Administration Of Corticotropin-releasing Hormone Research Articles

6917 Multiple Red Herrings Complicating the Diagnosis of Cyclic Cushing’s Syndrome

Abstract Disclosure: A. Grover: None. R. McGlotten: None. L.K. Nieman: None. Introduction: Cyclic Cushing’s syndrome (CCS) is a rare disorder characterized by intermittent hypercortisolemia. It may be caused by pituitary tumor (Cushing disease), ectopic ACTH tumor secretion (EAS), or primary adrenal disease. We present a case of CCS with multiple red herrings complicating the diagnosis. Case: A 57-year-old Cushingoid appearing woman presented elsewhere with weight gain, brain fog, weakness, hypertension, worsening diabetes, and OSA. Screening tests showed more than three episodes of hypercortisolism with interval eucortisolism: salivary and 24-urine cortisol (UFC) ranged from 0.06-0.34 µg/dL (reference range, RR, ≤0.09 µg/dL) and 59.7-137.1 µg/24 h (RR 4-50 µg/24 h) respectively. The patient was symptomatic throughout. Differential diagnosis was CCS vs a physiologic non-neoplastic condition. As she had no clear etiology for the latter, further testing was performed. ACTH was indeterminate (23-27 pg/mL, RR <46). Pituitary MRI showed a left 7 mm lesion. Inferior petrosal sinus sampling (IPSS) with Corticotropin Releasing Hormone (CRH) administration showed peripheral baseline ACTH levels of 9.0 and 10.0 pg/mL, suggesting that she had cycled out of a hypercortisolemic phase. The left petrosal baseline values were low (9 pg/mL,16 pg/mL), suggesting poor catheterization, which was confirmed by a low prolactin-normalized ACTH ratio. The petrosal levels were lower than expected (maximum 767 pg/ml), due to suppression of normal corticotropes vs poor tumor response. However, a central:peripheral step-up was consistent with Cushing's disease (CD) or pseudo-CS. She was referred to us for re-evaluation. A low FSH, LH, low normal TSH, and UFC of 160 µg/24h supported a diagnosis of CS. ACTH was 14.6 pg/mL. Pituitary MRI showed a 1.3 cm x 0.8 cm mass extending into the left cavernous sinus. She did not suppress cortisol during a dexamethasone suppression test (DST). After CRH administration ACTH levels doubled. Based on the macroadenoma and CRH response, CD was established; IPSS was not repeated. After transsphenoidal hypophysectomy, pathology revealed ACTH positive adenoma. Post-operative adrenal insufficiency required hydrocortisone replacement. Conclusion: CCS can pose a diagnostic challenge due to unpredictable duration and frequency of hypercortisolism. Intermittently elevated cortisol levels with CS symptoms should raise suspicion for CCS. In our case, low peripheral ACTH levels further suggested this possibility. DST may give spurious results in CCS owing to spontaneous falls or rises in cortisol at the time of testing. Prolonged hypercortisolism is required in all patients to ensure suppression of normal corticotropes, which if not complete, may confound results in patients with EAS. Finally, inadequate catheterization may affect accuracy of lateralization in any patient with CS and is ideally evaluated both by venography and prolactin measurement. Presentation: 6/1/2024

Psychological stress induces hair regenerative disorders through corticotropin-releasing hormone-mediated autophagy inhibition

Psychosocial stress is increasing, causing a growing number of people to suffer from hair loss. Stress-related corticotropin-releasing hormone (CRH) is associated with hair loss, but the mechanism by which hair follicles respond to stress and CRH remain poorly understood. The aim of the study is to elucidate the association between CRH and stress-related hair regenerative disorders, and reveal the potential pathological mechanisms. A chronic unpredictable stress mouse model and a chronic social defeat stress mouse model were used to examine the role of CRH and stress-related hair regrowth. Chronic unpredictable stress and chronic social defeat stress increased the expression of CRH and CRH receptors (CRHRs), and contributed to the onset of hair-cycle abnormalities. Psychoemotional stress and stress-related CRH blocked hair follicle regrowth, which could be restored by astressin, a CRHR antagonist. Long-term exposure to either chronic unpredictable stress or CRH induced a decrease in autophagy, which could be partially rescued by astressin. Activating CRHR, by stress or CRH administration, decreased autophagy via the mTOR-ULK1 signaling pathway to mediate hair regenerative disorders, which could be partially reversed through enhancing autophagy by administration of brefeldin A. These findings indicate that CRH-mediated autophagy inhibition play an important role in stress-induced hair regenerative disorders. CRH regulates the local hypothalamic-pituitary-adrenal axis of hair follicles, but also plays an independent pathogenic role in stress-related hair regenerative disorders through CRH-mediated autophagy inhibition. This work contributes to the present understanding of hair loss and suggests that enhancing autophagy may have a therapeutic effect on stress-induced hair loss.

Corticotropin-releasing hormone and vasopressin challenge affects metabolic, hematologic, and rumen fermentation parameters of growing beef steers.

The objective of this study was to evaluate the impacts of stress challenge duration on metabolic, hematologic, and rumen fermentation parameters of beef steers. Thirty steers (416 ± 19kg) were used in a randomized complete block design with 2 blocks and 3 treatments. Treatments were intravenous injection of (1) saline at 0, 24, 48, and 72h (n = 10; control); (2) corticotropin-releasing hormone (CRH) and vasopressin (VP) at 0h and saline at 24, 48, and 72h (n = 10; acute); or (3) CRH and VP at 0, 24, 48, and 72h (n = 10; chronic). Serum samples were collected at various time points for analysis of serum chemistry and nonesterified fatty acids (NEFA). Whole blood was collected for analysis of complete blood count, and ruminal fluid was collected via oral lavage to evaluate volatile fatty acid (VFA) composition. Serum cortisol was greater (treatment × hour; P ≤ 0.01) for cattle receiving acute and chronic than control at 1h (P < 0.01) and greater for chronic than acute and control at 25, 26, 49, 50, 73, and 74h (P < 0.01). Similarly, there was a treatment × hour interaction (P < 0.01) for serum glucose concentrations such that cattle receiving acute and chronic had greater glucose at 1h than control (P < 0.01), and cattle receiving chronic had greater glucose at 25, 49, 73, and 74h than acute and control (P ≤ 0.04). Serum insulin concentrations were greater (treatment × hour P < 0.01) in chronic and acute than control at 1h (P < 0.01) and greater for chronic compared to acute and control at 25, 49, and 73h (P ≤ 0.01). Serum NEFA tended (P = 0.09) to be greater in stressed cattle compared to control. There was a treatment × hour interaction (P = 0.003) for total white blood cell count such that chronic had greater concentration than control at 72h (P < 0.01). Conversely, monocyte concentration was less (treatment × hour interaction P < 0.01) for chronic than acute and control at 144h (P < 0.01) and eosinophil concentration was greater (treatment × hour interaction P = 0.02) for chronic than control steers at 48h (P = 0.02) and greater for chronic than acute at 72 and 144h (P ≤ 0.03). Minimal differences were observed in VFA concentrations with the exception of acetate (treatment × hour interaction P = 0.05). These results demonstrate that administration of CRH and VP affects complete blood count and serum chemistry, and longer duration of treatment exposure prolongs the physiological responses to a stress challenge.

Acute iv CRH administration significantly increases serum active ghrelin in postmenopausal PCOS women compared to postmenopausal controls.

In women with Polycystic Ovarian Syndrome (PCOS), an increased risk of disordered eating has been described. There is growing interest regarding a possible interconnection between psychological states and increased appetite in women with PCOS. Acute stress is characterized by increased Corticotropin Releasing Hormone (CRH) secretion. The aim was to estimate the ghrelin concentrations during CRH test. Twenty postmenopausal women with PCOS and twenty age- and BMI- matched postmenopausal control women were recruited at Aretaieion University Hospital. In the morning (9 am) all subjects had anthropometric measurements (weight, height, waist circumference) and a fasting sample for hormonal measurements. An intravenous (iv) CRH stimulation test conducted over 1 min. Serum active ghrelin levels were measured at 0, 15, 30, 60, 90, 120 min after iv CRH administration. The postmenopausal PCOS group had a higher waist circumference compared to postmenopausal controls. Active ghrelin concentrations increased significantly from 0 to 15 min, to 30 min, to 60 min, to 90 min and then decreased to 120 min. However, within the postmenopausal control group there were no significant changes in serum active ghrelin levels. Serum active ghrelin concentrations were significantly greater in the postmenopausal control group at 0, 15 and 120 min compared to the postmenopausal PCOS group. At 90 min active ghrelin concentrations were significantly greater in the postmenopausal PCOS group. Delta Area Under the Curve of active ghrelin (ΔAUCghr) was significantly greater in the postmenopausal PCOS group compared to controls. In postmenopausal PCOS, but not in postmenopausal controls, iv CRH administration induces increased serum active ghrelin secretion, suggesting a possible anti-stress adaptive mechanism. An increase in serum active ghrelin may induce hunger as a side-effect of this presumed adaptive mechanism.

Transcutaneous vagal nerve stimulation protects against stress-induced intestinal barrier dysfunction in healthy adults.

Intestinal barrier dysfunction is the likely initiating event in multiple human diseases. Currently, there are limited therapeutic strategies to address its dysfunction. Animal studies suggest that vagal nerve stimulation may improve intestinal barrier function, but this has not been evaluated in humans. This study aimed to determine the effect of vagal nerve stimulation on intestinal permeability in adults administered a bolus dose of intravenous corticotropin releasing hormone (CRH) which has been shown to increase small intestinal permeability in healthy human subjects. In a cross-over study, 16 volunteers (median age 34years, 11 female) were randomized to receive auricular transcutaneous vagal nerve or sham stimulation (10minutes each side) after intravenous administration of 100µg of CRH. Intestinal barrier function was measured before and 2h after each intervention with dual-sugar urine testing (lactulose:mannitol ratio) and intestinal fatty-acid binding protein (I-FABP). Exposure to CRH increased I-FABP concentrations by a median of 49 (IQR 4-71)% (p = 0.009). Lactulose:mannitol ratios were 0.029 (0.025-0.050) following vagal stimulation compared with 0.062 (0.032-0.170) following sham stimulation (p = 0.0092), representing a fall of 53 (22-71)%. I-FABP concentrations did not change (p = 0.90). Brief non-invasive vagal nerve stimulation consistently reduces paracellular permeability of the small intestine after CRH administration, but does not entirely mitigate I-FABP release from the epithelium. Studies of vagal nerve stimulation in disease states are warranted.

Beyond depression and anxiety; a systematic review about the role of corticotropin-releasing hormone antagonists in diseases of the pelvic and abdominal organs.

Evidence for beneficial effects of corticotropin releasing hormone (CRH) antagonists in abdominal and pelvic organs is emerging in preclinical studies. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement a compilation of preclinical studies using CRH receptor antagonists as a treatment for abdominal and pelvic disease was carried out. The Animal Research: Reporting of In Vivo Experiments (ARRIVE) essential 10 guidelines were used to determine quality of the included studies. A total of 40 studies from the last 15 years studying irritable bowel syndrome, inflammatory bowel disease, endometriosis, enteritis, stress impact on gastrointestinal processes and exogenous CRH administration effects were included. Blockage of the CRH receptor 1 was mainly associated with beneficial effects while that of CRH receptor 2 worsened studied effects. However, time of administration, route of administration and the animal model used, all had an impact on the beneficial outcomes. Frequency of drugs administered indicated that astressin-2B, astressin and antalarmin were among the most utilized antagonists. Of concern, studies included were predominantly carried out in male models only, representing a gender discrepancy in preclinical studies compared to the clinical scenario. The ARRIVE score average was 13 with ~60% of the studies failing to randomize or blind the experimental units. Despite the failure to date of the CRH antagonists in moving across the clinical trials pipeline, there is evidence for their beneficial effects beyond mood disorders. Future pre-clinical studies should be tailored towards effectively predicting the clinical scenario, including reduction of bias and randomization.

Corticotropin releasing hormone promotes inflammatory bowel disease via inducing intestinal macrophage autophagy

Psychosocial stress is a vital factor contributing to the pathogenesis and progression of inflammatory bowel disease (IBD). The contribution of intestinal macrophage autophagy to the onset and development of IBD has been widely studied. Herein, we investigated the underlying mechanism of psychosocial stress in an IBD mouse model pertaining to macrophage autophagy. Corticotropin releasing hormone (CRH) was peripherally administrated to induce psychosocial stress. For in vivo studies, dextran sulfate sodium (DSS) was used for the creation of our IBD mouse model. For in vitro studies, lipopolysaccharide (LPS) was applied on murine bone marrow-derived macrophages (BMDMs) as a cellular IBD-related challenge. Chloroquine was applied to inhibit autophagy. We found that CRH aggravated the severity of DSS-induced IBD, increasing overall and local inflammatory reactions and infiltration. The levels of autophagy in intestinal macrophages and murine BMDMs were increased under these IBD-related inflammatory challenges and CRH further enhanced these effects. Subsequent administration of chloroquine markedly attenuated the detrimental effects of CRH on IBD severity and inflammatory reactions via inhibition of autophagy. These findings illustrate the effects of peripheral administration of CRH on DSS-induced IBD via the enhancement of intestinal macrophage autophagy, thus providing a novel understanding as well as therapeutic target for the treatment of IBD.

Hypothalamic-pituitary-adrenal (HPA) axis response to exogenous corticotropin-releasing hormone (CRH) is attenuated in men with chronic insomnia.

Although insomnia is by far the most common sleep disorder, our understanding of its neurobiology is limited. Insomnia, particularly when associated with objective sleep disturbance, has been associated with activation of the hypothalamic-pituitary-adrenal axis. The objective of this experimental study was to compare the response of the hypothalamic-pituitary-adrenal axis to ovine corticotropin-releasing hormone, a stress test, in men with insomnia versus controls. Circulating adrenocorticotropic hormone and cortisol levels were assayed before (-30min, -15min), at (0min) and after (+5min, +15min, +30min, +60min, +90min, +120min) exogenous ovine corticotropin-releasing hormone administration in 23men (11 insomnia, 12 controls), who underwent four consecutive nights of in-lab polysomnography. Men with insomnia compared with controls demonstrated markedly and significantly shorter total sleep time (368.4±8.99 min versus 411.61±8.61min; p<0.01) and lower sleep efficiency (76.77±1.80% versus 86.04±1.72%; p<0.01) on polysomnography, and showed decreased adrenocorticotropic hormone and cortisol levels after ovine corticotropin-releasing hormone administration. Adrenocorticotropic hormone levels at 15 min and 30min were significantly lower in men with insomnia than in controls (p<0.05). Similarly, the peak levels of cortisol at +60min, and the total and net area under the curve levels of this hormone were significantly lower in men with insomnia than controls (all p<0.01). Adrenocorticotropic hormone and cortisol response to ovine corticotropin-releasing hormone administration was attenuated in men with insomnia associated with objective sleep disturbance, suggesting that objectively defined insomnia subtypes have a disrupted hypothalamic-pituitary-adrenal axis function and highlight the need to develop treatments targeting the underlying hypothalamic-pituitary-adrenal axis dysregulation.

Peripheral corticotropin-releasing hormone may protect the gastric musosa against indometacin-induced injury through involvement of glucocorticoids.

The hypothalamic-pituitary-adrenocortical (HPA) system is a key hormonal branch of the brain-gut axis in stress and corticotropin-releasing hormone (CRH) is a principal stimulator of the HPA system. According to our finding activation of the HPA system has gastroprotective role in stress and CRH may protect the gastric mucosa against stress-induced injury through involvement of glucocorticoids. To extend this idea to indomethacin-induced gastric injury in the present work we studied whether CRH may protect the gastric mucosa against ulcerogenic action of indomethacin (IM) through involvement of glucocorticoids. CRH administration (1.25 μg/kg and 2.5 μg/kg, i.p.) markedly, dose-dependently, increased plasma corticosterone level and significantly, dose-dependently, suppressed the occurrence of gastric erosion induced by IM (35 mg/kg, s.c.) in conscious rats. To estimate the role of glucocorticoids in CRH-induced gastroprotection, the effect of CRH (1.25 μg/kg) on the IM-induced gastric erosion was studied after acute reduction of corticosterone release by metyrapone (30 mg/kg, i.p., 30 min before CRH administration) or by CRH receptor type 1 antagonist NBI 27914 (10 mg/kg, i.p., 15 min before CRH administration) and also after occupation of glucocorticoid receptors by their antagonist RU-38486 (20 mg/kg, i.p., 2 h before CRH administration). The effects were compared with those in control rats without acute reduction of corticosterone release or occupation of glucocorticoid receptors. Both metyrapone and NBI 27914 injected shortly before CRH administration caused an inhibition of CRH-induced corticosterone response and prevented protective effect of CRH on the gastric mucosa against the IM-induced erosion. The gastroprotective effect of CRH was also eliminated by the pretreatment with glucocorticoid receptor antagonist RU-38486. The results obtained suggest that exogenous CRH may protect the gastric mucosa against IM-induced gastric injury through involvement of glucocorticoids.

The Dexamethasone-CRH Stimulation Test: A Single-Center Experience

Background: The diagnostic value of adding a Corticotropin Releasing Hormone (CRH) Stimulation Test to the 2-day Low Dose Dexamethasone Suppression Test (Dex-CRH Test) has been debated in the literature. We hypothesized that adding CRH to LDDST would provide additional case detection in patients suspected of having Cushing’s disease (CD). Methods: We identified 118 patients who underwent the Dex-CRH test to evaluate ACTH-dependent CS from a prospectively maintained pituitary database over 12 years. Seven patients were excluded (2 lost to follow up, 2 were on Dilantin with no available Dexamethasone (Dex) level, 2 had cyclic CD, and 1 suspected noncompliance with Dex intake). Three patients with ectopic ACTH Syndrome had very high cortisol levels after both LDDST and Dex-CRH tests. The remaining 108 patients are the subjects of this analysis. Patients were instructed to take 8 doses of Dex 0.5 mg PO every 6 hours starting at noon with the last dose of Dex taken at 6 AM. Ovine CRH injection (1 µg/kg, max 100 mcg) was given IV 2 hours afterwards. Cortisol was measured 2 hours after the last Dex dose prior to and 15 minutes after CRH administration. CD diagnosis was made based on positive ACTH staining on pituitary pathology and/or development of hypocortisolism postoperatively. Patients with no Cushing disease (NCD) are the group of patients in whom CD diagnosis could not be confirmed after a minimum follow up of 30 months. Results: Among 108 patients who underwent Dex-CRH test, 66 had CD and 42 had NCD. The female sex ratio, and median (range) for each of age, BMI, and follow-up duration in months were as follows with no statistically significant difference between the two groups: CD: 83%, 40 (15–82), 34 (30–42) and 63 (24–102). NCD: 88%, 40 (20–71), 37 (31–43) and 52 (30–67). Among 66 patients with CD, 5 patients (7.6%) had a cortisol level ≤ 1.4 µg/dl after LDDST but were appropriately classified as CD with a cortisol level >1.4 µg/dL at 15-min post CRH stimulation. In contrast, 3/42 patients (7.1%) in NCD had an abnormal Dex-CRH test. In only one of these three patients the LDDST was normal (cortisol post-Dex was 1.4 µg/dL and increased to 3.1 µg/dL 15-min post CRH). A cortisol cut-off value of > 1.4 µg/dL at 15 min during Dex-CRH test provided a sensitivity of 100%, specificity of 93%, and diagnostic accuracy of 97% to diagnose CD. When patients without a Dex level were excluded from the analysis (n=74), the sensitivity did not change but specificity and accuracy of Dex-CRH test further increased to 97% and 99%, respectively. Conclusion: The CRH test addition to the 2-day LDDST provided additional case detection in 5/66 (7.6%) of patients with CD. It resulted in one additional false-positive case compared to LDDST. Measurement of Dex level provided improved diagnostic accuracy of DEX-CRH test.

Outcome of Petrosal Venous Sampling in Consecutive 68 Patients From a Major Neurosurgical Center in the United Kingdom

Background: Cushing’s disease is a challenging endocrine disorder caused by non-physiological cortisol excess from adrenocorticotropic hormone (ACTH) secreting pituitary adenoma. Inferior petrosal venous sampling (IPSS) is considered the gold standard investigation to differentiate Cushing’s disease from ectopic ACTH syndrome. Methods: This retrospective study included all patients who underwent IPSS between January 2011 and October 2020 at The National Hospital for Neurology and Neurosurgery in London. Patients demographics, radiological, surgical, endocrinological and, histological data were retrieved. We assessed the accuracy of IPSS in localizing ACTH secreting pituitary adenoma and its concordance with neuroimaging and surgical findings at the time of tumor resection. Results: In total 68 patients underwent IPSS, 22 males and 46 females. The median age was 42 years. IPSS was performed prior to primary surgery in 61 patients (90%) and before secondary surgery in 4 patients (6%). Three patients (4%) are awaiting surgery at the time of our study. Fifty-two patients (80%) had positive histology of ACTH expressing adenoma. Four patients (8%) had ectopic ACTH syndrome. The sensitivity of IPSS in predicting Cushing’s disease prior to corticotropin-releasing hormone (CRH) stimulation was 91% (95% CI [83% to 97%]) and accuracy of 88% (95% CI [77% to 95%]). The sensitivity of IPSS post CRH administration was 96% (95% CI [87% to 100%]) with accuracy of 86% (95% CI [75% to 93%]). Data on lateralization of pituitary adenoma were available for 63 patients. Prior to CRH stimulation, lateralization was right sided in 35 patients (56%), left sided in 15 (24%), and 13 patients (20%) did not have adequate interpetrosal sinus ACTH ratio. Lateralization post CRH stimulation was right sided in 40 patients (64%), left sided in 20 (32%), and 3 patients (4%) did not achieve adequate ACTH gradient ratio between two sides. Eighteen patients (30%) switched adenoma lateralization between pre and post CRH stimulation. Post CRH IPSS was consistent with neuroradiology in localizing pituitary adenomas in 59% (29 out of 49 patients) and concordant with surgical findings in 41% (25 out of 61 patients). Patients with ectopic ACTH syndrome had negative IPSS at all stages. IPSS procedure failed in 2 patients (3%). No post procedure complications were reported. Conclusion: IPSS has high sensitivity in diagnosing pituitary driven Cushing’s disease with good safety profile. However, the reliability in lateralizing pituitary adenoma is debated. One third of patients in this cohort switched lateralization before and after CRH administration. Studies on monkeys and rats showed that CRH induces coronary vasodilation and reduction in systemic vascular resistance.This suggest that CRH might have vasoactive effect on pituitary blood vessels with subsequent influence on IPS:P ACTH gradient ratio between the two sides.

Concordant pattern of the HPA axis response to visceral stimulation and CRH administration

The physiological and psychological mechanisms explaining the individual variability in the stress response are poorly understood. We tested the hypothesis that hypothalamic-pituitary- adrenal (HPA) axis responses to colorectal stimulation affect HPA axis reactivity to corticotropin-releasing hormone (CRH), the visceral pain threshold, and perceived stress. We examined 31 healthy volunteers and 27 individuals with irritable bowel syndrome. According to the ACTH response to colorectal stimulation, the participants were classified into three groups: flattened, decreased, and increased. We found significant differences in the abdominal pain threshold, discomfort threshold, and sensitivity to anxiety among the groups. There were significant differences in the ACTH change and peak level after CRH administration among the groups. The area under the curve of the cortisol response to CRH was significantly different among the groups. The increased group showed a higher basal ACTH level, earlier peak level in the CRH administration test, and higher stress rating during the experiment. The increased group had an exaggerated psychological and physiological stress response, whereas the decreased group had a higher anticipatory endocrine response, stress, and sensitivity to anxiety. Further studies are needed to determine factors including gut microbiota on the individual difference in HPA response.

Sleep in pituitary insufficient patients compared to patients with depression and healthy controls at baseline and after challenge with CRH

Sleep disturbances are prevalent in both patients with pituitary insufficiency and with depression. The role of corticotropin releasing hormone (CRH), involved in sleep regulation, has not been fully clarified. Pituitary insufficiency is an ideal model for studying sleep-endocrine effects since no consecutive hormone releases and feedback effects occur after hormone administration. 11 male patients with a chronic insufficiency of the anterior pituitary gland (PI) and under stable hormonal substitution were studied during three consecutive nights in the sleep laboratory. The first night served for adapting to laboratory setting, during the second night placebo was administered and during the third night 4 × 50 μg CRH were injected in pulsatile fashion. Sleep parameters were additionally compared with those of 15 healthy male controls (C) and 15 male patients with depression (D). CRH administration was associated with a numerical increase of wake time (115 ± 15 to 131 ± 13 min) and a decrease of REM sleep (89 ± 8 to 80 ± 8 min), REM latency (69 ± 14 to 55 ± 9 min) and slow wave sleep (66 ± 16 to 57 ± 15 min). Yet, none of these changes reached statistical significance. PI showed a worse sleep profile as compared to both control groups, e.g. indicated by a significantly lower sleep efficiency index (PI:0.80 ± 0.03 vs. C:0.94 ± 0.01 vs. D:0.87 ± 0.03). In conclusion sleep-EEG changes after CRH in PI patients resemble those found in in part in patients with depression. Sleep in anterior pituitary insufficiency was impaired despite full hormonal substitution possibly suggesting an alteration of the receptor organisation of brain structures involved in sleep regulation.

Hypothalamic-Pituitary-Adrenal Axis Responses in Women with Endometriosis-Related Chronic Pelvic Pain.

Some chronic pain conditions and comorbidities suppress the hypothalamic-pituitary-adrenal (HPA) axis and response to dynamic testing. We measured HPA axis responses to corticotropin-releasing hormone (CRH) administration in relation to chronic pelvic pain and endometriosis. In a cross-sectional study of women (n = 54) with endometriosis-associated chronic pelvic pain (n = 22), chronic pelvic pain alone (n = 12), or healthy volunteers (n = 20), adrenocorticotropic-releasing hormone (ACTH) and cortisol levels were measured at 0, 15, 30, and 45min after intravenous ovine CRH administration. ACTH and cortisol delta (peak-baseline) and area under the curve (AUC) were compared by study group and assessed for association with race and menstrual and non-menstrual pain severity. HPA axis responses did not differ among the racially diverse groups or in those with pain compared with healthy volunteers. However, when stratified by race, ACTH delta (129.9 ± 130.7 vs. 52.5 ± 66.0pg/mL; p = 0.003), ACTH AUC (4813 ± 4707 vs. 2290 ± 2900min*pg/mL; p = 0.013), and cortisol delta (26.3 ± 21.5 vs. 13.2 ± 9.7μg/mL; p = 0.005) were significantly higher in black (n = 10) than predominately white (non-black) subjects (n = 44; 39/44 white). In analyses among primarily white (non-black) women, greater menstrual pain severity was associated with blunted ACTH delta (p = 0.015) and cortisol delta (p = 0.023), and greater non-menstrual pain severity with blunted cortisol delta (p = 0.017). Neuroendocrine abnormalities in women with chronic pelvic pain may differ by pain manifestations and may vary by race. The higher HPA axis response in black women merits investigation in pelvic pain studies stratified by race. In white (non-black) women experiencing pain, a blunted response was related to pain severity suggesting pain affects women independently of endometriosis lesions.

Insula Activity to Visceral Stimulation and Endocrine Stress Responses as Associated With Alexithymia in Patients With Irritable Bowel Syndrome.

Few studies have investigated associations between alexithymia and physiological mechanisms in psychosomatic diseases. We examined associations between alexithymia and 1) perception and brain processing of visceral stimulation and 2) the endocrine responses to corticotrophin-releasing hormone (CRH) in healthy individuals and patients with irritable bowel syndrome (IBS). The study included 29 patients with IBS and 35 age- and sex-matched healthy controls (HCs). Alexithymia was measured using the 20-item Toronto Alexithymia Scale (TAS-20). Brain responses to rectal distention and its anticipation were measured by functional magnetic resonance imaging and analyzed at a voxel-level threshold of puncorrected < .001 combined with a cluster-level threshold of pFWE-corrected < .05. On a different day, plasma adrenocorticotropic hormone and cortisol responses after intravenous CRH administration were measured. TAS-20 scores did not differ significantly between patients with IBS and HCs (p = .18). TAS-20 scores correlated positively with the individual rectal discomfort thresholds (βrobust = 0.49, p = .03) and negatively with the rating of fear before rectal distention (βrobust = -1.63, p = .04) in patients with IBS but not in HCs. Brain responses to rectal distention in the right insula and other brain regions were positively associated with TAS-20 scores to a greater extent in patients with IBS than in HCs. Individuals with higher TAS-20 scores (both patients with IBS and HCs) demonstrated stronger adrenocorticotropic hormone responses to CRH administration (F(4,224) = 3.54, p = .008). Higher alexithymia scores are associated with stronger physiological responses, but lower anticipatory fear ratings and higher discomfort thresholds, particularly in patients with IBS.

Effect of corticotropin releasing hormone and corticotropin releasing hormone antagonist on biosynthesis of gonadotropin relasing hormone and gonadotropin relasing hormone receptor in the hypothalamic-pituitary unit of follicular-phase ewes and contribution of kisspeptin.

This study aimed to determine the mechanisms governing Gonadotropin releasing hormone (GnRH) biosynthesis and luteinising hormone (LH) secretion in follicular-phase sheep after infusion of corticotropin releasing hormone (CRH) and/or CRH antagonist corticotropin releasing hormone nist (CRH-A) into the third cerebral ventricle. The study included two experimental approaches: first, we investigated the effect of CRH or CRH-A (α-helical CRH 9-41) on GnRH and GnRH receptor (GnRHR) biosynthesis in the preoptic area (POA), anterior (AH) and ventromedial hypothalamus (VMH), stalk/median eminence (SME), and on GnRHR in the anterior pituitary (AP) using an enzyme-linked immunosorbent assay (ELISA); second, we used real-time PCR to analyse the influence of CRH and CRH-A on the levels of kisspeptin (Kiss1) mRNA in POA and VMH including arcuate nucleus (VMH/ARC), and on Kiss1 receptor (Kiss1r) mRNA abundance in POA-hypothalamic structures. These analyses were supplemented by radioimmunoassay (RIA) and ELISA methods for measurement of LH and cortisol levels in the blood, respectively. Our results show that administration of CRH significantly decreased GnRH biosynthesis in the POA/hypothalamus. CRH also decreased GnRHR abundance in the hypothalamus and in the AP, but increased it in the POA. Furthermore, administration of CRH decreased plasma LH concentration and levels of Kiss1 mRNA in the POA and VMH/ARC as well as Kiss1r mRNA in these structures and in the SME. Significant increase in plasma cortisol concentration in the group treated with CRH was also observed. For CRH-A, all analysed effects were opposite to those induced by CRH. The study demonstrates that intracerebroventricular (i.c.v.) infusion of both CRH and CRH-A affects the GnRH/GnRHR biosynthesis and LH secretion in follicular-phase sheep conceivably via either central and peripheral mechanisms including Kiss1 neurons activity and cortisol signals. It has also been suggested that CRH and CRH-A infusion probably had effects directly at the AP.

Relationship between sympathoadrenal and pituitary-adrenal response during colorectal distention in the presence of corticotropin-releasing hormone in patients with irritable bowel syndrome and healthy controls.

Corticotropin-releasing hormone (CRH) mediates stress responses in the brain-gut axis. Administration of CRH modulates brain activation, for example by controlling the autonomic nervous system in response to colorectal distention. Here, we investigated the relationship between sympathoadrenal and hypothalamic-pituitary-adrenal (HPA) responses to colorectal distention in patients with irritable bowel syndrome (IBS). We enrolled 32 patients with IBS (16 women and 16 men) and 32 healthy subjects (16 women and 16 men), and randomly divided them between CRH and saline injection groups. The patients randomly underwent no (0 mmHg), mild (20 mmHg), or strong (40 mmHg) colorectal distension. CRH (2 μg/kg) or saline was then administered via injection, and the distention protocol was repeated. The heart rate (HR) and HR variability (HRV; calculated as the low [LF] to high frequency [HF] peak ratio, LF/HF) were analyzed using electrocardiography. Plasma noradrenaline, adrenaline, adrenocorticotropic hormone (ACTH), and cortisol levels were measured at the time of each distention. Plasma adrenaline levels were shown to be associated with plasma ACTH levels in HCs injected with CRH during distention using structural equation modeling analysis. Patients with IBS injected with placebo during distention displayed a closer association between these two parameters than those injected with CRH. Generalized estimating equation analysis revealed a significant distention × group × drug interaction for HF power. Moreover, there was a strong correlation between adrenaline and HRV upon CRH injection in controls, but not patients with IBS. The relationship between HPA-sympathoadrenal responses and CRH levels during colorectal distention differs between patients with IBS and controls. Modulation of adrenal gland activity in response to ACTH stimulation may contribute to the brain-gut pathophysiology characteristic of IBS.

Intravenous Corticotropin-releasing Hormone Administration Increases Esophageal Electrical Sensitivity in Healthy Individuals.

Background/AimsWhen a person is experiencing stress, corticotropin-releasing hormone (CRH) can modulate gut physiologies, such as visceral sensation or gastrointestinal motility, and its intravenous administration mimics stress-induced physiological changes. However, the influence of CRH on the esophagus is yet unknown. Accordingly, we investigated whether intravenous CRH administration increases esophageal sensitivity to electrical stimulation in healthy Japanese subjects.MethodsTwenty healthy subjects were recruited. We quantified the initial perception threshold (IPT) every 15 minutes after CRH injection. Venous blood was collected with a cannula, and both plasma adrenocorticotropic hormone (ACTH) and cortisol were measured at pre-stimulation, 0, 30, 60, 90, and 120 minutes. The results from each time point were compared against a baseline IPT obtained before electrical stimulation was initiated.ResultsWhen compared to the baseline IPT value (16.9 ± 4.5), CRH significantly decreased electrical threshold of the esophagus at 30, 45, 60, 75 minutes (14.1 ± 4.2, 13.1 ± 5.0, 12.1 ± 5.7, 14.0 ± 5.8 minutes, P < 0.01, respectively) after CRH injection, suggesting that CRH increased esophageal sensitivity to the electrical stimulus. CRH also significantly increased plasma ACTH levels at 30 minutes (50.3 ± 17.7, P < 0.01), and cortisol levels at 30 minutes (22.0 ± 6.7 minutes, P < 0.01) and 60 minutes (20.3 ± 6.7 minutes, P < 0.01) after CRH injection, when compared to the pre-stimulation ACTH and cortisol values.ConclusionIntravenous CRH administration increased esophageal electrical sensitivity in normal subjects, emphasizing the important role of stress in esophageal sensitivity.

Plasma cortisol response cannot be classically conditioned in a taste-endocrine paradigm in humans.

Peripheral immune responses can be modified by associative learning procedures. Less is known, however, whether and to what extent neuroendocrine parameters can be classically conditioned. In this randomized double-blind study, we modified an established paradigm to behaviorally condition endocrine responses in humans. Thirty-one healthy male participants received a distinctively flavored green drink as the conditioned stimulus (CS) and intravenous injections of corticotropin-releasing hormone (CRH) (CRH group, N=17) or NaCl (placebo group, N=14) as the unconditioned stimulus (US) during two subsequent acquisition trials. Plasma levels of cortisol and noradrenaline, heart rate, and psychological parameters were analyzed before and 15, 30, 60, 120, and 180min after injection. The two acquisition trials were followed by two evocation trials, during which participants underwent the same procedure but now receiving NaCl injections. CRH administration induced pronounced increases in cortisol and noradrenaline plasma concentrations, heart rate, and anxiety levels. However, re-exposure to the CS during evocations trials did not provoke conditioned increases in neuroendocrine parameters. Median split of the CRH group based on the cortisol baseline level into "cort-high" and "cort-low" subgroups showed that the "cort-high" subgroup displayed a significantly increased cortisol production on evocation days compared to the "cort-low" subgroup and the placebo group. This taste-endocrine paradigm employing CRH injection as the US in healthy male volunteers failed to induce a behaviorally conditioned cortisol release as a learned endocrine response. Future studies should clarify a possible role of higher baseline cortisol levels in perhaps facilitating a conditioned cortisol response.

Salivary alpha-amylase and noradrenaline responses to corticotropin-releasing hormone administration in humans

Salivary alpha-amylase (sAA) is a digestive enzyme mainly responsible for the hydrolysis of starch and glycogen in the oral cavity. Since the secretion of sAA is largely under the control of the sympathetic nervous system, sAA activity is also considered to be a non-invasive marker of sympathetic activation. However, the direct association between sAA activity and other sympathetic parameters remains questionable. Therefore, we employed the corticotropin-releasing hormone (CRH) stimulation test to pharmacologically activate the sympathetic nervous system and to analyze plasma noradrenaline response together with sAA activity. Thirty-one healthy male volunteers (mean age of 25.2±3.1years) were randomized into two groups and received injections with either CRH (100μg, N=17) or placebo (0.9% NaCl, N=14). Blood samples were taken at baseline and 15, 30, 60, 120min after injection. Results showed that CRH administration increased plasma noradrenaline and cortisol concentrations, sAA activity, heart rate, as well as self-reported side effects (i.e. flushing in the facial area, heart rate changes, giddiness, malaise and restlessness) and stress perception, while plasma adrenaline levels remained unaffected. In the CRH group, the total increase of sAA activity significantly correlated with noradrenaline release, indicating that sAA activity reflects pharmacologically induced sympathetic activation.