Glucocorticoid Receptors and Responsiveness of Normal and Neoplastic Human Adrenal Cortex*

Abstract

Glucocorticoids have been postulated to directlyinhibit adrenocortical steroid production in laboratory animals.To investigate this in the human, we measured specific[³H]dexamethasone-binding sites in cytosol samples from normaland neoplastic human adrenal tissues. All nine normaladrenocortical samples, six adenomas (four cortisol-producingand two aldosterone-producing), and two hyperplastic adrenocorticalsamples studied were devoid of measurable specificglucocorticoid-binding activity. In contrast, steroid binding withcharacteristics of the glucocorticoid receptor (concentration ofbinding sites, 32−146 fmol/mg cytosol protein; K_d, 1.7−3.1 ì 10⁻⁹M) was readily detectable in cytosol of all three adrenocorticalcarcinomas and all three pheochromocytomas examined. Toelucidate the in vivo role of glucocorticoids as direct regulatorsof adrenocortical function, five patients with hypopituitarismreceiving varying oral maintenance doses of dexamethasone weregiven ACTH iv. Increasing the orally administered dexamethasonedose from 1 to 8 mg/day did not alter the plasma cortisolresponse to a 4-h infusion of 250 μg synthetic ACTH in these patients. Collectively, these data cast doubt on the proposal that syntheticglucocorticoids directly suppress adrenocortical functionin the human. Whether glucocorticoid receptors in tumor tissuecould mediate the dexamethasone-induced suppression of hypercortisolismoccasionally reported in patients with adrenocorticalneoplasia remains to be investigated.