High Glucocorticoid Levels Research Articles

Glucocorticoid levels in free ranging resident mantled howlers: a study of coping strategies

A growing amount of data shows that a preference for passive-nonaggressive over active-aggressive problem solving is associated with higher levels of glucocorticoids (GC). For mantled howlers, the arrival of an adult male in a new group is a potential source of psychological stress for both resident males and females. Resident mantled howler males take an active stand and aggressively repel the entrance of solitary males, while females take a passive-nonaggressive stand. In order to study whether the relationship between coping strategies and the activation of the hypothalamic-pituitary-adrenal (HPA) axis observed in other species applies to the response of resident mantled howlers to the presence of solitary males, we examine the relationship between different group and subpopulation variables and the GC levels measured in feces collected from 10 groups living in six forest fragments, in Los Tuxtlas, Mexico. The results of our study suggest that the resident mantled howler females' passive response to the presence of solitary males is accompanied by the activation of the HPA axis, whereas resident males' aggressive response is not accompanied by any changes in the HPA axis. In contrast, a previous study suggests that resident male howlers respond by increasing their testosterone levels to the presence of solitary males (Cristobal-Azkarate et al., Hormones and Behavior 2006;49 261-267). These different behavioral and hormonal responses coincide with the active and passive coping styles described for other species. The conditions in which howlers live in our study area may be favoring the interaction between solitary and resident howlers, and inducing chronically high GC levels, which in turn could negatively affect the fitness of these subpopulations.

Glucocorticoid Conditioning of Myeloid Progenitors Enhances TLR4 Signaling via Negative Regulation of the Phosphatidylinositol 3-Kinase-Akt Pathway

The immunomodulatory effects of glucocorticoids (GCs) have been described as bimodal, with high levels of GCs exerting immunosuppressive effects and low doses of GCs being immunopermissive. While the mechanisms used by GCs to achieve immunosuppression have been investigated intensely, the molecular mechanisms underlying the permissive effects of GCs remain uncharacterized. Herein, we demonstrate that GC conditioning during the differentiation of myeloid progenitors into macrophages (Mphis) results in their enhanced LPS responsiveness, demonstrated by an overexpression of the inflammatory cytokines TNF-alpha, IL-6, and IL-12. Inflammatory cytokine overexpression resulted from an increased activation of NF-kappaB and the MAPK signaling cascade and a reduced activation of the PI3K-Akt pathway following LPS stimulation. GC conditioning during Mphi differentiation induced an increase in the expression of SHIP1, a phosphatase that negatively regulates the PI3K signaling pathway. Small interfering RNA-mediated knockdown of SHIP1 expression increased PI3K-dependent Akt activation and subsequently decreased inflammatory cytokine expression, suggesting GC-mediated up-regulation of SHIP1 expression is responsible for the augmentation in inflammatory cytokine production following LPS stimulation. We also show that splenic Mphis purified from normal mice that were implanted with timed-release GC pellets exhibited an enhanced LPS responsiveness and increased SHIP1 expression, indicating that GCs can regulate SHIP1 expression in vivo. Our results suggest that minor fluctuations in physiological levels of endogenous GCs can program endotoxin-responsive hemopoietic cells during their differentiation by regulating their sensitivity to stimulation.

Localization and glucocorticoid regulation of 11β-hydroxysteroid dehydrogenase type 1 mRNA in the male mouse forebrain

The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) converts the inactive 11-dehydrocorticosterone into the active glucocorticoid corticosterone. There is accumulating evidence indicating widespread expression of 11β-HSD1 in the brain. However, there is little information about regulation of 11β-HSD1 expression in this tissue. Using in situ hybridization involving use of 35S-labeled cRNA probe, we have studied the distribution of cells expressing 11β-HSD1 mRNA in the male mouse forebrain as well as the effects of adrenalectomy (ADX) and acute administration of corticosterone (3 and 24 h) on 11β-HSD1 mRNA levels. Cells expressing 11β-HSD1 mRNA were mostly detected in the cerebral cortex, hippocampus, amygdala and medial preoptic area, with the highest expression in the cerebral cortex (retrosplenial granular area) and hippocampus (CA3 and granular layer of the gyrus dentatus). Seven days following ADX, 11β-HSD mRNA levels were increased by 50% in the gyrus dentatus, by 100% in the CA3 area, and 105% in the cerebral cortex. Administration of corticosterone to ADX mice induced a significant decrease in mRNA, in both the hippocampus and cerebral cortex so that, at the 24 h time interval, the levels were similar to those observed in intact mice. These results clearly indicate that circulating corticosterone is downregulating the expression of 11β-HSD1 mRNA in the two forebrain areas studied. This downregulation might contribute to maintain low intracellular corticosterone levels in central regions and then prevent the deleterious effects induced by high glucocorticoid levels.

Expression of 11‐beta hydroxysteroid dehydrogenase type 2 in the murine placenta and its regulation in cultured placental trophoblasts

HSD2 is a microsomal enzyme responsible for the oxidation of 11-hydroxy glucocorticoids (GCs) to their biologically inert 11-keto forms in peripheral tissues. Placental HSD2 activity plays a key role in protecting the fetus from high levels of maternal GCs. Prenatal exposure to high levels of GCs has been linked the fetal programming of several adult cardiovascular and metabolic diseases. We examined HSD2 protein levels in the murine placenta during gestation and explored its regulation in cultured murine placental trophoblast cells (SM-10 cell line). Immunoblot analysis for HSD2 protein was performed on pooled placentas obtained from C57BL/6 mice on gestational days 9, 12, 14, or 18 (n=4 litters for each time point). Normalized placental HSD2 protein levels increased with gestational age, and were approximately two-fold higher on day 18 as compared to day 9. The effect of inflammatory cytokines on HSD2 protein levels was also examined in SM-10 cells cultured in the presence of TNF-alpha (10ng/mL) or IL-1 beta (10ng/mL) for 1, 2, or 24 hours. HSD2 was down-regulated in a time-dependent manner by the inflammatory cytokines. The reduction of HSD2 levels by these cytokines may provide a potential link between placental inflammation and fetal programming. These data demonstrate that SM-10 cells provide a useful model in which to study the regulation of HSD2 in the murine placenta.

Chronic treatment with high doses of corticosterone decreases cytoskeletal proteins in the rat hippocampus

Hypercortisolism is a common trait of Cushing's disease and depression. These two disorders also share hippocampal volume decrease and cognitive deficits. However, experimentally induced hypercortisolism induces neuronal atrophy, which has been proposed to be the phenomenon underlying the hippocampal shrinkage. We hypothesized that the above-mentioned atrophy is due to a deleterious effect of high concentrations of glucocorticoids on cytoskeletal proteins. One or two pellets (100 mg each) of corticosterone were subcutaneously implanted in adult rats. Twenty-one days later, light, medium and heavy subunits of intermediate neurofilaments (NFL, NFM and NFH) and the microtubule-associated protein 2 (MAP2) were quantified by immunohistochemistry in Ammon's horn and dentate gyrus. We also evaluated the in vitro glutamate release in hippocampal slices. Both doses of corticosterone induced a decrement of NFL, NFM and NFH in both hippocampal areas but only 200 mg decreased MAP2. This dose also diminished the potassium-stimulated glutamate release. All of these changes seemed not to be due to neuron loss, as no decrement in neuron-specific nuclear protein-positive cells was found. With the exception of NFL, the above-mentioned diminution was not observed in the globus pallidus, one of the brain regions with the lowest glucocorticoid receptor density. These results provide a subcellular insight into the trophic changes found in experimental models of hypercortisolism. The coincidence between decrements in MAP2 and glutamate release suggests possible links between high glucocorticoid levels, dendritic atrophy and the cognitive impairment reported in patients suffering from Cushing's disease and depression.

Glucocorticoids Increase Amyloid-β and Tau Pathology in a Mouse Model of Alzheimer’s Disease

Various environmental and genetic factors influence the onset and progression of Alzheimer's disease (AD). Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, which controls circulating levels of glucocorticoid hormones, occurs early in AD, resulting in increased cortisol levels. Disturbances of the HPA axis have been associated with memory impairments and may contribute to the cognitive decline that occurs in AD, although it is unknown whether such effects involve modulation of the amyloid beta-peptide (Abeta) and tau. Using in vitro and in vivo experiments, we report that stress-level glucocorticoid administration increases Abeta formation by increasing steady-state levels of amyloid precursor protein (APP) and beta-APP cleaving enzyme. Additionally, glucocorticoids augment tau accumulation, indicating that this hormone also accelerates the development of neurofibrillary tangles. These findings suggest that high levels of glucocorticoids, found in AD, are not merely a consequence of the disease process but rather play a central role in the development and progression of AD.

High dexamethasone concentration prevents stimulatory effects of TNF-α and LPS on IL-6 secretion from the precursors of human muscle regeneration

A frequent finding in patients surviving critical illness myopathy is chronic muscle dysfunction. Its pathogenesis is mostly unknown; one explanation could be that muscle regeneration, which normally follows myopathy, is insufficient in these patients because of a high glucocorticoid level in their blood. Glucocorticoids can prevent stimulatory effects of proinflammatory factors on the interleukin (IL)-6 secretion, diminishing in this way the autocrine and paracrine IL-6 actions known to stimulate proliferation at the earliest, myoblast stage of muscle formation. To test this hypothesis, we compared the effects of major proinflammatory agents [tumor necrosis factor (TNF)-alpha and endotoxin lipopolysaccharide (LPS)] on the IL-6 secretion from the muscle precursors and then studied the influence of dexamethasone (Dex) on these effects. Mononuclear myoblasts, which still proliferate, were compared with myotubes in which this capacity is already lost. For correct interpretation of results, cultures were examined for putative apoptosis and necrosis. We found that constitutive secretion of IL-6 did not differ significantly between myoblasts and myotubes; however, the TNF-alpha- and LPS-stimulated IL-6 release was more pronounced (P < 0.001) in myoblasts. Dex, applied at the 0.1-100 nM concentration range, prevented constitutive and TNF-alpha- and LPS-stimulated IL-6 release at both developmental stages but only at high concentration (P < 0.01). Although there are still missing links to it, our results support the concept that high concentrations of glucocorticoids, met in critically ill patients, prevent TNF-alpha- and LPS-stimulated IL-6 secretion. This results in reduced IL-6-mediated myoblast proliferation, leading to the reduced final mass of the regenerated muscle.

Targeting 11β-hydroxysteroid dehydrogenase type 1 in brain: therapy for cognitive aging?

Dementia care costs exceed those of cardiovascular diseases and cancer combined. Milder forms of functionally significant cognitive decline add further to the staggering human, societal and economic costs. However, the underlying mechanisms are poorly understood and few treatments are available. Cumulative exposure to high glucocorticoid levels is a major hypothesis of decline in cognitive function with aging. Current manipulations to maintain low circulating glucocorticoid levels throughout life (adrenalectomy with low-dose corticosterone replacement and neonatal handling), although effective in preventing the emergence of memory deficits with age in rodent models, are not clinically applicable. By contrast, recent data in cells, mice and humans suggest that inhibition of the tissue-selective glucocorticoid-amplifying enzyme, 11β-hydroxysteroid dehydrogenase type 1, may be an effective novel approach.

Skeletal Muscle Protein Synthesis after Active or Passive Ascent to High Altitude

The effects of acute exposure to high altitude on muscle protein synthesis rates in human volunteers were examined after active and passive ascent. Measurements were made initially at low altitude (550 m) and again after ascent to high altitude (4,559 m). To be able to separate the contribution of physical exercise, one group was flown by helicopter (air group, N=8), whereas the other group climbed to high altitude (foot group, N=9). Fractional rates of muscle protein synthesis rates (FSR) were determined from the incorporation of isotope into protein after injection of [H5ring] phenylalanine. In the air group, there was no change in FSR at high altitude, whereas in the foot group, there was a 35% increase in FSR (P<0.05 for interaction) measured 19-23 h after the end of climbing. At high altitude, the degree of hypoxia and alkalosis were not different between the groups. The plasma concentration of insulin-like growth factor-1, free thyroxin, free triiodothyronine, and thyroid-stimulating hormone were not different between the groups. Urinary 24-h cortisol excretion increased significantly in both groups after ascent, but the increase in the foot group was significantly higher compared with the air group. Physical exercise appeared to be responsible for the observed increase in muscle FSR. The significantly higher increase of 24-h cortisol excretion in the foot group suggests that the increase in FSR occurred despite higher levels of glucocorticoids, which generally affect muscle protein turnover by inhibiting protein synthesis.

Cytosolic glucocorticoid receptor in the testis of Bufo arenarum: Seasonal changes in its binding parameters

Glucocorticoids (GC) are the hormonal mediators of stress. In mammals, high levels of GC have negative effects on reproductive physiology. For instance, GC can inhibit testicular testosterone synthesis by acting via glucocorticoid receptors (GR), the extent of the inhibition being dependent on GC levels. However, the effect of GC on testicular function and even the presence of GR in amphibians are still unclear. The purpose of this work was to characterise testicular cytosolic GR in Bufo arenarum, determining the seasonal changes in its binding parameters as well as the intratesticular localisation. The binding assays were performed in testis cytosol with [ 3H]dexamethasone (DEX) and [ 3H]corticosterone (CORT). Binding kinetics of DEX and CORT fitted to a one-site model. Results were expressed as means ± standard error. Apparent number of binding sites (Bapp) was similar for both steroids (Bapp DEX = 352.53 ± 72.08 fmol/mg protein; Bapp CORT = 454.24 ± 134.97 fmol/mg protein) suggesting that both hormones bind to the same site. Competition studies with different steroids showed that the order of displacement of [ 3H]DEX and [ 3H]CORT specific binding is: DEX ∼ RU486 ∼ deoxycorticosterone (DOC) > CORT > aldosterone > RU28362 > progesterone >>> 11-dehydroCORT. The affinity of GR for DEX ( K d = 11.2 ± 1.5 nM) remained constant throughout the year while circulating CORT clearly increased during the reproductive season. Therefore, testis sensitivity to GC action would depend mainly on inactivating mechanisms (11β-hydroxysteroid dehydrogenase type 2) and CORT plasma levels. Since total and free CORT are higher in the reproductive than in the non-reproductive period, the magnitude of GC actions could be higher during the breeding season. The intratesticular localisation of the GR was determined after separation of cells by a Percoll density gradient followed by binding assays in each fraction. DEX binds to two different fractions corresponding to Leydig and Sertoli cells. In conclusion, in the testis of B. arenarum GC could regulate the function of both cellular types particularly during breeding when CORT reaches the highest plasma concentration.

Enhanced memory performance on an internal-internal source monitoring test following acute psychosocial stress.

Research on the effect of acute stress and high levels of glucocorticoids on memory has largely focused on memory tasks involving the medial temporal lobe (e.g., declarative memory). Less is known, however, about the effects of stress and glucocorticoids on more strategic memory processes regulated by the prefrontal cortex (e.g., source monitoring). In the current study, the authors investigated whether exposure to acute psychosocial stress would result in altered source monitoring performance relative to the performance of a nonstressed control group. To this end, the authors assigned nonsmoking, healthy, young men to either a stress (n = 22) or a control (n = 18) condition, after which the men were given an internal source monitoring test. Results show that relative to control participants, stressed participants made fewer source monitoring errors. This study suggests that stress may have differential effects on memory, depending on whether the memory test is regulated by the prefrontal cortex or the medial temporal lobe.

Rapid modulation of TRH and TRH-like peptide levels in rat brain and peripheral tissues by corticosterone

Disturbance of glucocorticoid signaling has been implicated in several neuropsychiatric disorders including unipolar and bipolar depression and anxiety induced by maternal deprivation. Antidepressants have been shown to be neuroprotective and able to reverse damage to glia and neurons. Thyrotropin-releasing hormone (TRH) is an endogenous antidepressant that reduces the expression of glycogen synthase kinase-3β (GSK-3β), an enzyme that hyperphosphorylates tau and is implicated in bipolar depression, diabetes and Alzheimer's disease. In order to understand the potential role of TRH and TRH-like peptides both as mediators of the depressogenic effects of glucocorticoids and as potential therapeutics for neuropsychiatric disease, 300 g male Sprague-Dawley rats were injected i.p. with 4 mg corticosterone/0.5 ml 50% DMSO + 50% ethanol and sacrificed 0, 2, 4 and 8 h later. Levels of TRH and TRH-like peptides were measured in various brain regions involved in mood regulation and pancreas and reproductive tissues that mediate the metabolic and reproductive impairments associated with high glucocorticoid levels. Significant increases, ranging from 2- to 12-fold, in TRH or TRH-like peptide levels were observed in almost all brain regions studied at 4 h after corticosterone injection. In cerebellum, TRH and TRH-like peptides increased 4–14-fold by 8 h. TRH-like peptide levels fell 86–98% at 4 h after treatment in testis. TRH, derived only from Leydig cells, was not affected. TRH and TRH-like peptides increased 2–4-fold at 8 h in pancreas. TRH and TRH-like peptide concentrations in prostate were not affected by corticosterone up to 8 h after injection. The 4 h needed to detect a highly significant change in the TRH and TRH-like peptide levels in brain and peripheral tissues is consistent with the mediation of most corticosterone-effects via alterations in gene transcription.

Glucocorticoids, 11beta-HSD1 and cognitive function with ageing

Cumulative exposure to high glucocorticoid levels is a major factor advanced to explain individual decline in cognitive function with ageing. Current manipulations to maintain low circulating glucocorticoid levels throughout life (adrenalectomy with low dose corticosterone replacement, neonatal handling), though effective in preventing the emergence of memory deficits with age in rodent models, are however not clinically applicable. 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) catalyses the intracellular regeneration of active glucocorticoids from circulating inert 11-keto steroids thus amplifying glucocorticoid levels within specific target cells. In primary hippocampal neurons in vitro, inhibition of 11beta-HSD1 attenuates glucocorticoid-associated neurotoxicity. To determine the importance of 11beta-HSD1 in the ageing brain in vivo, we examined the impact of enzyme loss on hippocampal function using transgenic mice lacking expression of 11beta-HSD1. Wildtype mice develop elevated plasma corticosterone levels with age that correlated with hippocampal specific learning deficits in the watermaze. In contrast, despite similar elevated plasma corticosterone levels, aged 11beta-HSD1 knockout mice show significantly better learning than age-matched wildtype controls; this implicates lower intracellular corticosterone levels through the lack of 11-dehydrocorticosterone re-activation. Consistent with this, aged 11beta-HSD1 knockout mice show lower hippocampal tissue corticosterone levels than in wildtype controls. At the cellular level, enhanced hippocampal long-term potentiation in the CA1 region of aged 11beta-HSD1 knockout mice may, in part, underlie the improved cognitive function.

Regulation of apelin mRNA expression by insulin and glucocorticoids in mouse 3T3-L1 adipocytes

The novel 36-amino acid peptide, apelin, is the endogenous ligand for the orphan receptor APJ. Apelin may play important roles in the regulation of the cardiovascular system and the hypothalamic–pituitary axis. It is a potent hypotensive agent and one of the most potent stimulators of cardiac contractility. In this study, we investigated the roles of apelin derived from adipocytes in the regulation of cardiovascular homeostasis. We found that both apelin and APJ mRNAs were expressed in isolated mouse adipocytes and that apelin mRNA levels increased during the differentiation of 3T3-L1 cells to adipocytes. We also found that the administration of insulin (1 nM–100 nM) increased, while that of dexamethasone (0.1 nM–100 nM) decreased the apelin mRNA levels in 3T3-L1 adipocytes in a dose-dependent manner, suggesting that insulin and glucocorticoids regulate apelin gene expression in adipocytes. We speculate that high glucocorticoid levels suppress apelin production and stimulate angiotensin II production in adipocyte, decreasing the counter-regulatory activity of apelin against the pressor action of angiotensin II, which might partly be involved in the mechanism underlying the development of obesity-related hypertension.

276 Prenatal Exposure to Dexamethasone Permanently Alters the Expression of 11Beta HSD1, Mineralcorticoid and 5HT1B Receptor in Rat Hippocampus

Changes in gene expression in the brain, pituitary, and adrenal have been reported in a number of prenatal stress studies. However, it is not clear whether the high maternal glucocorticoid (GC) level is directly responsible for these perturbations. We exposed rat dams to DEX during gestation days 14–19 and found a significant decrease in birth weight and adult weight of the male offspring. In addition, this treatment elicited a significant increase in serum ACTH and CORT. In contrast, circulating levels of serotonin were significantly lower in the DEX-exposed adult males. Using real time RT-PCR we measured a significant decrease in the hippocampal mineralcorticoid receptor (MR) and serotonin receptor, 5-HT1B. In contrast, the mRNA levels measured for hippocampal 5-HT1A, 5-HT2A, and glucocorticoid receptor (GR) were not significantly different from the control animals. Interestingly, males exposed to DEX in utero exhibited a significant increase in hippocampal 11 beta hydroxysteroid dehydrogenase 1 (11beta HSDI). Unlike the placental 11beta HSD2 isozyme which inactivates endogenous CORT, hippocampal 11beta HSD1 regenerates active corticosterone from inert 11dehydrocorticosterone. It is becoming increasingly apparent that glucocorticoid actions are not only mediated via intracellular GR and MR, but by the presence of 11beta HSDI and its capacity for regulating intracellular concentration of active GC. HPA axis hyperactivity may result, in part, from a reduced hippocampal tonic inhibition. It is possible that the significant changes in hippocampal corticosteroid receptor and 11beta HSD I gene expression contribute to this loss of inhibition. Moreover, since 5HT receptors in the rat hippocampus are normally under tonic inhibition by corticosteroid, the elevation of both circulating and intracellular CORT would suppress the serotonergic system in this region. These data demonstrate that exposure to DEX in utero has persistent effects on the adult brain thus supporting the prenatal origin of adult dysfunction hypothesis.

Fetal origins of insulin resistance and obesity

A number of epidemiological studies worldwide have demonstrated a relationship between poor early growth and an increased susceptibility to insulin resistance, visceral obesity, type 2 diabetes and other features of the metabolic syndrome in adulthood. However, the mechanistic basis of this relationship and the relative roles of genes and the environment remain a subject of debate. The 'thrifty phenotype' hypothesis proposes that poor fetal nutrition leads to programming of metabolism and an adult phenotype that is adapted to poor but not plentiful nutrition. The maternal reduced-protein rat model has been used to examine the importance of the maternal environment in determining susceptibility to adult disease. Pregnant and lactating rat dams are fed a diet containing 80 g protein/kg as compared with 200 g protein/kg, which leads to growth restriction in utero. Offspring of low-protein dams have increased susceptibility to diabetes, insulin resistance and hypertension when fed a palatable high-fat diet that promotes obesity. Administration of leptin during pregnancy and lactation to these protein-restricted dams produces offspring that have increased metabolic rate and do not become obese or insulin resistant when fed on a high-fat diet. Increased glucocorticoid exposure, particularly during late gestation, has been linked with insulin resistance in adulthood. High levels of fetal glucocorticoids may result from a decreased activity of placental 11beta-hydroxysteroid dehydrogenase (11beta-HSD) type 2, which normally protects the fetus from high maternal glucocorticoid levels. Leptin administration to protein-restricted dams inhibits the suppression of 11beta-HSD-2 and may be one mechanism by which the metabolic syndrome is prevented.

Coroidopatía serosa central como complicación de epitelitis en tratamiento con corticoides

We present cases of two patients who were examined in our department with the diagnosis of epitheliopathy following treatment with oral and topical glucocorticoids. They were referred because of loss of visual acuity. The ophthalmic examination established the diagnosis of central serous chorioretinopathy and it was decided to stop treatment with glucocorticoids. The pathogenesis of the central serous chorioretinopathy is still imprecisely known, but it has been related to several situations characterized by exposure to high levels of endogenous or exogenous glucocorticoids. Both of these cases provide more evidence of the potential association between corticosteroids and the acute manifestations of central serous chorioretinopathy.

Synthetic Glucocorticoids: Antenatal Administration and Long-term Implications

A clear relationship between intrauterine development and later life predisposition to long-term disease is well established. Weight at birth provides a surrogate measure for fetal development and low birth weight predicts changes in most endocrine axes in adulthood. The exposure of the fetus to elevated levels of either endogenous or synthetic glucocorticoids, pre and periconceptional nutritional status and immediate postnatal development including catch-up growth all contribute substantially to the development of adult onset disease. Fetal exposure to high levels of glucocorticoids has direct clinical relevance. Synthetic glucocorticoids (betamethasone/ dexamethasone) are administered to women at risk of preterm delivery to advance fetal maturation and reduce neonatal morbidity and mortality. However, in human pregnancy, evidence suggests that fetal exposure to synthetic glucocorticoids has detrimental effects on birth outcome, childhood cognition and long-term behavior. Studies in animals have established a link between prenatal exposure to synthetic glucocorticoids and alterations in fetal development as well as changes in placental function. These developmental alterations appear to be permanent. Whether this is the case in humans awaits long-term follow-up of children enrolled in randomized controlled trials of prenatal glucocorticoid therapy. The research challenges in this field are now centered on uncovering the mechanisms by which glucocorticoids are involved in programming the fetus for its future life, and discovering ways in which the effectiveness and safety of antenatal glucocorticoids can be enhanced. The purpose of this mini-review is to provide a background into the use of antenatal synthetic corticosteroids and to highlight and summarize recently published clinical and animal-based studies.

High faecal glucocorticoid levels predict mortality in ring-tailed lemurs ( Lemur catta )

Glucocorticoid levels are commonly used as measures of stress in wild animal populations, but their relevance to individual fitness in a wild population has not been demonstrated. In this study I followed 93 ring-tailed lemurs (Lemur catta) at Berenty Reserve in Madagascar, collecting 1089 faecal samples from individually recognized animals, and recording their survival over a 2 year period. I evaluated faecal glucocorticoid levels as predictors of individual survival to the end of the study. Animals with high glucocorticoid levels had a significantly higher mortality rate. This result suggests that glucocorticoid measures can be useful predictors of individual survival probabilities in wild populations. The 'stress landscape' indicated by glucocorticoid patterns may approximate the fitness landscape to which animals adapt.

Plasma cortisol levels, brain volumes and cognition in healthy elderly men

In ageing animals, exposure to chronic high levels of glucocorticoids is associated with cognitive impairment and hippocampal atrophy. However, there are few studies examining relationships among glucocorticoids, brain volumes and cognitive function in healthy older humans. This study examined the hypotheses that higher plasma cortisol levels and altered sensitivity to glucocorticoids are associated with worse cognition and more brain atrophy in elderly men. Ninety-seven healthy men aged 65-70 had plasma cortisol measured at 09:00, 14:30 h, and post-dexamethasone (0.25mg, 09:00 h), and had dermal sensitivity to glucocorticoids measured. They also underwent cognitive testing, with scores adjusted for estimated prior mental ability, and had MRI measurements of intracranial area (a validated estimate of intracranial capacity), and hippocampus, temporal lobe and frontal lobe volumes. Plasma cortisol levels at 09:00 h were significantly and negatively correlated with a summary General Cognitive Factor accounting for 51% of the variance of cognitive function (rho=-0.22, p=0.035), and specific cognitive tests: delayed paragraph recall (rho=-0.28, p=0.036) and processing speed (rho=-0.23, p=0.026). Regional brain volumes adjusted for intracranial area generally did not correlate with cortisol levels. Tissue glucocorticoid sensitivity did not correlate with any measure of cognition or brain volume. In healthy older men, higher plasma cortisol levels are associated with worse ageing-related overall cognitive change but not ageing-related brain atrophy.