Effects of loperamide on the human hypothalamo-pituitary-adrenal axis in vivo and in vitro.

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.