Arvat E, Ramunni J, Giordano R, Maccagno B, Broglio F, Benso A, Deghenghi R, Ghigo E
Dipartimento di Medicina Interna, Università di Torino, Italy.
J Endocrinol Invest. 1999 Jan;22(1):23-8. doi: 10.1007/BF03345474.
Hexarelin (HEX) is a peptidyl GH secretagogue (GHS) which markedly stimulates GH release but, like other GHS, possesses also CNS-mediated ACTH- and cortisol-releasing activity. Interestingly, the stimulatory effect of HEX on ACTH and cortisol release is exaggerated and higher than that of hCRH in patients with Cushing's disease (CD). To further clarify the mechanisms by which 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 subjects (CS, 7 women, 22-29 yr old) we studied the effects of HEX (2.0 microg/kg i.v.) and/or hCRH (2.0 microg/kg i.v.) on ACTH and cortisol (F) secretion. The GH responses to HEX alone and combined with hCRH were also studied in all subjects. Basal ACTH and F levels in CD were higher than in CS (66.3+/-5.1 vs 16.5+/-0.6 pg/ml and 217.8+/-18.5 vs 134.4+/-4.6 microg/l, respectively; p<0.02). In CS, the ACTH and F responses to HEX, evaluated as deltaAUC (mean+/-SE: 128.7+/-39.2 pg x min/ml and 328.5+/-93.2 microg x min/l, respectively) were lower, though not significantly, than those after hCRH (375.8+/-128.4 pg x min/ml and 1714.2+/-598.0 microg x 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 x min/ml) and F secretion (3452.9+/-648.6 microg x min/l). In fact, the ACTH and F responses to HEX+/-hCRH were significantly higher (p<0.01) than those elicited by single stimuli. In CD, HEX induced ACTH and F responses (3603.8+/-970.7 pg x min/ml and 10955.9+/-6184.6 microg x min/l, respectively) clearly higher (p<0.002) than those in CS. The HEX-induced ACTH and F responses in CD were higher, though not significantly, than those recorded after hCRH (1432.7+/-793.5 pg x min/ml and 4832.7+/-2146.5 microg x min/l, respectively). On the other hand, the hCRH-induced ACTH and F responses in CD were similar to those in CS. In CD, the coadministration of HEX and hCRH had an additive effect on ACTH (8035.7+/-1191.1 pg x min/ml) but not on F (10985.4+/-3900.8 microg x min/l) secretion. 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 present study demonstrates that in patients with Cushing's disease as well as in subjects control Hexarelin and hCRH have an additive effect on ACTH secretion. Considering that, at least in humans, differently from hCRH, GHS have no interaction with AVP, our present findings further agree with the hypothesis that the ACTH-releasing activity of GHS is, at least partially, independent of CRH-mediated mechanisms.
六肽生长激素释放肽（HEX）是一种肽基生长激素促分泌素（GHS），它能显著刺激生长激素释放，但与其他GHS一样，也具有中枢神经系统介导的促肾上腺皮质激素（ACTH）和皮质醇释放活性。有趣的是，在库欣病（CD）患者中，HEX对ACTH和皮质醇释放的刺激作用被夸大且高于促肾上腺皮质激素释放激素（hCRH）。为了进一步阐明HEX刺激人下丘脑 - 垂体 - 肾上腺（HPA）轴活性的机制，我们对6例CD患者（6名女性，38 - 68岁）和7名对照受试者（CS，7名女性，22 - 29岁）研究了HEX（2.0微克/千克静脉注射）和/或hCRH（2.0微克/千克静脉注射）对ACTH和皮质醇（F）分泌的影响。还在所有受试者中研究了单独使用HEX以及与hCRH联合使用时生长激素的反应。CD患者的基础ACTH和F水平高于CS（分别为66.3±5.1对16.5±0.6皮克/毫升和217.8±18.5对134.4±4.6微克/升；p<0.02）。在CS中，HEX引起的ACTH和F反应，以ΔAUC评估（平均值±标准误：分别为128.7±39.2皮克·分钟/毫升和328.5±93.2微克·分钟/升）低于hCRH后的反应（分别为375.8±128.4皮克·分钟/毫升和1714.2±598.0微克·分钟/升），尽管差异不显著，不过两种刺激引起的ACTH和F峰值反应相似。HEX和hCRH联合给药对ACTH（1189.6±237.2皮克·分钟/毫升）和F分泌（3452.9±648.6微克·分钟/升）有相加作用。实际上，HEX±hCRH引起的ACTH和F反应显著高于单一刺激引起的反应（p<0.01）。在CD患者中，HEX引起的ACTH和F反应（分别为3603.8±970.7皮克·分钟/毫升和10955.9±6184.6微克·分钟/升）明显高于CS（p<0.002）。CD患者中HEX引起的ACTH和F反应高于hCRH后记录的反应（分别为1432.7±793.5皮克·分钟/毫升和4832.7±2146.5微克·分钟/升），尽管差异不显著。另一方面，hCRH在CD患者中引起的ACTH和F反应与CS中的相似。在CD患者中，HEX和hCRH联合给药对ACTH（8035.7±1191.1皮克·分钟/毫升）分泌有相加作用，但对F（10985.4±3900.8微克·分钟/升）分泌没有。实际上，HEX + hCRH引起的ACTH反应显著高于单一刺激引起的反应（p<0.02），但F反应并非如此。总之，本研究表明，在库欣病患者以及对照受试者中，六肽生长激素释放肽和hCRH对ACTH分泌有相加作用。考虑到至少在人类中，与hCRH不同，GHS与血管加压素无相互作用，我们目前的发现进一步支持了GHS的促肾上腺皮质激素释放活性至少部分独立于CRH介导机制的假说。
