Diagnostic strategy for growth hormone deficiency: relevance of IGF-1 determination as a screening test

BACKGROUND: Adult growth hormone (GH) deficiency must be diagnosed before prescribing therapeutic recombinant human GH. We studied the clinical relevance of a diagnostic strategy for growth hormone deficiency (GHD) using IGF-1 determination as a first step. METHODS: In 2000 and 2001, we tested 142 adult patients with hypothalamo-pituitary disorders for somatotropic function using Insulin Tolerance Test (ITT), the reference test for the diagnosis of GHD, with concomitant Insulin-like growth factor-1 (IGF-1) determination, a marker of somatotropic function. Patients were classified as GHD (peak GH concentration<3 ng/ml with the ITT) or normal. SETTING: Monocenter prospective study in a tertiary referral center. RESULTS: GHD was diagnosed in 61 subjects. Using a ROC curve, a threshold IGF-1 concentration of 175 ng/ml yielded a negative predictive value of 89+/-5%. A diagnostic strategy with IGF-1 determination as the first step followed by ITT for patients with an IGF-1 concentration below 175 ng/ml missed five of the 61 GHD patients, avoided 46/142 ITT and reduced the cost of diagnosis by 15%. CONCLUSION: We propose the use of a strategy consisting of IGF-1 determination followed, if below 175 ng/ml by confirmatory ITT to diagnose GHD in adults.     

吡啶斯的明与左旋多巴联合激发试验对儿童生长激素缺乏症的诊断价值

目的　评价吡啶斯的明 (PD)加左旋多巴 (L dopa)联合激发试验对儿童生长激素缺乏症(GHD)的诊断价值。方法　 79例生长迟缓儿童 ,根据生长学资料、临床表现及血胰岛素样生长因子Ⅰ(IGF Ⅰ )、胰岛素样生长因子结合蛋白 3 (IGFBP 3 )水平分为临床拟诊GHD组 ( 3 9例 )与非GHD (NGHD)组 ( 4 0例 ) ,全部进行PD L dopa联合激发并随机分别另行精氨酸激发试验 (ARG ,43例 )或胰岛素耐量试验 (ITT ,3 6例 )。比较三种试验的生长激素 (GH)激发峰值及诊断敏感度、特异度、精确度 ,绘制受试者工作特性曲线 (ROC)及精确度曲线。结果　PD L dopa联合激发试验GH峰值在NGHD组高于ARG(P <0 .0 1)或ITT(P <0 .0 5 ) ,在GHD组差异无显著性。PD L dopa联合激发试验的准确度、特异度明显高于ARG或ITT ,敏感度与ARG或ITT相近。GH峰值取 7μg/L为正常截断值时 ,PD L dopa联合激发试验的敏感度、特异度与准确度均最高 ,超过 80 %。结论　PD L dopa联合激发试验对儿童GHD诊断价值优于ARG或ITT ,是一种适合儿童的有效、简便、安全的检测手段     

Pubertal growth and growth hormone secretion

A dramatic increase in linear growth velocity, often referred to as the pubertal growth spurt, is a central feature of pubertal development. Despite the existence of numerous investigative attempts, a precise understanding of the hormonal events subserving this process has proved elusive. Nevertheless, evidence has gradually accumulated that indicates that sex steroid-induced modulation of growth hormone secretion is a central and critical feature of the pubertal growth spurt. As a result, disorders of either growth hormone or sex steroid hormone production may result in clinical growth disorders during puberty.     

Growth hormone release after glucagon as a reliable test of growth hormone assessment in adults

OBJECTIVE: To investigate the GH response to glucagon in adult patients with GH deficiency and in controls compared with the GH response to the insulin tolerance test (ITT) in patients with GH deficiency and to determine whether the use of glucagon results in a diagnostic utility test. PATIENTS AND DESIGN: Seventy-three patients with adult GH deficiency and organic hypothalamic-pituitary disease were recruited, along with 46 controls. The patients were divided into five groups according to the number of associated hormone deficiencies present. MEASUREMENTS: Hypopituitary subjects underwent assessment of GH secretory status by the ITT, the glucagon test and measurement of serum IGF-I concentration. Controls underwent the glucagon test. After the ITT, glucose and GH levels were measured at baseline, 30, 60 and 90 minutes, and after glucagon at baseline, 90, 120, 150, 180, 210 and 240 minutes. RESULTS: The highest GH value after the ITT in the patient group was 3 microg/l (0.76 +/- 0.82 microg/l), and after the glucagon test the highest GH peak value was 2.9 microg/l (0.64 +/- 0.79 microg/l). A correlation was found between the GH peak and the progressive number of hormone deficiencies. After the glucagon test, the GH peak obtained in the controls at 180 minutes was 9.8 +/- 4.6 microg/l and, on an individual basis, none of the 46 controls failed to achieve peak GH levels higher than 3 microg/l. In the controls, a negative correlation was observed between the GH response to glucagon and age (r = -0.389, P = 0.0075) and body mass index (r = -0.329, P = 0.0254). The accuracy of the glucagon test for differentiating patients from controls, estimated by receiver operating characteristics (ROC) curve methodology, showed that the cut-off of 3 microg/l for the GH peak provides 100% sensitivity and 100% specificity and is a reliable decision threshold. CONCLUSIONS: The glucagon GH test is reliable and provides a clear separation between GH-deficient and normal adults. A single glucagon test with a cut-off of 3 microg/l for the GH peak is diagnostic of GH deficiency in adults and could be considered and studied as an alternative to the ITT.     

Ghrelin-induced growth hormone secretion in humans

Ghrelin is a novel growth hormone (GH) releaser acylated peptide that has recently been purified from stomach, and which potently binds to the GH secretagogue receptor. Ghrelin releases GH in vitro and in vivo in animal models, however its actions, potency and specificity in humans are unknown. In the present study, 12 healthy subjects were studied: 6 underwent four tests with ghrelin administered i.v. at the dose of 0 (placebo), 0.25, 0.5 and 1 microg/kg which corresponds to 0, 18, 37 and 75 microg total dose. A further 6 volunteers underwent two tests on different days with ghrelin at the dose of 3.3 or 6.6 microg/kg which corresponds to 250 microg and 500 microg total dose. Ghrelin-mediated GH secretion showed a dose-response curve, in which 1 microg/kg was the minimally effective dose in some individuals, but not as a group. On the contrary, the total doses of 250 microg and 500 microg elicited a powerful GH secretion, with a mean peak of 69.8+/-9.2 microg/l and 90.9+/-16.9 microg/l respectively, and areas under the curve of 4435+/-608 and 6125+/-1008 microg/l per 120 min respectively. All of them statistically significant vs placebo and vs the 1 microg/kg dose. Ghrelin administration also elicited a relevant dose-response mediated prolactin secretion suggesting no specificity of its actions. No relevant side effects were observed with ghrelin apart from a hyperhydrosis episode in two individuals tested with the higher ghrelin doses. In conclusion, ghrelin is a potent releaser of GH in normal individuals, with a dose-response pattern of operation. No saturating dose was observed.     

Differential effects of arginine on growth hormone releasing hormone and insulin induced growth hormone secretion

OBJECTIVE: We wished to investigate the interaction of arginine, GHRH and insulin stress on GH secretion. DESIGN: Six healthy, non-obese volunteers underwent seven separate studes in random order. They received (1) insulin alone at 0 minutes; (2) GHRH alone at 15 minutes; (3) arginine alone at 0-30 minutes; (4) arginine at 0-30 minutes and GHRH at 15 minutes; (5) insulin at 0 minutes and arginine at 0-30 minutes; (6) insulin at 0 minutes, GHRH at 15 minutes and arginine at 0-30 minutes; (7) insulin at 0 minutes and GHRH at 15 minutes. MEASUREMENTS: GH and PRL were measured from -30 to 150 minutes at intervals of 15 minutes. RESULTS: Arginine increased GH responses to GHRH and decreased GH responses to hypoglycaemia, but this inhibitory effect of arginine was reversed by GHRH. CONCLUSIONS: The findings suggest that arginine-induced GH release is mainly mediated by a decrease in somatostatinergic tone, while GH responses to insulin stress are probably mediated by both an increase in hypothalamic GHRH release and inhibition of somatostatin.     

Dietary regulation of human growth hormone secretion

The effect of diet on the secretion of human growth hormone (HGH) was investigated in eight normal subjects—each studied before and after four separate dietary regimens. A high-carbohydrate (525 g) diet of 3600 cal containing 75 g of protein for 23 days suppressed completely arginine-initiated HGH secretion. While subjects were ingesting a control diet, the mean maximal response to arginine was 21.5 ± 3.5 mμg/ml vs. 4.6 ± 0.9 mμg/ml (p < 0.01) following the experimental diet ($\text{X}$ ± SEM). The latter value did not differ from the mean maximal HGH response occurring “spontaneously” after control infusion of saline (3.5 ± 0.9 mμg/ml). This suppression of HGH secretion appeared related to the amount of carbohydrate rather than the total caloric level. An identical pattern occurred when carbohydrate was proportionately the same, but total intake was reduced to 2300 cal. With a high-carbohydrate diet of 2300 cal, the mean maximal HGH response to arginine was 4.7 ± 1.1 mμg/ml vs. a control response of 21.4 ± 4.7 mμg/ml (p < 0.01). Twenty-four-hour secretory patterns of HGH were assessed in three subjects befor and after the high-carbohydrate diet of 2300 cal. Overall HGH secretion was reduced significantly at the termination of the 23-day experimental period in two of these three subjects. HGH secretion was, likewise, significantly reduced by high-carbohydrate diets containing less protein. The change of HGH secretion could not be related in any study to differences in plasma-free fatty acid (FFA) or glucose concentration. FFA concentrations did decline in the first 3–7 days of each experimental period, but returned to basal values 7–8 days prior to reassessment of HGH secretion. Plasma glucose concentrations did not change significantly at any time.