Glucocorticoid exposure in utero: new model for adult hypertension

Benediktsson, Rafn; Lindsay, Robert; Noble, June; Seckl, Jonathan R.; Edwards, C. R. W.

doi:10.1016/0140-6736(93)90138-7

Cited by 817 publications

(560 citation statements)

References 9 publications

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“…The administration of dexamethasone (dex) to pregnant rats results in low birth weight offspring that develop hypertension (9), glucose intolerance, insulin resistance (10), and an overactive hypothalamic -pituitary-adrenal (HPA) axis (11) in later life. These adult manifestations of programming may be explained by tissue-specific differences in expression of glucocorticoid receptors (GR).…”

Section: Introductionmentioning

confidence: 99%

Is programming of glucocorticoid receptor expression by prenatal dexamethasone in the rat secondary to metabolic derangement in adulthood?

Cleasby

Livingstone²,

Nyirenda³

et al. 2003

European Journal of Endocrinology

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Objective: Glucocorticoids may contribute to the association between retarded growth in utero and insulin resistance in adulthood. Administration of dexamethasone (dex) to pregnant rats results in low birth weight offspring, which develop glucose intolerance, hyperinsulinaemia and hypercorticosteronaemia. This may be explained by tissue-specific differences in expression of glucocorticoid receptors (GR) in adult offspring: GR is increased in visceral fat and liver, and decreased in hippocampus and soleus muscle. However, cause and effect between altered GR expression, hypercorticosteronaemia, and hyperinsulinaemia remains to be established. Design and methods: Rats were treated with dex (100 mg/kg per day) or saline during the third week of pregnancy. In 5-8-month-old male offspring, GR expression in insulin target tissues was quantified by RNase protection assay in rats that were adrenalectomised (ADX group), sham operated (SHAM group), or adrenalectomised with supra-physiological corticosterone replacement (CORT group) (n ¼ 7 -8 per group), and in rats treated orally with vehicle, metformin (43 mg/kg per day) or rosiglitazone (1 mg/kg per day), after 3 weeks. Results: Manipulation of corticosterone concentration did not affect GR mRNA in skeletal muscle or adipose. In liver, sham-operated animals showed lower GR mRNA, but there was no difference between adrenalectomised and hypercorticosteronaemic animals (SHAM 0:11^0:01 ratio to b-actin, vs ADX 0:22^0:02; CORT 0:23^0:02; (values expressed as means^S.E.M.), P , 0:001). Rosiglitazone reduced GR mRNA by ,30% in liver of dex-and saline-treated offspring ðP , 0:05Þ; but had no effect on GR in adipose and skeletal muscle. Metformin abolished the 38% up-regulation of liver GR mRNA induced by antenatal dex and also reduced GR mRNA preferentially in muscle of dex-treated animals (0:14^0:01 vs 0:10^0:01; P ¼ 0:03). Conclusions: We conclude that neither hypercorticosteronaemia nor hyperinsulinaemia are sufficient to cause the changes in GR expression in dex-programmed rats, implying that these changes may be primary in determining the programmed insulin resistant phenotype. Normalisation of GR expression by metformin may be important in the mode of action of this anti-diabetic agent and may be especially useful to reverse-programmed up-regulation of GR.

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Section: Introductionmentioning

confidence: 99%

Is programming of glucocorticoid receptor expression by prenatal dexamethasone in the rat secondary to metabolic derangement in adulthood?

Cleasby

Livingstone²,

Nyirenda³

et al. 2003

European Journal of Endocrinology

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“…Endogenous glucocorticoids (cortisol in humans, corticosterone in rodents) are a key signal in late gestation, which alter developmental trajectories of fetal tissues, predominantly from a proliferative to differentiated state, in preparation for extrauterine life (2). Fetal overexposure to glucocorticoids in humans, primates, and rodents is detrimental for placental and fetal growth and development, and "programs" higher risk of cardiometabolic disease in later life (3)(4)(5)(6)(7)(8). Recent data suggest that the detrimental effects of excess glucocorticoids on fetal growth and development result from direct glucocorticoid actions on the placenta and on the fetus itself (9,10).…”

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confidence: 99%

Pravastatin ameliorates placental vascular defects, fetal growth, and cardiac function in a model of glucocorticoid excess

Wyrwoll

Noble

Thomson

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Fetoplacental glucocorticoid overexposure is a significant mechanism underlying fetal growth restriction and the programming of adverse health outcomes in the adult. Placental glucocorticoid inactivation by 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) plays a key role. We previously discovered that Hsd11b2 −/− mice, lacking 11β-HSD2, show marked underdevelopment of the placental vasculature. We now explore the consequences for fetal cardiovascular development and whether this is reversible. We studied Hsd11b2 +/+ , Hsd11b2 +/− , and Hsd11b2 −/− littermates from heterozygous (Hsd11b +/− ) matings at embryonic day (E)14.5 and E17.5, where all three genotypes were present to control for maternal effects. Using high-resolution ultrasound, we found that umbilical vein blood velocity in Hsd11b2 −/− fetuses did not undergo the normal gestational increase seen in Hsd11b2 +/+ littermates. Similarly, the resistance index in the umbilical artery did not show the normal gestational decline. Surprisingly, given that 11β-HSD2 absence is predicted to initiate early maturation, the E/A wave ratio was reduced at E17.5 in Hsd11b2 −/− fetuses, suggesting impaired cardiac function. Pravastatin administration from E6.5, which increases placental vascular endothelial growth factor A and, thus, vascularization, increased placental fetal capillary volume, ameliorated the aberrant umbilical cord velocity, normalized fetal weight, and improved the cardiac function of Hsd11b2 −/− fetuses. This improved cardiac function occurred despite persisting indications of increased glucocorticoid exposure in the Hsd11b2 −/− fetal heart. Thus, the pravastatin-induced enhancement of fetal capillaries within the placenta and the resultant hemodynamic changes correspond with restored fetal cardiac function. Statins may represent a useful therapeutic approach to intrauterine growth retardation due to placental vascular hypofunction.placenta | 11β-HSD2 | glucocorticoids | fetal heart | developmental programming

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“…3 In a number of animal models, exposure to glucocorticoids before birth results in increased blood pressure in the offspring. 3,4 To date, the data on subsequent blood pressure among human subjects exposed prenatally to glucocorticoids for prevention of RDS have been contradictory. One nonrandomized cohort study found that extremely premature neonates exposed prenatally to glucocorticoids had higher blood pressure in the first 48 hours after birth.…”

mentioning

confidence: 99%

Blood Pressure at 6 Years of Age After Prenatal Exposure to Betamethasone: Follow-up Results of a Randomized, Controlled Trial

Dalziel

Liang

Parag³

et al. 2004

Pediatrics

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ABSTRACT. Objective. To determine whether prenatal exposure to betamethasone for the prevention of neonatal respiratory distress syndrome (RDS) alters blood pressure in childhood.Design. Prospective follow-up study of a randomized, double-blind, placebo-controlled trial.Setting. National Women's Hospital (Auckland, New Zealand).Participants. Two hundred twenty-three 6-year-old children of mothers who presented with unplanned premature labor and took part in a randomized, controlled trial of prenatal betamethasone therapy for the prevention of neonatal RDS.Intervention. Mothers received 2 doses of betamethasone (12 mg) or placebo, administered through intramuscular injection, 24 hours apart.Main Outcome Measures. Systolic and diastolic blood pressure at 6 years of age.Results. Children exposed prenatally to betamethasone (n ‫؍‬ 121) did not differ in systolic or diastolic blood pressure from children exposed to placebo (n ‫؍‬ 102) (mean difference: systolic: ؊1.6 mm Hg; 95% confidence interval: ؊4.1 to 0.8 mm Hg; diastolic: ؊0.3 mm Hg; 95% confidence interval: ؊2.5 to 1.8 mm Hg).Conclusion. Prenatal exposure to betamethasone for prevention of neonatal RDS does not alter blood pressure at 6 years of age. Pediatrics 2004;114:e373-e377. URL: http://www.pediatrics.org/cgi/content/full/114/3/e373; prenatal glucocorticoids, respiratory distress syndrome, blood pressure, long-term follow-up.ABBREVIATIONS. RDS, respiratory distress syndrome; CI, confidence interval; RCT, randomized, controlled trial. N eonatal respiratory distress syndrome (RDS) is a major cause of early morbidity and death among the 10% of neonates who are born prematurely. Prenatal glucocorticoid therapy is recommended in the management of preterm labor, for the prevention of RDS, and is very widely used. Such prenatal use of glucocorticoids results in substantial decreases in the rates of neonatal morbidity and death, as well as considerable cost savings. However, the long-term physical effects remain poorly described. 1,2 Furthermore, fetal exposure to excess glucocorticoids has been proposed as one of the core mechanisms explaining the epidemiologic association between low birth weight and subsequent increased blood pressure (the fetal origins of adult disease hypothesis). 3 In a number of animal models, exposure to glucocorticoids before birth results in increased blood pressure in the offspring. 3,4 To date, the data on subsequent blood pressure among human subjects exposed prenatally to glucocorticoids for prevention of RDS have been contradictory. One nonrandomized cohort study found that extremely premature neonates exposed prenatally to glucocorticoids had higher blood pressure in the first 48 hours after birth. 5 Another nonrandomized cohort study of 177 fourteen-year-old children born preterm found that those exposed to glucocorticoids had higher mean systolic and diastolic blood pressures (mean difference: systolic: 4.1 mm Hg; 95% confidence interval [CI]: 0.1 to 8.0 mm Hg; diastolic: 2.8 mm Hg; 95% CI: 0.05 to 5.6 mm Hg). 6 In contrast, a ...

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Glucocorticoid exposure in utero: new model for adult hypertension

Cited by 817 publications

References 9 publications

Is programming of glucocorticoid receptor expression by prenatal dexamethasone in the rat secondary to metabolic derangement in adulthood?

Is programming of glucocorticoid receptor expression by prenatal dexamethasone in the rat secondary to metabolic derangement in adulthood?

Pravastatin ameliorates placental vascular defects, fetal growth, and cardiac function in a model of glucocorticoid excess

Blood Pressure at 6 Years of Age After Prenatal Exposure to Betamethasone: Follow-up Results of a Randomized, Controlled Trial

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