C. Pintor

Reduced growth hormone response to growth hormone-releasing hormone in children with simple obesity: evidence for somatomedin-C mediated inhibition.

We have evaluated the plasma GH response to a single injection of 1μg/kg of GH‐releasing hormone (GHRH)‐40 in 15 obese children and 15 age‐matched control children. Most of the obese children showed a subnormal plasma GH response to GHRH and the mean plasma GH integrated area (IC‐GH) following stimulation was significantly smaller in obese than control children. Plasma somatomedin‐C (SM‐C) levels were significantly higher in obese than control children, and were negatively correlated with the peak plasma GH levels (r=−0.616, P<001) and the IC‐GH (r=−0.554, P<0.02) after GHRH. Non‐esterified fatty acids (NEFA) and fasting plasma insulin levels were also elevated in obese children, but did not correlate with the extent of plasma GH response to GHRH. These data confirm previous observations on the refractoriness of obese children to release GH after GHRH, and imply that it may be due to the feedback inhibition operated by the elevated plasma levels of SM‐C.

CLONIDINE TREATMENT FOR SHORT STATURE

34 pubertal children with constitutional growth delay (CGD) were treated with clonidine orally twice a day. In 25 of the children the height velocity rose on clonidine treatment, and in 21 of them by more than 2 cm/yr during the first 6 months of treatment (mean [SD] growth increment 4.4 [0.5] cm/yr). Of the 22 who were treated for 12 months the increment in height velocity was maintained in 13 (3.4[0.4] cm/yr). Withdrawal of clonidine for 6 months did not stop the stimulatory effect of the drug on linear growth in 6 children, but in the other 8 children height velocities fell to pretreatment levels or below. In a few children reinstitution of clonidine for 2-4 months resulted in a new increment in height velocity. A high height standard deviation score and low growth velocity before treatment were predictive of a good growth response to clonidine. Clonidine did not induce noticeable side-effects. It may be a useful form of therapy for children with CGD.

ADRENAL AND GONADAL STEROIDS IN GIRLS DURING SEXUAL MATURATION

The peripheral venous plasma concentrations of gonadotrophins (LH and FSH), prolactin (Prl), cortisol, dehydroepiandrosterone (DHA), dehydroepiandrosterone‐sulphate (DHA‐S), pregnenolone (Δ5P), progesterone (P), 17‐hydroxyprogesterone (17P), androstenedione (A), testosterone (T), dihydrotestosterone (DHT) and oestradiol (E2) were measured in girls at different stages of sexual development (from P1 to P4–5 according to Tanner, 1962). Both gonadotrophins increase progressively during sexual maturation, to reach the highest concentrations in P4–5. However, the FSH values were significantly lower in these P4–5 pre‐menarchal girls than those found in adult women in the early follicular phase. No significant changes were found in plasma Prl, cortisol and 17P levels during pubertal development; in contrast, plasma concentrations of DHA tripled from P1 to P4–5, reaching adult levels. A progressive rise was also found in DHA‐S plasma levels. A significant, but less evident increase was found in Δ5P and P plasma concentrations, from group P1 to P4–5. A, T and DHT levels rose progressively and significantly from P1–2 to the end of sexual maturation. In the case of E2, only a moderate increase was found during pubertal development.

Synthetic hpGRF 1–40 stimulates growth hormone and inhibits prolactin secretion in normal children and children with isolated growth hormone deficiency

Intravenously administered synthetic hpGRF 1-40 at doses of 0.1, 0.33 and 1.0 microgram/kg increased plasma GH in a dose-dependent fashion in 4 normal prepubertal children. hpGRF 1-40 at the dose of 1.0 microgram/kg stimulated GH release, though to a lesser extent than in normals, in 7 children with isolated GH-deficiency (IGHD) but failed to do so in a patient with craniopharyngioma. In all normal children and 6/7 patients with IGHD, hpGRF 1-40 at all doses used induced a clear and sustained lowering of plasma prolactin levels; this effect was lacking in the patient with craniopharyngioma. hpGRF 1-40 had no effect on plasma FSH, LH, TSH or glucose levels nor did it influence pulse rate, blood pressure, or body temperature. These results indicate that hpGRF 1-40 is a potent stimulus to GH release in normal prepubertal children and holds promise for treatment of GH-deficient children. In addition, in both normal children and children with IGHD, hpGRF 1-40 is a potent suppressor of prolactin levels.

Evidence for Involvement of Endogenous Somatostatin in the Galanin-Induced Growth Hormone Secretion in Children

ABSTRACT: We have evaluated the effects of the combined administration of Galanin (Gal) plus growth hormone- releasing hormone (GHRH) and of pyridostigmine (PD), a cholinergic agonist, plus Gal on GH secretion in 15 children (12 males and three females, age 7.7-14.5 y) with short stature. Children were subdivided into two groups. In group 1 (n = 7) Gal (15 μg/kg h i.v.) plus GHRH (1 μg/kg i-v.) administration induced a higher GH rise (peak = 73.1 ± 10.2 ng/mL, mean ± SD; area under the curve (AUC) = 531.9 ± 78.7 ng · min · mL-1) than did GHRH alone (peak = 38.9 ± 26.5 ng/mL, p < 0.05; AUC = 256.9 ± 165.6 ng/mL/min-1, p < 0.005). Gal had a synergistic effect on the GHRH-induced GH response because the GHRH plus Gal AUC response was significantly higher (p <0.01) than the sum of the areas of response to GHRH and Gal alone. In group 2 (n = 8) PD administration (60 mg/kg p.o.) had no significant effects on the Gal-induced GH secretion (peak = 14.9 ± 8.8 and 16.0 ± 9.8 ng/mL after Gal and PD + Gal, respectively; AUC = 91.2 ± 52.1 and 125.2 ± 83.6 ng. mL. min-1 after Gal and PD + Gal, respectively). Our results confirm the ability of Gal to stimulate GH secretion in children, and strengthen the view that its mechanism of action involves modulation of endogenous somatostatin release.

Correlations between plasma levels of opioid peptides and adrenal androgens in prepuberty and puberty.

In 139 prepubertal children and in 38 pubertal adolescents plasma levels of ACTH, cortisol, beta-lipotropin (BLPH), beta-endorphin (BEP) and dehydroepiandrosterone sulphate (DHAS) were determined by specific radioimmunoassays directly (steroids) or after plasma purification (peptides). ACTH and cortisol concentrations remain stable during both prepuberty and puberty, while DHAS levels constantly increased from 5 to 16 years. Both BLPH and BEP increase from early infancy to late prepuberty when they reach adult values. During puberty both opioids remain constantly within the adult range. BLPH and BEP concentrations were significantly correlated to those of DHAS throughout prepuberty. These data suggest a possible role of BLPH and BEP in and/or other proopiocortin-related peptides in the development of adrenarche, while the lack of particular changes in these peptide levels during sexual maturation seems to exclude their role in gonadarche and pubertal development.

THE EFFECT OF GALANIN ON BASELINE AND GHRH-INDUCED GROWTH HORMONE SECRETION IN OBESE CHILDREN

We have evaluated the effect of the administration of galanin (Gal), a newly identified hypothalamic peptide, on baseline and GHRH‐induced GH rise in five obese children and in seven controls. The GH response to GHRH (hpGRF(1–29), 1 μg/kg i. v.), and to Gal (15 μg/kg/h for 1 h), evaluated both as the maximum GH peak and as integrated area under the curve (AUC), was significantly lower in the obese children than in the controls. Simultaneous administration of Gal plus GHRH significantly increased the GH response to GHRH in all the obese subjects, so that their mean peak GH levels and AUC after Gal plus GHRH were similar to those of the control children after GHRH. Also, in control children Gal caused a significant augmentation of the GH response to GHRH. Mean peak GH levels and mean AUC after Gal plus GHRH were significantly higher in the controls than in the obese children given the same treatment. Our data indicate that obese children have a blunted GH response to Gal, which, however, is able to enhance the GH response to GHRH. This observation strengthens the view that the mechanism of action of Gal involves modulation of endogenous somatostatin (SRIH) release. In addition, similarity between the effects of Gal and pyridostigmine on baseline and GHRH‐stimulated GH release in obese children may indicate the existence of a cholinergic link in the action of Gal.

A child with phenotypic Laron dwarfism and normal somatomedin levels

THE regulation of somatic growth is complex and requires a number of hormones, including growth hormone, somatomedin C (insulin-like growth factor I), thyroid hormones, insulin, and sex steroids. A...

Growth hormone response to oral clonidine test in normal and short children

We evaluated the growth hormone (GH) response to an acute Clonidine test (0.15 mg/m2 po) in 30 normal prepubertal children (stature between the 3rd and 97th centile), in 29 short children (stature <3rd centile for age) with height velocity (HV) >10th centile and in 20 short children with HV <10th centile. The three groups had comparable chronological ages. After clonidine administration mean peak GH levels were similar in the three groups (19.4±9.8, 17.7±8.8 and 14.6±8.9 μg/l, mean±SD, respectively). By chosing 10 μg/l as the limit for a normal response we found that stimulated GH levels had a sensitivity of 50% and a specificity of 83% in identifying children with suspected GHD (short children with subnormal HV). The diagnostic accuracy was almost superimposable, for cutoff values of 10 and 12 μg/l. Eight of the 10 children with subnormal HV and a GH peak <10 μg/l had a GH peak <10 μg/l also after a second stimulation test. Six of the 29 short children with normal HV had a GH peak <10 μg/l. Only one of them had a GH peak <10 μg/l after a second stimulation test. Five of the normal children had peak GH levels <10 μg/l. These results indicate that HV is a useful variable to predict the GH response to an acute GH stimulus, since the great majority of children with a normal growth rate had a normal GH response to at least one stimulation test.

THE EFFECT OF OXANDROLONE ON THE GROWTH HORMONE RESPONSE TO GROWTH HORMONE RELEASING HORMONE IN CHILDREN WITH CONSTITUTIONAL GROWTH DELAY

The effect of treatment with oxandrolone, an anabolic steroid, on GH response to GH‐releasing hormone (GHRH) has been evaluated in children with constitutional growth delay. Five subjects, four males and one female, aged 11·0–17·1 years were given oxandrolone 0·1 mg/kg p.o. daily for 2 months, and underwent acute administration of GHRH (GRF 1–40, 1 μg/kg i.v.) before and after withdrawal of oxandrolone therapy. GHRH administration induced a much greater GH response, evaluated either as a peak plasma GH levels or plasma GH integrated area, after than it did before oxandrolone treatment. These findings indicate that in children with constitutional growth delay oxandrolone increases the sensitivity of somatotrophs to exogenous GHRH and, likely, to the endogenously‐released neurohormone.