Patients with chronic immune-mediated arthritis exhibit abnormal hypothalamo-pituitary-adrenal (HPA) axis activity. The basis for this abnormality is not known. Immune-mediated arthritis is associated with increased extra-adrenal synthesis of active glucocorticoids by the 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme. 11β-HSD1 is expressed in the central nervous system, including regions involved in HPA axis regulation. We examined whether altered 11β-HSD1 expression within these regions contributes to HPA axis dysregulation during arthritis. The expression of 11β-HSD1, and other components of glucocorticoid signaling, were examined in various brain regions and the pituitary gland of mice with experimentally induced arthritis. Two arthritis protocols were employed: The K/BxN spontaneous arthritis model for chronic arthritis and the K/BxN serum transfer arthritis model for acute arthritis. 11β-HSD1 mRNA (Hsd11b1) was expressed in the hippocampus, hypothalamus, cortex, cerebellum and pituitary gland. Hypothalamic Hsd11b1 expression did not change in response to arthritis in either model. Pituitary Hsd11b1 expression was however significantly increased in both chronic and acute arthritis models. Hippocampal Hsd11b1 was decreased in acute but not chronic arthritis. Chronic, but not acute, arthritis was associated with a reduction in hypothalamic corticotropin-releasing hormone and arginine vasopressin expression. In both models, serum adrenocorticotropic hormone and corticosterone levels were no different from non-inflammatory controls. These findings demonstrate inflammation-dependent regulation of Hsd11b1 expression in the pituitary gland and hippocampus. The upregulation of 11β-HSD1 expression in the pituitary during both chronic and acute arthritis, and thus, an increase in glucocorticoid negative feedback, could contribute to the abnormalities in HPA axis activity seen in immune-mediated arthritis.
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Janko Sattler, Jinwen Tu, Shihani Stoner, Jingbao Li, Frank Buttgereit, Markus J Seibel, Hong Zhou and Mark S Cooper
Clara Odilia Sailer, Sophia Julia Wiedemann, Konrad Strauss, Ingeborg Schnyder, Wiebke Kristin Fenske and Mirjam Christ-Crain
Osmotic stimulus or stress results in vasopressin release. Animal and human in vitro studies have shown that inflammatory parameters, such as interleukin-8 (IL-8) and tumor necrosis factor-α (TNF-α), increase in parallel in the central nervous system and bronchial, corneal or intestinal epithelial cell lines in response to osmotic stimulus. Whether osmotic stimulus directly causes a systemic inflammatory response in humans is unknown. We therefore investigated the influence of osmotic stimulus on circulatory markers of systemic inflammation in healthy volunteers. In this prospective cohort study, 44 healthy volunteers underwent a standardized test protocol with an osmotic stimulus leading into the hyperosmotic/hypernatremic range (serum sodium ≥150 mmol/L) by hypertonic saline infusion. Copeptin – a marker indicating vasopressin activity – serum sodium and osmolality, plasma IL-8 and TNF-α were measured at baseline and directly after osmotic stimulus. Median (range) serum sodium increased from 141 mmol/L (136, 147) to 151 mmol/L (145, 154) (P < 0.01), serum osmolality increased from 295 mmol/L (281, 306) to 315 mmol/L (304, 325) (P < 0.01). Median (range) copeptin increased from 4.3 pg/L (1.1, 21.4) to 28.8 pg/L (19.9, 43.4) (P < 0.01). Median (range) IL-8 levels showed a trend to decrease from 0.79 pg/mL (0.37, 1.6) to 0.7 pg/mL (0.4, 1.9) (P < 0.09) and TNF-α levels decreased from 0.53 pg/mL (0.11, 1.1) to 0.45 pg/mL (0.12, 0.97) (P < 0.036). Contrary to data obtained in vitro, circulating proinflammatory cytokines tend to or decrease in human plasma after osmotic stimulus. In this study, osmotic stimulus does not increase circulating markers of systemic inflammation.
Peter Ergang, Anna Mikulecká, Martin Vodicˇka, Karla Vagnerová, Ivan Mikšík and Jirˇí Pácha
Stress is an important risk factors for human diseases. It activates the hypothalamic–pituitary–adrenal (HPA) axis and increases plasma glucocorticoids, which are powerful regulators of immune system. The response of the target cells to glucocorticoids depends not only on the plasma concentrations of cortisol and corticosterone but also on their local metabolism. This metabolism is catalyzed by 11β-hydroxysteroid dehydrogenases type 1 and 2, which interconvert glucocorticoid hormones cortisol and corticosterone and their 11-oxo metabolites cortisone and 11-dehydrocorticosterone. The goal of this study was to determine whether stress modulates glucocorticoid metabolism within lymphoid organs – the structures where immune cells undergo development and activation. Using the resident-intruder paradigm, we studied the effect of social stress on glucocorticoid metabolism in primary and secondary lymphoid organs of Fisher 344 (F344) and Lewis (LEW) rats, which exhibit marked differences in their HPA axis response to social stressors and inflammation. We show that repeated social defeat increased the regeneration of corticosterone from 11-dehydrocorticosterone in the thymus, spleen and mesenteric lymphatic nodes (MLN). Compared with the F344 strain, LEW rats showed higher corticosterone regeneration in splenocytes of unstressed rats and in thymic and MLN mobile cells after stress but corticosterone regeneration in the stroma of all lymphoid organs was similar in both strains. Inactivation of corticosterone to 11-dehydrocorticosterone was found only in the stroma of lymphoid organs but not in mobile lymphoid cells and was not upregulated by stress. Together, our findings demonstrate the tissue- and strain-dependent regeneration of glucocorticoids following social stress.
Carlo Cinque, Manuela Zinni, Anna Rita Zuena, Chiara Giuli, Sebastiano G Alemà, Assia Catalani, Paola Casolini and Roberto Cozzolino
Knowledge of animals’ hormonal status is important for conservation studies in wild or semi-free-ranging conditions as well as for behavioural and clinical experiments conducted in laboratory research, mostly performed on rats and mice. Faecal sampling is a useful non-invasive method to obtain steroid hormone assessments. Nevertheless, in laboratory studies, unlike other contexts, faecal sampling is less utilised. One of the issues raised is the necessity to collect samples belonging to different animals, separately. Usually, researchers using faecal sampling solve this problem through the isolation of animals or taking the cage rather than single animal as unit of study. These solutions though, could lead to unreliable measurements, and cannot be applied in many studies. Our aim was to show the biological reliability of individual faecal corticosterone metabolite (FCM) assessments in socially housed male and female Wistar rats. We analytically validated the enzyme immunoassay kit used for FCM assessments. Then, we exposed the animals to two different stress stimuli that are known to activate the hypothalamus–pituitary–adrenal axis and the following release of corticosterone to biologically validate the EIA kit: environmental enrichment and predator odour. Individual faecal sampling from social animals was collected through short-time handling. The results demonstrated that both the stimuli increased FCM levels in male and female rats showing the reliability of EIA kit assessment and the applicability of our sampling method. We also found a diurnal rhythm in FCM levels. These results could help to increase the use of faecal hormone metabolite determinations in studies conducted on rats.
S U Jayasinghe, S J Torres, C A Nowson, A J Tilbrook and A I Turner
We tested the hypothesis that overweight/obese men aged 50–70 years will have a greater salivary cortisol, salivary alpha amylase and heart rate (HR) responses to psychological stress compared with age matched lean men. Lean (BMI=20–25 kg/m2; n=19) and overweight/obese (BMI=27–35 kg/m2; n=17) men (50–70 years) were subjected to a well-characterised psychological stress (Trier Social Stress Test, TSST) at 1500 h. Concentrations of cortisol and alpha amylase were measured in saliva samples collected every 7–15 min from 1400 to 1700 h. HR was recorded using electrocardiogram. Body weight, BMI, percentage body fat, resting systolic and diastolic blood pressure and mean arterial pressure were significantly higher (P<0.05) in overweight/obese men compared with lean men. Both groups responded to the TSST with a substantial elevation in salivary cortisol (372%), salivary alpha amylase (123%) and HR (22%). These responses did not differ significantly between the groups (time×treatment interaction for salivary cortisol, salivary alpha amylase and HR; P=0.187, P=0.288, P=0.550, respectively). There were no significant differences between the groups for pretreatment values, peak height, difference between pretreatment values and peak height (reactivity) or area under the curve for salivary cortisol, salivary alpha amylase or HR (P>0.05 for all). The results showed that, for men with a moderate level of overweight/obesity who were otherwise healthy, the response of salivary cortisol, salivary alpha amylase and HR to acute psychological stress was not impaired.
Kush Dev Singh Jarial, Anil Bhansali, Vivek Gupta, Paramjeet Singh, Kanchan K Mukherjee, Akhilesh Sharma, Rakesh K Vashishtha, Suja P Sukumar, Naresh Sachdeva and Rama Walia
Bilateral inferior petrosal sinus sampling (BIPSS) using hCRH is currently considered the ‘gold standard’ test for the differential diagnosis of ACTH-dependent Cushing’s syndrome (CS). Vasopressin is more potent than CRH to stimulate ACTH secretion as shown in animal studies; however, no comparative data of its use are available during BIPSS.
To study the diagnostic accuracy and comparison of hCRH and lysine vasopressin (LVP) stimulation during BIPSS.
Patients and methods
29 patients (27-Cushing’s disease, 2-ectopic CS; confirmed on histopathology) underwent BIPSS and were included for the study. Patients were randomized to receive hCRH, 5 U LVP or 10 U LVP during BIPSS for ACTH stimulation. BIPSS and contrast-enhanced magnetic resonance imaging (CEMRI) were compared with intra-operative findings of trans-sphenoidal surgery (TSS) for localization and lateralization of the ACTH source.
BIPSS correctly localized the source of ACTH excess in 29/29 of the patients with accuracy of 26/26 patients, using any of the agent, whereas sensitivity and PPV for lateralization with hCRH, 5 U LVP and 10 U LVP was seen in 10/10, 6/10; 10/10,8/10 and 7/7,6/7 patients respectively. Concordance of BIPSS with TSS was seen in 20/27, CEMRI with BIPSS in 16/24 and CEMRI with TSS in 18/24 of patients for lateralizing the adenoma. Most of the side effects were transient and were comparable in all the three groups.
BIPSS using either hCRH or LVP (5 U or 10 U) confirmed the source of ACTH excess in all the patients, while 10 U LVP correctly lateralized the pituitary adenoma in three fourth of the patients.
Agnieszka Bogusz, Svenja Boekhoff, Monika Warmuth-Metz, Gabriele Calaminus, Maria Eveslage and Hermann L Müller
Quality of life (QoL) is frequently impaired in childhood-onset craniopharyngioma (CP) by hypothalamic syndrome. The debate, whether pretreatment hypothalamic involvement (HI) has apriori prognostic impact or surgical hypothalamic lesions (HL) determine outcome, is controversial.
Survival and outcome of CPs recruited between 2007 and 2014 in KRANIOPHARYNGEOM 2007 were analyzed with regard to reference-confirmed presurgical HI and surgical HL.
Radiological findings, BMI and QoL were assessed at diagnosis and during follow-up. QoL was assessed using Pediatric Quality of Life (PEDQOL) questionnaire.
One hundred sixty-nine CPs were included presenting with no HI (n = 11), anterior (n = 49) and anterior + posterior (a + p) HI (n = 109) prior to surgery. The latter 109 were analyzed for postoperative HL (no lesion: n = 23, anterior HL: n = 29, a + pHL: n = 57). Progression-free survival (PFS) was higher after complete resection. The highest PFS was observed in CP with a + pHL, especially when compared between non-irradiated subgroups (P = 0.006). Overall survival (OS) rates were 1.0 in all subgroups. CP with a + pHL developed higher BMI (P ≤ 0.001) during follow-up compared between subgroups. 55/109 pts with a + pHI completed PEDQOL at diagnosis (48/109 at 3 years follow-up). QoL was worse for a + pHL patients in terms of physical, social and emotional functionality when compared with the anterior HL and no HL subgroup. BMI development and QoL during follow-up were similar for patients with anterior HL and without HL.
Posterior hypothalamus-sparing surgical strategies are associated with higher QoL, decreased development of obesity and lower PFS in CP.
M de Fost, S M Oussaada, E Endert, G E Linthorst, M J Serlie, M R Soeters, J H DeVries, P H Bisschop and E Fliers
The water deprivation test is the gold standard test to differentiate central or nephrogenic diabetes insipidus (DI) from primary polydipsia (PP) in patients with polyuria and polydipsia. Few studies have addressed the diagnostic performance of this test. The aim of this retrospective cohort study was to evaluate the diagnostic performance of the standard water deprivation test, including plasma arginine vasopressin (AVP) measurements, in 40 consecutive patients with polyuria. We compared initial test results with the final clinical diagnosis, i.e., no DI, central DI, or nephrogenic DI. The median length of follow-up was 8 years. In a subset of ten patients, the novel marker copeptin (CP) was measured in plasma. Using the final diagnosis as a gold standard, a threshold for urine osmolality of >800 mOsmol/kg after water deprivation yielded a sensitivity and specificity of 96 and 100%, respectively, for diagnosing PP. Sensitivity increased to 100% if the cut-off value for urine osmolality was set at 680 mOsmol/kg. Plasma AVP levels did not differ between patient groups and did not differentiate among central DI, nephrogenic DI, or PP. In all three patients with central DI, plasma CP was <2.5 pmol/l with plasma osmolality >290 mOsmol/kg, and >2.5 pmol/l in patients without DI. The optimal cut-off value for differentiating PP from DI during a water deprivation test was urine osmolality >680 mOsmol/kg. Differentiating between central and nephrogenic DI should be based on clinical judgment as AVP levels did not discriminate.
Bettina Winzeler, Michelle Steinmetz, Julie Refardt, Nicole Cesana-Nigro, Milica Popovic, Wiebke Kristin Fenske and Mirjam Christ-Crain
Objective: The syndrome of inappropriate antidiuresis (SIAD) is a common condition in hospitalized patients. It is crucial to establish the cause of SIAD especially in order to exclude underlying malignancy. As malignant SIAD may be due to a paraneoplastic synthesis of arginine vasopressin, we hypothesized that its stable surrogate marker copeptin can be used as a diagnostic tool to differentiate between malignant and non-malignant SIAD.
Methods: Prospective observational study. We analyzed data from 146 SIAD patients of two different cohorts from Switzerland and Germany. Patients were included while presenting at the emergency department and underwent a standardized diagnostic assessment including the measurement of copeptin levels.
Results: 39 patients (median age: 63 years, 51% female) were diagnosed with cancer-related and 107 (median age: 73 years, 68% female) with non-malignant SIAD. Serum sodium levels were higher in cancer-related versus non-malignant SIAD: median (IQR) 124 mmol/l (120; 127) versus 120 mmol/l (117; 123) (P<0.001). Median (IQR) copeptin levels of patients with cancer-related SIAD were 11.1 pmol/l (5.2; 37.1) and 10.5 pmol/l (5.2; 25.2) with non-malignant SIAD (P = 0.38). Among different cancer entities, patients suffering from small cell lung cancer showed the highest copeptin values, but overall no significant difference in copeptin levels between cancer types was observed (P = 0.46).
Conclusions: Copeptin levels are similar in cancer-related and non-malignant SIAD. Copeptin seems, therefore, not suitable as a marker of malignant disease in SIAD.
S E Baldeweg, S Ball, A Brooke, H K Gleeson, M J Levy, M Prentice, J Wass and the Society for Endocrinology Clinical Committee
Cranial diabetes insipidus (CDI) is a treatable chronic condition that can potentially develop into a life-threatening medical emergency. CDI is due to the relative or absolute lack of the posterior pituitary hormone vasopressin (AVP), also known as anti-diuretic hormone. AVP deficiency results in uncontrolled diuresis. Complete deficiency can lead to polyuria exceeding 10 L/24 h. Given a functioning thirst mechanism and free access to water, patients with CDI can normally maintain adequate fluid balance through increased drinking. Desmopressin (DDAVP, a synthetic AVP analogue) reduces uncontrolled water excretion in CDI and is commonly used in treatment. Critically, loss of thirst perception (through primary pathology or reduced consciousness) or limited access to water (through non-availability, disability or inter-current illness) in a patient with CDI can lead to life-threatening dehydration. This position can be further exacerbated through the omission of DDAVP. Recent data have highlighted serious adverse events (including deaths) in patients with CDI. These adverse outcomes and deaths have occurred through a combination of lack of knowledge and treatment failures by health professionals. Here, with our guideline, we recommend treatment pathways for patients with known CDI admitted to hospital. Following these guidelines is essential for the safe management of patients with CDI.