Loperamide, an opiate agonist of high specificity for p-receptors,
was recently reported to suppress ACTH and cortisol levels in normal
subjects, but not in patients with proven ACTH-dependent Cushing’s
disease. However, there is little information on the site of action of
loperamide in the hypothalamo-pituitary-adrenal axis of man. We
investigated the effect of loperamide on pituitary hormone secretion in
uiuo and in vitro. In seven normal subjects, basal ACTH plasma levels
were significantly suppressed 3 h after loperamide administration (16
mg, orally) from 5 + 1 to 2 f 0 pmol/L (P < 0.0001). After the combined
pituitary stimulation test (100 pg human CRH, 100 rg GnRH, 100 pg
GH-releasing hormone, and 200 pg TRH), the ACTH peak (maximum
increase at 30 min) was significantly blunted by loperamide from 9 +
1 to 4 of: 1 pmol/L (P < 0.001) and the area under the curve of ACTH
from O-120 min was reduced from 35 + 5 to 23 + 4 pmol/L.2 h (P <
0.05). In the insulin-hypoglycemia test (0.15 IU/kg BW), neither the
ACTH peak nor the area under the curve of ACTH was affected by
loperamide. In six patients with Cushing’s disease and one patient with
secondary adrenal insufficency due to hypothalamic failure, neither
basal ACTH and cortisol levels nor CRH-stimulated levels were influenced
by loperamide. In four cultured human corticotropic adenomas,
loperamide was not able to reduce basal and CRH-induced ACTH
secretion. In summary, loperamide is able to reduce basal and CRHinduced
ACTH and cortisol levels in normal subjects, but not in
patients with Cushing’s disease or secondary adrenal failure of hypothalamic
origin. Loperamide has no significant effect on insulin-hypoglycemia-
induced ACTH and cortisol levels and, therefore, no effect
on stress-induced elevation of cortisol levels. Loperamide might act at
a suprapituitary site in man in viuo, but, nevertheless, a pituitary site
cannot be excluded.