Can Excess Glucocorticoid, in Utero, Predispose to Cardiovascular and Metabolic Disease in Middle Age?

Dodic, Miodrag; Peers, Arianne; Coghlan, John P.; Wintour, Marelyn

doi:10.1016/s1043-2760(98)00125-8

Cited by 56 publications

(42 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Our findings also suggest that these effects would be propagated further by increased local hepatic expression of GR. In light of these results, we speculate that fetal sheep exposed to increased cortisol might show a predisposition to hepatic changes leading to hyperglycaemia, insulin resistance and later programming of inappropriate glycaemic control (Dodic et al 1999). …”

Section: Discussionmentioning

confidence: 93%

Effects of cortisol and oestradiol on hepatic 11beta-hydroxysteroid dehydrogenase type 1 and glucocorticoid receptor proteins in late-gestation sheep fetus

Gupta¹,

Alfaidy²,

Holloway³

et al. 2003

Journal of Endocrinology

View full text Add to dashboard Cite

In the late-gestation sheep, increased fetal plasma cortisol concentration and placental oestradiol (E 2 ) output contribute to fetal organ maturation, in addition to the onset of parturition. Both cortisol and E 2 are believed to regulate the enzyme 11 -hydroxysteroid dehydrogenase type 1 (11 -HSD1), which interconverts bioactive 11-hydroxy glucocorticoids and their inactive 11-keto metabolites. 11 -HSD1, abundantly expressed in fetal liver, operates primarily as a reductase enzyme to produce bioactive cortisol and thus regulates local hepatic glucocorticoid concentrations. Cortisol acts through the glucocorticoid receptor (GR) present in the liver. In this study, we examined the effects of cortisol and E 2 on hepatic 11 -HSD1 and GR in the liver of chronically catheterized sheep fetuses treated with saline (n=5), cortisol (1·35 mg/ h; n=5), saline+4-hydroxyandrostendione, a P450 aromatase inhibitor (4-OHA; 1·44 mg/h; n=5), or cortisol+4-OHA (n=5). Cortisol infusion resulted in increased plasma concentrations of fetal cortisol and E 2 ; concurrent administration of 4-OHA attenuated the increase in plasma E 2 concentrations. Using immunohistochemistry, we showed that fetal hepatocytes expressed both 11 -HSD1 and GR proteins. Cortisol treatment increased GR in both cytosol and nuclei of hepatocytes; concurrent administration of 4-OHA was associated with distinct nuclear GR staining. Western blot revealed that cortisol, in the absence of increased E 2 concentrations, significantly increased concentrations of 11 -HSD1 (34 kDa) and GR (95 kDa) proteins. 11 -HSD1 enzyme activity was measured in the liver microsomal fraction in the presence of [ + (dehydrogenase activity) respectively. 11 -HSD1 reductase activity was significantly greater in the presence of cortisol. In summary, we found that, in sheep during late gestation, cortisol increased both 11 -HSD1 and GR in the fetal liver, and these effects were accentuated in the absence of increased E 2 .

show abstract

Section: Discussionmentioning

confidence: 93%

Effects of cortisol and oestradiol on hepatic 11beta-hydroxysteroid dehydrogenase type 1 and glucocorticoid receptor proteins in late-gestation sheep fetus

Gupta¹,

Alfaidy²,

Holloway³

et al. 2003

Journal of Endocrinology

View full text Add to dashboard Cite

show abstract

“…Several studies dealing with antenatal GC treatment suggest lifelong changes in cardiovascular function (4,5,19). These studies postulate that high concentrations of antenatal and perinatal GCs alter the number of steroid receptors in the hypothalamic-pituitary-adrenal axis and affect other systems such as the renin-angiotensin system.…”

Section: Discussionmentioning

confidence: 99%

Alterations in Adult Rat Heart after Neonatal Dexamethasone Therapy

et al. 2002

View full text Add to dashboard Cite

Glucocorticoid treatment in preterm babies to prevent chronic lung disease causes myocardial hypertrophy and increased myocardial protein content. Although these changes are thought to be transient, there is evidence that dexamethasone (DEX) induces permanent myocardial abnormalities as well. We investigated whether a therapeutic course of neonatal DEX in rat pups produces anatomic and biochemical alterations in rat hearts during adult life. Twenty-four rat pups were treated with DEX on d 1, 2, and 3 (0.5, 0.3, and 0.1 g/g) of life, with doses proportional to those used in preterm babies. Twenty-four control pups were treated with saline. At d 7, wk 8, or wk 45 (n ϭ 8 per group) rats were killed. The anatomic parameters measured were body weight (Bw, in grams), heart (myocardial) weight (Hw, in milligrams), and the Hw:Bw ratio. Myocardial total protein (Prot) and DNA content were determined, and the Prot:DNA ratio was calculated. Histopathology and morphometry were performed on 45-wk-old rat hearts. In DEX-treated rat pups, at d 7, Bw and Hw were lower and the Hw:Bw ratio was increased. DNA content was lower, Prot higher, and Prot:DNA ratio was increased. In 8-wk-old rats Bw, Hw, DNA content, Prot content or Prot:DNA ratio did not differ between groups, but the Prot:DNA ratio still tended to be higher in DEX-treated rats. In 45-wk-old rats Hw and Hw:Bw ratio were significantly lower and Prot:DNA ratio higher in DEX-treated rats. Histopathologic analysis showed larger cardiomyocyte volume, length, and width, indicating hypertrophy, and increased collagen, indicating early degeneration of individual myocytes. In conclusion, neonatal DEX treatment in rat pups causes a permanent decrease in heart weight, as well as hypertrophy and early degeneration of cardiomyocytes during adulthood. (Pediatr Res 52: 900-906, 2002) Abbreviations Bw, body weight DEX, dexamethasone GC, glucocorticoid Hw, heart weight Prot, total protein SAL, saline Chronic lung disease is a common outcome in extremely preterm neonates with severe respiratory distress syndrome and carries a high incidence of morbidity and mortality. Inflammation is an important factor in its pathogenesis. Because of their antiinflammatory properties GCs, particularly DEX, resulted in an impressive decrease in chronic lung disease (1, 2). Consequently GCs are frequently used and have become indispensable in all neonatal intensive care units in the Western world, especially inasmuch as an alternative therapy is not available at present. Despite the short-term benefits of GCs, major concern has emerged now because recent experimental studies report long-lasting adverse effects of perinatal GC treatment in later life, such as lifetime changes in cardiovascular function and reprogramming of the neuroendocrine system (3-5). Benediktsson et al. (6) reported that GC exposure during the perinatal period leads to hypertension during adult life, possibly related to a GC-induced reprogramming of the hypothalamic-pituitary-adrenal axis. Neonatal GCs also altered the epinephrine a...

show abstract

“…The fetal programming hypothesis has been proposed to explain these associations. Programming reflects the possibility of an intrauterine factor mediating cellular growth and development at a vulnerable time in gestation, subsequently resulting in permanent alterations in tissue and organ function that are apparent later in life (Dennison et al 1997, Dodic et al 1999, Hill 1999, Seckl & Chapman 2000.…”

Section: Introductionmentioning

confidence: 99%

Repeated maternal glucocorticoid administration and the developing liver in fetal sheep

Sloboda¹,

Newnham²,

Challis³

2002

Journal of Endocrinology

View full text Add to dashboard Cite

Prenatal glucocorticoid exposure has been associated with a reduction in birth weight and postnatal alterations in glucose homeostasis and hypothalamic-pituitary-adrenal (HPA) axis function. The mechanisms underlying these responses are unknown, although changes in fetal hepatic development may play an important role. The fetal liver produces key regulators of fuel metabolism and of the developing HPA axis that are altered by glucocorticoids. The local availability of glucocorticoids is regulated, in part, by corticosteroid-binding protein (CBG), glucocorticoid receptors (GR) and by the enzyme 11 -hydroxysteroid dehydrogenase (11 HSD), but the effects of maternal glucocorticoid administration on the expression of these genes in the fetal liver are unknown. 11 HSD1 is the predominant form of this enzyme present in the liver and is responsible for the conversion of cortisone to cortisol. To determine if prenatal glucocorticoid exposure alters fetal hepatic regulation of CBG, 11 HSD1 and GRs, we treated pregnant ewes with betamethasone (0·5 mg/kg) intramuscularly at 104, 111 and 118 days of gestation (term 150 days). Animals were killed at 125 or 146 days of gestation. Maternal betamethasone administration did not alter mean cord plasma glucose but significantly decreased cord plasma insulin levels (P<0·05) at 125 days of gestation. At 146 days of gestation, cord plasma glucose levels were significantly increased without alterations in insulin levels following maternal betamethasone treatment (P<0·05). Maternal betamethasone administration resulted in a significant increase in fetal hepatic 11 HSD1 mRNA and protein levels at 125 days of gestation (P<0·05). CBG mRNA levels were significantly elevated over control at 125 days although levels of CBG protein were not significantly different. GR protein levels were not statistically different at either 125 or 146 days of gestation following glucocorticoid administration. These data suggest that prenatal betamethasone exposure in the ovine fetus results in alterations in cord glucose and insulin levels as well as alterations in hepatic 11 HSD1 mRNA and protein expression. These changes in 11 HSD1 increase the potential to generate local cortisol from circulating cortisone. We speculate that this could affect expression of glucocorticoid-dependent hepatic enzymes involved with the regulation of glucose production and HPA responsiveness.

show abstract

Can Excess Glucocorticoid, in Utero, Predispose to Cardiovascular and Metabolic Disease in Middle Age?

Cited by 56 publications

References 50 publications

Effects of cortisol and oestradiol on hepatic 11beta-hydroxysteroid dehydrogenase type 1 and glucocorticoid receptor proteins in late-gestation sheep fetus

Effects of cortisol and oestradiol on hepatic 11beta-hydroxysteroid dehydrogenase type 1 and glucocorticoid receptor proteins in late-gestation sheep fetus

Alterations in Adult Rat Heart after Neonatal Dexamethasone Therapy

Repeated maternal glucocorticoid administration and the developing liver in fetal sheep

Contact Info

Product

Resources

About