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CL Boguszewski, C Jansson, MC Boguszewski, S Rosberg, KA Wikland, B Carlsson, and LM Carlsson

The proportion of non-22 kDa GH isoforms was evaluated in 93 healthy children (48 boys aged 6.8-18.4 years and 45 girls aged 3.9-18.4 years) of normal stature (height +/- 2 s.d. score) at different stages of puberty. In addition, correlations among the proportion of non-22 kDa GH isoforms, auxology, spontaneous GH secretion and biochemical measurements were investigated. Serum non-22 kDa GH levels, expressed as percentage of total GH concentration in the samples, were determined by the 22 kDa GH exclusion assay, in which monomeric and dimeric 22 kDa GH are removed from serum and the non-22 kDa GH isoforms are quantitated using a polyclonal antibody GH assay. Samples were selected from spontaneous GH peaks in 24-h GH profiles. For boys, the median proportion of non-22 kDa GH isoforms was 8.5% (range 3.2-26.6%) and for girls it was 9.6% (1.8-17.4%), with no influence of age and no sex-related difference in prepubertal (boys, 7.2%; girls, 8.8%) or pubertal children (boys, 9.1%; girls, 9.9%). However, the median proportion of non-22 kDa GH isoforms was significantly higher in pubertal boys (9.1%) than in prepubertal boys (7.2%; P = 0.03). In pubertal boys, height S.D. scores (SDS) were inversely correlated to the proportion of non-22 kDa GH isoforms (r = -0.38; P = 0.02), especially at mid-puberty (r = -0.7; P = 0.01), indicating that the presence of increased amounts of circulating non-22 kDa GH isoforms was associated with less growth. In prepubertal children, positive correlations between non-22 kDa GH and weight SDS (r = 0.46; P = 0.03), weight-for-height SDS (r = 0.51; P = 0.01) and body mass index (r = 0.42; P = 0.04) were observed. No significant correlations were seen with spontaneous GH secretion or measurements of IGF-1, IGF-binding protein-3, insulin and leptin. These findings in normal children indicate that the proportion of circulating non-22 kDa GH isoforms may have physiologic significance for growth and metabolism in different stages of development, and emphasize the importance of evaluating the circulating ratio of 22 kDa and non-22 kDa GH in children with growth disorders.

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M Boguszewski, J Dahlgren, R Bjarnason, S Rosberg, LM Carlsson, B Carlsson, and K Albertsson-Wikland

The product of the obese (ob) gene, leptin, is an adipocyte-derived hormone that is involved in the regulation of appetite and body weight. This study was undertaken in order to describe the basal serum levels of leptin in prepubertal short children born small for gestational age (SGA) and their relationship with growth parameters, before and during growth hormone (GH) treatment. Eighty-nine prepubertal short children (66 boys, 23 girls; height standard deviation score (SDS), -5.4 to -2.0; age, 2.0 to 12.8 years) born SGA, 12 of whom (9 boys, 3 girls) had signs of Silver-Russell syndrome, were included in the study. Serum leptin concentrations were measured by radioimmunoassay. Leptin levels in the children born SGA were compared with those in a reference group of 109 prepubertal healthy children born at an appropriate size for gestational age (AGA). The mean (S.D.) change in height SDS was 0.11 (0.22) during the year before the start of GH therapy (0.1 IU/kg/day) and increased to 0.82 (0.44) during the first year (P < 0.001) and to 1.28 (0.59) during the 2-year period of GH therapy (P < 0.001). The children born SGA were significantly leaner than the reference group. An inverse correlation was found between leptin and chronological age in the SGA group (r = -0.31, P < 0.01). The mean serum level of leptin in the children born SGA who were older than 5.5 years of age was 2.8 micrograms/l which was significantly lower than the mean value of 3.7 micrograms/l found in the children born AGA of the same age range. The difference remained after adjustment of leptin levels for sex, age, body mass index (BMI) and weight-for-height SDS (WHSDSSDS). Leptin correlated with WHSDSSDS (r = 0.32, P < 0.001) and BMI (r = 0.36, P < 0.01) in the reference population, but not in the SGA group. No correlation was found between leptin and spontaneous 24-h GH secretion, insulin-like growth factor (IGF)-I or IGF-binding protein-3 levels, or with fasting insulin or cortisol levels. Leptin levels at the start of GH treatment were correlated with the growth response over both 1 year (r = 0.46, P < 0.001) and 2 years (r = 0.51, P < 0.001) of GH therapy. Using multiple regression analysis, models including leptin levels at the start of GH therapy could explain 51% of the variance in the growth response after 1 year and 44% after 2 years of GH treatment. In conclusion, serum leptin levels are reduced in short children born SGA and are inversely correlated with chronological age. Leptin concentrations correlate with the growth response to GH treatment and might be used as a marker for predicting the growth response to GH treatment.

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M. H. Gons, J. H. Kok, W. H. H. Tegelaers, and J. J. M. de Vijlder

Abstract. In this paper we describe methods for the early aetiological diagnosis of congenital hypothyroidism, using beside the classical T4, T3 and TSH plasma concentrations, four additional parameters in plasma and urine. The first one is thyroglobulin (Tg). In normal children of more than one year of age and in adults, 5–35 ng/ml plasma is found, in neonates 2–3 weeks old, this level is 10–250 ng/ml. In patients with a stimulated thyroid gland, as in primary congenital hypothyroidism, plasma Tg levels increase. High Tg values are found in iodine deficiency and in organification defects. In the absence of the thyroid gland plasma Tg is undetectable. Low to normal levels are found in cases with hypoplasia of the gland. In patients with a disturbed synthesis of Tg, resulting in Tg deficiency of the gland, plasma Tg levels vary from undetectable to normal. The PBI-T4 plasma difference, which is caused by circulating abnormal iodoproteins is the second parameter. The products of thyroidal breakdown processes of the abnormal iodoproteins are excreted in the urine and used as the third parameter. We found that the excretion of this low molecular weight iodinated material (LOMWIOM) was increased only in Tg-deficient patients.

If the neonate is found to be hypothyroid, thyroid hormone substitution must be given immediately. Blood and urine sampling can be done just before or even directly after starting the therapy. The measurements extended with the determination of the total iodine excretion (fourth parameter) can be carried out within 1 week. With these additional methods it appeared to be possible to distinguish between several types of congenital hypothyroidism in neonates found by screening.

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Pierre Ferrier and Thérèse Lemarchand-Beraud

Very little is known yet about thyroid hormone transport capacity of the serum and thyroid hormone protein binding in children. Except for the studies by Haddad (1) and by Dreyer and Man (2), all observations so far published are concerned with hormone transport mechanisms in the adult. In order to establish reference values, thyroid function tests were performed in 35 eumetabolic children (20 boys and 15 girls) aged from 6 weeks to 11 years. In vitro erythrocyte uptake of T3 was measured according to the procedure of Hamolsky et al. (3). Protein binding of T4 was studied at progressive degrees of saturation by paper electrophoresis in tris-maleate buffer at pH 8.6 according to Ingbar et al. (4). Values were compared with those from a group of 21 euthyroid adults, tested in the same laboratory. PBI was found to be higher in children than in adults. This tendency has been noted

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ANKE A. EHRHARDT and HEINO F.L. MEYER-BAHLBURG

ABSTRACT

Precocious puberty in girls has endocrinological as well as behavioral implications. We present data from a first systematic controlled follow-up study of 16 adolescent girls with a history of idiopathic precocious puberty (IPP) compared to closely pairmatched adolescent control subjects of comparable pubertal status and normal pubertal history. Findings in four areas of behavior are reported: (1) Psychiatric sequelae: the IPP sample showed an increase in minor psychopathological symptoms. (2) Psychosexual development: The IPP sample was advanced in sociosexual milestones, albeit mostly within the normal range for adolescents. (3) Intelligence: IQ was not different from controls. However, school achievement was accelerated during childhood. (4) Cognitive pattern: The IPP sample had lower spatial perception scores than controls.

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L. Kanaris, K. Ntalles, K. Alevizaki, P. Lapatsanis, Ch. Velentzas, P. Katsichtis, E. Georgiou, Ch. Drossos, and D.G. Ikkos

The aim of the present work was to obtain bone mass estimates of healthy Greek children aged 6–18 years. This work was considered worthwhile since similar data are very few in the world litterature (Bonnard 1968, Gryfe et al. 1971), while those for Greece (Livadas et al. 1975) refer to 902 children only (462 boys and 440 girls) aged 5–13 years.

The material of the present study consists of 2.406 schoolboys and 2.451 schoolgirls aged 6–18 years, of whom 864 boys and 1.189 girls were living in Attica, while the remaining 1.542 boys and 1.262 girls were living in communities outside Attica (i.e. Atalanti, Arnea, Elatia and Karpenisi). Standing body height and body weight was measured in all subjects. Furthermore, a plain x–ray of the left hand was taken in all children, using a focal distance of 80 cm.

By means of a micrometer apparatus (Taschenmessloupe TM4, C. Zeiss) the

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Z Laron, X L Wang, B Klinger, A Silbergeld, and D E L Wilcken

Abstract

Background: elevated serum lipoprotein(a) (Lp(a)) is a strong risk factor for coronary artery disease (CAD). Genetic factors appear to account for the major variance in Lp(a) levels but the contribution hormones make in modulating Lp(a) levels is not yet clear. In the present investigation we determined the effects of human growth hormone (hGH) and insulin-like growth factor-I (IGF-I) on circulating Lp(a).

Methods: four groups of patients were studied. Group a: adults with GH deficiency (n=7) treated with hGH (0·05 U/kg/day, s.c.); group b: girls with Turner syndrome (n=7) treated with hGH (0·1 U/kg/day, s.c.); group c: prepubertal boys with idiopathic short stature (n=6) treated with the GH secretagogue (GHRP) hexarelin (60 μg t.i.d. intranasally); group d: Laron syndrome patients (n=10) treated with IGF-I (100–200 μg/kg/day, s.c.). Following overnight fasting, serum was sampled before the initiation of treatment and during 6–9 months treatment.

Results: serum IGF-I rose significantly in all the subjects in all four groups. In the first three groups in which IGF-I was elevated by exogenous or endogenous GH stimulation, serum Lp(a) increased significantly (119±35%, P<0·01; 126±44%, P<0·05; 102±29% P<0·01 for groups a, b, and c respectively). By contrast, serum Lp(a) levels decreased in group d to whom exogenous IGF-I was administered (–66±5%, P<0·001). The differential effect of endogenous vs exogenous IGF-I on serum Lp(a) paralleled the behaviour of serum insulin. Insulin was significantly increased in all the subjects receiving hGH or GHRP (65·2±31%, P=0·109; 93·7±53%, P=0·062; 3536·8±52·7%, P<0·01 for groups a, b, and c respectively) whereas insulin levels were reduced following exogenous administration of IGF-I (—34·1±9·1%, P<0·01).

Conclusions: we conclude that long-term GH treatment increases and IGF-I decreases circulating levels of Lp(a). These findings may have clinical relevance in view of the increasing use of hGH in children and adults and the role of Lp(a) as a CAD risk factor.

European Journal of Endocrinology 136 377–381

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Ian R. Lee, Linda E. Lawder, David C. Townend, John D. Wetherall, and Roland Hähnel

Abstract. The steroid binding capacity and concentration of plasma sex hormone binding globulin have been compared in 116 children aged between 2 and 14 years. Concentration was measured by electroimmunodiffusion standardised with reference to the mass of the pure protein and binding capacity by quantitating the binding of radiolabelled 5α-dihydrotestosterone. Binding capacity correlated highly with concentration in all subjects and neither differed significantly between the sexes before or during puberty. However, both were significantly lower in pubertal than in pre-pubertal children. These findings suggest the metabolism of the protein is similar in boys and girls and that the fall in its steroid binding capacity at puberty in fact is due to a fall in its concentration rather than to changes in its physicochemical properties.

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G.J. BRUINING, A.N BOSSCHAART, R.S.R. AARSEN, S.W.J. LAMBERTS, P.J.J. SAUER, and E. DEL POZO

ABSTRACT

A female child was admitted to the hospital few days after birth with severe hypoglycemia and convulsive episodes. Plasma insulin levels were elevated and oral and intravenous administration of glucose were unable to keep blood glucose above 2 mmol/l limit. Intravenous infusion of a long acting somatostatin analog, SMS 201-995, at a dosage gradually increasing from 2 to 50 μg/24 hr, was accompanied by a dramatic fall in circulating insulin levels. Normality of glucose homeostasis was restored and convulsive spells ceased. Fasting blood glucose levels stabilized between 3.4 and 4.7 mmol/l. No rebound phenomenon was observed during short term interruptions of the SMS 201-995 infusion. A subtotal pancreatectomy was performed during SMS treatment, and the diagnosis of nesidioblastosis was confirmed by immunocytologic and electron-microscopic studies. It is concluded that this new potent and long acting somatostatin derivative may be useful in the management of hyperinsulinism in the neonate.

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E. M. de Wijn and R. Steendijk

Abstract.

In 4 girls and 1 boy with pseudo-hypoparathyroidism growth and physical maturation were followed longitudinally for 7 – 13 years until adult height had been reached. As a result of early puberty and cessation of growth all patients were relatively shorter as adults than in their childhood years. The difference between average height at the age of 8.0 years and average adult height was 2.25 sd. This observation offers an explanation for the finding in the literature that short stature is more common in adults with this disease than in children. Skeletal age was advanced in all cases and the development of the tubular bones of the hand was more advanced than the development of the round bones. It is possible that this difference resulted from inappropriately early closure of the epiphyseal discs of disproportionally short metacarpals and phalanges. On the other hand it may be an aspecific phenomenon of advanced skeletal maturation.