Hexarelin, a growth‑hormone‑releasing peptide, causes a big jump in ACTH and cortisol in Cushing’s patients with small pituitary tumors, but only a small rise in those with larger tumors or healthy people. This shows the drug can strongly activate the stress‑hormone system in certain disease states.

We previously reported that in Cushing's disease (CD) the ACTH- and cortisol (F)-releasing activity of Hexarelin (HEX), a GH secretagogue, is exaggerated with respect to that in normal subjects and is higher than that of human CRH (hCRH), but it is absent in Cushing's syndrome. Our aim was to extend the study about the effects of HEX (2.0 microg/kg, iv) on ACTH and F secretion in 21 patients with CD (3 men and 18 women, 16-68 yr old). Based on magnetic resonance imaging, 15 CD patients had pituitary microadenoma, and 6 had macroadenoma. The results in CD patients were compared with those in 27 normal age-matched controls (NS; 10 men and 17 women, 24-69 yr old). Basal ACTH and F levels in CD were similar in patients with microadenom (mean+/-SEM, 78.3+/-7.2 pg/mL and 237.1+/-23.6 microg/L, respectively) and macroadenoma (57.4+/-9.0 pg/mL and 196.9+/-20.1 microg/L, respectively) and were higher (P < 0.001) than those in NS (17.7+/-2.0 pg/mL and 115.3+/-6.7 microg/L, respectively). In microadenoma CD patients, HEX induced marked ACTH and F increases (delta peak, mean+/-SEM: 261.2+/-77.6 pg/mL and 226.1+/-87.2 microg/L, respectively), which were higher (P < 0.04) than those induced by hCRH (45.6+/-16.9 pg/mL and 84.6+/-25.7 microg/L, respectively). Moreover, in microadenoma CD patients, the ACTH and F responses to HEX were higher (P < 0.001) than those in NS (18.5+/-4.0 pg/mL and 36.1+/-6.8 microg/L, respectively). In macroadenoma CD patients, HEX induced a slight, but significant increase (P < 0.02) in ACTH and F levels (33.9+/-18.0 pg/mL and 89.6+/-34.3 microg/L, respectively), which was not significantly different from that elicited by hCRH (20.0+/-7.0 pg/mL and 54.8+/-21.3 microg/L, respectively). In macroadenoma CD patients, the ACTH and F responses to HEX and hCRH were, in turn, similar to those in NS. In conclusion, our findings demonstrate that the ACTH and F hyperresponsiveness to HEX is present in Cushing's disease with micro-, but not macro- ACTH-secreting pituitary adenoma. This finding agrees with other evidence pointing toward differences in the hormonal behavior between micro- and ACTH-secreting pituitary macroadenomas.