Effects of a Met-Enkephalin Analog on Adrenocorticotropin (ACTH), Growth Hormone, and Prolactin in Patients with ACTH Hyper secretion*

Abstract

The effect of D-Ala2, MePhe4, Met-(0)enkephalinol (Sandoz FK 33-824; 0.5 mg, im) on pituitary hormone secretion was studied in 11 patients with Addison's disease and 11 patients with ACTH-dependent Cushing's disease. In patients with Addison's disease, a pronounced fall of plasma ACTH levels was observed (P less than 0.005). The ACTH response to FK 33--824 was partially reversed by naloxone (4 mg, iv). In patients with Cushing's disease, no unequivocal decrease in either ACTH or cortisol was seen. Moreover, FK 33--824 failed to influence the vasopressin-induced ACTH increase in 5 patients with Cushing's disease. In patients with cortisol deficiency due to either Addison's disease or bilateral adrenalectomy for Cushing's disease, FK 33--824 led to increases in PRL and GH similar to those described in normal subjects. However, in the presence of longstanding hypercortisolism, the PRL increase was significantly diminished, and the GH response to FK 33--824 was completely abolished. Our results suggest that in Addison's disease ACTH release is influenced by inhibitory opiate receptors. In patients with Cushing's disease, ACTH secretion is insensitive to FK 33-284, presumably because of an autonomous pituitary adenoma or hypothalamic derangement. The impairment of the PRL and GH responses to FK 33--824 in Cushing's syndrome seems to reflect a direct action of the elevated cortisol level, for it is not seen after bilateral adrenalectomy.

Adrenergic Stimulation of the Human Pituitary-Adrenal Axis Is Attenuated by an Analog of Met-Enkephalin

“…The rise in cortisol induced by amphetamine has been shown to be consequent on changes in ACTH [22]; further more, it is blocked by the specific ai-adrenoceptor antagonist, thymoxamine, suggesting that such receptors mediate the re sponse [20]. Similarly, methoxamine acts directly to activate aiadrenoceptors at central sites, which in turn lead to increases in circulating ACTH and cortisol [1], Previous studies have demonstrated that the met-enkephalin analog, DAMME, inhi bits the pituitary-adrenal axis by suppressing both ACTH [11,12] and cortisol [13] release; furthermore, we have recently found that the adrenal cortisol response to a sub-maximal dose (125 ng) of synthetic ACTH is unaltered by DAMME, sug gesting that DAMME has no direct effect on the adrenal cortex itself [T.A. Howlett and A. Grossman, unpubl.…”

The presence of methionine-enkephalin in plasma and urine in normal human subjects and various patients.

“…They have been assigned a role in the regulation of brain peptide hormones (del Pozo et al, 1980, Allolio et al, 1982 and catecholamines (Van Loon and Appel, 1981) as well as in the integration of cardiovascular functions (Lang et al, 1982).…”

Hormonal effects and metabolic clearance rate of the enkephalin analogue DAMME in man.

“…The clinical use of DAMME (FK33-824) has been studied (Allolio et al, 1982;Gaillard et al, 1981) in situations of chronic ACTH hypersecretion either due to ACTH dependant Cushing's syndrome or Addison's disease. Although the results have been conflicting, there is some indication that ACrH secretion can be inhibited by opiates.…”