Gasperi M, Aimaretti G, Scarcello G, Corneli G, Cosci C, Arvat E, Martino E, Ghigo E
Department of Endocrinology, University of Pisa, Italy.
J Clin Endocrinol Metab. 1999 Aug;84(8):2633-7. doi: 10.1210/jcem.84.8.5904.
GH deficiency (GHD) in adults must be shown by provocative testing of GH secretion. Insulin-induced hypoglycemia (ITT) is the test of choice, and severe GHD, treated with recombinant human GH replacement, is defined by a GH peak response to ITT of less than 3 microg/L. GHRH plus arginine (ARG) is a more provocative test and is as sensitive as ITT provided that appropriate cut-off limits are assumed. GH secretagogues are a family of peptidyl and nonpeptidyl GH-releasing molecules that strongly stimulate GH secretion and, even at low doses, truly synergize with GHRH. Our aim was to verify the diagnostic reliability of the hexarelin (HEX; 0.25 microg/kg, iv) and GHRH (1 microg/kg, iv) test for the diagnosis of adult GHD. To this goal, in the present study we 1) defined the normal ranges of the GH response to GHRH+HEX in a group of normal young adult volunteers (NS; n = 25; 18 men and 7 women; age, 28.5+/-0.6 yr) and in 11 of them verified its reproducibility in a second session, and 2) compared the GH response to GHRH+HEXwith that to ITT in a group of normal subjects (n = 33; 12 men and 21 women; age, 34.1+/-1.5 yr) and hypopituitaric adults with GHD (n = 19; 10 men and 9 women; age, 39.9+/-2.2 yr; GH peak <5 microg/L after ITT). The GH response to GHRH+ARG was also evaluated in all GHD and in 77 normal subjects (40 men and 37 women; age, 28.1+/-0.6 yr). The mean GH peak after GHRH+HEX in NS was 83.6+/-4.5 microg/L; the third and first percentile limits of the normal GH response were 55.5 and 51.2 microg/L, respectively). The GH response to GHRH+HEX in NS showed good intraindividual reproducibility. In GHD the mean GH peak after GHRH+HEX (2.6+/-0.7 microg/L) was similar to that after GHRH+ARG (3.6+/-1.0 microg/L), and both were higher (P < 0.001) than that after ITT (0.6+/-0.1 microg/L); the GH responses to GHRH+HEX were positively associated with those to ITT and GHRH+ARG. Analyzing individual GH responses, 100% had severe GHD after ITT (GH peak, <3 microg/L). After GHRH+HEX all GHD had GH peaks below the third percentile limit of normality appropriate for this test (i.e. 55.5 microg/L). Thirteen of 19 (68.4%) GHD subjects had GH peaks below 3 microg/L after GHRH+HEX but all 19 (100%) had GH peaks below the first percentile limit of normality (i.e. 51.2 microg/L). The GH responses to GHRH+HEX were highly concordant with those after GHRH+ARG. In conclusion, the present results define normal limits of the GH response to stimulation with low dose HEX+GHRH in normal adults and show that this test is as sensitive as ITT for the diagnosis of adult GHD provided that appropriate cut-off limits are considered.
成人生长激素缺乏症（GHD）必须通过生长激素分泌激发试验来确诊。胰岛素诱发低血糖试验（ITT）是首选检测方法，严重GHD患者经重组人生长激素替代治疗后，ITT时生长激素峰值反应低于3μg/L被定义为严重GHD。生长激素释放激素（GHRH）加精氨酸（ARG）是一种更具激发性的检测方法，只要设定合适的临界值，其与ITT一样敏感。生长激素促分泌素是一类肽基和非肽基生长激素释放分子，能强烈刺激生长激素分泌，即使在低剂量时也能与GHRH产生真正的协同作用。我们的目的是验证六肽生长激素释放肽（HEX；0.25μg/kg，静脉注射）和GHRH（1μg/kg，静脉注射）试验对成人GHD诊断的可靠性。为实现这一目标，在本研究中，我们：1）确定了一组正常年轻成年志愿者（NS组；n = 25；18名男性和7名女性；年龄28.5±0.6岁）对GHRH + HEX的生长激素反应正常范围，并在其中11名志愿者的第二次检测中验证了其可重复性；2）比较了一组正常受试者（n = 33；12名男性和21名女性；年龄34.1±1.5岁）和垂体功能减退的成年GHD患者（n = 19；10名男性和9名女性；年龄39.9±2.2岁；ITT后生长激素峰值<5μg/L）对GHRH + HEX与ITT的生长激素反应。还对所有GHD患者和77名正常受试者（40名男性和37名女性；年龄28.1±0.6岁）进行了GHRH + ARG的生长激素反应评估。NS组中GHRH + HEX后的平均生长激素峰值为83.6±4.5μg/L；正常生长激素反应的第三和第一百分位数界限分别为55.5和51.2μg/L。NS组中GHRH + HEX的生长激素反应显示出良好的个体内可重复性。在GHD患者中，GHRH + HEX后的平均生长激素峰值（2.6±0.7μg/L）与GHRH + ARG后的峰值（3.6±1.0μg/L）相似，且两者均高于ITT后的峰值（0.6±0.1μg/L，P < 0.001）；GHRH + HEX的生长激素反应与ITT和GHRH + ARG的反应呈正相关。分析个体生长激素反应，ITT后100%的患者患有严重GHD（生长激素峰值<3μg/L）。GHRH + HEX后，所有GHD患者的生长激素峰值均低于该检测正常范围的第三百分位数界限（即55.5μg/L）。19名GHD患者中有13名（68.4%）在GHRH + HEX后生长激素峰值低于3μg/L，但所有19名患者（100%）的生长激素峰值均低于正常范围的第一百分位数界限（即51.2μg/L）。GHRH + HEX的生长激素反应与GHRH + ARG后的反应高度一致。总之，本研究结果确定了正常成年人对低剂量HEX + GHRH刺激的生长激素反应正常范围，并表明该检测方法在考虑合适临界值时对成人GHD诊断与ITT一样敏感。
