Growth Hormone Secretion In Short Children Research Articles

Serum α-klotho levels are not informative for the evaluation of growth hormone secretion in short children.

α-Klotho is a transmembrane protein that can be cleaved and act as a circulating hormone (s-klotho). s-Klotho serum levels seem to reflect growth hormone (GH) secretory status. We investigated the role of s-klotho as a reliable marker of GH secretion in short children and the factors influencing its secretion. We enrolled 40 short Egyptian children (20 GH deficiency [GHD] and 20 idiopathic short stature [ISS]). They underwent a pegvisomant-primed insulin tolerance test (ITT) and were accordingly reclassified as 16 GHD and 24 ISS. The samples obtained before and 3 days after pegvisomant administration, prior to the ITT, were used for assaying insulin-like growth factor (IGF)-I and s-klotho. IGF-I and s-klotho serum levels were not significantly different (p=0.059 and p=0.212, respectively) between GHD and ISS. After pegvisomant, a significant reduction in IGF-I and s-klotho levels was found in both groups. s-Klotho significantly correlated only with IGF-I levels in both groups. s-Klotho mainly reflects the IGF-I status and cannot be considered a reliable biomarker for GH secretion in children.

Somatostatin pretreatment enhances growth hormone (GH) responsiveness to GH-releasing hormone: a potential new diagnostic approach to GH deficiency.

Despite the availability of numerous testing procedures to evaluate GH secretion in short children, there is still controversy about the most reliable test in the diagnosis of GH deficiency. We have recently demonstrated that in normal short children, priming with the long-acting somatostatin analog. SMS 201-995 (SMS), significantly potentiates their GH response to subsequent GHRH challenge. In the present study, we used the combined SMS + GHRH test in patients with GH deficiency to validate the hypothesis that this test would better discriminate between normal short children and those with truly diminished GH secretion. We studied 24 children classified into three groups according to their GH peak response to up to four conventional tests: 1) children with normal short stature and normal GH response (NSSA: GH peak > or = 10 micrograms/L, n = 6); 2) children with normal short stature with borderline GH response (NSSB: GH peak > or = 7 micrograms/L but < 10 micrograms/L, n = 4); and 3) GH-deficient children (GHD: GH peak < 7 micrograms/L, n = 14). Two study protocols were performed in all subjects: SMS (1 microgram/kg, sc) was randomly administered or omitted (control test) a 0800 h and GHRH (1 microgram/kg, iv) was given 5 h later. Plasma GH levels were measured every 30 min from 0800 h until 2 h after the GHRH injection. Pretreatment with SMS significantly augmented the GH peak response and the GH area under the GH concentration curve over 2 h after GHRH injection in the NSSA group, compared with control tests, but had no effect in the other two groups. While there was wide overlap of individual peak GH values to both the conventional tests and to the GHRH injection in the control test among the three groups of children, pretreatment with SMS resulted in complete discrimination between GHD and normal short children; the mean GH peak response to GHRH after SMS pretreatment was 8- to 9-fold lower in the GHD subjects (5.2 +/- 0.8 micrograms/L) compared with both the NSSA (44.0 +/- 14.3 micrograms/L; P < 0.01) and NSSB (42.9 +/- 5.0 micrograms/L; P < 0.01) groups and, more importantly, there was no overlap in the individual GH responses between GHD and normal short children. These results demonstrate that the combined SMS + GHRH test clearly discriminates normal short children from those with GHD. In view of its testing economy, safety, and accuracy, this combined test could become the test of choice to establish a diagnosis of GH deficiency in the slowly growing child.

Intranasal Administration of Neostigmine Potentiates both Intravenous and Intranasal Growth Hormone (GH)-Releasing Hormone-Induced GH Release in Short Children*

Administration of cholinergic agonists increases both basal and GH-releasing hormone (GHRH)-induced GH secretion, probably acting via inhibition of endogenous somatostatin release. The aim of our study was to verify in two groups of children with idiopathic short stature the effect of intranasal administration of neostigmine (inNS; 3 mg), a cholinesterase inhibitor, on basal GH levels as well as on the somatotroph response to GHRH when the peptide was administered either iv (ivGHRH; 1 microgram/kg) or intranasally (inGHRH; 10 micrograms/kg). In group A (n = 6; age, 10.6-16.0 yr) inNS induced a significant GH increase [inNS vs. saline, area under the curve (AUC; mean +/- SEM), 263.7 +/- 60.2 vs. 73.8 +/- 3.1 micrograms/L.h; P less than 0.03] and potentiated the somatotroph response to ivGHRH (inNS with ivGHRH vs. ivGHRH, 1316 +/- 183.0 vs. 644.9 +/- 154.5 micrograms/L.h; P less than 0.03). In group B (n = 6; age, 11.5-15.9 yr) ivGHRH induced a GH rise clearly higher than that induced by inGHRH (604.2 +/- 154.3 vs. 137.1 +/- 28.2 micrograms/L.h; P less than 0.03). Administration of inNS induced a GH rise similar to that occurring after inGHRH (AUC, 239.2 +/- 69.5 micrograms/L.h) and markedly increased the inGHRH-induced GH response (482.4 +/- 103.6 micrograms/L.h; P less than 0.05 and 0.03 vs. inNS and inGHRH, respectively), so that it overlapped with that induced by ivGHRH alone. In conclusion, cholinergic agonists such as neostigmine are able to increase both basal and GHRH-induced GH secretion in short children even when given intranasally. Combined intranasal administration of neostigmine and GHRH (10 micrograms/kg) is able to induce a GH rise similar to that induced by ivGHRH alone (1 microgram/kg), suggesting the potential usefulness of this combination cocktail and route of administration for the treatment of short stature.

Growth hormone (GH) release after administration of GH-releasing hormone in relation to endogenous 24-h GH secretion in short children

Endogenous GH secretion was measured every 20 min for 24 h in 36 short children. This was immediately followed by an i.v. injection of GH-releasing hormone (GHRH)(1-29)-NH2 (1 microgram/kg), and GH was estimated every 15 min for the following 2 h. The aim was to determine whether endogenous pulsatile GH secretion had any relation to, or influence on, the GH release induced by GHRH. A high variability was found both in the 24-h GH secretion expressed as area under the curve above the baseline (0-1588 mU/l x 24 h) and the maximal GH response to GHRH (5-296 mU/l), as well as after an arginine-insulin tolerance test (4-59 mU/l). We found a positive correlation (correlation coefficient of Spearman (rs) = 0.49; P less than 0.01) between the GH response to GHRH and the spontaneous GH secretion over a 24-h period, in spite of a negative correlation (rs = -0.80; P less than 0.01) with the GH secretion during the preceding 3 h. We conclude that the GH response to a GHRH test correlates with endogenous GH secretion in short children, and may be helpful in estimating the ability to release GH. It is important, however, to be aware of the influence of the spontaneous GH secretion during the 3 h immediately preceding administration of GHRH.

Recognition of Growth Hormone Secretory Disorders

The demonstration by Raben¹that only growth hormone (GH) extracted from human or primate pituitaries could stimulate growth in pituitary dwarfs was a milestone in clinical endocrinology. Because the supply of GH from human pituitaries was limited, endocrinologists concentrated on determining who was "truly" GH deficient by measuring serum GH levels after the induction of hypoglycemia or the administration of arginine, levodopa, clonidine, and other potent GH secretogogues. Rises in serum GH levels to more than 7 to 10 ng/mL were considered "normal." Because a minority of apparently normal children might fail to respond to any one stimuli, the National Pituitary Program required failure to respond to two appropriate stimuli to qualify for GH treatment. The prospect of the more general availability of bacterially synthesized methionyl GH has led to a reexamination of GH secretion in short children. There is legitimate concern that GH response to potent pharmacologic stimuli