The effects of sex and hormonal status on the physiological response to acute psychosocial stress.

A large body of human epidemiological data, as well as experimental studies, suggest that environmental factors operating early in life potently affect developing systems, permanently altering structure and function throughout life. This process with its persistent organizational effects has been called 'programming'. The brain is a key target for such effects. This review focuses on the effects of adverse early environments, notably exposure to stress or glucocorticoids, upon subsequent adult hypothalamus-pituitary-adrenal axis activity, behaviour and cognition. We discuss the effects observed, the proposed underlying molecular and cellular mechanisms and the consequences for pathophysiology. The data suggest that key targets for programming include glucocorticoid receptor gene expression and the corticotrophin-releasing hormone system. Increasing evidence for analogous processes in humans is also reviewed. Early life programming of neuroendocrine systems and behaviour by stress and exogenous or endogenous glucocorticoids appears to be a fundamental process underpinning common disorders. Approaches to minimize or reverse the consequences of such early life events may have therapeutic importance.

Prenatal Stress, Glucocorticoids and the Programming of the Brain

Glucocorticoid hormones, acting via nuclear receptors, regulate many metabolic processes, including hepatic gluconeogenesis. It recently has been recognized that intracellular glucocorticoid concentrations are determined not only by plasma hormone levels, but also by intracellular 11β-hydroxysteroid dehydrogenases (11β-HSDs), which interconvert active corticosterone (cortisol in humans) and inert 11-dehydrocorticosterone (cortisone in humans). 11β-HSD type 2, a dehydrogenase, thus excludes glucocorticoids from otherwise nonselective mineralocorticoid receptors in the kidney. Recent data suggest the type 1 isozyme (11β-HSD-1) may function as an 11β-reductase, regenerating active glucocorticoids from circulating inert 11-keto forms in specific tissues, notably the liver. To examine the importance of this enzyme isoform in vivo, mice were produced with targeted disruption of the 11β-HSD-1 gene. These mice were unable to convert inert 11-dehydrocorticosterone to corticosterone in vivo. Despite compensatory adrenal hyperplasia and increased adrenal secretion of corticosterone, on starvation homozygous mutants had attenuated activation of the key hepatic gluconeogenic enzymes glucose-6-phosphatase and phosphoenolpyruvate carboxykinase, presumably, because of relative intrahepatic glucocorticoid deficiency. The 11β-HSD-1 −/− mice were found to resist hyperglycamia provoked by obesity or stress. Attenuation of hepatic 11β-HSD-1 may provide a novel approach to the regulation of gluconeogenesis.

https://www.pnas.org/content/pnas/94/26/14924.full.pdf

11beta-hydroxysteroid dehydrogenase type 1 knockout mice show attenuated glucocorticoid-inducible responses and resist hyperglycemia on obesity or stress.

Epidemiological evidence suggests that low birth weight is associated with an increased risk of cardiovascular, metabolic and neuroendocrine disorders in adult life. Glucocorticoid administration during pregnancy reduces offspring birth weight and alters the maturation of the lung and other organs. We hypothesised that prenatal exposure to excess glucocorticoids or stress might represent a mechanism linking foetal growth with adult pathophysiology. In rats, birth weight is reduced following prenatal exposure to the synthetic steroid dexamethasone, which readily crosses the placenta, or to carbenoxolone, which inhibits 11b-hydroxysteroid dehydrogenase type 2 (11b-HSD2), the physiological fetoplacental ‘barrier’ to maternal glucocorticoids. As adults, the offspring exhibit permanent hypertension, hyperglycaemic, increased hypothalamic-pituitary-adrenal (HPA) axis activity and behaviour reminiscent of anxiety. Physiological variations in placental 11b-HSD2 activity correlate directly with foetal weight. In humans, 11b-HSD2 gene mutations cause low birth weight. Moreover, lowbirth-weight babies have higher plasma cortisol levels throughout adult life, indicating HPA axis programming. The molecular mechanisms may reflect permanent changes in the expression of specific transcription factors, key among which is the glucocorticoid receptor (GR) itself. The differential programming of the GR in different tissues reflects effects upon one or more of the multiple tissue-specific alternate first exons/promoters of the GR gene. Overall, the data suggest that both pharmacological and physiological exposure prenatally to excess glucocorticoids programmes cardiovascular, metabolic and neuroendocrine disorders in adult life. European Journal of Endocrinology 151 U49–U62

/pdf/prenatal-glucocorticoids-and-long-term-programming-4tis816ekj.pdf

Prenatal glucocorticoids and long-term programming.

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(96)11222-8.pdf

Does central obesity reflect Cushing's disease of the omentum?

The type 2 isoform of 11beta-hydroxysteroid dehydrogenase (11beta-HSD2), which inactivates cortisol (F) to cortisone (E), has been suggested to play a role in the ontogeny of the fetal pituitary-adrenal axis and also protect the developing fetus from the deleterious effects of circulating maternal glucocorticoids. The abundance of 11beta-HSD2 in the placenta and other fetal tissues was inferred from the F/E ratio in 17 term deliveries in both umbilical arterial (1.73 +/- 0.24, mean +/- SE) and umbilical venous blood (1.16 +/- 0.14) compared with adult peripheral venous blood (7.76 +/- 0.57, n = 70). Using sensitive assays for 11beta-HSD2 and an in-house human 11beta-HSD2 antibody, the expression and activity of this enzyme in fresh frozen human placenta increased progressively from first (8-12 weeks, n = 16) and second (13-20 weeks, n = 9) to third trimester (term) pregnancies (39-40 weeks, n = 50). Placental 11beta-HSD2 activity was significantly reduced in deliveries complicated by intrauterine growth restriction (IUGR) [25-36 weeks, n = 12, activity 380 pmol/mg/h median (225-671; 95% confidence interval)], compared with the term deliveries [888 (725-1362)] and with appropriately grown pre-term deliveries [27-36 weeks, n = 14, activity 810 (585-1269)], P < 0.05. In human pregnancy placental 11beta-HSD2 activity increases markedly in the third trimester of pregnancy at a time when maternal circulating levels of glucocorticoid are rising. The finding of attenuated placental 11beta-HSD2 activity in IUGR suggests that glucocorticoids may, in part, contribute to impaired fetal growth and that this is closely controlled in normal gestation through placental 11beta-HSD2 expression.

/pdf/11beta-hydroxysteroid-dehydrogenase-type-2-in-human-mkkz59tszr.pdf

A Gupta

Papers

11Beta-hydroxysteroid dehydrogenase type 2 in human pregnancy and reduced expression in intrauterine growth restriction.

Hypertension in the syndrome of apparent mineralocorticoid excess due to mutation of the 11β-hydroxysteroid dehydrogenase type 2 gene