We measured
cortisol and precursor
steroid production in response to
ACTH,
cholera toxin, and
forskolin by the dispersed adrenocortical cells prepared from the adrenal glands of 10 patients with different forms of
Cushing's syndrome. The cells prepared from the hyperplastic adrenal glands from 4 patients with
Cushing's disease responded in a dose-dependent manner to
ACTH,
cholera toxin, and
forskolin. The adrenal cells prepared from 4 encapsulated adrenal
adenomas showed no (n = 2), a lowered (n = 1), or a clear (n = 1) response of
cortisol release to
ACTH. The cells prepared from the adrenal glands of 1 patient with dysplastic micronodular adrenal glands showed a limited response to
ACTH, while the cells from an
adrenocortical carcinoma, which secreted very little
cortisol per cell, were unresponsive to
ACTH,
cholera toxin, and
forskolin. The reaction of the dispersed adrenal cells from these 10 patients to
ACTH,
cholera toxin, and
forskolin showed a close correlation (P less than 0.001 in all instances). This suggests that the defect in autonomous glands is not located at the level of the
ACTH receptor, but, rather, involves the
adenylate cyclase complex as a whole or its coupling to
cAMP-dependent protein kinase. The release into the medium of the
cortisol precursors deoxycortisol,
17-hydroxyprogesterone, and
progesterone showed that the four autonomous nodules were characterized by a significantly higher deoxycortisol/
cortisol ratio in the medium (P less than 0.01), suggesting a relative blockade of
11 beta-hydroxylase in these adrenal
adenomas. This was further substantiated in cells from several adrenals by a significant increase in the release of these precursors in response to
ACTH in the absence of a
cortisol response. We conclude the following. 1) Adrenal
adenoma formation in patients with
Cushing's syndrome is accompanied by a parallel decrease in the stimulation of the release of
steroid hormones in response to
ACTH,
cholera toxin, and
forskolin. This points to a defect in the
adenoma cells beyond the
ACTH receptor. 2) Adrenal
adenoma formation in patients with
Cushing's syndrome is accompanied by a relative blockade of
11 beta-hydroxylase activity. 3) By comparing the preoperative dynamic tests of the pituitary-adrenal axis, the plasma
ACTH concentration, the morphology of the adrenal glands, and their in vitro responsiveness, a gradual transition from pituitary to (partial) adrenal autonomy could be recognized in several patients.