Dexamethasone affects human fetal adrenal steroidogenesis and subsequent ACTH response in an ex vivo culture model.

Introduction: Administration of dexamethasone (DEX) has been used experimentally to suppress androgenization of external genitalia in 46,XX fetuses with congenital adrenal hyperplasia. Despite this, the prenatal biological mechanism-of-action of DEX on fetal development is not known. This study aimed to examine direct effects of DEX on human fetal adrenal (HFA) steroidogenic activity including possible effects on the subsequent response to ACTH-stimulation. Methods: Human fetal adrenal (HFA) tissue from 30 fetuses (1st trimester) were cultured ex vivo with A) DEX (10 µm) for 14 days, or B) DEX (10 µm) for 10 days followed by ACTH (1 nM) for 4 days. DEX-mediated effects on HFA morphology, viability, and apoptosis (immunohistochemistry), gene expression (quantitative PCR), and steroid hormone secretion (LC-MS/MS) were investigated. Results: DEX-treatment caused decreased androstenedione (p<0.05) and increased cortisol (p<0.01) secretion suggesting that direct effects on the adrenal gland may contribute to the negative feedback on the hypothalamic-pituitary-adrenal axis in vivo. An altered response to ACTH stimulation in HFA pre-treated with DEX included increased androgen (p<0.05) and reduced cortisol production (p<0.05), supporting clinical observations of a temporary decreased ACTH-response following prenatal DEX-treatment. Additionally, the secretion of corticosterone was decreased (p<0.0001) following ACTH-stimulation in the initially DEX-treated HFAs. Discussion: The observed effects suggest that prenatal DEX-treatment can cause direct effects on HFA steroidogenesis and in the subsequent response to ACTH-stimulation. This may indicate a requirement for careful monitoring of adrenal function in prenatally DEX-treated neonates, with particular focus on their mineralocorticoid levels.

Adrenal responsiveness and social status in intact and ovariectomized Macaca fascicularis.

Plasma cortisol (F) response to intravenous adrenocorticotropin (ACTH) infusion (following dexamethasone suppression) was examined in adult female Macaca fascicularis that had been living for 22 months in social groups consisting of four to six females and one male. A portion of these females were ovariectomized (n = 21), while the rest were reproductively intact (n = 23). The social behavior of all animals was monitored with a focal sampling procedure, and dominance ranks were determined on the basis of fight outcomes. Further, intact females were swabbed vaginally to determine onset of menstruation and were sampled for plasma progesterone (P) every three days during the luteal phase of their cycles. Among the results was that the plasma F response to ACTH infusion was greater in subordinate animals than in dominants (P < .02). Subordinates and dominants did not, however, differ in plasma F measured at baseline. It was found further that plasma F concentrations were greater in ovariectomized than in intact females at baseline and following ACTH injection (P < .01). Finally, there was an appreciable elevation in plasma F across all animals during the 15- and 30-minute post-ACTH injection measurements (P < .01). Subsequent analyses of data from intact females showed interrelationships among dominance rank, reproductive function (indicated by luteal phase plasma P concentrations), adrenal size, and adrenal response to ACTH infusion. These data indicated that subordinate females were at a reproductive disadvantage compared to dominants, a result that may have been mediated, in part, by the increased adrenal size and enhanced adrenal responsiveness of subordinate females.