Glucocorticoid receptors and responsiveness of normal and neoplastic human adrenal cortex.
Glucocorticoids have been postulated to directly inhibit adrenocortical steroid production in laboratory animals. To investigate this in the human, we measured specific [3H]dexamethasone-binding sites in cytosol samples from normal and neoplastic human adrenal tissues. All nine normal adrenocortical samples, six adenomas (four cortisol-producing and two aldosterone-producing), and two hyperplastic adrenocortical samples studied were devoid of measurable specific glucocorticoid-binding activity. In contrast, steroid binding with characteristics of the glucocorticoid receptor (concentration of binding sites, 32-146 fmol/mg cytosol protein; Kd, 1.7-3.1 X 10(-9) M) was readily detectable in cytosol of all three adrenocortical carcinomas and all three pheochromocytomas examined. To elucidate the in vivo role of glucocorticoids as direct regulators of adrenocortical function, five patients with hypopituitarism receiving varying oral maintenance doses of dexamethasone were given ACTH iv. Increasing the orally administered dexamethasone dose from 1 to 8 mg/day did not alter the plasma cortisol response to a 4-h infusion of 250 micrograms synthetic ACTH in these patients. Collectively, these data cast doubt on the proposal that synthetic glucocorticoids directly suppress adrenocortical function in the human. Whether glucocorticoid receptors in tumor tissue could mediate the dexamethasone-induced suppression of hypercortisolism occasionally reported in patients with adrenocortical neoplasia remains to be investigated.
Kontula
K
K
Pomoell
U M
UM
Gunsalus
G L
GL
Pelkonen
R
R
D000293:Adolescent; D000302:Adrenal Cortex / Q000378:metabolism*; D000306:Adrenal Cortex Neoplasms / Q000378:metabolism*; D000324:Adrenocorticotropic Hormone; D000328:Adult; D000368:Aged; D003600:Cytosol / Q000378:metabolism; D003907:Dexamethasone / Q000378:metabolism; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000097:blood / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D011987:Receptors, Steroid / Q000378:metabolism*
D011965:Receptors, Glucocorticoid; D011987:Receptors, Steroid; D003907:Dexamethasone; D000324:Adrenocorticotropic Hormone; D006854:Hydrocortisone