Effects of the combined administration of hexarelin, a synthetic peptidyl GH secretagogue, and hCRH on ACTH, cortisol and GH secretion in patients with Cushing's disease

Hexarelin (HEX) is a peptidyl GH secretagogue (GHS) which markedly stimulat es GH release but, like other GHS, possesses also CNS-mediated ACTH- and co rtisol-releasing activity. Interestingly, the stimulatory effect of HEX on ACTH and cortisol release is exaggerated and higher than that of hCRH in pa tients with Gushing's disease (CD). To further clarify the mechanisms by wh ich HEX stimulates the activity of hypothalamo-pituitary-adrenal (HPA) axis in man, in 6 patients with CD (6 women, 38-68 yr old) and in 7 control sub jects (CS, 7 women, 22-29 yr old) we studied the effects of HEX (2.0 mu g/k g iv) and/or hCRH (2.0 mu g/kg iv) on ACTH and cortisol (F) secretion. The GH responses to HEX alone and combined with hCRH were also studied in all s ubjects. Basal ACTH and F levels in CD were higher than in CS (66.3+/-5.1 v s 16.5+/-0.6 pg/ml and 217.8+/-18.5 vs 134.4+/-4.6 mu g/l, respectively; p< 0.02). In CS, the ACTH and F responses to HEX, evaluated as Delta AUC (mean +/-SE: 128.7+/-39.2 pg*min/ml and 328.5+/-93.2 mu g*min/l, respectively) we re lower, though not significantly, than those after hCRH (375.8+/-128.4 pg *min/ml and 1714.2+/-598.0 mu g*min/l, respectively), though the peak ACTH and F responses to both stimuli were similar. The co-administration of HEX and hCRH had an additive effect on both ACTH (1189.6+/-237.2 pg*min/ml) and F secretion (3452.9+/-648.6 mu g*min/l). In fact, the ACTH and F responses to HEX+hCRH were significantly higher (p<0.01) than those elicited by sing le stimuli. In GD, HEX induced ACTH and F responses (3603.8+/-970.7 pg*min/ ml and 10955.9+/-6184.6 mu g*min/l, respectively) clearly higher (p<0.002) than those in GS. The HEX-induced ACTH and F responses in GD were higher, t hough not Significantly, than those recorded after hCRH (1432.7+/-793.5 pg* min/ml and 4832.7+/-2146.5 mu g*min/l, respectively). On the other hand, th e hCRH-induced ACTH and F responses in CD were similar to those in CS. In G D, the coadministration of HEX and hCRH had an additive effect on ACTH (803 5.7+/-1191.1 pg*min/ml) but not on F (10985.4+/-3900.8 mu g*min/l) secretio n. In fact, the ACTH, but not the F response to HEX+hCRH was significantly higher (p<0.02) than that elicited by single stimuli. In conclusion, the pr esent study demonstrates that in patients with Gushing's disease as well as in subjects control Hexarelin and hCRH have an additive effect on ACTH sec retion. Considering that, at least in humans, differently from hCRH, GHS ha ve no interaction with AVP, our present findings further agree with the hyp othesis that the ACTH-releasing activity of GHS is, at least partially, ind ependent of CRH-mediated mechanisms. (J. Endocrinol. Invest. 22: 23-28, 199 9) (C)1999, Editrice Kurtis.