Christiane Maser-Gluth

G12-G13-LARG-mediated signaling in vascular smooth muscle is required for salt-induced hypertension.

The tone of vascular smooth muscle cells is a primary determinant of the total peripheral vascular resistance and hence the arterial blood pressure. Most forms of hypertension ultimately result from an increased vascular tone that leads to an elevated total peripheral resistance. Regulation of vascular resistance under normotensive and hypertensive conditions involves multiple mediators, many of which act through G protein–coupled receptors on vascular smooth muscle cells. Receptors that mediate vasoconstriction couple with the G-proteins Gq-G11 and G12-G13 to stimulate phosphorylation of myosin light chain (MLC) via the Ca2+/MLC kinase– and Rho/Rho kinase–mediated signaling pathways, respectively. Using genetically altered mouse models that allow for the acute abrogation of both signaling pathways by inducible Cre/loxP-mediated mutagenesis in smooth muscle cells, we show that Gq-G11–mediated signaling in smooth muscle cells is required for maintenance of basal blood pressure and for the development of salt-induced hypertension. In contrast, lack of G12-G13, as well as of their major effector, the leukemia-associated Rho guanine nucleotide exchange factor (LARG), did not alter normal blood pressure regulation but did block the development of salt-induced hypertension. This identifies the G12-G13–LARG–mediated signaling pathway as a new target for antihypertensive therapies that would be expected to leave normal blood pressure regulation unaffected.

Alterations in the neuroendocrinological stress response to acute psychosocial stress in adolescents engaging in nonsuicidal self-injury.

OBJECTIVE To investigate the neuroendocrinological stress response to acute psychosocial stress in a clinical sample of female adolescents engaging in nonsuicidal self-injury (NSSI). METHODS The Trier Social Stress Test (TSST), a standardized psychosocial stress protocol, was performed in 14 female patients who engaged in NSSI and 14 healthy control subjects. NSSI was assessed by the Functional Assessment of Self-Mutilation (FASM). Salivary cortisol, heart rate, and affective states, assessed by the Positive and Negative Affect Schedule (PANAS), were measured during the TSST. RESULTS We found an attenuated cortisol response to acute psychosocial stress in female adolescents with NSSI, whereas no group differences were observed in heart rate and emotional response to the TSST. CONCLUSIONS These findings indicate that the HPA axis is hyporesponsive in adolescents with NSSI. Therefore, reduced secretion of cortisol could play a role in promoting vulnerability of these individuals to acute stress and maladaptive stress responses.

TAK1 in brain endothelial cells mediates fever and lethargy

Expression of the MAP kinase kinase kinase TAK1 in brain endothelial cells is needed for production of prostaglandin E2, and for induction of fever and sickness behavior, in response to peripheral inflammation.

Glucocorticoid Measurements in Health and Disease - Metabolic Implications and the Potential of 24-h Urine Analyses

For examination of glucocorticoid metabolism and identification of hyper and hypocortisolism, various measurements and diagnostic tools are available. After a brief overview of the physiology of glucocorticoid secretion and glucocorticoid actions, the currently used measurements for blood, saliva, and urine samples and the corresponding physiological and metabolic implications are critically reviewed. A special emphasis is placed on the potential of 24-h urine analyses to assess not only glucocorticoid secretion, but also functional glucocorticoid activity.

Losartan and Angiotensin II Inhibit Aldosterone Production in Anephric Rats via Different Actions on the Intraadrenal Renin-Angiotensin System.

Angiotensin II (ANG II) is a major stimulator of aldosterone biosynthesis. When investigating the relative contribution of circulating and locally produced ANG II, we were therefore surprised to find that ANG II, given chronically sc (200 ng/kg·min), markedly inhibits a nephrectomy (NX)-induced rise of aldosterone concentrations (from 10 ± 2 to 465 ± 90 ng/100 ml in vehicle infused, and from 9 ± 2 to 177 ± 35 in ANG II infused rats 55 h after NX and hemodialysis). We further observed, by in situ hybridization, that bilateral NX increases the number of adrenocortical cells expressing renin and that this rise was prevented by ANG II. Moreover, the rise of aldosterone levels was also inhibited by the AT1-receptor antagonist, losartan (10 μg/kg·min, chronically ip from 8 ± 2 to 199 ± 26 ng/100 ml), despite the absence of circulating renin and a reduction of ANG I to less than 10%. These data demonstrate that aldosterone production, after NX, is regulated by an intraadrenal renin-angiotensin system and that th...

LONGITUDINAL EVALUATION OF SALIVARY CORTISOL LEVELS IN FULL-TERM AND PRETERM NEONATES

The aim of the present study was to test the practicability of sequential cortisol determinations in saliva of low birth weight neonates and to evaluate the impact of systemic and inhaled glucocorticoid therapy on saliva concentrations of cortisol in preterm neonates with bronchopulmonary dysplasia (BPD). Salivary cortisol levels were measured by RIA in saliva samples from 10 full-term and 10 preterm healthy neonates and from 20 preterm neonates with BPD during systemic [dexamethasone (DEX); n = 10] or topical steroid therapy [budesonide (BUD); n = 10]. Saliva samples of each individual were collected on 3 consecutive days at 06.00, 12.00, 18.00 and 24.00 h. Cortisol levels in saliva ranged from 0.8 to 60.6 nmol/l (median 6.5 nmol/l) in full-term neonates, from 0.6 to 52.1 nmol/l (median 5.5 nmol/l) in preterm neonates, from 0.4 to 14.0 nmol/l (median 1.0 nmol/l) in preterm neonates treated with DEX and from 0.4 to 15.2 nmol/l (median 2.5 nmol/l) in preterm neonates treated with BUD. Autocorrelation analysis revealed a distinct endogenous cortisol rhythm in 2 of the 10 healthy full-term neonates and in 3 of the 10 healthy preterm neonates with a wavelength of 12–30 h. Salivary cortisol levels in preterm neonates treated with DEX or BUD were significantly lower than those measured in healthy preterm neonates. These results demonstrate that the measurement of salivary cortisol levels is a reliable and practicable way of assessing adrenal function in full-term and preterm neonates. This study also shows for the first time that some neonates display an endogenous cortisol rhythm which is not coupled to the exogenous day/night cycle. Furthermore, systemic and nebulized glucocorticoids suppress adrenal function in low-birth-weight neonates. After treatment these children should be closely monitored for potential adrenal insufficiency.

Neuroendocrine Function following Traumatic Brain Injury and Subsequent Intensive Care Treatment: A Prospective Longitudinal Evaluation

Neuroendocrine dysfunction following traumatic brain injury (TBI) has been described extensively. However, few studies are longitudinal and most lack subtle radiological, clinical, and repetitive endocrine assessment in the acute phase. Accordingly, we prospectively assessed neuroendocrine function in 71 patients after TBI. Injury was documented by a computed tomography (CT). During the first week, critical clinical data (Glasgow Coma Score, APACHE score), treatment variables such as duration of analgosedation for mechanical ventilation, were related to basal pituitary function. More than 2 years later, a subgroup of patients was re-evaluated using dynamic testing with ACTH and GHRH-arginine tests. The Pearsons correlation analysis and Mann-Whitney rank sum test for group differences were used for statistical analysis. None of the CT findings predicted neuroendocrine dysfunction following TBI. The adaptive response to critical illness with significantly elevated cortisol levels on admission and decreased levels thereafter in patients ventilated for more than 24 h (p < 0.05) was attenuated following severe TBI (p < 0.05). However, the coincidence of low serum cortisol and increased urinary excretion of glucocorticoid metabolites in about 80% of patients challenges the relevance of basal hormone measurements. In ventilated patients, total T3 and free T4 were decreased (p < 0.05), TSH was low on day 3 (p < 0.05), and a gonadotropic insufficiency was present (p < 0.05). The thyrotropic and gonadotropic system recovered completely within the follow-up period. With regard to the somatotropic system, neither brain injury severity nor mechanical ventilation was associated with an insufficiency during the acute phase post-injury. However, initially low GH levels predicted a persistent deficiency (r = 0.731, p < 0.001). We conclude that both severe TBI and prolonged mechanical ventilation result in hormonal disturbances early after injury, suggesting a pathophysiological response to brain injury and subsequent intensive care treatment rather than morphological damage.

Intravenous Lipid and Heparin Infusion-Induced Elevation in Free Fatty Acids and Triglycerides Modifies Circulating Androgen Levels in Women: A Randomized, Controlled Trial

BACKGROUND The polycystic ovarian syndrome (PCOS) is characterized by hyperandrogenism and associated with obesity and impaired glucose metabolism. Despite the high prevalence of PCOS and the considerable clinical impact, the precise interplay between metabolism and hyperandrogenemia is not entirely clear. OBJECTIVE The objective of the study was to analyze the effects of iv lipid and heparin infusion on circulating androgen levels in healthy women. DESIGN This was a randomized, controlled, crossover trial. SETTING The study was conducted at an endocrinology center. PATIENTS Patients included 12 healthy young women during the early follicular phase of two subsequent cycles. INTERVENTION After an overnight fast, a 20% lipid/heparin or a saline/heparin infusion was administered in random order for 330 min. MAIN OUTCOME MEASURES A detailed characterization of androgen metabolism was performed. RESULTS Elevations in free fatty acids and triglycerides, induced by lipid/heparin infusion, elevates the levels of androstenedione, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), testosterone, 5alpha-dihydrotestosterone, estrone, and 17beta-estradiol. Urinary excretion of DHEA, DHEAS, 5-androstene-3beta,17beta-diol, and the sum of urinary excreted DHEA and its 16-hydroxylated downstream metabolites, 16alpha-hydroxy-DHEA and 5-androstene-3beta,16alpha,17beta-triol, were reduced. CONCLUSION The mechanism of iv lipid and heparin infusion-induced elevation of circulating androgens described here might contribute to the development of hyperandrogenism in women with PCOS and suggests that lowering of hyperlipidemia might be a potential therapeutic target in patients with PCOS to treat hyperandrogenemia.

Exaggerated adrenarche and altered cortisol metabolism in Type 1 diabetic children

Reported literature data strongly suggest that steroid metabolism is dysregulated in Type 1 diabetes mellitus. The aim of this study was to non-invasively examine the cortisol metabolism in children with Type 1 diabetes mellitus (T1DM) in detail and to test the hypothesis that adrenarche is affected under conventional intensive insulin therapy. In 24-h urine samples of 109 patients aged 4-18 years with T1DM of more than 1 year, steroids were profiled using gas chromatography-mass spectrometry. Additionally, urinary free cortisol (UFF) and cortisone (UFE) were quantified by RIA after extraction and chromatographic purification. Data on urinary steroids from 400 healthy controls served as reference values. Enzyme activities were assessed by established steroid metabolite ratios, e.g. 5alpha-reductase and 11beta-hydroxysteroid dehydrogenase Type 2 (11beta-HSD2) by 5alpha-tetrahydrocortisol/tetrahydrocortisol and UFE/UFF, respectively. Urinary markers of adrenarche, especially dehydroepiandrosterone and its direct metabolites were elevated in patients, as were urinary 6beta-hydroxycortisol, UFE, and 11beta-HSD2 activity. However, overall cortisol secretion, as reflected by the sum of major urinary cortisol metabolites, was mostly normal and activity of 5alpha-reductase clearly reduced. Our study provides evidence for an exaggerated adrenarche in T1DM children, which may help to understand reported sequelae in female patients like hyperandrogenic symptoms. The findings also suggest a reduced cortisol inactivation via 5alpha-reductase that is not compensated by a fall in cortisol secretion. Whether the elevated urinary 6beta-hydroxycortisol and cortisone excretion, observed in the patients, are also present in other forms of hypercortisolism and may thus serve as non-invasive clinical stress markers deserves further study.

Brief review: Glucocorticoid excretion in obesity

Cortisol secretion and glucocorticoid excretion rates are regularly increased in obesity and associate with indices of body size and visceral adiposity. Different mechanisms may underlie the elevated urinary excretion rates of cortisol metabolites in obesity. In the present brief overview, potential mechanisms are discussed, paying special attention to cortisol metabolism. Besides, potential confounding factors in the evaluation of urinary glucocorticoid excretion are highlighted.