Prenatal betamethasone exposure results in pituitary-adrenal hyporesponsiveness in adult sheep

Deborah Sloboda, T.J. Moss, Shaofu Li, Dorota Doherty, Ilias Nitsos, J.R.G. Challis, John Newnham

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    Abstract

    Fetal exposure to synthetic glucocorticoids in sheep results in increased fetal hypothalamic-pituitaryadrenal ( HPA) activity persisting to one year of age. We aimed to determine the effects of single or repeated maternal or fetal betamethasone injections on offspring HPA activity at 2 and 3 yr of age and whether changes in adrenal mediators of steroidogenesis contribute to changes in pituitary-adrenal function. Pregnant ewes or their fetuses received either repeated intramuscular saline or betamethasone injections ( 0.5 mg/kg) at 104, 111, 118, and 124 days of gestation ( dG) or a single betamethasone injection at 104 dG followed by saline at 111, 118, and 124 dG. Offspring were catheterized at 2 and 3 yr of age and given corticotrophin-releasing hormone + arginine vasopressin challenges. Adrenal tissue was collected for quantitative RT-PCR mRNA determination at 3.5 yr of age. In 2-yr-old offspring, maternal betamethasone injections did not alter basal ACTH or cortisol levels, but repeated injections elevated ACTH responses. At 3 yr of age, basal ACTH was elevated, and both basal and stimulated cortisol levels were suppressed by repeated maternal injections. Basal and stimulated cortisol-to-ACTH ratios and basal cortisol-to-cytochrome P-450 17 alpha-hydroxylase ( P450c17) mRNA ratios were suppressed by repeated injections. Repeated fetal betamethasone injections attenuated basal ACTH and cortisol levels in offspring at 2 but not 3 yr of age. Plasma changes were not associated with altered adrenal P450c17, ACTH receptor, beta-hydroxysteroid dehydrogenase, or glucocorticoid receptor mRNA levels. These data suggest that maternal, but not fetal, betamethasone administration results in adrenal suppression in adulthood.
    Original languageEnglish
    Pages (from-to)E61-E70
    JournalAmerican journal of physiology : endocrinology and metabolism
    Volume292
    Issue number1
    DOIs
    Publication statusPublished - 2007

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