Corticotropin-releasing Hormone Challenge Research Articles

High Expression of Adrenal Cortisol Synthases Is Acquired After Intrauterine Inflammation in Periviable Sheep Fetuses.

Intrauterine inflammation, a representative stressor for the fetus, has been shown to alter the hypothalamus-pituitary-adrenal (HPA) axis reactivity in preterm fetuses and increase postnatal cortisol production. However, the mechanism of this alteration has not yet been elucidated. We aimed to clarify the effects of endotoxin-induced intrauterine inflammation on the HPA axis of periviable sheep fetuses. Fetal sheep (0.63 term) were divided into 2 groups: (1) the endotoxin group, in which the endotoxin was injected into the amniotic fluid; and (2) the control group, in which the saline solution was injected instead. A corticotropin-releasing hormone (CRH) challenge test was performed on the third day after injection to evaluate the cortisol-producing capacity of each group. Gene expression levels in the fetal adrenal glands of each group were analyzed by RNA-seq. The cortisol levels were significantly higher in the endotoxin group than in the control group after CRH challenge (P = .02). There were no significant differences in the responsiveness of adrenocorticotropin and cortisone between the 2 groups. Gene expression levels of the following enzymes involved in cortisol synthesis were significantly elevated in the endotoxin group: cytochrome P450 family (CYP) 11 subfamily A member 1 (log2FC 1.75), CYP 17 subfamily A member 1 (log2FC 3.41), 3β-hydroxysteroid dehydrogenase type I (log2FC 1.13), steroidogenic acute regulatory protein (log2FC 1.09), and CYP 21 (log2FC 0.89). Periviable fetuses exposed to inflammation in utero have altered the responsiveness of the HPA axis with increased expression of enzymes involved in cortisol synthesis in the adrenal gland.

Clinical characteristics of patients with unexplainable hypothalamic disorder diagnosed by the corticotropin-releasing hormone challenge test: a retrospective study

The corticotropin-releasing hormone (CRH) challenge test can distinguish the disorders of the hypothalamus from those of the pituitary. However, the pathophysiology of hypothalamic disorder (HD) has not been fully understood. This study aimed to elucidate the clinical characteristics of patients with unexplainable HD, diagnosed by the CRH challenge test. We retrospectively reviewed patients who underwent the CRH challenge test. Patients were categorized into four groups as follows: patients with peak serum cortisol ≥18 μg/dL were assigned to the normal response (NR) group (n = 18), among patients with peak serum cortisol < 18 μg/dL and peak adrenocorticotropic hormone (ACTH) increase ≥two-fold, patients without obvious background pathology were assigned to the unexplainable-HD group (n = 18), whereas patients with obvious background pathology were assigned to the explainable-HD group (n = 38), and patients with peak serum cortisol < 18 μg/dL and peak ACTH increase <two-fold were assigned to the pituitary disorder (PD) group (n = 15). Inter-group comparisons were performed based on clinical characteristics. In the CRH challenge test, the peak plasma ACTH levels were significantly lower in the unexplainable-HD group than in the NR group, despite more than two-fold increase compared to basal levels. The increase in serum cortisol was significantly higher in the unexplainable-HD group than in the explainable-HD and PD groups. Although patients in the unexplainable-HD group showed a clear ACTH response in the insulin tolerance test, some patients had peak serum cortisol levels of < 18 μg/dL. Furthermore, attenuated diurnal variations and low normal levels of urinary free cortisol were observed. Most patients in the unexplainable-HD group were young women with chronic fatigue. However, supplementation with oral hydrocortisone at physiological doses reduced fatigue only in some patients. Patients with unexplainable HD diagnosed by the CRH challenge test had hypothalamic-pituitary-adrenal (HPA) axis dysfunction and some patients had mild central adrenal insufficiency. Hydrocortisone supplementation reduced fatigue only in some patients, suggesting that HPA axis dysfunction may be a physiological adaptation. Further investigation of these patients may help elucidate the pathophysiology of myalgic encephalitis/chronic fatigue syndrome.

Corticotropin-releasing hormone and dopamine release in healthy individuals

Corticotropin-releasing hormone (CRH) is a key component of the neuroendocrine response to stress. In animal models, CRH has been shown to modulate dopamine release, and this interaction is believed to contribute to stress-induced relapse in neuropsychiatric disorders. Here we investigated whether CRH administration induces dopamine release in humans, using positron emission tomography (PET). Eight healthy volunteers (5 female, 22–48 years old) completed two PET scans with the dopamine D2/3 receptor radioligand [11C]-(+)-PHNO: once after saline injection, and once after injection of corticorelin (synthetic human CRH). We also assessed subjective reports and measured plasma levels of endocrine hormones (adrenocorticotropic hormone and cortisol). Relative to saline, corticorelin administration decreased binding of the D2/3 PET probe [11C]-(+)-PHNO, suggesting dopamine release. Endocrine stress markers were also elevated, in line with activation of the hypothalamic-pituitary-adrenal axis, but we detected no changes in subjective ratings. Preliminary results from this proof-of-concept study suggests that CRH challenge in combination with [11C]-(+)-PHNO PET may serve as an assay of dopamine release, presenting a potential platform for evaluating CRH/dopamine interactions in neuropsychiatric disorders and CRH antagonists as potential treatment avenues.

Endocrine and hematological responses of beef heifers divergently ranked for residual feed intake following a bovine corticotropin-releasing hormone challenge.

The objective of this study was to determine if beef heifers divergently ranked on phenotypic residual feed intake (RFI) differed in their physiological stress response to an exogenous bovine corticotropin-releasing hormone (bCRH) challenge. Yearling Limousin × Friesian heifers ( = 86) were ranked by RFI. The 15 highest (mean 0.66 kg DM/d; high RFI) and 15 lowest (mean -0.72 kg DM/d; low RFI) ranking animals were used for this study. During the study period, heifers (mean age 485 ± 13 d; mean BW 408 ± 31.4 kg) were housed in a slatted-floor facility. To facilitate intensive blood collection, heifers were fitted aseptically with indwelling jugular catheters. All heifers received dexamethasone (DEX; 20 µg/kg BW i.m.) 12 h before the bCRH challenge (d 0). Heparinized blood samples were collected at -60 and 0 min before administration of DEX, and 12 h after DEX administration. Following DEX administration, cortisol and dehydroepiandrosterone (DHEA) concentrations similarly decreased ( ≥ 0.22) between high and low RFI groups. The response of the HPA axis to a standardized dose of bCRH (0.3 μg/kg BW) was examined. On d 0, serial blood samples were collected at -20, 0, 20, 40, 60, 80, 100, 120, 150, 180, 210, 240, 270, 330, and 390 min relative to the time of bCRH administration (0 min) and were analyzed for plasma cortisol and DHEA concentrations. Blood hematology variables were also determined at -20, 0, 20, 80, 150, 270, 330, and 390 min relative to bCRH administration. Neither an RFI × sampling time interaction nor a direct effect of RFI were detected ( ≥ 0.36) for plasma cortisol, DHEA concentrations, or cortisol:DHEA ratio. An effect of sample time was observed for cortisol ( < 0.001), DHEA ( = 0.04), and cortisol:DHEA ( = 0.02), with cortisol concentration peaking at 60 min post-CRH administration. The maximum concentration and rate of change in cortisol and DHEA concentrations following bCRH administration were not different ( ≥ 0.20) between the high and low RFI phenotypes. Similarly, an effect of RFI was not evident ( ≥ 0.16) for any of the hematology variables examined including neutrophil, lymphocyte, and leukocytes counts; white and red blood cell numbers; and hemoglobin concentrations. Our results suggest that responsiveness of the HPA to stress, at least at the level of the anterior pituitary gland, is not a significant contributor to variation in RFI among growing beef heifers.

Interferon-alpha-induced inflammation is associated with reduced glucocorticoid negative feedback sensitivity and depression in patients with hepatitis C virus

Major medical illnesses are associated with increased risk for depression and alterations in hypothalamic–pituitary–adrenal (HPA) axis function. Pathophysiological processes such as inflammation that occur as a part of medical illnesses and their treatments have been shown to cause depressive symptoms, and may also affect the HPA axis. We previously reported that patients with hepatitis C virus chronically administered interferon (IFN)-alpha develop increased evening plasma cortisol concentrations and a flattened diurnal cortisol slope, which correlated with increased tumor necrosis factor (TNF) and its soluble receptor 2 (sTNFR2). Increased TNF and sTNFR2 were further correlated with depression and fatigue scores. The current study examined whether flattened cortisol slope might be secondary to reduced glucocorticoid receptor (GR) sensitivity, by measuring glucocorticoid negative feedback to dexamethasone (DEX) administration followed by corticotropin releasing hormone (CRH) challenge. In an exploratory analysis, 28 male and female patients with hepatitis C virus were studied at baseline (Visit 1) and after 12weeks (Visit 2) of either IFN-alpha plus ribavirin (n=17) or no treatment (n=11). Patients underwent dexamethasone DEX–CRH challenge, neuropsychiatric assessments, and measurement of plasma TNF and sTNFR2 during each visit. IFN-alpha did not affect neuroendocrine responses following CRH but did increase post-DEX cortisol, which was correlated with flattening of the diurnal cortisol slope (r=0.57, p=0.002) and with increased depression scores (r=0.38, p=0.047). Furthermore, the change in post-DEX cortisol was associated with IFN-alpha-induced increase in sTNFR2 (r=0.51, p=006), which was in turn correlated with depression (r=0.63, p<0.001) and fatigue (r=0.51, p=0.005) scores. Whereas the relationship between sTNFR2 and depression scores were independent of the change in post-DEX cortisol, the correlation between post-DEX cortisol and depression scores was not significant when controlling for sTNFR2. These findings suggest that inflammation induced in patients with hepatitis C virus during IFN-alpha therapy precipitates decreased GR sensitivity to lead to a flattened diurnal cortisol slope. Decreased GR sensitivity may in turn further increase inflammation and its ultimate effects on behavior. Treatments that target inflammation and/or GR sensitivity may reduce depressive symptoms associated with medical illnesses.

(548) Trajectories of child pain and function in intensive interdisciplinary pediatric pain rehabilitation

s The Journal of Pain S113 (548) Trajectories of child pain and function in intensive interdisciplinary pediatric pain rehabilitation C Hoffart, R Anderson, D Feltrop, M Wilson, B Dorton, A Chapman, and D Wallace; Children’s Mercy Hospital, Kansas City, MO Given the prevalence of pediatric chronic pain, degree of disability, and compromise in quality of life, there is a critical need to identify the natural history of pain anddisability. Few studies investigate the effect of interdisciplinary treatment on pain and functional trajectories in children with chronic musculoskeletal pain. We hypothesized function would improve prior to decrease in pain. 22 patients (18 female) aged 11-18 with chronic musculoskeletal pain completed the modified Bruce Treadmill Test, Functional Disability Inventory (FDI-patient), and reported pain using a 100mm Visual Analog Scale (VAS 0-100) at program start, the end of each week, and 19 completed one-month follow-up. One parent from each family completed FDI-parent, a measure of parent perception of pain-related functional limitations. Mean treatment program duration was 3.64 weeks (6 0.9). Patients’ pain worsens before it improves approximately halfway through the program. Pain increased from 61.7 at baseline to 72.1 and 67.5 at the end of weeks 1 (P=0.03) and 2 (P=0.22), respectively, with subsequent significant decrease in pain to 31.9 through post-treatment follow-up (P=0.001). Baseline patient and parent FDI scores correlated (27.6 and 25.5, respectively, r=.861; P< .0001) and demonstrated steady declines at week one and throughout treatment, indicating improved function prior to pain decrease. Patient FDI improved to 13.9 by program end (P<.0001) and continues to improve following treatment to 7.6 (P=.002). Bruce treadmill endurance increased steadily from baseline of 7.11 minutes with continued improvement through program end to 10.4 minutes (P<.0001). Concurrent trajectories of patient outcomes suggest that function improves before pain. Whereas pain gets worse during the first weeks of treatment, patient function increases within the first week. These trajectories may aid in determining the projected course for patients requiring intensive interdisciplinary pain rehabilitation. (549) Relationships among fear of pain and movement, strength test performance, and indicators of hypothalamic pituitary adrenal axis (HPA axis) activity E Dannecker and P Hinton; University of Missouri, Columbia, MO Two studies were located that tested associations between fear of pain and movement and performance during strength testing. They reported mixed results. In this study, we advance the literature by incorporating measures of Hypothalamic Pituitary Adrenal (HPA) axis activity – cortisol and blood pressure, whichwe collected directly before upper extremity strength tests. During a single session, healthy, upper-body untrained participants (N = 32, 46.9%women, 78% Caucasian, 24 yrs old (SD = 5.18)) completed measures of fear of pain and movement and pain catastrophizing before two consecutive strength tests using the non-dominant elbow flexors. Immediately before the strength tests, we collected blood pressure readings and saliva via an oral swab for cortisol. We also recorded perceived exertion, pain intensity, pain unpleasantness, and force output during the strength tests. Contrary to our hypotheses, we detected no significant associations among fear of pain and movement and cortisol, blood pressure, perceived effort, pain, or force output. However, systolic and diastolic blood pressure and perceived effort positively correlated with force output (r’s = .49 .61, p < .01; r’s = .57 .60, p < .01; r’s = .35 .42, p < .05). In addition, the total score of the Pain Catastrophizing Scale (PCS) and rumination subscale of the PCS inversely correlated with force output (r’s = -.37 -.40, p < .04; r’s = -.42 .46, p < .02). These results support that pain catastrophizing is more strongly related to force output than fear of pain and movement, but none of the psychological constructs were significantly associated with indicators of HPA axis activity. Future studies should test relationships among these variables in samples with clinical pain, conduct alternative types of strength and function tests, and administer otherHPAmeasures such as the corticotropin-releasing hormone challenge test. (550) Functional disability through initial and follow-up evaluations in a multidisciplinary pediatric headache clinic A Caruso, E Mahoney, L Lazdowsky, and A LeBel; Boston Children’s Hospital,

Sexually dimorphic stress and pro-inflammatory cytokine responses to an intravenous corticotropin-releasing hormone challenge of Brahman cattle following transportation

This study was designed to characterize potential sexually dimorphic stress and immunological responses following a corticotropin-releasing hormone (CRH) challenge in beef cattle. Six female (heifers) and six male (bulls) Brahman calves (264 ± 12 d of age) were administered CRH intravenously (0.5 µg of CRH/kg body mass) after which serum concentrations of cortisol increased from 0.5 h to 4 h. From 1 h to 4 h after CRH administration, serum cortisol concentrations were greater in heifers than in bulls. In all cattle, increased serum concentrations of TNF-α, IL-6 and IFN-γ were observed from 2.5 h to 3 h after CRH, with greater concentrations of IFN-γ and IL-6 in heifers than bulls. Heifer total leukocyte counts decreased 1 h after CRH administration, while bull leukocyte counts and percent neutrophils decreased 2 h after CRH administration. Heifers had greater rectal temperatures than bulls, yet rectal temperatures did not change following administration of CRH. There was no effect of CRH administration on heart rate. However, bulls tended to have increased heart rate 2 h after CRH administration than before CRH. Heifer heart rate was greater than bulls throughout the study. These data demonstrate that acute CRH administration can elicit a pro-inflammatory response, and cattle exhibit a sexually dimorphic pro-inflammatory cytokine and cortisol response to acute CRH administration.

Endocrine response to acute stress in pigs with differing backtest scores

In an attempt to quantify a pig's behavioral reaction to stress, pigs in previous studies were subjected to a backtest. Pigs scoring high on the backtest were thought to have a greater reaction to stress than those scoring lower on the test. To further understand this reaction eighty-eight gilts from 19L were tested twice using the backtest. Gilts with the greatest (n=15, High) and least (n=15, Low) total time struggling were then selected for acute stress challenges. Pigs, in two replicates, were fitted with jugular cannulas at approximately 150d of age. An acclimation time of 24h was given between cannulation, testing and between tests. Blood samples were collected at 10 time points (−60, −30, 0, 5, 10, 15, 30, 60, 90, and 120m relative to the application of the stressor). Pigs were challenged with 0.11mol/kg BW of corticotropin releasing hormone (CRH) (n=9 High, n=9 Low) injected through the cannula to test the proposed model. The first stressor was snaring the pig with a nose-snare for 1min (n=10 High, n=9 Low). The second stressor was depriving the pigs of feed for 24h followed by placing feed next to the pig but out of reach (n=6 High, n=7 Low). Plasma samples were assayed for cortisol, epinephrine, and norepinephrine. Data were analyzed using a model including fixed effects of time, replicate, and group (High or Low) and all two-way interactions. In response to the CRH challenge, cortisol levels peaked at 10m and returned to basal levels by 90m. Least squares means response in norepinephrine of the High exceeded Low at 5m by 376±99pg/mL. Cortisol, epinephrine, and norepinephrine response to snaring was similar. Cortisol peaked at 10m and epinephrine and norepinephrine at 5m. The response to feed deprivation failed to exceed basal levels. Response to the CRH challenge demonstrated the appropriateness of the model and that High and Low pigs were equally capable of responding. The biological significance of differences between High and Low groups in norepinephrine levels at 5m following snaring is unknown.

Periconceptional undernutrition suppresses cortisol response to arginine vasopressin and corticotropin-releasing hormone challenge in adult sheep offspring.

Poor maternal nutrition during pregnancy can result in increased disease risk in adult offspring. Many of these effects are proposed to be mediated via altered hypothalamo-pituitary-adrenal axis (HPAA) function, and are sex and age specific. Maternal undernutrition around the time of conception alters HPAA function in foetal and early postnatal life, but there are limited conflicting data about later effects. The aim of this study was to investigate the effect of moderate periconceptional undernutrition on HPAA function of offspring of both sexes longitudinally, from juvenile to adult life. Ewes were undernourished from 61 days before until 30 days after conception or fed ad libitum. HPAA function in offspring was assessed by arginine vasopressin plus corticotropin-releasing hormone challenge at 4, 10 and 18 months. Plasma cortisol response was lower in males than in females, and was not different between singles and twins. Periconceptional undernutrition suppressed offspring plasma cortisol but not adrenocorticotropic hormone responses. In males, this suppression was apparent by 4 months, and was more profound by 10 months, with no further change by 18 months. In females, suppression was first observed at 10 months and became more profound by 18 months. Maternal undernutrition limited to the periconceptional period has a prolonged, sex-dependent effect on adrenal function in the offspring.

Poor sleep is associated with exaggerated cortisol response to the combined dexamethasone/CRH test in a non-clinical population

Although sleep disturbance has been shown to be associated with psychological distress and the hypothalamic-pituitary-adrenal (HPA) axis function, the simultaneous relationship between sleep, distress and HPA axis function is less clear. Here we examined the relationship between sleep quality as assessed with the Pittsburgh Sleep Quality Index, psychological distress as assessed with the Hopkins Symptom Checklist, and cortisol responses to the dexamethasone (DEX)/corticotropin-releasing hormone (CRH) test in 139 non-clinical volunteers. Poor sleep was significantly correlated with greater cortisol response to the combined DEX/CRH challenge, but not with the cortisol level just before CRH challenge. When subjects were divided into three groups based on the suppression pattern of cortisol (i.e., incomplete-, moderate-, and enhanced-suppressors), poor sleep was significantly associated with the incomplete suppression in women while no significant association was found between sleep and the enhanced suppression. The association between poor sleep and exaggerated cortisol response to the CRH challenge became more clear in the regression analysis where the confounding effect of psychological distress was taken into consideration. These results indicate that poor sleep would be associated with exaggerated cortisol reactivity. The observed association of poor sleep with reactive cortisol indices to the CRH challenge, but not with the cortisol level after DEX administration alone, might add to the well-established evidence demonstrating the role of CRH in the regulation of sleep. Our findings further suggest that the mediation model would work better than the bivariate approach in investigating the relationship between sleep, distress and HPA axis reactivity.

Sex differences in cortisol response to corticotropin releasing hormone challenge over puberty: Pittsburgh Pediatric Neurobehavioral Studies

Consistent sex differences in regulation of the hypothalamic pituitary adrenocortical (HPA) axis have been shown in animal models and emerge over puberty. However, parallel work in humans is lacking despite implications for elucidating the emergence of sex differences in depression over puberty. We investigated sex differences in HPA response to corticotropin releasing hormone (CRH) challenge over puberty in a carefully screened normative sample. Participants were 68 healthy children (41% girls), ages 6-16, with no personal or family history of psychiatric disorder. Pubertal maturation was determined by Tanner staging. Following 24h of adaptation, 9-10 plasma cortisol samples were collected over 30-40 min pre-infusion baseline, 1 μg/kg CRH infusion, and 90-180 min post-infusion recovery. Thirty-seven participants completed 2+ CRH challenges allowing inclusion of cross-sectional and longitudinal data in all analyses. The influence of gender and pubertal maturation on parameters of cortisol response to CRH challenge was investigated using nonlinear mixed model methodology. Girls showed increasing total cortisol output following CRH challenge over puberty, while boys showed little change in total cortisol output over puberty. Increased cortisol output in girls was explained by slower reactivity and recovery rates leading to prolonged time to reach peak cortisol and delayed return to baseline over puberty. Girls also showed increasing baseline cortisol over puberty, while boys showed declining baseline over puberty. Results reveal subtle normative sex differences in the influence of pubertal maturation on HPA regulation at the pituitary level. This normative shift may tip the balance towards stress response dysregulation in girls at high risk for depression, and may represent one potential mechanism underlying elevated rates of depression among pubescent girls.

Gender differences in the effect of early life trauma on hypothalamic-pituitary-adrenal axis functioning

The objective of this study was to examine the modifying effect of gender on the association between early life trauma and the hypothalamic-pituitary-adrenal (HPA) axis response to a pharmacologic challenge and a social stress task in men and women. Participants (16 men, 23 women) were the control sample of a larger study examining HPA axis function. Individuals with major depressive disorder, posttraumatic stress disorder, bipolar disorder, or psychotic or eating disorders were excluded. In two test sessions, subjects received 1 µg/kg of corticotropin-releasing hormone (CRH) intravenously and participated in the Trier Social Stress Test (TSST). Primary outcomes included plasma cortisol and corticotropin levels measured at baseline and more than five time points following the challenges. Predictors included gender and early life trauma, as measured by the Early Trauma Index. Using factor analysis, the domains general trauma, severe trauma, and the effects of trauma were established. Using regression, these constructs were used to predict differential HPA reactivity in men and women following the challenges. The three factors accounted for the majority of the variance in the ETI. Following the CRH challenge, women had higher overall corticotropin response as dictated by the area under the curve analysis. There were no significant associations between trauma and neuroendocrine response to the TSST. CRH challenge results indicate that gender differences in the impact of early trauma may help explain the differential gender susceptibility to psychopathology following adverse childhood events. This may help explain gender differences in some stress-sensitive psychiatric disorders.

Increased Glucocorticoid Receptor Expression and Activity Mediate the LPS Resistance of SPRET/EI Mice

SPRET/Ei mice are extremely resistant to acute LPS-induced lethal inflammation when compared with C57BL/6. We found that in vivo SPRET/Ei mice exhibit strongly reduced expression levels of cytokines and chemokines. To investigate the role of the potent anti-inflammatory glucocorticoid receptor (GR) in the SPRET/Ei phenotype, mice were treated with the GR antagonist RU486 or bilateral adrenalectomy. Under such conditions, both C57BL/6 and SPRET/Ei mice were strongly sensitized to LPS, and the differences in LPS response between SPRET/Ei and C57BL/6 mice were completely gone. These results underscore the central role of GR in the LPS hyporesponsiveness of SPRET/Ei mice. Compared with C57BL/6, SPRET/Ei mice were found to express higher GR levels, which were reflected in increased GR transactivation. Using a backcross mapping strategy, we demonstrate that the high GR transcription levels are linked to the Nr3c1 (GR) locus on chromosome 18 itself. Unexpectedly, SPRET/Ei mice exhibit a basal overactivation of the hypothalamic-pituitary-adrenal axis, namely strongly increased corticosterone levels, ACTH levels, and adrenocortical size. As a consequence of the excess of circulating glucocorticoids (GCs), levels of hepatic gluconeogenic enzymes are increased, and insulin secretion from pancreatic β-cells is impaired, both of which result in hyperglycemia and glucose intolerance in SPRET/Ei mice. We conclude that SPRET/Ei mice are unique as they display an unusual combination of elevated GR expression and increased endogenous GC levels. Hence, these mice provide a new and powerful tool for the study of GR- and GC-mediated mechanisms, including immune repressive functions, neuroendocrine regulation, insulin secretion, and carbohydrate metabolism.

Effects of sex and early maternal abuse on adrenocorticotropin hormone and cortisol responses to the corticotropin-releasing hormone challenge during the first 3 years of life in group-living rhesus monkeys.

In this study we investigated the development of the hypothalamic-pituitary-adrenal (HPA) axis in 21 group-living rhesus monkeys infants that were physically abused by their mothers in the first few months of life and in 21 nonabused controls. Cortisol and adrenocorticotropin hormone (ACTH) responses to a corticotropin-releasing hormone (CRH) challenge were assessed at 6-month intervals during the subjects' first 3 years of life. Abused infants exhibited greater cortisol responses to CRH than controls across the 3 years. Abused infants also exhibited blunted ACTH secretion in response to CRH, especially at 6 months of age. Although there were no significant sex differences in abuse experienced early in life, females showed a greater cortisol response to CRH than males at all ages. There were no significant sex differences in the ACTH response to CRH, or significant interactions between sex and abuse in the ACTH or cortisol response. Our findings suggest that early parental maltreatment results in greater adrenocortical, and possibly also pituitary, responsiveness to challenges later in life. These long-term alterations in neuroendocrine function may be one the mechanisms through which infant abuse results in later psychopathologies. Our study also suggests that there are developmental sex differences in adrenal function that occur irrespective of early stressful experience. The results of this study can enhance our understanding of the long-term effects of child maltreatment as well as our knowledge of the development of the HPA axis in human and nonhuman primates.

Corticotropin-releasing hormone (CRH) regulates macromolecular permeability via mast cells in normal human colonic biopsies in vitro

Objective:Persistent stress and life events affect the course of ulcerative colitis and irritable bowel syndrome by largely unknown mechanisms. Corticotropin-releasing hormone (CRH) has been implicated as an important mediator of...

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

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 cortisol levels at the age of 5.5 months (P < 0.01, P < 0.001 respectively) and with higher cortisol levels (P < 0.01) at 10 months of age than males. It is concluded that the HPA axis is programmable by altered nutrition in utero. The sensitivity of the axis to exogenous stimulation is enhanced during early postnatal life and attenuated with age, suggesting a role for the postnatal influences in resetting of the HPA axis and emphasizing the importance of identifying the impact of maternal undernutrition at several time points after birth.

Immune Reactivity Is More Suppressed in Patients with Alcoholic Liver Disease than in Patients with Virus‐Induced Cirrhosis after CRH Stimulation

The most frequent diagnoses for liver transplantation are virus-induced cirrhosis (VIC) and alcoholic liver disease (ALD), after an abstinence period of at least 6 months. Chronic ethanol consumption has been linked to an abnormal neuroendocrine-immune axis and to an altered surgical stress response inducing an increased infection rate. Preoperative stress testing might be relevant to detect stress-induced immune alteration. The aim of this study was to investigate the preoperative stress-like response to corticotrophin-releasing-hormone challenge (CRH) of patients with ALD compared with patients with VIC and their immune sequelae. Nine patients with ALD and 8 patients with VIC were included in this clinical study prior to transplantation. All patients received CRH in the morning. Blood samples were drawn before and after stress testing. In response to CRH, the ALD patients showed a significant decrease in the plasma interleukin (IL)-6/IL-10 ratio. After lipopolysaccharide stimulation of whole blood from CRH-challenged ALD patients, IL-10 increased significantly. The cytotoxic T1-(Tc1) to cytotoxic T2 (Tc2) ratio was significantly decreased in ALD patients after the stress test. Infections occurred significantly more often in ALD patients within the past year before study inclusion. ALD patients showed a stronger anti-inflammatory immune status and response than VIC patients. This difference was associated with a higher infection rate despite a median alcohol abstinence time of 3.5 years. Although an altered immune response is well known among patients with actual alcohol-use disorders, to the best of our knowledge, it is not described in patients after such a long abstinence time.

Changes in Hypothalamic–Pituitary–Adrenal Axis Measures After Vagus Nerve Stimulation Therapy in Chronic Depression

Little is known about the hypothalamic-pituitary-adrenal (HPA) axis stress system in chronic depression. This study examined the corticotropin-releasing hormone (CRH) challenge test in a group of patients with chronic depression, before and after 3 months of treatment with vagus nerve stimulation (VNS) therapy, and a matched group of healthy control subjects. Key inclusion criteria were DSM-IV-defined major depressive disorder, a history of a current episode lasting for at least 2 years, and unresponsiveness to at least two classes of antidepressant medications. Eleven test subjects and 11 matched control subjects underwent a CRH challenge. There were significant reductions in depression scores over the study period. The CRH/ACTH (adrenocorticotropic hormone) responses in the depressed group before VNS implantation were significantly higher than in the healthy group and were reduced to normal values after VNS treatment. Some measures of cortisol response were elevated before treatment and were reduced to normal over the study period. The only clinical measure correlated with HPA axis alterations was reduction in atypical depressive symptom scores. These preliminary results suggest that chronic depression, in contrast to acute melancholic depression, might be characterized by increased ACTH response to CRH challenge. Short-term treatment with VNS therapy was associated with normalization of this response.

Basal and Stimulated Hypothalamic-Pituitary-Adrenal Axis Activity in Patients With Functional Gastrointestinal Disorders and Healthy Controls

The aim of this study was to investigate alterations of pituitary-adrenal activity under both stimulated and unstimulated conditions in patients with functional gastrointestinal disorders. Thirty subjects who fulfilled the Rome Diagnostic Criteria for either irritable bowel syndrome or nonulcer dyspepsia and 24 healthy controls took part in the study. Free salivary morning cortisol and diurnal cortisol profiles were obtained for all subjects. On a second day, a low-dose dexamethasone suppression test was applied. Additionally, in all subjects a corticotropin-releasing hormone (CRH) challenge test was performed. The results show attenuated unstimulated cortisol levels in patients compared with controls. After CRH challenge, blunted adrenocorticotropic hormone and cortisol responses were observed. These findings suggest lower pituitary and adrenocortical activity in patients with functional gastrointestinal disorders. The observed pituitary-adrenal reactivity in these patients is discussed as a possible consequence of lower adrenocortical activity, possibly resulting in a disinhibition of CRH in the brain.

Effects of Chronic Social Stress on Neuroendocrine Responsiveness to Challenge with Ethanol, Dexamethasone and Corticotropin-Releasing Hormone

Neuroendocrine and behavioral profiles of group-housed rodents differ from those of singly-housed ones. Subordinate rats have elevated plasma corticosterone (CORT) concentration and impaired activity of the hypothalamic-pituitary-adrenal (HPA) axis compared to dominant cagemates. However, little is known about the effects of social hierarchy on other stress-related hormones. We examined plasma prolactin (PRL) and CORT responses to saline and ethanol (EtOH) injections, and 1 month later to dexamethasone (DEX) and corticotropin-releasing hormone (CRH) challenges of group- (triad) and single-housed male rats over a period of 225 days. Social status was determined from behaviors displayed upon initial triad housing. Subordinate rats had lower basal PRL and higher CORT compared to dominant rats. The injection of EtOH (1.25 g/kg) depressed PRL and elevated CORT levels significantly more than the saline injection only in dominant and singly-housed rats. DEX increased PRL levels, most strikingly in dominant rats, and suppressed CORT only in dominant rats. After CRH challenge, plasma CORT increased in all groups, subdominant and subordinate rats displaying blunted responses. Our data demonstrate that social rank and housing conditions affect plasma PRL and CORT concentrations, and modify responses to EtOH, possibly reflecting impairments of HPA axis regulation in socially-housed rats.