plasma levels (at 9 AM after the 10-mg dose) were 30 to 35 ng/mL. At all doses, prednisolone caused a larger suppression of salivary cortisol (approximately 20% after 2.5 mg, 30% to 35% after 5 mg, and 70% to 75% after 10 mg) than of plasma cortisol (approximately 5% after 2.5 mg, 10% after 5 mg, and 35% after 10 mg). Dexamethasone.5 mg gave 80% suppression of plasma cortisol and 90% suppression of salivary cortisol. Plasma and salivary cortisol levels were more consistently correlated in each subject after prednisolone than after dexamethasone. We propose that prednisolone at the 5-mg dosage (which gave partial HPA suppression), together with the assessment of salivary cortisol, can be used to investigate both impaired and enhanced glucocorticoid-mediated negative feedback in large samples of patients with psychiatric disorders.

  12. Fetal programming of hypothalamo-pituitary-adrenal function: prenatal stress and glucocorticoids

    PubMed Central

    Kapoor, Amita; Dunn, Elizabeth; Kostaki, Alice; Andrews, Marcus H; Matthews, Stephen G

    2006-01-01

    Prenatal stress (PS) and maternal exposure to exogenous glucocorticoids can lead to permanent modification of hypothalamo-pituitary-adrenal (HPA) function and stress-related behaviour. Both of these manipulations lead to increased fetal exposure to glucocorticoids. Glucocorticoids are essential for many aspects of normal brain development, but exposure of the fetal brain to an excess of glucocorticoids can have life-long effects on neuroendocrine function. Both endogenous glucocorticoid and synthetic glucocorticoid exposure have a number of rapid effects in the fetal brain, including modification of neurotransmitter systems and transcriptional machinery. Such fetal exposure permanently alters HPA function in prepubertal, postpubertal and ageing offspring, in a sex-dependent manner. Prenatal stress and exogenous glucocorticoid manipulation also lead to the modification of behaviour, brain and organ morphology, as well as altered regulation of other endocrine systems. It is also becoming increasingly apparent that the timing of exposure to PS or synthetic glucocorticoids has tremendous effects on the nature of the phenotypic outcome. Permanent changes in endocrine function will ultimately impact on health in both human and animal populations. PMID:16469780

  13. Hypothalamic-pituitary-adrenal axis activity in patients with pathological gambling and internet use disorder.

    PubMed

    Geisel, Olga; Panneck, Patricia; Hellweg, Rainer; Wiedemann, Klaus; Müller, Christian A

    2015-03-30

    Alterations in secretion of stress hormones within the hypothalamic-pituitary-adrenal (HPA) axis have repeatedly been found in substance-related addictive disorders. It has been suggested that glucocorticoids might contribute to the development and maintenance of substance use disorders by facilitatory effects on behavioral responses to substances of abuse. The objective of this pilot study was to investigate HPA axis activity in patients with non-substance-related addictive disorders, i.e. pathological gambling and internet use disorder. We measured plasma levels of copeptin, a vasopressin surrogate marker, adrenocorticotropic hormone (ACTH) and cortisol in male patients with pathological gambling (n=14), internet use disorder (n=11) and matched healthy controls for pathological gambling (n=13) and internet use disorder (n=10). Plasma levels of copeptin, ACTH and cortisol in patients with pathological gambling or internet use disorder did not differ among groups. However, cortisol plasma levels correlated negatively with the severity of pathological gambling as measured by the PG-YBOCS. Together with our findings of increased serum levels of brain-derived neurotrophic factor (BDNF) in pathological gambling but not internet use disorder, these results suggest that the pathophysiology of pathological gambling shares some characteristics with substance-related addictive disorders on a neuroendocrinological level, whereas those similarities could not be observed in internet use disorder.

  14. Vulnerability to Stroke: Implications of Perinatal Programming of the Hypothalamic-Pituitary-Adrenal Axis

    PubMed Central

    Craft, Tara K. S.; DeVries, A. Courtney

    2009-01-01

    Chronic stress is capable of exacerbating each major, modifiable, endogenous risk factor for cerebrovascular and cardiovascular disease. Indeed, exposure to stress can increase both the incidence and severity of stroke, presumably through activation of the hypothalamic-pituitary-adrenal (HPA) axis. Now that characterization of the mechanisms underlying epigenetic programming of the HPA axis is well underway, there has been renewed interest in examining the role of early environment on the evolution of health conditions across the entire lifespan. Indeed, neonatal manipulations in rodents that reduce stress responsivity, and subsequent life-time exposure to glucocorticoids, are associated with a reduction in the development of neuroendocrine, neuroanatomical, and cognitive dysfunctions that typically progress with age. Although improved day to day regulation of the HPA axis also may be accompanied by a decrease in stroke risk, evidence from rodent studies suggest that an associated cost could be increased susceptibility to inflammation and neuronal death in the event that a stroke does occur and the individual is exposed to persistently elevated corticosteroids. Given its importance in regulation of health and disease states, any long-term modulation of the HPA axis is likely to be associated with both benefits and potential risks. The goals of this review article are to examine (1) the clinical and experimental data suggesting that neonatal experiences can shape HPA axis regulation, (2) the influence of stress and the HPA axis on stroke incidence and severity, and (3) the potential for neonatal programming of the HPA axis to impact adult cerebrovascular health. PMID:20057937

  15. Modeling the hypothalamus-pituitary-adrenal axis: A review and extension

    PubMed Central

    Rahmandad, Hazhir; Wittenborn, Andrea K.

    2015-01-01

    Multiple models of the hypothalamus-pituitary-adrenal (HPA) axis have been developed to characterize the oscillations seen in the hormone concentrations and to examine HPA axis dysfunction. We reviewed the existing models, then replicated and compared five of them by finding their correspondence to a dataset consisting of ACTH and cortisol concentrations of 17 healthy individuals. We found that existing models use different feedback mechanisms, vary in the level of details and complexities, and offer inconsistent conclusions. None of the models fit the validation dataset well. Therefore, we re-calibrated the best performing model using partial calibration and extended the model by adding individual fixed effects and an exogenous circadian function. Our estimated parameters reduced the mean absolute percent error significantly and offer a validated reference model that can be used in diverse applications. Our analysis suggests that the circadian and ultradian cycles are not created endogenously by the HPA axis feedbacks, which is consistent with the recent literature on the circadian clock and HPA axis. PMID:26277048

  16. Dynamic transitions in a model of the hypothalamic-pituitary-adrenal axis

    NASA Astrophysics Data System (ADS)

    Čupić, Željko; Marković, Vladimir M.; Maćešić, Stevan; Stanojević, Ana; Damjanović, Svetozar; Vukojević, Vladana; Kolar-Anić, Ljiljana

    2016-03-01

    Dynamic properties of a nonlinear five-dimensional stoichiometric model of the hypothalamic-pituitary-adrenal (HPA) axis were systematically investigated. Conditions under which qualitative transitions between dynamic states occur are determined by independently varying the rate constants of all reactions that constitute the model. Bifurcation types were further characterized using continuation algorithms and scale factor methods. Regions of bistability and transitions through supercritical Andronov-Hopf and saddle loop bifurcations were identified. Dynamic state analysis predicts that the HPA axis operates under basal (healthy) physiological conditions close to an Andronov-Hopf bifurcation. Dynamic properties of the stress-control axis have not been characterized experimentally, but modelling suggests that the proximity to a supercritical Andronov-Hopf bifurcation can give the HPA axis both, flexibility to respond to external stimuli and adjust to new conditions and stability, i.e., the capacity to return to the original dynamic state afterwards, which is essential for maintaining homeostasis. The analysis presented here reflects the properties of a low-dimensional model that succinctly describes neurochemical transformations underlying the HPA axis. However, the model accounts correctly for a number of experimentally observed properties of the stress-response axis. We therefore regard that the presented analysis is meaningful, showing how in silico investigations can be used to guide the experimentalists in understanding how the HPA axis activity changes under chronic disease and/or specific pharmacological manipulations.

  17. Dynamic transitions in a model of the hypothalamic-pituitary-adrenal axis.

    PubMed

    Čupić, Željko; Marković, Vladimir M; Maćešić, Stevan; Stanojević, Ana; Damjanović, Svetozar; Vukojević, Vladana; Kolar-Anić, Ljiljana

    2016-03-01

    Dynamic properties of a nonlinear five-dimensional stoichiometric model of the hypothalamic-pituitary-adrenal (HPA) axis were systematically investigated. Conditions under which qualitative transitions between dynamic states occur are determined by independently varying the rate constants of all reactions that constitute the model. Bifurcation types were further characterized using continuation algorithms and scale factor methods. Regions of bistability and transitions through supercritical Andronov-Hopf and saddle loop bifurcations were identified. Dynamic state analysis predicts that the HPA axis operates under basal (healthy) physiological conditions close to an Andronov-Hopf bifurcation. Dynamic properties of the stress-control axis have not been characterized experimentally, but modelling suggests that the proximity to a supercritical Andronov-Hopf bifurcation can give the HPA axis both, flexibility to respond to external stimuli and adjust to new conditions and stability, i.e., the capacity to return to the original dynamic state afterwards, which is essential for maintaining homeostasis. The analysis presented here reflects the properties of a low-dimensional model that succinctly describes neurochemical transformations underlying the HPA axis. However, the model accounts correctly for a number of experimentally observed properties of the stress-response axis. We therefore regard that the presented analysis is meaningful, showing how in silico investigations can be used to guide the experimentalists in understanding how the HPA axis activity changes under chronic disease and/or specific pharmacological manipulations.

  18. Stress-induced sensitization: the hypothalamic-pituitary-adrenal axis and beyond.

    PubMed

    Belda, Xavier; Fuentes, Silvia; Daviu, Nuria; Nadal, Roser; Armario, Antonio

    2015-01-01

    Exposure to certain acute and chronic stressors results in an immediate behavioral and physiological response to the situation followed by a period of days when cross-sensitization to further novel stressors is observed. Cross-sensitization affects to different behavioral and physiological systems, more particularly to the hypothalamus-pituitary-adrenal (HPA) axis. It appears that the nature of the initial (triggering) stressor plays a major role, HPA cross-sensitization being more widely observed with systemic or high-intensity emotional stressors. Less important appears to be the nature of the novel (challenging) stressor, although HPA cross-sensitization is better observed with short duration (5-15 min) challenging stressors. In some studies with acute immune stressors, HPA sensitization appears to develop over time (incubation), but most results indicate a strong initial sensitization that progressively declines over the days. Sensitization can affect other physiological system (i.e. plasma catecholamines, brain monoamines), but it is not a general phenomenon. When studied concurrently, behavioral sensitization appears to persist longer than that of the HPA axis, a finding of interest regarding long-term consequences of traumatic stress. In many cases, behavioral and physiological consequences of prior stress can only be observed following imposition of a new stressor, suggesting long-term latent effects of the initial exposure.

  19. Prospective investigation of the hypothalamo-pituitary-adrenal axis in patients with tularemia.

    PubMed

    Demiraslan, Hayati; Şimşek, Yasin; Tanriverdi, Fatih; Doğanay, Mehmet; Keleştemur, Hasan Fahrettin

    2015-01-01

    To investigate prospectively the hypothalamo-pituitary-adrenal (HPA) axis by adrenocorticotropic hormone (ACTH) stimulation test. Tularemia was diagnosed according to guidelines. An ACTH stimulation test (1 µg) and a dexamethasone suppression test (DST; 1 mg) were performed in patients in the acute phase of tularemia before antibiotic treatment and in the chronic phase. Nineteen patients (mean age: 41.0 ± 13.2 years; 57.9% female) with tularemia were enrolled in the study in 2011 and 2012. Cortisol response to ACTH stimulation test was sufficient in all patients during the acute phase. After the DST, the cortisol was not suppressed during the acute phase in only one patient. The median control time of 11 patients after acute tularemia was 13 months. During the chronic phase, cortisol response to ACTH stimulation was normal in all patients, and after DST cortisol was suppressed in all patients. The peak cortisol level after the ACTH stimulation test in the acute phase was higher than that in the chronic phase, but the difference was not statistically significant. The HPA axis of patients with tularemia was not significantly affected in the acute and chronic phases.

  20. Resetting the dynamic range of hypothalamic-pituitary-adrenal axis stress responses through pregnancy.

    PubMed

    Brunton, P J

    2010-11-01

    The hypothalamic-pituitary-adrenal (HPA) axis plays a key role in the neuroendocrine response to stress. Dynamic changes in HPA axis regulation and hence HPA responsivity occur over the lifetime of an animal. This article focuses on two extremes of the spectrum. The first occurs naturally during pregnancy when stress responses are dampened. The second, at the opposite end of the scale, occurs in offspring of mothers who were exposed to stress during pregnancy and display exaggerated HPA axis stress responses. Reduced glucocorticoid output in response to stress in pregnancy may have important consequences for conserving energy supply to the foetus(es), in modulating immune system adaptations and in protecting against adverse foetal programming by glucocorticoids. Understanding the mechanisms underpinning this adaptation in pregnancy may provide insights for manipulating HPA axis responsiveness in later life, particularly in the context of resetting HPA axis hyperactivity associated with prenatal stress exposure, which may underlie several major pathologies, including cardiovascular disease, diabetes mellitus type 2, obesity, cognitive decline and mood disorders.

  1. Hypothalamus-Pituitary-Adrenal cell-mediated immunity regulation in the Immune Restoration Inflammatory Syndrome

    PubMed Central

    Khakshooy, Allen; Chiappelli, Francesco

    2016-01-01

    Over one third of the patients sero-positive for the human immunodeficiency virus (HIV) with signs of the acquired immune deficiency syndrome (AIDS), and under treatment with anti-retroviral therapy (ART), develop the immune reconstitution inflammatory syndrome (IRIS). It is not clear what variables are that determine whether a patient with HIV/AIDS will develop ART-related IRIS, but the best evidence base thus far indicates that HIV/AIDS patients with low CD4 cell count, and HIV/AIDS patients whose CD4 count recovery shows a sharp slope, suggesting a particularly fast "immune reconstitution", are at greater risk of developing IRIS. Here, we propose the hypothesis that one important variable that can contribute to low CD4 cell count number and function in ART-treated HIV/AIDS patients is altered hypothalamic-pituitary-adrenal (HPA) cell-mediated immune (CMI) regulation. We discuss HPA-CMI deregulation in IRIS as the new frontier in comparative effectiveness research (CRE) for obtaining and utilizing the best evidence base for treatment of patients with HIV/AIDS in specific clinical settings. We propose that our hypothesis about altered HPA-CMI may extend to the pathologies observed in related viral infection, including Zika PMID:27212842

  2. Sex differences in early-life programming of the hypothalamic-pituitary-adrenal axis in humans.

    PubMed

    Gifford, Robert M; Reynolds, Rebecca M

    2017-09-15

    Increasing evidence supports fetal glucocorticoid exposure with associated altered offspring hypothalamic-pituitary-adrenal (HPA) axis activity as a key mechanism linking early life events with later life disease. Alterations in HPA axis activity are linked to a range of cardiometabolic and psychiatric diseases. As many of these diseases manifest sex differences in presentation we review the evidence for programmed sex-differences in the HPA axis. Available literature suggests vulnerability of the female HPA axis to prenatal stressors with female offspring demonstrating increased HPA axis reactivity. This may be due to changes in placental glucocorticoid metabolism leading to increased fetal glucocorticoid exposure. We discuss the potential consequences of increased vulnerability of the female HPA axis for later life health and consider the underlying mechanisms. Further studies are needed to determine whether sex-differences in early-life programming of the HPA axis represent a pathway underpinning the sex-differences in common cardiometabolic and psychiatric diseases. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Hypothalamic-pituitary-adrenal axis and autonomic nervous system activity in disruptive children and matched controls.

    PubMed

    van Goozen, S H; Matthys, W; Cohen-Kettenis, P T; Buitelaar, J K; van Engeland, H

    2000-11-01

    To investigate whether a pattern of lower autonomic nervous system (ANS) and hypothalamic-pituitary-adrenal (HPA) axis activity is found in children with disruptive behavior disorders (DBD) under nonstressful and stressful conditions, and whether such a pattern would correspond with their feelings of control and negative emotionality. The effects of stress were studied by comparing cortisol response, heart rate (HR), skin conductance level (SCL), and subjective feelings of 26 children with DBD and 26 matched normal controls. An additional 12 normal control children were studied in a nonstress control condition. Baseline HR and SCL but not cortisol were lower in the DBD group. Stress significantly affected cortisol, HR, SCL, and negative moods, although children with DBD showed a weaker HPA stress response and the difference between the groups was greater under stress. Children with DBD are characterized by lower ANS activity and HPA axis responsivity, but higher levels of emotional arousal. It is possible that in children with DBD the HPA axis and ANS, on the one hand, and their emotional arousal, on the other, are less well coordinated. It is speculated that this could be due to differences in genetic makeup or to stressful conditions during pre- or postnatal life.

  4. The importance of the hypothalamo-pituitary-adrenal axis as a therapeutic target in anorexia nervosa.

    PubMed

    Bou Khalil, Rami; Souaiby, Lama; Farès, Nassim

    2017-03-15

    Anorexia nervosa (AN) is an eating disorder, mainly affecting women, with a lifetime prevalence of about 1%, that can run a chronic course. While an effective pharmacotherapy is lacking, it is hypothesized that the progesterone and type II glucocorticoid receptor antagonist mifepristone (RU486) might be useful, as it is well known that the hypothalamo-pituitary-adrenal axis (HPA) is activated in AN. Even if secondary to the eating disorder, an active HPA axis may contribute to maintaining the neuroendocrine, emotional and behavioral effects observed in AN. More specifically, it is suggested that the HPA axis interacts with limbic structures, including the insular and prefrontal cortices, to uphold the changes in interoceptive and emotional awareness seen in AN. As such, it is proposed that mifepristone (RU486) reverses these effects by acting on these limbic regions. In conclusion, the theoretical efficacy of mifepristone (RU486) in improving symptoms of AN should be tested in randomized clinical trials. Copyright © 2016 Elsevier Inc. All rights reserved.

  5. Transcriptome comparison in the pituitary-adrenal axis between Beagle and Chinese Field dogs after chronic stress exposure.

    PubMed

    Luo, Wei; Fang, Meixia; Xu, Haiping; Xing, Huijie; Nie, Qinghua

    2015-10-01

    Chronic stress can induce a series of maladjustments, and the response to stress is partly regulated by the hypothalamus-pituitary-adrenal axis. The aim of this study was to investigate the genetic mechanisms of this axis regulating stress responsiveness. The pituitary and adrenal cortex of Beagle and Chinese Field Dog (CFD) from a stress exposure group [including Beagle pituitary 1 (BP1), CFD pituitary 1 (CFDP1), Beagle adrenal cortex 1 (BAC1), CFD adrenal cortex 1 (CFDAC1)] and a control group [including Beagle pituitary 2 (BP2), CFD pituitary 2 (CFDP2), Beagle adrenal cortex 2 (BAC2), CFD adrenal cortex 2 (CFDAC2)], selected to perform RNA-seq transcriptome comparisons, showed that 40, 346, 376, 69, 70, 38, 57 and 71 differentially expressed genes were detected in BP1 vs. BP2, CFDP1 vs. CFDP2, BP1 vs. CFDP1, BP2 vs. CFDP2, BAC1 vs. BAC2, CFDAC1 vs. CFDAC2, BAC1 vs. CFDAC1 and BAC2 vs. CFDAC2 respectively. NPB was a gene common to BAC1 vs. BAC2 and CFDAC1 vs. CFDAC2, indicating it was a potential gene affecting response to chronic stress, regardless of the extent of chronic stress induced. PLP1 was a gene common to BP1 vs. CFDP1 and BP2 vs. CFDP2, suggesting its important roles in affecting the stress-tolerance difference between the two breeds, regardless of whether there was stress exposure or not. Pathway analysis found 12, 4, 11 and 1 enriched pathway in the comparisons of BP1 vs. CFDP1, BP2 vs. CFDP2, CFDP1 vs. CFDP2 and BAC1 vs. BAC2 respectively. Glutamatergic synapse, neuroactive ligand-receptor interaction, retrograde endocannabinoid signaling, GABAergic synapse, calcium signaling pathway and dopaminergic synapse were the most significantly enriched pathways in both CFDP1 vs. CFDP2 and BP1 vs. CFDP1. GO, KEGG pathway and gene network analysis demonstrated that GRIA3, GRIN2A, GRIN2B and NPY were important in regulating the stress response in CFD. Nevertheless, ADORA1, CAMK2A, GRM1, GRM7 and NR4A1 might be critical genes contributing to the stress

  6. Effects of short- and long-duration hypothyroidism on function of the rat hypothalamic-pituitary-adrenal axis.

    PubMed

    Johnson, E O; Kamilaris, T C; Calogero, A E; Konstandi, M; Chrousos, G P

    2013-02-01

    The effects of hypothyroidism on the functional integrity of the hypothalamic-pituitary-adrenal (HPA) axis were investigated in adult male rats. HPA axis function was examined in vivo in sham-thyroidectomized male Sprague-Dawley rats or in thyroidectomized rats for 7 (short-term hypothyroidism) or 60 (long-term hypothyroidism) days. Peripheral ACTH and corticosterone responses to insulin-induced hypoglycemia and interleukin (IL)-1α stimulation were used to indirectly assess the hypothalamic CRH neuron. Hypothyroidism resulted in exaggerated ACTH responses to both hypoglycemic stress and IL-1α administration. The adrenal cortex of hypothyroid animals showed a significant reduction in adrenal reserves, as assessed by its response to low-dose ACTH, following suppression of the HPA axis with dexamethasone. Hypothyroid rats were also associated with significant decreases in cerebrospinal fluid corticosterone concentrations and decreased adrenal weights. The findings suggest that experimentally induced hypothyroidism is associated with a mild, yet significant, adrenal insufficiency, which involves abnormalities in all components of the HPA axis.

  7. Handling during pregnancy in the blue fox (Alopex lagopus): the influence on the fetal pituitary-adrenal axis.

    PubMed

    Osadchuk, L V; Braastad, B O; Hovland, A L; Bakken, M

    2001-07-01

    Previous studies revealed that handling is a stressor for farmed blue foxes. The present study was designed to examine the effects of a 1-min daily handling stress applied to pregnant blue fox vixens on the function of the fetal pituitary-adrenal system. Plasma concentrations of adrenocorticotropin hormone (ACTH), cortisol, and progesterone, adrenal content of cortisol and progesterone, in vitro adrenal production of these steroids and response to ACTH, and adrenal weights were measured in control (C; n = 73) and stressed (S; n = 58) fetuses. The ACTH levels were lower in stressed fetuses than in the controls (C: males, 128.6 +/- 6.1 pg/ml; females, 165.9 +/- 6.1 pg/ml; S: males, 122.3 +/- 5.4 pg/ml; females, 145.0 +/- 8.1 pg/ml; P < 0.05). In contrast, increased plasma cortisol concentrations in both sexes were demonstrated in stressed compared with control fetuses (C: males, 9.2 +/- 0.4 ng/ml; females, 9.2 +/- 0.4 ng/ml; S: males, 11.8 +/- 0.7 ng/ml; females, 13.2 +/- 0.7 ng/ml; P < 0.00001). The same difference was observed in plasma progesterone concentrations (C: males, 1.54 +/- 0.07 ng/ml; females, 1.49 +/- 0.10 ng/ml; S: males, 1.86 +/- 0.11 ng/ml; females, 1.74 +/- 0.10 ng/ml; P < 0.01). Prenatal stress did not change the baseline adrenal production of cortisol but prevented the cortisol response to ACTH in female fetuses and decreased the progesterone production in both sexes. Additionally, prenatally stressed fetuses of both sexes had significantly lower adrenal weights than controls (C: males, 9.4 +/- 0.3 mg; females, 9.5 +/- 0.4 mg; S: males, 8.1 +/- 0.3 mg; females, 8.2 +/- 0.4 mg; P < 0.001). These results indicate that prenatal handling stress induces a dysregulation of the pituitary-adrenal axis in the fetus and suggest that increased plasma glucocorticoids in the stressed dam can cross the placenta and influence the fetal hypothalamicpituitary-adrenal axis.

  8. Stress Sensitivity in Metastatic Breast Cancer: Analysis of Hypothalamic-Pituitary-Adrenal Axis Function

    PubMed Central

    Spiegel, David; Giese-Davis, Janine; Taylor, C. Barr; Kraemer, Helena

    2006-01-01

    The normal diurnal cortisol cycle has a peak in the morning, decreasing rapidly over the day, with low levels during the night, then rising rapidly again to the morning peak. A pattern of flatter daytime slopes has been associated with more rapid cancer progression in both animals and humans. We studied the relationship between the daytime slopes and other daytime cortisol responses to both pharmacological and psychosocial challenges of hypothalamic-pituitary-adrenal (HPA) axis function as well as DHEA in a sample of 99 women with metastatic breast cancer, in hopes of elucidating the dysregulatory process. We found that the different components of HPA regulation: the daytime cortisol slope, the rise in cortisol from waking to 30 minutes later, and cortisol response to various challenges, including dexamethasone (DEX) suppression, corticotrophin releasing factor (CRF) activation, and the Trier Social Stress Task, were at best modestly associated. Escape from suppression stimulated by 1 mg of dexamethasone administered the night before was moderately but significantly associated with flatter daytime cortisol slopes (r=0..28 to .30 at different times of the post dexamethasone administration day, all p<.01) . Daytime cortisol slopes were also moderately but significant associated with the rise in cortisol from waking to 30 minutes after awakening (r=.29, p=.004, N=96), but not with waking cortisol level (r=−0.13, p=.19). However, we could not detect any association between daytime cortisol slope and activation of cortisol secretion by either CRF infusion or the Trier Social Stress Task. The CRF activation test (following 1.5 mg of dexamethasone to assure that the effect was due to exogenous CRF) produced ACTH levels that were correlated (r=0.66 p<.0001, N = 74) with serum cortisol levels, indicating adrenal responsiveness to ACTH stimulation. Daytime cortisol slopes were significantly correlated with the slope of DHEA (r=.21, p=.04, N=95). Our general findings

  9. Hypothalamic-pituitary-adrenal axis dysregulation and cortisol activity in obesity: A systematic review.

    PubMed

    Incollingo Rodriguez, Angela C; Epel, Elissa S; White, Megan L; Standen, Erin C; Seckl, Jonathan R; Tomiyama, A Janet

    2015-12-01

    Although there is substantial evidence of differential hypothalamic-pituitary-adrenal (HPA) axis activity in both generalized and abdominal obesity, consistent trends in obesity-related HPA axis perturbations have yet to be identified. To systematically review the existing literature on HPA activity in obesity, identify possible explanations for inconsistencies in the literature, and suggest methodological improvements for future study. Included papers used Pubmed, Google Scholar, and the University of California Library search engines with search terms body mass index (BMI), waist-to-hip ratio (WHR), waist circumference, sagittal diameter, abdominal versus peripheral body fat distribution, body fat percentage, DEXA, abdominal obesity, and cortisol with terms awakening response, slope, total daily output, reactivity, feedback sensitivity, long-term output, and 11β-HSD expression. Empirical research papers were eligible provided that they included at least one type of obesity (general or abdominal), measured at least one relevant cortisol parameter, and a priori tested for a relationship between obesity and cortisol. A general pattern of findings emerged where greater abdominal fat is associated with greater responsivity of the HPA axis, reflected in morning awakening and acute stress reactivity, but some studies did show underresponsiveness. When examined in adipocytes, there is a clear upregulation of cortisol output (due to greater expression of 11β-HSD1), but in hepatic tissue this cortisol is downregulated. Overall obesity (BMI) appears to also be related to a hyperresponsive HPA axis in many but not all studies, such as when acute reactivity is examined. The reviewed literature contains numerous inconsistencies and contradictions in research methodologies, sample characteristics, and results, which partially precluded the development of clear and reliable patterns of dysregulation in each investigated cortisol parameter. The literature to date is

  10. Modulation of the Hypothalamic-Pituitary-Adrenal Axis by Early Life Stress Exposure

    PubMed Central

    van Bodegom, Miranda; Homberg, Judith R.; Henckens, Marloes J. A. G.

    2017-01-01

    Exposure to stress during critical periods in development can have severe long-term consequences, increasing overall risk on psychopathology. One of the key stress response systems mediating these long-term effects of stress is the hypothalamic-pituitary-adrenal (HPA) axis; a cascade of central and peripheral events resulting in the release of corticosteroids from the adrenal glands. Activation of the HPA-axis affects brain functioning to ensure a proper behavioral response to the stressor, but stress-induced (mal)adaptation of the HPA-axis' functional maturation may provide a mechanistic basis for the altered stress susceptibility later in life. Development of the HPA-axis and the brain regions involved in its regulation starts prenatally and continues after birth, and is protected by several mechanisms preventing corticosteroid over-exposure to the maturing brain. Nevertheless, early life stress (ELS) exposure has been reported to have numerous consequences on HPA-axis function in adulthood, affecting both its basal and stress-induced activity. According to the match/mismatch theory, encountering ELS prepares an organism for similar (“matching”) adversities during adulthood, while a mismatching environment results in an increased susceptibility to psychopathology, indicating that ELS can exert either beneficial or disadvantageous effects depending on the environmental context. Here, we review studies investigating the mechanistic underpinnings of the ELS-induced alterations in the structural and functional development of the HPA-axis and its key external regulators (amygdala, hippocampus, and prefrontal cortex). The effects of ELS appear highly dependent on the developmental time window affected, the sex of the offspring, and the developmental stage at which effects are assessed. Albeit by distinct mechanisms, ELS induced by prenatal stressors, maternal separation, or the limited nesting model inducing fragmented maternal care, typically results in HPA

  11. Brain mast cells act as an immune gate to the hypothalamic-pituitary-adrenal axis in dogs.

    PubMed

    Matsumoto, I; Inoue, Y; Shimada, T; Aikawa, T

    2001-07-02

    Mast cells perform a significant role in the host defense against parasitic and some bacterial infections. Here we show that in the dog, degranulation of brain mast cells evokes hypothalamic-pituitary-adrenal responses via histamine release. A large number of mast cells were found in a circumscribed ventral region of the hypothalamus, including the pars tuberalis and median eminence. When these intracranial mast cells were passively sensitized with immunoglobulin E via either the intracerebroventricular or intravenous route, there was a marked increase in the adrenal cortisol secretion elicited by a subsequent antigenic challenge (whether this was delivered via the central or peripheral route). Comp.48/80, a mast cell secretagogue, also increased cortisol secretion when administered intracerebroventricularly. Pretreatment (intracerebroventricularly) with anti-corticotropin--releasing factor antibodies or a histamine H(1) blocker, but not an H(2) blocker, attenuated the evoked increases in cortisol. These data show that in the dog, degranulation of brain mast cells evokes hypothalamic-pituitary-adrenal responses via centrally released histamine and corticotrophin-releasing factor. On the basis of these data, we suggest that intracranial mast cells may act as an allergen sensor, and that the activated adrenocortical response may represent a life-saving host defense reaction to a type I allergy.

  12. Vitamin A regulates hypothalamic-pituitary-adrenal axis status in LOU/C rats.

    PubMed

    Marissal-Arvy, Nathalie; Hamiani, Rachel; Richard, Emmanuel; Moisan, Marie-Pierre; Pallet, Véronique

    2013-10-01

    The aim of this study was to explore the involvement of retinoids in the hypoactivity and hyporeactivity to stress of the hypothalamic-pituitary-adrenal (HPA) axis in LOU/C rats. We measured the effects of vitamin A deficiency administered or not with retinoic acid (RA) on plasma corticosterone in standard conditions and in response to restraint stress and on hypothalamic and hippocampal expression of corticosteroid receptors, corticotropin-releasing hormone and 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in LOU/C rats. Interestingly, under control conditions, we measured a higher plasma concentration of retinol in LOU/C than in Wistar rats, which could contribute to the lower basal activity of the HPA axis in LOU/C rats. Vitamin A deficiency induced an increased HPA axis activity in LOU/C rats, normalized by RA administration. Compared with LOU/C control rats, vitamin A-deficient rats showed a delayed and heightened corticosterone response to restraint stress. The expression of corticosteroid receptors was strongly decreased by vitamin A deficiency in the hippocampus, which could contribute to a less efficient feedback by corticosterone on HPA axis tone. The expression of 11β-HSD1 was increased by vitamin A deficiency in the hypothalamus (+62.5%) as in the hippocampus (+104.7%), which could lead to a higher production of corticosterone locally and contribute to alteration of the hippocampus. RA supplementation treatment restored corticosterone concentrations and 11β-HSD1 expression to control levels. The high vitamin A status of LOU/C rats could contribute to their low HPA axis activity/reactivity and to a protective effect against 11β-HSD1-mediated deleterious action on cognitive performances during ageing.

  13. Metabolic syndrome, activity of the hypothalamic-pituitary-adrenal axis and inflammatory mediators in depressive disorder.

    PubMed

    Martinac, Marko; Pehar, Davor; Karlović, Dalibor; Babić, Dragan; Marcinko, Darko; Jakovljević, Miro

    2014-03-01

    Depression has been associated with various cardiovascular risk factors such as hypertension, obesity, atherogenic dyslipidemia and hyperglycemia. In depressive disorder, hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis and changes in the immune system have been observed. On the other hand, somatic diseases such as obesity, hyperlipidemia, hypertension and diabetes mellitus type 2 are now perceived as important comorbid conditions in patients with depression. The pathogenesis of the metabolic syndrome and depression is complex and poorly researched; however, it is considered that the interaction of chronic stress, psychotrauma, hypercotisolism and disturbed immune functions contribute to the development of these disorders. The aim of the study was to investigate the relationship between depression and metabolic syndrome regarding the HPA axis dysfunction and altered inflammatory processes. Literature search in Medline and other databases included articles written in English published between 1985 and 2012. Analysis of the literature was conducted using a systematic approach with the search terms such as depression, metabolic syndrome, inflammation, cytokines, glucocorticoids, cortisol, and HPA axis. In conclusion, the relationship between depression and metabolic syndrome is still a subject of controversy. Further prospective studies are required to clarify the possible causal relationship between depression and metabolic syndrome and its components. Furthermore, it is important to explore the possibility of a common biologic mechanism in the pathogenesis of these two disorders, in which special attention should be paid to the immune system function, especially the possible specific mechanisms by which cytokines can induce and maintain depressive symptoms and metabolic disorders. The data presented here emphasize the importance of recognition and treatment of depressive disorders with consequent reduction in the incidence of metabolic syndrome, but

  14. The role of hypothalamus-pituitary-adrenal genes and childhood trauma in borderline personality disorder.

    PubMed

    Martín-Blanco, Ana; Ferrer, Marc; Soler, Joaquim; Arranz, Maria Jesús; Vega, Daniel; Calvo, Natalia; Elices, Matilde; Sanchez-Mora, Cristina; García-Martinez, Iris; Salazar, Juliana; Carmona, Cristina; Bauzà, Joana; Prat, Mónica; Pérez, Víctor; Pascual, Juan C

    2016-06-01

    Current knowledge suggests that borderline personality disorder (BPD) results from the interaction between genetic and environmental factors. Research has mainly focused on monoaminergic genetic variants and their modulation by traumatic events, especially those occurring during childhood. However, to the best of our knowledge, there are no studies on the genetics of hypothalamus-pituitary-adrenal (HPA) axis, despite its vulnerability to early stress and its involvement in BPD pathogenesis. The aim of this study was to investigate the contribution of genetic variants in the HPA axis and to explore the modulating effect of childhood trauma in a large sample of BPD patients and controls. DNA was obtained from a sample of 481 subjects with BPD and 442 controls. Case-control differences in allelic frequencies of 47 polymorphisms in 10 HPA axis genes were analysed. Modulation of genetic associations by the presence of childhood trauma was also investigated by dividing the sample into three groups: BPD with trauma, BPD without trauma and controls. Two FKBP5 polymorphisms (rs4713902-C and rs9470079-A) showed significant associations with BPD. There were also associations between BPD and haplotype combinations of the genes FKBP5 and CRHR1. Two FKBP5 alleles (rs3798347-T and rs10947563-A) were more frequent in BPD subjects with history of physical abuse and emotional neglect and two CRHR2 variants (rs4722999-C and rs12701020-C) in BPD subjects with sexual and physical abuse. Our findings suggest a contribution of HPA axis genetic variants to BPD pathogenesis and reinforce the hypothesis of the modulating effect of childhood trauma in the development of this disorder.

  15. Environmental stressors and epigenetic control of the hypothalamic-pituitary-adrenal-axis (HPA-axis)

    PubMed Central

    Lee, Richard; Sawa, Akira

    2015-01-01

    In this review, we provide a brief summary of several key studies that broaden our understanding of stress and its epigenetic control of the hypothalamic-pituitary-adrenal axis (HPA)-axis function and behavior. Clinical and animal studies suggest a link among exposure to stress, dysregulation of the HPA-axis, and susceptibility to neuropsychiatric illnesses. Recent studies have supported the notion that exposure to glucocorticoids and stress in various forms, duration, and intensity during different periods of development leads to long-lasting maladaptive HPA-axis response in the brain. They demonstrate that this maladaptive response is comprised of persistent epigenetic changes in the function of HPA-axis-associated genes that govern homeostatic levels of glucocorticoids. Stressors and/or disruption of glucocorticoid dynamics also target genes such as brain-derived neurotrophic factor (BDNF) and tyrosine hydroxylase (TH) that are important for neuronal function and behavior. While a definitive role for epigenetic mechanisms remains unclear, these emerging studies implicate glucocorticoid signaling and its ability to alter the epigenetic landscape as one of the key mechanisms that alter the function of the HPA-axis and its associated cascades. We also suggest some of the requisite studies and techniques that are important, such as additional candidate gene approaches, genome-wide epigenomic screens, and innovative functional and behavioral studies in order to further explore and define the relationship between epigenetics and HPA-axis biology. Additional studies examining stress-induced epigenetic changes of HPA-axis genes, aided by innovative techniques and methodologies are needed to advance our understanding of this relationship and lead to better preventive, diagnostic, and corrective measures. PMID:25427939

  16. Acute effects of intravenous heroin on the hypothalamic-pituitary-adrenal axis response: a controlled trial.

    PubMed

    Walter, Marc; Gerber, Hana; Kuhl, Hans Christian; Schmid, Otto; Joechle, Wolfgang; Lanz, Christian; Brenneisen, Rudolf; Schächinger, Hartmut; Riecher-Rössler, Anita; Wiesbeck, Gerhard A; Borgwardt, Stefan J

    2013-04-01

    Heroin dependence is associated with a stressful environment and with dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis. The present study examined the acute effects of intravenous heroin versus placebo on the HPA axis response in heroin-dependent patients. Twenty-eight heroin-dependent patients in heroin-assisted treatment and 20 age- and sex-matched healthy participants were included in a controlled trial in which patients were twice administered heroin or saline in a crossover design, and healthy controls were only administered saline. The HPA axis response was measured by adrenocorticotropic hormone (ACTH) levels and by cortisol levels in serum and saliva before and 20 and 60 minutes after substance administration. Craving, withdrawal, and anxiety levels were measured before and 60 minutes after substance application. Plasma concentrations of heroin and its main metabolites were assessed using high-performance liquid chromatography. Heroin administration reduces craving, withdrawal, and anxiety levels and leads to significant decreases in ACTH and cortisol concentrations (P < 0.01). After heroin administration, cortisol concentrations did not differ from healthy controls, and ACTH levels were significantly lower (P < 0.01). In contrast, when patients receive saline, all hormone levels were significantly higher in patients than in healthy controls (P < 0.01). Heroin-dependent patients showed a normalized HPA axis response compared to healthy controls when they receive their regular heroin dose. These findings indicate that regular opioid administration protects addicts from stress and underscore the clinical significance of heroin-assisted treatment for heroin-dependent patients.

  17. Basal hypothalamic pituitary adrenal axis activity and hippocampal volumes: the SMART-Medea study.

    PubMed

    Knoops, Arnoud J G; Gerritsen, Lotte; van der Graaf, Yolanda; Mali, Willem P Th M; Geerlings, Mirjam I

    2010-06-15

    It has frequently been hypothesized that high levels of glucocorticoids have deleterious effects on the hippocampus and increase risk for cognitive decline and dementia, but no large-scale studies in humans have examined the direct relation between hippocampal volumes and hypothalamic-pituitary-adrenal axis activity. Cross-sectional analyses within the Second Manifestations of ARTerial disease-Magnetic Resonance (SMART)-Medea study, an ancillary study to the SMART-MR study on brain changes on magnetic resonance imaging (MRI) among patients with arterial disease. In 575 patients (mean age 62 +/- 9 years), diurnal cortisol rhythm was assessed with six saliva samples, collected at awakening; at 30, 45, and 60 min thereafter; and at 10 pm and 11 pm. A low dose of dexamethasone (.5 mg) was administered at 11 pm, and saliva was sampled the next morning at awakening. Volumetric measurements of the hippocampus were performed on a three-dimensional fast field echo T1-weighted scan with isotropic voxels. Mean total relative hippocampal volume was 6.0 +/- .7 mL. Linear regression analyses, adjusted for age, sex, vascular risk factors, and global brain atrophy showed that participants with higher evening levels and higher awakening levels after dexamethasone had smaller hippocampal volumes [B per SD (4.2) increase = -.09 mL; 95% confidence interval -.15 to -.03 mL and B per SD (2.5) increase = -.07 mL; 95% confidence interval -.13 to -.01 mL, respectively]. The awakening response was not significantly associated with hippocampal volumes. In this population, higher evening cortisol levels and reduced suppression after dexamethasone were associated with smaller hippocampal volumes, independent of total brain volume. The cortisol response after awakening was not associated with hippocampal volume.

  18. Depression, hypothalamic pituitary adrenal axis, and hippocampal and entorhinal cortex volumes--the SMART Medea study.

    PubMed

    Gerritsen, Lotte; Comijs, Hannie C; van der Graaf, Yolanda; Knoops, Arnoud J G; Penninx, Brenda W J H; Geerlings, Mirjam I

    2011-08-15

    Structural brain changes have often been found in major depressive disorder (MDD), and it is thought that hypothalamic-pituitary-adrenal (HPA) axis hyperactivity may explain this relation. We investigated the association of MDD and history of depression with hippocampal and entorhinal cortex volumes and whether HPA axis activity explained this association. In 636 participants with a history of atherosclerotic disease (mean age 62 ± 9 years, 81% male) from the second Manifestation of ARTerial disease-Memory depression and aging (SMART-Medea) study, a 12-month diagnosis of MDD and history of depression were assessed. Age of first depressive episode was classified into early-onset depression (< 50 years) and late-onset depression (≥ 50 years). HPA axis regulation was assessed by four morning saliva samples, two evening samples, and one awakening sample after .5 mg dexamethasone. Hippocampus and entorhinal cortex volume were manually outlined on three-dimensional T1-weighted magnetic resonance images. General linear models adjusted for demographics, vascular risk, antidepressant use, and white matter lesions showed that ever having had MDD was associated with smaller hippocampal volumes but not with entorhinal cortex volumes. Remitted MDD was related to smaller entorhinal cortex volumes (p < .05). Participants with early-onset depression had smaller hippocampal volumes than those who were never depressed (p < .05), whereas participants with late-onset depression had smaller entorhinal cortex volumes (p < .05). HPA axis activity did not explain these differences. We found differential associations of age of onset of depression on hippocampal and entorhinal cortex volumes, which could not be explained by alterations in HPA axis regulation. Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  19. Mathematical modeling of the hypothalamic-pituitary-adrenal gland (HPA) axis, including hippocampal mechanisms.

    PubMed

    Andersen, Morten; Vinther, Frank; Ottesen, Johnny T

    2013-11-01

    This paper presents a mathematical model of the HPA axis. The HPA axis consists of the hypothalamus, the pituitary and the adrenal glands in which the three hormones CRH, ACTH and cortisol interact through receptor dynamics. Furthermore, it has been suggested that receptors in the hippocampus have an influence on the axis. A model is presented with three coupled, non-linear differential equations, with the hormones CRH, ACTH and cortisol as variables. The model includes the known features of the HPA axis, and includes the effects from the hippocampus through its impact on CRH in the hypothalamus. The model is investigated both analytically and numerically for oscillating solutions, related to the ultradian rhythm seen in data, and for multiple fixed points related to hypercortisolemic and hypocortisolemic depression. The existence of an attracting trapping region guarantees that solution curves stay non-negative and bounded, which can be interpreted as a mathematical formulation of homeostasis. No oscillating solutions are present when using physiologically reasonable parameter values. This indicates that the ultradian rhythm originate from different mechanisms. Using physiologically reasonable parameters, the system has a unique fixed point, and the system is globally stable. Therefore, solutions converge to the fixed point for all initial conditions. This is in agreement with cortisol levels returning to normal, after periods of mild stress, in healthy individuals. Perturbing parameters lead to a bifurcation, where two additional fixed points emerge. Thus, the system changes from having a unique stable fixed point into having three fixed points. Of the three fixed points, two are stable and one is unstable. Further investigations show that solutions converge to one of the two stable fixed points depending on the initial conditions. This could explain why healthy people becoming depressed usually fall into one of two groups: a hypercortisolemic depressive group or

  20. Activation of the hypothalamic-pituitary-adrenal axis in lithium-induced conditioned taste aversion learning.

    PubMed

    Jahng, Jeong Won; Lee, Jong-Ho

    2015-12-05

    Intraperitoneal injections (ip) of lithium chloride at large doses induce c-Fos expression in the brain regions implicated in conditioned taste aversion (CTA) learning, and also activate the hypothalamic-pituitary-adrenal (HPA) axis and increase the plasma corticosterone levels in rats. A pharmacologic treatment blunting the lithium-induced c-Fos expression in the brain regions, but not the HPA axis activation, induced CTA formation. Synthetic glucocorticoids at conditioning, but not glucocorticoid antagonist, attenuated the lithium-induced CTA acquisition. The CTA acquisition by ip lithium was not affected by adrenalectomy regardless of basal corticosterone supplement, but the extinction was delayed in the absence of basal corticosterone. Glucocorticoids overloading delayed the extinction memory formation of lithium-induced CTA. ip lithium consistently induced the brain c-Fos expression, the HPA activation and CTA formation regardless of the circadian activation of the HPA axis. Intracerebroventricular (icv) injections of lithium at day time also increased the brain c-Fos expression, activated the HPA axis and induced CTA acquisition. However, icv lithium at night, when the HPA axis shows its circadian activation, did not induce CTA acquisition nor activate the HPA axis, although it increased the brain c-Fos expression. These results suggest that the circadian activation of the HPA axis may affect central, but not peripheral, effect of lithium in CTA learning in rats, and the HPA axis activation may be necessary for the central effect of lithium in CTA formation. Also, glucocorticoids may be required for a better extinction; however, increased glucocorticoids hinder both the acquisition and the extinction of lithium-induced CTA. Copyright © 2015. Published by Elsevier B.V.

  1. Sleep restriction alters the hypothalamic-pituitary-adrenal response to stress

    NASA Technical Reports Server (NTRS)

    Meerlo, P.; Koehl, M.; van der Borght, K.; Turek, F. W.

    2002-01-01

    Chronic sleep restriction is an increasing problem in many countries and may have many, as yet unknown, consequences for health and well being. Studies in both humans and rats suggest that sleep deprivation may activate the hypothalamic-pituitary-adrenal (HPA) axis, one of the main neuroendocrine stress systems. However, few attempts have been made to examine how sleep loss affects the HPA axis response to subsequent stressors. Furthermore, most studies applied short-lasting total sleep deprivation and not restriction of sleep over a longer period of time, as often occurs in human society. Using the rat as our model species, we investigated: (i) the HPA axis activity during and after sleep deprivation and (ii) the effect of sleep loss on the subsequent HPA response to a novel stressor. In one experiment, rats were subjected to 48 h of sleep deprivation by placing them in slowly rotating wheels. Control rats were placed in nonrotating wheels. In a second experiment, rats were subjected to an 8-day sleep restriction protocol allowing 4 h of sleep each day. To test the effects of sleep loss on subsequent stress reactivity, rats were subjected to a 30-min restraint stress. Blood samples were taken at several time points and analysed for adrenocorticotropic hormone (ACTH) and corticosterone. The results show that ACTH and corticosterone concentrations were elevated during sleep deprivation but returned to baseline within 4 h of recovery. After 1 day of sleep restriction, the ACTH and corticosterone response to restraint stress did not differ between control and sleep deprived rats. However, after 48 h of total sleep deprivation and after 8 days of restricted sleep, the ACTH response to restraint was significantly reduced whereas the corticosterone response was unaffected. These results show that sleep loss not only is a mild activator of the HPA axis itself, but also affects the subsequent response to stress. Alterations in HPA axis regulation may gradually appear under

  2. Child mortality, hypothalamic-pituitary-adrenal axis activity and cellular aging in mothers.

    PubMed

    Barha, Cindy K; Salvante, Katrina G; Hanna, Courtney W; Wilson, Samantha L; Robinson, Wendy P; Altman, Rachel M; Nepomnaschy, Pablo A

    2017-01-01

    Psychological challenges, including traumatic events, have been hypothesized to increase the age-related pace of biological aging. Here we test the hypothesis that psychological challenges can affect the pace of telomere attrition, a marker of cellular aging, using data from an ongoing longitudinal-cohort study of Kaqchikel Mayan women living in a population with a high frequency of child mortality, a traumatic life event. Specifically, we evaluate the associations between child mortality, maternal telomere length and the mothers' hypothalamic-pituitary-adrenal axis (HPAA), or stress axis, activity. Child mortality data were collected in 2000 and 2013. HPAA activity was assessed by quantifying cortisol levels in first morning urinary specimens collected every other day for seven weeks in 2013. Telomere length (TL) was quantified using qPCR in 55 women from buccal specimens collected in 2013. Shorter TL with increasing age was only observed in women who experienced child mortality (p = 0.015). Women with higher average basal cortisol (p = 0.007) and greater within-individual variation (standard deviation) in basal cortisol (p = 0.053) presented shorter TL. Non-parametric bootstrapping to estimate mediation effects suggests that HPAA activity mediates the effect of child mortality on TL. Our results are, thus, consistent with the hypothesis that traumatic events can influence cellular aging and that HPAA activity may play a mediatory role. Future large-scale longitudinal studies are necessary to confirm our results and further explore the role of the HPAA in cellular aging, as well as to advance our understanding of the underlying mechanisms involved.

  3. Blunted hypothalamo-pituitary adrenal axis response to predator odor predicts high stress reactivity.

    PubMed

    Whitaker, Annie M; Gilpin, Nicholas W

    2015-08-01

    Individuals with trauma- and stress-related disorders exhibit increases in avoidance of trauma-related stimuli, heightened anxiety and altered neuroendocrine stress responses. Our laboratory uses a rodent model of stress that mimics the avoidance symptom cluster associated with stress-related disorders. Animals are classified as 'Avoiders' or 'Non-Avoiders' post-stress based on avoidance of predator-odor paired context. Utilizing this model, we are able to examine subpopulation differences in stress reactivity. Here, we used this predator odor model of stress to examine differences in anxiety-like behavior and hypothalamo-pituitary adrenal (HPA) axis function in animals that avoid a predator-paired context relative to those that do not. Rats were exposed to predator odor stress paired with a context and tested for avoidance (24h and 11days), anxiety-like behavior (48h and 5days) and HPA activation following stress. Control animals were exposed to room air. Predator odor stress produced avoidance in approximately 65% of the animals at 24h that persisted 11days post-stress. Both Avoiders and Non-Avoiders exhibited a heightened anxiety-like behavior at 48h and 5days post-stress when compared to unstressed Controls. Non-Avoiders exhibited significant increases in circulating adrenocorticotropin hormone (ACTH) and corticosterone (CORT) concentrations immediately following predator odor stress compared to Controls and this response was significantly attenuated in Avoiders. There was an inverse correlation between circulating ACTH/CORT concentrations and avoidance, indicating that lower levels of ACTH/CORT predicted higher levels of avoidance. These results suggest that stress effects on HPA stress axis activation predict long-term avoidance of stress-paired stimuli, and build on previous data showing the utility of this model for exploring the neurobiological mechanisms of trauma- and stress-related disorders.

  4. Blunted Hypothalamo-pituitary Adrenal Axis Response to Predator Odor Predicts High Stress Reactivity

    PubMed Central

    Whitaker, Annie M.; Gilpin, Nicholas W.

    2015-01-01

    Individuals with trauma- and stress-related disorders exhibit increases in avoidance of trauma-related stimuli, heightened anxiety and altered neuroendocrine stress responses. Our laboratory uses a rodent model of stress that mimics the avoidance symptom cluster associated with stress-related disorders. Animals are classified as ‘Avoiders’ or Non-Avoiders' post-stress based on avoidance of predator-odor paired context. Utilizing this model, we are able to examine subpopulation differences in stress reactivity. Here, we used this predator odor model of stress to examine differences in anxiety-like behavior and hypothalamo-pituitary adrenal (HPA) axis function in animals that avoid a predator-paired context relative to those that do not. Rats were exposed to predator odor stress paired with a context and tested for avoidance (24 hours and 11 days), anxiety-like behavior (48 hours and 5 days) and HPA activation following stress. Control animals were exposed to room air. Predator odor stress produced avoidance in approximately 65% of the animals at 24 hours that persisted 11 days post-stress. Both Avoiders and Non-Avoiders exhibited heightened anxiety-like behavior at 48 hours and 5 days post-stress when compared to unstressed Controls. Non-Avoiders exhibited significant increases in circulating adrenocorticotropin hormone (ACTH) and corticosterone (CORT) concentrations immediately following predator odor stress compared to Controls and this response was significantly attenuated in Avoiders. There was an inverse correlation between circulating ACTH/CORT concentrations and avoidance, indicating that lower levels of ACTH/CORT predicted higher levels of avoidance. These results suggest that stress effects on HPA stress axis activation predict long-term avoidance of stress-paired stimuli, and builds on previous data showing the utility of this model for exploring the neurobiological mechanisms of trauma- and stress-related disorders. PMID:25824191

  5. Disturbances of the hypothalamic-pituitary-adrenal axis and plasma electrolytes during experimental sepsis

    PubMed Central

    2011-01-01

    Background Sepsis continues to be a poorly understood syndrome with a high mortality rate. While we are beginning to decipher the intricate interplay of the inflammatory response during sepsis, the precise regulation of the hypothalamic-pituitary-adrenal (HPA) axis and its impact on electrolyte homeostasis during sepsis remains incompletely understood. Methods Sepsis was induced in adult male Sprague-Dawley rats by cecal ligation and puncture (CLP). Plasma samples were obtained as a function of time (6-48 hrs) after CLP and compared with healthy animals (neg ctrl). Samples were analyzed for adrenocorticotropin (ACTH), corticosterone, and aldosterone levels, as well as concentrations of sodium (Na+), potassium (K+), chloride (Cl-), and magnesium (Mg2+). Results ACTH levels were found to be significantly reduced 6-24 hrs after CLP in comparison to baseline levels and displayed gradual recovery during the later course (24-48 hrs) of sepsis. Plasma corticosterone concentrations exhibited a bell-shaped response, peaking between 6 and 12 hrs followed by rapid decline and concentrations below negative control levels 48 hrs after injury. Aldosterone levels in septic animals were continuously elevated between 6 and 48 hrs. Whereas plasma Na+ levels were found to be persistently elevated following CLP, levels of K+, Cl- and Mg2+ were significantly reduced as a function of time and gradually recovered during the later course of sepsis. Conclusions CLP-induced sepsis resulted in dynamic changes of ACTH, corticosterone, and aldosterone levels. In addition, electrolyte levels showed significant disturbances after CLP. These electrolyte perturbations might be evoked by a downstream effect or a dysfunctional HPA-axis response during sepsis and contribute to severe complications during sepsis. PMID:22208725

  6. Relationship between the hypothalamic-pituitary-adrenal-axis and fatty acid metabolism in recurrent depression.

    PubMed

    Mocking, Roel J T; Ruhé, Henricus G; Assies, Johanna; Lok, Anja; Koeter, Maarten W J; Visser, Ieke; Bockting, Claudi L H; Schene, Aart H

    2013-09-01

    Alterations in hypothalamic-pituitary-adrenal (HPA)-axis activity and fatty acid (FA)-metabolism have been observed in (recurrent) major depressive disorder (MDD). Through the pathophysiological roles of FAs in the brain and cardiovascular system, a hypothesized relationship between HPA-axis activity and FA-metabolism could form a possible missing link accounting for the association of HPA-axis hyperactivity with recurrence and cardiovascular disease in MDD. In 137 recurrent MDD-patients and 73 age- and sex-matched controls, we therefore investigated associations between salivary cortisol (morning and evening) and the following indicators of FA-metabolism measured in the red blood cell membrane: (I) three main FAs [eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and arachidonic acid (AA)], and (II) structural FA indices (unsaturation, chain length, peroxidation) calculated from concentrations of 29 FAs to delineate overall FA-characteristics. In addition, we compared these associations in patients with those in controls. In patients, evening cortisol concentrations were significantly negatively associated with DHA (B=-1.358; SE=0.499; t=-2.72; p=.006), the unsaturation index (B=-0.021; SE=0.009; t=-2.42; p=.018), chain length index (B=-0.060; SE=0.025; t=-2.41; p=.019), and peroxidation index (B=-0.029; SE=0.012; t=-2.48; p=.015). The relations between cortisol and the latter three variables were significantly negative in patients relative to controls. Significance remained after correction for confounders. Our results suggest a relationship between HPA-axis activity and FA-metabolism in recurrent MDD. Future randomized experimental intervention studies using clinical outcome measures could help to further elucidate the suggested effects of hypercortisolemia in the brain and cardiovascular system in recurrent MDD.

  7. Hypothalamic-pituitary-adrenal axis response to stress in male DUI recidivists.

    PubMed

    Couture, Sophie; Brown, Thomas G; Ouimet, Marie Claude; Gianoulakis, Christina; Tremblay, Jacques; Carbonneau, René

    2008-01-01

    Cortisol is a stress hormone mediated by the hypothalamic-pituitary-adrenal (HPA) axis and a psychobiological marker of genetic risk for alcoholism and other high-risk behavioural characteristics. In previous work with driving under the influence of alcohol (DUI) recidivists, we uncovered a significant inverse relationship between the frequency of past DUI convictions and salivary cortisol, whose strength surpassed those observed between DUI frequency and measures of alcohol abuse and other DUI-related characteristics. This finding emerged using a methodology not specifically contrived to test this relationship. The goals of this follow-up study were to (a) examine if a standardized stress-induction protocol would produce a significant inverse relationship between cortisol response and number of DUI offences; and (b) clarify whether HPA axis dysregulation could be linked to particular DUI-related behavioural correlates, such as alcohol use severity, sensation seeking, and antisocial features. Thirty male DUI recidivists were recruited as well as 11 male non-DUI drivers as a comparison group. Results indicated an inverse relationship between DUI frequency and cortisol response (r(39)=-0.36, p=0.021), as well as a lower cortisol response in DUI offenders than the comparison group (F(1,39)=5.71, p=0.022). Finally, for recidivists, hierarchical regression analyses indicated that experience seeking (R(2)=0.23, p=0.008), followed by number of cigarettes smoked daily ((Delta)R(2)=0.12, p=0.031), combined to explain 35% of the variance in cortisol (F(2,29)=7.26, p=0.003). These findings indicate that severe recidivism may have psychobiological underpinnings, and that HPA axis dysregulation appears to be a mechanism common to high-risk behaviours including DUI recidivism, sensation seeking, and cigarette smoking.

  8. Evolutionary functions of early social modulation of hypothalamic-pituitary-adrenal axis development in humans.

    PubMed

    Flinn, Mark V; Nepomnaschy, Pablo A; Muehlenbein, Michael P; Ponzi, Davide

    2011-06-01

    The hypothalamic-pituitary-adrenal axis (HPAA) is highly responsive to social challenges. Because stress hormones can have negative developmental and health consequences, this presents an evolutionary paradox: Why would natural selection have favored mechanisms that elevate stress hormone levels in response to psychosocial stimuli? Here we review the hypothesis that large brains, an extended childhood and intensive family care in humans are adaptations resulting from selective forces exerted by the increasingly complex and dynamic social and cultural environment that co-evolved with these traits. Variations in the modulation of stress responses mediated by specific HPAA characteristics (e.g., baseline cortisol levels, and changes in cortisol levels in response to challenges) are viewed as phenotypically plastic, ontogenetic responses to specific environmental signals. From this perspective, we discuss relations between physiological stress responses and life history trajectories, particularly the development of social competencies. We present brief summaries of data on hormones, indicators of morbidity and social environments from our long-term, naturalistic studies in both Guatemala and Dominica. Results indicate that difficult family environments and traumatic social events are associated with temporal elevations of cortisol, suppressed reproductive functioning and elevated morbidity. The long-term effects of traumatic early experiences on cortisol profiles are complex and indicate domain-specific effects, with normal recovery from physical stressors, but some heightened response to negative-affect social challenges. We consider these results to be consistent with the hypothesis that developmental programming of the HPAA and other neuroendocrine systems associated with stress responses may facilitate cognitive targeting of salient social challenges in specific environments. Copyright © 2011 Elsevier Ltd. All rights reserved.

  9. Child mortality, hypothalamic-pituitary-adrenal axis activity and cellular aging in mothers

    PubMed Central

    Barha, Cindy K.; Salvante, Katrina G.; Hanna, Courtney W.; Wilson, Samantha L.; Robinson, Wendy P.; Altman, Rachel M.

    2017-01-01

    Psychological challenges, including traumatic events, have been hypothesized to increase the age-related pace of biological aging. Here we test the hypothesis that psychological challenges can affect the pace of telomere attrition, a marker of cellular aging, using data from an ongoing longitudinal-cohort study of Kaqchikel Mayan women living in a population with a high frequency of child mortality, a traumatic life event. Specifically, we evaluate the associations between child mortality, maternal telomere length and the mothers’ hypothalamic-pituitary-adrenal axis (HPAA), or stress axis, activity. Child mortality data were collected in 2000 and 2013. HPAA activity was assessed by quantifying cortisol levels in first morning urinary specimens collected every other day for seven weeks in 2013. Telomere length (TL) was quantified using qPCR in 55 women from buccal specimens collected in 2013. Results: Shorter TL with increasing age was only observed in women who experienced child mortality (p = 0.015). Women with higher average basal cortisol (p = 0.007) and greater within-individual variation (standard deviation) in basal cortisol (p = 0.053) presented shorter TL. Non-parametric bootstrapping to estimate mediation effects suggests that HPAA activity mediates the effect of child mortality on TL. Our results are, thus, consistent with the hypothesis that traumatic events can influence cellular aging and that HPAA activity may play a mediatory role. Future large-scale longitudinal studies are necessary to confirm our results and further explore the role of the HPAA in cellular aging, as well as to advance our understanding of the underlying mechanisms involved. PMID:28542264

  10. Interaction of PGHS-2 and glutamatergic mechanisms controlling the ovine fetal hypothalamus-pituitary-adrenal axis.

    PubMed

    Knutson, Nathan; Wood, Charles E

    2010-07-01

    Prostaglandins, generated within the fetal brain, are integral components of the mechanism controlling the fetal hypothalamus-pituitary-adrenal (HPA) axis. Previous studies in this laboratory demonstrated that prostaglandin G/H synthase isozyme 2 (PGHS-2) inhibition reduces the fetal HPA axis response to cerebral hypoperfusion, blocks the preparturient rise in fetal plasma ACTH concentration, and delays parturition. We also discovered that blockade of N-methyl-d-aspartate (NMDA) receptors reduces the fetal ACTH response to cerebral hypoperfusion. The present study was designed to test the hypothesis that PGHS-2 action and the downstream effect of HPA axis stimulation are stimulated by NMDA-mediated glutamatergic neurotransmission. Chronically catheterized late-gestation fetal sheep (n = 8) were injected with NMDA (1 mg iv). All responded with increases in fetal plasma ACTH and cortisol concentrations. Pretreatment with resveratrol (100 mg iv, n = 5), a specific inhibitor of PGHS-1, did not alter the magnitude of the HPA axis response to NMDA. Pretreatment with nimesulide (10 mg iv, n = 6), a specific inhibitor of PGHS-2, significantly reduced the HPA axis response to NMDA. To further explore this interaction, we injected NMDA in six chronically catheterized fetal sheep that were chronically infused with nimesulide (n = 6) at a rate of 1 mg/day into the lateral cerebral ventricle for 5-7 days. In this group, there was no significant ACTH response to NMDA. Finally, we tested whether the HPA axis response to prostaglandin E(2) (PGE(2)) is mediated by NMDA receptors. Seven chronically catheterized late-gestation fetal sheep were injected with 100 ng of PGE(2), which significantly increased fetal plasma ACTH and cortisol concentrations. Pretreatment with ketamine (10 mg iv), an NMDA antagonist, did not alter the ACTH or cortisol response to PGE(2). We conclude that generation of prostanoids via the action of PGHS-2 in the fetal brain augments the fetal HPA axis response

  11. Adaptive responses of the maternal hypothalamic-pituitary-adrenal axis during pregnancy and lactation.

    PubMed

    Brunton, P J; Russell, J A; Douglas, A J

    2008-06-01

    Over the past 40 years, it has been recognised that the maternal hypothalamic-pituitary-adrenal (HPA) axis undergoes adaptations through pregnancy and lactation that might contribute to avoidance of adverse effects of stress on the mother and offspring. The extent of the global adaptations in the HPA axis has been revealed and the underlying mechanisms investigated within the last 20 years. Both basal, including the circadian rhythm, and stress-induced adrenocorticotrophic hormone and glucocorticoid secretory patterns are altered. Throughout most of pregnancy, and in lactation, these changes predominantly reflect reduced drive by the corticotropin-releasing factor (CRF) neurones in the parvocellular paraventricular nucleus (pPVN). An accompanying profound attenuation of HPA axis responses to a wide variety of psychological and physical stressors emerges after mid-pregnancy and persists until the end of lactation. Central to this suppression of stress responsiveness is reduced activation of the pPVN CRF neurones. This is consequent on the reduced effectiveness of the stimulation of brainstem afferents to these CRF neurones (for physical stressors) and of altered processing by limbic structures (for emotional stressors). The mechanism of reduced CRF neurone responses to physical stressors in pregnancy is the suppression of noradrenaline release in the PVN by an up-regulated endogenous opioid mechanism, which is induced by neuroactive steroid produced from progesterone. By contrast, in lactation suckling the young provides a neural stimulus that dampens the HPA axis circadian rhythm and reduces stress responses. Reduced noradrenergic input activity is involved in reduced stress responses in lactation, although central prolactin action also appears important. Such adaptations limit the adverse effects of excess glucocorticoid exposure on the foetus(es) and facilitate appropriate metabolic and immune responses.

  12. Suppression of hypothalamic-pituitary-adrenal axis responsiveness to stress in a rat model of acute cholestasis.

    PubMed Central

    Swain, M G; Patchev, V; Vergalla, J; Chrousos, G; Jones, E A

    1993-01-01

    Cholestatic patients undergoing surgery have increased mortality and demonstrate clinical features suggestive of adrenal insufficiency. To examine whether cholestasis influences the status of the hypothalamic-pituitary-adrenal axis, we evaluated rats with acute cholestasis caused by bile duct resection (BDR) and sham-operated and unoperated controls. Basal unstressed plasma concentrations of ACTH and corticosterone were similar in BDR and sham-operated and unoperated control rats. However, exposure of BDR rats to saturated ether vapor resulted in significantly less ACTH and corticosterone release in plasma than in the control animals. To understand the mechanism(s) of decreased HPA axis responsiveness to ether stress in cholestasis, we administered corticotropin-releasing factor (CRF) and measured hypothalamic content, mRNA levels and in vitro secretion of CRF and arginine vasopressin (AVP), the two principal secretagogues of ACTH. In BDR animals, ACTH responses to CRF were decreased and hypothalamic content of CRF and CRF mRNA expression in the paraventricular nucleus were decreased by 25 and 37%, respectively. Furthermore, CRF release from hypothalamic explants of BDR rats was 23% less than that of controls. In contrast to CRF, hypothalamic content of AVP was 35% higher, AVP mRNA in the paraventricular nucleus was increased by 6.6-fold, and hypothalamic explant release of AVP was 24% higher in BDR rats than in control animals. Pituitary ACTH contents were similar in BDR and sham resected rats, but higher than unoperated controls. These findings demonstrate that acute cholestasis in the rat is associated with suppression of hypothalamic-pituitary-adrenal axis responsiveness to stress and demonstrate a dissociation between mechanisms of ACTH regulation mediated by CRF and AVP. Images PMID:8387536

  13. Impact of study design on the evaluation of inhaled and intranasal corticosteroids' effect on hypothalamic-pituitary-adrenal axis function.

    PubMed

    Fan, Ying; Ma, Lian; Pippins, Jennifer; Limb, Susan; Xu, Yun; Sahajwalla, Chandrahas G

    2014-10-01

    In part I of this review, an overview of the designs of hypothalamic-pituitary-adrenal (HPA) axis studies in the setting of inhaled corticosteroids (ICS) or intranasal corticosteroids (INS) use was discussed. Part II provides detailed discussion on the HPA axis evaluation results for each common ICS and INS, and how these results are possibly affected by the factors of study design. Significant adrenal suppression at conventional ICS/INS doses appears to be rare in clinical settings. The magnitude of cortisol suppression varies widely among different study designs. Factors potentially impacting this variability include: the choice of dose, dosing duration, assay sensitivity, statistical methodology, study population, and compliance. All of these factors have the potential to affect the extent of HPA axis effects detected and should be considered when designing or interpreting the results of a HPA axis study.

  14. Diagnosis of adrenal insufficiency using the GHRP-6 Test: comparison with the insulin tolerance test in patients with hypothalamic-pituitary-adrenal disease.

    PubMed

    Alaioubi, B; Mann, K; Petersenn, S

    2010-03-01

    The insulin tolerance test (ITT) is considered the gold standard for the diagnosis of adrenal insufficiency (AI). However, the test is unpleasant to perform and has the risk of serious complications. We therefore evaluated the clinical applicability of GHRP6, which is a known activator of the hypothalamic-pituitary-adrenal (HPA) axis, to test for AI. For this purpose a comparative clinical study was designed. Forty-nine patients with suspected dysfunction of the HPA axis and 20 healthy controls were enrolled. The ITT was performed in patients, and GHRP6 (1 microg/kg) testing in patients and controls. Serum cortisol over 90 min after GHRP6, in comparison to the ITT, was the main outcome measure. Thirty-one patients had a peak cortisol response of less than 500 nmol/l during ITT and were considered adrenal insufficient. For GHRP6, the mean cortisol peak was 227+/-25.7 nmol/l in the AI group versus 395+/-35.3 nmol/l in the adrenal sufficient (AS) group. ROC analysis of peak cortisol levels during GHRP6 test suggested an optimal threshold of 299 nmol/l for the diagnosis of AI (Sens. 71.0%, Spec. 77.8%). Applying upper (416 nmol/l) and lower (137 nmol/l) thresholds with high specificities in combination with early morning cortisol established the diagnosis in nearly half of the patients, even when the GHRP6 test is limited to 30 min duration. GHRP6 led to significant activation of the HPA axis with no detectable side effects, but had limited accuracy in comparison to the ITT.

  15. Dissection of Glucocorticoid Receptor-mediated Inhibition of the Hypothalamic-pituitary-adrenal Axis by Gene Targeting in Mice

    PubMed Central

    Laryea, Gloria; Muglia, Lisa; Arnett, Melinda; Muglia, Louis J.

    2014-01-01

    Negative feedback regulation of glucocorticoid (GC) synthesis and secretion occurs through the function of glucocorticoid receptor (GR) at sites in the hypothalamic-pituitary-adrenal (HPA) axis, as well as in brain regions such as the hippocampus, prefrontal cortex, and sympathetic nervous system. This function of GRs in negative feedback coordinates basal glucocorticoid secretion and stress-induced increases in secretion that integrate GC production with the magnitude and duration of the stressor. This review describes the effects of GR loss along major sites of negative feedback including the entire brain, the paraventricular nucleus of the hypothalamus (PVN), and the pituitary. In genetic mouse models, we evaluate circadian regulation of the HPA axis, stress-stimulated neuroendocrine response and behavioral activity, as well as the integrated response of organism metabolism. Our analysis provides information on contributions of region-specific GR-mediated negative feedback to provide insight in understanding HPA axis dysregulation and the pathogenesis of psychiatric and metabolic disorders. PMID:25256348

  16. The stability of the extended model of hypothalamic-pituitary-adrenal axis examined by stoichiometric network analysis

    NASA Astrophysics Data System (ADS)

    Marković, V. M.; Čupić, Ž.; Ivanović, A.; Kolar-Anić, Lj.

    2011-12-01

    Stoichiometric network analysis (SNA) represents a powerful mathematical tool for stability analysis of complex stoichiometric networks. Recently, the important improvement of the method has been made, according to which instability relations can be entirely expressed via reaction rates, instead of thus far used, in general case undefined, current rates. Such an improved SNA methodology was applied to the determination of exact instability conditions of the extended model of the hypothalamic-pituitary-adrenal (HPA) axis, a neuroendocrinological system, whose hormone concentrations exert complex oscillatory evolution. For emergence of oscillations, the Hopf bifurcation condition was utilized. Instability relations predicted by SNA showed good correlation with numerical simulation data of the HPA axis model.

  17. Effects of short- and long-duration hypothyroidism on hypothalamic-pituitary-adrenal axis function in rats: in vitro and in situ studies.

    PubMed

    Johnson, Elizabeth O; Calogero, Aldo E; Konstandi, Mary; Kamilaris, Themis C; La Vignera, Sandro; Chrousos, George P

    2012-12-01

    The purpose of this study is to assess the effects of hypothyroidism on the hypothalamic-pituitary-adrenal (HPA) axis; the functional integrity of each component of the HPA axis was examined in short-term and long-term hypothyroidism. Neuropeptide synthesis, release, and content were evaluated in vitro both in the hypothalamus and anterior pituitary, and corticosterone release was assessed in primary adrenal cell cultures at 7 (short-term) and 60 days (long-term hypothyroidism) after thyroidectomy in male rats. Hypothyroid rats showed adrenal insufficiency in several parameters, which were associated with the duration of hypothyroidism. Cerebrospinal (CSF) ACTH was decreased in all hypothyroid animals, while CSF corticosterone levels were significantly decreased only in long-term hypothyroidism. Long-term hypothyroid animals showed decreased corticotropin-releasing hormone (CRH) mRNA expression in the hypothalamic paraventricular nucleus under both basal and stress conditions, decreased CRH release from hypothalamic organ cultures after KCL and arginine vasopressin stimulation, as well as an increased number of anterior pituitary CRH receptors. In contrast, short-term hypothyroid rats showed changes in anterior pituitary function with an increased responsiveness to CRH that was associated with an increase in CRH receptors. Although both short- and long-term hypothyroidism was associated with significant decreases in adrenal weights, only long-term hypothyroid rats showed changes in adrenal function with a significant decrease of ACTH-induced corticosterone release from cultured adrenal cells. The data suggest that long-term hypothyroidism is associated with adrenal insufficiency with abnormalities in all three components of the HPA axis. Short-term hypothyroidism, on the other hand, is associated with increased pituitary corticotroph responsiveness to CRH.

  18. Hypothalamic-pituitary-adrenal (HPA) axis functioning in relation to body fat distribution.

    PubMed

    Rutters, Femke; Nieuwenhuizen, Arie G; Lemmens, Sofie G T; Born, Jurriaan M; Westerterp-Plantenga, Margriet S

    2010-06-01

    To relate hypothalamic-pituitary-adrenal (HPA) axis functioning and HPA feedback functioning to body fat distribution in normal weight to obese subjects. 91 men and 103 women [age 18-45 years, BMI 19-35 kg/m(2), waist-to-hip ratio (WHR) 0.6-1.1]. Anthropometry, body composition using hydrodensitometry and deuterium dilution method, cortisol variability by measuring 5-h cortisol concentrations, HPA axis feedback functioning using a dexamethasone suppression test, and HPA axis functioning under a challenged condition consisting of a standardized high-intensity test with ingestion of 4 mg dexamethasone. In men, an inverse relationship was observed between 5-h cortisol exposure (nmol/ml) and fat mass index (FMI) (kg/m(2)) (r = -0.55, P < 0.001). In women, relationships were observed between 5-h cortisol exposure (nmol/ml.min) and WHR (r = -0.49, P < 0.001), maximal workload (r = 0.32, P < 0.001) as well as oral contraceptive use (r = 0.38, P < 0.001). Similarly, in men, an inverse relationship was observed between negative feedback expressed as baseline concentrations minus post dexamethasone cortisol concentrations (nmol/ml) and FMI (r = -0.53, P < 0.001). In women, relationships were observed between negative feedback expressed as baseline concentrations minus post dexamethasone cortisol concentrations (nmol/ml) and WHR (r = -0.43, P < 0.001), maximal workload (r = 0.30, P < 0.001) as well as oral contraceptive use (r = 0.43, P < 0.001) in women. Moreover, an inverse relationship was observed between HPA axis functioning in a challenged condition expressed as percentage increase of cortisol concentrations after standardized high-intensity test with ingestion of 4 mg dexamethasone (%) and waist circumference (r = -0.21, P < 0.10) in men and WHR (r = -0.21, P < 0.05) in women. In men, strong positive relationships were observed between FMI and waist circumference (r = 0.85, P < 0.001), as well as waist-to-hip ratio (r = 0.70, P < 0.001). Disturbance of HPA axis

  19. Fear potentiation is associated with hypothalamic-pituitary-adrenal axis function in PTSD.

    PubMed

    Jovanovic, Tanja; Norrholm, Seth D; Blanding, Nineequa Q; Phifer, Justine E; Weiss, Tamara; Davis, Michael; Duncan, Erica; Bradley, Bekh; Ressler, Kerry

    2010-07-01

    A central problem in posttraumatic stress disorder (PTSD) is the inability to suppress fear under safe conditions. We have previously shown that PTSD patients cannot inhibit conditioned fear. Another relevant finding in PTSD is the hypersensitivity of the hypothalamic-pituitary-adrenal (HPA) axis feedback. Given their common neurobiological pathways, alterations in HPA function in PTSD may be associated with impaired fear inhibition. The present study examined the relationship between HPA axis function and fear-potentiated startle and inhibition of conditioned fear in trauma-exposed individuals. We used a conditional discrimination procedure (AX+/BX-), in which one set of shapes (AX+) was paired with aversive airblasts to the throat (danger signal), and the same X shape with a different shape (BX-) were presented without airblasts (safety signal). The paradigm also included a transfer of fear inhibition test (AB). In addition to fear-potentiated startle, blood was drawn for neuroendocrine analysis and the dexamethasone suppression test (DEX) was performed; cortisol and ACTH were assessed at baseline and post-DEX. Ninety highly traumatized individuals recruited from Grady Hospital in Atlanta, GA participated in the study. The sample was divided into those who met DSM-IV criteria for PTSD (n=29) and Non-PTSD controls (n=61) using the PTSD symptom scale (PSS). Both groups showed significant reduction in cortisol and ACTH levels after DEX. Subjects with PTSD had higher fear-potentiated startle to the safety signal, BX- (F(1,88)=4.44, p<0.05) and fear inhibition trials, AB (F(1,88)=5.20, p<0.05), both indicative of less fear inhibition in the presence of B, compared to control subjects. In addition, fear-potentiated startle to AX+, BX-, and AB was positively correlated with baseline and post-DEX ACTH in PTSD subjects. These results suggest that impaired fear inhibition and associated alterations in HPA feedback may reflect amygdala hyperactivity in subjects with PTSD

  20. The inflamed axis: the interaction between stress, hormones, and the expression of inflammatory-related genes within key structures comprising the hypothalamic-pituitary-adrenal axis.

    PubMed

    Hueston, Cara M; Deak, Terrence

    2014-01-30

    Acute stress increases the expression of cytokines and other inflammatory-related factors in the CNS, plasma, and endocrine glands, and activation of inflammatory signaling pathways within the hypothalamic-pituitary-adrenal (HPA) axis may play a key role in later stress sensitization. In addition to providing a summary of stress effects on neuroimmune changes within the CNS, we present a series of experiments that characterize stress effects on members of the interleukin-1β (IL-1) super-family and other inflammatory-related genes in key structures comprising the HPA axis (PVN, pituitary and adrenal glands), followed by a series of experiments examining the impact of exogenous hormone administration (CRH and ACTH) and dexamethasone on the expression of inflammatory-related genes in adult male Sprague-Dawley rats. The results demonstrated robust, time-dependent, and asynchronous expression patterns for IL-1 and IL-1R2 in the PVN, with substantial increases in IL-6 and COX-2 in the adrenal glands emerging as key findings. The effects of exogenous CRH and ACTH were predominantly isolated within the adrenals. Finally, pretreatment with dexamethasone severely blunted neuroimmune changes in the adrenal glands, but not in the PVN. These findings provide novel insight into the relationship between stress, the expression of inflammatory signaling factors within key structures comprising the HPA axis, and their interaction with HPA hormones, and provide a foundation for better understanding the role of cytokines as modulators of hypothalamic, pituitary and adrenal sensitivity.

  1. Chronic administration of U50,488H fails to produce hypothalamo-pituitary-adrenal axis tolerance in neonatal rats.

    PubMed

    Ignar, D M; Windh, R T; Kuhn, C M

    1992-02-01

    The present study investigated the effect of chronic administration of a kappa opioid receptor agonist on the function of kappa and mu opioid, serotonergic and cholinergic regulation of secretion from the hypothalamo-pituitary-adrenal axis in neonatal rats. After chronic treatment with saline or U50,488H (trans-(+/-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]- benzeneacetamide methane sulfonate), a kappa opioid receptor agonist and subsequent pharmacological challenge, corticosterone (CS) in serum was determined. Kappa tolerance did not develop in pups treated on postnatal days 5-9 with increasing doses of U50,488H (0.5-2.5 mg/kg). When the rats were treated with the same chronic regimen of U50,488H at different stages of development from birth through weaning, only weanling rats became tolerant to U50,488H. In the absence of measurable kappa tolerance, the responses of corticosterone in serum to morphine, quipazine, a serotonin receptor agonist and physostigmine, an inhibitor of acetylcholinesterase, were attenuated in neonatal rats, treated with U50,488H. These studies suggest that kappa tolerance is more difficult to induce in developing rats than in adults and that regulation of the function of the hypothalamo-pituitary-adrenal axis by other neurotransmitter systems is altered by treatment with kappa opioid receptor agonists, even in the apparent absence of tolerance.

  2. Effect of Animal Facility Construction on Basal Hypothalamic-Pituitary-Adrenal and Renin-Aldosterone Activity in the Rat

    PubMed Central

    Bruder, Eric D.; Cullinan, William E.; Ziegler, Dana R.; Cohen, Eric P.

    2011-01-01

    Although loud noise and intense vibration are known to alter the behavior and phenotype of laboratory animals, little is known about the effects of nearby construction. We studied the effect of a nearby construction project on the classic stress hormones ACTH, corticosterone, renin, and aldosterone in rats residing in a barrier animal facility before, for the first 3 months of a construction project, and at 1 month after all construction was completed. During some of the construction, noise and vibrations were not obvious to investigators inside the animal rooms. Body weight matched for age was not altered by nearby construction. During nearby construction, plasma ACTH, corticosterone, and aldosterone were approximately doubled compared with those of pre- and postconstruction levels. Expression of CRH mRNA in the paraventricular nucleus of the hypothalamus, CRH receptor and POMC mRNA in the anterior pituitary, and most mRNAs for steroidogenic genes in the adrenal gland were not significantly changed during construction. We conclude that nearby construction can cause a stress response without long-term effects on hypothalamic-pituitary-adrenal axis gene expression and body weight. PMID:21248141

  3. Maternal cortisol in late pregnancy and hypothalamic-pituitary-adrenal reactivity to psychosocial stress postpartum in women.

    PubMed

    Meinlschmidt, Gunther; Martin, Cyrill; Neumann, Inga D; Heinrichs, Markus

    2010-03-01

    Hypothalamic-pituitary-adrenal (HPA) activity is altered postpartum and has been associated with several puerperal disorders. However, little is known about the association of maternal HPA activity during pregnancy with maternal HPA responsiveness to stress after parturition. Within a longitudinal study with an experimental component, we assessed in 22 women the salivary cortisol awakening response (CAR) at the 36th week of gestation and 6 weeks postpartum, as well as pituitary-adrenal and emotional responses to a psychosocial laboratory stressor at 8 weeks postpartum. CAR in late pregnancy negatively predicted maternal adrenocorticotropin (ACTH; ss = - 0.60; P = 0.003), plasma cortisol (ss = - 0.69, P < 0.001), and salivary cortisol (ss = - 0.66; P = 0.001) but not emotional stress reactivity (all P>0.05) at 8 weeks postpartum, whereas CAR at 6 weeks postpartum failed to predict hormonal (ACTH: ss = 0.02; P = 0.933, plasma cortisol: ss = - 0.23; P = 0.407, salivary cortisol: ss = - 0.15; P = 0.597) or emotional (all P>0.05) stress responses at 8 weeks postpartum. The activity of the HPA axis during pregnancy is associated with maternal HPA responsiveness to stress postpartum. Putative biological underpinnings warrant further attention. A better understanding of stress-related processes peripartum may pave the way for the prevention of associated puerperal disorders.

  4. [Influence of replacement growth hormone therapy (hGH) on pituitary-thyroid and pituitary-adrenal systems in prepubertal children with GH deficiency].

    PubMed

    Vyshnevs'ka, O A; Bol'shova, O V

    2013-06-01

    Today, the most pathogenic therapy of GH deficiency is hGH replacement therapy. Replacement hGH therapy a highly effective method of growth correction in children with GH deficiency, but further investigations are necessary for timely detection of disturbances of other organs and systems. The authors reported that hGH therapy supressed thyroid and adrenal functions. Besides, most patients with GH deficiency have multiple defficiency of pituitary hormones (both TSH and ACTH), so hGH therapy can enhances hypothyroidism and hypoadrenalism. In the Department of Pediatric Endocrinology of the Institute of Endocrinology and Metabolism a great experience was accumulated in the treatment of GH deficiency children and in the study of the efficacy and safety of this treatment.

  5. Effect of cortisol infusion on the pituitary-adrenal axis of the hypothalamo-pituitary-disconnected fetal sheep.

    PubMed

    Antolovich, G C; McMillen, I C; Robinson, P M; Silver, M; Young, I R; Perry, R A

    1992-09-01

    In order to determine whether cortisol acts directly at the level of the fetal pituitary to promote pars distalis corticotroph maturation, we have infused cortisol into the hypothalamo-pituitary-disconnected (HPD) fetal sheep from 111 to 117 days of gestation. In this study we have measured fetal plasma cortisol and immunoreactive adrenocorticotrophic hormone (ir-ACTH) concentrations between 105 and 116 days of gestation, and we have determined the proportions of adult- and fetal-type corticotrophs in the pars distalis of catheter control fetuses and in HPD fetuses infused with either saline (HPD+SAL) or cortisol (2 mg/day; HPD+F). The fetal plasma cortisol concentrations did not change significantly following HPD. The mean fetal plasma cortisol concentration between 113 and 116 days was threefold higher in the HPD+F fetuses than that measured in HPD fetuses. Following HPD, fetal plasma ir-ACTH concentrations were significantly higher than in catheter control fetuses. Despite the significant elevation in plasma cortisol concentrations in HPD+F fetuses between 113 and 116 days, plasma ir-ACTH concentrations were not different in these fetuses from HPD fetuses infused with saline. At 117 days of gestation in HPD+F fetuses, the proportion of fetal-type corticotrophs in the pars distalis was significantly less than in the HPD+SAL fetuses; however, there was no significant change in the proportion of adult-type corticotrophs in the pars distalis following cortisol infusion. We have shown that cortisol has a direct trophic effect on the maturation of the pars distalis corticotrophs; however, the full maturation of these cells requires an intact hypothalamo-pituitary axis. These findings demonstrate the importance of the fetal hypothalamus in anterior pituitary corticotroph maturation during the last third of gestation.

  6. Involvement of the adrenal glands and testis in gap junction formation via testosterone within the male rat anterior pituitary gland.

    PubMed

    Sakuma, Eisuke; Wada, Ikuo; Otsuka, Takanobu; Wakabayashi, Kenjiro; Ito, Kinya; Soji, Tsuyoshi; Herbert, Damon C

    2012-12-01

    We investigated the influence of testicular and adrenal androgens on the presence of gap junctions between folliculo-stellate cells in the anterior pituitary glands of 60-day-old Wistar-Imamichi strain male rats. The animals were separated into six groups: Group A served as the controls and had free access to a normal diet and water, Group B was given a normal diet and 0.9% NaCl for their drinking water as the controls of adrenalectomized groups, Group C was castrated, Group D was adrenalectomized, Group E was both castrated and adrenalectomized, and Group F was also both castrated and adrenalectomized. In addition, the animals of Group F were administered a dose of testosterone that is known to produce high physiological levels of the hormones in plasma. Five rats from each group were sacrificed 1, 2, 3, 4, 5, 6, and 7 days after their respective operation, and the anterior pituitary glands were removed and prepared for observation by transmission electron microscopy. We quantified the number of follicles and gap junctions and calculated the rate of occurrence as the ratio of the number of gap junctions existing between folliculo-stellate cells per intersected follicle profile. Simultaneous removal of adrenal glands with castration resulted in a significantly decrease in the number of gap junctions, whereas the administration of testosterone to these rats compensated for this change. These observations indicate that the preservation of gap junctions between folliculo-stellate cells is mainly dependent on androgens from both the testes and adrenal glands in adult male rats. Copyright © 2012 Wiley Periodicals, Inc.

  7. Effects of oral megestrol acetate administration on the hypothalamic-pituitary-adrenal axis of male bottlenose dolphins (Tursiops truncatus).

    PubMed

    Houser, Dorian S; Champagne, Cory D; Jensen, Eric D; Smith, Cynthia R; Cotte, Lara S; Meegan, Jenny M; Booth, Rebecca K; Wasser, Samuel K

    2017-07-15

    OBJECTIVE To evaluate the impact of oral megestrol acetate (MA) administration on adrenal function in male bottlenose dolphins (Tursiops truncatus). DESIGN Serial cross-sectional study. ANIMALS 8 adult male dolphins, all of which were receiving MA at various daily doses (range, 0 to 60 mg, PO) for the control of reproductive behavior. PROCEDURES Blood samples were collected every 2 weeks for 1 year from dolphins trained to voluntarily provide them. Cortisol, ACTH, and other hormone concentrations were measured in serum or plasma via radioimmunoassay or ELISA. Fecal samples, also provided by dolphins voluntarily, were assayed for glucocorticoid metabolite concentrations. Effects of daily MA dose on hormone concentrations were evaluated. RESULTS Daily MA doses as low as 10 mg strongly suppressed cortisol secretion in nearly all dolphins, and except for a single measurement, no dolphin had measurable serum concentrations at doses ≥ 20 mg. Variations in serum cortisol concentration were unrelated to season but were directly related to ACTH concentrations, suggesting primary effects upstream of the adrenal gland. Cessation of MA administration resulted in almost immediate restoration of measurable serum cortisol concentrations, although concentrations continued to rise in a few dolphins over the following weeks to months. CONCLUSIONS AND CLINICAL RELEVANCE Caution should be exercised when administering MA to control reproductive behavior in male dolphins. Because the hypothalamic-pituitary-adrenal axis appeared to be sensitive to even small doses of MA in dolphins, duration of treatment may be the most critical consideration.

  8. Multiple endocrine neoplasia type 1 knockout mice develop parathyroid, pancreatic, pituitary and adrenal tumours with hypercalcaemia, hypophosphataemia and hypercorticosteronaemia

    PubMed Central

    Harding, Brian; Lemos, Manuel C; Reed, Anita A C; Walls, Gerard V; Jeyabalan, Jeshmi; Bowl, Michael R; Tateossian, Hilda; Sullivan, Nicky; Hough, Tertius; Fraser, William D; Ansorge, Olaf; Cheeseman, Michael T; Thakker, Rajesh V

    2009-01-01

    Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized in man by parathyroid, pancreatic, pituitary and adrenal tumours. The MEN1 gene encodes a 610-amino acid protein (menin) which is a tumour suppressor. To investigate the in vivo role of menin, we developed a mouse model, by deleting Men1 exons 1 and 2 and investigated this for MEN1-associated tumours and serum abnormalities. Men1+/− mice were viable and fertile, and 220 Men1+/− and 94 Men1+/+ mice were studied between the ages of 3 and 21 months. Survival in Men1+/− mice was significantly lower than in Men1+/+ mice (<68% vs >85%, P<0.01). Men1+/− mice developed, by 9 months of age, parathyroid hyperplasia, pancreatic tumours which were mostly insulinomas, by 12 months of age, pituitary tumours which were mostly prolactinomas, and by 15 months parathyroid adenomas and adrenal cortical tumours. Loss of heterozygosity and menin expression was demonstrated in the tumours, consistent with a tumour suppressor role for the Men1 gene. Men1+/− mice with parathyroid neoplasms were hypercalcaemic and hypophosphataemic, with inappropriately normal serum parathyroid hormone concentrations. Pancreatic and pituitary tumours expressed chromogranin A (CgA), somatostatin receptor type 2 and vascular endothelial growth factor-A. Serum CgA concentrations in Men1+/− mice were not elevated. Adrenocortical tumours, which immunostained for 3-β-hydroxysteroid dehydrogenase, developed in seven Men1+/− mice, but resulted in hypercorticosteronaemia in one out of the four mice that were investigated. Thus, these Men1+/− mice are representative of MEN1 in man, and will help in investigating molecular mechanisms and treatments for endocrine tumours. PMID:19620250

  9. Caffeine-induced activated glucocorticoid metabolism in the hippocampus causes hypothalamic-pituitary-adrenal axis inhibition in fetal rats.

    PubMed

    Xu, Dan; Zhang, Benjian; Liang, Gai; Ping, Jie; Kou, Hao; Li, Xiaojun; Xiong, Jie; Hu, Dongcai; Chen, Liaobin; Magdalou, Jacques; Wang, Hui

    2012-01-01

    Epidemiological investigations have shown that fetuses with intrauterine growth retardation (IUGR) are susceptible to adult metabolic syndrome. Clinical investigations and experiments have demonstrated that caffeine is a definite inducer of IUGR, as children who ingest caffeine-containing food or drinks are highly susceptible to adult obesity and hypertension. Our goals for this study were to investigate the effect of prenatal caffeine ingestion on the functional development of the fetal hippocampus and the hypothalamic-pituitary-adrenal (HPA) axis and to clarify an intrauterine HPA axis-associated neuroendocrine alteration induced by caffeine. Pregnant Wistar rats were intragastrically administered 20, 60, and 180 mg/kg · d caffeine from gestational days 11-20. The results show that prenatal caffeine ingestion significantly decreased the expression of fetal hypothalamus corticotrophin-releasing hormone. The fetal adrenal cortex changed into slight and the expression of fetal adrenal steroid acute regulatory protein (StAR) and cholesterol side-chain cleavage enzyme (P450scc), as well as the level of fetal adrenal endogenous corticosterone (CORT), were all significantly decreased after caffeine treatment. Moreover, caffeine ingestion significantly increased the levels of maternal and fetal blood CORT and decreased the expression of placental 11β-hydroxysteroid dehydrogenase-2 (11β-HSD-2). Additionally, both in vivo and in vitro studies show that caffeine can downregulate the expression of fetal hippocampal 11β-HSD-2, promote the expression of 11β-hydroxysteroid dehydrogenase 1 and glucocorticoid receptor (GR), and enhance DNA methylation within the hippocampal 11β-HSD-2 promoter. These results suggest that prenatal caffeine ingestion inhibits the development of the fetal HPA axis, which may be associated with the fetal overexposure to maternal glucocorticoid and activated glucocorticoid metabolism in the fetal hippocampus. These results will be beneficial in

  10. Do topical ophthalmic corticosteroids suppress the hypothalmic-pituitary-adrenal axis in post-penetrating keratoplasty patients?

    PubMed Central

    Sandhu, S S; Smith, J M; Doherty, M; James, A; Figueiredo, F C

    2012-01-01

    Purpose To establish whether hypothalmic-pituitary-adrenal axis suppression is possible secondary to long-term topical ophthalmic corticosteroid use in patients who have undergone penetrating keratoplasty (PKP). Methods Patients who had undergone a PKP and had been using corticosteroid-based eye drops continuously for more than 6 months, with no history of concomitant steroid (oral, inhaled, or cutaneous) use, were included within the study. A low-dose short Synacthen (LDSST) test was performed in each patient followed later by a short Synacthen test (SST). The mean SST and LDSST after 30 min were calculated along with their corresponding 95% confidence intervals (CIs). Correlation between both baseline SST and baseline LDSST with duration of treatment was determined using Spearman's correlation. Results In all, 20 patients were included within the study. The mean duration treatment was 28.2 months (range 11–96 months). All patients had normal baseline cortisol levels in both SST and LDSST tests. The mean 30 min SST was 753.8 nmol/l (95%CI: 696.6 nmol/l, 811.0 nmol/l) and no patients displayed inadequate adrenal response. The mean 30 min LDSST was 709.8 nmol/l (95%CI: 665.1 nmol/l, 754.5 nmol/l) and only one patient had an inadequate adrenal response. There was no correlation between baseline SST or LDSST and duration of treatment. Conclusions This study found no evidence that patients using continuous long-term corticosteroid eye drops after PKP experienced inadequate adrenal response. We did not find any evidence of a negative correlation between length of treatment and SST or LDSST measurements at baseline. PMID:22344184

  11. Baseline morning cortisol level as a predictor of pituitary-adrenal reserve: a comparison across three assays.

    PubMed

    Sbardella, Emilia; Isidori, Andrea M; Woods, Conor P; Argese, Nicola; Tomlinson, Jeremy W; Shine, Brian; Jafar-Mohammadi, Bahram; Grossman, Ashley B

    2017-02-01

    The short ACTH stimulation test (250 μg) is the dynamic test most frequently used to assess adrenal function. It is possible that a single basal cortisol could be used to predict the dynamic response, but research has been hampered by the use of different assays and thresholds. To propose a morning baseline cortisol criterion of three of the most commonly used modern cortisol immunoassays - Advia Centaur (Siemens), Architect (Abbott) and the Roche Modular System (Roche) - that could predict adrenal sufficiency. Observational, retrospective cross-sectional study at two centres. Retrospective analysis of the results of 1019 Short Synacthen tests (SSTs) with the Advia Centaur, 449 SSTs with the Architect and 2050 SSTs with the Roche Modular System assay. Serum cortisol levels were measured prior to injection of 250 μg Synacthen and after 30 min. Overall, we were able to collate data from a total of 3518 SSTs in 3571 patients. Using receiver-operator curve analysis, baseline cortisol levels for predicting passing the SST with 100% specificity were 358 nmol/l for Siemens, 336 nmol/l for Abbott and 506 nmol/l for Roche. Utilizing these criteria, 589, 158 and 578 SSTs, respectively, for Siemens, Abbott and Roche immunoassays could have been avoided. We have defined assay-specific morning cortisol levels that are able to predict the integrity of the hypothalamo-pituitary-adrenal axis. We propose that this represents a valid tool for the initial assessment of adrenal function and has the potential to obviate the need for dynamic testing in a significant number of patients. © 2016 John Wiley & Sons Ltd.

  12. Caffeine-Induced Activated Glucocorticoid Metabolism in the Hippocampus Causes Hypothalamic-Pituitary-Adrenal Axis Inhibition in Fetal Rats

    PubMed Central

    Xu, Dan; Zhang, Benjian; Liang, Gai; Ping, Jie; Kou, Hao; Li, Xiaojun; Xiong, Jie; Hu, Dongcai; Chen, Liaobin; Magdalou, Jacques; Wang, Hui

    2012-01-01

    Epidemiological investigations have shown that fetuses with intrauterine growth retardation (IUGR) are susceptible to adult metabolic syndrome. Clinical investigations and experiments have demonstrated that caffeine is a definite inducer of IUGR, as children who ingest caffeine-containing food or drinks are highly susceptible to adult obesity and hypertension. Our goals for this study were to investigate the effect of prenatal caffeine ingestion on the functional development of the fetal hippocampus and the hypothalamic-pituitary-adrenal (HPA) axis and to clarify an intrauterine HPA axis-associated neuroendocrine alteration induced by caffeine. Pregnant Wistar rats were intragastrically administered 20, 60, and 180 mg/kg·d caffeine from gestational days 11–20. The results show that prenatal caffeine ingestion significantly decreased the expression of fetal hypothalamus corticotrophin-releasing hormone. The fetal adrenal cortex changed into slight and the expression of fetal adrenal steroid acute regulatory protein (StAR) and cholesterol side-chain cleavage enzyme (P450scc), as well as the level of fetal adrenal endogenous corticosterone (CORT), were all significantly decreased after caffeine treatment. Moreover, caffeine ingestion significantly increased the levels of maternal and fetal blood CORT and decreased the expression of placental 11β-hydroxysteroid dehydrogenase-2 (11β-HSD-2). Additionally, both in vivo and in vitro studies show that caffeine can downregulate the expression of fetal hippocampal 11β-HSD-2, promote the expression of 11β-hydroxysteroid dehydrogenase 1 and glucocorticoid receptor (GR), and enhance DNA methylation within the hippocampal 11β-HSD-2 promoter. These results suggest that prenatal caffeine ingestion inhibits the development of the fetal HPA axis, which may be associated with the fetal overexposure to maternal glucocorticoid and activated glucocorticoid metabolism in the fetal hippocampus. These results will be beneficial in

  13. Characterization of CRF, AVT, and ACTH cDNA and pituitary-adrenal axis function in Japanese quail divergently selected for tonic immobility.

    PubMed

    Hazard, D; Couty, M; Guémené, D

    2007-09-01

    Higher corticosterone (CORT) responses to acute stress have previously been reported in quail selected for short (STI) duration of tonic immobility (TI) than for long TI (LTI), although behavioral studies indicated that LTI quail were more fearful. To investigate adrenal and pituitary function in these quail lines and their possible involvement in the differences in hypothalamic-pituitary-adrenal (HPA) axis reactivity, we measured CORT responses to adrenocorticotropin (1-24 ACTH), corticotropin-releasing factor (CRF), and arginine vasotocin (AVT) after characterizing the nucleotide acid sequences of these peptides in quail. Although maximum adrenal responses, assessed by ACTH challenge, were higher in STI quail, adrenal sensitivity was comparable for the two genotypes. It is therefore unlikely that differences in HPA axis reactivity involved the adrenal level. AVT and ACTH induced comparable CORT responses in both genotypes, whereas those induced by CRF were much lower. AVT is thus more potent than CRF in quail, but the respective maximum pituitary capacity of both genotypes to secrete ACTH was similar, and it is doubtful that the AVT pathway is involved in the difference in HPA axis reactivity between genotypes. On the other hand, the higher CORT responses induced by CRF in STI quail suggest that CRF might be involved in the differences in HPA axis reactivity between LTI and STI genotypes.

  14. Ketamine and Etomidate Down-regulate the Hypothalamic-Pituitary-Adrenal Axis in an Endotoxemic Mouse Model.

    PubMed

    Besnier, Emmanuel; Clavier, Thomas; Tonon, Marie-Christine; Selim, Jean; Lefevre-Scelles, Antoine; Morin, Fabrice; Tamion, Fabienne; Dureuil, Bertrand; Castel, Hélène; Compere, Vincent

    2017-08-01

    We compared the effects of etomidate and ketamine on the hypothalamic-pituitary-adrenal axis during sepsis. Mice (n = 5/group) were injected intraperitoneally with lipopolysaccharide (10 mg/kg) and 6 h later randomized to receive ketamine (100 mg/kg), etomidate (30 mg/kg), or saline. At two time points (12 and 48 h), messenger RNA levels of hypothalamic corticotropin-releasing hormone, pituitary proopiomelanocortin, and four adrenal enzymes (P450 side-chain cleavage, 3β-hydroxysteroid deshydrogenase, 21-hydroxylase, and 11β-hydroxylase) were measured by in situ hybridization (results are presented as optical density), and plasma levels of corticosterone and adrenocorticotropin hormones were measured by enzyme-linked immunosorbent assay (mean ± SD). At 12 h, lipopolysaccharide induced an overexpression of corticotropin-releasing hormone (32 ± 5 vs. 18 ± 6, P < 0.01), proopiomelanocortin (21 ± 3 vs. 8 ± 0.9, P < 0.0001), P450 side-chain cleavage (32 ± 4 vs. 23 ± 10, P < 0.05), 21-hydroxylase (17 ± 5 vs. 12 ± 2, P < 0.05), and 11β-hydroxylase (11 ± 4 vs. 6 ± 0.5, P = 0.001), and an elevation of corticosterone (642 ± 165 vs. 98.3 ± 63 ng/ml, P < 0.0001). Etomidate and ketamine reduced P450 side-chain cleavage (19 ± 7 and 19 ± 3 vs. 32 ± 4, P < 0.01), 21-hydroxylase (8 ± 0.8 and 8 ± 1 vs. 17 ± 5, P < 0.001), 11β-hydroxylase (4 ± 0.5 and 7 ± 1 vs. 11 ± 4, P < 0.001 and P < 0.05), and corticosterone (413 ± 189 and 260 ± 161 vs. 642 ± 165 ng/ml, P < 0.05 and P < 0.01). Ketamine also inhibited adrenocorticotropin hormone production (2.5 ± 3.6 vs. 36 ± 15 pg/ml, P < 0.05). At 48 h, all four adrenal enzymes were down-regulated by lipopolysaccharide administration with corticosterone levels similar to the control group. Ketamine and etomidate did not modify corticosterone plasma levels. Our endotoxemic model induces an initial

  15. Bone loss is more severe in primary adrenal than in pituitary-dependent Cushing's syndrome.

    PubMed

    Minetto, M; Reimondo, G; Osella, G; Ventura, M; Angeli, A; Terzolo, M

    2004-11-01

    Either exogenous or endogenous glucocorticoid excess is an established cause of osteoporosis and fractures. Glucocorticoids exert their negative effects on bone through mechanisms that are not yet completely elucidated; however, as many as 50% of patients with Cushing's syndrome suffer from osteoporosis. Bone loss induced by glucocorticoids is potentially reversible after resolution of glucocorticoid excess. It is presently unknown if Cushing's disease (CD) sustained by a pituitary ACTH-producing adenoma and adrenal-dependent Cushing's syndrome (ACS) sustained by an adrenocortical adenoma have a different potential of inducing osteopenia. The aim of the present study was to retrospectively analyze bone mineral density (BMD) in 26 patients with CD (4 men, 22 women, aged 14-79 years), 12 patients with ACS (4 men, 8 women, aged 32-79 years) and 38 healthy subjects carefully matched for sex, age and body mass index (BMI). Measurement of BMD was performed by dual-energy X-ray absorptiometry (DXA) using the Hologic QDR 4500 W instrument. Data were analyzed using absolute BMD values (g/cm2), T-score and Z-score referred to the manufacturer's normative data for the lumbar spine and to the NHANES III dataset for the hip. The patients with CD and ACS were comparable for age, BMI, estimated duration of disease, urinary free cortisol (UFC) levels, midnight serum cortisol and gonadal function. The analysis of variance demonstrated that lumbar bone densitometric parameters were significantly different among the three groups. They were more reduced in patients with ACS (BMD, 0.76+/-0.03 g/cm2; T-score, -2.78+/-0.28; Z-score, -2.25+/-0.30) while patients with CD (BMD, 0.87+/-0.02 g/cm2; T-score, -1.74+/-0.24; Z-score, -0.99+/-0.32) showed DXA values between the first group and controls (BMD, 1.02+/-0.02 g/cm2; T-score, -0.35+/-0.19; Z-score, 0.33+/-0.16). The difference in BMD at the spine remained statistically significant ( P=0.04) after adjustment for the non

  16. Long-term effects of allogeneic bone marrow transplantation (BMT) on pituitary, gonad, thyroid and adrenal function in adults.

    PubMed

    Kauppila, M; Koskinen, P; Irjala, K; Remes, K; Viikari, J

    1998-08-01

    To evaluate the late-effects of allogeneic bone marrow transplantation (BMT) on endocrine function 20 adults (10 females, 10 males) with hematological malignancies were studied after a mean of 3.2 years (range 1.0-10.0) following BMT. The mean age of patients at the time of BMT was 39 years. Dynamic tests of the hypothalamic-pituitary axis included growth hormone releasing hormone (GHRH), gonadotropin releasing hormone (GnRH) and thyrotropin releasing hormone (TRH) stimulations with measurements of serum growth hormone (GH), follicle stimulating hormone (FSH), luteinizing hormone (LH), thyrotropin (TSH) and prolactin (PRL) responses. Adrenal function was assessed with the adrenocorticotropin (ACTH) test. Five patients (25%) had a subnormal GH response to GHRH stimulation, but all had a normal serum insulin-like growth factor I (IGF-I) value. There was an inverse nonlinear relationship between the body mass index (BMI; kg/m2) and GH response but no relation between the GH response and total body irradiation (TBI), intrathecal treatment or occurrence of graft-versus-host disease. In females, serum FSH and LH basal levels and responses to GnRH, in spite of oestrogen substitution therapy in 9/10 patients, indicated ovarian failure and early menopause. Most responses to GnRH were delayed. All males had elevated serum basal FSH levels indicating damage in seminiferous tubulus and infertility. Serum basal LH was elevated only in four males but testosterone values were all within normal limits. However, the mean free androgen index (FAI) was in the low normal range, and two subjects had abnormally low FAI. Serum free thyroxine (fT4) levels were normal in all but one, but an exaggerated TSH response to TRH occurred in seven patients (35%). Four of them had received TBI and one total nodal irradiation suggesting radiation-induced damage to the thyroid gland. In 19 of the 20 patients, adrenal function judged with ACTH test was normal. We conclude that functional impairments

  17. [The relationship of ultrastructure and function of hypothalamus-pituitary-adrenal axis in early stage of sepsis in rats].

    PubMed

    Zhang, Yu-xiang; Li, Hong-shan; Ma, Peng-lin

    2011-05-01

    To observe the changes in ultrastructure and function of hypothalamic-pituitary-adrenal axis (HPAA), and to approach the relationship between them in early stage of sepsis in rats. Thirty male Sprague-Dawley (SD) rats were randomly divided into normal control group, sham group, sepsis group. The sepsis model was reproduced by cecal ligation and puncture (CLP). The rats were sacrificed after collection of blood at 6 hours after CLP, and the levels of adrenocorticotropic hormone (ACTH) and corticosterone (CORT) in the plasma, and the corticotropin release hormone (CRH) in the tissue of hypothalamus were detected. The histopathological changes in HPAA were observed with transmission electron microscopy. The levels of ACTH and CORT in plasma, and the CRH in hypothalamus tissue of sepsis group were increased in the early stage of sepsis compared with the normal control group or sham group [ACTH (pmol/L): 5.78±0.36 vs. 1.94±0.31, 2.51±0.10; CORT (nmol/L): 88.48±4.47 vs. 22.02±1.62, 34.20±2.51; CRH (μg/L): 101.92±6.61 vs. 61.65±6.05, 66.65±4.03, P<0.05 or P<0.01]. The changes in ultrastructure of the hypothalamus, pituitary and adrenal were also found. In sepsis group, the ultrastructure of hypothalamus was as follows. Rough endoplasmic reticulum expansion and degranulation of rough endoplasmic reticulum, and swelling of Golgi complex were found. A large number of endocrine granules could be seen in ATCH cells in the pituitary with depletion of adrenal lipid droplets. In septic rats, the HPAA was excessively activated, and ACTH and CORT in plasma, and CRH in hypothalamus were significantly increased in early stage of sepsis. The changes in ultrastructure of HPAA were obvious, and the change in function was closely related to the ultrastructural changes.

  18. The peptide ACTH(1-39), adrenal growth and steroidogenesis in the sheep fetus after disconnection of the hypothalamus and pituitary.

    PubMed Central

    Phillips, I D; Ross, J T; Owens, J A; Young, I R; McMillen, I C

    1996-01-01

    1. We have investigated the role of the fetal hypothalamo-pituitary axis in the control of adrenocortical growth and steroidogenesis in the sheep fetus during late gestation. Plasma concentrations of ACTH(1-39) increased between 120-125 and 136-142 days (P < 0.05), but did not change after surgical disconnection of the fetal hypothalamus and pituitary (HPD) at 106-120 days gestation. There was no effect of either gestational age or HPD on the circulating concentrations of the ACTH-containing precursors pro-opiomelanocortin (POMC) and pro-ACTH (the 22 kDa N-terminal portion of POMC). 2. In the fetal sheep adrenal, the relative abundance of the mRNAs of the steroidogenic enzymes CYPIIA1 and CYP21A1 increased between 130-135 and 136-140 days gestation (P < 0.05) and remained high after 141 days, whereas that of CYP17 mRNA increased after 141 days gestation (P < 0.05). The abundance of adrenal 3 beta-HSD mRNA did not change between 130 and 145 days. 3. Hypothalamo-pituitary disconnection significantly reduced the abundance of of CYPIIA1 mRNA, 3 beta-HSD mRNA and CYP17 mRNA by 3.4, 3.1 and 3.7 times, respectively, at 140-142 days gestation (P < 0.05). 4. In the intact group of fetal sheep, adrenal weight increased between 130-135 and 141-145 days (P < 0.05), but there was no change in the abundance of adrenal insulin-like growth factor II (IGF-II) mRNA across this gestational age range. Hypothalamo-pituitary disconnection significantly reduced fetal adrenal weight to 66% that of intact sheep (P < 0.01), but did not alter the abundance of IGF-II mRNA in the fetal adrenal at 140-142 days. 5. Our results suggest that the prepartum changes in adrenal growth and steroidogenesis are under the control of an intact hypothalamo-pituitary axis in late gestation and are dependent on an increase in circulating ACTH(1-39), rather than on ACTH precursors. We have found no evidence, however, for a direct-relationship between fetal adrenal growth or steroidogenesis and adrenal IGF-II m

  19. Prematurity, Birth Weight, and Socioeconomic Status Are Linked to Atypical Diurnal Hypothalamic-Pituitary-Adrenal Axis Activity in Young Adults.

    PubMed

    Winchester, Suzy Barcelos; Sullivan, Mary C; Roberts, Mary B; Granger, Douglas A

    2016-02-01

    In a prospective, case-controlled longitudinal design, 180 preterm and fullterm infants who had been enrolled at birth participated in a comprehensive assessment battery at age 23. Of these, 149 young adults, 34 formerly full-term and 115 formerly preterm (22 healthy preterm, 48 with medical complications, 21 with neurological complications, and 24 small for gestational age) donated five saliva samples from a single day that were assayed for cortisol to assess diurnal variation of the hypothalamic-pituitary-adrenal (HPA) axis. Analyses were conducted to determine whether prematurity category, birth weight, and socioeconomic status were associated with differences in HPA axis function. Pre- and perinatal circumstances associated with prematurity influenced the activity of this environmentally sensitive physiological system. Results are consistent with the theory of Developmental Origins of Health and Disease and highlight a possible mechanism for the link between prematurity and health disparities later in life.

  20. [The hypothalamic-pituitary-adrenal axis, and reproductive system activity changing of female rats with prenatal stress during aging].

    PubMed

    Shamolina, T S; Pivina, S G; Ordian, N E

    2009-09-01

    The effect of female rat daily 1-hour immobilization in the period from the 15th to the 18th gestation days on the sex steroid secretion subject to estrous cycle, hypothalamic-pituitary-adrenal axis (HPA) activity and its sensitivity to regulatory signals based on the mechanism of negative feedback in ternale offspring during different ontogenesis stages, was studied. It has been shown that prenatal stress causes significant reproductive system activity disturbances, leading to a significant decrease in the HPA sensitivity to feedback signal in aging female rats. The obtained data indicate a modifying influence of mothers' stress on changing of female rat reproductive functions during aging together with influence on significant decrease in efficiency of HPAs' feedback path.

  1. Childhood adversity and allostatic overload of the hypothalamic-pituitary-adrenal axis: a vulnerability model for depressive disorders.

    PubMed

    Wilkinson, Paul O; Goodyer, Ian M

    2011-11-01

    Childhood adversity is associated with increased risk for onset of depressive episodes. This review will present evidence that allostatic overload of the hypothalamic-pituitary-adrenal axis (HPAA) partially mediates this association. The HPAA is the physiological system that regulates levels of the stress hormone cortisol. First, data from animals and humans has shown that early environmental adversity is associated with long-term dysregulation of the HPAA. This may occur due to permanent epigenetic modification of the glucocorticoid receptor. Second, data from humans has demonstrated that HPAA dysregulation is associated with increased risk of future depression onset in healthy individuals, and pharmacological correction of HPAA dysregulation reduces depressive symptoms. HPAA dysregulation may result in corticoid-mediated abnormalities in neurogenesis in early life and/or neurotoxicity on neural systems that subserve emotion and cognition.

  2. The hypothalamic-pituitary-adrenal axis and sex hormones in chronic stress and obesity: pathophysiological and clinical aspects.

    PubMed

    Pasquali, Renato

    2012-08-01

    Obesity, particularly the abdominal phenotype, has been ascribed to an individual maladaptation to chronic environmental stress exposure mediated by a dysregulation of related neuroendocrine axes. Alterations in the control and action of the hypothalamic-pituitary-adrenal axis play a major role in this context, with the participation of the sympathetic nervous system. The ability to adapt to chronic stress may differ according to sex, with specific pathophysiological events leading to the development of stress-related chronic diseases. This seems to be influenced by the regulatory effects of sex hormones, particularly androgens. Stress may also disrupt the control of feeding, with some differences according to sex. Finally, the amount of experimental data in both animals and humans may help to shed more light on specific phenotypes of obesity, strictly related to the chronic exposure to stress. This challenge may potentially imply a different pathophysiological perspective and, possibly, a specific treatment. © 2012 New York Academy of Sciences.

  3. Early-life glucocorticoid exposure: the hypothalamic-pituitary-adrenal axis, placental function, and long-term disease risk.

    PubMed

    Braun, Thorsten; Challis, John R; Newnham, John P; Sloboda, Deborah M

    2013-12-01

    An adverse early-life environment is associated with long-term disease consequences. Adversity early in life is hypothesized to elicit developmental adaptations that serve to improve fetal and postnatal survival and prepare the organism for a particular range of postnatal environments. These processes, although adaptive in their nature, may later prove to be maladaptive or disadvantageous if the prenatal and postnatal environments are widely discrepant. The exposure of the fetus to elevated levels of either endogenous or synthetic glucocorticoids is one model of early-life adversity that contributes substantially to the propensity of developing disease. Moreover, early-life glucocorticoid exposure has direct clinical relevance because synthetic glucocorticoids are routinely used in the management of women at risk of early preterm birth. In this regard, reports of adverse events in human newborns have raised concerns about the safety of glucocorticoid treatment; synthetic glucocorticoids have detrimental effects on fetal growth and development, childhood cognition, and long-term behavioral outcomes. Experimental evidence supports a link between prenatal exposure to synthetic glucocorticoids and alterations in fetal development and changes in placental function, and many of these alterations appear to be permanent. Because the placenta is the conduit between the maternal and fetal environments, it is likely that placental function plays a key role in mediating effects of fetal glucocorticoid exposure on hypothalamic-pituitary-adrenal axis development and long-term disease risk. Here we review recent insights into how the placenta responds to changes in the intrauterine glucocorticoid environment and discuss possible mechanisms by which the placenta mediates fetal hypothalamic-pituitary-adrenal development, metabolism, cardiovascular function, and reproduction.

  4. Adverse Effects of Two Nights of Sleep Restriction on the Hypothalamic-Pituitary-Adrenal Axis in Healthy Men

    PubMed Central

    Guyon, A.; Balbo, M.; Morselli, L. L.; Tasali, E.; Leproult, R.; L'Hermite-Balériaux, M.; Van Cauter, E.

    2014-01-01

    Context: Insufficient sleep is associated with increased cardiometabolic risk. Alterations in hypothalamic-pituitary-adrenal axis may underlie this link. Objective: Our objective was to examine the impact of restricted sleep on daytime profiles of ACTH and cortisol concentrations. Methods: Thirteen subjects participated in 2 laboratory sessions (2 nights of 10 hours in bed versus 2 nights of 4 hours in bed) in a randomized crossover design. Sleep was polygraphically recorded. After the second night of each session, blood was sampled at 20-minute intervals from 9:00 am to midnight to measure ACTH and total cortisol. Saliva was collected every 20 minutes from 2:00 pm to midnight to measure free cortisol. Perceived stress, hunger, and appetite were assessed at hourly intervals by validated scales. Results: Sleep restriction was associated with a 19% increase in overall ACTH levels (P < .03) that was correlated with the individual amount of sleep loss (rSp = 0.63, P < .02). Overall total cortisol levels were also elevated (+21%; P = .10). Pulse frequency was unchanged for both ACTH and cortisol. Morning levels of ACTH were higher after sleep restriction (P < .04) without concomitant elevation of cortisol. In contrast, evening ACTH levels were unchanged while total and free cortisol increased by, respectively, 30% (P < .03) and 200% (P < .04). Thus, the amplitude of the circadian cortisol decline was dampened by sleep restriction (−21%; P < .05). Sleep restriction was not associated with higher perceived stress but resulted in an increase in appetite that was correlated with the increase in total cortisol. Conclusion: The impact of sleep loss on hypothalamic-pituitary-adrenal activity is dependent on time of day. Insufficient sleep dampens the circadian rhythm of cortisol, a major internal synchronizer of central and peripheral clocks. PMID:24823456

  5. Effects of corticotropin-releasing factor 1 receptor antagonism on the hypothalamic-pituitary-adrenal axis of rodents.

    PubMed

    Gehlert, Donald R; Cramer, Jeffrey; Morin, S Michelle

    2012-06-01

    Corticotropin-releasing factor (CRF) is the major hypothalamic neuropeptide responsible for stimulation of the hypothalamic-pituitary-adrenal axis (HPAA), resulting in the synthesis and release of glucocorticoids from the adrenal cortex. In a recent study, we reported the discovery of the CRF1 receptor antagonist, 3-(4-chloro-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethylpropyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (MTIP), which has efficacy in preclinical models of stress-induced alcohol consumption. Because CRF1 is important in HPAA activation, we evaluated the effects of MTIP administration on rodent HPAA function. Initial studies established the MTIP doses required for brain and pituitary CRF1 occupancy and those associated with the inhibition of intracerebroventricular CRF on the HPAA in mice. Then, rat basal plasma corticosterone (CORT) concentrations were measured hourly by radioimmunoassay for 24 h after three daily doses of MTIP or vehicle. In these studies, the early phase of the nocturnal CORT surge was reduced; however, the area under the CORT curve was identical for the 24-h period. In subsequent studies, increases in plasma CORT due to direct pharmacological manipulation of the HPAA axis or by stressors were evaluated after MTIP treatment in mice. MTIP attenuated CORT responses generated by immediate bolus administration of insulin or ethanol; however, MTIP did not affect activation of the HPAA by other stressors and pharmacological agents. Therefore, MTIP can modulate basal HPAA activity during the CORT surge and reduced activation after a select number of stressors but does not produce a lasting suppression of basal CORT. The ability of MTIP to modulate plasma CORT after hyperinsulinemia may provide a surrogate strategy for a target occupancy biomarker.

  6. The effect of trans-resveratrol on post-stroke depression via regulation of hypothalamus-pituitary-adrenal axis.

    PubMed

    Pang, Cong; Cao, Liang; Wu, Fan; Wang, Li; Wang, Gang; Yu, Yingcong; Zhang, Meixi; Chen, Lichao; Wang, Weijie; Lv, Weihong; Chen, Ling; Zhu, Jiejin; Pan, Jianchun; Zhang, Hanting; Xu, Ying; Ding, Lianshu

    2015-10-01

    Post-stroke depression (PSD) occurs about 40% among all stroke survivors, but the effective pharmacotherapy is inadequately understood. The present study investigated the effects of a natural polyphenol trans-resveratrol (RES) on behavioral changes after middle cerebral artery occlusion (MCAO) and examined what its molecular targets may be. RES was shown to decrease the infarct size and neurological scores after MCAO, suggesting the amelioration of brain damage and motor activity. RES also reversed the depressive-like behaviors 13 days after MCAO, both in the forced swimming and sucrose consumption tests. Moreover, MCAO-induced series abnormalities related to depressive-like behaviors, such as an abnormal adrenal gland weight to body weight ratio, an increased expression of the corticotropin-releasing factor (CRF) in the frontal cortex, hippocampus and hypothalamus, the differential expression of glucocorticoid receptor (GR) in these three brain regions, and a decreased brain-derived neurotrophic factor (BDNF) level, were ameliorated after treatment with increasing doses of RES at 10, 20 and 40 mg/kg via gavage. These findings provide compelling evidence that RES protects the brain against focal cerebral ischemia-induced injury, but most of all is its antidepressant-like effect on PSD, which might at least in part be mediated by regulation of hypothalamus-pituitary-adrenal axis function. Copyright © 2015 Elsevier Ltd. All rights reserved.

  7. Facilitation of hypothalamic-pituitary-adrenal responses to novel stress following repeated social stress using the resident/intruder paradigm.

    PubMed

    Bhatnagar, Seema; Vining, Courtenay

    2003-01-01

    Our goal in these studies was to characterize some specific aspects of hypothalamic-pituitary-adrenal (HPA) activity in rats exposed to repeated social stress. We used a modification of the resident/intruder paradigm in which male intruder rats were subjected to defeat and then separated from the resident by an enclosure for a total of 30 min on Day 1. On Days 2-7, intruder rats were exposed to different resident rats every day through a wire mesh enclosure for 30 min in order to minimize injurious physical contact between the two rats. The intruder rats gained significantly less weight than controls over the 7-day period of stress though basal corticosterone levels and adrenal and thymus weights were not significantly different between the two groups. On Day 8, repeatedly stressed rats exhibited facilitation of HPA responses to novel restraint compared to controls but no differences in negative feedback sensitivity to dexamethasone (0.05 or 0.2 mg/kg) were observed. Thus, the HPA axis of socially stressed rats remains responsive to a stimulus that has never been encountered. Using this type of repeated presentation to an aggressive resident allows us to examine the neuroendocrine and behavioral consequences, and their underlying neural mechanisms, of exposure to a stressor that is social in nature and naturalistic for rodents.

  8. Response of the Hypothalamic-Pituitary-Adrenal System to Repeated Moderate Psychoemotional Stress Exposure Is Associated with Behavioral Parameters.

    PubMed

    Goncharova, N D; Chigarova, O A; Oganyan, T E

    2017-05-01

    Individual features of the response of the hypothalamic-pituitary-adrenal axis (HPAA) to repeated moderate stress exposure (daily 2-h restraint stress for 10 days) was studied in young female rhesus monkeys with healthy normal behavior and combined group of female rhesus monkeys with abnormal depression-like and anxious behavior. No between-group differences in the response of ACTH and cortisol were found on day 1. On day 10, a rapid and less pronounced increase in ACTH secretion was observed in all animals in comparison with day 1. Analysis of between-group differences in HPAA response showed higher increase in ACTH level and lower increase in cortisol concentration in animals with depression-like and anxious behavior. These changes were similar to the previously described differences in the response of the adenohypophysis and adrenal cortex to acute restraint stress in old monkeys with similar behavior. Thus, individuals with depression-like and anxious behavior demonstrate impaired stress-induced reactivity of HPAA as early as in young age.

  9. Impact of the hypothalamic-pituitary-adrenal/gonadal axes on trajectory of age-related cognitive decline.

    PubMed

    Conrad, Cheryl D; Bimonte-Nelson, Heather A

    2010-01-01

    Life expectancies have increased substantially in the last century, dramatically amplifying the proportion of individuals who will reach old age. As individuals age, cognitive ability declines, although the rate of decline differs amongst the forms of memory domains and for different individuals. Memory domains especially impacted by aging are declarative and spatial memories. The hippocampus facilitates the formation of declarative and spatial memories. Notably, the hippocampus is particularly vulnerable to aging. Genetic predisposition and lifetime experiences and exposures contribute to the aging process, brain changes and subsequent cognitive outcomes. In this review, two factors to which an individual is exposed, the hypothalamic-pituitary-adrenal (HPA) axis and the hypothalamic-pituitary-gonadal (HPG) axis, will be considered regarding the impact of age on hippocampal-dependent function. Spatial memory can be affected by cumulative exposure to chronic stress via glucocorticoids, released from the HPA axis, and from gonadal steroids (estrogens, progesterone and androgens) and gonadotrophins, released from the HPG axis. Additionally, this review will discuss how these hormones impact age-related hippocampal function. We hypothesize that lifetime experiences and exposure to these hormones contribute to the cognitive makeup of the aged individual, and contribute to the heterogeneous aged population that includes individuals with cognitive abilities as astute as their younger counterparts, as well as individuals with severe cognitive decline or neurodegenerative disease. Copyright 2010 Elsevier B.V. All rights reserved.

  10. The corticotropin-releasing hormone network and the hypothalamic-pituitary-adrenal axis: molecular and cellular mechanisms involved.

    PubMed

    Bonfiglio, Juan José; Inda, Carolina; Refojo, Damián; Holsboer, Florian; Arzt, Eduardo; Silberstein, Susana

    2011-01-01

    Corticotropin-releasing hormone (CRH) plays a key role in adjusting the basal and stress-activated hypothalamic-pituitary-adrenal axis (HPA). CRH is also widely distributed in extrahypothalamic circuits, where it acts as a neuroregulator to integrate the complex neuroendocrine, autonomic, and behavioral adaptive response to stress. Hyperactive and/or dysregulated CRH circuits are involved in neuroendocrinological disturbances and stress-related mood disorders such as anxiety and depression. This review describes the main physiological features of the CRH network and summarizes recent relevant information concerning the molecular mechanism of CRH action obtained from signal transduction studies using cells and wild-type and transgenic mice lines. Special focus is placed on the MAPK signaling pathways triggered by CRH through the CRH receptor 1 that plays an essential role in CRH action in pituitary corticotrophs and in specific brain structures. Recent findings underpin the concept of specific CRH-signaling pathways restricted to specific anatomical areas. Understanding CRH action at molecular levels will not only provide insight into the precise CRH mechanism of action, but will also be instrumental in identifying novel targets for pharmacological intervention in neuroendocrine tissues and specific brain areas involved in CRH-related disorders.

  11. Skin under the (Spot)-Light: Cross-Talk with the Central Hypothalamic-Pituitary-Adrenal (HPA) Axis.

    PubMed

    Jozic, Ivan; Stojadinovic, Olivera; Kirsner, Robert S F; Tomic-Canic, Marjana

    2015-06-01

    UV radiation is among the most prevalent stressors in humans and diurnal rodents, exerting direct and indirect DNA damage, free-radical production, and interaction with specific chromophores that affects numerous biological processes. In addition to its panoply of effects, UVB (290-320 nm) radiation can specifically affect various local neuroendocrine activities by stimulating the expression of corticotropin-releasing hormone (CRH), urocortin, proopiomelanocortin (POMC), and POMC-derived peptides. Although very little is known about the interplay between the central hypothalamic-pituitary-adrenal (HPA) axis and the skin HPA axis analog, in the current issue Skobowiat and Slominski propose a novel mechanism by which exposure to UVB activates a local HPA axis in skin, which in turn activates the central HPA axis, with the requirement of a functional pituitary gland. This is the first evidence of the local HPA axis in skin contributing to the central neuroendocrine response. This raises intriguing possibilities regarding how local production of cortisol and other HPA axis molecules in skin influence overall systemic levels of cortisol and help regulate local and central HPA axes in the context of homeostasis, skin injury, and inflammatory skin disorders.

  12. Hypothalamic-pituitary adrenal (HPAA) axis function in adult Fischer-344 rats exposed during development to neurotoxic chemicals perinatally.

    PubMed

    Rosecrans, J A; Johnson, J H; Tilson, H A; Hong, J S

    1984-01-01

    The major objective of these experiments was to determine long-term effects on the hypothalamic-pituitary adrenal axis (HPAA) of adult rats exposed during development to chlordecone, an organochlorine insecticide. Chlordecone was administered to mothers prenatally plus the first 12 days of the neonatal period (6 ppm in the diet) or neonatally via a single subcutaneous injection to rats at 4 days of age (1 mg/pup in 20 micrograms of DMSO). DMSO (20 microliters/pup) and dexamethasone (100 micrograms/pup in 20 microliters saline) were also injected on day 4. HPAA function was evaluated at 70-80 days of age. Responsiveness of the HPAA to a repeated stressor was evaluated by exposing rats of each treatment group to a 7-day stress-induced analgesia (SIA) paradigm consisting of a daily 15 sec foot-shock (0.9 mA) exposure which was preceded by a 15 sec white noise conditioned stimulus. The behavioral response to daily stress was evaluated by measuring tail-flick latencies immediately before and/or after each stress exposure. The conditioned response to stress was evaluated 24 hours after the last of 7 daily foot-shock sessions in which rats of each treatment and experimental group were exposed to the shock chamber only. All rats were killed 15 minutes after the final session and tissue (serum and adrenals) were removed and frozen for later chemical analysis; serum and adrenal corticosterone (CS) and serum prolactin (Prl) levels were measured. Perinatal exposure to chlordecone did not significantly alter the behavioral and/or neuroendocrine responses to stress. Ambient hormone levels (both CS and Prl), however, were uniformly attenuated by chlordecone.(ABSTRACT TRUNCATED AT 250 WORDS)

  13. Sex-specific prediction of hypothalamic-pituitary-adrenal axis activity by pituitary volume during adolescence: a longitudinal study from 12 to 17 years of age.

    PubMed

    Kaess, Michael; Simmons, Julian G; Whittle, Sarah; Jovev, Martina; Chanen, Andrew M; Yücel, Murat; Pantelis, Christos; Allen, Nicholas B

    2013-11-01

    To investigate the longitudinal relationship between pituitary gland volume (PGV) and parameters of hypothalamic-pituitary-adrenal axis (HPAA) functioning during adolescence. Participants were 49 adolescents (19 girls and 30 boys) selected from a larger longitudinal, population-based study of adolescent development. Assessments were conducted at three time points (S1, S2 and S3). MRI sessions were at S1 (age: M=12.62, SD=0.45 years) and S3 (M=16.48, SD=0.53 years) and multiple assessments of salivary cortisol were undertaken at S2 (M=15.51, SD=0.35 years). PGV was measured via previously validated manual tracing methods, and the cortisol awakening response (CAR) and diurnal slope (DSL) were used as indices of HPAA functioning. A significant sex-linked interaction was found for PGV at S1 predicting both CAR (p=0.025) and DSL (p=0.009) at S2. Specifically, PGV at S1 significantly predicted CAR (p=0.033) and DSL (p=0.010) in boys only, with no significant results found for girls. Neither CAR nor DSL at S2 predicted growth of PGV from S1 to S3. PGV in early adolescence predicted HPAA functioning in mid-adolescent boys but not in girls. The results suggest a significant influence of sex-specific development on the relationship between PGV and HPAA activity and reactivity. The findings have potential implications for understanding and interpreting sex-linked and stress related clinical disorders that emerge during mid-to-late adolescence. Copyright © 2013 Elsevier Ltd. All rights reserved.

  14. Activation of the Hypothalamic-Pituitary-Adrenal (HPA) Axis Following Extended Exposure to Atrazine (ATR)

    EPA Science Inventory

    While it is known that adrenal steroids impact reproduction and a variety of other physiological and behavioral fimctions, disruption of the HPA-axis is not typically considered in toxicological studies. Here we characterize changes in basal corticosterone (CORT) and progesterone...

  15. Activation of the Hypothalamic-Pituitary-Adrenal (HPA) Axis Following Extended Exposure to Atrazine (ATR)###

    EPA Science Inventory

    While it is known that adrenal steroids impact reproduction and a variety of other physiological and behavioral functions, disruption of the HPA-axis is not typically considered in toxicological studies. Here we characterize changes in basal corticosterone (CORT) and progesterone...

  16. Activation of the Hypothalamic-Pituitary-Adrenal (HPA) Axis Following Extended Exposure to Atrazine (ATR)###

    EPA Science Inventory

    While it is known that adrenal steroids impact reproduction and a variety of other physiological and behavioral functions, disruption of the HPA-axis is not typically considered in toxicological studies. Here we characterize changes in basal corticosterone (CORT) and progesterone...

  17. Activation of the Hypothalamic-Pituitary-Adrenal (HPA) Axis Following Extended Exposure to Atrazine (ATR)

    EPA Science Inventory

    While it is known that adrenal steroids impact reproduction and a variety of other physiological and behavioral fimctions, disruption of the HPA-axis is not typically considered in toxicological studies. Here we characterize changes in basal corticosterone (CORT) and progesterone...

  18. [Genetics and phenogenetics of the hormonal characteristics of animals. VI. Functional activity of certain chemoreceptors connected with the pituitary-adrenal system of silver foxes selected for their behavior].

    PubMed

    Naumenko, E V; Trut, L N; Pavlova, S I; Beliaev, D K

    1980-01-01

    Seasonal differences in the reaction of the pituitary-adrenal system in domesticated and non-domesticated silver foxes of both sexes to substances activating alpha-, beta-adrenoreceptors, and serotonin receptors were studied. It was shown that the reactivity of the pituitary-adrenal system in silver foxes of either type of behaviour is due, at least partially, to seasonal differences in the state of adrenergic and serotoninergic mechanisms. At the same time, in silver foxes selected for behaviour to man the reaction of the pituitary-adrenal system to the injection of substances activating adrenergic and serotoninergic receptors differs, during the year, from the reaction to these compounds in non-selected animals. The conclusion was made, that in the process of domestication changes take place in the state of serotonin- and noradrenaline mechanisms connected with the regulation of the hypothalamo-pituitary-adrenal complex.

  19. Molecular regulation of the hypothalamic-pituitary-adrenal axis in adult male guinea pigs after prenatal stress at different stages of gestation.

    PubMed

    Kapoor, Amita; Leen, Jason; Matthews, Stephen G

    2008-09-01

    Studies in humans and animals have demonstrated that maternal stress during fetal development can lead to altered hypothalamic-pituitary-adrenal (HPA) axis function and behaviour postnatally. We have previously shown adult male guinea pigs that were born to mothers exposed to a stressor during the phase of rapid fetal brain growth (gestational days (GD) 50, 51 and 52; prenatal stress (PS)50) exhibit significantly increased basal plasma cortisol levels. In contrast, male guinea pig offspring whose mothers were exposed to stress later in gestation (GD60, 61 and 62; PS60) exhibited a significantly higher plasma cortisol response to activation of the HPA axis. In the present study, we hypothesized that the endocrine changes in HPA axis function observed in male guinea pig offspring would be reflected by altered molecular regulation of the HPA axis. Corticosteroid receptors in the hippocampus, hypothalamus and pituitary were measured, as well as corticotropin-releasing hormone (CRH), pro-opiomelanocortin (POMC) and adrenal enzymes in the paraventricular nucleus, pituitary and adrenal cortex, respectively, by in situ hybridization and Western blot. PS50 male offspring exhibited a significant reduction in glucocorticoid receptor (GR) mRNA (P <0.01) in the CA3 region of the hippocampus and significantly increased POMC mRNA (P <0.05) in the pituitary, consistent with the increase in basal HPA axis activity observed. In line with elevated activity of the HPA axis, both PS50 and PS60 male offspring exhibited significantly higher steroidogenic factor (SF)-1 (P <0.001) and melanocortin 2 receptor (MC2-R) mRNA (P <0.001) in the adrenal cortex. This study demonstrates that short periods of prenatal stress during critical windows of neuroendocrine development affect the expression of key regulators of HPA axis activity leading to the changes in endocrine function observed in prenatally stressed male offspring. Further, these changes are dependent on the timing of the maternal

  20. The Effect of CRH, Dexamethasone and Naltrexone on the Mu, Delta and Kappa Opioid Receptor Agonist Binding in Lamb Hypothalamic-Pituitary-Adrenal Axis.

    PubMed

    Pierzchała-Koziec, Krystyna; Dziedzicka-Wasylewska, Marta; Oeltgen, Peter; Zubel-Łojek, Joanna; Latacz, Anna; Ocłon, Ewa

    2015-01-01

    The aim of the study was to evaluate changes in the opioid receptor binding (mu, delta and kappa) in the hypothalamus, anterior pituitary and adrenal cortex (HPA) of lambs treated in vivo with corticotrophin releasing hormone (CRH), naltrexone, an opioid receptor antagonist (NAL), and dexamethasone, a potent cortisol analog (DEX). Experiment was carried out on 3 months old female lambs of polish mountain strain. Lambs received a single i.v. injection of NaCl (control), CRH (alone or in combination with naltrexone), naltrexone or dexamethasone. One hour later animals were decapitated under anaesthesia, tissues were dissected out and receptor binding assays were performed with radioligands for each type of opioid receptors--3H-DAGO, 3H-DPDPE and 3H-EKC for mu, delta and kappa receptor, respectively. Coexistence of specific binding sites for each type of opioid receptor was demonstrated in all levels of HPA axis of control lambs, however their distribution was uneven. Acute treatment with CRH, DEX and NAL caused downregulation or upregulation of mu, delta, kappa receptor binding in each level of HPA axis. CRH effects on mu, delta and kappa opioid receptor binding varied within the HPA axis and were modulated by naltrexone. Treatment with naltrexone increased in vitro mu, delta and kappa receptor binding in most tested structures except delta receptor binding in adrenal (decrease by 52%) and kappa receptor binding in pituitary (decrease by 41%). Dexamethasone significantly decreased the mu, delta and kappa opioid receptor binding in adrenal cortex but differentially affected opioid receptor binding in hypothalamus and pituitary. It seems probable that endogenous opioid peptides acting through mu, delta and kappa receptors interact with the hormones released from the hypothalamic-pituitary-adrenal axis in physiological and pathophysiological situations.

  1. Pituitary Tumors

    MedlinePlus

    ... or milk production), sex hormones (control the menstrual cycle and other sexual functions), thyroid gland hormones (control the thyroid gland), adrenal gland hormones, and vasopressin (a hormone involved in water and electrolyte balance). Symptoms of pituitary adenoma and ...

  2. Adrenal Gland Disorders

    MedlinePlus

    ... adrenal gland disorders include Genetic mutations Tumors including pheochromocytomas Infections A problem in another gland, such as the pituitary, which helps to regulate the adrenal gland Certain medicines Treatment depends on which problem you have. Surgery or ...

  3. Activation of the hypothalamic-pituitary-adrenal (HPA) axis contributes to the immunosuppression of mice infected with Angiostrongylus cantonensis.

    PubMed

    Chen, Ai-Ling; Sun, Xi; Wang, Wei; Liu, Jin-Feng; Zeng, Xin; Qiu, Jing-Fan; Liu, Xin-Jian; Wang, Yong

    2016-10-12

    Immunosuppression has been described as a consequence of brain injury and infection by different mechanisms. Angiostrongylus cantonensis can cause injury to the central nervous system and eosinophilic meningitis to human. Both T cell and B cell immunity play an essential role in the resistance of the infection. However, whether brain injury caused by A. cantonensis infection can lead to immunosuppression is not clear. Therefore, the present study sought to observe the alteration of immune responses in mice infected with A. cantonensis. Mice were infected with 20 third-stage A. cantonensis larvae. The messenger RNA (mRNA) expression of inflammatory mediators in brain tissues was observed by qRT-PCR. Cell surface markers including CD3, CD4, CD8, CD19, B220, 7-AAD, annexin-V, IgM, AA4.1, and CD23 were evaluated by using flow cytometry. The immune functions of T and B lymphocytes were detected upon stimulation by ConA and antibody responses to a nonself antigen OVA, respectively. Activation of the hypothalamic-pituitary-adrenal axis was evaluated by analyzing the concentration of plasma corticosterone and levels of mRNA for corticotropin-releasing hormone, tyrosine hydroxylase, and c-fos. A. cantonensis infection results in obvious immunosuppression evidenced as progressive spleen and thymus atrophy and significant decrease in the number of lymphocyte subsets including B cells, CD3(+) T cells, CD4(+) T cells, and CD8(+) T cells, as well as reduced T cell proliferation at 21 days post-infection and antibody reaction to exogenous protein after infection. However, the sharp decrease of splenic and thymic cells was not due to cell apoptosis but to B cell genesis cessation and impairing thymocyte development. In addition, helminthicide treatment with albendazole on infected mice at 7 days post-infection could prevent immunosuppressive symptoms. Importantly, infected mice displayed hypothalamic-pituitary-adrenal axis activation, with peak responses occurring at 16

  4. Impact of maternal undernutrition on the hypothalamic-pituitary-adrenal axis responsiveness in sheep at different ages postnatal.

    PubMed

    Chadio, S E; Kotsampasi, B; Papadomichelakis, G; Deligeorgis, S; Kalogiannis, D; Menegatos, I; Zervas, G

    2007-03-01

    Epidemiological and experimental data support the hypothesis of 'fetal programming', which proposes that alterations in fetal nutrition and endocrine status lead to permanent adaptations in fetal homeostatic mechanisms, producing long-term changes in physiology and determine susceptibility to later disease. Altered hypothalamic-pituitary-adrenal (HPA) axis function has been proposed to play an important role in programming of disease risk. The aim of the present study was to examine the effects of maternal nutrient restriction imposed during different periods of gestation on the HPA axis function in sheep, at different ages postnatal. Pregnant ewes were fed a 50% nutrient-restricted diet from days 0-30 (group R1, n = 7), or from days 31-100 of gestation (group R2, n = 7) or a control 100% diet throughout pregnancy, (Control, n = 8). Blood samples were collected at 10-day intervals from day 40 of gestation to term. Lambs were born naturally and fed to appetite throughout the study period. At 2, 5.5, and 10 months of age lambs were given an i.v. injection of corticotrophin-releasing hormone (CRH) and blood samples were collected at -15, 0, 15, 30, 60, 120, and 180 min postinjection. Maternal cortisol levels were significantly higher (P < 0.05) in group R1 compared with the other two groups, whereas maternal insulin levels were lower (P < 0.05) in group R2 compared with control. Birth weight of lambs was not affected by the maternal nutritional manipulation. The area under the curve for ACTH and cortisol response to CRH challenge was greater (P < 0.05) in lambs of group R1 at two months of age, whereas no difference was detected at the ages of 5.5 and 10 months. However, significantly higher (P < 0.01) basal cortisol levels were observed in lambs of R1 group at 5.5 months of age. There was no interaction between treatment and sex for both pituitary and adrenal responses to the challenge. A significant sex effect was evident with females responding with higher ACTH and

  5. Attenuation of the hypothalamic-pituitary-adrenal axis responsivity to the Trier Social Stress Test by the benzodiazepine alprazolam.

    PubMed

    Fries, Eva; Hellhammer, Dirk H; Hellhammer, Juliane

    2006-11-01

    Little is known about effects of commonly used anxiolytic drugs on psychologically evoked responses of two major stress systems, the hypothalamic-pituitary-adrenal (HPA) and the sympathetic-adrenal-medullary (SAM) axis. The purpose of the present study was to assess effects of the anxiolytic alprazolam on responses of the HPA and the SAM axes to a standardized psychosocial stress protocol, the Trier Social Stress Test (TSST). Forty-six healthy, non-smoking, non-medicated males, aged between 18 and 45 years, were invited once to the laboratory and received a single oral dose of 1mg alprazolam or placebo, respectively, 1h prior to the TSST. The secretion of ACTH, cortisol, epinephrine, norepinephrine as well as changes in heart rate, blood pressure, and psychological states (anxiety, wakefulness, good mood, calmness) in response to the TSST were measured. Subjects pre-treated with alprazolam showed a strongly blunted response of ACTH as well as total and free cortisol to the TSST. Whereas alprazolam-treated subjects displayed significantly lower systolic blood pressure immediately before the TSST, neither the secretion of epinephrine, norepinephrine nor changes of heart rate in response to the stress test differed from placebo-treated subjects. Regarding psychological parameters, alprazolam clearly decreased subjective ratings on the questionnaire scale "wakefulness" and increased ratings on the scale "good mood", whereas ratings on scales assessing "state anxiety" or "agitation" were not affected. In healthy subjects, we observed a dissociation of the effects of alprazolam on the endocrine and the autonomic response to psychosocial stress. The psychological responses seemed to be masked by sedative properties of alprazolam.

  6. Effect of reproductive status on hypothalamic-pituitary-adrenal (HPA) activity and reactivity in male California mice (Peromyscus californicus).

    PubMed

    Harris, Breanna N; Saltzman, Wendy

    2013-03-15

    Previous studies indicate that reproductive condition can alter stress response and glucocorticoid release. Although the functional significance of hypothalamic-pituitary-adrenal (HPA) axis modulation by breeding condition is not fully understood, one possible explanation is the behavior hypothesis, which states that an animal's need to express parental behavior may be driving modulation of the HPA axis. This possibility is consistent with findings of blunted activity and reactivity of the HPA axis in lactating female mammals; however, effects of reproductive status on HPA function have not been well characterized in male mammals that express parental behavior. Therefore, we tested this hypothesis in the monogamous and biparental California mouse. Several aspects of HPA activity were compared in males from three reproductive conditions: virgin males (housed with another male), non-breeding males (housed with a tubally ligated female), and first-time fathers (housed with a female and their first litter of pups). In light of the behavior hypothesis we predicted that new fathers would differ from virgin and non-breeding males in several aspects of HPA function and corticosterone (CORT) output: decreased amplitude of the diurnal rhythm in CORT, a blunted CORT increase following predator-odor stress, increased sensitivity to glucocorticoid negative feedback, and/or a blunted CORT response to pharmacological stimulation. In addition, we predicted that first-time fathers would be more resistant to CORT-induced suppression of testosterone secretion, as testosterone is important for paternal behavior in this species. We found that virgin males, non-breeding males and first-time fathers did not display any CORT differences in diurnal rhythm, response to a predator-odor stressor, or response to pharmacological suppression or stimulation. Additionally, there were no differences in circulating testosterone concentrations. Adrenal mass was, however, significantly lower in new

  7. Hypothalamic-Pituitary-Adrenal Suppression and Iatrogenic Cushing's Syndrome as a Complication of Epidural Steroid Injections

    PubMed Central

    2013-01-01

    Epidural steroid injections are well accepted as a treatment for radicular back pain in appropriate candidates. While overall incidence of systemic side effects has not been well established, at least five biochemically proven cases of iatrogenic Cushing's Syndrome have been reported as complications of epidural steroid treatment. We present an additional case of iatrogenic Cushing's Syndrome and adrenal suppression in a middle-aged woman who received three epidural steroid injections over a four-month period. We review this case in the context of previous cases and discuss diagnostic and management issues. PMID:23991341

  8. The four-dimensional stress test: psychological, sympathetic-adrenal-medullary, parasympathetic and hypothalamic-pituitary-adrenal responses following inhalation of 35% CO2.

    PubMed

    Wetherell, Mark A; Crown, Anna L; Lightman, Stafford L; Miles, Jeremy N V; Kaye, Joey; Vedhara, Kavita

    2006-07-01

    Hypercapnia is a threat to homeostasis and results in neuroendocrine, autonomic and anxiogenic responses. The inhalation of carbon dioxide (CO2) may, therefore, provide a good paradigm for exploring the pathways by which stress can lead to increased susceptibility to ill-health through physiological and psychological stress reactivity. The current study was designed, therefore, to assess the psychological and physiological responses to the inhalation of CO2. Healthy participants (N = 24) inhaled a single vital capacity breath of a mixture of CO2 (35%) and oxygen (65%). Blood pressure and heart rate were recorded for 5 min before and after the test and blood and saliva samples were taken immediately before and 2, 10, 20 and 30 min post-inhalation for the measurement of noradrenaline, salivary and serum cortisol and salivary alpha amylase. In addition, psychosomatic symptoms were recorded immediately before and after the test. The same protocol was repeated 4-6 weeks later at the same time of day. A single inhalation of CO2 increased blood pressure, noradrenaline, salivary alpha amylase and psychosomatic symptoms, but decreased heart rate at both testing sessions. Analyses of salivary cortisol data revealed that 70% of the sample could be reliably classified as either responders (i.e. demonstrated a post-CO2 cortisol increase) or non-responders (i.e. responded with a decrease or no change in cortisol following CO2) at both test sessions. Responders also perceived the test to be more aversive than non-responders. Inhalation of 35% CO2 reliably stimulated the key mechanisms involved in the human stress response. The inter-individual differences in the reactivity of the hypothalamic-pituitary-adrenal axis were also related to differences in the perception of the test.

  9. Psychological Stress and Changes of Hypothalamic-Pituitary-Adrenal Axis in Patients with “De Novo” Parkinson’s Disease

    PubMed Central

    Ibrahimagic, Omer C.; Jakubovic, Amra Cickusic; Smajlovic, Dzevdet; Dostovic, Zikrija; Kunic, Suljo; Iljazovic, Amra

    2016-01-01

    Introduction: Psychological stress and changes in hypothalamic-pituitary-adrenal (HPA) axis in period after diagnosis of “de novo” Parkinson disease (PD) could be a big problem for patients. Materials and Methods: We measured psychological stress and changes in hypothalamic-pituitary-adrenal axis (HPA) in thirty patients (15:15) with “de novo” Parkinson’s disease, average age 64.17 ± 13.19 (28-82) years (Department of Neurology, University Clinical Center Tuzla). We used Impact of events scale (with 15 questions) to evaluate psychological stress. Normal level of morning cortisol was 201-681 nmol/l, and morning adrenocorticotropic hormone (ACTH) up to 50 pg/ml. Results: Almost 55% patients suffered from mild or serious psychological stress according to IES testing (Horowitz et al.). Non-iatrogenic changes in HPA axis were noticed at 30% patients. The differences between female and male patients regarding to the age (p=0.561), value of cortisol (p=0.745), value of ACTH (p=0.886) and IES testing (p=0.318) were not noticed. The value of cortisol was the predictor of value of ACTH (r=0.427). Conclusion: Psychological stress and changes in hypothalamic-pituitary-adrenal axis are present in patients with “de novo” PD. There is significant relation between values of cortisol and ACTH. Psychological stress is frequent problem for “de novo” PD patients. PMID:28210018

  10. Hypothalamic-pituitary-adrenal axis activity is not elevated in a songbird (Junco hyemalis) preparing for migration.

    PubMed

    Bauer, Carolyn M; Needham, Katie B; Le, Chuong N; Stewart, Emily C; Graham, Jessica L; Ketterson, Ellen D; Greives, Timothy J

    2016-06-01

    During spring, increasing daylengths stimulate gonadal development in migratory birds. However, late-stage reproductive development is typically postponed until migration has been completed. The hypothalamic-pituitary-adrenal (HPA) axis regulates the secretion of glucocorticoids, which have been associated with pre-migratory hyperphagia and fattening. The HPA-axis is also known to suppress the hypothalamic-pituitary-gonadal (HPG) axis, suggesting the possibility that final transition into the breeding life history stage may be slowed by glucocorticoids. We hypothesized that greater HPA-axis activity in individuals preparing for migration may foster preparation for migration while simultaneously acting as a "brake" on the development of the HPG-axis. To test this hypothesis, we sampled baseline corticosterone (CORT), stress-induced CORT, and negative feedback efficacy of Dark-eyed Juncos (Junco hyemalis) in an overwintering population that included both migratory (J.h. hyemalis) and resident (J.h. carolinensis) individuals. We predicted that compared to residents, migrants would have higher baseline CORT, higher stress-induced CORT, and weaker negative feedback. Juncos were sampled in western Virginia in early March, which was about 2-4wk before migratory departure for migrants and 4-5wk before first clutch initiation for residents. Contrary to our predictions, we found that migrants had lower baseline and stress-induced CORT and similar negative feedback efficacy compared with residents, which suggests that delayed breeding in migrants is influenced by other physiological mechanisms. Our findings also suggest that baseline CORT is not elevated during pre-migratory fattening, as migrants had lower baseline CORT and were fatter than residents.

  11. Disturbances in hypothalamo pituitary adrenal and thyroid axis identify different sleep EEG patterns in major depressed patients.

    PubMed

    Staner, L; Duval, F; Haba, J; Mokrani, M C; Macher, J P

    2003-01-01

    This study was aimed at investigating the relationships between sleep EEG abnormalities and hypothalamo pituitary adrenal (HPA) and hypothalamo pituitary thyroid (HPT) disturbances in major depressive disorder. Post dexamethasone (DXM) cortisol levels and the dual TSH response to 08:00 h and 23:00 h TRH administration were determined after a 2 weeks wash-out period in a group of 113 DSM-IV major depressed patients (72 females aged 44.3+/-13.0 and 41 males aged 45.7+/-11) who were consecutively admitted to undergo sleep EEG recordings. Post-DXM cortisolemia, 08:00 and 23:00 post-TRH TSH values, time spent in rapid eye movement sleep (REMS), in slow wave sleep (SWS), and in stage 2 as well as time awake after sleep onset were introduced in a principal component (PC) analysis. The four 3 PC scores explaining up to 74% of the data set were further calculated for each patients and used in a cluster analysis. A three-cluster solution was retained. Controlling for the effects of age and gender, patients belonging to these three clusters could clearly be differentiated on the basis of their neuroendocrine responses and on their sleep EEG profiles. Compared to the two other clusters, cluster I (n=26) patients showed the most severe sleep continuity disturbances. Post-DXM cortisol escape and sleep architecture disturbances (consisting of a shortening of REMS latency and a decreased SWS) identified patients belonging to cluster II (n=39). Patients in cluster III (n=48) had the lowest TSH response to TRH and the less marked sleep EEG alteration. Clinical or demographic variables were unable to differentiate the three clusters. Our results suggest that different biological dysfunctions could each underlie particular neuroendocrine and sleep EEG disturbances in major depression.

  12. Hypothalamic-pituitary-adrenal axis and behavioral dysfunction following early binge-like prenatal alcohol exposure in mice.

    PubMed

    Wieczorek, Lindsay; Fish, Eric W; O'Leary-Moore, Shonagh K; Parnell, Scott E; Sulik, Kathleen K

    2015-05-01

    The range of defects that fall within fetal alcohol spectrum disorder (FASD) includes persistent behavioral problems, with anxiety and depression being two of the more commonly reported issues. Previous studies of rodent FASD models suggest that interference with hypothalamic-pituitary-adrenal (HPA) axis structure and/or function may be the basis for some of the prenatal alcohol (ethanol) exposure (PAE)-induced behavioral abnormalities. Included among the previous investigations are those illustrating that maternal alcohol treatment limited to very early stages of pregnancy (i.e., gestational day [GD]7 in mice; equivalent to the third week post-fertilization in humans) can cause structural abnormalities in areas such as the hypothalamus, pituitary gland, and other forebrain regions integral to controlling stress and behavioral responses. The current investigation was designed to further examine the sequelae of prenatal alcohol insult at this early time period, with particular attention to HPA axis-associated functional changes in adult mice. The results of this study reveal that GD7 PAE in mice causes HPA axis dysfunction, with males and females showing elevated corticosterone (CORT) and adrenocorticotropic hormone (ACTH) levels, respectively, following a 15-min restraint stress exposure. Males also showed elevated CORT levels following an acute alcohol injection of 2.0 g/kg, while females displayed blunted ACTH levels. Furthermore, analysis showed that anxiety-like behavior was decreased after GD7 PAE in female mice, but was increased in male mice. Collectively, the results of this study show that early gestational alcohol exposure in mice alters long-term HPA axis activity and behavior in a sexually dimorphic manner.

  13. Hypothalamic-pituitary-adrenal axis and behavioral dysfunction following early binge-like prenatal alcohol exposure in mice

    PubMed Central

    Wieczorek, Lindsay; Fish, Eric W.; O’Leary-Moore, Shonagh K.; Parnell, Scott E.; Sulik, Kathleen K.

    2015-01-01

    The range of defects that fall within fetal alcohol spectrum disorder (FASD) includes persistent behavioral problems, with anxiety and depression being two of the more commonly reported issues. Previous studies of rodent FASD models suggest that interference with hypothalamic-pituitary-adrenal (HPA) axis structure and/or function may be the basis for some of the prenatal alcohol (ethanol) exposure (PAE)-induced behavioral abnormalities. Included among the previous investigations are those illustrating that maternal alcohol treatment limited to very early stages of pregnancy (i.e., gestational day [GD]7 in mice; equivalent to the third week post-fertilization in humans) can cause structural abnormalities in areas such as the hypothalamus, pituitary gland, and other forebrain regions integral to controlling stress and behavioral responses. The current investigation was designed to further examine the sequelae of prenatal alcohol insult at this early time period, with particular attention to HPA axis-associated functional changes in adult mice. The results of this study reveal that GD7 PAE in mice causes HPA axis dysfunction, with males and females showing elevated corticosterone (CORT) and adrenocorticotropic hormone (ACTH) levels, respectively, following a 15-min restraint stress exposure. Males also showed elevated CORT levels following an acute alcohol injection of 2.0 g/kg, while females displayed blunted ACTH levels. Furthermore, analysis showed that anxiety-like behavior was decreased after GD7 PAE in female mice, but was increased in male mice. Collectively, the results of this study show that early gestational alcohol exposure in mice alters long-term HPA axis activity and behavior in a sexually dimorphic manner. PMID:25709101

  14. Analysis by immunocytochemistry and in situ hybridization of renin and its mRNA in kidney, testis, adrenal, and pituitary of the rat.

    PubMed Central

    Deschepper, C F; Mellon, S H; Cumin, F; Baxter, J D; Ganong, W F

    1986-01-01

    Renin gene expression in cells and tissues of the rat was examined by in situ hybridization histochemistry and immunocytochemistry. By using a mouse cDNA probe, hybridization histochemistry revealed renin mRNA in the renal juxtaglomerular cells, testicular Leydig cells, adrenal zona glomerulosa cells, the intermediate lobe of the pituitary, and scattered cells of the anterior lobe of the pituitary. With four separate antisera to mouse submaxillary renin, there was immunoreactivity in the renal juxtaglomerular cells. However, only one of the antisera stained the Leydig cells, a second stained the adrenal zona glomerulosa, a third stained the intermediate lobe of the pituitary, and a fourth stained scattered cells of the anterior lobe of the pituitary that were identified as gonadotrophs. The variations with the different antisera in detecting extrarenal renin are unexplained but could imply that posttranslational proteolysis or glycosylation of preprorenin varies in different tissues with consequent variations in immunoreactivity. The finding of renin mRNA and renin-like immunoreactivity in these tissues supports the notion that these tissues are sites for production of renin. Images PMID:3532116

  15. Impact of maternal undernutrition during the periconceptional period, fetal number, and fetal sex on the development of the hypothalamo-pituitary adrenal axis in sheep during late gestation.

    PubMed

    Edwards, L J; McMillen, I Caroline

    2002-05-01

    Evidence from epidemiologic, clinical, and experimental studies has shown that a suboptimal intrauterine environment during early pregnancy can alter fetal growth and gestation length and is associated with an increased prevalence of adult hypertension and cardiovascular disease. It has been postulated that maternal nutrient restriction may act to reprogram the development of the pituitary-adrenal axis, resulting in excess glucocorticoid exposure and adverse health outcomes in later life. It is unknown, however, whether maternal nutrient restriction during the periconceptional period alters the development of the fetal pituitary-adrenal axis or whether the effects of periconceptional undernutrition can be reversed by the provision of an adequate level of maternal nutrition throughout the remainder of pregnancy. We have investigated the effect of restricted periconceptional nutrition (70% of control feed allowance) from 60 days before until 7 days after mating and the effect of restricted gestational nutrition from Day 8 to 147 of gestation on the development of the fetal hypothalamo-pituitary adrenal (HPA) axis in the sheep. In these studies, we have also investigated the effects of fetal number and sex on the pituitary-adrenal responses to periconceptional and gestational undernutrition. In ewes maintained on a control diet throughout the periconceptional and gestational periods, fetal plasma ACTH concentrations were higher and the prepartum surge in cortisol occurred earlier in singletons compared with twins. Plasma ACTH concentrations were also significantly higher in male compared with female singletons, and in twin fetuses, the prepartum surge in cortisol concentrations occurred earlier in males than in females. Periconceptional undernutrition resulted in higher fetal plasma concentrations of ACTH between 110 and 145 days of gestation and a significantly greater cortisol response to a bolus dose of corticotropin-releasing hormone in twin, but not singleton

  16. Total flavonoids extracted from xiaobuxin-tang on the hyperactivity of hypothalamic-pituitary-adrenal axis in chronically stressed rats.

    PubMed

    An, Lei; Zhang, You-Zhi; Liu, Xin-Min; Yu, Neng-Jiang; Chen, Hong-Xia; Zhao, Nan; Yuan, Li; Li, Yun-Feng

    2011-01-01

    Our previous studies have demonstrated that the total flavonoids (XBXT-2) isolated from the extract of Xiaobuxin-Tang (XBXT), a traditional Chinese herbal decoction, ameliorated behavioral alterations and hippocampal dysfunctions in chronically stressed rats. Studies over the last decades have suggested that the hyperactivity of hypothalamic-pituitary-adrenal (HPA) axis is one of the most consistent findings in stress-related depression. Herein, we used the same chronic mild stress model of rats as before to further investigate the effect of XBXT-2 on the hyperactivity of HPA axis, including the stress hormones levels and glucocorticoid receptors (GRs) expression. Our ELISA results showed that chronic administration of XBXT-2 (25, 50 mg kg(-1), p.o., 28 days, the effective doses for behavioral responses) significantly decreased serum corticosterone level and its upstream stress hormone adrenocorticotropic hormone (ACTH) level in chronically stressed rats. Furthermore, western blotting result demonstrated XBXT-2 treatment ameliorated stress-induced decrease of GRs expression in hippocampus, an important target involved in the hyperactivity of HPA axis. These results were similar to that of classic antidepressant imipramine treatment (10 mg kg(-1), p.o.). In conclusion, the modulation of HPA axis produced by XBXT-2, including the inhibition of stress hormones levels and up-regulation of hippocampal GRs expression, may be an important mechanism underlying its antidepressant-like effect in chronically stressed rats.

  17. Total Flavonoids Extracted from Xiaobuxin-Tang on the Hyperactivity of Hypothalamic-Pituitary-Adrenal Axis in Chronically Stressed Rats

    PubMed Central

    An, Lei; Zhang, You-Zhi; Liu, Xin-Min; Yu, Neng-Jiang; Chen, Hong-Xia; Zhao, Nan; Yuan, Li; Li, Yun-Feng

    2011-01-01

    Our previous studies have demonstrated that the total flavonoids (XBXT-2) isolated from the extract of Xiaobuxin-Tang (XBXT), a traditional Chinese herbal decoction, ameliorated behavioral alterations and hippocampal dysfunctions in chronically stressed rats. Studies over the last decades have suggested that the hyperactivity of hypothalamic-pituitary-adrenal (HPA) axis is one of the most consistent findings in stress-related depression. Herein, we used the same chronic mild stress model of rats as before to further investigate the effect of XBXT-2 on the hyperactivity of HPA axis, including the stress hormones levels and glucocorticoid receptors (GRs) expression. Our ELISA results showed that chronic administration of XBXT-2 (25, 50 mg kg−1, p.o., 28 days, the effective doses for behavioral responses) significantly decreased serum corticosterone level and its upstream stress hormone adrenocorticotropic hormone (ACTH) level in chronically stressed rats. Furthermore, western blotting result demonstrated XBXT-2 treatment ameliorated stress-induced decrease of GRs expression in hippocampus, an important target involved in the hyperactivity of HPA axis. These results were similar to that of classic antidepressant imipramine treatment (10 mg kg−1, p.o.). In conclusion, the modulation of HPA axis produced by XBXT-2, including the inhibition of stress hormones levels and up-regulation of hippocampal GRs expression, may be an important mechanism underlying its antidepressant-like effect in chronically stressed rats. PMID:20028718

  18. Hypothalamic-pituitary-adrenal axis activity, dehydroepiandrosterone sulphate and their relationships with aggression in early and late alcohol withdrawal.

    PubMed

    Ozsoy, Saliha; Esel, Ertugrul

    2008-02-15

    The study aims at investigating the relationship between hypothalamic-pituitary-adrenal (HPA) axis alterations and aggression level in alcoholic patients during early and late alcohol withdrawal. Serum levels of basal cortisol and dehydroepiandrosterone sulphate (DHEAS) were measured three times, and cortisol and DHEAS response to dexamethasone twice during the early and late withdrawal periods in alcohol dependent males (n=30) and once in healthy control males (n=20). Abnormal cortisol non-suppression response to dexamethasone in dexamethasone suppression test (DST) was observed in some proportion of the patients in early withdrawal, which normalized in late withdrawal. The study revealed reduced basal DHEAS levels and reduced DHEAS response to dexamethasone in late withdrawal. When the patients were assessed in two separate groups as high- and low-aggressives, in the high-aggression group abnormality in DST was observed during both early and late withdrawal periods, in the low-aggression group it was observed only in early withdrawal. While basal DHEAS levels were low in the high-aggression group only in early withdrawal, it was reduced in the low-aggression group during late withdrawal period. Some alterations of the HPA axis during alcohol withdrawal might be associated not only with alcohol use per se but also with aggressivity tendency of alcoholic patients.

  19. Investigating the effect of acute sleep deprivation on hypothalamic-pituitary-adrenal-axis response to a psychosocial stressor.

    PubMed

    Vargas, Ivan; Lopez-Duran, Nestor

    2017-05-01

    The hypothalamic-pituitary-adrenal (HPA) axis has been previously identified as one potential mechanism that may explain the link between sleep deprivation and negative health outcomes. However, few studies have examined the direct association between sleep deprivation and HPA-axis functioning, particularly in the context of stress. Therefore, the aim of the current study was to investigate the relationship between acute sleep deprivation and HPA-axis reactivity to a psychosocial stressor. Participants included 40 healthy, young adults between the ages of 18-29. The current protocol included spending two nights in the laboratory. After an adaptation night (night 1), participants were randomized into either a sleep deprivation condition (29 consecutive hours awake) or a control condition (night 2). Following the second night, all participants completed the Trier Social Stress Test (TSST). Salivary cortisol was collected before, during, and after the TSST. Results indicated that there were significant group differences in cortisol stress reactivity. Specifically, compared to participants in the control condition, participants in the sleep deprivation condition had greater baseline (i.e., pre-stress) cortisol, yet a blunted cortisol response to the TSST. Taken together, a combination of elevated baseline cortisol (and its subsequent effect on HPA-axis regulatory processes) and a relative 'ceiling' on the amount of cortisol a laboratory stressor can produce may explain why participants in the sleep deprivation condition demonstrated blunted cortisol responses. Copyright © 2017 Elsevier Ltd. All rights reserved.

  20. Relational victimization, friendship, and adolescents' hypothalamic-pituitary-adrenal axis responses to an in vivo social stressor.

    PubMed

    Calhoun, Casey D; Helms, Sarah W; Heilbron, Nicole; Rudolph, Karen D; Hastings, Paul D; Prinstein, Mitchell J

    2014-08-01

    Adolescents' peer experiences may have significant associations with biological stress-response systems, adding to or reducing allostatic load. This study examined relational victimization as a unique contributor to reactive hypothalamic-pituitary-adrenal (HPA) axis responses as well as friendship quality and behavior as factors that may promote HPA recovery following a stressor. A total of 62 adolescents (ages 12-16; 73% female) presenting with a wide range of life stressors and adjustment difficulties completed survey measures of peer victimization and friendship quality. Cortisol samples were collected before and after a lab-based interpersonally themed social stressor task to provide measures of HPA baseline, reactivity, and recovery. Following the stressor task, adolescents discussed their performance with a close friend; observational coding yielded measures of friends' responsiveness. Adolescents also reported positive and negative friendship qualities. Results suggested that higher levels of adolescents' relational victimization were associated with blunted cortisol reactivity, even after controlling for physical forms of victimization and other known predictors of HPA functioning (i.e., life stress or depressive symptoms). Friendship qualities (i.e., low negative qualities) and specific friendship behaviors (i.e., high levels of responsiveness) contributed to greater HPA regulation; however, consistent with theories of rumination, high friend responsiveness in the context of high levels of positive friendship quality contributed to less cortisol recovery. Findings extend prior work on the importance of relational victimization and dyadic peer relations as unique and salient correlates of adaptation in adolescence.

  1. Sleep apnoea and the hypothalamic-pituitary-adrenal axis in men and women: effects of continuous positive airway pressure.

    PubMed

    Kritikou, Ilia; Basta, Maria; Vgontzas, Alexandros N; Pejovic, Slobodanka; Fernandez-Mendoza, Julio; Liao, Duanping; Bixler, Edward O; Gaines, Jordan; Chrousos, George P

    2016-02-01

    Previous findings on the association of obstructive sleep apnoea (OSA) and the hypothalamic-pituitary-adrenal (HPA) axis are inconsistent, partly due to the confounding effect of obesity and infrequent sampling. Our goal was to examine whether in a relatively nonobese population, OSA is associated with elevated cortisol levels and to assess the effects of a 2-month placebo-controlled continuous positive airway pressure (sham-CPAP) use.72 subjects (35 middle-aged males and post-menopausal females with OSA, and 37 male and female controls) were studied in the sleep laboratory for four nights. 24-h blood sampling was performed every hour on the fourth day and night in the sleep laboratory at baseline, after sham-CPAP and after CPAP treatment.In both apnoeic men and women, OSA was associated with significantly higher 24-h cortisol levels compared with controls, whereas CPAP lowered cortisol levels significantly, close to those of controls.These results suggest that OSA in nonobese men and slightly obese women is associated with HPA axis activation, similar albeit stronger compared with obese individuals with sleep apnoea. Short-term CPAP use decreased cortisol levels significantly compared with baseline, indicating that CPAP may have a protective effect against comorbidities frequently associated with chronic activation of the HPA axis, e.g. hypertension.

  2. Cranial irradiation modulates hypothalamic-pituitary-adrenal axis activity and corticosteroid receptor expression in the hippocampus of juvenile rat.

    PubMed

    Velickovic, Natasa; Djordjevic, Ana; Drakulic, Dunja; Stanojevic, Ivana; Secerov, Bojana; Horvat, Anica

    2009-01-01

    Glucocorticoids, essential for normal hypothalamic-pituitary-adrenal (HPA) axis activity, exert their action on the hippocampus through two types of corticosteroid receptors: the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR). Recent studies report that exposure of juvenile rats to cranial irradiation adversely affects HPA axis stability leading to its activation along with radiation- induced inflammation. This study was aimed to examine the acute effects of radiation on HPA axis activity and hippocampal corticosteroid receptor expression in 18-day-old rats. Since immobilization was part of irradiation procedure, both irradiated and sham-irradiated animals were exposed to this unavoidable stress. Our results demonstrate that the irradiated rats exhibited different pattern of corticosteroid receptor expression and hormone levels compared to respective controls. These differences included upregulation of GR protein in the hippocampus with a concomitant elevation of GR mRNA and an increase in circulating level of corticosterone. In addition, the expression of MR, both at the level of protein and gene expression, was not altered. Taken together, this study demonstrates that cranial irradiation in juvenile rats leads to enhanced HPA axis activity and increased relative GR/MR ratio in hippocampus. The present paper intends to show that neuroendocrine response of normal brain tissue to localized irradiation comprise both activation of HPA axis and altered corticosteroid receptor balance, probably as consequence of innate immune activation.

  3. RasGRF1 Regulates the Hypothalamic-Pituitary-Adrenal Axis Specifically in Early-Adolescent Female Mice

    PubMed Central

    Uzturk, Belkis Gizem; Jin, Shan-xue; Rubin, Beverly; Bartolome, Christopher; Feig, Larry A.

    2015-01-01

    Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the induction and prolongation of a variety of psychiatric disorders. As such, much effort has been made to understand the molecular mechanisms involved in its control. However, the vast majority of the studies on the HPA axis have used adult animals, and among these the majority has used males. Here we show that in knockout mice lacking the guanine nucleotide exchange factor, RasGRF1, habituation to 30 minutes a day of restraint stress is markedly accelerated, such that these mice do not display elevated corticosterone levels or enhanced locomotion after 7 days of stress exposure, like WT mice do. Strikingly, this phenotype is present in early-adolescent female RasGRF1 knockout mice, but not in their early-adolescent male, mid-adolescent female, adult female or adult male counterparts. Moreover, not only is there a clear response to restraint stress in early-adolescent female RasGRF1 knockout mice, their response after 1, 3, and 5 exposures is magnified ~3-fold compared to WT mice. These findings imply that distinct mechanisms exist to regulate the HPA axis in early-adolescent females that involves RasGRF1. A full understanding of how RasGRF1 controls the HPA axis response to stress may be required to design effective strategies to combat stress-associated psychiatric disorders initiated in young females. PMID:26246084

  4. Acute administration of buspirone increases the escape of hypothalamic-pituitary-adrenal-axis hormones from suppression by dexamethasone in depression.

    PubMed

    Maes, M; Van Gastel, A; Meltzer, H Y; Cosyns, P; Blockx, P; Desnyder, R

    1996-01-01

    Recently, our laboratory found a significant enhancing effect of L-5-hydroxy-tryptophan (L-5-HTP) on post-dexamethasone (DST) plasma adrenocorticotropic hormone (ACTH) and cortisol levels in major-but not in minor-depression. To further elucidate the effects of central serotonin (5-HT) activity on the negative feedback of glucocorticoids on hypothalamic-pituitary-adrenal (HPA)-axis function in depression, this study investigates the effects of buspirone, a 5-HT1A receptor agonist, on post-DST ACTH and cortisol levels in 75 depressed subjects. Plasma post-DST ACTH and cortisol concentrations were significantly increased by the acute administration of buspirone (30 mg PO) compared to placebo. There were no differences in buspirone-induced post-DST ACTH or cortisol responses between minor and major depression. There were significant correlations between post-DST ACTH and cortisol, and between post-DST-buspirone ACTH and cortisol. The buspirone-induced post-DST cortisol responses were significantly higher in depressed women than men. It is concluded that buspirone may augment ACTH and, consequently, cortisol escape from suppression by dexamethasone in major as well as in minor depression.

  5. Quantifying Pituitary-Adrenal Dynamics and Deconvolution of Concurrent Cortisol and Adrenocorticotropic Hormone Data by Compressed Sensing

    PubMed Central

    Faghih, Rose T.; Dahleh, Munther A.; Adler, Gail K.; Klerman, Elizabeth B.; Brown, Emery N.

    2015-01-01

    Pulsatile release of cortisol from the adrenal glands is governed by pulsatile release of adrenocorticotropic hormone (ACTH) from the anterior pituitary. In return, cortisol has a negative feedback effect on ACTH release. Simultaneous recording of ACTH and cortisol is not typical, and determining the number, timing, and amplitudes of pulsatile events from simultaneously recorded data is challenging because of several factors: (I) stimulator ACTH pulse activity, (II) kinematics of ACTH and cortisol, (III) the sampling interval, and (IV) the measurement error. We model ACTH and cortisol secretion simultaneously using a linear differential equations model with Gaussian errors and sparse pulsatile events as inputs to the model. We propose a novel framework for recovering pulses and parameters underlying the interactions between ACTH and cortisol. We recover the timing and amplitudes of pulses using compressed sensing, and employ generalized cross validation for determining the number of pulses. We analyze serum ACTH and cortisol levels sampled at 10-minute intervals over 24 hours from 10 healthy women. We recover physiologically plausible timing and amplitudes for these pulses and model the feedback effect of cortisol. We recover 15 to 18 pulses over 24 hours, which is highly consistent with the results of another cortisol data analysis approach. Modeling the interactions between ACTH and cortisol allows for accurate quantification of pulsatile events, and normal and pathological states. This could lay the basis for a more physiologically-based approach for administering cortisol therapeutically. The proposed approach can be adapted to deconvolve other pairs of hormones with similar interactions. PMID:25935025

  6. Neuropeptide Y mediates the initial hypothalamic-pituitary-adrenal response to maternal separation in the neonatal mouse.

    PubMed

    Schmidt, Mathias V; Liebl, Claudia; Sterlemann, Vera; Ganea, Karin; Hartmann, Jakob; Harbich, Daniela; Alam, Stephanie; Müller, Marianne B

    2008-05-01

    The function of the hypothalamic-pituitary-adrenal (HPA) axis of the neonatal mouse or rat is characterized by a period of quiescence, where mild stimuli are unable to elicit a pronounced increase in circulating corticosterone. A disruption of this period by maternal separation has been shown to result in a variety of long-term consequences, including neuroendocrine and behavioral disturbances. We have recently shown that peripheral metabolic markers like glucose or ghrelin are altered by maternal separation and that these changes precede the effects on corticosterone secretion. In the current study, we investigated whether the initial activation of the HPA axis is mediated via neuropeptide Y (NPY). To test this hypothesis, we studied the effects of an 8 h maternal separation in NPY-deficient mice. In addition, we compared the effect of the genotype with the previously described pharmacological effect of a ghrelin receptor antagonist. We could show that the peripheral response to maternal separation is decreased in NPY heterozygous and homozygous animals. In addition, maternal separation effects on corticotropin releasing hormone and glucocorticoid receptor expression in the brain were prevented in NPY-deficient pups. These effects were similar to a pharmacological ghrelin receptor blockade. We conclude that metabolic signals via an NPY-mediated pathway play a crucial role in activating the stress system of the neonatal mouse.

  7. Hypothalamic-Pituitary-Adrenal Reactivity to Acute Stress: an Investigation into the Roles of Perceived Stress and Family Resources.

    PubMed

    Obasi, Ezemenari M; Shirtcliff, Elizabeth A; Cavanagh, Lucia; Ratliff, Kristen L; Pittman, Delishia M; Brooks, Jessica J

    2017-02-08

    Rurally situated African Americans suffer from chronic exposure to stress that may have a deleterious effect on health outcomes. Unfortunately, research on potential mechanisms that underlie health disparities affecting the African American community has received limited focus in the scientific literature. This study investigated the relationship between perceived stress, family resources, and cortisol reactivity to acute stress. A rural sample of African American emerging adults (N = 60) completed a battery of assessments, the Trier Social Stress Test (TSST), and provided four samples of salivary cortisol: prior to receiving TSST instructions, prior to conducting the speech task, immediately following the TSST, and 15-20 min following the TSST. As predicted, cortisol levels increased in response to a controlled laboratory inducement of acute stress. Moreover, diminished levels of family resources were associated with blunted cortisol reactivity to acute stress. Of note, higher levels of perceived stress over the past month and being male were independently associated with lower levels of cortisol at baseline. Lack of family resources had a blunting relationship on the hypothalamic-pituitary-adrenal axis reactivity. These findings provide biomarker support for the relationship between family resources-an indicator associated with social determinants of health-and stress physiology within a controlled laboratory experiment. Identifying mechanisms that work toward explanation of within-group differences in African American health disparities is both needed and informative for culturally informed prevention and intervention efforts.

  8. Analyses of hair and salivary cortisol for evaluating hypothalamic-pituitary-adrenal axis activation in patients with autoimmune disease.

    PubMed

    Montero-López, Eva; Santos-Ruiz, Ana; González, Raquel; Navarrete-Navarrete, Nuria; Ortego-Centeno, Norberto; Martínez-Augustín, Olga; Rodríguez-Blázquez, Manuel; Peralta-Ramírez, María Isabel

    2017-08-30

    Although many studies have shown that patients with autoimmune disease present a hypoactive hypothalamic-pituitary-adrenal axis (HPA), controversial results have been described. Our objective was to study HPA axis activity in women with autoimmune disease compared to healthy women. Therefore, we analyzed salivary cortisol over the course of a day, and hair cortisol concentrations from the three preceding months, from 65 women divided into two groups: healthy women (n = 30), with a mean age of 44.70 ± 11.65 years; and women with autoimmune disease (n = 35), with a mean age of 48.26 ± 9.04 years. The latter group comprises women with systemic lupus erythematosus (SLE), Sjögren's syndrome (SS), and systemic sclerosis (SSc). Perceived stress and psychopathological symptomatology were also evaluated. Autoimmune disease group scored higher on the somatization subscale SCL-90-R and lower on the anxiety subscale than the control group. Regarding HPA axis activation, the area under curve for cortisol levels during the day was higher for the autoimmune disease group. In addition, higher cortisol levels in hair were found in the group with autoimmune disease. Our findings show greater short and long-term HPA axis activity in women with autoimmune disease than in healthy women.

  9. Acute incremental exercise, performance of a central executive task, and sympathoadrenal system and hypothalamic-pituitary-adrenal axis activity.

    PubMed

    McMorris, Terry; Davranche, Karen; Jones, Glenys; Hall, Ben; Corbett, Jo; Minter, Charles

    2009-09-01

    The purposes of this study were to examine the effect of acute incremental exercise on the performance of a central executive task; the responses of the sympathoadrenal system (SAS) and hypothalamic-pituitary-adrenal axis (HPAA) during exercise, while simultaneously carrying out the central executive task; and the ability of Delta plasma concentrations of epinephrine, norepinephrine, adrenocorticotropin hormone (ACTH) and cortisol to predict Delta performance on the central executive task. Subjects undertook a flanker task at rest and during exercise at 50% and 80% maximum aerobic power (MAP). SAS and HPAA activity were measured pre- and post-treatment by plasma concentrations of catecholamines, and cortisol and ACTH, respectively. Reaction time (RT) and number of errors for congruent and incongruent trials on the flanker task showed significant main effects with performance at 80% MAP higher than in the other conditions. RT post-correct responses were significantly faster than RT post-error at rest and 50% MAP but not at 80%. Pre- and post-treatment catecholamines showed a main effect of exercise with a linear increase. Post-treatment ACTH concentrations at 80% MAP were significantly greater than in the other conditions. Delta epinephrine and ACTH combined were significant predictors of Delta RT and Delta norepinephrine was a significant predictor of Delta number of errors. It was concluded that exercise must be at a high intensity to affect performance on the flanker task. Both the SAS and HPAA appear to play a role in the exercise-cognition interaction.

  10. Hypothalamic--pituitary-- adrenal axis dysregulation in women with irritable bowel syndrome in response to acute physical stress.

    PubMed

    FitzGerald, Leah Z; Kehoe, Priscilla; Sinha, Karabi

    2009-11-01

    Irritable bowel syndrome (IBS) supports the concept of a dysregulated hypothalamic-pituitary-adrenal (HPA) axis. This study investigates the neuroendocrine and psychological responses to the acute physical stress of a lumbar puncture (LP) in women with diarrhea-predominant IBS by assessing central and peripheral HPA activity and affective measures. Blood samples have been collected at baseline and immediately post- and 1 hr following LP from 13 women with IBS and 13 controls. Plasma adrenocorticotropic hormone (ACTH), cortisol, epinephrine, and norepinephrine levels are analyzed. A single measure of cerebrospinal fluid (CSF) concentrations of corticotropin-releasing factor (CRF(CSF)) and norepinephrine(CSF) is noted. Affective assessments are used to rate anxiety and depression with the Hospital Anxiety and Depression Scale (HADS) and acute mood state is rated using the Stress Symptom Rating questionnaire (stress, anxiety, anger, arousal). The women with IBS display blunted ACTH and cortisol responses to the LP along with a profile of affective responsiveness suggestive of chronic psychosocial stress, although no CRF(CSF) differences between groups are observed.

  11. Relevance of perceived childhood neglect, 5-HTT gene variants and hypothalamus-pituitary-adrenal axis dysregulation to substance abuse susceptibility.

    PubMed

    Gerra, G; Zaimovic, A; Castaldini, L; Garofano, L; Manfredini, M; Somaini, L; Leonardi, C; Gerra, M L; Donnini, C

    2010-04-05

    The hypotheses of (1) gene x environment interaction in the susceptibility to experiment with drugs and (2) hypothalamus-pituitary-adrenal (HPA) axis involvement in mediating the effects of early adverse experiences and gene variants affecting serotonin function on substance abuse vulnerability were tested by investigating in 187 healthy adolescents the possible relevance of 5-HTT "S" polymorphism, childhood parental neglect reported retrospectively and HPA axis function to the susceptibility to experiment with illicit drugs. Higher frequency of the 5-HTT SS genotype seems to be associated with an increased susceptibility to use illegal psychotropic drugs among the adolescents. At the same time, reduced maternal care perception was found to represent a key intermediate factor of the association between SS polymorphism and drug use, suggesting that genetic factors and parental behavior concur to drug use susceptibility. Our results also confirm the relationship between basal plasma levels of cortisol and adrenocorticotropic hormone (ACTH) on the one hand, and retrospective measures of neglect during childhood: the higher the mother and father neglect CECA-Q scores, the higher the plasma levels of the two HPA hormones. Such positive relationship has been proved to be particularly effective and important when associated to the S-allele, both in homozygote and heterozygote individuals. However, when tested together with genotype and parental neglect, the effect of HPA hormones such as cortisol and ACTH was not found to improve significantly the explanatory power of the risk model.

  12. Elevation by Oxidative Stress and Aging of Hypothalamic-Pituitary-Adrenal Activity in Rats and Its Prevention by Vitamin E

    PubMed Central

    Kobayashi, Naoko; Machida, Taiji; Takahashi, Takeyuki; Takatsu, Hirokatsu; Shinkai, Tadashi; Abe, Kouichi; Urano, Shiro

    2009-01-01

    The present study was conducted in order to determine whether oxidative stress during aging involves dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis in association with the emergence of cognitive deficits. When young rats were subjected to oxidative stress in the form of hyperoxia, thiobarbituric acid reactive substances, conjugated diene and lipid hydroperoxides increased markedly in the HPA axis. Vitamin E inhibited such increases in lipid peroxides in each organ. Levels of corticotrophin-releasing hormone in the hypothalamus and plasma levels of adrenocorticotrophic hormone and corticosterone were markedly elevated in young rats exposed to hyperoxia. However, young rats fed vitamin E-supplemented diets showed no abnormal hormone secretion, even after being subjected to hyperoxia. Furthermore, glucocorticosteroid receptors (GR) in pyramidal cells in the Cornus ammonis 1 region of the hippocampus in young rats were markedly decreased by oxidative stress. Similar phenomena were also observed in normal aged rats and young rats fed vitamin E-deficient diet kept in a normal atmosphere. Vitamin E supplementation prevented the decrease in GR in the hippocampus and the increase in corticosterone secretion caused by hyperoxia. These results suggest that oxidative stress induces oxidative damage in the hippocampus and the HPA axis during aging, resulting in a cognitive deficit in rats, and that negative-feedback inhibition on HPA activity was markedly dampened due to an increase in corticosterone levels caused by loss of GR. PMID:19794930

  13. Dysregulation of the sympathetic nervous system, hypothalamic-pituitary-adrenal axis and executive function in individuals at risk for suicide.

    PubMed

    McGirr, Alexander; Diaconu, Gabriel; Berlim, Marcelo T; Pruessner, Jens C; Sablé, Rebecca; Cabot, Sophie; Turecki, Gustavo

    2010-11-01

    Suicidal behaviour aggregates in families, and the hypothalamic-pituitary-adrenal (HPA) axis and noradrenergic dysregulation may play a role in suicide risk. It is unclear whether stress dysregulation is a heritable trait of suicide or how it might increase risk. We investigated stress reactivity of the autonomic nervous system and the HPA axis in suicide predisposition and characterized the effect of this dysregulation on neuropsychologic function. In this family-based study of first-degree relatives (n = 14) of suicide completers and matched controls with no family or personal history of suicidal behaviour (n = 14), participants underwent the Trier Social Stress Test (TSST). We used salivary α-amylase and cortisol levels to characterize stress reactivity and diurnal variation. We administered a series of neuropsychologic and executive function tests before and after the TSST. Despite normal diurnal variation, relatives of suicide completers exhibited blunted cortisol and α-amylase TSST reactivity. Although there were no baseline differences in conceptual reasoning, sustained attention or executive function, the relatives of suicide completers did not improve on measures of inhibition upon repeated testing after TSST. Secondary analyses suggested that these effects were related to suicide vulnerability independent of major depression. The sample size was small, and the design prevents us from disentangling our findings from the possible traumatic consequences of losing a relative by suicide. Blunted stress response may be a trait of suicide risk, and impairment of stress-induced executive function may contribute to suicide vulnerability.

  14. Microinfusion of a nitric oxide donor in discrete brain regions activates the hypothalamic-pituitary-adrenal axis.

    PubMed

    Seo, D O; Rivier, C

    2001-11-01

    We previously showed that the intracerebroventricular injection of the nitric oxide (NO) donor 3-morpholino-sydnonimine (SIN-1) released adrenocorticotropic hormone (ACTH) and upregulated transcripts for corticotropin-releasing factor (CRF) and vasopressin in the paraventricular nucleus (PVN) of the rat hypothalamus. In the present work, we microinfused SIN-1 into the PVN itself, the amygdala, the hippocampus or the frontal cortex to identify the brain regions that modulate the influence of NO on the hypothalamic-pituitary-adrenal (HPA) axis. Microinfusion into the PVN, which contains most of the CRF and vasopressin neurones that control HPA axis activity, significantly released ACTH. Microinfusion into the amygdala or the hippocampus, areas which also regulate HPA axis activity, similarly increased plasma ACTH levels. However, these responses were smaller and showed a delayed onset, compared to that observed following PVN treatment. In contrast, microinfusion of SIN-1 into the frontal cortex, which is not believed to exert a major direct influence on the HPA axis, was without effect. The observation that compared to microinfusion into the PVN, peak ACTH levels were both smaller and delayed when SIN-1 was microinfused into the amygdala or the hippocampus, and that SIN-1 only increased NO levels when injected into the PVN, suggests that the NO donor injected outside the PVN activates this nucleus by targeting pathways that connect it to these other regions rather than by leakage. Collectively, our results provide important clues regarding the putative role of these regions in modulating the influence of NO on the HPA axis.

  15. Sex differences in the behavioural and hypothalamic-pituitary-adrenal response to contextual fear conditioning in rats.

    PubMed

    Daviu, Núria; Andero, Raül; Armario, Antonio; Nadal, Roser

    2014-11-01

    In recent years, special attention is being paid to sex differences in susceptibility to disease. In this regard, there is evidence that male rats present higher levels of both cued and contextual fear conditioning than females. However, little is known about the concomitant hypothalamic-pituitary-adrenal (HPA) axis response to those situations which are critical in emotional memories. Here, we studied the behavioural and HPA responses of male and female Wistar rats to context fear conditioning using electric footshock as the aversive stimulus. Fear-conditioned rats showed a much greater ACTH and corticosterone response than those merely exposed to the fear conditioning chamber without receiving shocks. Moreover, males presented higher levels of freezing whereas HPA axis response was greater in females. Accordingly, during the fear extinction tests, female rats consistently showed less freezing and higher extinction rate, but greater HPA activation than males. Exposure to an open-field resulted in lower activity/exploration in fear-conditioned males, but not in females, suggesting greater conditioned cognitive generalization in males than females. It can be concluded that important sex differences in fear conditioning are observed in both freezing and HPA activation, but the two sets of variables are affected in the opposite direction: enhanced behavioural impact in males, but enhanced HPA responsiveness in females. Thus, the role of sex differences on fear-related stimuli may depend on the variables chosen to evaluate it, the greater responsiveness of the HPA axis in females perhaps being an important factor to be further explored.

  16. Regulation of 5-HT receptors and the hypothalamic-pituitary-adrenal axis. Implications for the neurobiology of suicide.

    PubMed

    López, J F; Vázquez, D M; Chalmers, D T; Watson, S J

    1997-12-29

    Disturbances in the serotonin (5-HT) system is the neurobiological abnormality most consistently associated with suicide. Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis is also described in suicide victims. The HPA axis is the classical neuroendocrine system that responds to stress and whose final product, corticosteroids, targets components of the limbic system, particularly the hippocampus. We will review results from animal studies that point to the possibility that many of the 5-HT receptor changes observed in suicide brains may be a result of, or may be worsened by, the HPA overactivity that may be present in some suicide victims. The results of these studies can be summarized as follows: (1) chronic unpredictable stress produces high corticosteroid levels in rats; (2) chronic stress also results in changes in specific 5-HT receptors (increases in cortical 5-HT2A and decreases in hipocampal 5-HT1A and 5-HT1B); (3) chronic antidepressant administration prevents many of the 5-HT receptor changes observed after stress; and (4) chronic antidepressant administration reverses the overactivity of the HPA axis. If indeed 5-HT receptors have a partial role in controlling affective states, then their modulation by corticosteroids provides a potential mechanism by which these hormones may regulate mood. These data may also provide a biological understanding of how stressful events may increase the risk for suicide in vulnerable individuals and may help us elucidate the neurobiological underpinnings of treatment resistance.

  17. Effects of nutritional stress during different developmental periods on song and the hypothalamic-pituitary-adrenal axis in zebra finches.

    PubMed

    Kriengwatana, B; Wada, H; Schmidt, K L; Taves, M D; Soma, K K; MacDougall-Shackleton, S A

    2014-03-01

    In songbirds, developmental stress affects song learning and production. Altered hypothalamic-pituitary-adrenal (HPA) axis function resulting in elevated corticosterone (CORT) may contribute to this effect. We examined whether developmental conditions affected the association between adult song and HPA axis function, and whether nutritional stress before and after nutritional independence has distinct effects on song learning and/or vocal performance. Zebra finches (Taeniopygia guttata) were raised in consistently high (HH) or low (LL) food conditions until post-hatch day (PHD) 62, or were switched from high to low conditions (HL) or vice versa (LH) at PHD 34. Song was recorded in adulthood. We assessed the response of CORT to handling during development and to dexamethasone (DEX) and adrenocorticotropic hormone (ACTH) challenges during adulthood. Song learning and vocal performance were not affected by nutritional stress at either developmental stage. Nutritional stress elevated baseline CORT during development. Nutritional stress also increased rate of CORT secretion in birds that experienced stress only in the juvenile phase (HL group). Birds in the LL group had lower CORT levels after injection of ACTH compared to the other groups, however there was no effect of nutritional stress on the response to DEX. Thus, our findings indicate that developmental stress can affect HPA function without concurrently affecting song.

  18. Associations of childhood trauma with hypothalamic-pituitary-adrenal function in borderline personality disorder and major depression.

    PubMed

    Carvalho Fernando, Silvia; Beblo, Thomas; Schlosser, Nicole; Terfehr, Kirsten; Otte, Christian; Löwe, Bernd; Wolf, Oliver Tobias; Spitzer, Carsten; Driessen, Martin; Wingenfeld, Katja

    2012-10-01

    Alterations of the hypothalamus-pituitary-adrenal (HPA) axis are hallmarks in major depressive disorder (MDD) and there is some evidence about similar patterns in borderline personality disorder (BPD). This study examines HPA axis abnormalities with respect to clinical characteristics in both BPD (n=24) and MDD patients (n=33) as well as in healthy control participants (n=41). A 0.5mg dexamethasone suppression test was administered to evaluate basal cortisol release and HPA feedback sensitivity via salivary cortisol. Traumatic experiences in childhood as well as severity of borderline and depressive symptom severity and dissociation were obtained by self-report questionnaires. Compared to the healthy control group, BPD and MDD patients exhibited both enhanced cortisol concentrations before and after the administration of 0.5mg dexamethasone. Higher cortisol levels were positively correlated to a history of childhood trauma, current dissociative symptoms and severity of borderline and depressive symptoms. Regression analyses revealed that some aspects of early trauma were associated with cortisol release before and after dexamethasone, whereas psychopathology did not contribute to the regression model. HPA dysfunctions appear to be related rather to childhood trauma than to psychopathology in adulthood. Exposure to childhood trauma may contribute to long-lasting alterations in HPA activity and might enhance the risk for the development of later mental disorder. Copyright © 2012 Elsevier Ltd. All rights reserved.

  19. Hypothalamic-pituitary-adrenal axis functioning and dysfunctional attitude in depressed patients with and without childhood neglect

    PubMed Central

    2014-01-01

    Background To date, the relationships between childhood neglect, hypothalamic-pituitary-adrenal (HPA) axis functioning and dysfunctional attitude in depressed patients are still obscure. Methods The Childhood Trauma Questionnaire (CTQ) was used to assess childhood emotional neglect and physical neglect. Twenty-eight depressed patients with childhood neglect and 30 depressed patients without childhood neglect from Guangzhou Psychiatric Hospital were compared with 29 age- and gender-matched control subjects without childhood neglect and 22 control subjects with childhood neglect. Cortisol awakening response, the difference between the cortisol concentrations at awakening and 30 minutes later, provided a measure of HPA axis functioning. The Dysfunctional Attitude Scale measured cognitive schema. Results HPA axis functioning was significantly increased in depressed patients with childhood neglect compared with depressed patients without childhood neglect (p < 0.001). HPA axis activity in the control group with childhood neglect was significantly higher than in the depressed group without childhood neglect (p < 0.001). Total scores of childhood neglect were positively correlated with HPA axis functioning and dysfunctional attitude scores, but not with severity of depression. We did not find correlations with HPA axis functioning and dysfunctional attitude or with the Hamilton Rating Scale for Depression scores. Conclusions Childhood neglect may cause hyperactivity of the HPA axis functioning and dysfunctional attitude, but does not affect depression severity. PMID:24548345

  20. Hypothalamic-pituitary-adrenal axis functioning and dysfunctional attitude in depressed patients with and without childhood neglect.

    PubMed

    Peng, Hongjun; Long, Ying; Li, Jie; Guo, Yangbo; Wu, Huawang; Yang, YuLing; Ding, Yi; He, Jianfei; Ning, Yuping

    2014-02-18

    To date, the relationships between childhood neglect, hypothalamic-pituitary-adrenal (HPA) axis functioning and dysfunctional attitude in depressed patients are still obscure. The Childhood Trauma Questionnaire (CTQ) was used to assess childhood emotional neglect and physical neglect. Twenty-eight depressed patients with childhood neglect and 30 depressed patients without childhood neglect from Guangzhou Psychiatric Hospital were compared with 29 age- and gender-matched control subjects without childhood neglect and 22 control subjects with childhood neglect. Cortisol awakening response, the difference between the cortisol concentrations at awakening and 30 minutes later, provided a measure of HPA axis functioning. The Dysfunctional Attitude Scale measured cognitive schema. HPA axis functioning was significantly increased in depressed patients with childhood neglect compared with depressed patients without childhood neglect (p < 0.001). HPA axis activity in the control group with childhood neglect was significantly higher than in the depressed group without childhood neglect (p < 0.001). Total scores of childhood neglect were positively correlated with HPA axis functioning and dysfunctional attitude scores, but not with severity of depression. We did not find correlations with HPA axis functioning and dysfunctional attitude or with the Hamilton Rating Scale for Depression scores. Childhood neglect may cause hyperactivity of the HPA axis functioning and dysfunctional attitude, but does not affect depression severity.

  1. Income, cumulative risk, and longitudinal profiles of hypothalamic-pituitary-adrenal axis activity in preschool-age children.

    PubMed

    Zalewski, Maureen; Lengua, Liliana J; Thompson, Stephanie F; Kiff, Cara J

    2016-05-01

    Environmental risk predicts disrupted basal cortisol levels in preschool children. However, little is known about the stability or variability of diurnal cortisol morning levels or slope patterns over time in young children. This study used latent profile analysis to identify patterns of the hypothalamic-pituitary-adrenal axis activity during the preschool period. Using a community sample (N = 306), this study measured income, cumulative risk, and children's diurnal cortisol (morning level and slope) four times across 2.5 years, starting when children were 36 months old. Latent profile analysis profiles indicated that there were predominantly stable patterns of diurnal cortisol level and slope over time and that these patterns were predicted by income and cumulative risk. In addition, there were curvilinear relations of income and cumulative risk to profiles of low morning cortisol level and flattened diurnal slope across time, suggesting that both lower and higher levels of income and cumulative risk were associated with a stress-sensitive physiological system. Overall, this study provides initial evidence for the role of environmental risk in predicting lower, flattened basal cortisol patterns that remain stable over time.

  2. The hypothalamic-pituitary-adrenal axis and serotonin abnormalities: a selective overview for the implications of suicide prevention.

    PubMed

    Pompili, Maurizio; Serafini, Gianluca; Innamorati, Marco; Möller-Leimkühler, Anne Maria; Giupponi, Giancarlo; Girardi, Paolo; Tatarelli, Roberto; Lester, David

    2010-12-01

    Suicidal behavior and mood disorders are one of the world's largest public health problems. The biological vulnerability for these problems includes genetic factors involved in the regulation of the serotonergic system and stress system. The hypothalamic-pituitary-adrenal (HPA) axis is a neuroendocrine system that regulates the body's response to stress and has complex interactions with brain serotonergic, noradrenergic and dopaminergic systems. Corticotropin-releasing hormone and vasopressin act synergistically to stimulate the secretion of ACTH that stimulates the biosynthesis of corticosteroids such as cortisol from cholesterol. Cortisol is a major stress hormone and has effects on many tissues, including on mineralocorticoid receptors and glucocorticoid receptors in the brain. Glucocorticoids produce behavioral changes, and one important target of glucocorticoids is the hypothalamus, which is a major controlling center of the HPA axis. Stress plays a major role in the various pathophysiological processes associated with mood disorders and suicidal behavior. Serotonergic dysfunction is a well-established substrate for mood disorders and suicidal behavior. Corticosteroids may play an important role in the relationship between stress, mood changes and perhaps suicidal behavior by interacting with 5-HT1A receptors. Abnormalities in the HPA axis in response to increased levels of stress are found to be associated with a dysregulation in the serotonergic system, both in subjects with mood disorders and those who engage in suicidal behavior. HPA over-activity may be a good predictor of mood disorders and perhaps suicidal behavior via abnormalities in the serotonergic system.

  3. Hair cortisol as a marker of hypothalamic-pituitary-adrenal Axis activity in female patients with major depressive disorder.

    PubMed

    Pochigaeva, Ksenia; Druzhkova, Tatiana; Yakovlev, Alexander; Onufriev, Mikhail; Grishkina, Maria; Chepelev, Aleksey; Guekht, Alla; Gulyaeva, Natalia

    2017-04-01

    Hair cortisol is regarded as a promising marker of hypothalamic-pituitary-adrenal axis (HPAA) activity alterations due to stress, somatic and mental health conditions. Hair cortisol was previously reported to be elevated in patients with depression, however the data related to remission and recurrent depressive episodes are different. In this study, levels of hair cortisol were assessed in female patients with major depressive disorder (MDD) and the validity of hair cortisol as a marker of HPAA activity in this condition was evaluated. Hair cortisol was measured in 1 cm hair segments of 21 female patients with MDD and 22 female age-matched controls using enzyme-immunoassay analysis. Concurrently, serum cortisol was assessed and psychological status was evaluated using 17-item Hamilton Depression Rating Scale (HAMD-17), Beck Depression Inventory (BDI) and the Spielberger state trait anxiety inventory (STAI). The levels of hair cortisol were significantly lower in the MDD group, while serum cortisol levels were significantly higher in patients, as compared with controls. A significant negative correlation was found between HAMD-17 scores and hair cortisol. Decreased hair cortisol found in female patients with MDD as compared to controls suggests downregulation of HPAA activity during the preceding month. Further studies are needed to investigate the profiles of hair cortisol at different stages of depressive disorder to establish this parameter as a handy clinical tool.

  4. Critical features of acute stress-induced cross-sensitization identified through the hypothalamic-pituitary-adrenal axis output

    PubMed Central

    Belda, Xavier; Nadal, Roser; Armario, Antonio

    2016-01-01

    Stress-induced sensitization represents a process whereby prior exposure to severe stressors leaves animals or humans in a hyper-responsive state to further stressors. Indeed, this phenomenon is assumed to be the basis of certain stress-associated pathologies, including post-traumatic stress disorder and psychosis. One biological system particularly prone to sensitization is the hypothalamic-pituitary-adrenal (HPA) axis, the prototypic stress system. It is well established that under certain conditions, prior exposure of animals to acute and chronic (triggering) stressors enhances HPA responses to novel (heterotypic) stressors on subsequent days (e.g. raised plasma ACTH and corticosterone levels). However, such changes remain somewhat controversial and thus, the present study aimed to identify the critical characteristics of the triggering and challenging stressors that affect acute stress-induced HPA cross-sensitization in adult rats. We found that HPA cross-sensitization is markedly influenced by the intensity of the triggering stressor, whereas the length of exposure mainly affects its persistence. Importantly, HPA sensitization is more evident with mild than strong challenging stressors, and it may remain unnoticed if exposure to the challenging stressor is prolonged beyond 15 min. We speculate that heterotypic HPA sensitization might have developed to optimize biologically adaptive responses to further brief stressors. PMID:27511270

  5. The link between aberrant hypothalamic-pituitary-adrenal axis activity during development and the emergence of aggression-Animal studies.

    PubMed

    Walker, Sophie E; Papilloud, Aurélie; Huzard, Damien; Sandi, Carmen

    2016-10-14

    Aggressive behavior is not uniform, including proactive and reactive forms of aggression. Aberrant functioning of the hypothalamic-pituitary-adrenal (HPA) axis is frequently associated with abnormal aggression. Here, we review the rodent literature in order to assess whether developmental abnormalities in the HPA axis can be causally linked with the emergence of abnormal aggression. We examine studies that involve genetic models and life challenges (e.g., early life stress, drug exposure) that course with developmental alterations in the HPA axis. Although the lack of systematic studies hinders development of an integrated model, existing evidence supports a U-shaped function regarding differences in HPA axis functioning during development and the emergence of aggressive phenotypes. Thus, developmentally low or high HPA axis reactivity are typically found to be aligned with the emergence of aggressive phenotypes; however, existing information is insufficient to causally link divergent HPA axis aberration with specific types of aggression. Progress in this field is needed to support interventions in children aimed at ameliorating social dysfunctions associated with aberrations in HPA axis function. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. Autonomic reactivity and hypothalamic pituitary adrenal axis dysregulation in spouses of Oklahoma City bombing survivors 7 years after the attack

    PubMed Central

    Pfefferbaum, Betty; Tucker, Phebe; North, Carol S.; Jeon-Slaughter, Haekyung

    2012-01-01

    Objective The objective of this exploratory pilot study was to examine autonomic reactivity and hypothalamic pituitary adrenal axis dysregulation in spouses of highly exposed survivors of the 1995 Oklahoma City bombing. Methods This study compared psychiatric diagnoses and biological stress markers (physiological reactivity and cortisol measures) in spouses of bombing survivors and matched community participants. Spouses were recruited through bombing survivors who participated in prior studies. Individuals with medical illnesses and those taking psychotropic medications that would confound biological stress measures were excluded. The final sample included 15 spouses and 15 community participants. The primary outcome measures were psychiatric diagnoses assessed with the Diagnostic Interview Schedule for DSM-IV (DIS-IV). Biological stress markers were physiological reactivity and recovery in heart rate and blood pressure responses to a trauma interview and cortisol (morning, afternoon, and diurnal variation). Results Compared to the community participants, spouses evidenced greater reactivity in heart rate, systolic blood pressure, and diastolic blood pressure; delayed recovery in systolic blood pressure; and higher afternoon salivary cortisol. Conclusions The results support the need for further research in this area to clarify post-disaster effects on biological stress measures in the spouses of survivors and the potential significance of these effects and to address the needs of this important population which may be overlooked in recovery efforts. PMID:22520087

  7. Metabolic changes, hypothalamo-pituitary-adrenal axis and oxidative stress after short-term starvation in healthy pregnant women.

    PubMed

    Schraag, Sabrina; Mandach, Ursula von; Schweer, Horst; Beinder, Ernst

    2007-01-01

    To compare metabolic effects and oxidative stress in pregnant and non-pregnant women after 12 h of fasting. Twenty-six healthy women with uncomplicated singleton pregnancies between the 24(th) and 28(th) gestational week were recruited. After an overnight fast, venous blood samples and urine samples were tested for metabolic parameters characteristic for starvation, cortisol and oxidative stress products. Healthy non-pregnant women matched by age, body mass index and length of fasting comprised the control group. The metabolic parameters beta-hydroxybutyrate and free fatty acids in blood and ketones in urine showed no differences in pregnant and non-pregnant women. However, the oxidative stress parameters, 8,12-iso-iPF(2alpha)-VI, isoprostanes and malondialdehyde were significantly higher in pregnant subjects, as was cortisol. Healthy pregnant women are exposed to oxidative stress and activation of the hypothalamo-pituitary-adrenal axis, but not to metabolic changes resembling starvation during short fasting periods in comparison to non-pregnant healthy women.

  8. Quantifying Pituitary-Adrenal Dynamics and Deconvolution of Concurrent Cortisol and Adrenocorticotropic Hormone Data by Compressed Sensing.

    PubMed

    Faghih, Rose T; Dahleh, Munther A; Adler, Gail K; Klerman, Elizabeth B; Brown, Emery N

    2015-10-01

    Pulsatile release of cortisol from the adrenal glands is governed by pulsatile release of adrenocorticotropic hormone (ACTH) from the anterior pituitary. In return, cortisol has a negative feedback effect on ACTH release. Simultaneous recording of ACTH and cortisol is not typical, and determining the number, timing, and amplitudes of pulsatile events from simultaneously recorded data is challenging because of several factors: 1) stimulator ACTH pulse activity, 2) kinematics of ACTH and cortisol, 3) the sampling interval, and 4) the measurement error. We model ACTH and cortisol secretion simultaneously using a linear differential equations model with Gaussian errors and sparse pulsatile events as inputs to the model. We propose a novel framework for recovering pulses and parameters underlying the interactions between ACTH and cortisol. We recover the timing and amplitudes of pulses using compressed sensing and employ generalized cross validation for determining the number of pulses. We analyze serum ACTH and cortisol levels sampled at 10-min intervals over 24 h from ten healthy women. We recover physiologically plausible timing and amplitudes for these pulses and model the feedback effect of cortisol. We recover 15 to 18 pulses over 24 h, which is highly consistent with the results of another cortisol data analysis approach. Modeling the interactions between ACTH and cortisol allows for accurate quantification of pulsatile events, and normal and pathological states. This could lay the basis for a more physiologically-based approach for administering cortisol therapeutically. The proposed approach can be adapted to deconvolve other pairs of hormones with similar interactions.

  9. Long-term anti-tumor necrosis factor antibody therapy in rheumatoid arthritis patients sensitizes the pituitary gland and favors adrenal androgen secretion.

    PubMed

    Straub, Rainer H; Pongratz, Georg; Schölmerich, Jürgen; Kees, Frieder; Schaible, Thomas F; Antoni, Christian; Kalden, Joachim R; Lorenz, Hanns-Martin

    2003-06-01

    New insights into the role of tumor necrosis factor (TNF) in the pathogenesis of rheumatoid arthritis (RA) have expanded our understanding about the possible mechanisms by which anti-TNF antibody therapy reduces local synovial inflammation. Beyond local effects, anti-TNF treatment may modulate systemic antiinflammatory pathways such as the hypothalamic-pituitary-adrenal (HPA) axis. This longitudinal anti-TNF therapy study was designed to assess these effects in RA patients. RA patients were given 5 infusions of anti-TNF at weeks 0, 2, 6, 10, and 14, with followup observation until week 16. We measured serum levels of interleukin-6 (IL-6), adrenocorticotropic hormone (ACTH), 17-hydroxyprogesterone (17[OH]progesterone), cortisol, cortisone, androstenedione (ASD), dehydroepiandrosterone (DHEA), and DHEA sulfate in 19 RA patients. Upon treatment with anti-TNF, we observed a fast decrease in the levels of serum IL-6, particularly in RA patients who did not receive parallel prednisolone treatment (P = 0.043). In these RA patients who had not received prednisolone, the mean serum ACTH levels sharply increased after every injection of anti-TNF, which indicates a sensitization of the pituitary gland (not observed for the adrenal gland). During treatment, the ratio of serum cortisol to serum ACTH decreased, which also indicates a sensitization of the pituitary gland (P < 0.001), and which was paralleled by constant cortisol secretion. The adrenal androgen ASD significantly increased relative to its precursor 17(OH)progesterone (P = 0.013) and relative to cortisol (P = 0.009), which indicates a normalization of adrenal androgen production. The comparison of patients previously treated with prednisolone and those without previous prednisolone revealed marked differences in the central and adrenal level of this endocrine axis during long-term anti-TNF therapy. Long-term therapy with anti-TNF sensitizes the pituitary gland and improves adrenal androgen secretion in patients who

  10. The impact of maternal overnutrition and obesity on hypothalamic-pituitary-adrenal axis response of offspring to stress.

    PubMed

    Long, N M; Nathanielsz, P W; Ford, S P

    2012-05-01

    We evaluated the effect of maternal obesity before and throughout gestation on offspring hypothalamic-pituitary-adrenal axis function. Multiparous Rambouillet by Columbia crossbred ewes were fed either 100% of National Research Council (NRC) recommendations (control, C) or 150% of NRC recommendations (obese, OB) from 60 d before mating until lambing. Ten lambs born to OB ewes (five males and five females), and eight lambs born to C ewes (three male and five female) were studied. From delivery to weaning lambs were maintained with their mothers, who were all fed 100% NRC recommendations. After weaning, all lambs were group housed and fed the same diet to meet NRC requirements. At 19 mo of age lambs were placed in individual pens and fed a pelletized diet to meet maintenance requirements. Jugular vein catheters were placed and 2 d later lambs received an intravenous (i.v.) adrenocorticotropic hormone (ACTH) challenge followed by an i.v. corticotropin-releasing hormone (CRH)/arginine vasopressin (AVP) challenge 1 d later. Thirty d later offspring were again catheterized and placed into metabolism crates for 2 d before receiving an isolation stress test. ACTH and cortisol responses to the isolation stress test and CRH/AVP challenge and cortisol responses to ACTH challenge were determined. Cortisol was quantified via radioimmunoassay and ACTH was quantified using an Immulite 1000; both were analyzed using repeated measures using the MIXED procedure of SAS. Offspring from OB ewes had elevated basal plasma ACTH and cortisol compared with C offspring before all three challenges (P < 0.05). Offspring from OB mothers tended (P = 0.06) to have a greater ACTH response after an i.v. CRH/AVP injection than offspring from C mothers (12,340 ± 1,430 vs 8,170 ± 1,570 area under the curve, respectively). Cortisol response to the CRH/AVP and ACTH challenges was not influenced by maternal nutrition (P = 0.46) and averaged 4.77 ± 0.2 μg/dL and 1.94 ± 0.01 μg/dL, respectively. The

  11. The effect of hypothalamo-pituitary disconnection on the functional and morphologic development of the pituitary-adrenal axis in the fetal sheep in the last third of gestation.

    PubMed

    Antolovich, G C; McMillen, I C; Robinson, P M; Silver, M; Young, I R; Perry, R A

    1991-09-01

    We have investigated the effect of hypothalamo-pituitary disconnection (HPD) on the maturation of basal ir-ACTH and cortisol concentrations in fetal sheep plasma, and on the development of the anterior pituitary corticotroph population in the last third of gestation. After HPD, fetal plasma ir-ACTH concentrations were significantly elevated, and continued to rise with increasing gestational age. However, despite elevated ir-ACTH concentrations, there was no increase in fetal plasma cortisol concentrations, and parturition was delayed for at least 8 days beyond normal term. Furthermore, HPD resulted in a significant disruption of the maturation of the pars distalis corticotrophs. We also examined the change in fetal plasma concentrations of ir-ACTH and cortisol to exogenous CRF after HPD. There was a significant increase in plasma ir-ACTH in response to CRF administration in the HPD fetuses, which was qualitatively similar to that observed in sham-operated fetuses. In contrast, the plasma cortisol response was less in HPD fetuses when compared to that in sham-operated fetuses. The results of this study demonstrate that ir-ACTH secretion is not maintained by the fetal hypothalamus in the last third of gestation, and that ir-ACTH secretion is tonically inhibited by the hypothalamus during this time. The disconnection of the pituitary from the hypothalamus disrupts the maturation of the pituitary-adrenal axis, thus demonstrating the fundamental importance of the hypothalamo-pituitary axis in the normal maturational cascade which culminates in birth in this species.

  12. Adrenal insufficiency.

    PubMed

    Auron, Moises; Raissouni, Nouhad

    2015-03-01

    Adrenal insufficiency is a life-threatening condition that occurs secondary to impaired secretion of adrenal glucocorticoid and mineralocorticoid hormones. This condition can be caused by primary destruction or dysfunction of the adrenal glands or impairment of the hypothalamic-pituitary-adrenal axis. In children, the most common causes of primary adrenal insufficiency are impaired adrenal steroidogenesis (congenital adrenal hyperplasia) and adrenal destruction or dysfunction (autoimmune polyendocrine syndrome and adrenoleukodystrophy), whereas exogenous corticosteroid therapy withdrawal or poor adherence to scheduled corticosteroid dosing with long-standing treatment constitute the most common cause of acquired adrenal insufficiency. Although there are classic clinical signs (eg, fatigue, orthostatic hypotension, hyperpigmentation, hyponatremia, hyperkalemia, and hypoglycemia) of adrenal insufficiency, its early clinical presentation is most commonly vague and undefined, requiring a high index of suspicion. The relevance of early identification of adrenal insufficiency is to avoid the potential lethal outcome secondary to severe cardiovascular and hemodynamic insufficiency. The clinician must be aware of the need for increased corticosteroid dose supplementation during stress periods.

  13. Acupuncture Relieves the Excessive Excitation of Hypothalamic-Pituitary-Adrenal Cortex Axis Function and Correlates with the Regulatory Mechanism of GR, CRH, and ACTHR.

    PubMed

    Wang, Shao-Jun; Zhang, Jiao-Jiao; Qie, Li-Li

    2014-01-01

    It had been indicated in the previous studies that acupuncture relieved the excessive excitation of hypothalamic-pituitary-adrenal cortex axis (HPAA) function induced by stress stimulation. But the changes in glucocorticoid receptor (GR) induced by acupuncture have not been detected clearly. The objective of the study was to observe the impacts of acupuncture on the protein expressions of corticotrophin releasing hormone (CRH), adrenocorticotropic hormone receptor (ACTHR), and GR under the physiological and stress states. The results showed that under the stress state, acupuncture upregulated the protein expression of GR in the hippocampus, hypothalamic paraventricular nucleus (PVN), and pituitary gland, downregulated the protein expression of GR in the adrenal cortex, and obviously reduced the protein expressions of CRH and ACTHR. Under the physiological state, acupuncture promoted GR protein expression in the hippocampus and CRH protein expression in the hippocampus and PVN. The results explained that acupuncture regulated the stress reaction via promoting the combination of glucocorticoids (GC) with GR, and GR protein expression. The increase of GR protein expression induced feedback inhibition on the overexpression of CRH and ACTHR, likely decreased GC level, and caused the reduction of GR protein expression in the adrenal cortex.

  14. Acupuncture Relieves the Excessive Excitation of Hypothalamic-Pituitary-Adrenal Cortex Axis Function and Correlates with the Regulatory Mechanism of GR, CRH, and ACTHR

    PubMed Central

    Wang, Shao-Jun; Zhang, Jiao-Jiao; Qie, Li-Li

    2014-01-01

    It had been indicated in the previous studies that acupuncture relieved the excessive excitation of hypothalamic-pituitary-adrenal cortex axis (HPAA) function induced by stress stimulation. But the changes in glucocorticoid receptor (GR) induced by acupuncture have not been detected clearly. The objective of the study was to observe the impacts of acupuncture on the protein expressions of corticotrophin releasing hormone (CRH), adrenocorticotropic hormone receptor (ACTHR), and GR under the physiological and stress states. The results showed that under the stress state, acupuncture upregulated the protein expression of GR in the hippocampus, hypothalamic paraventricular nucleus (PVN), and pituitary gland, downregulated the protein expression of GR in the adrenal cortex, and obviously reduced the protein expressions of CRH and ACTHR. Under the physiological state, acupuncture promoted GR protein expression in the hippocampus and CRH protein expression in the hippocampus and PVN. The results explained that acupuncture regulated the stress reaction via promoting the combination of glucocorticoids (GC) with GR, and GR protein expression. The increase of GR protein expression induced feedback inhibition on the overexpression of CRH and ACTHR, likely decreased GC level, and caused the reduction of GR protein expression in the adrenal cortex. PMID:24761151

  15. Hypothalamic pituitary adrenal axis and hypothalamic-neurohypophyseal responsiveness in water-deprived rats.

    PubMed

    Grinevich, V; Ma, X M; Verbalis, J; Aguilera, G

    2001-10-01

    The differential effects of osmotic stimulation on magnocellular and parvocellular hypothalamic neurons were studied by analysis of corticotropin-releasing hormone (CRH) and vasopressin (VP) expression in controls and 48-h water-deprived rats subjected to either restraint for 1 h or a single lipopolysaccharide injection (250 microg/100 g). Water deprivation reduced basal CRH mRNA levels but the increments following 4 h of restraint or 6 h lipopolysaccharide (LPS) injection were similar to those in controls. In contrast, water deprivation had no effect on basal VP heteronuclear RNA (hnRNA) and mRNA levels in parvocellular neurons, but responses to restraint or LPS injection were reduced. VP expression in magnocellular paraventricular and supraoptic nuclei, and plasma sodium and vasopressin were higher in water-deprived rats, changes which were unaffected by restraint. LPS injection reduced VP mRNA but not hnRNA levels in magnocellular neurons and increased plasma vasopressin levels only in water-deprived rats independently of changes in plasma sodium. This was accompanied by an increase in vasopressin mRNA content in the posterior pituitary. The data show that the blunted ACTH responses to acute stress during chronic osmotic stimulation are correlated with the inability of parvocellular neurons to increase VP rather than CRH expression. In addition, LPS-induced endotoxemia causes disturbances of the magnocellular vasopressinergic system with an unexpected potentiation of osmotic simulated VP secretion. The lack of increase in VP transcription after LPS and changes in VP mRNA distribution suggest that endotoxemia affect the secretory process at the levels of the neurohypophyseal axon terminal.

  16. Developmental methamphetamine exposure results in short- and long-term alterations in hypothalamic-pituitary-adrenal-axis-associated proteins.

    PubMed

    Zuloaga, Damian G; Siegel, Jessica A; Acevedo, Summer F; Agam, Maayan; Raber, Jacob

    2013-01-01

    Developmental exposure to methamphetamine (MA) causes long-term behavioral and cognitive deficits. One pathway through which MA might induce these deficits is by elevating glucocorticoid levels. Glucocorticoid overexposure during brain development can lead to long-term disruptions in the hypothalamic-pituitary-adrenal (HPA) axis. These disruptions affect the regulation of stress responses and may contribute to behavioral and cognitive deficits reported following developmental MA exposure. Furthermore, alterations in proteins associated with the HPA axis, including vasopressin, oxytocin, and glucocorticoid receptors (GR), are correlated with disruptions in mood and cognition. We therefore hypothesized that early MA exposure will result in short- and long-term alterations in the expression of HPA axis-associated proteins. Male mice were treated with MA (5 mg/kg daily) or saline from postnatal day (P) 11 to P20. At P20 and P90, mice were perfused and their brains processed for vasopressin, oxytocin, and GR immunoreactivity within HPA axis-associated regions. At P20, there was a significant decrease in the number of vasopressin-immunoreactive cells and the area occupied by vasopressin immunoreactivity in the paraventricular nucleus (PVN) of MA-treated mice, but no difference in oxytocin immunoreactivity in the PVN, or GR immunoreactivity in the hippocampus or PVN. In the central nucleus of the amygdala, the area occupied by GR immunoreactivity was decreased by MA. At P90, the number of vasopressin-immunoreactive cells was still decreased, but the area occupied by vasopressin immunoreactivity no longer differed from saline controls. No effects of MA were found on oxytocin or GR immunoreactivity at P90. Thus developmental MA exposure has short- and long-term effects on vasopressin immunoreactivity and short-term effects on GR immunoreactivity.

  17. Effects of specific mu and kappa opiate tolerance and abstinence on hypothalamo-pituitary-adrenal axis secretion in the rat.

    PubMed

    Ignar, D M; Kuhn, C M

    1990-12-01

    Chronic administration of opiates to rats results in HPA axis tolerance and abstinence-induced hypersecretion. The effects of specific mu and kappa tolerance and withdrawal on the functional secretion of the HPA axis were evaluated in this study. Adult male rats were injected s.c. twice daily with saline, morphine or U50,488 for 5 days. Serum adrenocorticotrophic hormone (ACTH) or corticosterone (CS) were determined by radioimmunoassay as measures of HPA axis function. Tolerance to morphine (10 mg/kg) and U50,488 (1 mg/kg), but no cross-tolerance, was observed suggesting the development of mu- or kappa-specific tolerance, respectively. Tolerance does not occur at the pituitary or adrenal levels after these paradigms because ACTH and CS responses to exogenous corticotropin-releasing factor and ACTH, respectively, were not attenuated. CS secretion in response to novelty stress was not affected by either chronic opiate treatment, but the circadian variation of CS levels was slightly blunted after chronic morphine. In contrast, the elevation of CS secretion by quipazine (0.5 mg/kg) and physostigmine (0.1 mg/kg) was attenuated after chronic U50,488, but not morphine administration. Both spontaneous and antagonist-precipitated withdrawal from morphine, but not U50,488, resulted in elevation of CS levels. Low doses of morphine suppressed morphine abstinence-induced CS hypersecretion, whereas, U50,488 and clonidine had no effect. In conclusion, alterations of HPA axis function occur during chronic mu or kappa opiate administration that are receptor-specific and involve multiple neural controls of the HPA axis.

  18. Cat odor causes long-lasting contextual fear conditioning and increased pituitary-adrenal activation, without modifying anxiety.

    PubMed

    Muñoz-Abellán, Cristina; Daviu, Nuria; Rabasa, Cristina; Nadal, Roser; Armario, Antonio

    2009-10-01

    A single exposure to a cat or cat odors has been reported by some groups to induce contextual and auditory fear conditioning and long-lasting changes in anxiety-like behaviour, but there is no evidence for parallel changes in biological stress markers. In the present study we demonstrated in male rats that exposure to a novel environment containing a cloth impregnated with cat fur odor resulted in avoidance of the odor, lower levels of activity and higher pituitary-adrenal (PA) response as compared to those exposed to the novel environment containing a clean cloth, suggesting increased levels of stress in the former animals. When re-exposed 9 days later to the same environment with a clean cloth, previously cat fur exposed rats again showed avoidance of the cloth area and lower levels of activity, suggesting development of contextual fear conditioning, which again was associated with a higher PA activation. In contrast, unaltered both anxiety-like behaviour and PA responsiveness to an elevated plus-maze were found 7 days after cat odor exposure. It is concluded that: (i) PA activation is able to reflect both the stressful properties of cat fur odor and odor-induced contextual fear conditioning; (ii) development of cat odor-induced contextual fear conditioning is independent of the induction of long-lasting changes in anxiety-like behaviour; and (iii) greater PA activation during exposure to the odor context is not explained by non-specific sensitization of the PA axis caused by previous exposure to cat fur odor.

  19. Leptin fails to blunt the lipopolysaccharide-induced activation of the hypothalamic-pituitary-adrenal axis in rats.

    PubMed

    Basharat, Saadia; Parker, Jennifer A; Murphy, Kevin G; Bloom, Stephen R; Buckingham, Julia C; John, Christopher D

    2014-05-01

    Obesity is a risk factor for sepsis morbidity and mortality, whereas the hypothalamic-pituitary-adrenal (HPA) axis plays a protective role in the body's defence against sepsis. Sepsis induces a profound systemic immune response and cytokines serve as excellent markers for sepsis as they act as mediators of the immune response. Evidence suggests that the adipokine leptin may play a pathogenic role in sepsis. Mouse endotoxaemic models present with elevated leptin levels and exogenously added leptin increased mortality whereas human septic patients have elevated circulating levels of the soluble leptin receptor (Ob-Re). Evidence suggests that leptin can inhibit the regulation of the HPA axis. Thus, leptin may suppress the HPA axis, impairing its protective role in sepsis. We hypothesised that leptin would attenuate the HPA axis response to sepsis. We investigated the direct effects of an i.p. injection of 2 mg/kg leptin on the HPA axis response to intraperitoneally injected 25 μg/kg lipopolysaccharide (LPS) in the male Wistar rat. We found that LPS potently activated the HPA axis, as shown by significantly increased plasma stress hormones, ACTH and corticosterone, and increased plasma interleukin 1β (IL1β) levels, 2 h after administration. Pre-treatment with leptin, 2 h before LPS administration, did not influence the HPA axis response to LPS. In turn, LPS did not affect plasma leptin levels. Our findings suggest that leptin does not influence HPA function or IL1β secretion in a rat model of LPS-induced sepsis, and thus that leptin is unlikely to be involved in the acute-phase endocrine response to bacterial infection in rats.

  20. Changes in the maternal hypothalamic-pituitary-adrenal axis during the early puerperium may be related to the postpartum 'blues'.

    PubMed

    O'Keane, V; Lightman, S; Patrick, K; Marsh, M; Papadopoulos, A S; Pawlby, S; Seneviratne, G; Taylor, A; Moore, R

    2011-11-01

    Most women experience time-limited and specific mood changes in the days after birth known as the maternity blues (Blues). The maternal hypothalamic-pituitary-adrenal (HPA) axis undergoes gradual changes during pregnancy because of an increasing production of placental corticotrophin-releasing hormone (CRH). The abrupt withdrawal of placental CRH at birth results in a re-equilibration of the maternal HPA axis in the days post-delivery. These changes may be involved in the aetiology of the Blues given the central role of the HPA axis in the aetiology of mood disorders in general, and in perinatal depression in particular. We aimed to test the novel hypothesis that the experience of the Blues may be related to increased secretion of hypothalamic adrenocorticotrophic hormone (ACTH) secretagogue peptides, after the reduction in negative-feedback inhibition on the maternal hypothalamus caused by withdrawal of placental CRH. We therefore examined hormonal changes in the HPA axis in the days after delivery in relation to daily mood changes: our specific prediction was that mood changes would parallel ACTH levels, reflecting increased hypothalamic peptide secretion. Blood concentrations of CRH, ACTH, cortisol, progesterone and oestriol were measured in 70 healthy women during the third trimester of pregnancy, and on days 1-6 post-delivery. Blues scores were evaluated during the postpartum days. Oestriol, progesterone and CRH levels fell rapidly from pregnancy up to day 6, whereas cortisol levels fell modestly. ACTH concentrations declined from pregnancy to day 3 post-delivery and thereafter increased up to day 6. Blues scores increased, peaking on day 5, and were positively correlated with ACTH; and negatively correlated with oestriol levels during the postpartum days, and with the reduction in CRH concentrations from pregnancy. These findings give indirect support to the hypothesis that the 'reactivation' of hypothalamic ACTH secretagogue peptides may be involved in the

  1. Dysregulation of the hypothalamic pituitary adrenal (HPA) axis and physical performance at older ages: An individual participant meta-analysis

    PubMed Central

    Gardner, Michael P.; Lightman, Stafford; Sayer, Avan Aihie; Cooper, Cyrus; Cooper, Rachel; Deeg, Dorly; Ebrahim, Shah; Gallacher, John; Kivimaki, Mika; Kumari, Meena; Kuh, Diana; Martin, Richard M.; Peeters, Geeske; Ben-Shlomo, Yoav

    2013-01-01

    Summary The association between functioning of the hypothalamic pituitary adrenal (HPA) axis and physical performance at older ages remains poorly understood. We carried out meta-analyses to test the hypothesis that dysregulation of the HPA axis, as indexed by patterns of diurnal cortisol release, is associated with worse physical performance. Data from six adult cohorts (ages 50–92 years) were included in a two stage meta-analysis of individual participant data. We analysed each study separately using linear and logistic regression models and then used meta-analytic methods to pool the results. Physical performance outcome measures were walking speed, balance time, chair rise time and grip strength. Exposure measures were morning (serum and salivary) and evening (salivary) cortisol. Total sample sizes in meta-analyses ranged from n = 2146 for associations between morning Cortisol Awakening Response and balance to n = 8448 for associations between morning cortisol and walking speed. A larger diurnal drop was associated with faster walking speed (standardised coefficient per SD increase 0.052, 95% confidence interval (CI) 0.029, 0.076, p < 0.001; age and gender adjusted) and a quicker chair rise time (standardised coefficient per SD increase −0.075, 95% CI −0.116, −0.034, p < 0.001; age and gender adjusted). There was little evidence of associations with balance or grip strength. Greater diurnal decline of the HPA axis is associated with better physical performance in later life. This may reflect a causal effect of the HPA axis on performance or that other ageing-related factors are associated with both reduced HPA reactivity and performance. PMID:22658392

  2. Novel mechanism within the paraventricular nucleus reduces both blood pressure and hypothalamic pituitary-adrenal axis responses to acute stress

    PubMed Central

    Erdos, Benedek; Clifton, Rebekah R.; Liu, Meng; Li, Hongwei; McCowan, Michael L.; Sumners, Colin

    2015-01-01

    Macrophage migration inhibitory factor (MIF) counteracts pressor effects of angiotensin II (ANG II) in the paraventricular nucleus of the hypothalamus (PVN) in normotensive rats, but this mechanism is absent in spontaneously hypertensive rats (SHRs) due to a lack of MIF in PVN neurons. Since endogenous ANG II in the PVN modulates stress reactivity, we tested the hypothesis that replacement of MIF in PVN neurons would reduce baseline blood pressure and inhibit stress-induced increases in blood pressure and plasma corticosterone in adult male SHRs. Radiotelemetry transmitters were implanted to measure blood pressure, and then an adeno-associated viral vector expressing either enhanced green fluorescent protein (GFP) or MIF was injected bilaterally into the PVN. Cardiovascular responses to a 15-min water stress (1-cm deep, 25°C) and a 60-min restraint stress were evaluated 3–4 wk later. MIF treatment in the PVN attenuated average restraint-induced increases in blood pressure (37.4 ± 2.0 and 27.6 ± 3.5 mmHg in GFP and MIF groups, respectively, P < 0.05) and corticosterone (42 ± 2 and 36 ± 3 μg/dl in GFP and MIF groups, respectively, P < 0.05). MIF treatment in the PVN also reduced stress-induced elevations in the number of c-Fos-positive cells in the rostral ventrolateral medulla (71 ± 5 in GFP and 47 ± 5 in MIF SHRs, P < 0.01) and corticotropin-releasing factor mRNA expression in the PVN. However, MIF had no significant effects on the cardiovascular responses to water stress in SHRs or to either stress in Sprague-Dawley rats. Therefore, viral vector-mediated restoration of MIF in PVN neurons of SHRs attenuates blood pressure and hypothalamic pituitary adrenal axis responses to stress. PMID:26071542

  3. Effect of single-dose sertraline on the hypothalamus-pituitary-adrenal system, autonomic nervous system, and platelet function.

    PubMed

    Ahrens, Thorben; Frankhauser, Pascal; Lederbogen, Florian; Deuschle, Michael

    2007-12-01

    Pharmacological treatment with selective serotonin reuptake inhibitors (SSRIs) is thought to decrease coronary risk in patients with depressive disorder. Selective serotonin reuptake inhibitor intake may (1) attenuate the hypothalamus-pituitary-adrenal (HPA) system, (2) improve disturbances of the autonomous nervous system, and (3) dampen the aggregability of platelets. There is only limited information about the influence of acute treatment with SSRIs on these systems, which is especially important for the initiation of therapy in high-risk cardiac patients. We compared the reaction of these systems to physical stress with single-dose SSRI treatment (100 mg) with that of placebo treatment. Using a double-blind, crossover, placebo-controlled design, we assessed HPA system activity via serum cortisol and corticotropin as well as sympathetic nervous system by determining serum norepinephrine and epinephrine levels at baseline and as a response to stress. Analysis of heart rate variability (HRV) provided information on sympathetic/parasympathetic balance. Platelet activity was measured via flow-cytometric determination of platelet surface activation markers along with the serotonin (5-HT) uptake of platelets. We studied 12 healthy young men under placebo and verum conditions. We found higher HPA system activity at baseline and after physical activity under sertraline when compared with placebo, no difference in sympathetic nervous system activity after physical exertion and only slightly heightened baseline epinephrine values after sertraline intake. No difference was seen between sertraline and placebo intake regarding platelet activity and 5-HT uptake, HRV, blood pressure, and HR. Initiating sertraline treatment increases HPA system activity and epinephrine concentrations. We found no clinically relevant effect of single-dose sertraline treatment on autonomous nervous function, platelet activity, or platelet 5-HT uptake. These findings may not be extrapolated to

  4. Time-course of hypothalamic-pituitary-adrenal axis activity and inflammation in juvenile rat brain after cranial irradiation.

    PubMed

    Veličković, Nataša; Drakulić, Dunja; Petrović, Snježana; Grković, Ivana; Milošević, Maja; Stanojlović, Miloš; Horvat, Anica

    2012-10-01

    Recent studies reported that exposure of juvenile rats to cranial irradiation affects hypothalamic-pituitary-adrenal (HPA) axis stability, leading to its activation along with radiation-induced inflammation. In the present study, we hypothesized whether inflammatory reaction in the CNS could be a mediator of HPA axis response to cranial irradiation (CI). Therefore, we analyzed time-course changes of serum corticosterone level, as well IL-1β and TNF-α level in the serum and hypothalamus of juvenile rats after CI. Protein and gene expression of the glucocorticoid receptor (GR) and nuclear factor kappaB (NFκB) were examined in the hippocampus within 24 h postirradiation interval. Cranial irradiation led to rapid induction of both GR and NFκB mRNA and protein in the hippocampus at 1 h. The increment in NFκB protein persisted for 2 h, therefore NFκB/GR protein ratio was turned in favor of NFκB. Central inflammation was characterized by increased IL-1β in the hypothalamus, with maximum levels at 2 and 4 h after irradiation, while both IL-1β and TNF-α were undetectable in the serum. Enhanced hypothalamic IL-1β probably induced the relocation of hippocampal NFκB to the nucleus and decreased NFκB mRNA at 6 h, indicating promotion of inflammation in the key tissue for HPA axis regulation. Concomitant increase of corticosterone level and enhanced GR nuclear translocation in the hippocampus at 6 h might represent a compensatory mechanism for observed inflammation. Our results indicate that acute radiation response is characterized by increased central inflammation and concomitant HPA axis activation, most likely having a role in protection of the organism from overwhelming inflammatory reaction.

  5. Angiotensin type 1 receptors in the subfornical organ mediate the drinking and hypothalamic-pituitary-adrenal response to systemic isoproterenol.

    PubMed

    Krause, Eric G; Melhorn, Susan J; Davis, Jon F; Scott, Karen A; Ma, Li Y; de Kloet, Annette D; Benoit, Stephen C; Woods, Stephen C; Sakai, Randall R

    2008-12-01

    Circulating angiotensin II (ANGII) elicits water intake and activates the hypothalamic-pituitary-adrenal (HPA) axis by stimulating angiotensin type 1 receptors (AT1Rs) within circumventricular organs. The subfornical organ (SFO) and the organum vasculosum of the lamina terminalis (OVLT) are circumventricular organs that express AT1Rs that bind blood-borne ANGII and stimulate integrative and effector regions of the brain. The goal of these studies was to determine the contribution of AT1Rs within the SFO and OVLT to the water intake and HPA response to increased circulating ANGII. Antisense oligonucleotides directed against the AT1R [AT1R antisense (AT1R AS)] were administered into the OVLT or SFO. Quantitative receptor autoradiography confirmed that AT1R AS decreased ANGII binding in the SFO and OVLT compared with the scrambled sequence control but did not affect AT1R binding in other nuclei. Subsequently, water intake, ACTH, and corticosterone (CORT) were assessed after administration of isoproterenol, a beta-adrenergic agonist that decreases blood pressure and elevates circulating ANGII. Delivery of AT1R AS into the SFO attenuated water intake, ACTH, and CORT after isoproterenol, whereas similar treatment in the OVLT had no effect. To determine the specificity of this blunted drinking and HPA response, the same parameters were measured after treatment with hypertonic saline, a stimulus that induces drinking independently of ANGII. Delivery of AT1R AS into the SFO or OVLT had no effect on water intake, ACTH, or CORT after hypertonic saline. The results imply that AT1R within the SFO mediate drinking and HPA responses to stimuli that increase circulating ANGII.

  6. The hypothalamo-pituitary-adrenal (HPA) axis in sheep is attenuated during lactation in response to psychosocial and predator stress

    PubMed Central

    Ralph, C.R.; Tilbrook, A.J.

    2016-01-01

    Activation of the hypothalamo-pituitary-adrenal (HPA) axis by psychosocial stress is attenuated during lactation. We tested the hypothesis that lactating ewes will have attenuated HPA axis responses to isolation and restraint but will have greater responses to predator stress in the form of barking dogs. We imposed two 4 h stressors: psychosocial stress (isolation and restraint of ewes) and predator stress (barking dogs). Blood was collected intravenous every 10 min from nonlactating ewes (n = 6), lactating ewes with lambs present but not able to be suckled (n = 6), and lactating ewes with lambs present and able to be suckled (n = 6). Plasma cortisol and oxytocin were measured. For nonlactating ewes, cortisol increased (P < 0.01) in response to both stressors, and these increases were greater (P < 0.01) than that in the lactating animals. For lactating ewes with lambs present but unable to be suckled, cortisol increased (P < 0.05) in response to both stressors with a greater response to barking dogs (P < 0.05). For lactating ewes with lambs present and able to be suckled, cortisol increased (P < 0.01) in response to barking dogs only. Plasma oxytocin was greater (P < 0.01) in lactating ewes than in nonlactating ewes and did not change in response to the stressors. In conclusion, lactating ewes are likely to have a greater HPA axis response to a stressor that may be perceived to threaten the welfare of themselves and/or their offspring. The role of oxytocin in attenuation of the HPA axis to stress in sheep is unclear from the current research and requires further investigation. PMID:26773370

  7. The role of vasopressin in diabetes mellitus-induced hypothalamo-pituitary-adrenal axis activation: studies in Brattleboro rats.

    PubMed

    Zelena, Dóra; Mergl, Zsuzsa; Makara, Gábor B

    2006-03-15

    Chronic diabetes mellitus (DM) induces hyperactivity of the hypothalamo-pituitary-adrenal axis (HPA). Our present study addresses the role of vasopressin (AVP) in maintaining adrenocortical responsiveness during DM. AVP-deficient mutant Brattleboro rats were used with heterozygous controls and the V2 agonist, desmopressin was infused to replace peripheral AVP. To induce DM the rats were injected by streptozotocin (STZ, 60 mg/ml/kg i.v.) and studied 2 weeks later. The acute stress stimulus was 60 min restraint. The signs of DM (the increase in water consumption and in blood glucose levels) were discovered in all rats. The diuretic effect of the lack of AVP was additional to the DM-induced osmotic diuresis. DM induced significant, chronic stress-like somatic changes on which AVP-deficiency had no effect and although desmopressin infusion normalized the water consumption and the body weight gain in AVP-deficient rats, it had no effect on DM-induced changes. The acute stress-induced plasma ACTH elevation was smaller in AVP-deficient or DM rats but these effects were not additive. Desmopressin did not normalize the decreased ACTH-elevation of AVP-deficient animals. The resting morning plasma corticosterone level was elevated both in DM and AVP-deficient rats without interaction. The restraint-induced corticosterone rise was influenced neither by the lack of AVP nor by DM and the basal and stress-induced prolactin levels were smaller in DM rats without any effect of AVP-deficiency. In conclusion, our data suggest that AVP does not play a crucial role in HPA axis regulation during DM-induced chronic stress. In contrast, the role of AVP seems to be more important during acute stress, however, it is restricted to the ACTH regulation. According to the water consumption data diabetes insipidus seems to be an additional risk factor for DM.

  8. Role of the dorsomedial hypothalamus in glucocorticoid-mediated feedback inhibition of the hypothalamic-pituitary-adrenal axis.

    PubMed

    Stamper, Christopher E; Hennessey, Patrick A; Hale, Matthew W; Lukkes, Jodi L; Donner, Nina C; Lowe, Kenneth R; Paul, Evan D; Spencer, Robert L; Renner, Kenneth J; Orchinik, Miles; Lowry, Christopher A

    2015-01-01

    Previous studies suggest that multiple corticolimbic and hypothalamic structures are involved in glucocorticoid-mediated feedback inhibition of the hypothalamic-pituitary-adrenal (HPA) axis, including the dorsomedial hypothalamus (DMH), but a potential role of the DMH has not been directly tested. To investigate the role of the DMH in glucocorticoid-mediated negative feedback, adult male Sprague Dawley rats were implanted with jugular cannulae and bilateral guide cannulae directed at the DMH, and finally were either adrenalectomized (ADX) or were subjected to sham-ADX. ADX rats received corticosterone (CORT) replacement in the drinking water (25 μg/mL), which, based on initial studies, restored a rhythm of plasma CORT concentrations in ADX rats that was similar in period and amplitude to the diurnal rhythm of plasma CORT concentrations in sham-ADX rats, but with a significant phase delay. Following recovery from surgery, rats received microinjections of either CORT (10 ng, 0.5 μL, 0.25 μL/min, per side) or vehicle (aCSF containing 0.2% EtOH), bilaterally, directly into the DMH, prior to a 40-min period of restraint stress. In sham-ADX rats, bilateral intra-DMH microinjections of CORT, relative to bilateral intra-DMH microinjections of vehicle, decreased restraint stress-induced elevation of endogenous plasma CORT concentrations 60 min after the onset of intra-DMH injections. Intra-DMH CORT decreased the overall area under the curve for plasma CORT concentrations during the intermediate time frame of glucocorticoid negative feedback, from 0.5 to 2 h following injection. These data are consistent with the hypothesis that the DMH is involved in feedback inhibition of HPA axis activity at the intermediate time frame.

  9. Novel mechanism within the paraventricular nucleus reduces both blood pressure and hypothalamic pituitary-adrenal axis responses to acute stress.

    PubMed

    Erdos, Benedek; Clifton, Rebekah R; Liu, Meng; Li, Hongwei; McCowan, Michael L; Sumners, Colin; Scheuer, Deborah A

    2015-08-15

    Macrophage migration inhibitory factor (MIF) counteracts pressor effects of angiotensin II (ANG II) in the paraventricular nucleus of the hypothalamus (PVN) in normotensive rats, but this mechanism is absent in spontaneously hypertensive rats (SHRs) due to a lack of MIF in PVN neurons. Since endogenous ANG II in the PVN modulates stress reactivity, we tested the hypothesis that replacement of MIF in PVN neurons would reduce baseline blood pressure and inhibit stress-induced increases in blood pressure and plasma corticosterone in adult male SHRs. Radiotelemetry transmitters were implanted to measure blood pressure, and then an adeno-associated viral vector expressing either enhanced green fluorescent protein (GFP) or MIF was injected bilaterally into the PVN. Cardiovascular responses to a 15-min water stress (1-cm deep, 25°C) and a 60-min restraint stress were evaluated 3-4 wk later. MIF treatment in the PVN attenuated average restraint-induced increases in blood pressure (37.4 ± 2.0 and 27.6 ± 3.5 mmHg in GFP and MIF groups, respectively, P < 0.05) and corticosterone (42 ± 2 and 36 ± 3 μg/dl in GFP and MIF groups, respectively, P < 0.05). MIF treatment in the PVN also reduced stress-induced elevations in the number of c-Fos-positive cells in the rostral ventrolateral medulla (71 ± 5 in GFP and 47 ± 5 in MIF SHRs, P < 0.01) and corticotropin-releasing factor mRNA expression in the PVN. However, MIF had no significant effects on the cardiovascular responses to water stress in SHRs or to either stress in Sprague-Dawley rats. Therefore, viral vector-mediated restoration of MIF in PVN neurons of SHRs attenuates blood pressure and hypothalamic pituitary adrenal axis responses to stress.

  10. Estrogen alters baseline and inflammatory-induced cytokine levels independent from hypothalamic-pituitary-adrenal axis activity.

    PubMed

    Shivers, Kai-Yvonne; Amador, Nicole; Abrams, Lisa; Hunter, Deirtra; Jenab, Shirzad; Quiñones-Jenab, Vanya

    2015-04-01

    Although estrogen reduces inflammatory-mediated pain responses, the mechanisms behind its effects are unclear. This study investigated if estrogen modulates inflammatory signaling by reducing baseline or inflammation-induced cytokine levels in the injury-site, serum, dorsal root ganglia (DRG) and/or spinal cord. We further tested whether estrogen effects on cytokine levels are in part mediated through hypothalamic-pituitary-adrenal (HPA) axis activation. Lumbar DRG, spinal cord, serum, and hind paw tissue were analyzed for cytokine levels in 17β-estradiol-(20%) or vehicle-(100% cholesterol) treated female rats following ovariectomy/sham adrenalectomy (OVX), adrenalectomy/sham ovariectomy (ADX) or ADX+OVX operation at baseline and post formalin injection. Formalin significantly increased pro-inflammatory interleukin (IL)-6 levels in the paw, as well as pro- and anti-inflammatory cytokine levels in the DRG, spinal cord and serum in comparison to naïve conditions. Estrogen replacement significantly increased anti-inflammatory IL-10 levels in the DRG. Centrally, estradiol significantly decreased pro-inflammatory tumor necrosis factor (TNF)-α and IL-1β levels, as well as IL-10 levels, in the spinal cord in comparison to cholesterol treatment. At both sites, most estradiol modulatory effects occurred irrespective of pain or surgical condition. Estradiol alone had no influence on cytokine release in the paw or serum, indicating that estrogen effects were site-specific. Although cytokine levels were altered between surgical conditions at baseline and following formalin administration, ADX operation did not significantly reverse estradiol's modulation of cytokine levels. These results suggest that estrogen directly regulates cytokines independent of HPA axis activity in vivo, in part by reducing cytokine levels in the spinal cord.

  11. A novelty seeking phenotype is related to chronic hypothalamic-pituitary-adrenal activity reflected by hair cortisol

    PubMed Central

    Laudenslager, Mark L.; Jorgensen, Matthew J.; Grzywa, Rachel; Fairbanks, Lynn A.

    2011-01-01

    Reduced hypothalamic pituitary adrenal (HPA) activity is associated with greater novelty seeking in humans. Hair cortisol represents an integrated proxy measure of total cortisol production/release over an extended period of time and may be a valuable tool for tracking the HPA system. Sampling approaches (collection of blood, saliva, urine, or feces) for socially housed nonhuman primates present a number of technical challenges for collection particularly when repeated sampling is necessary. Herein we describe a relationship between cortisol levels measured in hair collected from 230 socially housed female vervet (Chlorocebus aethiops sabaeus) monkeys and a free-choice novelty seeking phenotype. A predator-like object was placed at the periphery of the outdoor enclosures for 30 min and speed of approach (latency to approach within 1 m) and persistence of interest (number of 1 min intervals within 1 m) were scored. A composite Novelty Seeking score, combining these two measures, was calculated. The intra-class correlation coefficient (ICC=.68) for two different objects across years indicated that this score reflects a stable aspect of temperament. Hair samples were collected from each subject approximately 3–6 months following the second assessment; cortisol levels were determined from the hair. A significant inverse relationship of Novelty Seeking score with hair cortisol level (p < .01) was noted. The high hair cortisol groups had significantly lower Novelty Seeking scores than the low cortisol groups both years (p’s < .05). These results suggest that low average cortisol levels promote novelty seeking, while high average levels inhibit novelty seeking behavior. PMID:21396388

  12. Disturbances in Hypothalamic-Pituitary-Adrenal Axis and Immunological Activity Differentiating between Unipolar and Bipolar Depressive Episodes

    PubMed Central

    Hoencamp, Erik; Penninx, Brenda W. J. H.

    2015-01-01

    Introduction Differentiating bipolar depression (BD) from unipolar depression (UD) is difficult in clinical practice and, consequently, accurate recognition of BD can take as long as nine years. Research has therefore focused on the discriminatory capacities of biomarkers, such as markers of the hypothalamic-pituitary-adrenal (HPA) axis or immunological activity. However, no previous study included assessments of both systems, which is problematic as they may influence each other. Therefore, this study aimed to explore whether cortisol indicators and inflammatory markers were a) independently associated with and/or b) showed effect modification in relation to a lifetime (hypo)manic episode in a large sample of depressed patients. Methods Data were derived from the Netherlands Study of Depression and Anxiety and comprised 764 patients with a DSM-IV depressive disorder at baseline, of which 124 (16.2%) had a lifetime (hypo)manic episode at the 2-year assessment, or a more recent episode at the 4-year or 6-year assessment. Baseline cortisol awakening response, evening cortisol and diurnal cortisol slope were considered as cortisol indicators, while baseline C-reactive Protein (CRP), Interleukin-6 (IL-6), and Tumor Necrosis Factor Alpha (TNF-α) were included as inflammatory markers. Results In depressed men and women, none of the cortisol indicators and inflammatory markers were (independently) associated with a (hypo)manic episode. However, effect modification was found of diurnal cortisol slope and CRP in relation to a (hypo)manic episode. Further analyses showed that depressed men with high levels of diurnal cortisol slope and CRP had an increased odds (OR=10.99, p=.001) of having a (hypo)manic episode. No significant differences were found in women. Conclusion Our findings suggest that the combination of high diurnal cortisol slope and high CRP may differentiate between UD and BD. This stresses the importance of considering HPA-axis and immunological activity

  13. The role of the hypothalamus-pituitary-adrenal/interrenal axis in mediating predator-avoidance trade-offs.

    PubMed

    Harris, Breanna N; Carr, James A

    2016-05-01

    Maintaining energy balance and reproducing are important for fitness, yet animals have evolved mechanisms by which the hypothalamus-pituitary-adrenal/interrenal (HPA/HPI) axis can shut these activities off. While HPA/HPI axis inhibition of feeding and reproduction may have evolved as a predator defense, to date there has been no review across taxa of the causal evidence for such a relationship. Here we review the literature on this topic by addressing evidence for three predictions: that exposure to predators decreases reproduction and feeding, that exposure to predators activates the HPA/HPI axis, and that predator-induced activation of the HPA/HPI axis inhibits foraging and reproduction. Weight of evidence indicates that exposure to predator cues inhibits several aspects of foraging and reproduction. While the evidence from fish and mammals supports the hypothesis that predator cues activate the HPA/HPI axis, the existing data in other vertebrate taxa are equivocal. A causal role for the HPA axis in predator-induced suppression of feeding and reproduction has not been demonstrated to date, although many studies report correlative relationships between HPA activity and reproduction and/or feeding. Manipulation of HPA/HPI axis signaling will be required in future studies to demonstrate direct mediation of predator-induced inhibition of feeding and reproduction. Understanding the circuitry linking sensory pathways to their control of the HPA/HPI axis also is needed. Finally, the role that fear and anxiety pathways play in the response of the HPA axis to predator cues is needed to better understand the role that predators have played in shaping anxiety related behaviors in all species, including humans.

  14. Enhancing offspring hypothalamic-pituitary-adrenal (HPA) regulation via systematic novelty exposure: the influence of maternal HPA function.

    PubMed

    Dinces, Sarah M; Romeo, Russell D; McEwen, Bruce S; Tang, Akaysha C

    2014-01-01

    In the rat, repeated brief exposures to novelty early in life can induce long-lasting enhancements in adult cognitive, social, emotional, and neuroendocrine function. Family-to-family variations in these intervention effects on adult offspring are predicted by the mother's ability to mount a rapid corticosterone (CORT) response to the onset of an acute stressor. Here, in Long-Evans rats, we investigated whether neonatal and adulthood novelty exposure, each individually and in combination, can enhance offspring hypothalamic-pituitary-adrenal (HPA) regulation. Using a 2 × 2 within-litter design, one half of each litter were exposed to a relatively novel non-home environment for 3-min (Neo_Novel) daily during infancy (PND 1-21) and the other half of the litter remained in the home cage (Neo_Home); we further exposed half of these two groups to early adulthood (PND 54-63) novelty exposure in an open field and the remaining siblings stayed in their home cages. Two aspects of HPA regulation were assessed: the ability to maintain a low level of resting CORT (CORTB) and the ability to mount a large rapid CORT response (CORTE) to the onset of an acute stressor. Assessment of adult offspring's ability to regulate HPA regulation began at 370 days of age. We further investigated whether the novelty exposure effects on offspring HPA regulation are sensitive to the context of maternal HPA regulation by assessing maternal HPA regulation similarly beginning 7 days after her pups were weaned. We found that at the population level, rats receiving neonatal, but not early adulthood exposure or both, showed a greater rapid CORTE than their home-staying siblings. At the individual family level, these novelty effects are positively associated with maternal CORTE. These results suggest that early experience of novelty can enhance the offspring's ability to mount a rapid response to environmental challenge and the success of such early life intervention is critically dependent upon the

  15. Orexin 2 receptor regulation of the hypothalamic-pituitary-adrenal (HPA) response to acute and repeated stress.

    PubMed

    Grafe, Laura A; Eacret, Darrell; Luz, Sandra; Gotter, Anthony L; Renger, John J; Winrow, Chris J; Bhatnagar, Seema

    2017-04-21

    Orexins are hypothalamic neuropeptides that have a documented role in mediating the acute stress response. However, their role in habituation to repeated stress, and the role of orexin receptors (OX1R and OX2R) in the stress response, has yet to be defined. Orexin neuronal activation and levels in the cerebrospinal fluid (CSF) were found to be stimulated with acute restraint, but were significantly reduced by day five of repeated restraint. As certain disease states such as panic disorder are associated with increased central orexin levels and failure to habituate to repeated stress, the effect of activating orexin signaling via Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) on the hypothalamic-pituitary-adrenal (HPA) response was evaluated after repeated restraint. While vehicle-treated rats displayed habituation of Adrenocorticotropic Hormone (ACTH) from day 1 to day 5 of restraint, stimulating orexins did not further increase ACTH beyond vehicle levels for either acute or repeated restraint. We delineated the roles of orexin receptors in acute and repeated stress using a selective OX2R antagonist (MK-1064). Pretreatment with MK-1064 reduced day 1 ACTH levels, but did not allow further habituation on day 5 compared with vehicle-treated rats, indicating that endogenous OX2R activity plays a role in acute stress, but not in habituation to repeated stress. However, in restrained rats with further stimulated orexins by DREADDs, MK-1064 decreased ACTH levels on day 5. Collectively, these results indicate that the OX2R plays a role in acute stress, and can prevent habituation to repeated stress under conditions of high orexin release.

  16. Developmental methamphetamine exposure results in short- and long-term alterations in hypothalamic-pituitary-adrenal axis-associated proteins

    PubMed Central

    Zuloaga, Damian G.; Siegel, Jessica A.; Acevedo, Summer F.; Agam, Maayan; Raber, Jacob

    2013-01-01

    Developmental exposure to methamphetamine (MA) causes long-term behavioral and cognitive deficits. One pathway through which MA might induce these deficits is by elevating glucocorticoid levels. Glucocorticoid overexposure during brain development can lead to long-term disruptions in the hypothalamic-pituitary-adrenal (HPA) axis. These disruptions affect the regulation of stress responses and may contribute to behavioral and cognitive deficits reported following developmental MA exposure. Furthermore, alterations in proteins associated with the HPA axis, including vasopressin, oxytocin, and glucocorticoid receptors (GR), are correlated with disruptions in mood and cognition. We therefore hypothesized that early MA exposure will result in short- and long-term alterations in the expression of HPA axis-associated proteins. Male mice were treated with MA (5 mg/kg daily) or Saline from postnatal day (P) 11–20. At P20 and P90, mice were perfused and their brains processed for vasopressin, oxytocin, and GR-immunoreactivity within HPA axis-associated regions. At P20, there was a significant decrease in the number of vasopressin-immunoreactive cells and area occupied by vasopressin-immunoreactiviy in the paraventricular nucleus (PVN) of MA-treated mice, but no difference in oxytocin-immunoreactivity in the PVN, or GR-immunoreactivity in the hippocampus or PVN. In the central nucleus of the amygdala, area occupied by GR-immunoreactivity was decreased by MA. At P90, the number of vasopressin-immunoreactive cells was still decreased, but the area occupied by vasopressin-immunoreactivity no longer differed from Saline controls. No effects of MA were found on oxytocin or GR-immunoreactivity at P90. Thus developmental MA exposure has short- and long-term effects on vasopressin-immunoreactivity and short-term effects on GR-immunoreactivity. PMID:23860125

  17. Effects of early childhood trauma on hypothalamic-pituitary-adrenal (HPA) axis function in patients with Chronic Fatigue Syndrome.

    PubMed

    Kempke, Stefan; Luyten, Patrick; De Coninck, Sarah; Van Houdenhove, Boudewijn; Mayes, Linda C; Claes, Stephan

    2015-02-01

    There is a paucity of studies that have investigated the assumption that early childhood trauma is associated with hypothalamic-pituitary-adrenal (HPA) axis dysfunction in Chronic Fatigue Syndrome (CFS). The current study is the first to simultaneously investigate relationships among early childhood trauma, cortisol activity, and cortisol stress reactivity to psychosocial stress in a sample of well-screened CFS patients. We also examined whether self-critical perfectionism (SCP) plays a mediating role in the potential relationship between early trauma and neurobiological stress responses. A total of 40 female patients diagnosed with CFS were asked to provide morning saliva cortisol samples (after awakening, 30min later, and 1h later) for seven consecutive days as a measure of cortisol activity. In addition, patients were exposed to the Trier Social Stress Test, a well-validated stress test, to investigate the relationship between early childhood trauma and cortisol stress reactivity. Before the start of the study, patients completed the Childhood Trauma Questionnaire-Short form (CTQ-SF) as a measure of early childhood trauma (i.e. sexual, physical and emotional traumatic experiences). SCP was measured with the Depressive Experiences Questionnaire (DEQ). Data were analyzed by calculating several indices of cortisol secretion (i.e. Cortisol Awakening Response and Area Under the Curve). There was no association between early childhood trauma and cortisol as measured over the 7-day period. However, emotional neglect was significantly negatively related to cortisol reactivity in the TSST. SCP did not significantly mediate this association. Findings of this study suggest that emotional neglect is associated with blunted HPA axis reactivity, congruent with the assumption that CFS may reflect loss of adaptability of the neuroendocrine stress response system in at least a subgroup of patients. Copyright © 2014 Elsevier Ltd. All rights reserved.

  18. Reduced hippocampal volume and hypothalamus-pituitary-adrenal axis function in first episode psychosis: evidence for sex differences.

    PubMed

    Pruessner, Marita; Lepage, Martin; Collins, D Louis; Pruessner, Jens C; Joober, Ridha; Malla, Ashok K

    2015-01-01

    Hippocampal volume (HV) decline is an important marker of psychosis and has been associated with hypothalamus-pituitary-adrenal (HPA) axis dysregulation in various disorders. Given recent findings of sex differences in HPA axis function in psychosis, the current study investigated differences in HV in male and female first episode psychosis (FEP) patients and controls and the interaction of HV with the cortisol awakening response (CAR) and symptoms. Fifty-eight patients with a diagnosis of FEP (39 men, 19 women) and 27 healthy community controls (15 men, 12 women) underwent structural magnetic resonance imaging (MRI) on a 1.5 T scanner. Hippocampal volume was determined using previously established segmentation protocols. Saliva samples for cortisol assessment were collected at 0, 30 and 60 min after awakening. Psychotic symptoms were assessed with the Scale for Assessment of Positive Symptoms (SAPS), the Scale for Assessment of Negative Symptoms (SANS) and the Global Assessment of Functioning (GAF) scale. Male patients had significantly smaller left and right HVs compared to male controls, which appeared to be secondary to global brain volume differences. However, even when controlling for overall brain size, male patients showed smaller HV compared to female patients. The CAR was significantly lower in male patients compared to male controls and female patients. Only in male patients, smaller left HV was significantly associated with a blunted CAR, and smaller HV bilaterally was related to positive psychotic symptoms and lower levels of functioning. We propose that reduced hippocampal volume and an attenuated cortisol awakening response are related markers of increased stress vulnerability in male psychosis patients and that both contribute to the unfavorable clinical picture in men.

  19. The association of hypothalamic-pituitary-adrenal axis activity and blood pressure in an Afro-Caribbean population.

    PubMed

    Boyne, Michael S; Woollard, Alexander; Phillips, David I W; Taylor-Bryan, Carolyn; Bennett, Franklyn I; Osmond, Clive; Thomas, Tamika Y Royal; Wilks, Rainford J; Forrester, Terrence E

    2009-06-01

    Hyperactivity of the hypothalamic-pituitary-adrenal axis (HPAA) resulting from fetal programming may play a role in the development of high blood pressure (BP) in black people. We assessed the diurnal salivary cortisol profile in children with and without increased BP and evaluated their mother's HPAA. In a cross-sectional study, 20 Afro-Caribbean children (mean age 9.6 years) with higher blood pressures and 20 children with lower blood pressures were chosen from a prospective study of 569 mothers and children in Jamaica. Daytime salivary cortisol profiles were collected in the children and their mothers. The mothers were also assessed for features of the metabolic syndrome. Children with higher BP had higher mean morning salivary cortisol concentrations than those with lower BP (7.9 S.D. 1.9 vs. 4.5 S.D. 2.4nmol/l; p=0.03). Their mothers also had increased morning salivary cortisol concentrations (9.9 S.D. 1.8 vs. 5.5 S.D. 2.5nmol/l; p=0.02), but no changes in fasting glucose, insulin, lipids, BP or adiposity. Maternal and offspring cortisol concentrations correlated significantly (r=0.465, p=0.004). Maternal cortisol concentrations were significantly associated with the child's BP. We conclude that Afro-Caribbean children with higher BP have higher morning salivary cortisol concentrations. The children's cortisol concentrations correlate significantly with the mother's cortisol concentrations. These findings suggest that the HPAA may play a role in the development of raised BP in Afro-Caribbean people.

  20. Apparent Hypothalamic-Pituitary-Adrenal Axis Suppression via Reduction of Interleukin-6 by Glucocorticoid Therapy in Systemic Autoimmune Diseases

    PubMed Central

    Fujio, Natsuki; Masuoka, Shotaro; Shikano, Kotaro; Kusunoki, Natsuko; Nanki, Toshihiro; Kawai, Shinichi

    2016-01-01

    Context Suppression of the hypothalamic-pituitary-adrenal (HPA) axis is a serious complication of systemic glucocorticoid therapy. Objective To clarify the influence of proinflammatory cytokines on the HPA axis after onset of glucocorticoid therapy in patients with systemic autoimmune diseases. Patients and Methods Forty-eight glucocorticoid-naïve patients with systemic autoimmune diseases (28 women) who were starting prednisolone therapy according to our standard regimens were prospectively observed. Patients were classified into high-dose and low-dose groups depending on the dose of prednisolone administered as indicated for their diseases. Plasma adrenocorticotropic hormone (ACTH) and serum cortisol levels were measured by electrochemiluminescence immunoassay. The corticotropin-releasing hormone (CRH) test was performed at baseline and second and forth weeks after starting glucocorticoid therapy. The increased levels of ACTH (ΔACTH) and cortisol (Δcortisol) were investigated. Serum levels of 10 proinflammatory cytokines were measured simultaneously by a multi-spot assay system. Results In the high-dose group, both basal and stimulated levels of ACTH and cortisol were significantly decreased by glucocorticoid therapy. In the low-dose group, basal ACTH and cortisol levels were also significantly decreased by glucocorticoid therapy, but ΔACTH and Δcortisol were unchanged. Among 10 cytokines, only interleukin (IL)-6 was significantly decreased by glucocorticoid therapy in both groups and was more closely correlated with cortisol than ACTH. Basal cortisol level was positively correlated with serum IL-6 level in all patients before glucocorticoid therapy. Conclusion In patients with systemic autoimmune diseases, apparent suppression of cortisol during glucocorticoid therapy may be partly mediated by reduced production of IL-6. PMID:27930715

  1. Effects of Acupuncture, RU-486 on the Hypothalamic-Pituitary-Adrenal Axis in Chronically Stressed Adult Male Rats.

    PubMed

    Eshkevari, Ladan; Mulroney, Susan E; Egan, Rupert; Lao, Lixing

    2015-10-01

    We have recently reported that pretreatment with electroacupuncture (EA) at stomach meridian point 36 (St36) prevents the chronic cold-stress increase in the hypothalamus-pituitary-adrenal axis (HPA), an action that may be under central control. Given that treatment for stress-related symptoms usually begins after onset of the stress responses, the objectives of the present study were to determine the efficacy of EA St36 on HPA hormones when EA St36 is given after stress was initiated, if the results are long lasting, and if blocking the glucocorticoid receptor (GR) using RU-486 had the same effects as EA St36. Adult male rats were placed in 4 groups of animals, 3 of which were exposed to cold and 1 of which was a nontreatment control group. After exposure to the cold stress, 2 groups were treated with either EA St36 or sham-EA, repeated over 10 days. The increase in ACTH and corticosterone observed in stress-only rats was prevented in EA St36 animals, and the effects remained intact 4 days after withdrawal of EA but continuation of cold stress. When the GR was blocked with RU-486, the efficacy of EA St36 remained unchanged. GR blockade did significantly elevate ACTH, which is not seen with EA St36, suggesting that EA St36 does act centrally. The elevated HPA hormones in stress-only rats were associated with a significant increase in depressive and anxious behavior; this was not observed in the stressed EA St36 animals. The results indicate that EA specifically at St36 vs sham-EA is effective in treating chronic poststress exposure.

  2. Role of the dorsomedial hypothalamus in glucocorticoid-mediated feedback inhibition of the hypothalamic-pituitary-adrenal axis

    PubMed Central

    Stamper, Christopher E.; Hennessey, Patrick A.; Hale, Matthew W.; Lukkes, Jodi L.; Donner, Nina C.; Lowe, Kenneth R.; Paul, Evan D.; Spencer, Robert L.; Renner, Kenneth J.; Orchinik, Miles; Lowry, Christopher A.

    2015-01-01

    Previous studies suggest that multiple corticolimbic and hypothalamic structures are involved in glucocorticoid-mediated feedback inhibition of the hypothalamic-pituitary-adrenal (HPA) axis, including the dorsomedial hypothalamus (DMH), but a potential role of the DMH has not been directly tested. To investigate the role of the DMH in glucocorticoid-mediated negative feedback, adult male Sprague Dawley rats were implanted with jugular cannulae and bilateral guide cannulae directed at the DMH, and finally were either adrenalectomized (ADX) or were subjected to sham-ADX. Adrenalectomized rats received CORT replacement in the drinking water (25 µg/ml), which, based on initial studies, restored a rhythm of plasma CORT concentrations in ADX rats that was similar in period and amplitude to the diurnal rhythm of plasma CORT concentrations in sham-ADX rats, but with a significant phase delay. Following recovery from surgery, rats received microinjections of either CORT (10 ng, 0.5 µL, 0.25 µL/min, per side) or vehicle (aCSF containing 0.2% EtOH), bilaterally, directly into the DMH, prior to a 40 min period of restraint stress. In sham-ADX rats, bilateral intra-DMH microinjections of CORT, relative to bilateral intra-DMH microinjections of vehicle, decreased restraint stress-induced elevation of endogenous plasma CORT concentrations 60 minutes after the onset of intra-DMH injections. Intra-DMH CORT decreased the overall area under the curve for plasma CORT concentrations during the intermediate time frame of glucocorticoid negative feedback, from 0.5–2 h following injection. These data are consistent with the hypothesis that the DMH is involved in feedback inhibition of HPA axis activity at the intermediate time frame. PMID:25556980

  3. Decreased maternal hypothalamic-pituitary-adrenal axis activity in very severely obese pregnancy: Associations with birthweight and gestation at delivery.

    PubMed

    Stirrat, Laura I; O'Reilly, James R; Barr, Sarah M; Andrew, Ruth; Riley, Simon C; Howie, Alexander F; Bowman, Maria; Smith, Roger; Lewis, John G; Denison, Fiona C; Forbes, Shareen; Seckl, Jonathan R; Walker, Brian R; Norman, Jane E; Reynolds, Rebecca M

    2016-01-01

    The maternal hypothalamic-pituitary-adrenal-axis (HPAA) undergoes dramatic activation during pregnancy. Increased cortisol and corticotrophin-releasing-hormone (CRH) associate with low birthweight and preterm labor. In non-pregnant obesity, the HPAA is activated but circulating cortisol levels are normal or lower than in lean women. We hypothesized that maternal cortisol levels would be lower in obese pregnancy, and would associate with increased fetal size and length of gestation. Fasting serum cortisol was measured at 16, 28 and 36 weeks gestation and at 3-6 months postpartum in 276 severely obese and 135 lean women. In a subset of obese (n=20) and lean (n=20) we measured CRH, hormones that regulate bioavailable cortisol (corticosteroid-binding-globulin, estradiol, estriol, and progesterone). Urinary glucocorticoid metabolites were measured in pregnant (obese n=6, lean n=5) and non-pregnant (obese n=7, lean n=7) subjects. Maternal cortisol and HPAA hormones were lower in obese pregnancy. Total urinary glucocorticoid metabolites increased significantly in lean pregnancy, but not in obese. Lower maternal cortisol in obese tended to be associated with increased birthweight (r=-0.13, p=0.066). In obese, CRH at 28 weeks correlated inversely with gestational length (r=-0.49, p=0.04), and independently predicted gestational length after adjustment for confounding factors (mean decrease in CRH of -0.25 pmol/L (95% CI -0.45 to -0.043 pmol/L) per/day increase in gestation). In obese pregnancy, lower maternal cortisol without an increase in urinary glucocorticoid clearance may indicate a lesser activation of the HPAA than in lean pregnancy. This may offer a novel mechanism underlying increased birthweight and longer gestation in obese pregnancy. Copyright © 2015 Elsevier Ltd. All rights reserved.

  4. Interleukin-6 is an afferent signal to the hypothalamo-pituitary-adrenal axis during local inflammation in mice.

    PubMed

    Turnbull, Andrew V; Prehar, Sukhpal; Kennedy, Adam R; Little, Roderick A; Hopkins, Stephen J

    2003-05-01

    The cytokines IL-1 and IL-6 are able to induce prostaglandin (PG)-dependent activation of the hypothalamo-pituitary-adrenal axis (HPAA) and are thought to play key roles in immune-neuroendocrine interactions during inflammation. The present study shows that inflammation induced by im injection of turpentine (TPS) in the hind limb of mice causes an increase in the plasma concentration of IL-6, but not that of IL-1 alpha or IL-1 beta, together with a prolonged (>18-h) activation of the HPAA. IL-6 plays a causal role in the TPS-induced elevation in HPAA activity, because the sustained (8-18 h) increases in 1) plasma corticosterone, 2) plasma ACTH, and 3) induction of c-Fos in the hypothalamic paraventricular nucleus are all markedly blunted in IL-6-deficient (IL-6(-/-)) mice. Peripheral administration of a neutralizing IL-6 antiserum inhibited the plasma corticosterone response of normal (C57BL/6) mice to hind limb inflammation to an extent similar to that seen in IL-6(-/-) mice, suggesting that the IL-6 responsible for the increased HPAA activity is produced, or acts, on the blood side of the blood-brain barrier. We also show that IL-6 in the circulation is induced almost exclusively at the local inflammatory site, where IL-1 beta is produced. Induction of IL-6 and activation of the HPAA are dependent upon prior activation of an IL-1 type I receptor, as both are inhibited in type I IL-1 receptor-deficient mice. Furthermore, hind limb inflammation induced cyclooxygenase-2 protein expression around the cerebrovasculature of normal (IL-6(+/+)), but not IL-6(-/-), mice. Based on these data, we propose that IL-6 is produced at the local inflammatory site under the control of IL-1 beta and is the circulating afferent signal that is in part responsible for elevated HPAA activity, possibly acting via eicosanoid production within the cerebrovasculature.

  5. Increased hypothalamic-pituitary-adrenal drive is associated with decreased appetite and hypoactivation of food motivation neurocircuitry in anorexia nervosa

    PubMed Central

    Lawson, Elizabeth A.; Holsen, Laura M.; DeSanti, Rebecca; Santin, McKale; Meenaghan, Erinne; Herzog, David B.; Goldstein, Jill M.; Klibanski, Anne

    2013-01-01

    Objective Corticotropin releasing hormone (CRH)-mediated hypercortisolemia has been demonstrated in anorexia nervosa (anorexia), a psychiatric disorder characterized by food restriction despite low body weight. While CRH is anorexigenic, downstream cortisol stimulates hunger. Using a food-related fMRI paradigm, we have demonstrated hypoactivation of brain regions involved in food motivation in women with anorexia, even after weight-recovery. The relationship between hypothalamic-pituitary-adrenal (HPA) axis dysregulation and appetite, and the association with food motivation neurocircuitry hypoactivation is unknown in anorexia. We investigated the relationship between HPA activity, appetite and food motivation neurocircuitry hypoactivation in anorexia. Design Cross-sectional study of 36 women [13 anorexia (AN), 10 weight-recovered AN (ANWR), 13 healthy controls (HC)]. Methods Peripheral cortisol and ACTH levels were measured fasting and 30, 60, and 120min after a standardized mixed meal. The Visual Analogue Scale was used to assess homeostatic and hedonic appetite. fMRI was performed during visual processing of food and non-food stimuli to measure brain activation pre- and post-meal. Results In each group, serum cortisol levels decreased following the meal. Mean fasting, 120min post-meal, and nadir cortisol levels were high in AN vs. HC. Mean postprandial ACTH levels were high in ANWR compared to HC and AN. Cortisol levels were associated with lower fasting homeostatic and hedonic appetite, independent of BMI and depressive symptoms. Cortisol levels were also associated with between-group variance in activation in food-motivation brain regions (e.g., hypothalamus, amygdala, hippocampus, OFC and insula). Conclusions HPA activation may contribute to the maintenance of anorexia by suppression of appetitive drive. PMID:23946275

  6. Hypothalamic-pituitary-adrenal axis response to acute psychosocial stress: Effects of biological sex and circulating sex hormones.

    PubMed

    Stephens, Mary Ann C; Mahon, Pamela B; McCaul, Mary E; Wand, Gary S

    2016-04-01

    Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis influences the risk for developing stress-related disorders. Sex-dependent differences in the HPA axis stress response are believed to contribute to the different prevalence rates of stress-related disorders found in men and women. However, studies examining the HPA axis stress response have shown mixed support for sex differences, and the role of endogenous sex hormones on HPA axis response has not been adequately examined in humans. This study utilized the largest sample size to date to analyze the effects of biological sex and sex hormones on HPA axis social stress responses. Healthy, 18- to 30- year-old community volunteers (N=282) completed the Trier Social Stress Test (TSST), a widely used and well-validated stress-induction laboratory procedure. All women (n=135) were tested during the follicular phase of their menstrual cycle (when progesterone levels are most similar to men). Adrenocorticotropic hormone (ACTH) and cortisol measures were collected at multiple points throughout pre- and post-TSST. Testosterone and progesterone (in men) and progesterone and estradiol (in women) were determined pre-TSST. Following the TSST, men had greater ACTH and cortisol levels than women. Men had steeper baseline-to-peak and peak-to-end ACTH and cortisol response slopes than women; there was a trend for more cortisol responders among men than women. Testosterone negatively correlated with salivary cortisol response in men, while progesterone negatively correlated with ACTH and cortisol responses in women. These data confirm that men show more robust activation of the HPA axis response to the TSST than do women in the follicular phase of the menstrual cycle. Testosterone results suggest an inhibitory effect on HPA axis reactivity in men. Progesterone results suggest an inhibitory effect on HPA axis reactivity in women. Future work is needed to explain why men mount a greater ACTH and cortisol response to the

  7. The hypothalamo-pituitary-adrenal (HPA) axis in sheep is attenuated during lactation in response to psychosocial and predator stress.

    PubMed

    Ralph, C R; Tilbrook, A J

    2016-04-01

    Activation of the hypothalamo-pituitary-adrenal (HPA) axis by psychosocial stress is attenuated during lactation. We tested the hypothesis that lactating ewes will have attenuated HPA axis responses to isolation and restraint but will have greater responses to predator stress in the form of barking dogs. We imposed two 4 h stressors: psychosocial stress (isolation and restraint of ewes) and predator stress (barking dogs). Blood was collected intravenous every 10 min from nonlactating ewes (n = 6), lactating ewes with lambs present but not able to be suckled (n = 6), and lactating ewes with lambs present and able to be suckled (n = 6). Plasma cortisol and oxytocin were measured. For nonlactating ewes, cortisol increased (P < 0.01) in response to both stressors, and these increases were greater (P < 0.01) than that in the lactating animals. For lactating ewes with lambs present but unable to be suckled, cortisol increased (P < 0.05) in response to both stressors with a greater response to barking dogs (P < 0.05). For lactating ewes with lambs present and able to be suckled, cortisol increased (P < 0.01) in response to barking dogs only. Plasma oxytocin was greater (P < 0.01) in lactating ewes than in nonlactating ewes and did not change in response to the stressors. In conclusion, lactating ewes are likely to have a greater HPA axis response to a stressor that may be perceived to threaten the welfare of themselves and/or their offspring. The role of oxytocin in attenuation of the HPA axis to stress in sheep is unclear from the current research and requires further investigation. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  8. Gut Microbiota-brain Axis

    PubMed Central

    Wang, Hong-Xing; Wang, Yu-Ping

    2016-01-01

    Objective: To systematically review the updated information about the gut microbiota-brain axis. Data Sources: All articles about gut microbiota-brain axis published up to July 18, 2016, were identified through a literature search on PubMed, ScienceDirect, and Web of Science, with the keywords of “gut microbiota”, “gut-brain axis”, and “neuroscience”. Study Selection: All relevant articles on gut microbiota and gut-brain axis were included and carefully reviewed, with no limitation of study design. Results: It is well-recognized that gut microbiota affects the brain's physiological, behavioral, and cognitive functions although its precise mechanism has not yet been fully understood. Gut microbiota-brain axis may include gut microbiota and their metabolic products, enteric nervous system, sympathetic and parasympathetic branches within the autonomic nervous system, neural-immune system, neuroendocrine system, and central nervous system. Moreover, there may be five communication routes between gut microbiota and brain, including the gut-brain's neural network, neuroendocrine-hypothalamic-pituitary-adrenal axis, gut immune system, some neurotransmitters and neural regulators synthesized by gut bacteria, and barrier paths including intestinal mucosal barrier and blood-brain barrier. The microbiome is used to define the composition and functional characteristics of gut microbiota, and metagenomics is an appropriate technique to characterize gut microbiota. Conclusions: Gut microbiota-brain axis refers to a bidirectional information network between the gut microbiota and the brain, which may provide a new way to protect the brain in the near future. PMID:27647198

  9. The alkyl-ether phospholipid platelet-activating factor is a stimulator of the hypothalamic-pituitary-adrenal axis in the rat.

    PubMed

    Bernardini, R; Calogero, A E; Ehrlich, Y H; Brucke, T; Chrousos, G P; Gold, P W

    1989-08-01

    Platelet-activating factor (PAF) is a naturally occurring alkyl-ether phospholipid which serves as an extracellular mediator in various cellular processes. Here we examined the effects of PAF on the activity of the hypothalamic-pituitary-adrenal axis in vivo and in vitro. PAF injected iv to rats (125, 250, and 500 ng/100 g BW) caused significant stimulation of pituitary ACTH and adrenal corticosterone secretion. The peak of PAF effect was recorded 10 min after the injection. Intraperitoneal injection of the PAF receptor antagonist BN 52021 prevented the ACTH-releasing effect of PAF. In explanted rat hypothalami maintained viable in vitro, PAF stimulated immunoreactive CRH secretion in a bell-shaped dose-response fashion. The maximal stimulatory effect occurred at the concentration of 10 nM. Higher concentrations appeared to cause desensitization. Alprazolam (1 microM) and BN 52021 (1 microM), two structurally different PAF receptor antagonists, inhibited this effect. The inhibitors of arachidonic acid metabolism, indomethacin, eicosatetraynoic acid, and the calcium channel blocker verapamil, inhibited PAF-stimulated CRH secretion, suggesting mediation by Ca2+ influx and phospholipase-A2 activation. In addition, we found that 1 nM PAF weakly stimulated ACTH secretion by dispersed rat pituicytes. This stimulatory effect of PAF was also inhibited by the receptor antagonists alprazolam and BN 52021. Our data suggest that PAF plays a role in the activation of the hypothalamic-pituitary-adrenal axis and glucocorticoid secretion and can perhaps serve as a mediator in the interactions of the immune system with the central nervous system.

  10. [Activity of the hypothalamo-pituitary-adrenals axis in the Siberian tiger (Panthera tigris altaica) in captivity and in the wild, and their dynamics throughout the year].

    PubMed

    Naidenko, S V; Ivanov, E A; Lukarevskiĭ, V S; Hernandez-Blanko, J A; Sorokin, P A; Litvinov, M N; Kotliar, A K; Rozhnov, V V

    2011-01-01

    A noninvasive evaluation method of hypothalamo-pituitary-adrenals axis (HPA) activity in the Siberian tiger was verified. Comparison of the activity level of HPA in Siberian tigers in the wild and in captivity, and their alterations over the year was carried out. Significant seasonal deviations between activity levels of HPA in tigers in captivity were not found. In the wild, this level was significantly higher, reaching the maximum from November to January, which can be related with an unfavorable influence on tigers in low temperatures and deep snow cover.

  11. Vitamin E-supplemented diets reduce lipid peroxidation but do not alter either pituitary-adrenal, glucose, and lactate responses to immobilization stress or gastric ulceration.

    PubMed

    Armario, A; Campmany, L; Borras, M; Hidalgo, J

    1990-01-01

    It has been suggested that antioxidant administration to rats would reduce the physiological response to stress. In the present experiment adult male rats were given diets supplemented with vitamin E for one or seven days before they were subjected to immobilization stress. Vitamin E administration reduced hepatic and gastric lipid peroxidation in unstressed rats but did not modify the pituitary-adrenal, glucose and lactose responses to 1 or 18 h immobilization. Similarly, gastric ulceration caused by 18 h immobilization was unaffected by the diets. These results indicate that the inhibition of lipid peroxidation does not modify the response of several, well-known, stress-markers in the rat.

  12. [Brain-gut interactions].

    PubMed

    Bonaz, B

    2010-08-01

    Our digestive tract has an autonomous functioning but also has a bidirectional relation with our brain known as brain-gut interactions. This communication is mediated by the autonomous nervous system, i.e., the sympathetic and parasympathetic nervous systems, with a mixed afferent and efferent component, and the circumventricular organs located outside the blood-brain barrier. The vagus nerve, known as the principal component of the parasympathetic nervous system, is a mixed nerve composed of 90% afferent fibers, which has physiological roles due to its putative vegetative functions. The vagus nerve has also anti-inflammatory properties both through the hypothalamic pituitary adrenal axis (through its afferents) and the cholinergic anti-inflammatory pathway (through its efferents). The sympathetic nervous system has a classical antagonist effect on the parasympathetic nervous system at the origin of an equilibrated sympathovagal balance in normal conditions. The brain is able to integrate inputs coming from the digestive tract inside a central autonomic network organized around the hypothalamus, limbic system and cerebral cortex (insula, prefrontal, cingulate) and in return to modify the autonomic nervous system and the hypothalamic pituitary adrenal axis in the frame of physiological loops. A dysfunction of these brain-gut interactions, favoured by stress, is most likely involved in the pathophysiology of digestive diseases such as irritable bowel syndrome or even inflammatory bowel diseases. A better knowledge of these brain-gut interactions has therapeutic implications in the domain of pharmacology, neurophysiology, behavioural and cognitive management.

  13. Ethanol induction of steroidogenesis in rat adrenal and brain is dependent upon pituitary ACTH release and de novo adrenal StAR synthesis

    PubMed Central

    Boyd, Kevin N.; Kumar, Sandeep; O'Buckley, Todd K.; Porcu, Patrizia; Morrow, A. Leslie

    2011-01-01

    The mechanisms of ethanol actions that produce its behavioral sequelae involve the synthesis of potent GABAergic neuroactive steroids, specifically the GABAergic metabolites of progesterone, (3α,5α)-3-hydroxypregnan-20-one (3α,5α-THP), and deoxycorticosterone, (3α,5α)-3,21-dihydroxypregnan-20-one. We investigated the mechanisms that underlie the effect of ethanol on adrenal steroidogenesis. We found that ethanol effects on plasma pregnenolone, progesterone, 3α,5α-THP and cortical 3α,5α-THP are highly correlated, exhibit a threshold of 1.5 g/kg, but show no dose dependence. Ethanol increases plasma adrenocorticotropic hormone (ACTH), adrenal steroidogenic acute regulatory protein (StAR), and adrenal StAR phosphorylation, but does not alter levels of other adrenal cholesterol transporters. The inhibition of ACTH release, de novo adrenal StAR synthesis or cytochrome P450 side chain cleavage activity prevents ethanol-induced increases in GABAergic steroids in plasma and brain. ACTH release and de novo StAR synthesis are independently regulated following ethanol administration and both are necessary, but not sufficient, for ethanol-induced elevation of plasma and brain neuroactive steroids. As GABAergic steroids contribute to ethanol actions and ethanol sensitivity, the mechanisms of this effect of ethanol may be important factors that contribute to the behavioral actions of ethanol and risk for alcohol abuse disorders. PMID:20021565

  14. Differential effects of sympathetic nervous system and hypothalamic-pituitary-adrenal axis on systemic immune cells after severe experimental stroke.

    PubMed

    Mracsko, Eva; Liesz, Arthur; Karcher, Simone; Zorn, Markus; Bari, Ferenc; Veltkamp, Roland

    2014-10-01

    Infectious complications are the leading cause of death in the post-acute phase of stroke. Post-stroke immunodeficiency is believed to result from neurohormonal dysregulation of the sympathetic nervous system (SNS) and hypothalamic-pituitary-adrenal (HPA) axis. However, the differential effects of these neuroendocrine systems on the peripheral immune cells are only partially understood. Here, we determined the impact of the hormones of the SNS and HPA on distinct immune cell populations and characterized their interactions after stroke. At various time points after cortical or extensive hemispheric cerebral ischemia, plasma cortisone, corticosterone, metanephrine and adrenocorticotropic hormone (ACTH) levels were measured in mice. Leukocyte subpopulations were flow cytometrically analyzed in spleen and blood. To investigate their differential sensitivity to stress hormones, splenocytes were incubated in vitro with prednisolone, epinephrine and their respective receptor blockers. Glucocorticoid receptor (GCR) and beta2-adrenergic receptor (β2-AR) on leukocyte subpopulations were quantified by flow cytometry. In vivo effects of GCR and selective β2-AR blockade, respectively, were defined on serum hormone concentrations, lymphopenia and interferon-γ production after severe ischemia. We found elevated cortisone, corticosterone and metanephrine levels and associated lymphocytopenia only after extensive brain infarction. Prednisolone resulted in a 5 times higher cell death rate of splenocytes than epinephrine in vitro. Prednisolone and epinephrine-induced leukocyte cell death was prevented by GCR and β2-AR blockade, respectively. In vivo, only GCR blockade prevented post ischemic lymphopenia whereas β2-AR preserved interferon-γ secretion by lymphocytes. GCR blockade increased metanephrine levels in vivo and prednisolone, in turn, decreased β2-AR expression on lymphocytes. In conclusion, mediators of the SNS and the HPA axis differentially affect the systemic

  15. Pituitary, adrenal, immune and performance responses of mature Holstein x Friesian bulls housed on slatted floors at various space allowances.

    PubMed

    Gupta, S; Earley, B; Crowe, M A

    2007-05-01

    The effect of various space allowances on the pituitary, adrenal and immune responses and on performance was investigated in 72 mature Holstein x Friesian beef bulls. The animals (weighing 403+/-3.5 kg) were blocked by weight and randomly assigned to two groups (familiar, F, and unfamiliar, UF) x three treatments (1.2, 2.7 and 4.2m(2) per bull; n=24 per space allowance), and housed for 83 days in 18 pens (n=4 per pen). Blood samples were collected on days -1, 0, 3, 14, 36 and 77 with respect to mixing and housing on day 0. The bulls were given exogenous adrenocorticotrophic hormone (ACTH) on day 3 and corticotrophin-releasing hormone (CRH) on days 14, 36 and 77. Basal plasma cortisol concentration was not affected (P>0.05) by mixing F and UF bulls. On day 3, basal cortisol was greater (P<0.05) in bulls housed at 1.2 than those at 2.7 and 4.2m(2) space allowances while no effect was observed in ACTH-induced plasma cortisol concentration among treatments. Following CRH administration, there was no effect (P>0.05) of treatment and treatment x time on plasma ACTH concentration. On day 14, interferon-gamma production was lower (P<0.05) in the bulls housed at 4.2 vs. 2.7 m(2) and was intermediate but not significantly different (P>0.05) for those housed at 1.2m(2). Animals housed at either space allowances had significant (P<0.05) neutrophilia, lymphopenia, eosinopenia and decreased haemoglobin on day 3 compared with day 0. The liveweight gain from days 0 to 83 was lower (P<0.05) in bulls housed at 1.2 compared with those at 2.7 and 4.2m(2). Housing bulls at 1.2m(2) space allowance had a detrimental effect on their growth and was associated with an acute rise in plasma cortisol concentration (on day 3) compared with those having space allowances of 2.7 and 4.2m(2)/bull.

  16. Evidence of hypothalamic-pituitary-adrenal axis suppression during moderate-to-high-dose inhaled corticosteroid use.

    PubMed

    Cavkaytar, Ozlem; Vuralli, Dogus; Arik Yilmaz, Ebru; Buyuktiryaki, Betul; Soyer, Ozge; Sahiner, Umit M; Kandemir, Nurgun; Sekerel, Bulent E

    2015-11-01

    The possible risk of adverse effects due to regular use of inhaled corticosteroids (ICS) is a real concern. Our aim was to describe the factors that have an impact on hypothalamic-pituitary-adrenal axis suppression (HPA-AS) in children and adolescents taking ICS regularly. The HPA axis status of patients who were on moderate-to-high-dose ICS [>176 and >264 μg/day fluticasone propionate-hydrofluoroalkane (FP-HFA) for patients 0-11 and ≥12 years, respectively] was investigated. Various types of ICS were converted to FP-HFA equivalent according to National Asthma Education and Prevention Program (NAEPP) guidelines. Participants with a baseline (8 a.m.) serum cortisol <15 μg/dL underwent a low-dose ACTH stimulation test (LDAT) to diagnose HPA-AS. Among 91 patients, 60 (75.9 %) participants underwent LDAT, and seven (7.7, 95 % CI 3.5-15.3 %) were diagnosed with HPA-AS. Ciclesonide was more frequently used by the participants with HPA-AS compared to patients with a normal HPA axis (42.9 vs. 4.8 %, p = 0.009). Use of ICS at moderate-to-high doses for at least 7 months distinguished participants with HPA-AS from those with a normal HPA axis. Among the duration, type, and dose of ICS, solely the use of ICS with a body mass index (BMI)-adjusted daily dose of ≥22 μg FP was found to increase the risk for HPA-AS (odds ratio (OR) 7.22, 95 % confidence interval (CI) 1.23-42.26, p = 0.028). The receiver operating characteristics (ROC) curve analysis revealed a cutoff value of 291 μg/day FP (area under the curve (AUC) = 0.840, p = 0.003) for predicting HPA-AS Conclusion: The prevalence of HPA-AS was found to be 7.7 % in children taking not only high-dose ICS but also moderate-dose ICS. Dose alone was found to be an actual risk factor for HPA-AS.

  17. Breast-Milk Cortisol and Cortisone Concentrations Follow the Diurnal Rhythm of Maternal Hypothalamus-Pituitary-Adrenal Axis Activity.

    PubMed

    van der Voorn, Bibian; de Waard, Marita; van Goudoever, Johannes B; Rotteveel, Joost; Heijboer, Annemieke C; Finken, Martijn Jj

    2016-11-01

    hypothalamus-pituitary-adrenal axis activity and are lower in mothers who deliver very preterm. © 2016 American Society for Nutrition.

  18. Recovery of the hypothalamic-pituitary-adrenal axis in children and adolescents after surgical cure of Cushing's disease.

    PubMed

    Lodish, Maya; Dunn, Somya Verma; Sinaii, Ninet; Keil, Margaret F; Stratakis, Constantine A

    2012-05-01

    Recovery of the hypothalamic-pituitary-adrenal axis (HPAA) after transsphenoidal surgery (TSS) for Cushing's disease (CD) in children has not been adequately studied. Our objective was to assess time to recovery of the HPAA after TSS in children with CD. This was a case series at the National Institutes of Health Clinical Center. Fifty-seven patients with CD (6-18 yr, mean 13.0 ± 3.1 yr) given a standard regimen of glucocorticoid tapering after TSS were studied out of a total of 73 recruited. ACTH (250 μg) stimulation tests were administered at approximately 6-month intervals for up to 36 months. Age, sex, pubertal status, body mass index, length of disease, midnight cortisol, and urinary free cortisol at diagnosis were analyzed for effects on recovery. The main outcome measure was complete recovery of the HPAA as defined by a cortisol level of at least 18 μg/dl in response to 250 μg ACTH. Full recovery was reached by 43 (75.4%) of 57 patients, with 29 of the 43 (67.4%) and 41 of the 43 (95.3%) recovering by 12 and 18 months, respectively. The overall mean time to recovery was 12.6 ± 3.3 months. Kaplan-Meier survivor function estimated a 50% chance of recovering by 12 months after TSS and 75% chance of recovering within 14 months. By receiver operating characteristic curve assessment, the cutoff of at least 10-11 μg/dl of cortisol as the peak of ACTH stimulation testing at 6 months after TSS yielded the highest sensitivity (70-80%) and specificity (64-73%) to predict full recovery of the HPAA at 12 months. Two of the four patients that recovered fully within 6 months had recurrent CD. Although this is not a randomized study, we present our standardized tapering regimen for glucocorticoid replacement after TSS that led to recovery of the HPAA in most patients within the first postoperative year. Multiple factors may affect this process, but an early recovery may indicate disease recurrence.

  19. Recovery of the Hypothalamic-Pituitary-Adrenal Axis in Children and Adolescents after Surgical Cure of Cushing's Disease

    PubMed Central

    Dunn, Somya Verma; Sinaii, Ninet; Keil, Margaret F.; Stratakis, Constantine A.

    2012-01-01

    Context: Recovery of the hypothalamic-pituitary-adrenal axis (HPAA) after transsphenoidal surgery (TSS) for Cushing's disease (CD) in children has not been adequately studied. Objective: Our objective was to assess time to recovery of the HPAA after TSS in children with CD. Design and Setting: This was a case series at the National Institutes of Health Clinical Center. Patients: Fifty-seven patients with CD (6–18 yr, mean 13.0 ± 3.1 yr) given a standard regimen of glucocorticoid tapering after TSS were studied out of a total of 73 recruited. Interventions: ACTH (250 μg) stimulation tests were administered at approximately 6-month intervals for up to 36 months. Age, sex, pubertal status, body mass index, length of disease, midnight cortisol, and urinary free cortisol at diagnosis were analyzed for effects on recovery. Main Outcome Measure: The main outcome measure was complete recovery of the HPAA as defined by a cortisol level of at least 18 μg/dl in response to 250 μg ACTH. Results: Full recovery was reached by 43 (75.4%) of 57 patients, with 29 of the 43 (67.4%) and 41 of the 43 (95.3%) recovering by 12 and 18 months, respectively. The overall mean time to recovery was 12.6 ± 3.3 months. Kaplan-Meier survivor function estimated a 50% chance of recovering by 12 months after TSS and 75% chance of recovering within 14 months. By receiver operating characteristic curve assessment, the cutoff of at least 10–11 μg/dl of cortisol as the peak of ACTH stimulation testing at 6 months after TSS yielded the highest sensitivity (70–80%) and specificity (64–73%) to predict full recovery of the HPAA at 12 months. Two of the four patients that recovered fully within 6 months had recurrent CD. Conclusions: Although this is not a randomized study, we present our standardized tapering regimen for glucocorticoid replacement after TSS that led to recovery of the HPAA in most patients within the first postoperative year. Multiple factors may affect this process, but an

  20. Hypothalamic-pituitary-adrenal axis response to acute psychosocial stress: Effects of biological sex and circulating sex hormones

    PubMed Central

    Stephens, Mary Ann C.; Mahon, Pamela B.; McCaul, Mary E.; Wand, Gary S.

    2016-01-01

    Summary Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis influences the risk for developing stress-related disorders. Sex-dependent differences in the HPA axis stress response are believed to contribute to the different prevalence rates of stress-related disorders found in men and women. However, studies examining the HPA axis stress response have shown mixed support for sex differences, and the role of endogenous sex hormones on HPA axis response has not been adequately examined in humans. This study utilized the largest sample size to date to analyze the effects of biological sex and sex hormones on HPA axis social stress responses. Healthy, 18- to 30- year-old community volunteers (N=282) completed the Trier Social Stress Test (TSST), a widely used and well-validated stress-induction laboratory procedure. All women (n=135) were tested during the follicular phase of their menstrual cycle (when progesterone levels are most similar to men). Adrenocorticotropic hormone (ACTH) and cortisol measures were collected at multiple points throughout pre- and post-TSST. Testosterone and progesterone (in men) and progesterone and estradiol (in women) were determined pre-TSST. Following the TSST, men had greater ACTH and cortisol levels than women. Men had steeper baseline-to-peak and peak-to-end ACTH and cortisol response slopes than women; there was a trend for more cortisol responders among men than women. Testosterone negatively correlated with salivary cortisol response in men, while progesterone negatively correlated with ACTH and cortisol responses in women. These data confirm that men show more robust activation of the HPA axis response to the TSST than do women in the follicular phase of the menstrual cycle. Testosterone results suggest an inhibitory effect on HPA axis reactivity in men. Progesterone results suggest an inhibitory effect on HPA axis reactivity in women. Future work is needed to explain why men mount a greater ACTH and cortisol response to

  1. Hypothalamic-pituitary-adrenal axis activation and immune regulation in heat-stressed sheep after supplementation with polyunsaturated fatty acids.

    PubMed

    Caroprese, M; Ciliberti, M G; Annicchiarico, G; Albenzio, M; Muscio, A; Sevi, A

    2014-07-01

    The aim of this study was to assess the effects of supplementation with polyunsaturated fatty acids from different sources on immune regulation and hypothalamic-pituitary-adrenal (HPA) axis activation in heat-stressed sheep. The experiment was carried out during the summer 2012. Thirty-two Comisana ewes were divided into 4 groups (8 sheep/group): (1) supplemented with whole flaxseed (FS); (2) supplemented with Ascophyllum nodosum (AG); (3) supplemented with a combination of flaxseed and A. nodosum (FS+AG); and (4) control (C; no supplementation). On d 22 of the experiment, cortisol concentrations in sheep blood were measured after an injection of ACTH. Cellular immune response was evaluated by intradermic injection of phytohemagglutinin (PHA) at 0, 15, and 30 d of the trial. Humoral response to ovalbumin (OVA) was measured at 0, 15, and 30 d. At 0, 15, and 30 d of the experiment, blood samples were collected from each ewe to determine production of T-helper (Th)1 cytokines (IL-12 and IFN-γ), and Th2 cytokines (IL-10, IL-4, IL-13), and concentrations of heat shock proteins (HSP) 70 and 90. Ewes supplemented with flaxseed alone had greater cortisol concentrations and a longer-lasting cell-mediated immune response compared with ewes in the control and other groups. Anti-OVA IgG concentrations increased in all groups throughout the trial, even though ewes in the FS+AG group had the lowest anti-OVA IgG concentrations at 15 d. The level of IL-10 increased in all groups throughout the experiment; the FS+AG group had the lowest IL-13 concentration at 15 and 30 d. The concentration of HSP 70 increased in AG ewes at the end of the experiment and decreased in FS ewes, whereas that of HSP 90 increased in FS ewes compared with FS+AG ewes. Flaxseed supplementation was found to influence in vivo HPA activation in heat-stressed sheep, resulting in increased cortisol concentrations, probably to meet increased energy demand for thermoregulation. Flaxseed supplementation also

  2. Recovery by N-acetylcysteine from subchronic exposure to Imidacloprid-induced hypothalamic-pituitary-adrenal (HPA) axis tissues injury in male rats.

    PubMed

    Annabi, Alya; Dhouib, Ines Bini; Lamine, Aicha Jrad; El Golli, Nargès; Gharbi, Najoua; El Fazâa, Saloua; Lasram, Mohamed Montassar

    2015-01-01

    Imidacloprid is the most important example of the neonicotinoid insecticides known to target the nicotinic acetylcholine receptor in insects, and potentially in mammals. N-Acetyl-l-cysteine (NAC) has been shown to possess curative effects in experimental and clinical investigations. The present study was designed to evaluate the recovery effect of NAC against Imidacloprid-induced oxidative stress and cholinergic transmission alteration in hypothalamic-pituitary-adrenal (HPA) axis of male rats following subchronic exposure. About 40 mg/kg of Imidacloprid was administered daily by intragastric intubation and 28 days later, the rats were sacrificed and HPA axis tissues were removed for different analyses. Imidacloprid increased adrenal relative weight and cholesterol level indicating an adaptive stage of the general alarm reaction to stress. Moreover, Imidacloprid caused a significant increase in malondialdehyde level, the antioxidants catalase, superoxide dismutase and glutathione-S-transferase showed various alterations following administration and significant depleted thiols content was only recorded in hypothalamic tissue. Furthermore, the hypothalamic and pituitary acetylcholinesterase activity and calcium level were significantly increased highlighting the alteration of cholinergic activity. The present findings revealed that HPA axis is a sensitive target to Imidacloprid (IMI). Interestingly, the use of NAC for only 7 days post-exposure to IMI showed a partial therapeutic effect against Imidacloprid toxicity.

  3. Childhood adversity and DNA methylation of genes involved in the hypothalamus-pituitary-adrenal axis and immune system: whole-genome and candidate-gene associations.

    PubMed

    Bick, Johanna; Naumova, Oksana; Hunter, Scott; Barbot, Baptiste; Lee, Maria; Luthar, Suniya S; Raefski, Adam; Grigorenko, Elena L

    2012-11-01

    In recent years, translational research involving humans and animals has uncovered biological and physiological pathways that explain associations between early adverse circumstances and long-term mental and physical health outcomes. In this article, we summarize the human and animal literature demonstrating that epigenetic alterations in key biological systems, the hypothalamus-pituitary-adrenal axis and immune system, may underlie such disparities. We review evidence suggesting that changes in DNA methylation profiles of the genome may be responsible for the alterations in hypothalamus-pituitary-adrenal axis and immune system trajectories. Using some preliminary data, we demonstrate how explorations of genome-wide and candidate-gene DNA methylation profiles may inform hypotheses and guide future research efforts in these areas. We conclude our article by discussing the many important future directions, merging perspectives from developmental psychology, molecular genetics, neuroendocrinology, and immunology, that are essential for furthering our understanding of how early adverse circumstances may shape developmental trajectories, particularly in the areas of stress reactivity and physical or mental health.

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

    PubMed

    Steiner, Michel A; Sciarretta, Carla; Brisbare-Roch, Catherine; Strasser, Daniel S; Studer, Rolf; Jenck, Francois

    2013-04-01

    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.

  5. Mu-opioid receptor A118G polymorphism in healthy volunteers affects hypothalamic-pituitary-adrenal axis adrenocorticotropic hormone stress response to metyrapone.

    PubMed

    Ducat, Elizabeth; Ray, Brenda; Bart, Gavin; Umemura, Yoshie; Varon, Jack; Ho, Ann; Kreek, Mary Jeanne

    2013-03-01

    The mu-opioid receptor encoded by the gene OPRM1 plays a primary role in opiate, alcohol, cocaine and nicotine addiction. Studies using opioid antagonists demonstrate that the mu-opioid receptor (MOP-r) also mediates the hypothalamic-pituitary-adrenal (HPA) axis stress response. A common polymorphism in exon one of the MOP-r gene, A118G, has been shown to significantly alter receptor function and MOP-r gene expression; therefore, this variant likely affects HPA-axis responsivity. In the current study, we have investigated whether the presence of the 118AG variant genotype affects HPA axis responsivity to the stressor metyrapone, which transiently blocks glucocorticoid production in the adrenal cortex. Forty-eight normal and healthy volunteers (32 men, 16 women) were studied, among whom nine men and seven women had the 118AG genotype. The 118G allele blunted the adrenocorticotropic hormone (ACTH) response to metyrapone. Although there was no difference in basal levels of ACTH, subjects with the 118AG genotype had a more modest rise and resultant significantly lower ACTH levels than those with the prototype 118AA at the 8-hour time point (P < 0.02). We found no significant difference between genders. These findings suggest a relatively greater tonic inhibition at hypothalamic-pituitary sites through the mu-opioid receptor and relatively less cyclical glucocorticoid inhibition in subjects with the 118G allele.

  6. Programming of the hypothalamic-pituitary-adrenal axis by neonatal intermittent hypoxia: effects on adult male ACTH and corticosterone responses are stress specific.

    PubMed

    Chintamaneni, Kathan; Bruder, Eric D; Raff, Hershel

    2014-05-01

    Intermittent hypoxia (IH) is an animal model of apnea-induced hypoxia, a common stressor in the premature neonate. Neonatal stressors may have long-term programming effects in the adult. We hypothesized that neonatal exposure to IH leads to significant changes in basal and stress-induced hypothalamic-pituitary-adrenal (HPA) axis function in the adult male rat. Rat pups were exposed to normoxia (control) or 6 approximately 30-second cycles of IH (5% or 10% inspired O₂) daily on postnatal days 2-6. At approximately 100 days of age, we assessed the diurnal rhythm of plasma corticosterone and stress-induced plasma ACTH and corticosterone responses, as well as mRNA expression of pertinent genes within the HPA axis. Basal diurnal rhythm of plasma corticosterone concentrations in the adult rat were not affected by prior exposure to neonatal IH. Adults exposed to 10% IH as neonates exhibited an augmented peak ACTH response and a prolonged corticosterone response to restraint stress; however, HPA axis responses to insulin-induced hypoglycemia were not augmented in adults exposed to neonatal IH. Pituitary Pomc, Crhr1, Nr3c1, Nr3c2, Avpr1b, and Hif1a mRNA expression was decreased in adults exposed to neonatal 10% IH. Expression of pertinent hypothalamic and adrenal mRNAs was not affected by neonatal IH. We conclude that exposure to neonatal 10% IH programs the adult HPA axis to hyperrespond to acute stimuli in a stressor-specific manner.

  7. An Investigation of the Effects of Maternal Separation and Novelty on Central Mechanisms Mediating Pituitary-Adrenal Activity in Infant Guinea Pigs (Cavia porcellus)

    PubMed Central

    Maken, Deborah S.; Weinberg, Joanne; Cool, David R.; Hennessy, Michael B.

    2016-01-01

    In mammalian species in which the young exhibit a strong filial attachment (e.g., monkeys, guinea pigs), numerous studies have shown that even brief separation from the attachment figure potently elevates circulating concentrations of glucocorticoids and adrenocorticotropic hormone (ACTH). However, effects of separation on central regulation of this stress response are not known. Therefore, we investigated central mechanisms mediating pituitary-adrenal activation during maternal separation and novelty exposure in guinea pig (Cavia porcellus) pups. Corticotropin-releasing factor (CRF) mRNA expression in the hypothalamic paraventricular nucleus (PVN), and plasma cortisol and ACTH levels, were elevated only during separation in a novel environment. C-Fos activity was elevated in the medial amygdala (MeA) and reduced in the bed nucleus of the stria terminalis (BNST) during novelty exposure, regardless of separation. On the other hand, c-Fos activity was elevated in the PVN during separation, regardless of novelty exposure. These results demonstrate independent and combined effects of separation and novelty in regions of the guinea pig CNS that regulate pituitary-adrenal activity. Moreover, they suggest that a pathway from MeA to BNST to PVN mediates responses to novelty in the guinea pig pup, as in the adult rat, though inputs from other cell populations appear required to fully account for the HPA activity observed here. PMID:21038937

  8. Effects of acupuncture at Zu-San-Li (ST36) on the activity of the hypothalamic--pituitary--adrenal axis during ethanol withdrawal in rats.

    PubMed

    Zhao, ZhengLin; Lee, Bong Hyo; Lin, Feng; Guo, YanQin; Wu, YiYan; In, Sunghyeon; Park, Sang Mi; Chan Kim, Sang; Yang, Chae Ha; Zhao, RongJie

    2014-10-01

    The current study investigated the effects of acupuncture at Zu-San-Li (ST36) on the hypothalamic-pituitary-adrenal axis during ethanol withdrawal in rats. Rats were intraperitoneally treated with 3 g/kg/day of ethanol or saline for 28 days. Following 24 hours of ethanol withdrawal, acupuncture was applied at bilateral ST36 points or non-acupoints (tail) for 1 minute. Plasma levels of corticosterone (CORT) and adrenocorticotropic hormone (ACTH) were measured by radioimmunoassay (RIA), and the corticotropin-releasing factor (CRF) protein levels in the paraventricular nucleus of the hypothalamus were also examined by RIA 20 minutes after the acupuncture treatment. RIA showed significantly increased plasma levels of CORT and ACTH in the ethanol-withdrawn rats compared with the saline-treated rats, which were inhibited significantly by the acupuncture at the acupoint ST36 but not at the non-acupoint. Additionally, ethanol withdrawal promoted CRF protein expressions in the paraventricular nucleus of the hypothalamus, which were also blocked by the acupuncture at ST36. These findings suggest that acupuncture at the specific acupoint ST36 can inhibit ethanol withdrawal-induced hyperactivation of hypothalamic-pituitary-adrenal axis, and it may be mediated via the modulation of hypothalamic CRF. Copyright © 2014. Published by Elsevier B.V.

  9. Multigenerational effects of fetal dexamethasone exposure on the hypothalamic-pituitary-adrenal axis of first- and second-generation female offspring.

    PubMed

    Long, Nathan M; Ford, Stephen P; Nathanielsz, Peter W

    2013-03-01

    Synthetic glucocorticoid (sGC) administration to women threatening preterm delivery increases neonatal survival. Evidence shows that fetal exposure to glucocorticoid levels higher than appropriate for current maturation programs offspring development. We examined fetal sGC multigenerational effects on F1 and F2 female offspring hypothalamo-pituitary-adrenal axis (HPAA) function. At 0.7 gestation, pregnant F0 ewes received 4 dexamethasone injections (2 mg, approximately 60 μg/kg(-1) per day(-1), 12 hours apart) or saline (control). F1 female offspring were bred to produce F2 female offspring. Postpubertal HPAA function was tested in F1 and F2 ewes. F1 and F2 ewe lambs showed reduced birthweight and morphometrics. Dexamethasone increased baseline but reduced stimulated HPAA activity in F1 and F2 female offspring. This is the first demonstration that sGC doses in the clinical range have multigenerational effects on hypothalamo-pituitary-adrenal activity in a precocial species, indicating the need for the study of long-term effects of fetal sGC exposure. Copyright © 2013 Mosby, Inc. All rights reserved.

  10. Changes of adrenomedullin and its receptor components mRNAs expression in the brain stem and hypothalamus-pituitary-adrenal axis of stress-induced hypertensive rats.

    PubMed

    Li, Xia; Li, Liang; Shen, Lin-Lin; Qian, Yuan; Cao, Yin-Xiang; Zhu, Da-Nian

    2004-12-25

    In this study, reverse transcription-polymerase chain reaction (RT-PCR) was used to detect the changes in mRNAs levels of preproadrenomedullin (ppADM) gene encoding adrenomedullin (ADM) and the essential receptor components of ADM, calcitonin receptor-like receptor (CRLR), and the receptor activity modifying protein 2 and 3 (RAMP2 and RAMP3) in the medulla oblongata, hypothalamus, midbrain, pituitary gland and adrenal gland of the stress-induced hypertensive rats. It was shown that chronic foot-shock and noise stress for 15 consecutive days induced a significant increase in systolic blood pressure (SBP) and unique changes in ppADM and its receptor components mRNAs in all areas studied. As compared with the control group, the level of ppADM mRNA, normalized against a glyceraldehydes-3-phosphate dehydrogenase (GAPDH) control, was up-regulated in the hypothalamus-pituitary-adrenal (HPA) axis, but down-regulated in the medulla oblongata and midbrain (P<0.01 and P<0.05, respectively). The relative amount of CRLR mRNA was higher in the hypothalamus than that in other areas. The level of CRLR mRNA expression was significantly increased in the medulla oblongata of the stress group (P<0.01), but decreased in the midbrain (P<0.01) as well as hypothalamus(P<0.05), as compared with that of the control group. Chronic stress for 15 consecutive days produced an increase in the level of RAMP2 mRNA expression in the medulla oblongata (P<0.01) and a decrease in the adrenal gland (P<0.01), as compared with the control. No significant stress-related changes in RAMP2 mRNA were observed in the midbrain, hypothalamus and pituitary gland. The amount of RAMP3 mRNA was relatively higher in the midbrain and hypothalamus than that in the medulla oblongata, adrenal gland and adrenal gland. Stress-induced hypertensive rats exhibited an increased RAMP3 mRNA expression in the hypothalamus and pituitary gland (P<0.01 and P<0.05, respectively) and a decrease in the adrenal gland and midbrain (P<0

  11. Effects of aging on hypothalamic-pituitary-adrenal (HPA) axis activity and reactivity in virgin male and female California mice (Peromyscus californicus).

    PubMed

    Harris, Breanna N; Saltzman, Wendy

    2013-06-01

    Life history theory posits that organisms face a trade-off between current and future reproductive attempts. The physiological mechanisms mediating such trade-offs are still largely unknown, but glucocorticoid hormones are likely candidates as elevated, post-stress glucocorticoid levels have been shown to suppress both reproductive physiology and reproductive behavior. Aged individuals have a decreasing window in which to reproduce, and are thus predicted to invest more heavily in current as opposed to future reproduction. Therefore, if glucocorticoids are important in mediating the trade-off between current and future reproduction, aged animals are expected to show decreased hypothalamic-pituitary-adrenal (HPA) axis responses to stressors and to stimulation by corticotropin-releasing hormone (CRH), and enhanced responses to glucocorticoid negative feedback, as compared to younger animals. We tested this hypothesis in the monogamous, biparental California mouse by comparing baseline and post-stress corticosterone levels, as well as corticosterone responses to dexamethasone (DEX) and CRH injections, between old (∼18-20months) and young (∼4months) virgin adults of both sexes. We also measured gonadal and uterine masses as a proxy for investment in potential current reproductive effort. Adrenal glands were weighed to determine if older animal had decreased adrenal mass. Old male mice had lower plasma corticosterone levels 8h after DEX injection than did young male mice, suggesting that the anterior pituitary of older males is more sensitive to DEX-induced negative feedback. Old female mice had higher body-mass-corrected uterine mass than did young females. No other differences in corticosterone levels or organ masses were found between age groups within either sex. In conclusion, we did not find strong evidence for age-related change in HPA activity or reactivity in virgin adult male or female California mice; however, future studies investigating HPA activity and

  12. Central organization of androgen-sensitive pathways to the hypothalamic-pituitary-adrenal axis: implications for individual differences in responses to homeostatic threat and predisposition to disease.

    PubMed

    Williamson, Martin; Bingham, Brenda; Viau, Victor

    2005-12-01

    Despite clear evidence of the potency by which sex steroids operate on the hypothalamic-pituitary-adrenal (HPA) axis and genuine sex differences in disorders related to HPA dysfunction, the biological significance of this remains largely ignored. Stress-induced increases in circulating glucocorticoid levels serve to meet the metabolic demands of homeostatic threat head-on. Thus, the nature of the stress-adrenal axis is to protect the organism. As one develops, matures, and ages, still newer and competing physiological and environmental demands are encountered. These changing constraints are also met by shifts in sex steroid release, placing this class of steroids beyond the traditional realm of reproductive function. Here we focus on the dose-related and glucocorticoid-interactive nature by which testosterone operates on stress-induced HPA activation. This provides an overview on how to exploit these characteristics towards developing an anatomical framework of testosterone's actions in the brain, and expands upon the idea that centrally projecting arginine vasopressin circuits in the brain act to register and couple testosterone's effects on neuroendocrine and behavioural responses to stress. More generally, the work presented here underscores how a dual adrenal and gonadal systems approach assist in unmasking the bases by which individuals resist or succumb to stress.

  13. The CRF₁ receptor antagonist SSR125543 attenuates long-term cognitive deficit induced by acute inescapable stress in mice, independently from the hypothalamic pituitary adrenal axis.

    PubMed

    Philbert, J; Pichat, P; Palme, R; Belzung, C; Griebel, G

    2012-09-01

    The selective antagonist at the CRF₁ receptor, SSR125543, has been shown to produce anxiolytic-like effects in a number of animal models. The aim of the present study was to verify whether these effects are mediated by an action on the hypothalamic pituitary adrenal (HPA) axis. SSR125543 effects were evaluated in a mouse model of post-traumatic stress disorder. Animals received two unavoidable electric foot-shocks (1.5 mA/2 s). Two weeks later they were placed in the shock context and fecal and plasma corticosterone levels were measured by enzyme-immunoassay. Their cognitive performances were evaluated using the object recognition task following administration of SSR125543 at 3, 10 and 30 mg/kg or paroxetine at 20 mg/kg (i.p.), used as positive control. To assess the involvement of the HPA axis in the drug effects, a separate group of animals was subjected to the same procedure and drug regimen, but was treated with dexamethasone to blunt the HPA axis. Stressed mice had higher levels of corticosterone following re-exposure to the context and displayed impaired cognitive performance as compared to control animals. Corticosterone levels were normalized in stressed mice by SSR125543 and the cognitive deficit was significantly attenuated by SSR125543 and paroxetine, whether the HPA axis was blunted or not. These findings confirm that SSR125543 is able to attenuate the deleterious effects of stressful exposure. Importantly, the observation that these effects were still present in dexamethasone-treated mice indicates that this action does not necessarily involve pituitary-adrenal axis blockade, thereby suggesting that extra-pituitary CRF₁ receptors may play a role in these effects.

  14. Serum total cortisol and free cortisol index give different information regarding the hypothalamus-pituitary-adrenal axis reserve in patients with liver impairment.

    PubMed

    Vincent, Royce P; Etogo-Asse, Frédérique E; Dew, Tracy; Bernal, William; Alaghband-Zadeh, Jamshid; le Roux, Carel W

    2009-11-01

    The short synacthen test (SST) is used to investigate patients with suspected hypothalamus-pituitary-adrenal (HPA) axis pathology. A rise of serum total cortisol (total cortisol) above 550 nmol/L is accepted as sufficient adrenal reserve. In total, 80% of cortisol is bound to cortisol-binding globulin (CBG) and 10% to albumin. In the acute phase responses CBG concentrations decrease and can influence the interpretation of SST. The free cortisol index (FCI) is a surrogate marker for free cortisol and is defined as total cortisol (nmol/L)/CBG (mg/L) with an FCI > 12 representing sufficient adrenal reserve. The aim of this study was to compare total cortisol and FCI in the interpretation of SST in patients with liver impairment. SST was done on 26 patients with liver impairment. Total cortisol was measured on Advia Centaur; serum CBG by radioimmunoassay and FCI calculated. Eleven (42%) patients had a total cortisol >550 nmol/L (range 555-2070) and FCI > 12 (12.0-68.9) suggesting sufficient cortisol reserve. Three patients (13%) had total cortisol <550 nmol/L (268-413) and FCI < 12 (3.5-11.6) consistent with cortisol deficiency. Twelve patients (46%) had a total cortisol <550 nmol/L (144-529), but an FCI > 12 (12.0-52.9). None of the patients had a total cortisol >550 nmol/L and FCI < 12. When total cortisol alone is used to interpret SST in patients with liver impairment, 46% may have been classified as having adrenal insufficiency because of low CBG. FCI may be better for the evaluation of HPA axis insufficiency in patients with liver impairment.

  15. The effect of local injection of methylprednisolone acetate on the hypothalamic-pituitary-adrenal axis among patients with greater trochanteric pain syndrome.

    PubMed

    Habib, George; Elias, Shada; Abu-Elhaija, Muhanned; Sakas, Fahed; Khazin, Fadi; Artul, Suheil; Jabbour, Adel; Jabaly-Habib, Haneen

    2017-04-01

    Greater trochanteric pain syndrome (GTPS) is a common clinical entity for which the most effective treatment is local corticosteroid injection (LCI). There are no studies on the effect of LCI among patients with GTPS on the hypothalamic-pituitary-adrenal axis. The present study recruited nonselected patients diagnosed with GTPS. After consenting, participants received low dose (1 μg) of adrenocorticotropin hormone (ACTH) stimulation test at 09:00. Immediately following the test, participants received a LCI of 80 mg of methylprednisolone acetate at the greater trochanteric region. The ACTH stimulation test was repeated 1, 2, 4, and 6 weeks following the LCI. Cortisol samples were obtained at just prior to (basal) and 30 min (post-stimulation) following every ACTH stimulation test. Serum cortisol levels of <500 μmol/l obtained 30 min following the ACTH stimulation test were considered evidence of secondary adrenal insufficiency. The study enrolled 22 patients, 21 of whom completed participation. There were 19 female participants (~90%), and mean age of all the participants was 55.2 ± 8.6 years. Four participants showed evidence of secondary adrenal insufficiency, which was observed only at weeks 1 and 2 following the LCI. Mean serum cortisol level among these four participants 30 min following the ACTH stimulation test was 354 μmol/l, with a range of 268-430 μmol/l. LCI of 80 mg of methylprednisolone acetate in the greater trochanteric area among patients with GTPS was associated with transient secondary adrenal insufficiency in ~20% of the patients, mainly 1 week following the injection.

  16. Effect of Schisandra chinensis on interleukins, glucose metabolism, and pituitary-adrenal and gonadal axis in rats under strenuous swimming exercise.

    PubMed

    Li, Jie; Wang, Jian; Shao, Jia-Qing; Du, Hong; Wang, Yang-Tian; Peng, Li

    2015-01-01

    To investigate the effect of Chinese medicine (CM) Schisandra chinensis on interleukin (IL), glucose metabolism, and pituitary-adrenal and gonadal axis of rats after strenuous navigation and exercise. A total of 45 Sprague-Dawley rats were randomized into the quiet control group, the stress group, and the CM group (15 in each group). The CM group received 2.5 g/kg of Schisandra chinensis twice per day for one week before modeling. Except the quiet controls, rats were trained using the Bedford mode for 10 days. On the 11th day, they performed 3 h of stressful experimental navigation and 3 h of strenuous treadmill exercise. The levels of serum testosterone (T), cortisol (CORT), luteinizing hormone (LH), IL-1, IL-2, and IL-6 were tested by radioimmunoassay and enzyme-linked immunosorbent assay, respectively. The adrenal cortex ultrastructure was observed using electron microscopy. Compared with the quiet control group, after navigation and strenuous exercise, blood glucose was increased, and T level was decreased in the stress group (both P<0.01). The blood glucose, CORT, IL-1 and IL-2 levels were significantly reduced in the CM group (P<0.05 or P<0.01) as compared with the stress group. Electron microscopy revealed that the rats in the CM group had a smaller decrease in adrenal intracellular lipid droplets and higher levels of apoptosis than those in the stress group. Schisandra chinensis can reduce serum CORT and blood glucose levels in stressed rats. It appears to protect the cell structure of the adrenal cortex, and offset the negative effects of psychological stress and strenuous exercise related to immune dysfunction. Schisandra chinensis plays a regulatory role in immune function, and can decrease the influence of stress in rats.

  17. Up-regulation of the fetal baboon hypothalamo-pituitary-adrenal axis in intrauterine growth restriction: coincidence with hypothalamic glucocorticoid receptor insensitivity and leptin receptor down-regulation.

    PubMed

    Li, Cun; Ramahi, Emma; Nijland, Mark J; Choi, Jaeyhek; Myers, Dean A; Nathanielsz, Peter W; McDonald, Thomas J

    2013-07-01

    Intrauterine growth restriction (IUGR) is an important fetal developmental problem resulting from 2 broad causes: maternal undernutrition and/or decreased fetal nutrient delivery to the fetus via placental insufficiency. IUGR is often accompanied by up-regulation of the hypothalamo-pituitary-adrenal axis (HPAA). Sheep studies show fetal HPAA autonomy in late gestation. We hypothesized that IUGR, resulting from poor fetal nutrient delivery, up-regulates the fetal baboon HPAA in late gestation, driven by hypothalamo-pituitary glucocorticoid receptor (GR) insensitivity and decreased fetal leptin in peripheral plasma. Maternal baboons were fed as ad libitum controls or nutrient restricted to produce IUGR (fed 70% of the control diet) from 0.16 to 0.9 gestation. Peripheral ACTH, cortisol, and leptin were measured by immunoassays. CRH, arginine vasopressin (AVP), GR, leptin receptor (ObRb), and pro-opiomelanocortin peptide expression were determined immunohistochemically. IUGR fetal peripheral cortisol and ACTH, but not leptin, were increased (P < .05). IUGR increased CRH peptide expression, but not AVP, in the fetal hypothalamic paraventricular nucleus (PVN) and median eminence (P < .05). PVN ObRb peptide expression, but not GR, was decreased (P < .05) with IUGR. ObRb and pro-opiomelanocortin were robustly expressed in the anterior pituitary gland, but ∼1% of cells showed colocalization. We conclude that (1) CRH, not AVP, is the major releasing hormone driving ACTH and cortisol secretion during primate IUGR, (2) fetal HPAA activation was aided by GR insensitivity and decreased ObRb expression in the PVN, and (3) the anterior pituitary is not a site for ObRb effects on the HPAA.

  18. Concentrations of the adrenocorticotropic hormone, corticosterone and sex steroid hormones and the expression of the androgen receptor in the pituitary and adrenal glands of male turkeys (Meleagris gallopavo) during growth and development.

    PubMed

    Kiezun, J; Kaminska, B; Jankowski, J; Dusza, L

    2015-01-01

    Androgens take part in the regulation of puberty and promote growth and development. They play their biological role by binding to a specific androgen receptor (AR). The aim of this study was to evaluate the expression of AR mRNA and protein in the pituitary and adrenal glands, to localize AR protein in luteinizing hormone (LH)-producing pituitary and adrenocortical cells, to determine plasma concentrations of adrenocorticotropic hormone (ACTH) and corticosterone and the concentrations of corticosterone, testosterone (T), androstenedione (A4) and oestradiol (E2) in the adrenal glands of male turkeys at the age of 4, 8, 12, 16, 20, 24 and 28weeks. The concentrations of hormones and the expression of AR varied during development. The expression of AR mRNA and protein in pituitary increased during the growth. The increase of AR mRNA levels in pituitary occurred earlier than increase of AR protein. The percentage of pituitary cells expressing ARs in the population of LH-secreting cells increased in week 20. It suggests that AR expression in LH-producing pituitary cells is determined by the phase of development. The drop in adrenal AR mRNA and protein expression was accompanied by an increase in the concentrations of adrenal androgens. Those results could point to the presence of a compensatory mechanism that enables turkeys to avoid the potentially detrimental effects of high androgen concentrations. Our results will expand our knowledge of the role of steroids in the development of the reproductive system of turkeys from the first month of age until maturity. Copyright © 2015 Elsevier Inc. All rights reserved.

  19. Hormonal status modifies renin-angiotensin system-regulating aminopeptidases and vasopressin-degrading activity in the hypothalamus-pituitary-adrenal axis of female mice.

    PubMed

    García, María Jesús; Martínez-Martos, José Manuel; Mayas, María Dolores; Carrera, María Pilar; De la Chica, Susana; Cortés, Pedro; Ramírez-Expósito, María Jesús

    2008-07-01

    The hypothalamus-pituitary-adrenal axis (HPA) participates in the maintenance of cardiovascular functions and in the control of blood pressure. By other hand, it is known that blood pressure regulation and HPA activity are affected by sex hormones. The aim of the present work is to analyze the influence of estradiol and progesterone on renin-angiotensin system (RAS)-regulating aminopeptidase A, aminopeptidase B and aminopeptidase N activities and vasopressin-degrading activity in the HPA axis of ovariectomized mice and ovariectomized mice treated subscutaneously with different doses of estradiol and progesterone. Our data suggest that in female mice, estradiol and progesterone influence RAS-regulating and vasopressin-degrading activities at different levels of the HPA axis.

  20. Short-term safety assessment of clobetasol propionate 0.05% shampoo: hypothalamic-pituitary-adrenal axis suppression, atrophogenicity, and ocular safety in subjects with scalp psoriasis.

    PubMed

    Andres, Philippe; Poncet, Michel; Farzaneh, Sidou; Soto, Pascale

    2006-04-01

    Clobetasol propionate is known to be a very effective treatment for psoriasis; however, its use is limited by potent corticosteroid class related side effects such as hypothalamic-pituitary-adrenal (HPA) axis suppression and atrophogenicity. The aim of this single-center, parallel group, randomized study was to assess the HPA axis suppression potential, atrophogenicity, and ocular tolerability of clobetasol propionate shampoo in 26 patients with scalp psoriasis. Suitable subjects were treated once daily for 4 weeks with clobetasol propionate shampoo, to be rinsed off after 15 minutes or with a leave-on clobetasol propionate gel. The study demonstrated that clobetasol propionate shampoo did not lead to HPA axis suppression or to skin atrophy. Conversely, the gel led to HPA axis suppression and a decrease in skin thickness. Neither formulation had an impact on ocular safety. Despite the short contact application time, the clobetasol propionate shampoo provides similar efficacy results to the gel.

  1. Expression of hypothalamic-pituitary-adrenal axis in common skin diseases: evidence of its association with stress-related disease activity.

    PubMed

    Kim, Jung Eun; Cho, Baik Kee; Cho, Dae Ho; Park, Hyun Jeong

    2013-07-06

    Hypothalamic-pituitary-adrenal (HPA) axis hormones and their receptors expressed in the skin are known to function locally, but how these hormones affect the maintenance of skin homeostasis or the pathogenesis of skin diseases is not fully understood. We comprehensively reviewed the distribution and function of the central and peripheral HPA axis in various stress-related skin diseases. Previous studies have shown altered expression of central and peripheral HPA axis hormones in chronic inflammatory skin diseases and skin tumours, and that hyper-active lesional HPA axis hormones may negatively feedback to the central HPA axis and interact with some cytokines and neuropeptides, leading to symptom deterioration. This provides an evidence-based understanding of the expression of the central and peripheral HPA axis in common skin diseases and its association with disease activity.

  2. Adaptation of the hypothalamus-pituitary-adrenal axis to daily repeated stress does not follow the rules of habituation: A new perspective.

    PubMed

    Rabasa, Cristina; Gagliano, Humberto; Pastor-Ciurana, Jordi; Fuentes, Silvia; Belda, Xavier; Nadal, Roser; Armario, Antonio

    2015-09-01

    Repeated exposure to a wide range of stressors differing in nature and intensity results in a reduced response of prototypical stress markers (i.e. plasma levels of ACTH and adrenaline) after an acute challenge with the same (homotypic) stressor. This reduction has been considered to be a habituation-like phenomenon. However, direct experimental evidence for this assumption is scarce. In the present work we demonstrate in adult male rats that adaptation of the hypothalamus-pituitary-adrenal (HPA) axis to repeated stress does not follow some of the critical rules of habituation. Briefly, adaptation was stronger and faster with more severe stressors, maximally observed even with a single exposure to severe stressors, extremely long-lasting, negatively related to the interval between the exposures and positively related to the length of daily exposure. We offer a new theoretical view to explain adaptation to daily repeated stress.

  3. Orexin receptor expression in the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes of free-living European beavers (Castor fiber L.) in different periods of the reproductive cycle.

    PubMed

    Czerwinska, Joanna; Chojnowska, Katarzyna; Kaminski, Tadeusz; Bogacka, Iwona; Smolinska, Nina; Kaminska, Barbara

    2017-01-01

    Orexins are hypothalamic neuropeptides acting via two G protein-coupled receptors in mammals: orexin receptor 1 (OX1R) and orexin receptor 2 (OX2R). In European beavers, which are seasonally breeding animals, the presence and functions of orexins and their receptors remain unknown. Our study aimed to determine the expression of OXR mRNAs and the localization of OXR proteins in hypothalamic-pituitary-adrenal/gonadal (HPA/HPG) axes in free-living beavers. The expression of OXR genes (OX1R, OX2R) and proteins was found in all analysed tissues during three periods of beavers' reproductive cycle (April, July, November). The expression of OXR mRNAs in the beaver HPA axis varied seasonally (P<0.05). The levels of OX1R mRNA also differed between the sexes (P<0.05). In the mediobasal hypothalamus, OX1R transcript content increased in pregnant females in April (P<0.05) and OX2R expression increased in males in July (P<0.05). In the pituitary and adrenals, OX1R mRNA levels were relatively constant in females and peaked in July in males (P<0.05), whereas the OX2R was most highly expressed in males in November and in females in April (P<0.05). In gonads, OX1R expression did not fluctuate between seasons or sexes, but transcript levels were elevated in the testes in November and in the ovaries in July (P<0.05). In turn, OX2R mRNA levels varied between the sexes (P<0.05) and were higher in females (July and November) than in males (P<0.05). The circannual variations in OXR mRNA levels in HPA and HPG axes suggest that the expression of these receptors is associated with sex-specific changes in beavers' reproductive activity and their environmental adaptations.

  4. Effect of lyophilized powder made from enzymolyzed honeybee larvae on tinnitus-related symptoms, hearing levels, and hypothalamus-pituitary-adrenal axis-related hormones.

    PubMed

    Aoki, Mitsuhiro; Wakaoka, Yoshinori; Hayashi, Hisamitsu; Kuze, Bunya; Mizuta, Keisuke; Ito, Yatsuji

    2012-01-01

    Tinnitus interferes with sleep and concentration which is associated with depression; however, no drug has been effective in treating tinnitus. Our purpose is to evaluate our hypothesis that the treatment with lyophilized powder of enzymolyzed honeybee larvae as a complementary medicine may provide a therapeutic effect on tinnitus-related symptoms. Sixty tinnitus sufferers participated in a randomized double-blind placebo-controlled trial using the lyophilized powder of enzymolyzed honeybee larvae or a placebo. The Tinnitus Handicap Inventory, a visual analog scale to rate the severity of tinnitus, hearing levels, and hypothalamus-pituitary-adrenal axis-related hormones drawn early in the morning were measured upon entry into the study and after 12 wk of follow-up. The lyophilized powder of enzymolyzed honeybee larvae was not superior to placebo with regard to the total score on the Tinnitus Handicap Inventory and the visual analog scale. However, subjects in the honeybee larvae group showed significant improvements in some items about depression associated with tinnitus, whereas subjects in the placebo group showed no improvement in any items. The honeybee larvae group showed significant improvements in the hearing levels at 2 and 4 kHz in the audiogram of the better ear. The intervention of the lyophilized powder of enzymolyzed honeybee larvae was associated with lower serum cortisol levels, serum prolactin levels, and cortisol/dehydroepiandrosterone sulfate ratios. The ratios in the placebo group significantly were increased. Our results suggest that the lyophilized powder of enzymolyzed honeybee larvae represents an effective complementary medicine to alleviate depression associated with tinnitus by regulating the activity of the hypothalamus-pituitary-adrenal axis.

  5. Hypothalamic-pituitary-adrenal axis activity, personality traits, and BCL1 and N363S polymorphisms of the glucocorticoid receptor gene in metabolically obese normal-weight women.

    PubMed

    Porzezińska-Furtak, Joanna; Krzyżanowska-Świniarska, Barbara; Miazgowski, Tomasz; Safranow, Krzysztof; Kamiński, Ryszard

    2014-09-01

    We sought associations among metabolic profiles, copeptin levels, emotional control, personality traits, and hypothalamic-pituitary-adrenal axis activity in metabolically obese normal-weight young women (MONW). We assessed body composition, including fat-free mass; body fat (BF) and android and gynoid fat depots; fasting blood glucose, insulin, copeptin, cortisol (baseline and after dexamethasone), adrenocorticotropin (ACTH), triglycerides, total cholesterol, low- (LDL) and high-density (HDL) lipoproteins; and the BCL1 and N363S polymorphisms of the glucocorticoid receptor gene in 59 MONW and 71 healthy women aged 20-40 years. We also evaluated personality traits using the NEO-Five Factor Inventory and the subjective extent of emotional suppression by the Courtauld Emotional Control Scale. Compared to the controls, MONW had significantly higher insulin, cholesterol, LDL, triglycerides, and waist circumference, but lower HDL. MONW also had increased BF (>30 % of weight) and unfavorable regional fat distribution with excess android fat. The android/BF ratio was 8.29 % (MONW) versus 7.89 % (controls) (p = 0.005), while the gynoid/BF ratio was 31.99 versus 34.1 %, respectively (p = 0.008). Despite similar ACTH levels in both groups, MONW had higher cortisol levels both at the baseline (p < 0.001) and in the dexamethasone suppression test (p = 0.003). Copeptin levels and the distribution of glucocorticoid receptor polymorphisms were similar in both groups. There were also no significant differences in psychological features between MONW and controls. In conclusion, the MONW phenotype was associated with hypothalamic-pituitary-adrenal axis dysregulation, unfavorable metabolic profiles, and fat accumulation, but normal distribution of glucocorticoid receptor gene polymorphisms and copeptin levels, and no significant differences in psychological features between MONW and controls.

  6. Exploration of the Hypothalamic-Pituitary-Adrenal Axis to Improve Animal Welfare by Means of Genetic Selection: Lessons from the South African Merino

    PubMed Central

    Hough, Denise; Swart, Pieter; Cloete, Schalk

    2013-01-01

    Simple Summary Breeding sheep that are robust and easily managed may be beneficial for both animal welfare and production. Sheep that are more readily able to adapt to stressful situations and a wide variety of environmental conditions are likely to have more resources available for a higher expression of their production potential. This review explores the utilization of one of the stress response pathways, namely the hypothalamic-pituitary-adrenal axis, to locate potential sites where genetic markers might be identified that contribute to sheep robustness. A South African Merino breeding programme is used to demonstrate the potential benefits of this approach. Abstract It is a difficult task to improve animal production by means of genetic selection, if the environment does not allow full expression of the animal’s genetic potential. This concept may well be the future for animal welfare, because it highlights the need to incorporate traits related to production and robustness, simultaneously, to reach sustainable breeding goals. This review explores the identification of potential genetic markers for robustness within the hypothalamic-pituitary-adrenal axis (HPAA), since this axis plays a vital role in the stress response. If genetic selection for superior HPAA responses to stress is possible, then it ought to be possible to breed robust and easily managed genotypes that might be able to adapt to a wide range of environmental conditions whilst expressing a high production potential. This approach is explored in this review by means of lessons learnt from research on Merino sheep, which were divergently selected for their multiple rearing ability. These two selection lines have shown marked differences in reproduction, production and welfare, which makes this breeding programme ideal to investigate potential genetic markers of robustness. The HPAA function is explored in detail to elucidate where such genetic markers are likely to be found. PMID:26487412

  7. Neonatal hydrocortisone therapy does not have a serious suppressive effect on the later function of the hypothalamus-pituitary-adrenal axis.

    PubMed

    Takayanagi, Toshimitsu; Matsuo, Koji; Egashira, Tomoko; Mizukami, Tomoko

    2015-05-01

    This study investigated whether providing extremely low birthweight (ELBW) infants with a large amount of hydrocortisone had a serious suppressive effect on the later function of the hypothalamus-pituitary-adrenal (HPA) axis. We evaluated the function of the HPA axis in 58 ELBW infants receiving 9.0 ± 7.2 mg/kg of intravenous and 68.1 ± 34.1 mg/kg of oral hydrocortisone using a human corticotropin-releasing hormone stimulation test. The mean age at investigation was 12.0 ± 5.2 months. The response was judged to be normal when the maximum to minimum ratio of the plasma adrenocorticotropic hormone (ACTH) concentration was >2, the peak value of the serum cortisol concentration was >552 nmol/L, or the increment was >193 nmol/L than baseline concentration. Of the 58 infants studied, 51 (88%) displayed a normal response to both the ACTH and cortisol secretion and seven infants (12%) who were judged to be poor responders exhibited a peak cortisol value of >386 nmol/L without any episode of adrenal insufficiency. Providing ELBW infants with a daily low dose of long-term hydrocortisone therapy should not lead to a serious suppressive effect on the later function of the HPA axis, regardless of the administration method. ©2015 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.

  8. Dynamic changes in the hypothalamic-pituitary-adrenal axis during growth hormone therapy in children with growth hormone deficiency: a multicenter retrospective study.

    PubMed

    Wang, Limin; Wang, Qian; Li, Guimei; Liu, Wendong

    2015-09-01

    The objective of this study was to investigate changes in the hypothalamic-pituitary-adrenal (HPA) axis after recombinant human growth hormone (rhGH) therapy. Subjects included children with growth hormone deficiency (GHD). We conducted a multicenter, retrospective study that assessed 72 GHD patients treated with rhGH during 6 months. Patients were classified into two groups: isolated GHD (IGHD; n=20) and multiple pituitary hormone deficiencies (MPHD; n=52). The HPA axis and other hormones were evaluated at baseline and every 3 months. In the MPHD group, 32 patients had adrenocorticotrophic hormone deficiency and received hydrocortisone before rhGH therapy. In the other 20/52 MPHD patients, the cortisol (COR) level was significantly reduced after rhGH therapy. Moreover, 10 patients showed low COR levels. In the IGHD group, COR levels also decreased, but remained within the normal range. During rhGH therapy, COR levels were reduced, particularly in patients with MPHD. HPA axis should be monitored during rhGH therapy.

  9. Sex- and age-specific effects of nutrition in early gestation and early postnatal life on hypothalamo-pituitary-adrenal axis and sympathoadrenal function in adult sheep

    PubMed Central

    Poore, Kirsten R; Boullin, Julian P; Cleal, Jane K; Newman, James P; Noakes, David E; Hanson, Mark A; Green, Lucy R

    2010-01-01

    The early-life environment affects risk of later metabolic disease, including glucose intolerance, insulin resistance and obesity. Changes in hypothalamo-pituitary-adrenal (HPA) axis and sympathoadrenal function may underlie these disorders. To determine consequences of undernutrition in early gestation and/or immediately following weaning on HPA axis and sympathoadrenal function, 2- to 3-year-old Welsh Mountain ewes received 100% (C, n= 39) or 50% nutritional requirements (U, n= 41) from 1–31 days gestation, and 100% thereafter. From weaning (12 weeks) to 25 weeks of age, male and female offspring were then either fed ad libitum (CC, n= 22; UC, n= 19) or were undernourished (CU, n= 17; UU, n= 22) such that body weight was reduced to 85% of their individual target, based on a growth trajectory calculated from weights taken between birth and 12 weeks. From 25 weeks, ad libitum feeding was restored for all offspring. At 1.5 and 2.5 years, adrenocorticotropic hormone (ACTH) and cortisol concentrations were measured at baseline and in response to corticotropin-releasing factor (CRF) (0.5 μg kg−1) plus arginine vasopressin (AVP) (0.1 μg kg−1). At 2.5 years, HPA axis and sympathoadrenal (catecholamine) responses to a transport and isolation stress test were also measured. In females, post-weaning undernutrition reduced pituitary output (ACTH) but increased adrenocortical responsiveness (cortisol:ACTH area under curve) during CRF/AVP challenge at 1.5 years and increased adrenomedullary output (adrenaline) to stress at 2.5 years. In males, cortisol responses to stress at 2.5 years were reduced in those with slower growth rates from 12 to 25 weeks. Early gestation undernutrition was associated with increased adrenocortical output in 2.5-year-old females only. Pituitary and adrenal responses were also related to adult body composition. Thus, poor growth in the post-weaning period induced by nutrient restriction has sex- and age-specific effects on HPA and

  10. Sex- and age-specific effects of nutrition in early gestation and early postnatal life on hypothalamo-pituitary-adrenal axis and sympathoadrenal function in adult sheep.

    PubMed

    Poore, Kirsten R; Boullin, Julian P; Cleal, Jane K; Newman, James P; Noakes, David E; Hanson, Mark A; Green, Lucy R

    2010-06-15

    The early-life environment affects risk of later metabolic disease, including glucose intolerance, insulin resistance and obesity. Changes in hypothalamo-pituitary-adrenal (HPA) axis and sympathoadrenal function may underlie these disorders. To determine consequences of undernutrition in early gestation and/or immediately following weaning on HPA axis and sympathoadrenal function, 2- to 3-year-old Welsh Mountain ewes received 100% (C, n = 39) or 50% nutritional requirements (U, n = 41) from 1-31 days gestation, and 100% thereafter. From weaning (12 weeks) to 25 weeks of age, male and female offspring were then either fed ad libitum (CC, n = 22; UC, n = 19) or were undernourished (CU, n = 17; UU, n = 22) such that body weight was reduced to 85% of their individual target, based on a growth trajectory calculated from weights taken between birth and 12 weeks. From 25 weeks, ad libitum feeding was restored for all offspring. At 1.5 and 2.5 years, adrenocorticotropic hormone (ACTH) and cortisol concentrations were measured at baseline and in response to corticotropin-releasing factor (CRF) (0.5 microg kg(1)) plus arginine vasopressin (AVP) (0.1 microg kg(1)). At 2.5 years, HPA axis and sympathoadrenal (catecholamine) responses to a transport and isolation stress test were also measured. In females, post-weaning undernutrition reduced pituitary output (ACTH) but increased adrenocortical responsiveness (cortisol:ACTH area under curve) during CRF/AVP challenge at 1.5 years and increased adrenomedullary output (adrenaline) to stress at 2.5 years. In males, cortisol responses to stress at 2.5 years were reduced in those with slower growth rates from 12 to 25 weeks. Early gestation undernutrition was associated with increased adrenocortical output in 2.5-year-old females only. Pituitary and adrenal responses were also related to adult body composition. Thus, poor growth in the post-weaning period induced by nutrient restriction has sex- and age-specific effects on HPA and

  11. Mechanisms for pituitary tumorigenesis: the plastic pituitary

    PubMed Central

    Melmed, Shlomo

    2003-01-01

    The anterior pituitary gland integrates the repertoire of hormonal signals controlling thyroid, adrenal, reproductive, and growth functions. The gland responds to complex central and peripheral signals by trophic hormone secretion and by undergoing reversible plastic changes in cell growth leading to hyperplasia, involution, or benign adenomas arising from functional pituitary cells. Discussed herein are the mechanisms underlying hereditary pituitary hypoplasia, reversible pituitary hyperplasia, excess hormone production, and tumor initiation and promotion associated with normal and abnormal pituitary differentiation in health and disease. PMID:14660734

  12. Therapeutic effects of Chinese herbal medicine against neuroendocrinological diseases especially related to hypothalamus-pituitary-adrenal and hypothalamus-pituitary-gonadal axis.

    PubMed

    Wang, Di; Lu, Cheng-Yu; Teng, Le-Sheng; Guo, Zhi-Hua; Meng, Qing-Fan; Liu, Yan; Zhong, Linda Ld; Wang, Wei; Xie, Jing; Zhang, Zhang-Jin

    2014-05-01

    This is a systemic review of plants used traditionally for neuroendocrinological diseases related to hypothalamus-pitutary-adrenal (HPA) and hypothalamus-pitutary-gland (HPG) axis. By searching from PubMed literature search system (1950-2013), Medline (1950-2013) and CNKI (China Journals of Full-text database; 1989-2013), 105 papers met the inclusion criteria were displayed in this review. 96 herbal drugs were classified into two parts which include hormones mainly related to HPA and HPG axis. The full scientific name of each herbal medicine, dose ranges and routes, models or diseases, affect on hormones and pertinent references are presented via synoptic tables. Herbal remedies that have demonstrable the activities of hormones have provided a potential to various diseases related to neunoendocrine and deserve increased attention in future studies. This review provides a basis for herbs use in neuroendocrinological diseases. The data collected here will benefit to further research associated to herbal medicines and hormones.

  13. Alterations of the hypothalamic-pituitary-adrenal axis in systemic immune diseases - a role for misguided energy regulation.

    PubMed

    Straub, R H; Buttgereit, F; Cutolo, M

    2011-01-01

    The investigation of the hypothalamicpituitary-adrenal (HPA) axis in chronic inflammation has demonstrated: 1) an anti-inflammatory influence of the HPA axis; 2) low serum levels of adrenal androgen; 3) equivocal results with respect to levels of adrenocorticotropic hormone and cortisol; 4) inadequately low secretion of adrenal hormones in relation to inflammation (the disproportion principle); 5) modulating role of TNF and IL-6 on the HPA axis; 6) disturbed cooperativity of HPA axis and sympathetic nervous system (uncoupling); 7) observable glucocorticoid resistance; 8) the circadian rhythmicity explains morning symptoms; 9) new medications based on malfunction of the HPA axis (e.g. adapted to the circadian rhythm of hormones and cytokines); and 10) the newly described role of the HPA axis in the context of misguided energy regulation in chronic inflammatory diseases. This review discusses items 1-6 and 10, while the other items are presented elsewhere in this Supplement. Evidence is presented that the basis for many alterations is in an adaptive program positively selected for short-lived inflammatory responses (energy appeal reaction), which becomes a disease-inherent pathogenetic factor, if it continues too long, that can drive systemic disease sequelae of chronic inflammatory diseases such as the metabolic syndrome.

  14. Activation of 5-HT1A receptors in the rat dorsomedial hypothalamus inhibits stress-induced activation of the hypothalamic-pituitary-adrenal axis.

    PubMed

    Stamper, Christopher E; Hassell, James E; Kapitz, Adam J; Renner, Kenneth J; Orchinik, Miles; Lowry, Christopher A

    2017-03-27

    Acute activation of the hypothalamic-pituitary-adrenal (HPA) axis, leading to the release of corticosteroid hormones into the circulation, is an adaptive response to perceived threats. Persistent activation of the HPA axis can lead to impaired physiological or behavioral function with maladaptive consequences. Thus, efficient control and termination of stress responses is essential for well-being. However, inhibitory control mechanisms governing the HPA axis are poorly understood. Previous studies suggest that serotonergic systems, acting within the medial hypothalamus, play an important role in inhibitory control of stress-induced HPA axis activity. To test this hypothesis, we surgically implanted chronic jugular cannulae in adult male rats and conducted bilateral microinjection of vehicle or the 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino) tetralin hydrobromide (8-OH-DPAT; 8 nmol, 0.2 μL, 0.1 μL/min, per side) into the dorsomedial hypothalamus (DMH) immediately prior to a 40 min period of restraint stress. Repeated blood sampling was conducted using an automated blood sampling system and plasma corticosterone concentrations were determined using enzyme-linked immunosorbent assay. Bilateral intra-DMH microinjections of 8-OH-DPAT suppressed stress-induced increases in plasma corticosterone within 10 min of the onset of handling prior to restraint and, as measured by area-under-the-curve analysis of plasma corticosterone concentrations, during the 40 min period of restraint. These data support an inhibitory role for serotonergic systems, acting within the DMH, on stress-induced activation of the HPA axis. Lay summary: Inhibitory control of the hypothalamic-pituitary-adrenal (HPA) stress hormone response is important for well-being. One neurochemical implicated in inhibitory control of the HPA axis is serotonin. In this study we show that activation of serotonin receptors, specifically inhibitory 5-HT1A receptors in the dorsomedial

  15. The effects of probiotics on mental health and hypothalamic-pituitary-adrenal axis: A randomized, double-blind, placebo-controlled trial in petrochemical workers.

    PubMed

    Mohammadi, Ali Akbar; Jazayeri, Shima; Khosravi-Darani, Kianoush; Solati, Zahra; Mohammadpour, Nakisa; Asemi, Zatollah; Adab, Zohre; Djalali, Mahmoud; Tehrani-Doost, Mehdi; Hosseini, Mostafa; Eghtesadi, Shahryar

    2016-11-01

    The aim of this study was to determine effects of probiotic yogurt and multispecies probiotic capsule supplementation on mental health and hypothalamic-pituitary-adrenal axis in petrochemical workers. The present randomized double-blind, placebo-controlled trial was conducted on 70 petrochemical workers. Subjects were randomly divided into three groups to receive 100 g/day probiotic yogurt + one placebo capsule (n = 25) or one probiotic capsule daily + 100 g/day conventional yogurt (n = 25) or 100 g/day conventional yogurt + one placebo capsule (n = 20) for 6 weeks. Mental health parameters including general health questionnaire (GHQ) and depression anxiety and stress scale (DASS) scores were measured. Fasting blood samples were obtained at the beginning and 6 weeks after the intervention to quantify hypothalamic-pituitary-adrenal axis. After 6 weeks of intervention, a significant improvement of GHQ was observed in the probiotic yogurt (18.0 ± 1.5 vs. 13.5 ± 1.9, P = 0.007) and in the probiotic capsule group (16.9 ± 1.8 vs. 9.8 ± 1.9, P = 0.001), as well as a significant improvement in DASS scores in the probiotic yogurt (23.3 ± 3.7 vs. 13.0 ± 3.7, P = 0.02) and the probiotic capsule group (18.9 ± 3.2 vs. 9.4 ± 4.0, P = 0.006). However, there was no significant improvement in the conventional yogurt group (P = 0.05 for GHQ and P = 0.08 for DASS). The consumption of probiotic yogurt or a multispecies probiotic capsule had beneficial effects on mental health parameters in petrochemical workers.

  16. Intra-articular methylprednisolone acetate injection at the knee joint and the hypothalamic-pituitary-adrenal axis: a randomized controlled study.

    PubMed

    Habib, George; Jabbour, Adel; Artul, Suheil; Hakim, Geries

    2014-01-01

    The objective of this study was to evaluate the effect of intra-articular corticosteroid injection (IACI) of methylprednisolone acetate (MPA) on the hypothalamic-pituitary-adrenal (HPA) axis in patients with osteoarthritis of the knee. Patients with symptomatic osteoarthritis of the knee who failed to respond to nonsteroidal anti-inflammatory medications and physical therapy were randomized between group 1 and group 2. Group 1 patients had an IACI of 80 mg of MPA at the knee joint and group 2 patients had an intra-articular injection (IAI) of 6 ml (60 mg) of sodium hyaluronate (control group). Immediately prior to the IAI and on weeks 1, 2, 3, 4, and 8 following IAI, patients from both groups underwent a low-dose (1 μg) adrenocorticotropin hormone (ACTH) stimulation test. Demographic, clinical, laboratory, and radiologic variables were documented in all patients. Both criteria of <7 μg/dl increase in the serum cortisol level and absolute levels of <18 μg/dl 30 min following the ACTH stimulation test were used to define secondary adrenal insufficiency (SAI). Twenty patients were randomized in each group. In group 1, 25 % of patients had SAI vs. none in group 2 (p = 0.0471). The earliest SAI was observed at week 2, and latest SAI was observed at week 4. SAI was observed at one time point, two consecutive time points, or two separate time points in the same patient. There was no correlation between SAI and any of the demographic, clinical, or laboratory variables. An IACI of 80 mg MPA at the knee joint induced a transient SAI in 25 % of the patients, an effect that was observed between week 2 and week 4 following the IACI.

  17. Variation in the ovine cortisol response to systemic bacterial endotoxin challenge is predominantly determined by signalling within the hypothalamic-pituitary-adrenal axis

    SciTech Connect

    You Qiumei; Karrow, Niel A. Cao Honghe; Rodriguez, Alexander; Mallard, Bonnie A.; Boermans, Herman J.

    2008-07-01

    Bi-directional communication between the neuroendocrine and immune systems is designed, in part, to maintain or restore homeostasis during physiological stress. Exposure to endotoxin during Gram-negative bacterial infection for example, elicits the release of pro-inflammatory cytokines that activate the hypothalamic-pituitary-adrenal axis (HPAA). The secretion of adrenal glucocorticoids subsequently down regulates the host inflammatory response, minimizing potential tissue damage. Sequence and epigenetic variants in genes involved in regulating the neuroendocrine and immune systems are likely to contribute to individual differences in the HPAA response, and this may influence the host anti-inflammatory response to toxin exposure and susceptibility to inflammatory disease. In this study, high (HCR) and low (LCR) cortisol responders were selected from a normal population of 110 female sheep challenged iv with Escherichia coli endotoxin (400 ng/kg) to identify potential determinants that contribute to variation in the cortisol response phenotype. This phenotype was stable over several years in the HCR and LCR animals, and did not appear to be attributed to differences in expression of hepatic immune-related genes or systemic pro-inflammatory cytokine concentrations. Mechanistic studies using corticotrophin-releasing factor (0.5 {mu}g/kg body weight), arginine vasopressin (0.5 {mu}g/kg), and adrenocorticotropic hormone (0.5 {mu}g/kg) administered iv demonstrated that variation in this phenotype is largely determined by signalling within the HPAA. Future studies will use this ovine HCR/LCR model to investigate potential genetic and epigenetic variants that may contribute to variation in cortisol responsiveness to bacterial endotoxin.

  18. CENTRAL 5-ALPHA REDUCTION OF TESTOSTERONE IS REQUIRED FOR TESTOSTERONE’S INHIBITION OF THE HYPOTHALAMO-PITUITARY-ADRENAL AXIS RESPONSE TO RESTRAINT STRESS IN ADULT MALE RATS

    PubMed Central

    Handa, Robert J.; Kudwa, Andrea E.; Donner, Nina C.; McGivern, Robert F.; Brown, Roger

    2013-01-01

    In rodents, the hypothalamo-pituitary-adrenal (HPA) axis is controlled by a precise regulatory mechanism that is influenced by circulating gonadal and adrenal hormones. In males, gonadectomy increases the adrenocorticotropic hormone (ACTH) and corticosterone (CORT) response to stressors, and androgen replacement returns the response to that of the intact male. Testosterone (T) actions in regulating HPA activity may be through aromatization to estradiol, or by 5α-reduction to the more potent androgen, dihydrotestosterone (DHT). To determine if the latter pathway is involved, we assessed the function of the HPA axis response to restraint stress following hormone treatments, or after peripheral or central treatment with the 5α-reductase inhibitor, finasteride. Initially, we examined the timecourse whereby gonadectomy alters the CORT response to restraint stress. Enhanced CORT responses were evident within 48hrs following gonadectomy. Correspondingly, treatment of intact male rats with the 5α-reductase inhibitor, finasteride, for 48 hrs, enhanced the CORT and ACTH response to restraint stress. Peripheral injections of gonadectomized male rats with DHT or T for 48 hrs reduced the ACTH and CORT response to restraint stress. The effects of T, but not DHT, could be blocked by the third ventricle administration of finasteride prior to stress application. These data indicate that the actions of T in modulating HPA axis activity involve 5α-reductase within the central nervous system. These results further our understanding of how T acts to modulate the neuroendocrine stress responses and indicate that 5α reduction to DHT is a necessary step for T action. PMID:23880372

  19. Palatable solutions during paradoxical sleep deprivation: reduction of hypothalamic-pituitary-adrenal axis activity and lack of effect on energy imbalance.

    PubMed

    Suchecki, D; Antunes, J; Tufik, S

    2003-09-01

    Paradoxical sleep deprivation (PSD) induces increased energy expenditure in rats, insofar as rats eat more but loose weight throughout the deprivation period. In the present study, rats were offered water, saccharin or sucrose to drink during the deprivation period, since it has been proposed that carbohydrates reduce the hypothalamic-pituitary-adrenal (HPA) axis response to stress. Rats were submitted to the flower pot technique for 96 h. During the PSD period, they were weighed daily and food and fluid intake was assessed twice a day. At the end of the PSD period, rats were killed and plasma concentrations of glucose, adrenocorticotropic hormone (ACTH) and corticosterone were assayed. Compared to their control counterparts, all paradoxical sleep-deprived rats consumed more food, but lost weight. Paradoxical sleep-deprived rats given sucrose drank more than their control counterparts (especially in the light phase of the light/dark cycle). Paradoxical sleep-deprived rats showed increased food intake during all periods throughout the experiment, with peak intake during the dark phase and nadir during the light phase of the light/dark cycle. All paradoxical sleep-deprived rats showed lower glucose plasma levels than control rats and increased relative adrenal weight. However, when given saccharin or sucrose, paradoxical sleep-deprived rats showed lower concentrations of ACTH and corticosterone than their water-provided counterparts, indicating that palatable fluids were capable of lowering HPA axis activation produced by PSD. The fact that PSD induced energy imbalance regardless of the relative attenuation of the HPA axis activity produced by saccharin or sucrose suggests that the HPA axis may play only a secondary role in this phenomenon, and that other mechanisms may account for this effect. The data also suggest that supply of palatable fluids can be an additional modification to reduce the stress of the flower pot method.

  20. Hypothalamic-pituitary-adrenal-axis dysregulation and double product increases potentiate ischemic heart disease risk in a Black male cohort: the SABPA study.

    PubMed

    Malan, Leoné; Schutte, Christiaan E; Alkerwi, Ala'a; Stranges, Saverio; Malan, Nicolaas T

    2017-06-01

    Emotional distress has been associated with a poorer prognosis in myocardial infarction patients. Elevated adrenocorticotrophic hormone (ACTH), lower cortisol, dehydroepiandrosterone sulfate (DHEAS) and cortisol:DHEAS, as measures of emotional distress, might correlate with silent myocardial ischemia (SMI) and workload. Thus, we assessed the relationship between emotional distress, SMI and double product (systolic blood pressure (SBP) × heart rate). Cross-sectional South African biethnic single-set cohorts (N=378), aged 44.7±9.52 years, were investigated. Depressive symptoms (Patient Health Questionnaire-9), anthropometric, fasting blood, 24-h double product and 24-h 2-lead electrocardiogram (ST-segment depression) values were obtained. Blacks, mostly men, had increased depressive symptoms, hyperglycemia, SMI, double product, SBP hypertension and ACTH but lower cortisol, DHEAS and cortisol:DHEAS than their White counterparts. Black men had the highest combined SBP hypertension and below-median cortisol prevalence, 38%, compared with 5.9-13.8% in the other groups. Their SMI was associated with ACTH and cortisol:DHEAS (adj. R(2) 0.29; β 0.27-0.31 (0.12-0.64); P⩽0.05), double product (adj. R(2) 0.29; β 0.38 (0.18-0.57); P=0.050) and SBP hypertension (area under the curve: 0.68 (95% CI: 0.56, 0.80); P=0.042; sensitivity/specificity 49/85%). Double product was positively associated with central obesity in all sex groups and with cortisol in the Black men (P<0.05). A dysregulated hypothalamic-pituitary-adrenal-axis (HPAA) showed signs of a hyporesponsive adrenal cortex, suggesting chronic emotional stress in the Black male cohort. In this cohort, HPAA dysregulation and compensatory increases in double product occur as a potential defense mechanism to alleviate perfusion deficits, thereby potentiating ischemic heart disease risk.

  1. Suppression of hypothalamic-pituitary-adrenal axis by acute heroin challenge in rats during acute and chronic withdrawal from chronic heroin administration

    PubMed Central

    Zhou, Yan; Leri, Francesco; Ho, Ann; Kreek, Mary Jeanne

    2013-01-01

    It is known that heroin dependence and withdrawal are associated with changes in the hypothalamic-pituitary-adrenal (HPA) axis. The objective of these studies in rats was to systematically investigate the level of HPA activity and response to a heroin challenge at two time points during heroin withdrawal, and to characterize the expression of associated stress-related genes 30 minutes after each heroin challenge. Rats received chronic (10-day) intermittent escalating-dose heroin administration (3×2.5 mg/kg/day on day 1; 3×20 mg/kg/day by day 10). Hormonal and neurochemical assessments were performed in acute (12 hours after last heroin injection) and chronic (10 days after the last injection) withdrawal. Both plasma ACTH and corticosterone levels were elevated during acute withdrawal, and heroin challenge at 20 mg/kg (the last dose of chronic escalation) at this time point attenuated this HPA hyperactivity. During chronic withdrawal, HPA hormonal levels returned to baseline, but heroin challenge at 5 mg/kg decreased ACTH levels. In contrast, this dose of heroin challenge stimulated the HPA axis in heroin naïve rats. In the anterior pituitary, pro-opiomelanocortin (POMC) mRNA levels were increased during acute withdrawal and retuned to control levels after chronic withdrawal. In the medial hypothalamus, however, the POMC mRNA levels were decreased during acute withdrawal, and increased after chronic withdrawal. Our results suggest a long-lasting change in HPA abnormal responsivity during chronic heroin withdrawal. PMID:23771528

  2. Suppression of hypothalamic-pituitary-adrenal axis by acute heroin challenge in rats during acute and chronic withdrawal from chronic heroin administration.

    PubMed

    Zhou, Yan; Leri, Francesco; Ho, Ann; Kreek, Mary Jeanne

    2013-09-01

    It is known that heroin dependence and withdrawal are associated with changes in the hypothalamic-pituitary-adrenal (HPA) axis. The objective of these studies in rats was to systematically investigate the level of HPA activity and response to a heroin challenge at two time points during heroin withdrawal, and to characterize the expression of associated stress-related genes 30 min after each heroin challenge. Rats received chronic (10-day) intermittent escalating-dose heroin administration (3 × 2.5 mg/kg/day on day 1; 3 × 20 mg/kg/day by day 10). Hormonal and neurochemical assessments were performed in acute (12 h after last heroin injection) and chronic (10 days after the last injection) withdrawal. Both plasma ACTH and corticosterone levels were elevated during acute withdrawal, and heroin challenge at 20 mg/kg (the last dose of chronic escalation) at this time point attenuated this HPA hyperactivity. During chronic withdrawal, HPA hormonal levels returned to baseline, but heroin challenge at 5 mg/kg decreased ACTH levels. In contrast, this dose of heroin challenge stimulated the HPA axis in heroin naïve rats. In the anterior pituitary, pro-opiomelanocortin (POMC) mRNA levels were increased during acute withdrawal and retuned to control levels after chronic withdrawal. In the medial hypothalamus, however, the POMC mRNA levels were decreased during acute withdrawal, and increased after chronic withdrawal. Our results suggest a long-lasting change in HPA abnormal responsivity during chronic heroin withdrawal.

  3. Pituitary deficiencies.

    PubMed

    Greco, Deborah S

    2012-02-01

    Diabetes insipidus, arising from damage to or congenital abnormalities of the neurohypophysis, is the most common pituitary deficiency in animals. Hypopituitarism and isolated growth hormone or thyrotropin deficiency may result in growth abnormalities in puppies and kittens. In addition, treatment of associated hormone deficiencies, such as hypothyroidism and hypoadrenocorticism, in patients with panhypopituitarism is vital to restore adequate growth in dwarfed animals. Secondary hypoadrenocorticism is an uncommon clinical entity; however differentiation of primary versus secondary adrenal insufficiency is of utmost importance in determining optimal therapy. This article will focus on the pathogenesis, diagnosis and treatment of hormone deficiencies of the pituitary gland and neurohypophysis. Copyright © 2012. Published by Elsevier Inc.

  4. Shilajit attenuates behavioral symptoms of chronic fatigue syndrome by modulating the hypothalamic-pituitary-adrenal axis and mitochondrial bioenergetics in rats.

    PubMed

    Surapaneni, Dinesh Kumar; Adapa, Sree Rama Shiva Shanker; Preeti, Kumari; Teja, Gangineni Ravi; Veeraragavan, Muruganandam; Krishnamurthy, Sairam

    2012-08-30

    Shilajit has been used as a rejuvenator for ages in Indian ancient traditional medicine and has been validated for a number of pharmacological activities. The effect of processed shilajit which was standardized to dibenzo-α-pyrones (DBPs;0.43% w/w), DBP-chromoproteins (DCPs; 20.45% w/w) and fulvic acids (56.75% w/w) was evaluated in a rat model of chronic fatigue syndrome (CFS). The mitochondrial bioenergetics and the activity of hypothalamus-pituitary-adrenal (HPA) axis were evaluated for the plausible mechanism of action of shilajit. CFS was induced by forcing the rats to swim for 15mins for 21 consecutive days. The rats were treated with shilajit (25, 50 and 100mg/kg) for 21 days before exposure to stress procedure. The behavioral consequence of CFS was measured in terms of immobility and the climbing period. The post-CFS anxiety level was assessed by elevated plus maze (EPM) test. Plasma corticosterone and adrenal gland weight were estimated as indices of HPA axis activity. Analysis of mitochondrial complex chain enzymes (Complex I, II, IV and V) and mitochondrial membrane potential (MMP) in prefrontal cortex (PFC) were performed to evaluate the mitochondrial bioenergetics and integrity respectively. Shilajit reversed the CFS-induced increase in immobility period and decrease in climbing behavior as well as attenuated anxiety in the EPM test. Shilajit reversed CFS-induced decrease in plasma corticosterone level and loss of adrenal gland weight indicating modulation of HPA axis. Shilajit prevented CFS-induced mitochondrial dysfunction by stabilizing the complex enzyme activities and the loss of MMP. Shilajit reversed CFS-induced mitochondrial oxidative stress in terms of NO concentration and, LPO, SOD and catalase activities. The results indicate that shilajit mitigates the effects of CFS in this model possibly through the modulation of HPA axis and preservation of mitochondrial function and integrity. The reversal of CFS-induced behavioral symptoms and

  5. Single-nucleotide polymorphisms in genes related to the hypothalamic-pituitary-adrenal axis as risk factors for posttraumatic stress disorder.

    PubMed

    Carvalho, Carolina M; Coimbra, Bruno M; Ota, Vanessa K; Mello, Marcelo F; Belangero, Sintia I

    2017-10-01

    Posttraumatic stress disorder (PTSD) is a common psychiatric disorder. The etiology of PTSD is multifactorial, depending on many environmental and genetic risk factors, and the exposure to life or physical integrity-threatening events. Several studies have shown significant correlations of many neurobiological findings with PTSD. Hypothalamic-pituitary-adrenal (HPA) axis dysfunction is strongly correlated with this disorder. One hypothesis is that HPA axis dysfunction may precede the traumatic event, suggesting that genes expressed in the HPA axis may be involved in the development of PTSD. This article reviews molecular genetic studies related to PTSD collected through a literature search performed in PubMed, MEDLINE, ScienceDirect, and Scientific Electronic Library Online (SciELO). The results of these studies suggest that several polymorphisms in the HPA axis genes, including FKBP5, NR3C1, CRHR1, and CRHR2, may be risk factors for PTSD development or may be associated with the severity of PTSD symptoms. © 2017 Wiley Periodicals, Inc.

  6. Neuroregulation of the hypothalamus-pituitary-adrenal (HPA) axis in humans: effects of GABA-, mineralocorticoid-, and GH-Secretagogue-receptor modulation.

    PubMed

    Giordano, Roberta; Pellegrino, Micaela; Picu, Andreea; Bonelli, Lorenza; Balbo, Marcella; Berardelli, Rita; Lanfranco, Fabio; Ghigo, Ezio; Arvat, Emanuela

    2006-01-17

    The hypothalamus-pituitary-adrenal (HPA) axis exerts a variety of effects at both the central and peripheral level. Its activity is mainly regulated by CRH, AVP, and the glucocorticoid-mediated feedback action. Moreover, many neurotransmitters and neuropeptides influence HPA axis activity by acting at the hypothalamic and/or suprahypothalamic level. Among them, GABA and Growth Hormone Secretagogues (GHS)/GHS-receptor systems have been shown to exert a clear inhibitory and stimulatory effect, respectively, on corticotroph secretion. Alprazolam (ALP), a GABA-A receptor agonist, shows the most marked inhibitory effect on both spontaneous and stimulated HPA axis activity, in agreement with its peculiar efficacy in panic disorders and depression where an HPA axis hyperactivation is generally present. Ghrelin and synthetic GHS possess a marked ACTH/cortisol-releasing effect in humans and the ghrelin/GHS-R system is probably involved in the modulation of the HPA response to stress and nutritional/metabolic variations. The glucocorticoid-mediated negative feedback action is mediated by both glucocorticoid (GR) and mineralocorticoid (MR) receptors activation at the central level, mainly in the hippocampus. In agreement with animal studies, MRs seem to play a crucial role in the maintenance of the circadian ACTH and cortisol rhythm, through the modulation of CRH and AVP release. GABA agonists (mainly ALP), ghrelin, as well as MR agonists/antagonists, may represent good tools to explore the activity of the HPA axis in both physiological conditions and pathological states characterized by an impaired control of the corticotroph function.

  7. The involvement of noradrenergic mechanisms in the suppressive effects of diazepam on the hypothalamic-pituitary-adrenal axis activity in female rats

    PubMed Central

    Švob Štrac, Dubravka; Muck-Šeler, Dorotea; Pivac, Nela

    2012-01-01

    Aim To elucidate the involvement of noradrenergic system in the mechanism by which diazepam suppresses basal hypothalamic-pituitary-adrenal (HPA) axis activity. Methods Plasma corticosterone and adrenocorticotropic hormone (ACTH) levels were determined in female rats treated with diazepam alone, as well as with diazepam in combination with clonidine (α2-adrenoreceptor agonist), yohimbine (α2-adrenoreceptor antagonist), alpha-methyl-p-tyrosine (α-MPT, an inhibitor of catecholamine synthesis), or reserpine (a catecholamine depleting drug) and yohimbine. Results Diazepam administered in a dose of 2.0 mg/kg suppressed basal HPA axis activity, ie, decreased plasma corticosterone and ACTH levels. Pretreatment with clonidine or yohimbine failed to affect basal plasma corticosterone and ACTH concentrations, but abolished diazepam-induced inhibition of the HPA axis activity. Pretreatment with α-MPT, or with a combination of reserpine and yohimbine, increased plasma corticosterone and ACTH levels and prevented diazepam-induced inhibition of the HPA axis activity. Conclusion The results suggest that α2-adrenoreceptors activity, as well as intact presynaptic noradrenergic function, are required for the suppressive effect of diazepam on the HPA axis activity. PMID:22661134

  8. Effects of Acute Confinement Stress-induced Hypothalamic-Pituitary Adrenal Axis Activation and Concomitant Peripheral and Central Transforming Growth Factor-β1 Measures in Nonhuman Primates

    PubMed Central

    Coplan, Jeremy D.; Gopinath, Srinath; Abdallah, Chadi G.; Margolis, Jeffrey; Chen, Wei; Scharf, Bruce A.; Rosenblum, Leonard A.; Batuman, Olcay A.; Smith, Eric L. P.

    2017-01-01

    Transforming growth factor-β1 (TGF-β1) is a multifunctional cytokine with anti-inflammatory, immunosuppressive and neuroprotective properties. The hypothalamic-pituitary-adrenal (HPA) axis and immune system exert bidirectional influences on each other, via cortisol and TGF-β1, but the exact nature of the interaction is not well characterized. The current study examined the effects, in bonnet macaques (Macaca radiata), of two consecutive acute confinement stress periods in an unfamiliar room while mildly restrained, first without and then with dexamethasone pretreatment (0.01 mg/kg IM). Preceding the confinement studies, a non-stress control condition obtained contemporaneous levels of cortisol and TGF-β1 in both plasma and cerebrospinal fluid (CSF) to match the confinement stress studies. Subjects were reared under either normative or variable foraging demand (VFD) conditions. Since there were no rearing effects at baseline or for any of the conditions tested -- either for cortisol or TGF-β -- the study analyses were conducted on the combined rearing groups. The stress condition increased both plasma and CSF cortisol levels whereas dexamethasone pretreatment decreased cortisol concentrations to below baseline levels despite stress. The stress condition decreased TGF-β1 concentrations only in CSF but not in serum. Together the data suggested that stress-induced reductions of a centrally active neuroprotective cytokine occurs in the face of HPA axis activation, potentially facilitating glucocortoid-induced neurotoxicity. Stress-induced reductions of neuroprotective cytokines prompts exploration of protective measures against glucocorticoid-induced neurotoxicity.

  9. Different pituitary. beta. -endorphin and adrenal cortisol response to ethanol in individuals with high and low risk for future development of alcoholism

    SciTech Connect

    Gianoulakis, C.G.; Beliveau, D.; Angelogianni, P.; Meaney, M.; Thavundayil, J.; Tawar, V.; Dumas, M. )

    1989-01-01

    The purpose of the present studies was to investigate the activity of the adrenal gland and the pituitary {beta}-endorphin system in individuals from families with a 3 generation history of alcoholism, High Risk group, or from families without history of alcoholism, Low Risk group. On the day of testing, blood sample was taken at 9:00 a.m., then the subject drank a placebo drink or an ethanol solution. Additional blood samples were taken at 15, 45 and 120 minutes post-drink. Results indicated that individuals of the High Risk group had lower basal levels of {beta}-endorphin like immunoreactivity ({beta}-EPLIR) than individuals of the Low Risk group. The dose of 0.5 g ethanol/kg B.Wt. induced an induce an increase in the plasma content of {beta}-EPLIR of the High Risk group, but not of the Low Risk group. In the Low Risk group ethanol did not induce an increase above the 9:00 a.m. levels, however, it attenuated the {beta}-endorphin decrease overtime, observed following the placebo drink. Analysis of {beta}-endorphin-like peptides in the plasma of the High Risk group, with Sephadex G-75 chromatography indicated that the major component of the plasma {beta}-EPLIR was {beta}-lipotropin. Plasma cortisol levels, following ethanol intake, presented a small increase in the High Risk group but not in the Low Risk group.

  10. Repeated amphetamine administration in rats revealed consistency across days and a complete dissociation between locomotor and hypothalamic-pituitary-adrenal axis effects of the drug.

    PubMed

    Gagliano, Humberto; Andero, Raül; Armario, Antonio; Nadal, Roser

    2009-12-01

    Most drugs of abuse stimulate both locomotor activity and the hypothalamic-pituitary-adrenal (HPA) axis, but the relationship between the two responses within the same subjects and their reliabilities has been scarcely studied. Our objectives were to study: (1) the consistency and stability across time of locomotor and HPA activation induced by repeated d-amphetamine (AMPH); (2) the relationship between locomotor and hormonal responses to AMPH; and (3) the relationship between novelty-induced activity and both types of responses to the drug. Male adult rats were exposed to a novel environment to study the locomotor response. Later, they were injected with AMPH (2 mg/kg, sc) for 5 days. In Experiment 1, Plasma adrenocorticotropin (ACTH) and corticosterone levels in response to AMPH were studied on days 1, 3, and 5, and locomotor response on days 2 and 4. In Experiment 2, ACTH and corticosterone responses were studied on days 2 and 4, and locomotor response on days 1, 3, and 5. Across days, both locomotor and HPA responses to the drug were consistent, but independent measures, unrelated to the reactivity to novelty. As measured by the area under the curve, the HPA response to AMPH desensitized with the repeated injection, whereas the initial locomotor response to the drug increased. Dissociation exists between HPA and locomotor activation induced by AMPH, which seemed to be both reliable individual traits. Locomotor reactivity to novelty was related neither to HPA nor to locomotor responses to AMPH.

  11. Metoclopramide as pharmacological tool to assess vasopressinergic co-activation of the hypothalamus-pituitary-adrenal (HPA) axis: a study in healthy volunteers.

    PubMed

    Jacobs, G E; Hulskotte, E G J; de Kam, M L; Zha, G; Jiang, J; Hu, P; Zhao, Q; van Pelt, J; Goekoop, J G; Zitman, F G; van Gerven, J M A

    2010-12-01

    The synthetic vasopressin (AVP) analogue desmopressin (dDAVP) has been used as pharmacological function test to quantify vasopressinergic co-activation of the hypothalamus-pituitary-adrenal (HPA) axis in the past. Such exogenous vasopressinergic stimulation may induce confounding cardiovascular, pro-coagulatory and anti-diuretic effects and low endogenous corticotrophin-releasing-hormone (CRH) levels may limit its potential to reliably assess co-activation. Alternatively, the dopamine-2-(D2)-antagonist metoclopramide is believed to induce co-activation indirectly by releasing endogenous AVP. We investigated this indirect co-activation with metoclopramide under conditions of low and enhanced endogenous CRH release in healthy volunteers. A randomized, double-blind, placebo-controlled, four-way crossover study was performed in 12 healthy males. CRH release was induced by administering an oral 5-hydroxytryptophan (5-HTP) 200 mg function test. Co-activation was investigated by administering metoclopramide 10mg intravenously around the expected maximal effect of 5-HTP. The neuroendocrine effects were compared to those of metoclopramide alone, the 5-HTP test alone and matching placebo. Metoclopramide safely induced HPA-axis activation by itself, and potently synergized 5-HTP-induced corticotrophinergic activation of the HPA axis. These findings are indicative of vasopressinergic co-activation and suggest a role for metoclopramide as a practical function test for co-activation of the HPA axis. However, its application will be hampered pending clarification of the exact pharmacological mechanism by which metoclopramide induces co-activation of the HPA axis.

  12. Stressor-responsive central nesfatin-1 activates corticotropin-releasing hormone, noradrenaline and serotonin neurons and evokes hypothalamic-pituitary-adrenal axis

    PubMed Central

    Yoshida, Natsu; Maejima, Yuko; Sedbazar, Udval; Ando, Akihiko; Kurita, Hideharu; Damdindorj, Boldbaatar; Takano, Eisuke; Gantulga, Darambazar; Iwasaki, Yusaku; Kurashina, Tomoyuki; Onaka, Tatsushi; Dezaki, Katsuya; Nakata, Masanori; Mori, Masatomo; Yada, Toshihiko

    2010-01-01

    A recently discovered satiety molecule, nesfatin-1, is localized in neurons of the hypothalamus and brain stem and colocalized with stress-related substances, corticotropin-releasing hormone (CRH), oxytocin, proopiomelanocortin, noradrenaline (NA) and 5-hydroxytryptamine (5-HT). Intracerebroventricular (icv) administration of nesfatin-1 produces fear-related behaviors and potentiates stressor-induced increases in plasma adrenocorticotropic hormone (ACTH) and corticosterone levels in rats. These findings suggest a link between nesfatin-1 and stress. In the present study, we aimed to further clarify the neuronal network by which nesfatin-1 could induce stress responses in rats. Restraint stress induced c-Fos expressions in nesfatin-1-immunoreactive neurons in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) of the hypothalamus, and in the nucleus of solitary tract (NTS), locus coeruleus (LC) and dorsal raphe nucleus (DR) in the brain stem, without altering plasma nesfatin-1 levels. Icv nesfatin-1 induced c-Fos expressions in the PVN, SON, NTS, LC, DR and median raphe nucleus, including PVN-CRH, NTS-NA, LC-NA and DR-5-HT neurons. Nesfatin-1 increased cytosolic Ca2+ concentration in the CRH-immunoreactive neurons isolated from PVN. Icv nesfatin-1 increased plasma ACTH and corticosterone levels. These results indicate that the central nesfatin-1 system is stimulated by stress and activates CRH, NA and 5-HT neurons and hypothalamic-pituitary-adrenal axis, evoking both central and peripheral stress responses. PMID:20966530

  13. Dihydrotestosterone differentially modulates the cortisol response of the hypothalamic-pituitary-adrenal axis in male and female rhesus macaques, and restores circadian secretion of cortisol in females

    PubMed Central

    Toufexis, Donna J.; Wilson, Mark E.

    2011-01-01

    Here we used a within-subject design to evaluate hypothalamic-pituitary-adrenal (HPA) activity following replacement of low and high physiological levels of testosterone (T) to adult, gonadally-suppressed, male rhesus macaques, and replacement with sex-specific low and high physiological doses of dihydrotestosterone (DHT) in the same adult males as well as in adult, gonadally-suppressed, female rhesus macaques. As indexes of HPA axis activation following T and DHT replacement, serum levels of cortisol (CORT) were measured before and following dexamethasone (DEX) inhibition, and corticotrophin-releasing factor (CRF) induced activation. Female monkeys were assessed for differences in response associated with dominant (DOM) and subordinate (SUB) social status. Data show that the high physiological dose of DHT significantly decreased basal CORT in both male and female monkeys irrespective of social status, but reduced CRF-stimulated CORT only in males. SUB female monkeys showed a trend towards increased CRF-stimulated CORT release under high-dose DHT replacement compared to DOM females or males given the same treatment, indicating that androgens likely have no influence on reducing HPA activation under chronic psychosocial stress in females. The normal circadian rhythm of CORT release was absent in placebo-replaced SUB and DOM females and was restored with low-dose DHT replacement. These results indicate that DHT significantly reduces CRF-stimulated CORT release only in male monkeys, and plays a role in maintaining circadian changes in CORT release in female monkeys. PMID:22088823

  14. Infralimbic cortex controls the activity of the hypothalamus-pituitary-adrenal axis and the formation of aversive memory: Effects of environmental enrichment.

    PubMed

    Ronzoni, Giacomo; Antón, Maria; Mora, Francisco; Segovia, Gregorio; Del Arco, Alberto

    2016-01-15

    The aim of the present study was to investigate the effects of the stimulation and inhibition of the ventral part of the medial prefrontal cortex (infralimbic cortex) on basal and stress-induced plasma levels of corticosterone and on the acquisition of aversive memory in animals maintained in control and environmental enrichment (EE) conditions. Intracortical microinjections of the GABAA antagonist picrotoxin and agonist muscimol were performed in male Wistar rats to stimulate and inhibit, respectively, the activity of the infralimbic cortex. Injections were performed 60 min before foot shock stress and training in the inhibitory avoidance task. Picrotoxin injections into the infralimbic cortex increased basal plasma levels of corticosterone. These increases were higher in EE rats which suggest that EE enhances the control exerted by infralimbic cortex over the hypothalamus-pituitary-adrenal (HPA) axis and corticosterone release. Muscimol injections into the infralimbic cortex reduced the stress-induced plasma levels of corticosterone and the retention latency 24h after training in the inhibitory avoidance performance in control and EE animals, respectively. These results further suggest that the infralimbic cortex is required for the activation of the HPA axis during stress and for the acquisition of contextual aversive memories.

  15. Dopamine D1 and D2 dopamine receptors regulate immobilization stress-induced activation of the hypothalamus-pituitary-adrenal axis.

    PubMed

    Belda, Xavier; Armario, Antonio

    2009-10-01

    Whereas the role of most biogenic amines in the control of the hypothalamus-pituitary-adrenal (HPA) response to stress has been extensively studied, the role of dopamine has not. We studied the effect of different dopamine receptor antagonists on HPA response to a severe stressor (immobilization, IMO) in adult male Sprague-Dawley rats. Haloperidol administration reduced adrenocorticotropin hormone and corticosterone responses to acute IMO, particularly during the post-IMO period. This effect cannot be explained by a role of dopamine to maintain a sustained activation of the HPA axis as haloperidol did not modify the response to prolonged (up to 6 h) IMO. Administration of more selective D1 and D2 receptor antagonists (SCH23390 and eticlopride, respectively) also resulted in lower and/or shorter lasting HPA response to IMO. Dopamine, acting through both D1 and D2 receptors, exerts a stimulatory role on the activation of the HPA axis in response to a severe stressor. The finding that dopamine is involved in the maintenance of post-stress activation of the HPA axis is potentially important because the actual pathological impact of HPA activation is likely to be related to the area under the curve of plasma glucocorticoid levels, which is critically dependent on how long after stress high levels of glucocorticoid are maintained.

  16. The lipocalin-type prostaglandin D2 synthase knockout mouse model of insulin resistance and obesity demonstrates early hypothalamic-pituitary-adrenal axis hyperactivity.

    PubMed

    Evans, Jodi F; Islam, Shahidul; Urade, Yoshihiro; Eguchi, Naomi; Ragolia, Louis

    2013-02-01

    Obesity and diabetes are closely associated with hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis. In this study, the diet-induced obese C57BL/6 mouse was used to test the hypothesis that chronically elevated metabolic parameters associated with the development of obesity such as cholesterol and glucose can aggravate basal HPA axis activity. Because the lipocalin-type prostaglandin D(2) synthase (L-PGDS) knockout (KO) mouse is a model of accelerated insulin resistance, glucose intolerance, and obesity, it was further hypothesized that HPA activity would be greater in this model. Starting at 8 weeks of age, the L-PGDS KO and C57BL/6 mice were maintained on a low-fat or high-fat diet. After 20 or 37 weeks, fasting metabolic parameters and basal HPA axis hormones were measured and compared between genotypes. Correlation analyses were performed to identify associations between obesity-related chronic metabolic changes and changes in the basal activity of the HPA axis. Our results have identified strong positive correlations between total cholesterol, LDL-cholesterol, glucose, and HPA axis hormones that increase with age in the C57BL/6 mice. These data confirm that obesity-related elevations in cholesterol and glucose can heighten basal HPA activity. Additionally, the L-PGDS KO mice show early elevations in HPA activity with no age-related changes relative to the C57BL/6 mice.

  17. Activity of the Hypothalamic-Pituitary-Adrenal System in Prenatally Stressed Male Rats on the Experimental Model of Post-Traumatic Stress Disorder.

    PubMed

    Pivina, S G; Rakitskaya, V V; Akulova, V K; Ordyan, N E

    2016-03-01

    Using the experimental model of post-traumatic stress disorder (stress-restress paradigm), we studied the dynamics of activity of the hypothalamic-pituitary-adrenal system (HPAS) in adult male rats, whose mothers were daily subjected to restraint stress on days 15-19 of pregnancy. Prenatally stressed males that were subjected to combined stress and subsequent restress exhibited not only increased sensitivity of HPAS to negative feedback signals (manifested under restress conditions), but also enhanced stress system reactivity. These changes persisted to the 30th day after restress. Under basal conditions, the number of cells in the hypothalamic paraventricular nucleus of these animals expressing corticotropin-releasing hormone and vasopressin was shown to decrease progressively on days 1-30. By contrast, combined stress and restress in control animals were followed by an increase in the count of CRH-immunopositive cells in the magnocellular and parvocellular parts of the paraventricular nucleus and number of vasopressin-immunopositive cells in the magnocellular part of the nucleus (to the 10th day after restress). Our results indicate a peculiar level of functional activity of HPAS in prenatally stressed males in the stress-restress paradigm: decreased activity under basal conditions and enhanced reactivity during stress.

  18. A Fall in plasma free fatty acid (FFA) level activates the hypothalamic-pituitary-adrenal axis independent of plasma glucose: evidence for brain sensing of circulating FFA.

    PubMed

    Oh, Young Taek; Oh, Ki-Sook; Kang, Insug; Youn, Jang H

    2012-08-01

    The brain responds to a fall in blood glucose by activating neuroendocrine mechanisms for its restoration. It is unclear whether the brain also responds to a fall in plasma free fatty acids (FFA) to activate mechanisms for its restoration. We examined whether lowering plasma FFA increases plasma corticosterone or catecholamine levels and, if so, whether the brain is involved in these responses. Plasma FFA levels were lowered in rats with three independent antilipolytic agents: nicotinic acid (NA), insulin, and the A1 adenosine receptor agonist SDZ WAG 994 with plasma glucose clamped at basal levels. Lowering plasma FFA with these agents all increased plasma corticosterone, but not catecholamine, within 1 h, accompanied by increases in plasma ACTH. These increases in ACTH or corticosterone were abolished when falls in plasma FFA were prevented by Intralipid during NA or insulin infusion. In addition, the NA-induced increases in plasma ACTH were completely prevented by administration of SSR149415, an arginine vasopressin receptor antagonist, demonstrating that the hypothalamus is involved in these responses. Taken together, the present data suggest that the brain may sense a fall in plasma FFA levels and activate the hypothalamic-pituitary-adrenal axis to increase plasma ACTH and corticosterone, which would help restore FFA levels. Thus, the brain may be involved in the sensing and control of circulating FFA levels.

  19. Exploration of the Hypothalamic-Pituitary-Adrenal Axis to Improve Animal Welfare by Means of Genetic Selection: Lessons from the South African Merino.

    PubMed

    Hough, Denise; Swart, Pieter; Cloete, Schalk

    2013-05-17

    It is a difficult task to improve animal production by means of genetic selection, if the environment does not allow full expression of the animal's genetic potential. This concept may well be the future for animal welfare, because it highlights the need to incorporate traits related to production and robustness, simultaneously, to reach sustainable breeding goals. This review explores the identification of potential genetic markers for robustness within the hypothalamic-pituitary-adrenal axis (HPAA), since this axis plays a vital role in the stress response. If genetic selection for superior HPAA responses to stress is possible, then it ought to be possible to breed robust and easily managed genotypes that might be able to adapt to a wide range of environmental conditions whilst expressing a high production potential. This approach is explored in this review by means of lessons learnt from research on Merino sheep, which were divergently selected for their multiple rearing ability. These two selection lines have shown marked differences in reproduction, production and welfare, which makes this breeding programme ideal to investigate potential genetic markers of robustness. The HPAA function is explored in detail to elucidate where such genetic markers are likely to be found.

  20. The hypothalamus-pituitary-adrenal axis does not influence the protective effects of nociceptin/orphanin FQ on the rat gastric mucosa.

    PubMed

    Grandi, Daniela; Solenghi, Elvira; Guerrini, Remo; Broccardo, Maria; Agostini, Simona; Petrella, Carla; Scaccianoce, Sergio; Improta, Giovanna; Morini, Giuseppina

    2009-04-10

    The participation of hypothalamus-pituitary-adrenal axis in the gastroprotective effects of nociceptin/orphanin FQ (N/OFQ) has been investigated. Gastric mucosal lesions were induced by intragastric administration of 50% ethanol, 1 ml/rat. Rats received N/OFQ either by the intracerebroventricular (icv) route, at 3 microg/rat, or by the intraperitoneal (ip) route, at 10 microg/kg, 30 min before ethanol administration. The protective effect of icv and ip administered N/OFQ was assessed in adrenalectomized rats and in rats pretreated with the glucocorticoid receptor antagonist, mifepristone, or with the CRF receptor antagonist, alpha-helical CRF(9-41). The damaging effect of ethanol was apparently not influenced by adrenalectomy. N/OFQ markedly reduced macroscopically and histologically assessed gastric mucosal damage. The extent of reduction by N/OFQ was comparable in adrenalectomized and in sham-operated rats, with either icv or ip route of administration. Pretreatment with mifepristone, both icv (80 microg/rat) and ip (10 mg/kg) injected, did not modify the response to icv and ip N/OFQ. Pretreatment with alpha-helical CRF(9-41) (25 microg/rat icv or 250 microg/kg ip), had no effect on the reduction of gastric damage produced by icv or ip N/OFQ. Present findings suggest that the gastroprotective effects of N/OFQ on ethanol-induced damage do not involve the endocrine pathway through the HPA axis.

  1. Hypothalamic-pituitary-adrenal axis hyperactivity accounts for anxiety- and depression-like behaviors in rats perinatally exposed to bisphenol A

    PubMed Central

    Chen, Fang; Zhou, Libin; Bai, Yinyang; Zhou, Rong; Chen, Ling

    2015-01-01

    Abstract Accumulating studies have proved that perinatal exposure to environmental dose causes long-term potentiation in anxiety/depression-related behaviors in rats. Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis is one of the most consistent biological findings in anxiety- and depression-related disorders. The HPA axis is reported to be susceptible to developmental reprogramming. The present study focused on HPA reactivity in postnatal day (PND) 80 male rats exposed perinatally to environmental-dose BPA. When female breeders were orally administered 2 μg/(kg.day) BPA from gestation day 10 to lactation day 7, their offspring (PND 80 BPA-exposed rats) showed obvious anxiety/depression-like behaviors. Notably, significant increase in serum corticosterone and adrenocorticotropin, and corticotropin-releasing hormone mRNA were detected in BPA-exposed rats before or after the mild stressor. Additionally, the level of glucocorticoid receptor mRNA in the hippocampus, but not the hypothalamus, was decreased in BPA-exposed rats. The levels of hippocampal mineralocorticoid receptor mRNA, neuronal nitric oxide synthase and phosphorylated cAMP response element binding protein were increased in BPA-exposed rats. In addition, the testosterone level was in BPA-exposed rats. The results indicate that reprogramming-induced hyperactivity of the HPA axis is an important link between perinatal BPA exposure and persistent potentiation in anxiety and depression. PMID:26060449

  2. Neonatal repetitive pain in rats leads to impaired spatial learning and dysregulated hypothalamic-pituitary-adrenal axis function in later life

    PubMed Central

    Chen, Mengying; Xia, Dongqing; Min, Cuiting; Zhao, Xiaoke; Chen, Yinhua; Liu, Li; Li, Xiaonan

    2016-01-01

    Preterm birth is a major health issue. As part of their life-saving care, most preterm infants require hospitalization and are inevitably exposed to repetitive skin-breaking procedures. The long-term effects of neonatal repetitive pain on cognitive and emotional behaviors involving hypothalamic-pituitary-adrenal (HPA) axis function in young and adult rats are unknown. From P8 to P85, mechanical hypersensitivity of the bilateral hindpaws was observed in the Needle group (P < 0.001). Compared with the Tactile group, the Needle group took longer to find the platform on P30 than on P29 (P = 0.03), with a decreased number of original platform site crossings during the probe trial of the Morris water maze test (P = 0.026). Moreover, the Needle group spent more time and took longer distances in the central area than the Tactile group in the Open-field test, both in prepubertal and adult rats (P < 0.05). The HPA axis function in the Needle group differed from the Tactile group (P < 0.05), with decreased stress responsiveness in prepuberty and puberty (P < 0.05) and increased stress responsiveness in adulthood (P < 0.05). This study indicates that repetitive pain that occurs during a critical period may cause severe consequences, with behavioral and neuroendocrine disturbances developing through prepuberty to adult life. PMID:27966656

  3. Neuropeptide Y in the amygdala induces long-term resilience to stress-induced reductions in social responses but not hypothalamic-adrenal-pituitary axis activity or hyperthermia.

    PubMed

    Sajdyk, Tammy J; Johnson, Philip L; Leitermann, Randy J; Fitz, Stephanie D; Dietrich, Amy; Morin, Michelle; Gehlert, Donald R; Urban, Janice H; Shekhar, Anantha

    2008-01-23

    Resilience to mental and physical stress is a key determinant for the survival and functioning of mammals. Although the importance of stress resilience has been recognized, the underlying neural mediators have not yet been identified. Neuropeptide Y (NPY) is a peptide known for its anti-anxiety-like effects mediated via the amygdala. The results of our current study demonstrate, for the first time that repeated administration of NPY directly into the basolateral nucleus of the amygdala (BLA) produces selective stress-resilient behavioral responses to an acute restraint challenge as measured in the social interaction test, but has no effect on hypothalamic-adrenal-pituitary axis activity or stress-induced hyperthermia. More importantly, the resilient behaviors observed in the NPY-treated animals were present for up to 8 weeks. Antagonizing the activity of calcineurin, a protein phosphatase involved in neuronal remodeling and present in NPY receptor containing neurons within the BLA, blocked the development of long-term, but not the acute increases in social interaction responses induced by NPY administration. This suggests that the NPY-induced long-term behavioral resilience to restraint stress may occur via mechanisms involving neuronal plasticity. These studies suggest one putative physiologic mechanism underlying stress resilience and could identify novel targets for development of therapies that can augment the ability to cope with stress.

  4. Eugenol as an anti-stress agent: modulation of hypothalamic-pituitary-adrenal axis and brain monoaminergic systems in a rat model of stress.

    PubMed

    Garabadu, Debapriya; Shah, Ankit; Ahmad, Ausaf; Joshi, Vijaya B; Saxena, Bhagawati; Palit, Gautam; Krishnamurthy, Sairam

    2011-03-01

    Stress is the leading psychopathological cause for several mental disorders. Physiological and psychological responses to stress are mediated by the hypothalamic?pituitary?adrenal (HPA), sympathoadrenal system (SAS), and brain monoaminergic systems (BMS). Eugenol is reported to substantially modulate brain functions by regulating voltage-gated cation channels and release of neurotransmitters. This study was designed to evaluate the anti-stress effect of eugenol in the 4-h restraint model using rats. Ulcer index was measured as a parameter of the stress response. HPA axis and the SAS were monitored by estimating plasma corticosterone and norepinephrine (NE), respectively. Analysis of NE, serotonin (5-HT), dopamine, and their metabolites in discrete brain regions was performed to understand the role of BMS in the anti-stress effect of eugenol. Stress exposure increased the ulcer index as well as plasma corticosterone and NE levels. Eugenol pretreatment for 7 days decreased the stress-induced increase in ulcer index and plasma corticosterone but not NE levels, indicating a preferential effect on the HPA axis. Furthermore, eugenol showed a ?U?-shaped dose?response curve in decreasing ulcer index and plasma corticosterone levels. Eugenol also reversed the stress-induced changes in 5-HT levels in all brain regions, whereas NE levels were reversed in all brain regions except hippocampus. These results suggest that eugenol possesses significant anti-stress activity in the 4-h restraint model and the effect is due to modulation of HPA and BMS.

  5. Hypothalamic-pituitary-adrenal axis responses to stress in subjects with 3,4-methylenedioxy-methamphetamine ('ecstasy') use history: correlation with dopamine receptor sensitivity.

    PubMed

    Gerra, Gilberto; Bassignana, Sara; Zaimovic, Amir; Moi, Gabriele; Bussandri, Monica; Caccavari, Rocco; Brambilla, Francesca; Molina, Enzo

    2003-09-30

    Fifteen 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') users who did not have other drug dependencies or prolonged alcohol abuse and 15 control subjects were studied. All the subjects were exposed to the same psychosocial stressor (Stroop Color-Word Interference Task, public speaking and mental arithmetic in front of an audience) 3 weeks after MDMA discontinuation. Plasma concentrations of adrenocorticotropic hormone (ACTH) and cortisol were measured immediately before the tests began and at their end, 30 min later. Growth hormone (GH) responses to the dopaminergic agonist bromocriptine and psychometric measures (Tridimensional Personality Questionnaire, Minnesota Multiphasic Personality Inventory, Buss-Durkee Hostility Inventory) were also obtained 4 weeks after MDMA discontinuation for the same subjects. ACTH and cortisol basal levels were significantly higher in ecstasy users than in control subjects. In contrast, ACTH and cortisol responses to stress were significantly blunted in MDMA users. The sensitivity of dopamine D2 receptors, reflected by GH responses to bromocriptine challenge, was reduced in MDMA users compared with controls. The responsiveness of the hypothalamic-pituitary-adrenal (HPA) axis (ACTH and cortisol delta peaks) correlated directly with GH areas under curves in response to bromocriptine, and inversely with psychometric measures of aggressiveness and novelty seeking. No correlation was found between hormonal measures and the extent of MDMA exposure. Reduced D2 receptor sensitivity, HPA basal hyperactivation and reduced responsiveness to stress may represent a complex neuroendocrine dysfunction associated with MDMA use. The present findings do not exclude the possibility that dopamine dysfunction partly predated MDMA exposure.

  6. Coupling of inositol phospholipid hydrolysis to peptide hormone receptors expressed from adrenal and pituitary mRNA in Xenopus laevis oocytes

    SciTech Connect

    McIntosh, R.P.; Catt, K.J.

    1987-12-01

    The expression of several neurotransmitter and drug receptors from injected exogenous mRNA in Xenopus laevis oocytes has been demonstrated by electrophysiological measurements of ion channel activation. The expression of specific receptors for peptide hormones in such a translation system would facilitate studies on the structure and regulation of cell-surface receptors as well as their coupling to membrane transduction mechanisms. The expression of receptors for calcium-mobilizing hormones in Xenopus oocytes was sought by analysis of phospholipid turnover in hormone-stimulated oocytes. For this purpose, Xenopus oocytes were injected with mRNA extracted from bovine adrenal and pituitary glands and incubated with myo-(/sup 3/H)inositol to label plasma-membrane phosphatidylinositol phosphates. The expression of functionally active receptors for angiotensin II (AII) and thyrotropin-releasing hormone (TRH) was demonstrated by the stimulation of (/sup 3/H)inositol phosphate production by AII and TRH in the mRNA-injected, (/sup 3/H)inositol-prelabeled oocytes. The ability of AII and TRH to act by way of newly synthesized receptors from mammalian endocrine tissues to stimulate phosphatidylinositol polyphosphate hydrolysis in Xenopus oocytes suggests a generalized and conserved mechanism of receptor coupling to the transduction mechanism responsible for activation of phospholipase C in the plasma membrane.

  7. Reducing treatments in cattle superovulation protocols by combining a pituitary extract with a 5% hyaluronan solution: Is it able to diminish activation of the hypothalamic pituitary adrenal axis compared to the traditional protocol?

    PubMed

    Biancucci, Andrea; Sbaragli, Tatiana; Comin, Antonella; Sylla, Lakamy; Monaci, Maurizio; Peric, Tanja; Stradaioli, Giuseppe

    2016-03-15

    Traditional superovulation protocols that include multiple gonadotropin treatments are time-consuming and labor intensive. These protocols require multiple handling and restraining of embryo donors. This will likely increase the risks of injuries in both animals and humans and induce stress that may lead to a reduced superovulatory response. These are more evident when working with cattle that are rarely handled or raised on extensive grazing. The objectives of this experiment were to compare the efficacy of a split-injection protocol of porcine pituitary-derived porcine FSH (pFSH) preparation (slow release [SR] group) to the traditional 4-day treatment with pFSH administered twice daily (C group) and to determine the concentrations of cortisol in the hair as a marker of activation of the hypothalamic-pituitary-adrenal (HPA) axis during the two superovulatory treatments. Thirty-two heifers were stimulated twice in a 2 × 2 crossover design and compared for ovarian response and numbers and characteristics of recovered ova-embryo among treatments. No differences between SR and C groups were found in terms of percentage of responsive animals (100% vs. 93.8%) and ovulation rate (83.7 ± 1.1 vs. 79.5 ± 1.0%). A positive correlation was found between the number of follicles responsive to pFSH (2-8 mm) at the beginning of treatments and the superovulatory response, and no differences were found in these follicular populations between the two treatment groups. The numbers of CLs, ova-embryos, fertilized ova, transferable and freezable embryos recovered per cow were found to be significantly higher in SR compared with C group (14.0 ± 1.6 vs. 10.6 ± 1.0, 12.1 ± 1.6 vs. 7.6 ± 1.0, 11.1 ± 1.1 vs. 7.3 ± 1.0, 9.6 ± 1.4 vs. 6.6 ± 1.0, and 9.4 ± 1.4 vs. 6.0 ± 1.0 for SR and C group, respectively). The SR group produced also a significantly greater number of excellent- and/or good-quality embryos compared with the C group. The concentrations of cortisol in the hair at

  8. Neuroanatomy and physiology of the avian hypothalamic/pituitary axis: clinical aspects.

    PubMed

    Ritchie, Midge

    2014-01-01

    This article describes the anatomy of the avian hypothalamic/pituitary axis, the hypothalamic-pituitary-thyroid axis, the hypothalamic-pituitary-adrenal axis, the hypothalamic-pituitary-gonadal axis, the somatotrophic axis, and neurohypophysis.

  9. Pituitary-gonadal hormones and adrenal androgens in non-cirrhotic female alcoholics after cessation of alcohol intake.

    PubMed

    Välimäki, M; Pelkonen, R; Härkönen, M; Tuomala, P; Koistinen, P; Roine, R; Ylikahri, R

    1990-04-01

    To investigate the sex-hormone profiles associated with chronic alcoholism in women we examined 16 non-cirrhotic alcohol abusers (aged 18-46 years). They were admitted for the treatment of alcoholism (duration of 2-16 yrs) to a social hospital for 6 weeks. Their mean daily alcohol consumption was 170 g. Blood samples for serum LH, FSH, prolactin (PRL), oestrone (E1), oestradiol (E2), progesterone (P), 17-alpha-hydroxyprogesterone (17-OHP), androstenedione (A) and dehydroepiandrosterone (DHEA) were drawn three times a week during the hospital stay. Similar blood samples were taken from 10 control women during one menstrual cycle. The cycles were anovulatory in two patients and in none of controls. Serum LH and FSH levels were similar in alcoholic and control women but serum concentrations of PRL were increased 2-4-fold in alcoholic women. In the patients serum, concentrations of E1 and E2 tended to be lower during the follicular and midcycle phases, as did those of P and 17-OHP during the luteal phase. Compared with the controls, serum levels of A were increased 2-3-fold in the patients. A parallel difference between the two groups was seen in serum DHEA concentrations. We conclude that until liver injury, even heavy alcohol drinking has only minor effects on the secretion of gonadotrophins and ovarian steroids. Hypersecretion of PRL and adrenal androgens may well be an initiating mechanism for sexual dysfunction of female alcoholics.

  10. Effects of prenatal restraint stress on the hypothalamus-pituitary-adrenal axis and related behavioural and neurobiological alterations.

    PubMed

    Maccari, Stefania; Morley-Fletcher, Sara

    2007-08-01

    Chronic hyper-activation of the hypothalamus-pituitary axis is associated with the suppression of reproductive, growth, thyroid and immune functions that may lead to various pathological states. Although many individuals experiencing stressful events do not develop pathologies, stress seems to be a provoking factor in those individuals with particular vulnerability, determined by genetic factors or earlier experience. Exposure of the developing brain to severe and/or prolonged stress may result in hyper-activity of the stress system, defective glucocorticoids-negative feedback, altered cognition, novelty seeking, increased vulnerability to addictive behaviour, and mood-related disorders. Therefore, stress-related events that occur in the perinatal period can permanently change brain and behaviour of the developing individual. Prenatal restraint stress (PRS) in rats is a well-documented model of early stress known to induce long-lasting neurobiological and behavioural alterations including impaired feedback mechanisms of the HPA axis, disruption of circadian rhythms and altered neuroplasticity. Chronic treatments with antidepressants at adulthood have proven high predictive validity of the PRS rat as animal model of depression and, reinforce the idea of the usefulness of the PRS rat as an interesting animal model for the design and testing of new pharmacologic strategies in the treatment of stress-related disorders.

  11. Recovery rate of adrenal function after surgery in patients with acromegaly is higher than in those with non-functioning pituitary tumors: a large single center study.

    PubMed

    Yedinak, Chris; Hameed, Nadia; Gassner, Marika; Brzana, Jessica; McCartney, Shirley; Fleseriu, Maria

    2015-10-01

    To compare hypothalamus-pituitary-adrenal (HPA) axis integrity at diagnosis and recovery after transsphenoidal surgery (TSS), in acromegaly patients, compared with tumor size matched non-functioning adenoma (NFA) patients. A retrospective 7-year evaluation of acromegaly patients, who underwent TSS with 52 weeks follow-up at a single institution, was undertaken. 50 acromegaly with complete follow-up data at all points and 50 NFA patients were matched for tumor size; HPA axis was similarly assessed pre-operatively and at 6, 12 and 52 weeks post-operatively. Recovery of HPA axis and gender specific prevalence of adrenal insufficiency (AI), were analyzed in both groups. We also studied AI in acromegaly patients requiring medical therapy post-operatively vs those in remission after surgery. AI remained less prevalent in acromegaly vs NFA (acromegaly, p = 0.01; NFA, p = 0.15) at 52 weeks after surgery, although the prevalence of AI decreased in both groups from baseline by 52 weeks. Additionally, recovery from baseline AI was significantly greater by 52 weeks in acromegaly patients over NFA patients (p = 0.001). Recovery of HPA axis in acromegaly patients remained significant (p = 0.03) despite the need for medical therapy. AI at baseline was proportionately more prevalent in acromegalic males at baseline (p = 0.002) but no gender difference was apparent at 52 weeks (p = 0.35). Conversely, in NFA patients, no gender difference was apparent pre-operatively (p = 0.49), but AI was more prevalent in males at 52 weeks (p = 0.001). In the longest comparative study to date using a standard assessment modality, HPA axis recovery was more frequent in acromegaly compared to NFA patients, independent of tumor size, cavernous sinus invasion (CSI), and body mass index (BMI). HPA axis integrity must be carefully and periodically monitored in acromegaly patients during short- and long-term follow-up to prevent overtreatment with glucocorticoids.

  12. [Effect of electroacupuncture at different acupoints on hormones and neurotransmitters of hypotha- lamic-pituitary-adrenal axis in rats under simulated weightlessness].

    PubMed

    Zhang, Hei; Zhao, Guozhen; Wang, Desheng; Zhao, Baixiao; Ji, Bo; Song, Yan; Zhang, Ping; Liu, Yali; Li, Yinghui

    2015-12-01

    To explore the change pattern of hypothalamic-pituitary-adrenal (HPA) axis and related neurotransmitters under simulated weightlessness. A total of 40 clean-grade male Wistar rats were randomly divided into a normal group, a tail-suspension group, an electroacupuncture (EA) at Neiguan (PC 6) group, an EA at Sanyinjiao (SP 6) group, 10 rats in each group. Rats in the tail-suspension group, EA at "Neiguan" (PC 6) group and EA at "Sanyinjiao" (SP 6) group were treated with tail suspension to simulate weightlessness effect. Rats in the normal group were treated with normal diet. Rats in the tail-suspension group were treated with tail suspension for 28 d. During the time of tail suspension, rats in the EA at "Neiguan" (PC 6) group were treated with EA at "Neiguan" (PC 6), 30 min per treatment, once every two days for 14 treatments, while rats in the EA at "Sanyinjiao" (SP 6) group were treated with EA at "Sanyinjiao" (SP 6), 30 min per treatment, once every two days for 14 treatments. Samples were all collected after 4 weeks. The contents of corticotropin releasing hormone (CRH) , adrenocorticotropic hormone (ACTH), corticosterone (CORT) in as well as 5-hydroxy tryptamine (5-HT), dopamine (DA), norepinephrine (NE) were measured by using radioimmunoassay. Compared with the normal group, in the tail-suspension group the content of ACTH in pituitary was significantly decreased (P< 0.05), and the content of 5-HT in hypothalamus was significantly decreased (P < 0.01); the content of CRH and 5-HT in hypothalamus was significantly decreased (P < 0.01, P < 0.05) in the EA at "Neiguan" (PC 6) group; the content of CRH and 5-HT in hypothalamus was significantly decreased (P < 0.01), and the content of CORT in serum was significantly decreased (P < 0.05) in the EA at "Sanyinjiao" (SP 6) group. Compared with the tail-suspension group, the content of ACTH in hypothalamus was significantly decreased (P< 0.05) in the EA at "Neiguan" (PC 6) group; the content of CRH, ACTH and CORT was

  13. Acute hypernatremia promotes anxiolysis and attenuates stress-induced activation of the hypothalamic-pituitary-adrenal axis in male mice.

    PubMed

    Smith, Justin A; Wang, Lei; Hiller, Helmut; Taylor, Christopher T; de Kloet, Annette D; Krause, Eric G

    2014-09-01

    Previous investigation by our laboratory found that acute hypernatremia potentiates an oxytocinergic tone that inhibits parvocellular neurosecretory neurons in the paraventricular nucleus of the hypothalamus (PVN), attenuates restraint-induced surges in corticosterone (CORT), and reduces anxiety-like behavior in male rats. To investigate the neural mechanisms mediating these effects and extend our findings to a more versatile species, we repeated our studies using laboratory mice. In response to 2.0M NaCl injections, mice had increased plasma sodium concentrations which were associated with a blunted rise in CORT subsequent to restraint challenge relative to 0.15M NaCl injected controls. Immunofluorescent identification of the immediate early gene product Fos found that 2.0M NaCl treatment increased the number of activated neurons producing oxytocin in the PVN. To evaluate the effect of acute hypernatremia on PVN neurons producing corticotropin-releasing hormone (CRH), we used the Cre-lox system to generate mice that produced the red fluorescent protein, tdTomato, in cells that had Cre-recombinase activity driven by CRH gene expression. Analysis of brain tissue from these CRH-reporter mice revealed that 2.0M NaCl treatment caused a dramatic reduction in Fos-positive nuclei specifically in CRH-producing PVN neurons. This altered pattern of activity was predictive of alleviated anxiety-like behavior as mice administered 2.0M NaCl spent more time exploring the open arms of an elevated-plus maze than 0.15M NaCl treated controls. Taken together, these results further implicate an oxytocin-dependent inhibition of CRH neurons in the PVN and demonstrate the impact that slight elevations in plasma sodium have on hypothalamic-pituitary-adrenocortical axis output and anxiety-like behavior. Copyright © 2014 Elsevier Inc. All rights reserved.

  14. Acute hypernatremia promotes anxiolysis and attenuates stress-induced activation of the hypothalamic-pituitary-adrenal axis in male mice

    PubMed Central

    Smith, Justin A.; Wang, Lei; Hiller, Helmut; Taylor, Christopher T.; de Kloet, Annette D.; Krause, Eric G.

    2014-01-01

    Previous investigation by our laboratory found that acute hypernatremia potentiates an oxytocinergic tone that inhibits parvocellular neurosecretory neurons in the paraventricular nucleus of the hypothalamus (PVN), attenuates restraint-induced surges in corticosterone (CORT), and reduces anxiety-like behavior in male rats. To investigate the neural mechanisms mediating these effects and extend our findings to a more versatile species, we repeated our studies using laboratory mice. In response to 2.0 M NaCl injections, mice had increased plasma sodium concentrations which were associated with a blunted rise in CORT subsequent to restraint challenge relative to 0.15 M NaCl injected controls. Immunofluorescent identification of the immediate early gene product Fos found that 2.0 M NaCl treatment increased the number of activated neurons producing oxytocin in the PVN. To evaluate the effect of acute hypernatremia on PVN neurons producing corticotropin-releasing hormone (CRH), we used the Cre-lox system to generate mice that produced the red fluorescent protein, tdTomato, in cells that had Cre-recombinase activity driven by CRH gene expression. Analysis of brain tissue from these CRH-reporter mice revealed 2.0 M NaCl treatment caused a dramatic reduction in Fos-positive nuclei specifically in CRH-producing PVN neurons. This altered pattern of activity was predictive of alleviated anxiety-like behavior as mice administered 2.0 M NaCl spent more time exploring the open arms of an elevated-plus maze than 0.15 M NaCl treated controls. Taken together, these results further implicate an oxytocin-dependent inhibition of CRH neurons in the PVN and demonstrate the impact that slight elevations in plasma sodium have on hypothalamic-pituitary-adrenocortical axis output and anxiety-like behavior. PMID:24704193

  15. Immediate and lasting effects of chronic daily methamphetamine exposure on activation of cells in hypothalamic-pituitary-adrenal axis-associated brain regions.

    PubMed

    Zuloaga, Damian G; Johnson, Lance A; Weber, Sydney; Raber, Jacob

    2016-02-01

    Chronic methamphetamine (MA) abuse leads to dependence and symptoms of withdrawal after use has ceased. Negative mood states associated with withdrawal, as well as drug reinstatement, have been linked to drug-induced disruption of the hypothalamic-pituitary-adrenal (HPA) axis. However, effects of chronic MA exposure or acute MA exposure following withdrawal on neural activation patterns within brain regions that regulate the HPA axis are unknown. In this study, neural activation patterns were assessed by quantification of c-Fos protein in mice exposed to different regimens of MA administration. (Experiment 1) Adult male mice were treated with MA (5 mg/kg) or saline once or once daily for 10 days. (Experiment 2) Mice were treated with MA or saline once daily for 10 days and following a 10-day withdrawal period were re-administered a final dose of MA or saline. c-Fos was quantified in brains after the final injection. (Experiment 1) Compared to exposure to a single dose of MA (5 mg/kg), chronic MA exposure decreased the number of c-Fos expressing cells in the paraventricular hypothalamus, dorsomedial hypothalamus, central amygdala, basolateral amygdala, bed nucleus of the stria terminalis (BNST), and CA3 hippocampal region. (Experiment 2) Compared to mice receiving their first dose of MA, mice chronically treated with MA, withdrawn, and re-administered MA, showed decreased c-Fos expressing cells within the central and basolateral amygdala, BNST, and CA3. HPA axis-associated amygdala, extended amygdala, and hippocampal regions endure lasting effects following chronic MA exposure and therefore may be linked to stress-related withdrawal symptoms.

  16. Sexually diergic hypothalamic-pituitary-adrenal (HPA) responses to single-dose nicotine, continuous nicotine infusion, and nicotine withdrawal by mecamylamine in rats

    PubMed Central

    Gentile, Natalie E.; Andrekanic, Julie D.; Karwoski, Tracy E.; Czambel, R. Kenneth; Rubin, Robert T.; Rhodes, Michael E.

    2011-01-01

    Hypothalamic-pituitary-adrenal (HPA) responses to single-dose nicotine (NIC) are sexually diergic: Female rats have higher adrenocorticotropic hormone (ACTH) and corticosterone (CORT) responses than do males. In the present study we determined HPA responses in male and female rats following single doses of NIC, a single-dose of NIC immediately following continuous NIC for two weeks, and NIC withdrawal by single-dose mecamylamine (MEC) following continuous NIC infusion for two weeks. Blood sampling occurred before and after MEC and NIC administrations for determination of ACTH and CORT. In accordance with our previous findings, female ACTH and CORT responses to single-dose NIC were greater than male responses. This sex difference remained after single-dose NIC followed continuous NIC infusion, but HPA responses in both sexes were significantly lower in magnitude and duration than in the single-dose NIC alone groups. Sex differences also were observed following NIC withdrawal by MEC: The HPA responses to pretreatment with MEC were significantly higher in magnitude and duration in the continuous NIC groups than in the single-dose NIC groups. These results demonstrate that HPA responses to NIC are reduced and transient following continuous NIC infusion but are enhanced and sustained following NIC withdrawal by MEC after continuous NIC, suggesting that NIC habituation and withdrawal influence the stress responses in a diergic manner. These findings highlight the importance of sex differences in the effect of NIC on HPA axis activity and stress responsiveness, which may have implications for directing NIC-addiction treatment specifically towards men and women. PMID:21396990

  17. Changes in hypothalamic-pituitary-adrenal function, body temperature, body weight and food intake with repeated social stress exposure in rats.

    PubMed

    Bhatnagar, S; Vining, C; Iyer, V; Kinni, V

    2006-01-01

    These present studies aimed to compare changes in hypothalamic-pituitary-adrenal (HPA) activity and body temperature in response to acute social defeat, to repeated social stress and to novel restraint after repeated stress, as well as to assess effects on metabolic parameters by measuring body weight gain and food and water intake. We found that social defeat produced a marked increase in both adrenocorticotrophic hormone and corticosterone compared to placement in a novel cage. Similarly, body temperature was also increased during social defeat and during 30 min of recovery from defeat. We then examined the effects of 6 days of repeated social stress and observed minimal HPA responses to repeated social stress compared to control rats. These neuroendocrine responses were contrasted by robust increases in body temperature during stress and during recovery from stress during 6 days of repeated stress. However, in response to novel restraint, repeatedly stressed rats displayed facilitated body temperature responses compared to controls, similar to our previous findings with HPA activity. Food intake was increased during the light period during which defeat took place, but later intake during the dark period was not affected. Repeated stress decreased body weight gain in the dark period but food intake was increased overall during the 6 days of repeated stress in the light period. As a result, repeated stress increased cumulative food intake during the light period in the stressed rats but these relatively small increases in food intake were unable to prevent the diminished total weight gain in repeatedly stressed rats. Overall, the results demonstrate that, although acute social defeat has similar effects on temperature and HPA activity, repeated exposure to social stress has divergent effects on HPA activity compared to body temperature and that dampened weight gain produced by repeated social stress cannot be fully explained by changes in food intake.

  18. Effect of continuous positive airway pressure therapy on hypothalamic-pituitary-adrenal axis function and 24-h blood pressure profile in obese men with obstructive sleep apnea syndrome.

    PubMed

    Carneiro, Gláucia; Togeiro, Sônia Maria; Hayashi, Lílian F; Ribeiro-Filho, Fernando Flexa; Ribeiro, Artur Beltrame; Tufik, Sérgio; Zanella, Maria Teresa

    2008-08-01

    Obstructive sleep apnea syndrome (OSAS) increases the risk of cardiovascular events. Sympathetic nervous system and hypothalamic-pituitary-adrenal (HPA) axis activation may be the mechanism of this relationship. The aim of this study was to evaluate HPA axis and ambulatory blood pressure monitoring in obese men with and without OSAS and to determine whether nasal continuous positive airway pressure therapy (nCPAP) influenced responses. Twenty-four-hour ambulatory blood pressure monitoring and overnight cortisol suppression test with 0.25 mg of dexamethasone were performed in 16 obese men with OSAS and 13 obese men controls. Nine men with severe apnea were reevaluated 3 mo after nCPAP therapy. Body mass index and blood pressure of OSAS patients and obese controls were similar. In OSAS patients, the percentage of fall in systolic blood pressure at night (P = 0.027) and salivary cortisol suppression postdexamethasone (P = 0.038) were lower, whereas heart rate (P = 0.022) was higher compared with obese controls. After nCPAP therapy, patients showed a reduction in heart rate (P = 0.036) and a greater cortisol suppression after dexamethasone (P = 0.001). No difference in arterial blood pressure (P = 0.183) was observed after 3 mo of nCPAP therapy. Improvement in cortisol suppression was positively correlated with an improvement in apnea-hypopnea index during nCPAP therapy (r = 0.799, P = 0.010). In conclusion, men with OSAS present increased postdexamethasone cortisol levels and heart rate, which were recovered by nCPAP.

  19. Multi-Level Risk Factors for Suicidal Ideation Among at-Risk Adolescent Females: The Role of Hypothalamic-Pituitary-Adrenal Axis Responses to Stress

    PubMed Central

    Calhoun, Casey D.; Hastings, Paul D.; Rudolph, Karen D.; Nock, Matthew K.; Prinstein, Mitchell J.

    2014-01-01

    Adopting a multi-level approach, this study examined risk factors for adolescent suicidal ideation, with specific attention to (a) hypothalamic-pituitary-adrenal (HPA) axis stress responses and (b) the interplay between HPA-axis and other risk factors from multiple domains (i.e., psychological, interpersonal and biological). Participants were 138 adolescent females (Mage=14.13 years, SD=1.40) at risk for suicidal behaviors. At baseline, lifetime suicidal ideation and a number of risk factors were assessed (i.e., depressive symptoms, impulsiveness, pubertal status and peer stress). Participants were exposed to a psychosocial stress task and HPA-axis responses were assessed by measuring cortisol levels pre- and post-stressor. At 3 months post-baseline, suicidal ideation again was assessed. Using group-based trajectory modeling, three groups of cortisol stress-response patterns were identified (i.e., hyporesponsive, normative, and hyperresponsive). As compared to females in the normative and hyporesponsive group, females in the hyperresponsive group were more likely to report a lifetime history of suicidal ideation at baseline, above and beyond the effects of the other predictors. Moreover, as compared to females in the normative group, females in the hyperresponsive group were at increased risk for reporting suicidal ideation 3 months later, after controlling for prior ideation. No interactions between cortisol group and the other risk factors were significant, with the exception of a non-significant trend between impulsiveness and cortisol group on lifetime suicidal ideation. Findings highlight the importance of HPA-axis responses to acute stressors as a risk factor for suicidal ideation among adolescents. PMID:24958308

  20. The stress-, but not corticotropin-releasing hormone-induced activation of the pituitary-adrenal axis in man is blocked by alprazolam.

    PubMed

    Rohrer, T; von Richthofen, V; Schulz, C; Beyer, J; Lehnert, H

    1994-04-01

    A number of experimental studies clearly suggest that benzodiazepines attenuate the corticotropin-releasing hormone (CRH) secretion possibly through inhibitory GABAergic neurons. There is some evidence that benzodiazepines act to inhibit stress-induced activation of the hypothalamic-pituitary-adrenal axis. A comparison of the effects of a benzodiazepine on the stress- and CRH-induced activation in man has not been undertaken so far. We thus investigated the effects of the triazolobenzodiazepine alprazolam on both the stress- and CRH-induced changes in ACTH, cortisol, and prolactin secretion in ten healthy volunteers. In addition, hemodynamic parameters were studied. The subjects received either alprazolam (0.5 mg orally) or placebo 90 min prior to administration of CRH (100 ug i.v.) and to the performance of a mental stress technique. Blood samples, blood pressure and heart rate were taken every 15 min. The administration of alprazolam led to a highly significant attenuation of the ACTH increase following the stress interview. While ACTH increased from 12.4 to 26.7 pg/ml 15 min after the stress procedure in the placebo condition, there was almost no increase following alprazolam intake. An identical effect was found for cortisol secretion. Basal levels of prolactin were slightly enhanced in the alprazolam situation, while the stress-induced increase was not attenuated. Basal and stimulated systolic and diastolic blood pressure levels and heart rate were also significantly attenuated by alprazolam intake. Following administration of CRH, the ACTH augmentation was only slightly affected following alprazolam, while there were no changes in cortisol and prolactin secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

  1. Reduced hypothalamic-pituitary-adrenal axis activity in chronic multi-site musculoskeletal pain: partly masked by depressive and anxiety disorders

    PubMed Central

    2014-01-01

    Background Studies on hypothalamic-pituitary-adrenal axis (HPA-axis) function amongst patients with chronic pain show equivocal results and well-controlled cohort studies are rare in this field. The goal of our study was to examine whether HPA-axis dysfunction is associated with the presence and the severity of chronic multi-site musculoskeletal pain. Methods Data are from the Netherlands Study of Depression and Anxiety including 1125 subjects with and without lifetime depressive and anxiety disorders. The Chronic Pain Grade questionnaire was used to determine the presence and severity of chronic multi-site musculoskeletal pain. Subjects were categorized into a chronic multi-site musculoskeletal pain group (n = 471) and a control group (n = 654). Salivary cortisol samples were collected to assess HPA-axis function (awakening level, 1-h awakening response, evening level, diurnal slope and post-dexamethasone level). Results In comparison with the control group, subjects with chronic multi-site musculoskeletal pain showed significantly lower cortisol level at awakening, lower evening level and a blunted diurnal slope. Lower cortisol level at awakening and a blunted diurnal slope appeared to be restricted to those without depressive and/or anxiety disorders, who also showed a lower 1-h awakening response. Conclusions Our results suggest hypocortisolemia in chronic multi-site musculoskeletal pain. However, if chronic pain is accompanied by a depressive or anxiety disorder, typically related to hypercortisolemia, the association between cortisol levels and chronic multi-site musculoskeletal pain appears to be partly masked. Future studies should take psychopathology into account when examining HPA-axis function in chronic pain. PMID:25007969

  2. Increased hypothalamic-pituitary-adrenal drive is associated with decreased appetite and hypoactivation of food-motivation neurocircuitry in anorexia nervosa.

    PubMed

    Lawson, Elizabeth A; Holsen, Laura M; Desanti, Rebecca; Santin, McKale; Meenaghan, Erinne; Herzog, David B; Goldstein, Jill M; Klibanski, Anne

    2013-11-01

    Corticotrophin-releasing hormone (CRH)-mediated hypercortisolemia has been demonstrated in anorexia nervosa (AN), a psychiatric disorder characterized by food restriction despite low body weight. While CRH is anorexigenic, downstream cortisol stimulates hunger. Using a food-related functional magnetic resonance imaging (fMRI) paradigm, we have demonstrated hypoactivation of brain regions involved in food motivation in women with AN, even after weight recovery. The relationship between hypothalamic-pituitary-adrenal (HPA) axis dysregulation and appetite and the association with food-motivation neurocircuitry hypoactivation are unknown in AN. We investigated the relationship between HPA activity, appetite, and food-motivation neurocircuitry hypoactivation in AN. Cross-sectional study of 36 women (13 AN, ten weight-recovered AN (ANWR), and 13 healthy controls (HC)). Peripheral cortisol and ACTH levels were measured in a fasting state and 30, 60, and 120 min after a standardized mixed meal. The visual analog scale was used to assess homeostatic and hedonic appetite. fMRI was performed during visual processing of food and non-food stimuli to measure the brain activation pre- and post-meal. In each group, serum cortisol levels decreased following the meal. Mean fasting, 120 min post-meal, and nadir cortisol levels were high in AN vs HC. Mean postprandial ACTH levels were high in ANWR compared with HC and AN subjects. Cortisol levels were associated with lower fasting homeostatic and hedonic appetite, independent of BMI and depressive symptoms. Cortisol levels were also associated with between-group variance in activation in the food-motivation brain regions (e.g. hypothalamus, amygdala, hippocampus, orbitofrontal cortex, and insula). HPA activation may contribute to the maintenance of AN by the suppression of appetitive drive.

  3. Perinatal exposure to 50 ppb sodium arsenate induces Hypothalamic-Pituitary-Adrenal Axis dysregulation in male C57BL/6 mice

    PubMed Central

    Goggin, Samantha L.; Labrecque, Matthew T.; Allan, Andrea M.

    2012-01-01

    Over the past two decades, key advancements have been made in understanding the complex pathology that occurs following not only high levels of arsenic exposure (>1ppm) but also levels previously considered to be low (<100 ppb). Past studies have characterized the deleterious effects of arsenic on the various functions of cardiovascular, pulmonary, immunological, respiratory, endocrine and neurological systems. Other research has demonstrated an elevated risk of a multitude of cancers and increased rates of psychopathology, even at very low levels of arsenic exposure. The hypothalamic-pituitary-adrenal (HPA) axis represents a multisite integration center that regulates a wide scope of biological and physiological processes: breakdown within this system can generate an array of far-reaching effects, making it an intriguing candidate for arsenic-mediated damage. Using a mouse model, we examined the effects of perinatal exposure to 50 ppb sodium arsenate on the functioning of the HPA axis through the assessment of corticotrophin-releasing factor (CRF), proopiomelanocortin (Pomc) mRNA, adrenocorticotrophin hormone (ACTH), corticosterone (CORT), 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD 1), and glucocorticoid receptor (GR) protein and mRNA. Compared to controls, we observed that the perinatal arsenic-exposed offspring exhibit an increase in hypothalamic CRF, altered CORT secretion both at baseline and in response to a stressor, decreased hippocampal 11β-HSD 1 and altered subcellular GR distribution in the hypothalamus. These data indicate significant HPA axis impairment at post-natal day 35 resulting from perinatal exposure to 50 ppb sodium arsenate. Our findings suggest that the dysregulation of this critical regulatory axis could underlie important molecular and cognitive pathology observed following exposure to arsenic. PMID:22960421

  4. The Effects of a Korean Ginseng, GINST15, on Hypo-Pituitary-Adrenal and Oxidative Activity Induced by Intense Work Stress.

    PubMed

    Flanagan, Shawn D; DuPont, William H; Caldwell, Lydia K; Hardesty, Vincent H; Barnhart, Emily C; Beeler, Matthew K; Post, Emily M; Volek, Jeff S; Kraemer, William J

    2017-10-05

    The effect of GINST15, an enzyme fermented ginseng supplement, on hormonal and inflammatory responses to physical stress in humans is unknown. The purpose of this investigation was to examine the constitutive and stress-induced effects of GINST15 supplement on hypo-pituitary-adrenal (HPA) and antioxidant activity in addition to muscle damage. Ten women (age: 38.7 ± 7.8 years; height: 163.81 ± 4.4 cm; body mass 76.0 ± 11.6 kg) and nine men (age: 41.2. ± 9.7 years; height: 177.4 ± 5.3 cm; body mass: 88.5 ± 5.0 kg) participated in a double-blinded, placebo-controlled, counterbalanced within-group study. Participants completed three 14-day treatment cycles with different doses (high: 960 mg; low: 160 mg; placebo: 0 mg) separated by a 1-week washout period. At the end of treatment, physical stress was imposed with intense resistance exercise work stress. Participants provided blood at rest and various time points after exercise (immediately [IP], 30 min [30], 60 min [60], 24 h [+24HR]). Cortisol (CORT), superoxide dismutase (SOD), total glutathione, nonspecific antioxidant activity, total antioxidant power (TAP), and creatine kinase were measured. GINST15 supplementation produced stress-inducible dose-dependent reductions in circulating cortisol and increased enzymatic and nonspecific antioxidant activity. Twenty-four hours after intense exercise, a high dose GINST15, a bioactive ginsenoside metabolite, significantly reduces muscle damage and HPA responses to physical stress in humans; these effects may result from increased antioxidant expression.

  5. CORTICOTROPIN-RELEASING-HORMONE RECEPTORS IN THE MEDIAL PREFRONTAL CORTEX REGULATE HYPOTHALAMIC-PITUITARY-ADRENAL ACTIVITY AND ANXIETY-RELATED BEHAVIOR REGARDLESS OF PRIOR STRESS EXPERIENCE

    PubMed Central

    Jaferi, Azra; Bhatnagar, Seema

    2007-01-01

    The hypothalamic-pituitary-adrenal (HPA) axis habituates, or gradually decreases its activity, with repeated exposure to the same stressor. During habituation, the HPA axis likely requires input from cortical and limbic regions involved in processing of cognitive information that is important in coping to stress. Brain regions such as the medial prefrontal cortex (mPFC) are recognized as important in mediating these processes. The mPFC modulates stress-related behavior and some evidence suggests that the mPFC regulates acute and repeated stress-induced HPA responses. Interestingly, corticotropin releasing hormone(CRH)-1 receptors, which integrate neuroendocrine, behavioral and autonomic responses to stress, are localized in the mPFC but have not been specifically examined with respect to HPA regulation. We hypothesized that CRH receptor activity in the mPFC contributes to stress-induced regulation of HPA activity and anxiety-related behavior, and that CRH release in the mPFC may differentially regulate HPA responses in acutely- compared to repeatedly-stressed animals. In the present experiments, we found that blockade of CRH receptors in the mPFC with the non-selective receptor antagonist, D-Phe-CRH (50ng or 100ng) significantly inhibited HPA responses compared to vehicle regardless of whether animals were exposed to a single, acute 30min restraint or to the eighth 30min restraint. We also found that intra-mPFC injections of CRH (20ng) significantly increased anxiety-related behavior in the elevated plus maze in both acutely- and repeatedly-restrained groups compared to vehicle. Together, these results suggest an excitatory influence of CRH in the mPFC on stress-induced HPA activity and anxiety-related behavior regardless of prior stress experience. PMID:18001698

  6. A hypothalamic-pituitary-adrenal axis-associated neuroendocrine metabolic programmed alteration in offspring rats of IUGR induced by prenatal caffeine ingestion.

    PubMed

    Xu, D; Wu, Y; Liu, F; Liu, Y S; Shen, L; Lei, Y Y; Liu, J; Ping, J; Qin, J; Zhang, C; Chen, L B; Magdalou, J; Wang, H

    2012-11-01

    Caffeine is a definite factor of intrauterine growth retardation (IUGR). Previously, we have confirmed that prenatal caffeine ingestion inhibits the development of hypothalamic-pituitary-adrenal (HPA) axis, and alters the glucose and lipid metabolism in IUGR fetal rats. In this study, we aimed to verify a programmed alteration of neuroendocrine metabolism in prenatal caffeine ingested-offspring rats. The results showed that prenatal caffeine (120 mg/kg.day) ingestion caused low body weight and high IUGR rate of pups; the concentrations of blood adrenocorticotropic hormone (ACTH) and corticosterone in caffeine group were significantly increased in the early postnatal period followed by falling in late stage; the level of blood glucose was unchanged, while blood total cholesterol (TCH) and triglyceride (TG) were markedly enhanced in adult. After chronic stress, the concentrations and the gain rates of blood ACTH and corticosterone were obviously increased, meanwhile, the blood glucose increased while the TCH and TG decreased in caffeine group. Further, the hippocampal mineralocorticoid receptor (MR) expression in caffeine group was initially decreased and subsequently increased after birth. After chronic stress, the 11β-hydroxysteroid dehydrogenase-1, glucocorticoid receptor (GR), MR as well as the MR/GR ratio were all significantly decreased. These results suggested that prenatal caffeine ingestion induced the dysfunction of HPA axis and associated neuroendocrine metabolic programmed alteration in IUGR offspring rats, which might be related with the functional injury of hippocampus. These observations provide a valuable experimental basis for explaining the susceptibility of IUGR offspring to metabolic syndrome and associated diseases. Copyright © 2012 Elsevier Inc. All rights reserved.

  7. Common marmosets (Callithrix jacchus) as a potential animal model for studying psychological disorders associated with high and low responsiveness of the hypothalamic-pituitary-adrenal axis.

    PubMed

    Galvão-Coelho, Nicole L; Silva, Hélderes Peregrino A; Leão, Adriano de Castro; de Sousa, Maria Bernardete Cordeiro

    2008-01-01

    Social non-human primates are potential animal models for studying changes in social dynamics because they build strong emotional bonds inside the group, much as do humans. The common marmoset, a small neotropical primate, is a suitable model because of its low maintenance cost and high reproductive output in captivity associated with the presence of affiliative relationships among the members of the social group and pair bond formation. The paradigm of involuntary separation is frequently used to study the physiological repercussions of social deprivation. In this review we point out the advantages of using social non-human primates as animal models for studying psychological disorders. We focused on New World primates, adding some original findings for common marmosets. Forty-eight adult individuals (24 females) were monitored over 25 days in two situations: baseline phase and separation phase. Variability in basal cortisol levels was recorded for both males and females, and three types of cortisol profile were drawn for the subjects in this population: high, medium and low. Basal cortisol levels were a predictor of hormonal reactivity to social separation. The animals with low and high cortisol levels were hyper- and hyporeactive to separation, respectively. Significant positive correlations between hormonal reactivity and scent-marking behavior were found for low profile males and females. These findings show that common marmosets display behavioral changes during challenging situations and different cortisol profiles within a population. Thus, this species appears to be a suitable animal model for studying mental disorders associated with high and low responsiveness of the hypothalamic-pituitary-adrenal axis.

  8. Immediate and prolonged effects of alcohol exposure on the activity of the hypothalamic-pituitary-adrenal axis in adult and adolescent rats

    PubMed Central

    ALLEN, Camryn D.; LEE, Soon; KOOB, George F.; RIVIER, Catherine

    2011-01-01

    Alcohol stimulates the hypothalamic-pituitary-adrenal (HPA) axis. Part of this influence is likely exerted directly at the level of the corticotropin-releasing factor (CRF) gene, but intermediates may also play a role. Here we review the effect of alcohol on this axis, provide new data on the effects of binge drinking during adolescence, and argue for a role of catecholaminergic circuits. Indeed, acute injection of this drug activates brain stem adrenergic and noradrenergic circuits, and their lesion, or blockade of α1 adrenergic receptors significantly blunts alcohol-induced ACTH release. As alcohol can influence the HPA axis even once discontinued, and alcohol consumption in young people is associated with increased adult drug abuse (a phenomenon possibly mediated by the HPA axis), we determined whether alcohol consumption during adolescence modified this axis. The number of CRF-immunoreactive (ir) cells/section was significantly decreased in the central nucleus of the amygdala of adolescent self-administering binge-drinking animals, compared to controls. When another group of adolescent binge-drinking rats was administered alcohol in adulthood, the number of colocalized c-fos-ir and PNMT-ir cells/brain stem section in the C3 area was significantly decreased, compared to controls. As the HPA axis response to alcohol is blunted in adult rats exposed to alcohol vapors during adolescence, a phenomenon which was not observed in our model of self-administration, it is possible that the blood alcohol levels achieved in various models play a role in the long-term consequences of exposure to alcohol early in life. Collectively, these results suggest an important role of brain catecholamines in modulating the short- and long-term consequences of alcohol administration. PMID:21300146

  9. Frequent cellular phone use modifies hypothalamic-pituitary-adrenal axis response to a cellular phone call after mental stress in healthy children and adolescents: A pilot study.

    PubMed

    Geronikolou, Styliani A; Chamakou, Aikaterini; Mantzou, Aimilia; Chrousos, George; Kanaka--Gantenbein, Christina

    2015-12-01

    The hypothalamic-pituitary-adrenal (HPA) axis is the main "gate-keeper" of the organism's response to every somatic or mental stress. This prospective study aims to investigate the HPA-axis response to a cellular phone call exposure after mental stress in healthy children and adolescents and to assess the possible predictive role of baseline endocrine markers to this response. Two groups of healthy school-age children aged 11-14 (12.5±1.5) years were included in the study, the one comprising those who are occasional users of a cellular phone (Group A) while the second those who do regularly use one (Group B). Blood samples were obtained from all participants at 8.00 am after a 12-hour overnight fasting for thyroid hormone, glucose, insulin, and cortisol levels determination. The participants performed the Trier Social Stress Test for Children (TSST-C) (5 minoral task followed by 5 min arithmetic task). Salivary cortisol samples were obtained at baseline, 10' and 20' min after the TSST-C and 10' and 20' after a 5 minute cellular phone call. Significant changes in the salivary cortisol levels were noted between 10' and 20' mins after the cellular phone call with different responses between the two groups. Baseline thyroid hormone levels seem to predict the cortisol response to mental stress mainly in group A, while HOMA had no impact on salivary cortisol response at any phase of the test, in either group. HPA axis response to cellular phone after mental stress in children and adolescents follow a different pattern in frequent users than in occasional users that seems to be influenced by the baseline thyroid hormone levels. Copyright © 2015 Elsevier B.V. All rights reserved.

  10. Psychological and physiological responses to stress: the right hemisphere and the hypothalamo-pituitary-adrenal axis, an inquiry into problems of human bonding.

    PubMed

    Henry, J P

    1997-01-01

    In addition to repeated reexperiencing of the event, the delayed effects of severe psychological trauma, i.e., post traumatic stress disorder (PTSD), present a paradoxical mix of symptoms. There is enhancement of the self-preservative catecholamine states; anger and fear with a contrasting sense of meaninglessness and blunting of the emotional responses of the attachment behavior so critical for species preservation. Hormonally, there is a striking separation of the catecholamine response, which stays elevated and that of the hypothalamo-pituitary-adrenal (HPA) axis, which may remain at normal levels. Pathophysiologically, the reexperienceing of the trauma and the arousal may be associated with dysfunction of the locus coeruleus, amygdala and hippocampal systems. This article explores the consequences of an additional dysfunction: a dissociation of the hemispheres that appears to be responsible for the alexithymic avoidance and failure of the cortisol response that so often follow severe psychological trauma. There is neurophysiological evidence that the left the right hemispheres subserve different emotional sets that correspond to "control" and "appraisal," i.e., very approximately to the self and species preservative behavioral complexes, respectively. Several studies point to physiological dissociation of hemispheric functions during alexithymia. This raises the question: What has been lost if in this condition the right side no longer fully contributes to integrated cerebral function? Right hemispheric damaged children lose critical social skills and in adults the related sense of familiarity critical for bonding is lost. Such losses of social sensibilities may account for the lack of empathy and difficulties with bonding found in sociopathy and borderline personality: conditions now believed to result from repeated psychological trauma during development. On the other hand, systems that promote right hemispheric contributions provide solacing access to a

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

    PubMed

    van Liempt, Saskia; Arends, Johan; Cluitmans, Pierre J M; Westenberg, Herman G M; Kahn, René S; Vermetten, Eric

    2013-01-01

    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. Copyright © 2012 Elsevier Ltd. All rights reserved.

  12. Acute oral administration of the novel, competitive and selective glucocorticoid receptor antagonist ORG 34517 reduces the severity of ethanol withdrawal and related hypothalamic- pituitary-adrenal axis activation

    PubMed Central

    Reynolds, Anna R.; Saunders, Meredith A.; Brewton, Honoree’ W.; Winchester, Sydney R.; Elgumati, Ibrahim S.; Prendergast, Mark A.

    2015-01-01

    Background The development of ethanol dependence is associated with alterations in hypothalamic-pituitary-adrenal (HPA) axis and activation of type II glucocorticoid receptors (GR). These effects may contribute to withdrawal-associated anxiety, craving and relapse to drinking. The present studies examined acute and oral administration of the novel, selective and competitive GR antagonist ORG 34517 on the severity of ethanol withdrawal. Methods Adult, male Sprague-Dawley rats were administered ethanol (4g/kg/i.g.) twice daily for 5 days followed by 2 days of withdrawal for 1, 2 or 3 consecutive cycles. Blood ethanol levels (BELs) were determined at 0930 on Day 4 of each week, while blood corticosterone levels (BCLs) were obtained at 1100 hrs on the first day of each ethanol withdrawal. During early withdrawal, subjects received oral administration of ORG 345617 (60 mg/kg/i.g.) or a placebo and withdrawal was monitored. Results Peak BELs of 225.52 mg/dl were observed during the third week. Withdrawal from three cycles of the regimen produced marked behavioral abnormalities (e.g. aggression, rigidity, and hypoactivity) and significant increases in BCLs of ethanol-dependent subjects. Acute, oral administration of ORG 34517 during early withdrawal significantly reduced both the severity of ethanol withdrawal, as reflected in reduced rigidity, aggression, and hypoactivity, and elevations in BCL without producing any sedative-like effects. Conclusions The present findings demonstrate that repeated ethanol exposure and withdrawal is associated with significant behavioral abnormalities and dysregulation of HPA axis activation. Further these data suggest that selective GR antagonists should be further considered as putative pharmacotherapies for treatment of ethanol dependence. PMID:26143299

  13. Adaptation of the pituitary-adrenal axis to daily repeated forced swim exposure in rats is dependent on the temperature of water.

    PubMed

    Rabasa, Cristina; Delgado-Morales, Raúl; Gómez-Román, Almudena; Nadal, Roser; Armario, Antonio

    2013-11-01

    Comparison of exposure to certain predominantly emotional stressors reveals a qualitatively similar neuroendocrine response profile as well as a reduction of physiological responses after daily repeated exposure (adaptation). However, particular physical components of the stressor may interfere with adaptation. As defective adaptation to stress can enhance the probability to develop pathologies, we studied in adult male rats (n = 10/group) swimming behavior (struggling, immobility and mild swim) and physiological responses (ACTH, corticosterone and rectal temperature) to daily repeated exposure to forced swim (20 min, 13 d) at 25 or 36 °C (swim25 or swim36). Rats were repeatedly blood-sampled by tail-nick and hormones measured by radioimmunoassay. Some differences were observed between the two swim temperature groups after the first exposure to forced swim: (a) active behaviors were greater in swim25 than swim36 groups; (b) swim25 but not swim36 caused hypothermia; and (c) swim36 elicited the same ACTH response as swim25, but plasma corticosterone concentration was lower for swim36 at 30 min post-swim. After daily repeated exposure, adaptation in ACTH secretion was observed with swim36 already on day 4, whereas with swim25 adaptation was not observed until day 13 and was of lower magnitude. Nevertheless, after repeated exposure to swim25 a partial protection from hypothermia was observed and the two swim conditions resulted in progressive reduction of active behaviors. Thus, daily repeated swim at 25 °C impairs adaptation of the hypothalamic-pituitary-adrenal axis as compared to swim at 36 °C, supporting the hypothesis that certain physical components of predominantly emotional stressors can interfere with the process of adaptation.

  14. Neonatal vaginal irritation results in long-term visceral and somatic hypersensitivity and increased hypothalamic-pituitary-adrenal axis output in female mice.

    PubMed

    Pierce, Angela N; Zhang, Zhen; Fuentes, Isabella M; Wang, Ruipeng; Ryals, Janelle M; Christianson, Julie A

    2015-10-01

    Experiencing early life stress or injury increases a woman's likelihood of developing vulvodynia and concomitant dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. To investigate the outcome of neonatal vaginal irritation (NVI), female mouse pups were administered intravaginal zymosan on postnatal days 8 and 10 and were assessed as adults for vaginal hypersensitivity by measuring the visceromotor response to vaginal balloon distension (VBD). Western blotting and calcium imaging were performed to measure transient receptor potential ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1) in the vagina and innervating primary sensory neurons. Serum corticosterone (CORT), mast cell degranulation, and corticotropin-releasing factor receptor 1 (CRF1) expression were measured as indicators of peripheral HPA axis activation. Colorectal and hind paw sensitivity were measured to determine cross-sensitization resulting from NVI. Adult NVI mice had significantly larger visceromotor response during VBD than naive mice. TRPA1 protein expression was significantly elevated in the vagina, and calcium transients evoked by mustard oil (TRPA1 ligand) or capsaicin (TRPV1 ligand) were significantly decreased in dorsal root ganglion from NVI mice, despite displaying increased depolarization-evoked calcium transients. Serum CORT, vaginal mast cell degranulation, and CRF1 protein expression were all significantly increased in NVI mice, as were colorectal and hind paw mechanical and thermal sensitivity. Neonatal treatment with a CRF1 antagonist, NBI 35965, immediately before zymosan administration largely attenuated many of the effects of NVI. These results suggest that NVI produces chronic hypersensitivity of the vagina, as well as of adjacent visceral and distant somatic structures, driven in part by increased HPA axis activation.

  15. Maternal hypothalamic-pituitary-adrenal axis response to foraging uncertainty: A model of individual vs. social allostasis and the "Superorganism Hypothesis".

    PubMed

    Coplan, Jeremy D; Gupta, Nishant K; Karim, Asif; Rozenboym, Anna; Smith, Eric L P; Kral, John G; Rosenblum, Leonard A

    2017-01-01

    Food insecurity is a major global contributor to developmental origins of adult disease. The allostatic load of maternal food uncertainty from variable foraging demand (VFD) activates corticotropin-releasing factor (CRF) without eliciting hypothalamic-pituitary-adrenal (HPA) activation measured on a group level. Individual homeostatic adaptations of the HPA axis may subserve second-order homeostasis, a process we provisionally term "social allostasis." We postulate that maternal food insecurity induces a "superorganism" state through coordination of individual HPA axis response. Twenty-four socially-housed bonnet macaque maternal-infant dyads were exposed to 16 weeks of alternating two-week epochs of low or high foraging demand shown to compromise normative maternal-infant rearing. Cerebrospinal fluid (CSF) CRF concentrations and plasma cortisol were measured pre- and post-VFD. Dyadic distance was measured, and blinded observers performed pre-VFD social ranking assessments. Despite marked individual cortisol responses (mean change = 20%) there was an absence of maternal HPA axis group mean response to VFD (0%). Whereas individual CSF CRF concentrations change = 56%, group mean did increase 25% (p = 0.002). Our "dyadic vulnerability" index (low infant weight, low maternal weight, subordinate maternal social status and reduced dyadic distance) predicted maternal cortisol decreases (p < 0.0001) whereas relatively "advantaged" dyads exhibited maternal cortisol increases in response to VFD exposure. In response to a chronic stressor, relative dyadic vulnerability plays a significant role in determining the directionality and magnitude of individual maternal HPA axis responses in the service of maintaining a "superorganism" version of HPA axis homeostasis, provisionally termed "social allostasis."

  16. Cortisol reactivity and suicidal behavior: Investigating the role of hypothalamic-pituitary-adrenal axis responses to stress in suicide attempters and ideators.

    PubMed

    O'Connor, Daryl B; Green, Jessica A; Ferguson, Eamonn; O'Carroll, Ronan E; O'Connor, Rory C

    2017-01-01

    Every 40s a person dies by suicide somewhere in the world. The causes of suicidal behavior are not fully understood. Dysregulated hypothalamic-pituitary-adrenal (HPA) axis activity, as measured by cortisol levels, is one potential risk factor. The current study aimed to investigate whether cortisol reactivity to a laboratory stress task differentiated individuals who had previously made a suicide attempt from those who had thought about suicide (suicide ideators) and control participants. One hundred and sixty participants were recruited to a previous attempt, a suicidal ideation or a control group. Participants completed background questionnaires before completing the Maastricht Acute Stress Test (MAST). Cortisol levels were assessed throughout the stress task. Measures of suicide behavior were measured at baseline, 1 month and 6 month follow-up. Participants who had made a previous suicide attempt exhibited significantly lower aggregate cortisol levels during the MAST compared to participants in the control group; suicide ideators were intermediate to both groups. This effect, however, was driven by participants who made an attempt within the past year, and to some degree by those with a family history of attempt. Participants who made a suicide attempt and had a family history of suicide exhibited the lowest levels of cortisol in response to stress. Finally, lower levels of cortisol in response to the MAST were associated with higher levels of suicidal ideation at 1-month follow-up in the suicide attempter group. These results are consistent with other findings indicating that blunted HPA axis activity is associated with some forms of suicidal behavior. The challenge for researchers is to elucidate the precise causal mechanisms linking stress, cortisol and suicide risk.

  17. Saturated high-fat feeding independent of obesity alters hypothalamus-pituitary-adrenal axis function but not anxiety-like behaviour.

    PubMed

    Hryhorczuk, Cecile; Décarie-Spain, Léa; Sharma, Sandeep; Daneault, Caroline; Rosiers, Christine Des; Alquier, Thierry; Fulton, Stephanie

    2017-09-01

    Overconsumption of dietary fat can elicit impairments in emotional processes and the response to stress. While excess dietary lipids have been shown to alter hypothalamus-pituitary-adrenal (HPA) axis function and promote anxiety-like behaviour, it is not known if such changes rely on elevated body weight and if these effects are specific to the type of dietary fat. The objective of this study was to investigate the effect of a saturated and a monounsaturated high-fat diet (HFD) on HPA axis function and anxiety-like behaviour in rats. Biochemical, metabolic and behavioural responses were evaluated following eight weeks on one of three diets: (1) a monounsaturated HFD (50%kcal olive oil), (2) a saturated HFD (50%kcal palm oil), or (3) a control low-fat diet. Weight gain was similar across the three diets while visceral fat mass was elevated by the two HFDs. The saturated HFD had specific actions to increase peak plasma levels of corticosterone and tumour-necrosis-factor-alpha and suppress mRNA expression of glucocorticoid and mineralocorticoid receptors, corticotropin-releasing hormone and 11β-hydroxysteroid dehydrogenase-1 in the paraventricular nucleus of the hypothalamus. Both HFDs enhanced the corticosterone-suppressing response to dexamethasone administration without affecting the physiological response to a restraint stress and failed to increase anxiety-like behaviour as measured in the elevated-plus maze and open field tests. These findings demonstrate that prolonged intake of saturated fat, without added weight gain, increases CORT and modulates central HPA feedback processes. That saturated HFD failed to affect anxiety-like behaviour can suggest that the anxiogenic effects of prolonged high-fat feeding may rely on more pronounced metabolic dysfunction. Copyright © 2017 Elsevier Ltd. All rights reserved.

  18. Sex differences in early-life programming of the hypothalamic-pituitary-adrenal axis in humans suggest increased vulnerability in females: a systematic review.

    PubMed

    Carpenter, T; Grecian, S M; Reynolds, R M

    2017-04-01

    Fetal glucocorticoid overexposure is a key mechanism linking early development with later-life disease. In humans, low birth weight associates with increased fasting cortisol, hypothalamic-pituitary-adrenal (HPA) axis reactivity, and with cardiovascular risk and cognitive decline. As there are sex differences in these adult diseases, we hypothesized that there may be sex differences in programming of the HPA axis in response to prenatal stressors. We conducted a systematic review following Meta-Analysis of Observational Studies in Epidemiology and Preferred Reporting Items for Systematic Reviews and Meta-Analysis. We searched Embase, MEDLINE and Web of Science from inception to 31 October 2016. We included studies related to sex differences, prenatal exposures and HPA axis. We excluded studies investigating specific disease states. The 23 included studies investigated the consequences of low birth weight, preterm birth and maternal stressors of asthma, psychosocial stress and glucocorticoid medications on HPA axis outcomes of placental glucocorticoid biology and offspring HPA axis function in early life and later life. Female offspring exposed to stressors had increased HPA axis reactivity compared with males. Furthermore, the female placenta increased its permeability to maternal glucocorticoids following maternal stress with changes in the expression of 11β-hydroxysteroid dehydrogenase enzymes in response to maternal glucocorticoid exposure or asthma. Among males there was some evidence of altered diurnal cortisol secretion. We conclude that although there is some evidence of male vulnerability leading to altered diurnal cortisol secretion, the female HPA axis is more vulnerable to programming, particularly in terms of its reactivity; this suggests a mechanism underlying sex differences in later-life diseases.

  19. The cochlea as an independent neuroendocrine organ: expression and possible roles of a local hypothalamic-pituitary-adrenal axis-equivalent signaling system.

    PubMed

    Basappa, Johnvesly; Graham, Christine E; Turcan, Sevin; Vetter, Douglas E

    2012-06-01

    A key property possessed by the mammalian cochlea is its ability to dynamically alter its own sensitivity. Because hair cells and ganglion cells are prone to damage following exposure to loud sound, extant mechanisms limiting cochlear damage include modulation involving both the mechanical (via outer hair cell motility) and neural signaling (via inner hair cell-ganglion cell synapses) steps of peripheral auditory processing. Feedback systems such as that embodied by the olivocochlear system can alter sensitivity, but respond only after stimulus encoding, allowing potentially damaging sounds to impact the inner ear before sensitivity is adjusted. Less well characterized are potential cellular signaling systems involved in protection against metabolic stress and resultant damage. Although pharmacological manipulation of the olivocochlear system may hold some promise for attenuating cochlear damage, targeting this system may still allow damage to occur that does not depend on a fully functional feedback loop for its mitigation. Thus, understanding endogenous cell signaling systems involved in cochlear protection may lead to new strategies and therapies for prevention of cochlear damage and consequent hearing loss. We have recently discovered a novel cochlear signaling system that is molecularly equivalent to the classic hypothalamic-pituitary-adrenal (HPA) axis. This cochlear HPA-equivalent system functions to balance auditory sensitivity and susceptibility to noise-induced hearing loss, and also protects against cellular metabolic insults resulting from exposures to ototoxic drugs. This system may represent a local cellular response system designed to mitigate damage arising from various types of insult. Copyright © 2012 Elsevier B.V. All rights reserved.

  20. Influence of the hypothalamic-pituitary-adrenal axis dysregulation on the metabolic profile of patients affected by diabetes mellitus-associated late onset hypogonadism.

    PubMed

    Tirabassi, G; Chelli, F M; Ciommi, M; Lenzi, A; Balercia, G

    2016-01-01

    Functional hypercortisolism (FH) is generated by clinical states able to chronically activate the hypothalamic-pituitary-adrenal (HPA) axis [e.g. diabetes mellitus (DM)]. No study has evaluated FH influence in worsening the metabolic profile of male patients affected by DM-associated hypogonadism. In this retrospective work, we assess the possible association between HPA axis-dysregulation and cardiovascular risk factors in men simultaneously affected by DM and late-onset hypogonadism (LOH). Fourteen DM and LOH subjects affected by FH (Hypercort-DM-LOH) and fourteen DM and LOH subjects who were not suffering from FH (Normocort-DM-LOH) were retrospectively considered. Clinical, hormonal and metabolic parameters were retrieved. All metabolic parameters, except for systolic blood pressure, were significantly worse in Hypercort-DM-LOH than in Normocort-DM-LOH. After adjustment for body mass index, waist and total testosterone, Hypercort-DM-LOH subjects showed significantly worse metabolic parameters than Normocort-DM-LOH ones. In Normocort-DM-LOH, no significant correlation between general/hormonal parameters and metabolic variables was present. In Hypercort-DM-LOH, positive and significant correlations of cortisol area under the curve (AUC) after corticotropin releasing hormone with glycemia, triglycerides and blood pressure were evident; on the other hand, negative and significant correlation was present between cortisol AUC and high density lipoprotein (HDL) cholesterol. The associations of AUC cortisol with glycemia, HDL cholesterol and diastolic blood pressure (DBP) were further confirmed at quantile regression after adjustment for therapy. FH may determine a worsening of the metabolic profile in DM-associated hypogonadism. Copyright © 2015 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by

  1. Differences in cardiovascular and hypothalamic-pituitary-adrenal axis functions between high-altitude visitors and natives during a trek on the Annapurna circuit.

    PubMed

    Park, Jai Y; Hwang, Tae K; Park, Hyun K; Ahn, Ryun S

    2014-01-01

    Differences in the cardiovascular and hypothalamic-pituitary-adrenal (HPA) axis functions at high altitudes (HAs) between visitors to and natives of HA were examined. The cardiovascular functions and peripheral oxygen saturation (SPO2) were monitored, and the cortisol awakening response (CAR) and nighttime cortisol concentration (NCC), as indices of the HPA axis function, were determined in 25 trekkers and 21 Sherpas during an Annapurna circuit trek. SPO2 decreased less in the Sherpas than in the trekkers at HAs (3,540, 3,800, and 4,800 m). Blood pressure and heart rate in the Sherpas changed concurrently during the trek; however, a tachycardic response occurred without changes in blood pressure in the trekkers at HAs. The CAR and NCC at HAs in the trekkers differed from those observed at 1,100 m and those observed at HAs in the Sherpas. The trekkers exhibited an elevated morning cortisol level at 3,540 and 3,800 m, a heightened CAR at 4,800 m, and an elevated NCC at 3,800 m. Alteration of the CAR resulted in an increase in the integrated volume of cortisol released within the first hour after awakening (CARauc) in the trekkers. The changes in SPO2 occurred concurrently with the changes in the CARauc and the heart rate in the trekkers. The alterations of CAR occurred at HAs where blood pressure levels reached a peak plateau, which is associated with an increase in heart rate at HAs in the trekkers. The CAR was unaltered in the Sherpas during the trek. © 2014 S. Karger AG, Basel.

  2. Longitudinal Evaluation of the Hypothalamic-Pituitary-Testicular Function in 8 Boys with Adrenal Hypoplasia Congenita (AHC) Due to NR0B1 Mutations

    PubMed Central

    Galeotti, Caroline; Lahlou, Zineb; Goullon, Domitille; Sarda-Thibault, Hélène; Cahen-Varsaux, Juliette; Bignon-Topalovic, Joëlle; Bashamboo, Anu; McElreavey, Ken; Brauner, Raja

    2012-01-01

    Background Boys carrying mutations in the NR0B1 gene develop adrenal hypoplasia congenita (AHC) and impaired sexual development due to the combination of hypogonadotropic hypogonadism (HH) and primary defects in spermatogenesis. Methods We analysed the evolution of hypothalamic-pituitary-testicular function of 8 boys with AHC due to NR0B1 mutations. Our objective was to characterize and monitor the progressive deterioration of this function. Results The first symptoms appeared in the neonatal period (n = 5) or between 6 months and 8.7 years (n = 3). Basal plasma adrenocorticotrophic hormone (ACTH) concentrations increased in all boys, whilst cortisol levels decreased in one case. The natremia was equal or below 134 mmol/L and kaliemia was over 5 mmol/L. All had increased plasma renin. In 3 of 4 patients diagnosed in the neonatal period and evaluated during the first year, the basal plasma gonadotropins concentrations, and their response to gonadotropin releasing hormone (GnRH) test (n = 2), and those of testosterone were normal. The plasma inhibin B levels were normal in the first year of life. With the exception of two cases these concentrations decreased to below the normal for age. Anti-Müllerian hormone concentrations were normal for age in all except one case, which had low concentrations before the initiation of testosterone treatment. In 3 of the 8 cases the gene was deleted and the remaining 5 cases carried frameshift mutations that are predicted to introduce a downstream nonsense mutation resulting in a truncated protein. Conclusions The decreases in testosterone and inhibin B levels indicated a progressive loss of testicular function in boys carrying NR0B1 mutations. These non-invasive examinations can help to estimate the age of the testicular degradation and cryopreservation of semen may be considered in these cases as investigational procedure with the aim of restoring fertility. PMID:22761912

  3. A single exposure to an acute stressor has lasting consequences for the hypothalamo-pituitary-adrenal response to stress in free-living birds.

    PubMed

    Lynn, Sharon E; Prince, Leslie E; Phillips, Megan M

    2010-01-15

    In vertebrates, activation of the hypothalamo-pituitary-adrenal (HPA) axis in response to unpredictable events results in elevated glucocorticoid secretion. Repeated exposure to stressors alters subsequent glucocorticoid secretion, either by inducing chronic stress or as a result of habituation. However, most studies of repeated stress focus on the impacts of multiple and frequent exposures to acute stressors, and few have been carried out in free-living animals. We investigated whether a single exposure to a novel stressor was sufficient to produce long-lasting alterations in HPA function in free-living eastern bluebirds (Sialia sialis). We subjected adult females to a capture/restraint protocol in which we collected serial blood samples over an hour of restraint to be analyzed for corticosterone. We administered this protocol to three groups of females during the nestling phase of their first and/or second brood of the season: Repeaters (sampled during brood 1 and brood 2), Naïve-Brood 1 (sampled only during brood 1), and Naïve-Brood 2 (sampled only during brood 2). Repeaters had attenuated corticosterone responses to the second restraint bout compared to the first, and in brood 2, Repeaters had lower responses than Naïve-Brood 2 females. However, Naïve-Brood 1 and Naïve-Brood 2 birds did not differ in their responses to restraint. Thus, as little as one prior experience with an acute stressor was sufficient to alter subsequent HPA responsiveness, and this effect was not due to a natural change in HPA responsiveness as the breeding season progressed. These data may have important implications for understanding how acute stressors can alter a free-living animal's ability to cope in the face of subsequent stressors, and for longitudinal field studies in which individuals are repeatedly sampled for glucocorticoid responsiveness.

  4. Immediate and prolonged effects of alcohol exposure on the activity of the hypothalamic-pituitary-adrenal axis in adult and adolescent rats.

    PubMed

    Allen, Camryn D; Lee, Soon; Koob, George F; Rivier, Catherine

    2011-06-01

    Alcohol stimulates the hypothalamic-pituitary-adrenal (HPA) axis. Part of this influence is likely exerted directly at the level of the corticotropin-releasing factor (CRF) gene, but intermediates may also play a role. Here we review the effect of alcohol on this axis, provide new data on the effects of binge drinking during adolescence, and argue for a role of catecholaminergic circuits. Indeed, acute injection of this drug activates brain stem adrenergic and noradrenergic circuits, and their lesion, or blockade of α1 adrenergic receptors significantly blunts alcohol-induced ACTH release. As alcohol can influence the HPA axis even once discontinued, and alcohol consumption in young people is associated with increased adult drug abuse (a phenomenon possibly mediated by the HPA axis), we determined whether alcohol consumption during adolescence modified this axis. The number of CRF-immunoreactive (ir) cells/section was significantly decreased in the central nucleus of the amygdala of adolescent self-administering binge-drinking animals, compared to controls. When another group of adolescent binge-drinking rats was administered alcohol in adulthood, the number of colocalized c-fos-ir and PNMT-ir cells/brain stem section in the C3 area was significantly decreased, compared to controls. As the HPA axis response to alcohol is blunted in adult rats exposed to alcohol vapors during adolescence, a phenomenon which was not observed in our model of self-administration, it is possible that the blood alcohol levels achieved in various models play a role in the long-term consequences of exposure to alcohol early in life. Collectively, these results suggest an important role of brain catecholamines in modulating the short- and long-term consequences of alcohol administration.

  5. Maternal hypothalamic-pituitary-adrenal axis response to foraging uncertainty: A model of individual vs. social allostasis and the "Superorganism Hypothesis"

    PubMed Central

    Coplan, Jeremy D.; Karim, Asif; Rozenboym, Anna; Smith, Eric L. P.; Kral, John G.; Rosenblum, Leonard A.

    2017-01-01

    Introduction Food insecurity is a major global contributor to developmental origins of adult disease. The allostatic load of maternal food uncertainty from variable foraging demand (VFD) activates corticotropin-releasing factor (CRF) without eliciting hypothalamic-pituitary-adrenal (HPA) activation measured on a group level. Individual homeostatic adaptations of the HPA axis may subserve second-order homeostasis, a process we provisionally term “social allostasis.” We postulate that maternal food insecurity induces a “superorganism” state through coordination of individual HPA axis response. Methods Twenty-four socially-housed bonnet macaque maternal-infant dyads were exposed to 16 weeks of alternating two-week epochs of low or high foraging demand shown to compromise normative maternal-infant rearing. Cerebrospinal fluid (CSF) CRF concentrations and plasma cortisol were measured pre- and post-VFD. Dyadic distance was measured, and blinded observers performed pre-VFD social ranking assessments. Results Despite marked individual cortisol responses (mean change = 20%) there was an absence of maternal HPA axis group mean response to VFD (0%). Whereas individual CSF CRF concentrations change = 56%, group mean did increase 25% (p = 0.002). Our "dyadic vulnerability" index (low infant weight, low maternal weight, subordinate maternal social status and reduced dyadic distance) predicted maternal cortisol decreases (p < 0.0001) whereas relatively “advantaged” dyads exhibited maternal cortisol increases in response to VFD exposure. Comment In response to a chronic stressor, relative dyadic vulnerability plays a significant role in determining the directionality and magnitude of individual maternal HPA axis responses in the service of maintaining a “superorganism” version of HPA axis homeostasis, provisionally termed “social allostasis.” PMID:28880949

  6. Effects of early- and late-gestational maternal stress and synthetic glucocorticoid on development of the fetal hypothalamus-pituitary-adrenal axis in sheep.

    PubMed

    Rakers, Florian; Frauendorf, Vilmar; Rupprecht, Sven; Schiffner, Rene; Bischoff, Sabine J; Kiehntopf, Michael; Reinhold, Petra; Witte, Otto W; Schubert, Harald; Schwab, Matthias

    2013-01-01

    Prenatal maternal stress (PMS) programs dysregulation of the hypothalamus-pituitary-adrenal axis (HPAA) in postnatal life, though time periods vulnerable to PMS, are still unclear. We evaluated in pregnant sheep the effect of PMS during early gestation [30-100 days of gestation (dGA); term is 150 dGA] or late gestation (100-120 dGA) on development of fetal HPAA function. We compared the effects of endogenous cortisol with synthetic glucocorticoid (GC) exposure, as used clinically to enhance fetal lung maturation. Pregnant sheep were exposed to repeated isolation stress twice per week for 3 h in a separate box with no visual, tactile, or auditory contact with their flock-mates either during early (n = 7) or late (n = 7) gestation. Additional groups received two courses of betamethasone (BM; n = 7; 2 × 110 μg kg(- 1) body weight, 24 h apart) during late gestation (106/107 and 112/113 dGA, n = 7) or acted as controls (n = 7). Fetal cortisol responses to hypotensive challenge, a physiological fetal stressor, were measured at 112 and 129 dGA, i.e. before and during maturation of the HPAA. Hypotension was induced by fetal infusion of sodium nitroprusside, a potent vasodilator. At 112 dGA, neither PMS nor BM altered fetal cortisol responses. PMS, during early or late gestation, and BM treatment increased fetal cortisol responses at 129 dGA with the greatest increase achieved in stressed early pregnant sheep. Thus, development of the HPAA is vulnerable to inappropriate levels of GCs during long periods of fetal life, whereas early gestation is most vulnerable to PMS.

  7. Blunted hypothalamic-pituitary-adrenal axis and insulin response to psychosocial stress in young adults born preterm at very low birth weight.

    PubMed

    Kaseva, Nina; Wehkalampi, Karoliina; Pyhälä, Riikka; Moltchanova, Elena; Feldt, Kimmo; Pesonen, Anu-Katriina; Heinonen, Kati; Hovi, Petteri; Järvenpää, Anna-Liisa; Andersson, Sture; Eriksson, Johan G; Räikkönen, Katri; Kajantie, Eero

    2014-01-01

    Young adults born preterm at very low birth weight (VLBW, ≤1500 g) have higher levels of cardiovascular risk factors, including impaired glucose regulation, than their term-born peers. This could be mediated through altered hypothalamic-pituitary-adrenal axis (HPAA) response to stress. To compare HPAA, glucose and insulin responses provoked by psychosocial stress in VLBW subjects versus a comparison group of term-born controls. We studied 54 unimpaired young adults, aged 19-27 years, born at VLBW and a comparison group of 40 adults born at term, group-matched for age, sex and birth hospital, from one regional centre in southern Finland. The participants underwent a standardized psychosocial stress test (Trier Social Stress Test, TSST). In conjunction with TSST, we measured salivary cortisol, plasma ACTH, cortisol, glucose and insulin. Data were analysed with mixed-effects model and multiple linear regression analyses. Baseline concentrations for cortisol, ACTH, insulin and glucose were similar in VLBW and comparison groups. During TSST, analysed with mixed-effects model, overall concentrations of plasma cortisol were 17·2% lower (95% CI; 3·5 to 28·9) in the VLBW group. The VLBW group also had lower salivary (P = 0·04) and plasma cortisol (P = 0·02) responses to TSST. Insulin and glucose concentrations correlated with changes in cortisol concentrations. Accordingly, VLBW subjects had 26·5% lower increment in insulin (95% CI; 9·8-40·1). Analyses were adjusted for age, sex, body mass index, hormonal contraception, menstrual cycle phase, time of day and parental education. VLBW adults have lower HPAA responses to psychosocial stress than term-born controls. This is accompanied by a lower insulin response. © 2013 John Wiley & Sons Ltd.

  8. Acute stress-induced sensitization of the pituitary-adrenal response to heterotypic stressors: independence of glucocorticoid release and activation of CRH1 receptors.

    PubMed

    Belda, Xavier; Daviu, Núria; Nadal, Roser; Armario, Antonio

    2012-09-01

    A single exposure to some severe stressors causes sensitization of the hypothalamic-pituitary-adrenal (HPA) response to novel stressors. However, the putative factors involved in stress-induced sensitization are not known. In the present work we studied in adult male rats the possible role of glucocorticoids and CRH type 1 receptor (CRH-R1), using an inhibitor of glucocorticoid synthesis (metyrapone, MET), the glucocorticoid receptor (GR) antagonist RU38486 (mifepristone) and the non-peptide CRH-R1 antagonist R121919. In a first experiment we demonstrated with different doses of MET (40-150 mg/kg) that the highest dose acted as a pharmacological stressor greatly increasing ACTH release and altering the normal circadian pattern of HPA hormones, but no dose affected ACTH responsiveness to a novel environment as assessed 3 days after drug administration. In a second experiment, we found that MET, at a dose (75 mg/kg) that blocked the corticosterone response to immobilization (IMO), did not alter IMO-induced ACTH sensitization. Finally, neither the GR nor the CRH-R1 antagonists blocked IMO-induced ACTH sensitization on the day after IMO. Thus, a high dose of MET, in contrast to IMO, was unable to sensitize the HPA response to a novel environment despite the huge activation of the HPA axis caused by the drug. Neither a moderate dose of MET that markedly reduced corticosterone response to IMO, nor the blockade of GR or CRH-R1 receptors was able to alter stress-induced HPA sensitization. Therefore, stress-induced sensitization is not the mere consequence of a marked HPA activation and does not involve activation of glucocorticoid or CRH-R1 receptors.

  9. Multi-Level Risk Factors for Suicidal Ideation Among at-Risk Adolescent Females: The Role of Hypothalamic-Pituitary-Adrenal Axis Responses to Stress.

    PubMed

    Giletta, Matteo; Calhoun, Casey D; Hastings, Paul D; Rudolph, Karen D; Nock, Matthew K; Prinstein, Mitchell J

    2015-07-01

    Adopting a multi-level approach, this study examined risk factors for adolescent suicidal ideation, with specific attention to (a) hypothalamic-pituitary-adrenal (HPA) axis stress responses and (b) the interplay between HPA-axis and other risk factors from multiple domains (i.e., psychological, interpersonal and biological). Participants were 138 adolescent females (M(age) = 14.13 years, SD = 1.40) at risk for suicidal behaviors. At baseline, lifetime suicidal ideation and a number of risk factors were assessed (i.e., depressive symptoms, impulsiveness, pubertal status and peer stress). Participants were exposed to a psychosocial stress task and HPA-axis responses were assessed by measuring cortisol levels pre- and post-stressor. At 3 months post-baseline, suicidal ideation again was assessed. Using group-based trajectory modeling, three groups of cortisol stress-response patterns were identified (i.e., hyporesponsive, normative, and hyperresponsive). As compared to females in the normative and hyporesponsive group, females in the hyperresponsive group were more likely to report a lifetime history of suicidal ideation at baseline, above and beyond the effects of the other predictors. Moreover, as compared to females in the normative group, females in the hyperresponsive group were at increased risk for reporting suicidal ideation 3 months later, after controlling for prior ideation. No interactions between cortisol group and the other risk factors were significant, with the exception of a non-significant trend between impulsiveness and cortisol group on lifetime suicidal ideation. Findings highlight the importance of HPA-axis responses to acute stressors as a risk factor for suicidal ideation among adolescents.

  10. Alcohol administration attenuates hypothalamic-pituitary-adrenal (HPA) activity in healthy men at low genetic risk for alcoholism, but not in high-risk subjects.

    PubMed

    Mick, Inge; Spring, Konstanze; Uhr, Manfred; Zimmermann, Ulrich S

    2013-09-01

    Acute alcohol challenge studies in rodents and naturalistic observations in drinking alcoholics suggest that alcohol stimulates the hypothalamic-pituitary-adrenal (HPA) system. The literature on respective studies in healthy volunteers is more inconsistent, suggesting differential alcohol effects depending on dosage, recent drinking history, family history of alcoholism and alcohol-induced side effects. These papers and the putative pharmacologic mechanisms underlying alcohol effects on the HPA system are reviewed here and compared with a new study, in which we investigated how secretion of adrenocorticotrophin (ACTH) and cortisol is affected by ingestion of 0.6 g/kg ethanol in 33 young healthy socially drinking males with a paternal history of alcoholism (PHP) versus 30 family history negative (FHN) males. Alcohol and placebo were administered in a 2-day, double-blind, placebo controlled crossover design with randomized administration sequence. After administration of placebo, ACTH and cortisol decreased steadily over 130 minutes. In FHN subjects, secretion of both hormones was even more attenuated after alcohol, resulting in significantly lower levels compared with placebo. In PHP subjects, no alcohol effect on hormone secretion could be detected. The ratio of cortisol to ACTH secretion, each expressed as area under the secretion curve, was significantly increased by alcohol in FHN and PHP participants. These results argue against HPA stimulation being a mechanism that promotes the transition from moderate to dependent drinking. The fact that alcohol-induced HPA suppression was not detected in PHP males is consistent with the general concept that subjects at high risk for alcoholism exhibit less-pronounced alcohol effects. © 2012 The Authors, Addiction Biology © 2012 Society for the Study of Addiction.

  11. Pituitary Apoplexy.

    PubMed

    Briet, Claire; Salenave, Sylvie; Bonneville, Jean-François; Laws, Edward R; Chanson, Philippe

    2015-12-01

    Pituitary apoplexy, a rare clinical syndrome secondary to abrupt hemorrhage or infarction, complicates 2%-12% of pituitary adenomas, especially nonfunctioning tumors. Headache of sudden and severe onset is the main symptom, sometimes associated with visual disturbances or ocular palsy. Signs of meningeal irritation or altered consciousness may complicate the diagnosis. Precipitating factors (increase in intracranial pressure, arterial hypertension, major surgery, anticoagulant therapy or dynamic testing, etc) may be identified. Corticotropic deficiency with adrenal insufficiency may be life threatening if left untreated. Computed tomography or magnetic resonance imaging confirms the diagnosis by revealing a pituitary tumor with hemorrhagic and/or necrotic components. Formerly considered a neurosurgical emergency, pituitary apoplexy always used to be treated surgically. Nowadays, conservative management is increasingly used in selected patients (those without important visual acuity or field defects and with normal consciousness), because successive publications give converging evidence that a wait-and-see approach may also provide excellent outcomes in terms of oculomotor palsy, pituitary function and subsequent tumor growth. However, it must be kept in mind that studies comparing surgical approach and conservative management were retrospective and not controlled.

  12. The effects of cosmic particle radiation on pocket mice aboard Apollo XVII: appendix I. Condition of flight animals on recovery; food intake; observations on hypothalamus, pituitary, and adrenal glands.

    PubMed

    Ordy, J M; Brizzee, K R; Samorajski, T

    1975-04-01

    The rationale for studying certain hypothalamic nuclei and the pituitary and adrenal glands of the pocket mice that flew on Apollo XVII was the need to evaluate the effects of the potentially severe stress on these animals in the foreign environment of flight canister, weightlessness, increased G forces, and other unnatural conditions. Decrease in body weight and variability of food intake were significant among the four flight animals that were recovered alive. The mean nuclear diameter of neurons in the arcuate and ventromedial hypothalamic nuclei did not differ significantly from the values obtained in the control animals. On the other hand, the mean nuclear diameter of neurons in the supraoptic nucleus of the flight mice was significantly greater than in the control groups. Comparisons of the adeno- and neuropypophysis revealed no significant differences among the three groups. Insofar as they were studied, the adrenals were similar in all groups.

  13. Chronic stress adaptation of the nitric oxide synthases and IL-1β levels in brain structures and hypothalamic-pituitary-adrenal axis activity induced by homotypic stress.

    PubMed

    Gadek-Michalska, A; Tadeusz, J; Rachwalska, P; Bugajski, J

    2015-06-01

    β level in response to homotypic stress after 3 days and after 14 days. The present results indicate time-related similarities in the potent alterations in IL-1β and iNOS protein levels in brain structures. Single restraint induced a significant increase of plasma IL-1β level which was abolished by pretreatment with IL-1 receptor antagonist (IL-1Ra). A parallel strong increase of plasma ACTH and corticosterone levels were significantly impaired by IL-1Ra suggesting a marked involvement of stress-induced stimulation of ACTH and corticosterone by IL-1β in single restraint. In repeatedly restrained rats IL-1Ra significantly blunted plasma IL-1β level induced by homotypic stress. A parallel strong increase in plasma ACTH level by homotypic stress was not substantially altered by pretreatment with IL-1Ra in repeatedly stressed rats. Plasma a corticosterone level increased by homotypic stress in rats restrained for 3 and 14 days was not affected by pretreatment with IL-1Ra, but after for 7 days its level was significantly enhanced. These results suggest that repeated stress desensitizes IL-1β-induced stimulatory component in a single restraint stress-induced hypothalamic-pituitary-adrenal (HPA) axis stimulation. A sensitization by homotypic stress of corticosterone response after restraint for 7 days may depend on other stimulatory systems acting within adrenal glands during prolonged stress. Comparative data from the same model of rather mild psychological stress allows for the comparison of functional adaptive changes of NO synthases and IL-1β in brain structures involved in stress regulation. In general, the iNOS system is strongly sensitized by repeated stress for 3 days in prefrontal cortex and hippocampus. Increased plasma IL-1β level by a single restraint stress is significantly involved in ACTH and corticosterone secretion. Repeated stress for 3-14 days reduces this participation of IL-1β in pituitary-adrenal stimulation.

  14. [Influence of interleukin-1 and interleukin-6 on modulation of hypothalamo-pituitary-adrenal axis in pregnancy at term and in spontaneous and oxytocin-induced delivery].

    PubMed

    Ochedalski, Tomasz; Lachowicz, Agnieszka

    2003-10-01

    During the pregnancy the placenta and hypothalamus produce trophic hormones for hypothalamo-pituitary-adrenal axis (HPA), i.e. corticotropin releasing hormone (CRH) and adrenocorticotropin (ACTH). The HPA axis of pregnant women is differentially modulated in comparison to non-pregnant ones. Beside steroids, the influence on CRH release may be modulated by cytokines, especially interleukin 1 (IL-1) and interleukin 6 (IL-6). To evaluate the effects of IL-1 and IL-6 on modulation of HPA axis in pregnancy, we have examined the group of women with spontaneous delivery, and second group consists of women delivered after intravenous oxytocin infusion. All women were at term and in the same pregnancy age. Blood was sampled from a maternal peripheral vein days before labour, during the second stage of labour and on the second postnatal day, the levels of IL-1, IL-6, CRH, ACTH and cortisol were measured. The concentrations of hormones were measured using RIA method. The level of IL-1 before the delivery was significantly higher in the group with oxytocin-induction. CRH concentration before the labour was much higher in the group with spontaneous contractions. The levels of IL-1 and CRH in both groups decreased during the labour and were lowest after the delivery. Concentration of IL-6 did not changed dependently of group and time of blood sampling. Changes in CRH in time concentration did not correlate with changes in ACTH levels. ACTH concentrations were similar in both groups, low before delivery raised during the delivery and low again after labour. Cortisol concentration in spontaneous labour was much lower before delivery in comparison with second examined group, then lowered during and after the delivery. In group with oxytocin induction, cortisol levels raised during the delivery and maintained almost the same level after the labour. The time-changes in IL-1 concentration and ACTH and cortisol levels were similar in shape in group with spontaneous delivery. These

  15. Marked dissociation between hypothalamic-pituitary-adrenal activation and long-term behavioral effects in rats exposed to immobilization or cat odor.

    PubMed

    Muñoz-Abellán, C; Andero, R; Nadal, R; Armario, A

    2008-09-01

    Exposure of rodents to cats or certain cat odors results in long-term behavioral effects reminiscent of enhanced anxiety that have been considered to model post-traumatic stress disorder. However, other severe stressors such as tail-shock or immobilization in wooden boards (IMO) appear to induce shorter lasting changes in anxiety. In addition, there are controversial results regarding the effects of urine/feces odors. In the present work, we studied in two experiments the relationship between the degree of stress experienced by the animals during exposure to IMO, urine odors or fur odors (as assessed by hypothalamic-pituitary-adrenal activation and plasma glucose) and the short- and long-term behavioral consequences. In the first experiment, rats were individually exposed for 15 min to a novel environment (white large cages) containing either clean cat litter (controls) or litter soiled by cats (urine odors). Half of the rats in each condition were left to freely explore the environment whereas the others were subjected to immobilization (IMO) within the cages. Although ACTH, corticosterone and glucose responses to IMO were much stronger than those to the white cages with clean litter or urine odors (which did not differ from each other), no effect of treatments on anxiety-like behavior in the elevated plus-maze (EPM) were found one week later. However, previous IMO exposure did cause sensitization of the ACTH response to the EPM. In the second experiment, the response to white large cages containing either no odor (controls), litter soiled by cats (urine odor) or a cloth impregnated with cat odor (fur odor) was compared. Urine and fur odors elicited similar ACTH and corticosterone responses that were higher than those of controls, but plasma glucose levels were slightly higher in rats exposed to fur odor. When compared to controls, activity was only diminished in the novel cages containing fur odor. Similarly, fur odor-exposed rats, but not those exposed to urine

  16. Hypothalamic-pituitary-adrenal axis and depression symptom effects of an arginine vasopressin type 1B receptor antagonist in a one-week randomized Phase 1b trial.

    PubMed

    Katz, David A; Locke, Charles; Greco, Nicholas; Liu, Wei; Tracy, Katherine A

    2017-03-01

    Arginine vasopressin 1B receptor (V1B) antagonists may have utility for the treatment of major depressive disorder (MDD). The V1B antagonist ABT-436 (N = 31) or matching placebo (N = 20) was administered to MDD subjects for 7 days. The main study objectives were to assess the safety and hypothalamic-pituitary-adrenal axis (HPA) effects of ABT-436 in MDD subjects. MDD symptoms were assessed using the 17-item Hamilton Depression Rating Scale (HAM-D-17) and the subject-rated Mood and Anxiety Symptom Questionnaire (MASQ). The most prevalent safety finding associated with ABT-436 800 mg QD was increased mild-moderate diarrhea (68% v 5%, p < 0.001). Increased nausea (26% v 5%, p < 0.10), decreased systolic blood pressure (3.15-3.44 mmHg, p < 0.10) and increased heart rate (3.42-4.01 bpm, p < 0.05) were also associated with ABT-436 800 mg QD. Basal HPA activity measured by 24-hr urine total glucocorticoids was 25% lower with ABT-436 than placebo (p < 0.001). The reduction was, on average, larger in subjects with higher baseline urine total glucocorticoids. Results on plasma adrenocorticotrophic hormone (ACTH), urine, serum and saliva cortisol, and saliva cortisone also showed basal HPA attenuation with ABT-436. Dynamic HPA activity measured by plasma ACTH and serum cortisol responses to corticotrophin releasing hormone (CRH) were 30-46% lower in ABT-436 subjects (all p < 0.001). Each ABT-436 subject showed response to CRH in or near the baseline range of responses. ABT-436 was associated with more favorable symptom changes on two of five MASQ subscales (estimated effect size 1.47-1.86, p < 0.01) but not on HAM-D-17. The results support further clinical study of the antidepressant potential of ABT-436.

  17. The stimulatory effect of canrenoate, a mineralocorticoid antagonist, on the activity of the hypothalamus-pituitary-adrenal axis is abolished by alprazolam, a benzodiazepine, in humans.

    PubMed

    Grottoli, S; Giordano, R; Maccagno, B; Pellegrino, M; Ghigo, E; Arvat, E

    2002-10-01

    Mineralocorticoid receptors (MR) in the hippocampus play a major role in the control of the hypothalamus-pituitary-adrenal (HPA) axis, mediating the proactive feedback of glucocorticoids in the maintenance of basal activity. Intracerebroventricular and intrahippocampal MR blockade stimulates HPA axis in animals; the systemic administration of mineralocorticoid antagonists enhances spontaneous and CRH-stimulated ACTH and cortisol secretion in humans. Benzodiazepines, namely alprazolam, activate central gamma-aminobutyric acid (GABA)ergic receptors, which are mainly distributed in the hippocampus. Alprazolam has a inhibitory effect on HPA axis either in basal conditions or after central nervous system-mediated stimuli. In humans, alprazolam strongly reduces the corticotroph responsiveness to removal of glucocorticoid feedback by metyrapone. We studied the effect of alprazolam (0.02 mg/kg, orally) on the effect of canrenoate (CAN), an MR antagonist (200 mg as an iv bolus, followed by 200 mg infused in 250 ml saline) or placebo on ACTH, cortisol, and dehydroepiandrosterone (DHEA) secretion in six normal young women (aged 25-32 yr; body mass index, 19-23 kg/m(2)). During placebo, ACTH, cortisol, and DHEA secretion showed a progressive decrease (baseline vs. nadir, mean +/- SEM, from 1830-2400 h, 2.6 +/- 0.3 vs. 1.4 +/- 0.3 pmol/liter, 133.2 +/- 16.4 vs. 46.9 +/- 5.2 nmol/liter, and 22.6 +/- 2.3 vs. 18.6 +/- 2.3 nmol/liter, respectively), although statistical significance was obtained for ACTH and cortisol only (P < 0.05). During CAN treatment, ACTH, cortisol, and DHEA secretion showed a progressive rise, which began at approximately 2100 h and peaked between 2300 and 2400 h (2.9 +/- 0.3 pmol/liter, 172.6 +/- 27.9 nmol/liter, and 45.3 +/- 10.7 nmol/liter, respectively; P < 0.05). Alprazolam abolished the CAN-induced increases in ACTH, cortisol, and DHEA levels (1.8 +/- 0.1 pmol/liter, 59.7 +/- 8.6 nmol/liter, and 19.8 +/- 6.7 nmol/liter; P < 0.05), inducing hormonal

  18. Associations between anthropometrical measurements, body composition, single-nucleotide polymorphisms of the hypothalamus/pituitary/adrenal (HPA) axis and HPA axis functioning.

    PubMed

    Rutters, Femke; Nieuwenhuizen, Arie G; Lemmens, Sofie G T; Bouwman, Freek; Mariman, Edwin; Westerterp-Plantenga, Margriet S

    2011-06-01

    The relationship between hypothalamus/pituitary/adrenal (HPA) axis functioning and (visceral) obesity may be explained by single-nucleotide polymorphisms (SNPs) of the HPA axis. Objective  To investigate the relationship between the HPA axis SNP's 'BclI' in the glucocorticoid receptor gene and C8246T in the POMC gene and anthropometric measurements, body composition, 5-h cortisol concentrations, HPA axis feedback sensitivity, as well as HPA axis feedback sensitivity under stress in men and women. D