R. Puggioni

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.

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 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.

The Effects of Galanin on Growth Hormone Secretion in Children of Normal and Short Stature1

ABSTRACT: We have evaluated the effect of galanin (Gal), a newly identified hypothalamic peptide, on growth hormone (GH) secretion in 10 children with normal stature (NS), nine with constitutional growth delay (CGD), and five with isolated GH deficiency (IGHD). Gal was infused intravenously at a rate of 8 or 15 μg/kg/h. All children also underwent an acute oral clonidine test (0.15 mg/m2). In CGD children the mean plasma GH peak after 8 μg/kg/h of Gal infusion (13.3 ± 1.7 ng/mL; mean ± SEM) was higher (p < 0.02) than in NS children (8.5 ± 0.8 ng/mL). When the dose of Gal was increased to 15 μg/kg/h the mean plasma GH peak in CGD children (18.5 ± 3.5 ng/ mL) was still higher than in the NS group (13.2 ± 2.9 ng/ mL), although not significantly so. In IGHD children the mean plasma GH peak elicited by 8 or 15 μg/kg/h of Gal (3.8 ± 0.7 and 3.9 ± 0.5 ng/mL, respectively) was lower than that obtained in either CGD (p<0.0002) or NS children (p<0.001). In NS children the mean plasma GH peak after acute clonidine administration (22.3 ± 3.0 ng/ mL) was higher than that observed after either dose of Gal used (p<0.001 and p < 0.05 with 8 and 15 μg/kg/h, respectively). In CGD or IGHD children mean plasma GH peak after acute clonidine (14.8 ± 2.6 and 4.1 ± 1.2 ng/ mL, respectively) was not significantly different from that observed after either dose of Gal. No correlation was found between peak plasma GH responses to clonidine and to Gal infusion at either dose used. Gal infusion did not cause any significant change in LH, FSH, prolactin, and TSH plasma levels. We conclude that Gal stimulates GH secretion in CGD as well in NS children but not in children with isolated GH deficiency. Gal, at least under our experimental conditions, does not seem to be of help in the differential diagnosis of children with short stature.

Adrenal and testicular function in boys affected by thalassemia

The adrenal androgen secretion and testicular function were studied in 6 thalassemic boys aged between 16 and 20 years. Six normal boys of the same age and 6 at the same pubertal stage (P1 according to Tanner) were also studied as controls. Plasma testosterone levels were found significantly lower (p < 0.001) in the thalassemic boys (0.8 ± 0.1 ng/ml) than in healthy boys of the same age (3.4 ± 1.01 ng/ml), but within the range of the healthy boys at the same pubertal stage (0.69 ± 0.1 ng/ml). DHA-S, a marker of adrenal maturation, showed a similar pattern. The hCG test showed a significant (p < 0.001) testosterone response in all 3 groups. The response of thalassemic boys (1.5 ± 0.18 ng/ml) was similar to that of normal boys at stage P1 (1.8 ± 0.31 ng/ml), but significantly lower (p < 0.001) than the group of normal boys of the same age (12.5 ± 3.2 ng/ml). The impaired adrenal and testicular activity is probably due to iron deposits in the endocrine glands.

Growth-hormone releasing factor and clonidine in children with constitutional growth delay. Evidence for defective pituitary growth hormone reserve

Six male prepubertal children with constitutional growth delay (CGD), and a subnormal growth hormone (GH) response to insulin hypoglycemia, and four normal prepubertal children were given in different occasions 1 μg/Kg iv synthetic hpGRF-40 or a single oral dose of 0.15 mg/m2 clonidine (Clon), an effective growth hormone (GH) secretagogue. In the normal children brisk and clear-cut GH rises were detected in plasma after hpGRF-40 (peak GH levels at 15–30 min) or clonidine (peak GH levels 60–90 min). In CGD children hpGRF-40 induced a biphasic response, e.g. a slight increase in plasma GH at 15 min followed by a delayed and erratic GH rise occurring 45–120 min post-injection. Also the GH response to Clon was sluggish and delayed and peak plasma GH levels were attained only 90–180 min post-drug administration. These data indicate that the CGD children of our study have a defect in the pituitary GH reserve.

Sexual maturation and adrenal function in girls with thalassemia

Adrenal steroid production was evaluated in 12 thalassemic girls aged between 18 and 22 years and at stage P1 of sexual maturation according to Tanner. The values found in these patients were compared with those in 12 normal girls of the same age at stage P4–5 of sexual maturation. Pregnelone, dehydroepiandrosterone, dehydroepiandosterone sulfate, progesterone, 17-OH-P, androstenedione, testosterone, dihydrotestosterone and estradiol were found to be significantly reduced (p < 0.001) in the thalassemic group, while Cortisol levels showed a slight but not statistically significant reduction. Plasma ferritin levels were greatly increased and showed a highly significant (p < 0.001) correlation coefficient when plotted against each hormone. The present results suggest that the impaired adrenal function plays an important role in determining the delayed sexual maturation almost always present in the thalassemic patients and that this disorder may be due to iron overload.

Growth hormone response to hpGRF-40 in different forms of growth retardation and endocrine-metabolic diseases

The effect of one of the new human pancreatic growth hormone releasing factors (hpGRFs) was assessed in children or young adults with different forms of growth retardation or endocrine-metabolic diseases. Intravenously administered synthetic hpGRF-40 (1 μg/kg) induced a clear-cut and prompt rise in plasma growth hormone (GH) levels in 8 normal prepubertal children and a definite GH rise in 11 out of 14 children with isolated GH deficiency (IGHD) and one child with the Silver-Russel syndrome. In two out of three subjects with craniopharyngioma hpGRF-40 did not induce any plasma GH increase.In seven out of ten children with constitutional growth delay (CGD), hpGRF-40 induced a biphasic GH response, with a prompt small GH increment followed by a second, more consistent rise. Both in children with IGHD and with CGD the rise in plasma GH following hpGRF-40 was markedly lower than in controls. In children with CGD the GH response to hpGRF-40 was defective, despite the fact that in most of them the GH response to standard pharmacological stimuli was normal according to generally accepted criteria.hpGRF induced a small but sustained plasma GH rise in four hypothyroid subjects, while in three out of four children with idiopathic obesity the GH response to hpGRF was strikingly reduced. These data demonstrate that hpGRF is a potent stimulus of GH release in normal prepubertal children and a physiological means of investigating GH function in diseases associated with growth impairment.

Puerperal breast feeding does not stimulate circulating opioids in humans

ACTH, βlipotropin (βLPH), βendorphin (βEP), Prolactin (PRL) and Cortisol were measured in the first five days of Puerperium at 9:00, before and 30 minutes after suckling, in 7 healthy lactating women. With the exception of PRL plasma levels which decline, although remaining at high concentrations during the observation period, all the other parameters showed a sudden fall from the high levels found at delivery, reaching stable normal levels (βLPH, βEP, Cortisol) or concentrations which were 50% lower than normal (ACTH), from the second day of Puerperium. Suckling confirms its capacity to release plasma PRL, while all the other indices remain unmodified. Despite the experimental evidence that serotoninergic neurons are involved both in the PRL response to suckling and the circadian rhythmicity and stress response of proopiocortin-related peptides, the present results suggest that breast feeding is not a stressful situation, as no typical proopiocortin-related peptide response is evident, and that the activation of PRL release is related to stimulation of serotoninergic neurons which differ from those involved in the control of proopiocortin-related peptide secretion.

Growth hormone deficiency states: approach by CNS-acting compounds

Over the past few years, a number of new findings have led to a better understanding of the pathophysiology of growth hormone (GH) secretion. The isolation of GH-releasing hormone (GHRH) (Guillemin et al. 1982; Rivier et al. 1982) has led to the conclusion that most GH-deficient patients can produce normal amounts of GH when stimulated with GHRH (Grossman et al. 1983; Pintor et al. 1983; Thorner et al. 1983; Schriock et al. 1984). GH hyposecretory states may therefore result from a primitive abnormality of the somatotrophs or, more frequently, from reduced GHRH synthesis and/or release. The latter may be caused by hypofunction of stimulatory neurotransmitter pathways. More recently, it has been observed that a number of short children, with normal GH responses to Standard pharmacological stimuli, have low 24-h GH secretion (IC-GH) and show a positive response to treatment with exogenous GH. This has strengthened the argument for the existence of a central abnormality of GH neuroregulation (Spiliotis et ai 1984; Zadik et al. 1985).