Inhibition of growth hormone release after the combined administration of CHRH and GHRP-6 in patients with Cushing's syndrome

OBJECTIVE In patients with Cushing's syndrome there is a blunted OH response to all types of stimuli. Although Inferential data point towards a direct perturbation in the pituitary exerted by glucocorticoids, the bask mechanism is unknown. His-d -TRP-ALA-TRP-d -Phe-Lys-NH₂ (GHRP-6) is a synthetic hexapeptlde which releases GH by a direct pituitary effect through receptors other than GHRH receptors. Furthermore, the combined administration of GHRH and GHRP-6 is able to induce a large OH discharge even in some pathological states such as obesity, associated with GH blockade. To gain further insight into the disrupted mechanisms of GH secretion, Cushing's syndrome patients were challenged with either GHRH, GHRP-6 or GHRH together with GHRP-6. A group of normal subjects was included for control purposes. DESIGN Three different tests were undertaken: (a) GHRH 100 μg I.v.; (b) GHRP-6 100 μg I.v. and (c) GHRH plus GHRP-6 100 μg I.v. of each; administered to each subject on different days, at least 4 days apart. PATIENTS Ten patients (8 women, 2 men) with untreated Cushing's syndrome, 9 Cushing's disease and 1 adrenal adenoma. Five healthy volunteers (3 women, 2 men) of similar ages served as a control group. MEASUREMENTS Plasma OH levels were measured by immunoradiometric assay. RESULTS The areas under the curve (AUC) of OH secretion (mean ± SEM In μ/1/120 mi) in the control subjects after each test were: GHRH, 1420 ± 330; GHRP-6, 2278 ± 290 and GHRH plus GHRP-6,7332 ± 592 (P < 0·05 vs each compound alone). The AUCs for Cushing's syndrome patients were: GHRH, 248 ± 165; GHRP-6 530 ±170 and for GHRH plus GHRP-6, 870 ± 258 (P < 0·05 vs GHRH alone). After the combined stimulus only one out of the ten patients with hypercortisolism showed a GH peak over 20 μ/l, while ail the controls had a peak over 04mU/l. CONCLUSIONS GHRP-6 induced OH secretion as well as the OH discharge elicited by GHRH and GHRP-6 are considerably reduced in Cushing's syndrome patients. This suggests that the main impairment of GH secretion in that pathological state resides at pituitary level.