INHIBITION OF GROWTH-HORMONE RELEASE AFTER THE COMBINED ADMINISTRATION OF GHRH AND GHRP-6 IN PATIENTS WITH CUSHINGS-SYNDROME

OBJECTIVE In patients with Cushing's syndrome there is a blunted GH response to all types of stimuli. Although inferential data point towards a direct perturbation in the pituitary exerted by glucocorticoids, the basic mechanism is unknown. His-D-TRP-ALA-TRP-D-Phe-Lys-NH2 (GHRP-6) is a synthetic hexapeptide 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 GH 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 mu g i.v.; (b) GHRP-6 100 mu g i.v. and (c) GHRH plus GHRP-6 100 mu g 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 GH levels were measured by immunoradiometric assay. RESULTS The areas under the curve (AUC) of GH secretion (mean +/- SEM in mU/l/120 min) 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 mU/l, while all the controls had a peak over 84 mU/l. CONCLUSIONS GHRP-6 induced GH secretion as well as the GH 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.