OBJECTIVE: Neonatal treatment of male monkeys with a gonadotropin-releasing hormone antagonist (Ant) increased the incidence of delayed puberty. Using blood samples that had been collected from monkeys with normal or delayed puberty, we assessed the potential involvement of leptin and thyroxine (T4) in sexual development. DESIGN AND METHODS: Monkeys were treated from birth until 4 months of age with vehicle, Ant or Ant/androgen and blood samples were drawn from 10 to 62 months of age. RESULTS: Serum leptin and total T4 concentrations declined in parallel throughout adolescence in all treatment groups. There was no transient rise in leptin before or in association with the onset of puberty. Also, leptin did not differ during the peripubertal period between animals experiencing puberty at that time versus those in which puberty was being delayed. Neonates treated with Ant either alone or with androgen replacement had higher leptin levels than controls throughout development. While leptin exhibited no significant changes during the peripubertal period, T4 values increased and declined in parallel with the peripubertal changes in hypothalamic-pituitary-testicular activity. CONCLUSIONS: These data do not support the concept that a transient rise in leptin triggers the onset of puberty in male monkeys. However, the disruption of neonatal activity of the pituitary-testicular axis alters the developmental pattern of leptin. The changes in T4 levels during the peripubertal period suggest that thyroid status may be a significant contributor to the process of sexual development in the male monkey and that peripubertal changes in secretion of this hormone may serve as an effective physiological response during a critical period of elevated energy expenditure.
ML Hartoft-Nielsen, AK Rasmussen, A Kaas, U Feldt-Rasmussen, and K Buschard
OBJECTIVE: Changes in the functional state of beta cells by neonatal stimulation or adolescent suppression have reduced the incidence of type 1 diabetes mellitus in animal models. The aim of this study was to evaluate the effect of manipulation of the activity of the thyroid gland by neonatal stimulation or by adolescent suppression on the prevalence of spontaneous autoimmune thyroiditis (AIT) in rats. METHODS: Bio-Breeding/Worcester (BB) rats were treated neonatally with sodium iodine (NaI) or thyroid stimulating hormone (TSH), or during adolescence by triiodothyronine (T(3)), and the lymphocytic infiltration in the thyroid gland was evaluated. RESULTS: Neonatal treatment with NaI decreased the prevalence of AIT to 32+/-9% compared with 66+/-5% in the controls (P<0.002), mainly caused by a reduction among the female rats (13+/-9% vs 52+/-8%, P<0.006). TSH had no effect. Post neonatal suppression of the thyroid gland by T(3) had a biphasic response. Early in adolescence the overall prevalence was 14+/-7% compared with 66+/-5% in the controls (P<10(-5)); for female rats AIT was prevented (0+/-0%) compared with 52+/-8% in the controls (P<0.0003) and in male rats the values were 29+/-13% compared with 80+/-6% in the controls (P<0.001). Treatment with T(3) later in adolescence increased the overall prevalence to 81+/-7% compared with 66+/-5% in the controls (not significant). For female rats the prevalence increased to 78+/-9% compared with 52+/-8% in the controls (P=0.04). The degree of thyroiditis among the affected animals was similar in all groups. CONCLUSION: Neonatal stimulation of the thyroid gland by iodine or early adolescent suppression by T(3) reduced the prevalence of AIT whereas T(3) given later increased the prevalence of thyroiditis in rats. Thyroid activity at various ages seems to be of importance for the development of autoimmune thyroiditis.
M Salerno, T Lettiero, A Esposito-Del Puente, V Esposito, D Capalbo, A Carpinelli, S Padula, and A Del Puente
OBJECTIVE: To evaluate whether long-term l-thyroxine therapy in young adults with congenital hypothyroidism may affect bone mineral density (BMD). DESIGN: Thirty-seven subjects with congenital hypothyroidism, detected by neonatal screening and longitudinally followed from the time of diagnosis and treatment (26+/-4 days) up to the age of 17.8+/-1.0 years, were studied. METHODS: Spinal (L2-L4) BMD, measured by dual-energy X-ray densitometry, and bone quality, measured as amplitude-dependent speed of sound (Ad-SoS) by quantitative ultrasound, were evaluated. RESULTS: Z-score mean values (+/-s.d.) of BMD (-0.3+/-0.7) and Ad-SoS (-0.7+/-1. 1) were slightly below the average but within the normal range. Ad-SoS resulted in a z-score below -1 in 38% of patients as compared with BMD which resulted in a z-score below -1 in only 13.5% of subject. No significant differences were observed between males (BMD, -0.3+/-0.7; Ad-SoS, -0.9+/-1.0) and females (BMD, -0.3+/-0.7; Ad-SoS, -0.5+/-1.2) or when dividing patients on the basis of aetiological defects; ectopic gland (BMD, -0.3+/-0.6; Ad-SoS, -0.8+/-0.9), athyreosis (BMD, -0.3+/-0.9; Ad-SoS, -0.8+/-1.0) and eutopic gland (BMD, -0.3+/-0.8; Ad-SoS, -0.4+/-1.3). No significant relationships were observed between BMD or Ad-SoS z-score and hormonal status or l-thyroxine dosages at the time of the study or during the pubertal period. CONCLUSIONS: The careful monitoring of serum thyroid-stimulating hormone and adjustment of l-thyroxine dosage avoided the significant deleterious effects of prolonged l-thyroxine replacement therapy on bone tissue in adolescents and young adults with congenital hypothyroidism treated from the neonatal period.
Muneo Yoshibayashi, Tetsuro Kamiya, Yoshihiko Saito, Kazuwa Nakao, Kenya Nishioka, Shinji Temma, Hiroaki Itoh, Gotaro Shirakami, and Hisayuki Matsuo
Yoshibayashi M, Kamiya T. Saito Y. Nakao K, Nishioka K, Temma S, Itoh H, Shirakami G, Matsuo H. Plasma brain natriuretic peptide concentrations in healthy children from birth to adolescence: marked and rapid increase after birth. Eur J Endocrinol 1995;133:207–9. ISSN 0804–4643
The aim of the present study is to establish the normal range and to determine the developmental changes of plasma brain natriuretic peptide (BNP) concentrations in children. We measured plasma BNP concentrations as well as atrial natriuretic peptide (ANP) concentrations in 58 healthy children from birth to adolescence and in the umbilical vein of 20 healthy neonates using highly sensitive immunoradiometric assays. The plasma BNP concentration was the highest at 0 days of age and descended through maturation to be almost constant and to be at the adult level at 3 months of age. The plasma BNP concentration at 0 days of age (56.7 ± 49.6 fmol/ml; mean±sd) was 25 to 30 times higher than the adult level and 21 times higher than that in the umbilical vein (2.7 ± 1.4fmol/ml), The plasma ANP concentration at 0 days of age was not significantly different from that in the umbilical vein. The ratio of BNP to ANP was also the highest at 0 days of age (1.39 ± 0.72) and decreased through maturation to be at the adult level at 3 months of age. Thus, the plasma BNP concentration in healthy subjects showed a marked, rapid and preferential increase immediately after birth, suggesting that BNP has a physiological role distinct from that of ANP in the perinatal circulatory changes from fetus to neonate.
Muneo Yoshibayashi, Department of Pediatrics, National Cardiovascular Center, 5-7-1 Fujishirodai, Suita, Osaka 565, Japan
Michel Polak, Jo Blair, Primoz Kotnik, Effie Pournara, Birgitte Tønnes Pedersen, and Tilman R Rohrer
To investigate the effect of age at growth hormone (GH) treatment start on near adult height (NAH) in children with isolated GH deficiency (GHD).
NordiNet® International Outcome Study (IOS) (Nbib960128), a non-interventional, multicentre study, evaluates the long-term effectiveness and safety of Norditropin® (somatropin) (Novo Nordisk A/S) in the real-life clinical setting.
Patients (n = 172) treated to NAH (height at ≥18 years, or height velocity <2 cm/year at ≥16 (boys) or ≥15 (girls) years) were grouped by age (years) at treatment start (early (girls, <8; boys, <9), intermediate (girls, 8–10; boys, 9–11) or late (girls, >10; boys, >11)) and GHD severity (<3 ng/mL or 3 to ≤10 ng/mL). Multiple regression analysis was used to evaluate the effect of age at treatment start (as a categorical and continuous variable) on NAH standard deviation score (SDS).
Age at treatment start had a marked effect on NAH SDS; NAH SDS achieved by patients starting treatment early (n = 40 (boys, 70.0%); least squares mean (standard error) −0.76 (0.14)) exceeded that achieved by those starting later (intermediate, n = 42 (boys, 57.1%); −1.14 (0.15); late, n = 90 (boys, 68.9%); −1.21 (0.10)). Multiple regression analysis showed a significant association between NAH SDS and age at treatment start (P < 0.0242), baseline height SDS (HSDS) (P < 0.0001), target HSDS (P < 0.0001), and GHD severity (P = 0.0012). Most (78.5%) patients achieved a normal NAH irrespective of age at treatment start.
Early initiation of GH treatment in children with isolated GHD improves their chance of achieving their genetic height potential.
Kerstin Hall, Gösta Enberg, Martin Ritzén, Håkan Svan, Linda Fryklund, and Kazue Takano
Serum somatomedin A (SMA) has been determined in healthy children (n = 188) in relation to age using both a radioimmunoassay and a radioreceptor assay. The SMA levels, only 50% of adult values at birth, rise gradually with age and reach adult levels at 10 years of age. There is a significant correlation (r = 0.46, P < 0.001) between SMA determined by the two methods throughout childhood except during puberty. Immunoreactive SMA shows a marked pubertal rise in values with a peak 2 years earlier for girls than boys, which is not observed by the radioreceptor assay technique. In boys with delayed puberty the increase in immunoreactive SMA is seen first when the testes reach a size of 5 ml. Children with growth hormone deficiency (n = 30) had significantly lower levels of SMA than healthy age-matched controls. Immunoreactive SMA gives a better separation of these groups than the values obtained by radioreceptor assay.
A. Parra, S. Villalpando, E. Junco, B. Urquieta, S. Alatorre, and G. García-Bulnes
Serum thyrotrophin (TSH), thyroxine (T4), triiodothyronine (T3), thyroxine-binding globulin (TBG) and reverse T3 (rT3) were measured by radioimmunoassay in 175 girls and 187 boys aged 6.0 to 16.9 years, who were clinically healthy, and had negative serum antithyroglobulin and antimicrosomal antibodies. All the children had normal weight and height and were grouped at 12 months' intervals. In girls, TSH levels ranged between 5.3 ± 0.4 and 6.9 ± 0.5 μU/ml without significant changes with age; serum T4 decreased up to 13.9 years and rose afterwards; serum TBG was constant up to 13.9 years, decreased subsequently and rose after 15.9 years; serum T3 levels were lower after 13.0 years than previously; serum rT3 decreased between 11.0 and 11.9 years and rose thereafter; the calculated serum free T4 (FT4) and free T3 (FT3) concentrations had a significant rise from 14.0 to 15.9 years followed by a sharp decline; T3:T4, rT3:T3 and rT3:T4 ratios were constant up to 11.9 years, then a rise was seen in T3:T4 and a fall in the later ratios, followed by a drop in T3:T4 ratio and a sustained rise in rT3:T3 and rT3:T4 ratios. In boys, TSH levels were constant between 5.2 ± 0.4 and 6.6 ± 0.4 μU/ml; serum T4 decreased with increasing age; serum TBG was constant up to 13.9 years, and had a sustained fall thereafter; serum T3 was constant over the age range studied; serum rT3 levels decreased up to 13.9 years and rose thereafter; FT4 had no changes with increasing age while FT3, although constant up to 13.9 years, had a sustained rise afterwards; T3:T4 ratio did not change with age, while rT3:T3 and rT3:T4 ratios, although constant up to 13.9 years, showed a tendency toward a sustained rise thereafter. These sex-different variations in serum thyroid hormone concentrations might be related to the fact that girls mature at an earlier chronological age than boys and may represent a partial response of the body to the qualitatively and quantitatively different energy needs in girls as compared with boys, consecutive to the differences in body composition first appearing at puberty.
Yasuo Akamine, Ken-ichi Kato, and Hiroshi Ibayashi
A cross-sectional study was undertaken to investigate the correlation of the level of serum adrenal androgens with clinical signs of puberty and to assess the participation of genetic factors in the onset and progression of puberty. Serum concentrations of 11-deoxy-17-ketosteroids (11-deoxy-17-KS), dehydroepiandrosterone (DHEA) and androstenedione (4-A-dione) were measured in 74 monozygotic and 24 dizygotic twin pairs during the years of puberty. The mean serum concentrations of the adrenal androgens increased significantly with the advancement of bone age. A comparison of the adrenal androgen concentrations at a bone age of 15 years revealed the trend of earlier progression of puberty in girls than in boys. Serum 11-deoxy-17-KS and DHEA levels correlated fairly well with the stages of pubic and axillary hair growth in both sexes. No correlation of adrenal androgen levels with pituitary gonadotrophins or prolactin was observed in either sex during puberty. These results strongly suggest the importance of the specific action of adrenal androgens on the onset and progression of puberty, and further suggest that the maturation of the hypothalamic-pituitary-gonadal axis is not involved primarily in the maturation of the adrenal cortex during puberty.
From the viewpoint of twin zygosity, intra-pair differences of serum adrenal androgen levels were compared between monozygotic and dizygotic pairs of twins. Serum 11-deoxy-17-KS and 4-A-dione levels in monozygotic pairs of twins showed a significantly higher intrapair similarity than in dizygotic pairs of twins. These findings suggest that during puberty the maturation of the adrenal cortex is regulated by genetic factors.
A. Parra, C. Cervantes, M. Sánchez, L. Fletes, G. García-Bulnes, R. M. Argote, I. Sojo, A. Carranco, R. Arias, and V. Cortés-Gallegos
Plasma concentrations of luteinizing hormone (LH), follicle-stimulating hormone (FSH), 17 alpha-hydroxyprogesterone (17α-OHP), 17β-oestradiol (Oe2) and progesterone (P) were measured in 352 healthy girls aged 6.0 to 15.9 years, as a function of age (CA), weight, height and calculated lean body mass (LBM) and total body fat (TBF). The earliest hormonal changes were a fall in mean plasma FSH concentrations together with a small but significant rise in plasma Oe2 well in advance of any sign of pubertal development. The next changes were a progressive rise in plasma FSH and 17α-OHP concentrations without further increments in plasma Oe2; these changes corresponded to a mean body weight of 29.8 kg, a mean height of 132.0 cm (initiation of the adolescent growth spurt), a mean LBM of 24.7 kg and a mean TBF of 5.1 kg. The last events were a progressive rise in plasma LH and Oe2 and less marked in P, which occurred in association with a mean body weight of 40.0 kg, a mean height of 142.0 cm (time of peak velocity of weight and height gain), a mean LBM of 31.8 kg and a mean TBF of 9.1 kg. Significant quadratic equations were disclosed between plasma FSH and LH versus CA, weight, height and LBM, and a significant linear correlation was observed between each gonadotrophin and TBF. These results show an association, not necessarily causal, between a 'critical level' of body composition and hormonal changes at the start of the adolescent growth spurt, as well as with late hormonal events at the time of peak velocity in weight and height gain. On the other hand, LBM rather than TBF seems more closely associated with the initiation and progression of puberty.
G. García-Bulnes, C. Cervantes, M. A. Cerbón, H. Tudon, R. M. Argote, and A. Parra
Serum thyrotrophin (TSH), triiodothyronine (T3) and thyroxine (T4) were measured by radioimmunoassay in 165 boys and 171 girls, clinically healthy, aged 6.1 to 16.0 years with normal weight and height, grouped at 12 months' intervals. The TSH values in boys ranged from 5.0 ± 0.6 to 6.1 ± 0.6 μU/ml without significant age differences. In girls, TSH level was 5.3 ± 0.5 μU/ml at the age of 6.0 to 7.0 and 7.4 ± 0.5 μU/ml at the age of 10.1 to 11.0 (P < 0.001). Girls had higher values than boys from 9.1 to 11.0 years (P < 0.025). In boys the T3 level was 182 ± 10 ng/100 ml at age 6.0 to 7.0 and 230 ± 15 ng/100 ml at age 11.1 to 12.0 (P < 0.025). Girls had higher values from the age of 9.1 on (215 ± 12 ng/100 ml), but after 13.1 years they decreased (P < 0.025). Girls had higher T3 levels than boys at age 10.1 to 11.0 (P < 0.025), but this difference disappeared when T3 concentrations in girls of this age were compared to boys aged 11.1 to 12.0. In boys and girls, T4 levels tended to be lower with increasing age (r = −0.860, P < 0.01) and there was a significant difference between the values seen up to 9.0 years and those after 13.1 years (P < 0.025 − < 0.001). Girls had lower values than boys at the age of 8.1 to 9.0; however, this difference disappeared when girls of this age were compared to boys 9.1 to 10.0 years old.
It is concluded that previous to and around puberty initiation in both sexes, there is a rise in T3, followed by a progressive decrease in T4 with a rise in TSH only in girls. These changes occurred one year earlier in girls than in boys. These observations may represent transient adaptation responses to the increasing energy needs during periods of rapid growth.