Changes In Glucocorticoid Sensitivity Research Articles

Glucocorticoid Receptor Expression Pattern in Very Low Birth Weight Infants Changes Drastically within the First Week of Life

Introduction: We herein examined changes in expression levels of the glucocorticoid receptor subtypes GRα and GRβ in very low birth weight (VLBW) and term infants to clarify time-dependent changes in glucocorticoid sensitivity after birth. Methods: Whole blood samples were collected at birth and on postnatal days 4–7, and the mRNA expression levels of GRα and GRβ were measured using RT-qPCR. The relative gene expression levels of GRα and GRβ as the target genes normalized to actin beta as the endogenous control were calculated by the comparative cycle threshold method. Results: The GRα/GRβ expression ratio at birth was significantly lower in 32 VLBW cesarean section (CS) infants than in term planned CS infants (median [IQR], 1.5 [1.1–1.8]- and 1.1 [0.7–1.6]-fold change, p < 0.05). Furthermore, the GRα/GRβ expression ratio increased from day 0 to days 4–7 (1.0 [0.6–1.4]- and 1.7 [0.6–1.4]-fold change, p < 0.01) in 43 VLBW infants. Discussion/Conclusion: The present results suggest that glucocorticoid sensitivity in VLBW infants increases after birth and this rapid change may play a role in surviving critical postnatal events.

Postnatal Overfeeding in Rodents by Litter Size Reduction Induces Major Short- and Long-Term Pathophysiological Consequences

AbstractNumerous studies have demonstrated that the early postnatal environment can influence body weight and energy homeostasis into adulthood. Rodents raised in small litters have been shown to be a useful experimental model to study the short- and long-term consequences of early overnutrition, which can lead to modifications not only in body weight but also of several metabolic features. Postnatal overfeeding (PNOF) induces early malprogramming of the hypothalamic system, inducing acquired persisting central leptin and insulin resistance and an increase in orexigenic signals. Visceral white adipose tissue, lipogenic activity, and inflammatory status are increased in PNOF rodents, while brown adipose tissue shows reduced thermogenic activity. Pancreatic and hepatic glucose responsiveness is persistently reduced in PNOF rodents, which also frequently present disturbances in plasma lipids. PNOF rodents present increased circulating concentrations of leptin, elevated corticosterone secretion, and significant changes in glucocorticoid sensitivity. PNOF also influences nephrogenesis and renal maturation. Increased oxidative stress is also described in circulating blood and in some tissues, such as the heart or liver. At the cardiovascular level, a moderate increase in arterial blood pressure is sometimes observed and rapid cardiac hypertrophy is observed at weaning; however, during maturation, impaired contractility and fibrosis are observed. Myocardial genome expression is rapidly modified in overfed mice. Moreover, hearts of PNOF rodents are more sensitive to ischemia-reperfusion injury. Together, these results suggest that the nutritional state in the immediate postnatal period should be taken into account, because it may have an impact on cardiometabolic risk in adulthood.

125. HPA axis habituation to repeated acute psychosocial stress is related to lower sensitization of plasma interleukin-6 responses

Adaptation to repeated acute stress is understood to be beneficial for health. However, not much is known about the interplay between stress-related (e.g. cortisol) and health relevant biomarkers (e.g. interleukin-6, IL-6) with regard to repeated stress. While HPA axis habituation is regarded as an adaptive response pattern, lower HPA axis responses to repeated stress might theoretically allow disinhibition of inflammatory stress responses, which would be maladaptive. We exposed n = 26 healthy individuals to the Trier Social Stress Test (TSST) on two consecutive days. Salivary cortisol and plasma interleuking-6 (IL-6) were measured repeatedly before and until 2 h after stress on both days. Cortisol and IL-6 significantly increased in response to stress exposure (cortisol p < 0.001; IL-6 p < 0.001). On day 2, average cortisol responses were lower than on day 1, consistent with habituation ( p = 0.011), while IL-6 responses were higher, consistent with sensitization ( p = 0.041). Greater cortisol habituation was a significant predictor of less pronounced IL-6 sensitization ( r = −0.61; p = 0.002). Our findings corroborate the assumption that HPA axis habituation to repeated stress is an adaptive, and not a maladaptive response pattern, because it was related with lower IL-6 responses to repeated stress. Our findings are incompatible with the assumption that high cortisol responses are required for inflammatory control. Intermediate regulatory steps, for example changes in glucocorticoid sensitivity, might explain this finding. Future studies will be needed to understand this intermediate mechanism.

Intense physical exercise increases systemic 11β-hydroxysteroid dehydrogenase type 1 activity in healthy adult subjects

Intense physical exercise activates the hypothalamic-pituitary-adrenocortical axis but little is known about changes in glucocorticoid sensitivity at the target cell level. No data are available on the acute effects of exercise on 11beta-hydroxysteroid dehydrogenase (11beta-HSD) type 1 activity, which generates biologically active cortisol from inactive cortisone and is expressed also in skeletal muscle. Fifteen healthy, trained males (age mean +/- SE 28 +/- 1) were assessed on three non-consecutive days: at rest, during an endurance and strength sessions. During each session, between 1000 and 1600 hours, 6-h urine and four salivary samples were collected. Urinary total tetrahydrocortisol (THF) + alloTHF, tetrahydrocortisone (THE), cortisol (F) and cortisone (E) were measured with HPLC-tandem mass spectrometry; urinary-unconjugated F and E were measured by HPLC-UV. Salivary cortisol and interleukin (IL)-6 were measured by RIA and ELISA, respectively. Both endurance and strength exercises caused an increase in (THF + alloTHF)/THE ratio (mean +/- SE 1.90 +/- 0.07 and 1.82 +/- 0.05 vs. 1.63 +/- 0.06, P < 0.01 and P = 0.03, respectively), consistent with increased systemic 11beta-HSD type 1 activity. No relationship was found with age, BMI, VO(2max) maximal power load or perceived exertion. No significant change was apparent in F/E ratio, an index of 11beta-HSD type 2 activity. No effect of exercise on salivary cortisol and IL-6 was observed, whereas a significant effect of sampling time was found. Intense physical exercise acutely increases systemic 11beta-HSD type 1 activity in humans. Such an increase may lead to higher cortisol concentration in target tissues, notably in skeletal muscle where it could contribute to limit exercise-induced muscle inflammatory response.

Impact of Prolonged Physical Training on the Pituitary Glucocorticoid Sensitivity Determined by Very Low Dose Intravenous Dexamethasone Suppression Test

The activity of the hypothalamic-pituitary-adrenal axis is usually modulated by several stress factors, including exercise. Different responses are induced by physical training according to duration and intensity of exercise. During prolonged training, cortisol remains normal or decreased as a consequence of altered cortisol secretion, metabolism and excretion, and possibly by changes in glucocorticoid sensitivity. The aim of this study was to evaluate the impact of prolonged physical training on the glucocorticoid sensitivity. Eighteen cadets of the Air Force Academy, mean (SD) age: 18.7 (1.0) years, underwent an intensive 6-week preparatory training-period considered adequate by inducing significant changes on body composition measured by bioelectrical impedance. Measurement of individual's pituitary glucocorticoid sensitivity was done by an intravenous very low dose dexamethasone suppression test (20 microg/m (2)) that was performed before and after the training period. Cortisol levels were obtained at basal condition and 120 minutes after the dexamethasone infusion. Basal cortisol showed a significant decrease after prolonged training. The percent cortisol suppression after dexamethasone tended to be lower after the training period. Overall, our data suggest that prolonged physical training is able to reduce glucocorticoid sensitivity, which can have a beneficial impact in chronic stress conditions.

Glucocorticoid sensitivity: pathology, mutations and clinical implications

Glucocorticoids exert diverse effects on virtually all cell types and tissues. Subtle changes in sensitivity may be generalized and congenital or acquired in a tissue-specific manner. Such changes may lead to altered susceptibility to metabolic diseases, such as ischemic heart disease, or to insensitivity to the therapeutic actions of synthetic glucocorticoids such as in inflammatory disease. This review will cover current theories of how glucocorticoids exert genetic and other congenital effects on glucocorticoid sensitivity, and acquired changes in glucocorticoid sensitivity seen principally in inflammatory and malignant disease. Recent important developments in the field include the impact of genetic variation within the glucocorticoid receptor gene, the effects of early life experience on long-term glucocorticoid sensitivity, studies identifying the role of nuclear factor κB in modulating glucocorticoid sensitivity in vitro and in vivo, and the action of macrophage migration inhibitory factor in modulating the anti-inflammatory effects of glucocorticoids. The role of chromatin organization in regulating glucocorticoid action on proinflammatory genes is discussed, as is the regulation of glucocorticoid sensitivity in human malignancy in the context of pathogenesis and treatment response.

Developmental regulation of the lung in preparation for life after birth: hormonal and nutritional manipulation of local glucocorticoid action and uncoupling protein–2

Glucocorticoid action has a major role in regulating fetal and postnatal lung development, although its impact on mitochondrial development is less well understood. Critically, the consequences of any change in glucocorticoid action and mitochondrial function in early life may not be limited to the postnatal period, but may extend into later life. This paper focuses on more recent findings on the impact of ontogeny, fetal cortisol status, maternal nutrient restriction and postnatal leptin administration on mitochondrial uncoupling protein (UCP)-2, glucocorticoid receptor (GR) and 11 beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) isoform abundance in the lung. For example, in sheep, GR and 11betaHSD1 mRNA are maximal at 140 days' gestation (term approximately 147 days), while UCP2 mRNA peaks at 1 day after birth and then decreases with advancing age. In the fetus, chronic umbilical cord compression enhances the abundance of these genes, an outcome that can also be produced after birth following chronic, but not acute, leptin administration. Irrespective of the timing of maternal nutrient restriction in pregnancy, glucocorticoid sensitivity and UCP2 abundance are both upregulated in the lungs of the resulting offspring. In conclusion, prenatal and postnatal endocrine challenges have distinct effects on mitochondrial development in the lung resulting from changes in glucocorticoid action, which can persist into later life. As a consequence, changes in glucocorticoid sensitivity and mitochondrial protein abundance have the potential to be used to identify those at greatest risk of developing later lung disease.

Age and sex steroid-related changes in glucocorticoid sensitivity of pro-inflammatory cytokine production after psychosocial stress

Aging is associated with an increased susceptibility to infections and chronic inflammatory diseases. This might be caused by dysregulations of the endocrine system with increased activity of the hypothalamus–pituitary–adrenal (HPA) axis and decreased levels of sex steroids. Therefore, we investigated the stress-response of the HPA axis and glucocorticoid (GC) sensitivity of pro-inflammatory cytokine production in elderly men, compared to testosterone-treated elderly men and young controls. Stress-induced increases in cortisol did not differ significantly between experimental groups ( F=2.10; p>0.10), but GC sensitivity increased significantly in young controls and testosterone-treated elderly men, while a decrease was found in untreated elderly men ( F=5.28; p<0.01). We conclude that the increase in GC sensitivity after stress serves to protect the individual from detrimental increases of pro-inflammatory cytokines, a mechanism that is disturbed in elderly men and partly restored by testosterone treatment.

Diurnal changes in glucocorticoid sensitivity in human peripheral blood samples

The secretion of cortisol, a principle homeostatic regulator in humans, shows a circadian rhythm, with high concentrations in the morning and low levels in the evening and at night. Tissue response to hormones is dependent on hormone concentrations but also on a variety of cellular factors, such as hormone receptors, transcription factors, and activators. In this report, we evaluated whether cell sensitivity to glucocorticoids (GCs) is also subject to diurnal variation using a whole cell system (whole blood samples) stimulated by lipopolysacharide to induce the production of tumor necrosis factor (TNF-α); the induction of TNF-α is inhibited by dexamethasone. Blood samples obtained in the morning (08.30–09.00 h) and in the evening (22.30–23.00 h) from 37 healthy individuals (18 males, 19 females) aged 29 ± 3 years were treated with lipopolysacharide in the presence or absence of 10 −6 M dexamethasone, and the percentage of inhibition of TNF-α production was used as an index of sensitivity to GCs. The mean ± SD in morning samples was 43.5 ± 13.8% for the general population, 42.3 ± 14.0% for males and 44.6 ± 13.8% for females, whereas that in the evening samples was 36.5 ± 15.7%, 35.6 ± 13.8% and 37.4 ± 17.7%, respectively. The results support a significantly increased sensitivity to GCs in the morning hours compared with that in the evening in the general population ( P < 0.001) as well as in males ( P < 0.001) and in females ( P < 0.001). No sex related differences in sensitivity to GCs were observed in the morning or in the evening hours. The sensitive and reproducible assay utilized in this study could also be used to investigate the sensitivity to GCs in various diseases characterized by resistance to GCs and/or alterations in glucocorticoid receptor function.

Age- and sex-steroid-related changes in glucocorticoid sensitivity as measured by dexamethasone-suppressed cytokine production at baseline and after psychosocial stress

Age- and sex-steroid-related changes in glucocorticoid sensitivity as measured by dexamethasone-suppressed cytokine production at baseline and after psychosocial stress

Disuse atrophy of skeletal muscle is associated with an increase in number of glucocorticoid receptors.

Atrophy of muscles due to disuse is similar in form to glucocorticoid atrophy of the general body musculature. Because of this similarity, a hypothesis was formed which attributed the selective muscle atrophy resulting from immobilization to an increase in glucocorticoid sensitivity. As an initial test of this hypothesis, the thermodynamic characteristics of 3H-dexamethasone binding were examined in cytosol prepared from immobilized and contralateral control gastrocnemius muscles. We report here an increase in numbers of glucocorticoid receptors in immobilized muscles relative to contralateral controls, with no change in binding affinity. These findings support the hypothesis that selective muscle atrophy is a result of changes in glucocorticoid sensitivity.