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FK 33-824, a Met-Enkephalin Analog, Blocks Corticotropin-Releasing Hormone-Induced Adrenocorticotropiii Secretion in Normal Subjects but not in Patients with Cushing’s Disease^*

Innere Medizin II der Uniuersität zu Köln, Medizinische Klinik Köln-Merheim 5000 Köln 91
Neurochirurgische Universitätsklinik 5000 Köln 41, West Germany

Address all correspondence and requests for reprints to: Dr. Bruno Allolio, Medizinische Klinik Köln-Merheim, Ostmerheimer Straβe 200, 5000 Köln 91, West Germany.

To further elucidate the site of action of opioids on the pituitary-adrenal axis, we studied the effect of D-Ala²,MePhe⁴,met-(O)enkephalin-ol (Sandoz, FK 33–824) on plasma ACTH and /S-endorphin immunoreactivity and serum cortisol in 7 normal subjects and 11 patients with Cushing's syndrome (Cushing's disease, n = 7; adrenal adenoma, n = 2; ectopic Cushing's syndrome, n = 2) after administration of human corticotropin-releasing hormone (hCRH). hCRH (0.1 mg; Bachem) was injected iv after pretreatment with 0.5 mg FK 33–824, im, or 0.9% saline. In normal subjects, the hCRHinduced ACTH, β-endorphin, and cortisol increases were almost completely abolished by pretreatment with FK 33-824. Mean peak (±SEM) hormone concentrations were significantly reduced (ACTH, 16.7 ± 3.5 vs. 45.3 ± 7.8 pg%ml; β-endorphin, 151 ± 25 vs. 277 ± 51 pg%ml; cortisol, 8.1 ± 1.2 vs. 19.5 ± 2.6 µg%dl; P < 0.02), as were secretory areas (P < 0.02). These results indicate a direct pituitary action of the synthetic met-enkephalin. In contrast, in patients with Cushing’s disease, FK 33–824 did not inhibit hCRH-induced hormone release. Instead, maximum ACTH and β-endorphin concentrations were slightly but not significantly higher after the administration of FK 33–824 (ACTH, 292 ± 143 vs. 131 ± 32 pg/ml; β-endorphin, 2409 ± 763 vs. 1921 ± 600 pg/ml).

These findings indicate a defect in inhibitory opiodergic control of ACTH secretion in patients with Cushing’s disease, which may contribute to the pathological ACTH hypersecretion. In patients with Cushing's syndrome due to an adrenal adenoma or ectopic ACTH secretion, neither hCRH nor FK 33–824 altered hormone concentrations.

^* This work was supported by Landesamt für Forschung NRW (Düsseldorf, West Germany).

Received September 9, 1985.

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