DECREASED HYPOTHALAMIC-PITUITARY-ADRENAL AXIS SENSITIVITY TO CORTISOLFEEDBACK INHIBITION IN HUMAN AGING

Aging-related reduction in the sensitivity of the hypothalamic-pituita ry-adrenal (HPA) axis to glucocorticoid feedback inhibition has been d emonstrated in rodents, but aging effects on glucocorticoid feedback i nhibition in humans are unclear. This study assessed the influence of aging on the sensitivity of the human HPA axis to feedback inhibition induced by cortisol. Endogenous cortisol feedback inhibition was remov ed by treatment with metyrapone, which reduces cortisol synthesis by i nhibiting 11 beta-hydroxylase. Feedback inhibition was then reintroduc ed by infusing exogenous cortisol. Sixteen young (26 +/- 1 years old) and 16 older (70 +/- 2 years old) subjects underwent three study condi tions in random order. In the two cortisol infusion conditions, oral m etyrapone treatment was followed by intravenous infusion of 0.03 mg/kg /h (83 nmol/kg/h) or 0.06 mg/kg/h (166 nmol/kg/h) cortisol for 150 min . Feedback sensitivity was estimated by the latency to and extent of d ecline of plasma ACTH concentration during and following the cortisol infusion. In a placebo condition, placebo tablets were substituted for metyrapone and normal saline infusion was substituted for cortisol. B lood samples were drawn twice prior to and at 15-min intervals for 4 h following the onset of the infusions, and plasma was assayed for 11-d eoxycortisol, cortisol and ACTH. Plasma cortisol suppression and ACTH and 11-deoxycortisol elevations did not differ between age groups afte r metyrapone. Older subjects exhibited delayed and blunted ACTH respon ses to infused cortisol. Within older subjects, the ACTH response to t he higher dose cortisol infusion was blunted in older women compared t o older men. These data provide direct evidence for reduced responsive ness to glucocorticoid feedback inhibition in human aging.