Endocrine Abstracts

Glucocorticoids have profound effects on the brain, particularly during development and during the ageing process. The glucocorticoid metabolising enzymes, 11beta-hydroxysteroid dehydrogenases (11β-HSDs) type 1 and 2, interconvert active corticosterone (or cortisol) and inactive 11keto-derivatives to modify intracellular glucocorticoid levels. Hence, these enzymes add another layer of complexity to glucoocorticoid action in addition to circulating hormone and receptor (MR...

Prenatal exposure to excess glucocorticoids may be causal in programming mood disorders in later life. In support of this hypothesis, maternal stress, treatment during pregnancy with dexamethasone (which crosses the placenta) or inhibitors of feto-placental 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), the physiological ‘barrier’ to maternal glucocorticoids, reduces birth weight and programmes offspring cardio-metabolic and affective behaviours. The e...

Placental 11β-hydroxysteroid dehydrogenase-2 (11β-HSD2) rapidly converts glucocorticoids to inactive metabolites, thus protecting the developing fetus from high maternal glucocorticoids. Genetic deficiency or inhibition of 11β-HSD2 associates with fetal growth restriction, low birth weight, and cardiometabolic disease in adulthood. Similar ‘programming’ effects are seen with maternal malnutrition or stress; these challenges associate with reduced place...

Prenatal glucocorticoid overexposure is a key risk factor for susceptibility to neuropsychiatric disorders in adult life. Fetal exposure to glucocorticoids is regulated by 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) an enzyme which inactivates glucocorticoids and is highly expressed in the placenta and fetus. Previous work has established that 11β-HSD2−/− offspring generated by heterozygous matings exhibit altered placental developm...

Fetal glucocorticoid exposure is a key mechanism involved in adverse programming outcomes in the adult, including hypertension, anxiety and insulin resistance. While glucocorticoids may exert their effects directly on the fetus, they may also affect fetal growth through indirect effects on placental function. Regulation of fetal glucococorticoid exposure is achieved by the placental glucocorticoid barrier, which involves glucocorticoid inactivation within the labyrinth zone of...

Increased intake of sodium is postulated to be controlled by aldosterone-sensitive cells in a select region of the adult mouse brain, the nucleus of the solitary tract (NTS). These cells express the enzyme 11β-hydroxysteroid dehydrogenase type 2 (HSD2) which inactivates glucocorticoids, allowing selective activation of mineralocorticoid receptors by aldosterone. However in the developing brain, HSD2 is widely expressed to protect against adverse glucocorticoid action, whi...

Background: Chronically elevated brain glucocorticoid (GC) levels impair cognition. In rodents, raised GC levels prior to lipopolyaccharide (LPS) administration potentiate neuroinflammation although GC suppresses neuroinflammation if administered after LPS. 11β-hydroxysteroid dehydrogenase-1 (11β-HSD1) activity can increase intracellular GC levels, including in the brain, without alteration in circulating levels. 11β-HSD1 deficiency/inhibition protects against a...

In addition to their essential role in fetal lung development, glucocorticoids promote late-gestation maturation of the fetal heart as shown by severe functional impairment, structural disorganisation and transcriptome immaturity in fetal hearts of glucocorticoid receptor-deficient (GR-/-) mice. Here we use primary fetal mouse cardiomyocytes (E16-E17.5) to investigate whether these effects of glucocorticoids result from direct actions of GR and whether they are independent of ...

Chronically elevated glucocorticoid (GC) levels alter cognition and increase cardio-metabolic disease risk. Negative feedback suppression of the hypothalamic–pituitary–adrenal (HPA) axis, including at the hippocampus, maintains low/basal circulating GC levels. Intracellular GC can be increased, without alteration in circulating levels, by the activity of 11β-hydroxysteroid dehydrogenase type1 (11β-HSD1). In some tissues, 11β-HSD1 expression is increase...

Glucocorticoid signalling is essential for cardiac maturation late gestation. In mice, global glucocorticoid receptor deficiency (GR−/−) severely impairs cardiac function and ultrastructure at embryonic day (E) 17.5. To dissect direct effects of GR deficiency in the heart from effects on other systems, Sm22α-Cre mice were crossed with ‘floxed’ GR mice to generate SMGRKO mice with disrupted GR signalling in cardiomyocytes and vascular smoot...