Endocrine Abstracts

Epidemiological evidence suggests that an adverse fetal environment permanently programmes physiology leading to increased risks of cardiometabolic, neuroendocrine and psychiatric disorders in adulthood. We originally hypothesised that prenatal stress via fetal glucocorticoid excess might explain this link. Indeed, in rodents, prenatal stress, glucocorticoid exposure or inhibition/knockout of 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), the feto-placental &#14...

Chronic elevation of glucocorticoids adversely impacts on cognition and the integrity of hippocampal cells. Moreover, inter-individual differences in memory with ageing correlate directly with blood glucocorticoid levels in rodents and humans. Beyond plasma steroid levels, glucocorticoid action on target tissues is determined by the density of nuclear receptors and by intracellular metabolism by 11β-hydroxysteroid dehydrogenases (11β-HSDs) which catalyse interconvers...

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...

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...

Background: One in five women is obese at antenatal booking. Maternal obesity increases risk of offspring complications including higher birthweight. We hypothesised that this is mediated by altered action of maternal glucocorticoids, key regulators of fetal growth and development. We compared cortisol levels during pregnancy and placental glucocorticoid sensitivity in obese and lean women.Methods: With ethical approval serum cortisol levels were measure...

Obesity is associated with metabolic and vascular dysfunction. Many models have shown insulin resistance reduces endothelium-dependent vasodilation but this is also seen in obese subjects with normal glucose tolerance. There is also evidence of increased response to vascular injury in obese animals, although the mechanisms underpinning this are not fully understood. This study used a mouse model of diet-induced obesity (DIO) to address the hypothesis that obesity causes metabo...

Although obesity affects men and women, the risks of associated metabolic disturbances (e.g. type 2 diabetes) differ between the sexes. Altered peripheral glucocorticoid metabolism may underpin the metabolic consequences of obesity; however, most research exploring this has focused on male animals. This study used a mouse model to investigate the hypothesis that alterations in glucocorticoid metabolism caused by diet-induced obesity (DIO) will be more profound in males than in...