Plasma Adrenocorticotropic Hormone Levels Research Articles

Single intranasal neuropeptide Y infusion attenuates development of PTSD-like symptoms to traumatic stress in rats

Exposure to severe stress leads to development of neuropsychiatric disorders, including depression and Post-Traumatic Stress Disorder (PTSD) in at-risk individuals. Neuropeptide Y (NPY) is associated with resilience or improved recovery. Therefore exogenous administration to the brain has therapeutic potential although peripheral administration can trigger undesirable side effects. Here, we established conditions with intranasal (IN) NPY infusion to rats to obtain CSF concentrations in the proposed anxiolytic range without significant change in plasma NPY. Rats were pretreated with IN NPY or vehicle before exposure to single prolonged stress (SPS) animal model of PTSD and compared to untreated controls. The IN NPY appeared to lessen the perceived severity of stress, as these animals displayed less time immobile in forced swim part of the SPS. Thirty minutes after SPS the elevation of plasma adrenocorticotropic hormone (ACTH) and corticosterone was not as pronounced in NPY-infused rats and the induction of tyrosine hydroxylase (TH) in locus coeruleus (LC) was attenuated. Seven days after SPS, they displayed lower depressive-like behavior on Forced Swim Test and reduced anxiety-like behavior on Elevated Plus Maze. The prolonged effect of SPS on Acoustic Startle Response was also lower in NPY-infused rats. Plasma ACTH, corticosterone, and hippocampal glucocorticoid receptor levels were significantly above controls only in the vehicle – but not IN NPY-treated group 1week after SPS. Baseline TH mRNA levels in LC did not differ among groups, but increased with forced swim in the vehicle – but not NPY-pretreated animals. Administration of IN NPY after exposure to SPS led to similar, but not identical, reduction in development of anxiety, depressive-like behavior and hyperarousal. The results show that single IN NPY can alter stress-triggered dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis and activation of central noradrenergic activity. These findings provide proof of concept for potential of IN NPY for non-invasive prophylactic treatment or early intervention in response to traumatic stress.

Hematologic recovery of pancytopenia after treatment of Hashimoto′s thyroiditis and primary adrenal insufficiency

Dear Editor, Pancytopenia is not a common hematologic complication of endocrinopathies. The characteristic hematologic manifestation of hypothyroidism is normocytic normochromic anemia. The pathogenesis of this anemia is hypothesized to reflect either a lack of erythropoietin production or a physiologic adaptation to the decreased tissue oxygen requirements resulting from a decrease in the basal metabolic rate.[1] In most cases of pancytopenia, hypothyroidism was related to hypopituitarism.[2] This is to our knowledge the first case report of pancytopenia related to Hashimoto's thyroiditis and adrenal insufficiency that was completely treated with thyroid and steroid replacement therapy. A 57-year-old woman presented to the emergency room with complaints of restlessness, increasing fatigue, and weight gain. The patient had also noticed that her face and extremities appeared puffier. She denied any medication or illicit drug use. She had no history of any prior pregnancies. Her menstrual period was regular and unremarkable. On physical examination, she was found to be obese with myxedema in extremities and her reflexes were sluggish. Her blood pressure was 85/60 mmHg. The patient did not have goiter and did not exhibit any hyperpigmentation or signs of dehydration. The patient's laboratory tests revealed a pancytopenia with white blood cell 2.5 × 109/L (segmented neutrophil count was 0.8 × 109/L), Hemoglobin 8.4 g/dl, and platelet count 95 × 109/L. The reticulocyte count was 2.0%. The mean cell volume (MCV) was 95.6 fl, mean cell hemoglobin (MCH) 34.0 pg, and mean cell hemoglobin concentration (MCHC) 35.0 g/dl. She had normal iron studies, Vitamin B12, and folate levels. The results of rapid human immunodeficiency virus test, direct Coombs test, and anti-nuclear antibody titer were negative for her. She had normal sodium and potassium levels. Lactate dehydrogenase and bilirubin levels were normal, and hence, possibility of hemolysis was excluded. Serial stool occult blood test results were negative. Her thyroid stimulating hormone level was 422 mU/L (reference range, 0.4~5.0 mU/L), Total T3 0.33, free T4 0.22 (reference range, 5~12 mg/dl). Her baseline 8-am cortisol level was 5.4 μg/dl (reference range, 5~25 μg/dl). Computed tomography (CT) scans of the head, chest, and abdomen were unremarkable. Bone marrow biopsy revealed normal hematopoietic features lacking any atypical features. Serum anti-thyroid peroxidase antibodies were elevated at 250 IU/L (reference range, <100 IU/L), and this confirmed the diagnosis of Hashimoto's thyroiditis. Remainder of endocrinology workup including luteinizing hormone (17 IU/L), FSH (11 mIU/ml), and insulin-like growth factor-1 (210 ng/ml) were within normal limits. The patient was subsequently started on levothyroxine 25 μg IV q12 hrs and levothyroxine 75 μg PO daily. An adrenocorticotropic hormone (ACTH) stimulation test was done; the baseline cortisol level was 5.4 μg/dl and the ACTH stimulation raised it to 25 μg/dl. The plasma ACTH level was 80 μg/dl. The results were consistent with primary adrenal insufficiency. Patient was given Dexamethasone 2 mg IV q12 hrs. After treatment for 1 week, she improved clinically, but what was surprising was that her WBC count improved to 5.2 × 109/L, Hemoglobin 10.0 g/dl, and platelets 200 × 109/L. Subsequently, the patient was discharged on levothyroxine 125 μg PO daily and prednisone 5 mg daily. At 3-month follow-up, outpatient laboratory tests revealed that she maintained her hematologic stability. As this patient had both hypothyroidism and adrenal insufficiency, it may be difficult to specifically identify the precise role of each hormone deficit that contributed to this patient's pancytopenia. The bone marrow biopsy revealed no evidence of aplastic anemia, which is a common etiologic factor.[3] Nevertheless, recent data suggests that hypothyroidism is the major contributing factor in the pathogenesis of pancytopenia in patients with hypopituitarism. Song, et al. reported that the pancytopenia in patients with myxedema coma was secondary to marrow hypoplasia as documented by bone marrow biopsy.[4] Other authors have suggested that the normal and effective bone marrow hematopoeisis was affected by an autoimmune reaction, which was a plausible explanation in this case.[5] There was a prior report of pancytopenia in a patient with hypopituitarism and autoimmune hypothyroidism, which resolved following the initiation of corticosteroid and thyroid replacement therapy.[6] Unlike that fascinating case, our patient's diagnostics revealed no evidence of hypopituitarism. In conclusion, in light of our experience, we recommend that a systematic endocrine work-up (thyroid function tests including anti-thyroid peroxidase antibodies, etc) should be part of the standard diagnostic work-up of unexplained pancytopenia so that effective management and treatment can be implemented.

Comparative Analysis of Clinical, Hormonal and Morphological Studies in Patients with Neuroendocrine ACTH-Producing Tumours.

This paper highlights the problem of neuroendocrine tumours (NETs) with clinical symptoms of hypercorticism caused by hypersecretion of adrenocorticotropic hormone (ACTH) by tumour cells. In most cases (85%), the tumours were localized in the pituitary gland (Cushing's disease); 15% of the patients had an extrapituitary tumour that manifest as an ectopic ACTH secretion (EAS). Comparative analysis of clinical, hormonal, histological, and immunohistochemical characteristics of pituitary and extrapituitary ACTH-secreting NET was performed. It included 46 patients with CD and 38 ones exhibiting ectopic ACTH secretion (EAS). Results of the study suggest differences between CD and EAS in terms of the severity of clinical manifestations and duration of the disease. Hormonal studies showed that EAS unlike CD was associated with high plasma ACTH and cortisol levels, late-evening salivary cortisol and daily urinary free cortisol, the absence of a 60% or greater reduction of cortisol in the HDDST test, and the presence of a low (less than 2) ACTH gradient in response to desmopressin administration with catheterization of cavernous sinuses. The study of morphofunctional characteristics of the removed NET demonstrated the ability of both pituitary and extrapituitary NETs to express ACTH as well as GH, PRL, LH, and FSH. The angiogenic markers (CD31 and VEGF) were detected with equal frequency regardless of the NET localization. The histological structure of all corticotropinomas suggested their benign origin, but extrapituitary NETs were represented by different morphological types with varying malignancy, invasiveness, and metastatic properties. A higher cell proliferation potential (Ki-67) was documented for NET in patients presenting with an ectopic ACTH secretion compared to those having corticotropinomas.

Stress-related activities induced by predator odor may become indistinguishable by hinokitiol odor

Predator odors, such as 2,5-dihydro-2,4,5-trimethylthiazoline (TMT), induce a stress-like behavior in some rodents, and there is activation of a complex mix of brain regions including the anterior piriform cortex (APC) and the bed nucleus of stria terminalis (BST). In contrast, rose odor can counteract TMT-induced activation of the ventrorostral part of APC and the medial part of BST. In the present study, two novel odors, woody (hinokitiol) and caraway [S(+)-carvone] odors, were evaluated to determine whether they have an antistress effect. Plasma adrenocorticotropic hormone levels, a marker of stress, and the number of c-Fos-immunopositive cells were determined in APC and BST. Plasma adrenocorticotropic hormone levels were increased by TMT alone and in combination with S(+)-carvone; however, hinokitiol with or without TMT did not have an effect. The number of activated cells in the medial part of BST was increased by TMT alone and in combination with S(+)-carvone or hinokitiol. Although TMT alone activated the medial part of BST, a mixture of TMT and hinokitiol activated both the medial and the lateral part of BST. These data suggest that the selective responses to TMT in the medial part of BST were obscured by activation of more odor-related regions by hinokitiol with TMT. In addition, the ratio of medial to lateral BST activation may be critical in stress-related behavior. In conclusion, hinokitiol can alleviate TMT-induced stress; however, the underlying mechanism appears to be different from that of the rose odor, as found in our previous study.

Effect of DA‐9701, a novel prokinetic agent, on stress‐induced delayed gastric emptying and hormonal changes in rats

DA-9701 is a novel prokinetic agent formulated with Pharbitis Semen and Corydalis Tuber. This study aimed to evaluate the effect of DA-9701 on stress-induced delay in gastric emptying and changes in plasma adrenocorticotropic hormone and ghrelin levels in rats. Changes in gastric emptying in response to different durations of stress were evaluated. Gastric emptying was compared between the following groups: (i) nonstressed vehicle- or DA-9701-treated group, (ii) nonstressed vehicle- or mosapride-treated group, (iii) 2-h stressed vehicle- or DA-9701-treated group, and (iv) 2-h stressed vehicle- or mosapride-treated group. Water immersion restraint stress was used as the stressor. DA-9701 or mosapride at 3 mg kg(-1) was administered to the rats after subjecting them to 2-h stress, and then gastric emptying was measured using the phenol red method. Gastric emptying was significantly delayed in the 2-h stressed group compared with the nonstressed group. Mosapride administration resulted in significant recovery from the stress-induced delay in gastric emptying. Gastric emptying in the rats that underwent 2-h stress followed by DA-9701 administration was not significantly different from that in the nonstressed group. The plasma adrenocorticotropic hormone and active ghrelin levels in the 2-h stressed group were significantly higher than those in the nonstressed group. These increases were significantly inhibited by DA-9701. The administration of DA-9701 improved delayed gastric emptying and inhibited the hormonal changes induced by stress, suggesting that DA-9701 can be used as a gastroprokinetic agent for the treatment of delayed gastric emptying, particularly that associated with stress.

Adrenal-Specific Scavenger Receptor BI Deficiency Induces Glucocorticoid Insufficiency and Lowers Plasma Very-Low-Density and Low-Density Lipoprotein Levels in Mice

We determined the physiological consequences of adrenocortical-specific deletion of scavenger receptor BI (SR-BI) function in C57BL/6 wild-type mice. One adrenal from 10-day-old SR-BI knockout (KO) mice or wild-type controls was transplanted under the renal capsule of adrenalectomized C57BL/6 recipient mice. The fasting plasma corticosterone level increased over time in transplanted mice. Corticosterone values in SR-BI KO transplanted mice remained ≈50% lower (P<0.001) as compared with wild-type transplanted mice, which coincided with adrenocortical lipid depletion. A 6.5-fold higher (P<0.01) plasma adrenocorticotropic hormone level was present in SR-BI KO transplanted mice reminiscent of primary glucocorticoid insufficiency. On feeding with cholic acid-containing high cholesterol/high fat diet, SR-BI KO transplanted mice exhibited a 26% (P<0.05) reduction in their liver triglyceride level. Hepatic myosin regulatory light chain interacting protein/inducible degrader of the low-density lipoprotein receptor mRNA expression was 48% (P<0.01) decreased in adrenal-specific SR-BI KO mice, which was paralleled by a marked decrease (-46%; P<0.01) in proatherogenic very-low-density and low-density lipoprotein levels. Adrenal-specific disruption of SR-BI function induces glucocorticoid insufficiency and lowers plasma very-low-density and low-density lipoprotein levels in atherogenic diet-fed C57BL/6 mice. These findings further highlight the interaction between adrenal high-density lipoprotein-cholesterol uptake by SR-BI, adrenal steroidogenesis, and the regulation of hepatic lipid metabolism.

Antidepressant-like effects of the extract from Cimicifuga foetida L.

Ethnopharmacological relevance: Cimicifuga foetida L., a traditional Chinese medicine, has been developed for the treatment of perimenopausal symptoms including depression in China (Brand name: XIMINGTING®, XMT). The primary active constituents are believed to be the triterpene glycosides. Nevertheless, there are no studies about the antidepressant-like effects of XMT in rodents. Aims of the studyThe present study aimed to evaluate antidepressant-like effects of XMT. Materials and methodsAntidepressant-like activity of XMT was studied using forced swimming test (FST) and tail suspension test (TST) in female mice, as well as chronic mild stress (CMS) procedure in female rats. In addition, 5-hydroxytryptophan (5-HTP)-induced head-twitch test and yohimbine toxicity potentiation test in female mice were conducted to propose the possible serotonergic or noradrenergic mechanisms in the antidepressant-like effects of XMT. In mice, XMT was administrated acutely and for 7 consecutive days (20, 40 and 80mg/kg/day, p.o.); and in rats for 28 consecutive days (10, 20 and 40mg/kg/day, p.o.). ResultsXMT significantly reduced immobility duration in FST and TST without affecting locomotor activity, increased swimming and climbing durations in FST, and enhanced 5-HTP-induced head-twitch response while did not affect yohimbine-induced lethality in female mice. XMT also normalized the inhibition of sucrose intake and decreased the levels of plasma adrenocorticotropic hormone and serum corticosterone and adrenal gland weight in CMS-treated female rats. ConclusionsThese data indicate XMT processes antidepressant-like properties in rodents, which could be related to its serotonergic and noradrenergic activation and normalization of the hypothalamic-pituitary-adrenal axis.

Efficacy of inpatient treatment for atopic dermatitis evaluated by changes in serum cortisol levels

When dealing with patients with severe atopic dermatitis (AD), inpatient treatment is useful for alleviating skin symptoms in short periods of time. We previously found that many severe AD patients had low serum cortisol levels at admission. The present study was undertaken to evaluate the efficacy of inpatient treatment in 29 adults with AD through comparisons of serum cortisol, plasma adrenocorticotropic hormone (ACTH), serum thymus and activation-regulated chemokine (TARC), and serum lactate dehydrogenase (LDH) levels at admission with those at the time of discharge. Serum cortisol and plasma ACTH levels were significantly higher at discharge. On the other hand, serum TARC and serum LDH were significantly lower at discharge. We examined whether the suppression of hypothalamic-pituitary-adrenocortical function that was seen at admission was attributable to disturbed circadian rhythms due to sleep disorders by analyzing hypothalamic-pituitary-adrenocortical function in relation to the presence/absence of sleep disorders, serum cortisol levels and daily urinary free cortisol. Of the 17 patients with low serum cortisol levels upon admission, 15 (88.2%) had sleep disorders upon admission. However, the daily urinary free cortisol increased significantly from 8.0±5.5μg/day (at admission) to 18.5±17.2μg/day (at discharge). These results suggested that the suppression of endocrine function seen at admission was not attributable to disturbed circadian rhythms due to sleep disorders but represented true suppression of the endocrine system. These results indicated that inpatient care was useful for treating patients with severe AD, enabling efficient improvement of the skin condition and recovery from suppressed endocrine function.

18F-DOPA PET/CT But Not 68Ga-DOTA-TOC PET/CT Revealed the Underlying Cause of Ectopic Cushing Syndrome

F-DOPA PET/CT but not Ga-DOTA-TOC PET/CT revealed the cause of ectopic Cushing syndrome in a 61-year-old man. The patient presented with rapid weight gain, swollen legs, and sleep disturbances. Plasma potassium level was 2.7 mM (reference range, 3.3-4.9 mM), 24-hour urinary cortisol level was 13,124 nmol (reference range, 30-144 nmol), and plasma adrenocorticotropin level was 61 ng/L (reference range, <48 g/L). CT demonstrated prominent lymph nodes in the left lung hilus and hyperplastic adrenals but no primary tumor. Ga-DOTA-TOC PET/CT, which is recommended as the first-line PET imaging, was performed, but it was not diagnostic. Imaging with F-DOPA PET/CT revealed the underlying cause.

Do Premenopausal Women with Major Depression Have Low Bone Mineral Density? A 36-Month Prospective Study

BackgroundAn inverse relationship between major depressive disorder (MDD) and bone mineral density (BMD) has been suggested, but prospective evaluation in premenopausal women is lacking.MethodsParticipants of this prospective study were 21 to 45 year-old premenopausal women with MDD (n = 92) and healthy controls (n = 44). We measured BMD at the anteroposterior lumbar spine, femoral neck, total hip, mid-distal radius, trochanter, and Ward's triangle, as well as serum intact parathyroid hormone (iPTH), ionized calcium, plasma adrenocorticotropic hormone (ACTH), serum cortisol, and 24-hour urinary-free cortisol levels at 0, 6, 12, 24, and 36 months. 25-hydroxyvitamin D was measured at baseline.ResultsAt baseline, BMD tended to be lower in women with MDD compared to controls and BMD remained stable over time in both groups. At baseline, 6, 12, and 24 months intact PTH levels were significantly higher in women with MDD vs. controls. At baseline, ionized calcium and 25-hydroxyvitamin D levels were significantly lower in women with MDD compared to controls. At baseline and 12 months, bone-specific alkaline phosphatase, a marker of bone formation, was significantly higher in women with MDD vs. controls. Plasma ACTH was also higher in women with MDD at baseline and 6 months. Serum osteocalcin, urinary N-telopeptide, serum cortisol, and urinary free cortisol levels were not different between the two groups throughout the study.ConclusionWomen with MDD tended to have lower BMD than controls over time. Larger and longer studies are necessary to extend these observations with the possibility of prophylactic therapy for osteoporosis.Trial RegistrationClinicalTrials.gov NCT 00006180

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

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

The involvement of noradrenergic mechanisms in the suppressive effects of diazepam on the hypothalamic-pituitary-adrenal axis activity in female rats

AimTo elucidate the involvement of noradrenergic system in the mechanism by which diazepam suppresses basal hypothalamic-pituitary-adrenal (HPA) axis activity.MethodsPlasma 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.ResultsDiazepam 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.ConclusionThe 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.

Spectral Entropy Monitoring Reduces Anesthetic Dosage for Patients Undergoing Off-Pump Coronary Artery Bypass Graft Surgery

The measurement of the depth of anesthesia is of clinical interest for patients undergoing off-pump coronary artery bypass graft (OPCAB) surgery in order to avoid intraoperative awareness and cardiac depression. Entropy recently was introduced as a monitor of anesthetic depth. This study was conducted to investigate the feasibility of entropy monitoring during the conduct of OPCAB surgery and to find out whether it reduced the anesthetic dosage for patients undergoing OPCAB surgery. A prospective, randomized, single-blind, controlled study. A teaching hospital. Seventy patients scheduled for OPCAB surgery were randomized to receive propofol-sufentanil anesthesia either with the entropy values visible (the entropy group, n = 35) or without the entropy values visible (the control group, n = 35). In the entropy group, propofol and sufentanil infusion rates were titrated to maintain a state entropy (SE) value of 45 to 55 and a response entropy (RE)-SE difference below 10 U. In the control group, patients were anesthetized to keep the heart rate and blood pressure within 25% of the baseline values. The course of surgery, the consumption of anesthetics, and intraoperative recall were recorded. Plasma levels of adrenocorticotropic hormone (ACTH) and cortisol were measured. The average SE during anesthesia was 50 ± 5 in the entropy group; the entropy values were lower in the control group (p < 0.05). Compared with the control group, propofol and sufentanil consumption were significantly less in the entropy group, which shortened the time to tracheal extubation (p < 0.05). Significantly, patients in the control group needed more phenylephrine to maintain arterial pressure than patients in the entropy group (p < 0.05). ACTH and cortisol release were prevented completely, and there was no intraoperative recall reported in the 2 groups. Entropy monitoring reduced propofol and sufentanil dosage for patients undergoing OPCAB surgery.

Association between plasma lipid, glucose, cortisol and adrenocorticotropic hormone levels and GR and ACTHR gene polymorphisms

To explore the association between plasma fat and glucose, cortisol and adrenocorticotropic hormone (ACTH) levels and genotypes of GR and ACTHR genes in healthy Chinese Han subjects. Two hundred healthy subjects were analyzed for GR and ACTHR gene polymorphisms using PCR-restriction fragment length polymorphism method. Plasma lipid, glucose, cortisol, ACTH levels were determined and correlated with the genotypes. No significant difference was found between plasma lipid and glucose levels and various GR and ACTHR genotypes. Subjects with AG genotype of GR 5556A/G polymorphism had lower plasma cortisol levels than AA genotype. Compared with subjects with GG genotype of GR 4534-4536GAG/AAA [GAGAGG (GluArg)>GAAAAG(GluLys)] polymorphism, those with AG genotype had significantly lower plasma cortisol levels. Subjects with CC and CG genotypes of GR 6294C/G polymorphism also had significantly lower plasma cortisol levels compared with those with GG genotype. With regard to plasma ACTH levels, those with TT genotype of ACTHR 2T/C polymorphism were significantly lower than CC and CT genotypes, and those with AG genotype for GR 5556 A/G polymorphism were also significantly lower than AA genotype. There was no difference in plasma cortisol and glucose levels between subjects with GR and ACTHR gene variants. GR gene variants (5556A/G, 4534-4536GAG/AAA and 6294C/G polymorphisms) may influence plasma cortisol level, and ACTHR 2T/C, GR 5556A/G polymorphisms may decrease plasma ACTH level.

Central Actions of the Chemokine Stromal Cell-Derived Factor 1 Contribute to Neurohumoral Excitation in Heart Failure Rats

The ample expression of chemokines and their receptors by neurons in the brain suggests that they play a functional role beyond the coordination of inflammatory and immune responses. Growing evidence implicates brain chemokines in the regulation of neuronal activity and neurohormonal release. This study examined the potential role of brain chemokines in regulating hemodynamic, sympathetic, and neuroendocrine mechanisms in rats with ischemia-induced heart failure (HF). Immunohistochemical analysis revealed that the chemokine stromal cell-derived factor 1 (SDF-1)/CXCL12 was highly expressed in the hypothalamic paraventricular nucleus and subfornical organ and that SDF-1 expression was significantly increased in HF rats compared with sham-operated (SHAM) control rats. ICV injection of SDF-1 induced substantial and long-lasting increases in blood pressure, heart rate, and renal sympathetic nerve activity in both SHAM and HF rats, but responses were exaggerated in HF rats. Bilateral microinjection of SDF-1 into the paraventricular nucleus also elicited exaggerated increases in blood pressure, heart rate, and renal sympathetic nerve activity in the HF rats. A 4-hour ICV infusion of SDF-1 increased plasma levels of arginine vasopressin, adrenocorticotropic hormone, and norepinephrine in normal rats, responses that were prevented by pretreatment with ICV SDF-1 short-hairpin RNA (shRNA). ICV administration of SDF-1 shRNA also reduced plasma arginine vasopressin, adrenocorticotropic hormone, and norepinephrine levels in HF rats. These data suggest that the chemokine SDF-1, acting within the brain, plays an important role in regulating sympathetic drive, neuroendocrine release, and hemodynamic function in normal and pathophysiological conditions and so may contribute to the neural and humoral activation in HF.

Anticipation of public speaking and sleep and the hypothalamic‐pituitary‐adrenal axis in women with irritable bowel syndrome

Evidence suggests that subgroups of patients with irritable bowel syndrome (IBS) are hyper-responsive to a variety of laboratory stress conditions. This study compared sleep quality and night time plasma adrenocorticotropic hormone (ACTH) and serum cortisol levels in response to anticipation of public speaking between 43 women with IBS and 24 healthy control women. In addition, comparisons were made between subgroups within the IBS sample based on predominant stool patterns, 22 IBS-constipation and 21 IBS-diarrhea. Subjects slept three nights in a sleep laboratory, and on the third night serial blood samples were drawn every 20 min from 08:00 PM until awakening. As the subjects had different sleep onsets, each subject's results were synchronized to the first onset of stage 2 sleep. Compared the healthy control group, women with IBS had significantly worse sleep efficiency, and higher cortisol but not ACTH levels over the night. However, there were no IBS bowel pattern subgroup differences. Among IBS subjects, cortisol levels early in the night were higher than found in our previous study with a similar protocol but without the threat of public speaking. These results suggest that a social stressor, such as public speaking prior to bedtime, increases cortisol but not ACTH levels suggesting HPA dysregulation in women with IBS. This response to a social stressor contributes to our understanding of the relationship of stress to symptom expression in IBS.

Comparison of the effects of pantethine and fursultiamine on plasma levels of adrenocorticotropic hormone and neuropeptide Y under continual stress exposure

Some abnormalities of gastrointestinal function are presumed to result from changes in levels of stress-related hormones from the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system (SNS), represented by adrenocorticotropic hormone (ACTH) and neuropeptide Y (NPY), respectively. We examined the effects of pantethine and fursultiamine on plasma levels of ACTH- and NPY-like immunoreactive substances (IS) in healthy subjects under continual stress from repetitive blood sampling. An open-labelled crossover study was conducted on five healthy volunteers. Each subject was administered a single oral dose each of pantethine, fursultiamine and placebo at intervals of one month. Venous blood samples were collected before and at 20, 40, 60, 90, 120, 180 and 240minutes after each administration. Plasma levels of ACTH- and NPY-IS were measured using a highly sensitive enzyme immunoassay. Serial blood sampling increased plasma ACTH-IS and NPY-IS levels, presumably due to stress. Oral administration of pantethine resulted in a significant decrease in plasma ACTH-IS level compared to placebo. Fursultiamine administration resulted in a significant decrease in plasma NPY-IS level compared to placebo. These findings suggest that pantethine and fursultiamine may have modulatory effects on the HPA axis and SNS, respectively, and may be useful to treat postoperative ileus not only by improving gastrointestinal motility but also by ameliorating mental stress.

A 12-Month Phase 3 Study of Pasireotide in Cushing's Disease

BackgroundCushing's disease is associated with high morbidity and mortality. Pasireotide, a potential therapy, has a unique, broad somatostatin-receptor–binding profile, with high binding affinity for somatostatin-receptor subtype 5.MethodsIn this double-blind, phase 3 study, we randomly assigned 162 adults with Cushing's disease and a urinary free cortisol level of at least 1.5 times the upper limit of the normal range to receive subcutaneous pasireotide at a dose of 600 μg (82 patients) or 900 μg (80 patients) twice daily. Patients with urinary free cortisol not exceeding 2 times the upper limit of the normal range and not exceeding the baseline level at month 3 continued to receive their randomly assigned dose; all others received an additional 300 μg twice daily. The primary end point was a urinary free cortisol level at or below the upper limit of the normal range at month 6 without an increased dose. Open-label treatment continued through month 12.ResultsTwelve of the 82 patients in the 600-μg group and 21 of the 80 patients in the 900-μg group met the primary end point. The median urinary free cortisol level decreased by approximately 50% by month 2 and remained stable in both groups. A normal urinary free cortisol level was achieved more frequently in patients with baseline levels not exceeding 5 times the upper limit of the normal range than in patients with higher baseline levels. Serum and salivary cortisol and plasma corticotropin levels decreased, and clinical signs and symptoms of Cushing's disease diminished. Pasireotide was associated with hyperglycemia-related adverse events in 118 of 162 patients; other adverse events were similar to those associated with other somatostatin analogues. Despite declines in cortisol levels, blood glucose and glycated hemoglobin levels increased soon after treatment initiation and then stabilized; treatment with a glucose-lowering medication was initiated in 74 of 162 patients.ConclusionsThe significant decrease in cortisol levels in patients with Cushing's disease who received pasireotide supports its potential use as a targeted treatment for corticotropin-secreting pituitary adenomas. (Funded by Novartis Pharma; ClinicalTrials.gov number, NCT00434148.)

The Effects of Dexamethasone Treatment in Early Gestation on Hypothalamic–Pituitary–Adrenal Responses and Gene Expression at 7 Months of Postnatal Age in Sheep

We determined the effects of prenatal dexamethasone administration in early gestation on development of the hypothalamic-pituitary-adrenal (HPA) axis up to 7 months of postnatal age with measurements of hormone levels and gene expression. Plasma adrenocorticotropic hormone and cortisol levels after corticotropin-releasing hormone (CRH)/arginine vasopressin challenge were lower in treatment females than in control females and treatment males. Calculation of cortisol to adrenocorticotropic hormone ratios indicated however that the adrenals of treatment females were more responsive to adrenocorticotropic hormone than control females or treatment males. Effects of treatment and sex dependence at 7 months of age were observed in levels of hypothalamic CRH messenger RNA (mRNA), hypothalamic arginine vasopressin mRNA, pituitary proopiomelanocortin mRNA, pituitary prohormone convertase 1 and prohormone convertase 2, glucocorticoid receptor and mineralocorticoid receptor in the hypothalamus and hippocampus, adrenal adrenocorticotropic hormone receptor, steroidogenic acute regulatory, 3β hydroxysteroid dehydrogenase, and 11β hydroxysteroid dehydrogenase type 2 mRNA. The results indicate that exposure to glucocorticoids in early pregnancy produces persisting and sex-dependent effects on the hypothalamic-pituitary-adrenal axis at 7 months of age.

Modulation of hypothalamic–pituitary–interrenal axis function by social status in rainbow trout

Juvenile rainbow trout (Oncorhynchus mykiss) form stable dominance hierarchies when confined in pairs. These hierarchies are driven by aggressive competition over limited resources and result in one fish becoming dominant over the other. An important indicator of low social status is sustained elevation of circulating cortisol levels as a result of chronic activation of the hypothalamic–pituitary–interrenal (HPI) axis. In the present study it was hypothesized that social status modulates the expression of key proteins involved in the functioning of the HPI axis. Cortisol treatment and fasting were used to assess whether these characteristics seen in subordinate fish also affected HPI axis function. Social status modulated plasma adrenocorticotropic hormone (ACTH) levels, cortisol synthesis, and liver glucocorticoid receptor (GR) expression. Plasma ACTH levels were lower by approximately 2-fold in subordinate and cortisol-treated fish, consistent with a negative feedback role for cortisol in modulating HPI axis function. Although cortisol-treated fish exhibited differences in corticotropin-releasing factor (CRF) and CRF-binding protein (CRF-BP) mRNA relative abundances in the preoptic area and telencephalon, respectively, no effect of social status on CRF or CRF-BP was detected. Head kidney melanocortin 2 receptor (MC2R) mRNA relative levels were unaffected by social status, while mRNA relative abundances of steroidogenic acute regulatory protein (StAR) and cytochrome P450 side chain cleavage (P450scc) enzyme were elevated in dominant fish. Liver GR2 mRNA and total GR protein levels in subordinate fish were lower than control values by approximately 2-fold. In conclusion, social status modulated the functioning of the HPI axis in rainbow trout. Our results suggest altered cortisol dynamics and reduced target tissue response to this steroid in subordinate fish, while the higher transcript levels for steroid biosynthesis in dominant fish leads us to propose an adaptive role for responding to subsequent stressors.