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Growth hormone (GH) deficiency in children results in increased body fat, reduced fat-free mass (FFM) including muscle (protein) and bone, and abdominal obesity. Thus, proper GH secretion likely has major developmental influences on later health risks including cardiovascular diseases and osteoporosis. However, the in vivo control of the development of the body composition and fat distribution by GH has not yet been accurately investigated using children with GH deficiency as a model. We determined the effect of GH therapy (GH replacement, n = 3; GH + physiologic cortisol and thyroxine replacement, n = 3) on body composition, the proportional composition of the FFM, and body fat distribution in GH-deficient prepubertal children compared with healthy control children (n = 6) not treated with GH. The GH-deficient and control children were initially matched for gender, bone age, and weight. As assessed by a 4-compartment model, GH therapy reduced percent body fat during the first 3 months of therapy but not thereafter. This change was primarily due to FFM, which increased 3-fold more in the GH-deficient group and accounted for 91.5% of the increase in body weight. Fat mass increased in the controls but was unchanged in the GH-deficient group. Therapy temporarily increased the proportional contribution of water to the FFM, decreased the proportion of mineral, and slightly increased the proportion of protein. Using magnetic resonance imaging (MRI), abdominal visceral fat was reduced in the GH-deficient group and unchanged in the controls. Abdominal subcutaneous fat measured in the same image was not changed. The abdominal and suprailiac skinfold thicknesses also were not decreased in the GH-deficient group. In conclusion, within 1 to 3 months, GH therapy accelerates lean tissue accrual, especially the water and protein components, but has a smaller effect on reducing fat mass. GH therapy has site-specific effects on reducing abdominal adiposity.

BACKGROUND Estimates of energy intake are required for an understanding of growth and disease; however, few methods of energy intake in children have been validated. OBJECTIVE Our objective was to validate energy intake estimated by the Youth-Adolescent Food-Frequency Questionnaire (YAQ) against the criterion total energy expenditure (TEE) by doubly labeled water (DLW). DESIGN Twenty-three boys and 27 girls (8.6-16.2 y of age) completed the YAQ and TEE measurements in 1 y. RESULTS Energy intake by the YAQ (10. 03 +/- 3.12 MJ) and energy expenditure by DLW (9.84 +/- 1.79 MJ) were similar (P: = 0.91) with large lower (-6.30 MJ) and upper (6.67 MJ) +/-2 SD limits of agreement. When within-subject CVs of repeated measures of the DLW and YAQ methods were used, 25 of the 50 subjects were deemed to have misreported their energy intake. The discrepancy in energy intake (YAQ - TEE) was related to body weight (r = -0.25, P: = 0.077) and percentage body fat (r = -0.24, P: = 0.09) but not to age (r = -0.07, P: = 0.63) or the time between measures. From logistic regression, fatter boys were more likely to underreport energy intake than were fatter girls. CONCLUSION The YAQ provides an accurate estimation of mean energy intake for a group but not for an individual.

Growth Hormone Stimulation Testing in Both Short and Normal Statured Children: Use of an Immunofunctional Assay

The longitudinal growth of an individual child is a dynamic statement of the general health of that child. Measurements should be performed often and accurately to detect alterations from physiologic growth. Although any single point on the growth chart is not very informative, when several growth points are plotted over time, it should become apparent whether that individual's growth is average, a variant of the norm, or pathologic. Somatic growth and maturation are influenced by several factors that act independently or in concert to modify an individual's genetic growth potential. Linear growth within the first 2 y of life generally decelerates but then remains relatively constant throughout childhood until the onset of the pubertal growth spurt. Because of the wide variation among individuals in the timing of the pubertal growth spurt, there is a wide range of physiologic variations in normal growth. Nutritional status and heavy exercise training are only 2 of the major influences on the linear growth of children. In the United States, nutritional deficits result from self-induced restriction of energy intake. That single factor, added to the marked energy expenditure of training and competition for some sports, and in concert with the self-selection of certain body types, makes it difficult to identify the individual factors responsible for the slow linear growth of some adolescent athletes, for example, those who partake in gymnastics, dance, or wrestling.

Clarifying the time evolution, and underlying neuroendocrine regulation, of hormone secretion during puberty is of pivotal importance both physiologically and clinically. We sought to determine whether clinical growth and elevated growth hormone (GH) release in pubertal boys are associated with shifts in the irregularity of GH secretory patterns. We studied GH release in 23 healthy boys longitudinally at ∼4-mo intervals over a 6-yr period throughout puberty, by repetitive blood sampling at 20-min intervals for 24 h on each study date. To quantify serial irregularity in the GH profiles, we utilized approximate entropy (ApEn), a scale- and model-independent quantification of the extent of sequential “randomness.” Complementary statistical analyses establish that on a per-subject basis, serum GH concentration-time series show greatest secretory disorderliness (maximal ApEn) in prepuberty and mid-to-late puberty, followed by a steep decline in ApEn to maximal orderliness in postpubertal adolescence ( P< 0.0001, ANOVA). Pooling all subject comparisons, we observed a persistent positive correlation between ApEn and growth velocity (GrVel), Pearson r = 0.467 ( P < < 10−10). Moreover, in general, ApEn(GH) preceded GrVel evolution, with a time frame lead of 4–8 mo providing the most pronounced correlations between ApEn and GrVel. In the setting of low postpubertal growth, per-subject ApEn values fell to approximately one-half of maximal ApEn values and, on average, were in the 13th percentile from minimal ( P < < 10−10) for fully mature boys. Thus, in a longitudinal transpubertal analysis, greater irregularity in GH secretion corresponds to greater linear growth in boys, which culminates in highly regular GH secretory dynamics after sexual maturity. In addition to clinical utility, there may be added experimental merit in knowing that GH dynamics typically predict accelerated linear growth in 4–8 mo.

To elucidate whether the cause of sexual maturation arrest in thalassaemia is of gonadal or pituitary etiology, 10 males with thalassaemia and delayed puberty and 10 with constitutional delay of growth and pubertal maturation (CSS) were extensively studied. Their spontaneous nocturnal gonadotropin secretion and gonadotropin response to intravenous 100 micrograms gonadotropin-releasing hormone (GnRH) were evaluated. Circulating testosterone concentration and clinical response were evaluated after 3 days, 4 weeks and 6 months of intramuscular administration of human chorionic gonadotropin (HCG) (2500 U/m2/dose). Thalassaemic boys had significantly lower circulating concentrations of testosterone compared to those with constitutional delay of growth and sexual maturation (CSS) at the same pubertal stage. Short- and long-term testosterone response to administrations of HCG was markedly decreased in thalassaemic boys. After 6 months of HCG administration 50 per cent (5/10) of the boys did not show significant testicular enlargement or genital changes. Despite the low circulating concentrations of testosterone, none of the patients had high basal or exaggerated gonadotropin response to gonadotropin releasing hormone (GnRH) stimulation. Luteinizing hormone (LH) peak responses to GnRH were significantly lower as compared to controls. Follicle-stimulating hormone (FSH) peak responses to GnRH did not differ among the two study groups. The mean nocturnal LH and FSH secretion was significantly decreased in all thalassaemic boys as compared to boys with CSS at the same pubertal stage (testicular volume). These data proved that hypogonadotropic hypogonadism is the main cause of delayed/failed puberty in adolescents with thalassaemia major. MRI studies revealed complete empty sella (n = 5), marked diminution of the pituitary size (n = 5), thinning of the pituitary stalk (n = 3) with its posterior displacement (n = 2), and evidence of iron deposition in the pituitary gland and midbrain (n = 8) in thalassaemic patients, denoting a high incidence of structural abnormalities (atrophy) of the pituitary gland. Moreover, in many of the thalassaemic boys, the defective testosterone response to long-term (6 months) HCG therapy denoted significant testicular atrophy and/or failure secondary to siderosis. It appears that testosterone replacement might be superior to HCG therapy in these patients. This therapy should be introduced at the proper time in these hypogonadal patients to induce their sexual development and to support their linear growth spurt and bone mineral accretion.

The growth and hormonal status of 23 prepubertal and early pubertal normally growing boys were evaluated for at least 6 years as they entered and progressed through puberty. Each subject was observed during a 24-hr hospital admission approximately every 4 months. Standing height was measured upon arising. At the same time an early morning (0600hr) serum level of testosterone was obtained. A mean growth hormone level was determined from a pool of equal quantities of serum from 72 samples obtained every 20 min for 24 hr. The early morning testosterone level was used as an index of pubertal status. The effect of the chronological age, mean growth hormone, and testosterone levels on the growth velocity was investigated. In addition to age, the interaction between the mean growth hormone level and testosterone concentration has a significant effect on the velocity of growth. Several nonlinear models were explored to describe growth velocity, mean growth hormone level, and testosterone concentration in terms of chronological age of each subject. Models used were chosen for simplicity, interpretability of the model itself and its parameters, and the ability to estimate (and then test) the parameters. Unknown parameters of the model were estimated using ordinary least squares (OLS), which minimizes the L(2) norm of the observed and the predicted values. The L(2) norm may be unduly influenced by outlying observations which commonly occur in many biological data sets. Hence, in addition to the OLS estimators, the least absolute deviation (LAD) estimator which minimizes the L(1) norm of the observed and the predicted values was also considered. Typically, the LAD estimators are more robust than OLS estimators. From a clinical point of view it may be important to know the "normal" values of growth velocity, mean growth hormone level, and testosterone at a given age during puberty. For this reason population models for each of these variables along with their 90% confidence regions were developed. These will permit identification of those children who are outside the boundaries of normal growth for the purpose of evaluation for the etiology of the deviation. Am. J. Hum. Biol. 12:814-824, 2000. Copyright 2000 Wiley-Liss, Inc.

Growth retardation in children with thalassaemia major is multifactorial. We studied the growth hormone (GH) response to provocation by clonidine and glucagon, measured the circulating concentrations of insulin, insulin-like growth factor-I (IGF-I), IGF-binding protein-3 (IGFBP3), and ferritin, and evaluated the spontaneous nocturnal (12 h) GH secretion in prepubertal patients with thalassaemia and age-matched children with constitutional short stature (CSS) (height SDS < -2, but normal GH response to provocation). The anatomy of the hypothalamic pituitary area was studied in patients with abnormal GH secretion using MRI scanning. Children with thalassaemia had significantly lower peak GH response to provocation by clonidine and glucagon (8.8 +/- 2.3 micrograms/l and 8.2 +/- 3.1 micrograms/l respectively) than did controls (17.6 +/- 2.7 micrograms/l and 15.7 +/- 3.7 micrograms/l respectively). They had significantly decreased circulating concentrations of IGF-I and IGFBP3 (68.5 +/- 19 ng/ml and 1.22 +/- 0.27 mg/l respectively) compared to controls (153 +/- 42 ng/ml and 2.16 +/- 0.37 mg/l respectively). Seven of the thalassaemic children had a GH peak response of < 7 micrograms/l after provocation. Those with a normal GH response after provocation also had significantly lower IGF-I and IGFBP3 concentrations than controls. Analysis of their spontaneous nocturnal GH secretion revealed lower mean (2.9 +/- 1.77 micrograms/l) and integrated (2.53 +/- 1.6 micrograms/l) concentrations compared to controls (4.9 +/- 0.29 micrograms/l and 5.6 +/- 0.52 micrograms/l respectively). Five of them had mean nocturnal GH concentration < 2 micrograms/l and four had maximum nocturnal peak below 10 micrograms/l. These data denoted defective spontaneous GH secretion in some of these patients. MRI studies revealed complete empty sella (n = 2), marked diminution of the pituitary size (n = 4), thinning of the pituitary stalk (n = 3) with its posterior displacement (n = 2), and evidence of iron deposition in the pituitary gland and midbrain (n = 7) in those patients with defective GH secretion (n = 9). Serum ferritin concentration was correlated significantly with the circulating IGF-I (r = -0.47, p < 0.01) and IGFBP3 (r = -0.43, p < 0.01) concentrations. These data prove a high prevalence of defective GH secretion in thalassaemic children associated with structural abnormality of their pituitary gland.

The sections in this article are: 1 Variations of Normal Growth 1.1 Normal Variations in Infancy 1.2 Constitutional Delay of Growth and Adolescence 1.3 Constitutional Accelerated Growth 1.4 Premature Adrenarche 1.5 Premature Thelarche 1.6 Gynecomastia 2 Abnormal Growth 2.1 Intrinsic Disorders of Growth Deficiency 2.2 Extrinsic Disorders of Growth Deficiency 2.3 Intrinsic Disorders of Increased Growth 2.4 Extrinsic Disorders of Increased Growth 3 Assessment of Growth 3.1 Growth Standards 3.2 Standards for Pubertal Development 3.3 Terminology 3.4 Measurement Techniques 3.5 Anthropometry 3.6 Body Composition Assessment 3.7 Assessment of Biological Maturity 3.8 Mathematical Modeling of Growth Data and Prediction of Adult Height 3.9 Methods for Assessment of Growth in Laboratory Animals 4 Assessment of the Regulation of Growth 4.1 General Considerations 4.2 Screening Procedures 4.3 Static Hormone Levels 4.4 Serial Growth Hormone Sampling 4.5 Stimulation Testing 4.6 Suppression Tests 5 Summary

Leptin, the product of the ob/ob gene in rodents, regulates energy balance and fertility. Two genetic models, the ob/ob mouse (deletion of leptin protein) and the db/db mouse (deletion of leptin receptor) have markedly augmented research in obesity. Human obesity is more closely linked to leptin resistance than to the absence of leptin. Serum leptin concentrations reflect the size of the subcutaneous fat depot better than total fat mass or abdominal visceral fat. At the initiation of puberty there is a divergence in circulating leptin concentrations between boys and girls. In boys, leptin concentrations increase and then markedly decrease to prepubertal concentration levels. In girls there are only increasing concentrations. The authors believe these patterns are relevant to the markedly different alterations in the regional distribution of body fat that occurs in boys and girls at puberty.

In adults, abdominal visceral adiposity is related to an increased risk of cardiovascular diseases, Type 2 diabetes mellitus, and stroke. The antecedents of these conditions likely begin with the alterations in body fat distribution during childhood and adolescence. The sexually dimorphic alterations in fat distribution are influenced by sex differences in hormone concentrations, anatomical differences in the number and density of specific hormone receptors, capillary blood flow, and the activity of enzymes promoting lipid synthesis or degradation. Hormones influencing the amount and regional distribution of adipose tissue during puberty include cortisol, insulin, growth hormone, and the sex steroids. Cortisol and insulin promote fat deposition while the sex steroids and GH stimulate lipolysis. An overly sensitive hypothalamic-pituitary-adrenal axis may exist in obesity and disrupt the balance between the lipogenic effects of cortisol and insulin and the lipolytic effects of sex steroids and growth hormone. Leptin is released from the adipocytes and may act as a metabolic signal to the hypothalamic areas controlling satiety, energy expenditure, and the regulation of cortisol, insulin, sex steroid and growth hormone release. The complex issues of the hormonal control of alterations in body fat distribution during puberty are developed and a working model is proposed. Am. J. Hum. Biol. 11:209-224, 1999. Copyright 1999 Wiley-Liss, Inc.

Purpose: To examine the effects of repeated bouts of exercise on the blood lactate [HLa]-ratings of perceived exertion (RPE) relation. Methods: Six moderately trained males were studied on two occasions: a sequential exercise bouts day (SEB: 1000 h, 1130 h, and 1300 h) and a delayed exercise bouts day (DEB: 1000 h. 1400 h, and 1800 h). Each of the three exercise bouts within a given condition were 30 min in duration at the power output (PO) associated with 70% of VO 2peak on a cycle ergometer. A standardized meal was provided at 0600 h. VO 2 , PO. HR. and RER were recorded every min during exercise and blood [HLa] and RPE were measured every 5 min during exercise. Results: A × 3 analysis of variance with repeated measures revealed that blood [HLa] decreased significantly with each repeated exercise bout (X± SEM: bout 1: SEB = 3.5 (0.3), DEB =3.8 (0.4); bout 2: SEB = 2.6 (0.3), DEB = 2.8 (0.3); bout 3: SEB = 2.0 (0.2), DEB = 2.1 (0.4); mM). No differences were observed in the blood [HLa] response to repeated bouts of exercise between SEB and DEB. RPE-peripheral (legs, RPE-L) was higher during bout 3 compared with bout 1 (P < 0.05) (bout 1: SEB = 11.8 (0.8), DEB = 12.3 (0.2): bout 2: SEB = 12.3 (0.5), DEB = 13.3 (0.4); bout 3: SEB = 13.5 (0.8), DEB = 14.0 (0.7)); RPE-central (chest and breathing, RPE-C) was not affected by repeated bouts of exercise, whereas RPE-Overall (RPE-O) was higher during bout 3 compared with bouts I and 2 (P< 0.05) (bout I: SEB = 12.5 (0.2), DEB = 12.3 (0.4); bout 2: SEB = 12.8 (0.4), DEB = 12.7 (0.4); bout 3: SEB = 13.7 (0.7), DEB = 13.2 (0.3)), No interaction for RPE × condition was observed. HR increased with repeated bouts of exercise with HR during exercise bout 3 being higher than HR during exercise bout 1 (164 vs. 156 bpm, P < 0.05). There was also a strong trend for HR during exercise bout 3 to be higher than HR during exercise bout 2 (P < 0.06). A trend for a reduction in VO 2 with repeated exercise was observed (P < 0.07). with the reduction apparently related to the SEB condition (P < 0.12 for VO 2 x condition). PO and kcal.min -1 were not affected by repeated bouts of exercise. RER decreased significantly with each repeated bout of exercise (from RER =0.96 to RER = 0.89, P < 0.05) with no difference observed between SEB and DEB. Conclusions: We conclude that the blood [HLa]-RPE relation is altered by repeated bouts of exercise and that this alteration does not appear to be affected by recovery time between exercise bouts (up to 3.5 h of recovery). These data suggest that, after the first exercise bout, RPE should not be used to produce a specific blood [HLa] on subsequent exercise bouts.

Monozygotic twin sisters are reported who have discordant pubertal growth and sexual development. Although both sisters were physiologically appropriate for chronological age in their pubertal development, their adolescent development was considerably different from that expected of monozygotic twin sisters. The more pubertally advanced sister by magnetic resonance imaging had an optic pathway glioma while none was present in her twin sister. Precocious puberty is not an unexpected complication of neurofibromatosis type 1 and is always associated with the presence of an optic pathway glioma. These sisters emphasize the striking similarity that is expected of monozygotic twins and the need for investigation when intertwin differences in growth and/or development arise.

We examined the relationships among gender, sexual maturation, four-compartment model estimates of body composition, body fat distribution (magnetic resonance imaging for abdominal visceral fat and anthropometrics), aerobic fitness, basal and total energy expenditure, and overnight GH release in an ultrasensitive chemiluminescence assay in healthy prepubertal and pubertal boys (n = 18 and 11, respectively) and girls (n = 12 and 18, respectively). Blood samples were withdrawn every 10 min from 1800–0600 h to determine the area under the serum GH-time curve (AUC), sum of the GH peak heights (Σ GH peak heights), and the mean nadir GH concentration. GH release was greater in the pubertal than prepubertal subjects due to an increase in Σ GH peak heights (43.8 ± 3.6 vs. 24.1 ± 3.5 ng·mL−1, P = 0.0002) and mean nadir (1.7 ± 0.2 vs. 0.7 ± 0.2 ng·mL−1, P = 0.0002), but not peak number (4.3 ± 0.2 vs. 4.5 ± 0.2). The girls had a greater Σ GH peak heights (39.0 ± 3.5 vs. 28.8 ± 3.6 ng·mL−1, P = 0.05) and mean nadir concentration (1.4 ± 0.2 vs. 0.9 ± 0.2 ng·mL−1, P = 0.05) than the boys. Significant inverse relationships existed between Σ GH peak heights (r = −0.35, P = 0.06) or mean nadir (r = −0.39, P = 0.04) and four-compartment percent body fat for all boys but not for all girls or when combining all subjects. For all girls, significant inverse relationships existed between Σ GH peak heights (r = −0.39, P = 0.03) or mean nadir (r = −0.37, P = 0.04) and waist/hip ratio. Similar inverse relationships in all boys or all subjects were not significant. Forward stepwise regression analysis determined that bone age (i.e. maturation, primary factor) and gender were the significant predictors of AUC, Σ GH peak heights, and mean nadir. The influence of maturation reflects rising sex steroid concentrations, and the gender differences appear to be because of differences in estradiol concentrations rather than to body composition or body fat distribution.

Roemmich, James N., Pamela A. Clark, Arthur Weltman, and Alan D. Rogol. Alterations in growth and body composition during puberty. I. Comparing multicompartment body composition models. J. Appl. Physiol. 83(3): 927–935, 1997.—A four-compartment (4C) model of body composition was used as a criterion to determine the accuracy of three-compartment (3C) and two-compartment (2C) models to estimate percent body fat (%BF) in prepubertal and pubertal boys (genital I & II, n = 17; genital III & IV, n = 7) and girls (breast I & II, n = 8; breast III & IV, n = 15). The 3C water-density (3C-H2O) and 3C mineral-density models, dual-energy X-ray absorptiometry, the Lohman age-adjusted equations, the Slaughter et al. skinfold equations, and the Houtkooper et al. and Boileau bioelectrical impedance equations were evaluated. Agreement with the 4C model increased with the number of compartments (i.e., body water, bone mineral) measured. Except for the 3C-H2O model, the limits of agreement were large and did not perform well for individuals. The mean %BF by dual-energy X-ray absorptiometry (23.6%) was greater than that of the criterion 4C method (21.7%). For the field methods, the Slaughter et al. skinfold equations performed better than did the Houtkooper et al. and Boileau bioimpedance equations. The hydration of the fat-free mass decreased (genital I & II = 75.7%, genital III & IV = 74.8%, breast I & II = 75.5%, breast III & IV = 74.4%) and the mineral content increased (genital I & II = 4.9%, genital III & IV = 5.0%, breast I & II = 5.1%, breast III & IV = 5.7%) with maturation. The density of the fat-free mass also increased (genital I & II = 1.084 g/ml, genital III & IV = 1.087 g/ml, breast I & II = 1.086 g/ml, breast III & IV = 1.091 g/ml) with maturation. All of the models reduced the %BF overprediction of the Siri 2C model, but only the 4C and 3C-H2O models should be used as criterion methods for body composition validation in children and adolescents.

The release of growth hormone (GH) is sensitive to many pharmacologic and physiologic stimuli, including exercise. Although the role of the increased amount of GH released during exercise is not fully understood, it most likely contributes to metabolic fuel adaptations during exercise, and tissue repair after the exercise session. The GH response to exercise is altered by many factors, including sex steroid concentrations, fitness level, and the intensity of previous exercise sessions. For both endurance and resistance exercise, greater activation of anaerobic glycolysis and lactate formation increases the amount of GH released. Whether an endurance exercise session or an endurance exercise training regimen influences the total amount of GH released during a 24-hour period is not clear; this may depend on the gender of the person, the intensity of the exercise, and the duration of exercise training. The influence of a single session of resistance exercise or resistance training on 24-hour GH secretion has not been studied. Preexercise diet modulation (especially modulation of fat intake) may also influence the release of GH during endurance exercise. Studies that measure the 12- to 24-hour GH response to resistance exercise after the ingestion of various macronutrient diets have not been completed.

The purpose of this study was to assess the effect of interferential current (IFC) on perceived pain and serum Cortisol levels in subjects with delayed onset muscle soreness (DOMS). DOMS was induced in 10 subjects through repeated eccentric contractions of the elbow flexors. Forty-eight hours later subjects were evaluated. Starting at t = 0:00, blood samples were withdrawn from a superficial vein every 5 min for 65 min. At t = 0:05, subjects received IFC of 10 bps or IFC of 100 bps. Perceived pain levels were evaluated prior to catheter insertion and at t = 0:35, 0:50, and 0:65. Two mixed-model analyses of variance revealed a significant decrease in perceived pain scores across time for both treatment groups but no significant difference in serum Cortisol for the two groups. It was concluded that IFC of high and low beat frequency is effective in controlling the pain of DOMS but does not elicit a generalized stress response as indexed by increasing serum Cortisol levels.

Leptin, the product of the ob gene, is an adipocyte-derived hormone that signals the amount of adipose tissue energy stores to the brain and exerts major effects on energy homeostasis and neuroendocrine function. Leptin has recently been shown to affect reproductive function in leptin-deficient and normal rodents. As puberty, the process of sexual maturation and acquisition of reproductive competence, has been proposed to be triggered by the attainment of a critical amount and/or distribution of fat, we examined whether changes in circulating leptin levels could represent the hormonal signal responsible for triggering the onset of puberty in humans. Eight prepubertal boys (Tanner genital stage 1 or early stage 2 at the initiation of the study) were evaluated longitudinally for 2.5-5.1 yr depending on when Tanner stage 5 of genital development was achieved. Sera for the determination of leptin, testosterone, and dehydroepiandrosterone sulfate were obtained every 4 months during the period of the study. Compared to baseline prepubertal levels (8 months before the onset of puberty, as defined by the initial rise in testosterone above the detection limit of the assay), leptin levels rose by approximately 50% just before the onset of puberty and decreased to approximately baseline values after the initiation of puberty (P < 0.01, by ANOVA), remaining stable for more than 2 yr. These changes occurred despite constantly increasing body mass index (P < 0.05, by ANOVA). No significant association between leptin and dehydroepiandrosterone sulfate concentrations was detected. In conclusion, the levels of circulating leptin are consistent with the hypothesis that this molecule is an important signal responsible for triggering the onset of puberty. The stimulus for a surge in leptin levels just before the onset of puberty is currently unknown.

To study the onset of the action of gonadal sex steroids on the GH axis in spontaneous puberty, which is prolonged and sparingly predictable, we present a clinical investigative paradigm in which six previously untreated boys with isolated hypogonadotropic hypogonadism were exposed to progressively higher testosterone levels designed to mimic the androgen environment recognized during the early stages of puberty. We administered three incremental doses of testosterone (25-, 50-, and 100-mg im injections), each over a period of 4 weeks. Studies of overnight pulsatile GH secretion and GH responses to GHRH alone or combined with l-arginine (a functional somatostatin antagonist) were performed before testosterone administration and after each dose of testosterone. Serum testosterone, but not estrogen, levels increased progressively in all subjects during therapy. Deconvolution analysis of GH release profiles disclosed that GH secretory burst mass was stimulated significantly even by 25 mg testosterone. This p...

This study compared the lipid profile of women runners with menstrual cycle irregularities with their normally menstruating counterparts. Relationships among selected steroid hormones and serum lipid levels in 10 eumenorrheic (EU) and 8 oligo-/amenorrheic (O/A) women runners and 6 eumenorrheic controls (CON) were examined. Serum 17 β-estradiol (E2), progesterone (Prog), and dehydroepiandrosterone-sulfate (DHEAS) concentrations were determined in daily blood samples for 21 days, and integrated concentrations were calculated. Fasting blood samples were analyzed far total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), HDL2, HDL3, triglycerides (Trig), and apolipoproteins A-I, A-II, and B. The O/A group had significantly lower E2 and Prog than EU or CON groups. Women in the CON group had lower HDL-C and HDL3 than the runners. With all women grouped together, E2 was not significantly correlated with any measured blood lipid parameters. On the other hand, DHEAS was significantly correlated with HDL-C, HDL2, and apolipoprotein A-I. These data demonstrate that women runners, regardless of menstrual cycle status, exhibit higher HDL-C concentrations than CON and supports previous research reporting a positive association between DHEAS and HDL-C. Key words: estradiol, DHEAS, cholesterol, exercise, amenorrhea

Chronic stress leads to suppression of the hypothalamic-pituitary-gonadal (HPG) axis with decreased plasma LH concentrations. This is believed to be due to the influence of elevated levels of endogenous CRH mediated via the endogenous opiate peptide receptor. Efforts to reproduce this phenomenon with exogenous CRH have produced varied results depending on the dose and route of administration of CRH as well as on the species, gonadal state, and endogenous opiate peptide system tone of the experimental subjects. In humans, conflicting results for CRH-induced suppression of the HPG axis exist for women, and the issue has not been addressed sufficiently in men. We, therefore, studied the effects of a 4-h infusion of ovine CRH (oCRH) on LH secretion in 11 healthy, nonobese young adult men (age range, 20–33 yr). Subjects were admitted to the General Clinical Research Center on 4 occasions in randomized order. They underwent blood sampling for LH at 10-min intervals from 1800–0600 h. From 2200–0200 h, subjects r...

To determine how accurately the Roche-Wainer-Thissen (RWT), Tanner-Whitehouse (TW2), and Bayley-Pinneau (BP) prediction models estimated adult height, serial height predictions were made for 23 healthy boys (mean initial age 10.4 ± 1.1 years) every 8 months from 8-15 years of age. The RWT model was tested using Greulich-Pyle (RWT-GP) and Fels (RWT-Fels) bone ages. Stature was measured every 4 months until near final height was attained (growth rate

Testosterone (T) drives normal male sexual development both in utero and at puberty. Aberrant T exposure manifests as virilization of a female fetus, contrasexual precocity in girls, and isosexual precocity in boys. Evidence of pathologic T exposure warrants a prompt evaluation.The authors introduce the topic of T exposure in children by reviewing its physiology in the fetus and during childhood and adolescence. Pathologic conditions leading to virilization of a female fetus as well as androgen-mediated gonadotropin-independent precocious puberty in both genders are then discussed. The authors finish by noting exogenous T exposure in children and adolescents, focusing specifically on secondary exposure to topical T preparations.Contrasexual precocity in a girl or sexual precocity in a boy should prompt evaluation for causes of gonadotropin-independent pubertal changes. Initial biochemical evaluation includes a bone age, T, 17-hydroxyprogesterone, androstenedione, dehydroepiandrosterone sulfate (DHEA-S) and high sensitivity gonadotropin levels. The provider must query exposure to topical androgen-containing preparations as unintentional secondary exposure to topical T must be considered. Hyperandrogenism is temporally related to exposure of topical T and removal of exposure results in a marked decrease in serum T as well as resolution or stabilization of the signs and symptoms.

Cross-sectional studies demonstrating that physiological GH secretion varies widely among normally and slowly growing children as well as adults have created uncertainty over the definition of normal GH secretion. Furthermore, recent data indicate that the pattern of GH released under identical physiological conditions may be unique for each individual, and suggest that normality may be an individually defined condition. To investigate and develop further this concept and to avoid the confounding effects of fluctuating gonadal steroid hormone levels, we chose as a model normally growing prepubertal boys and performed a longitudinal assessment of spontaneous GH release characteristics (36 24-h GH secretion studies in 9 boys over 9-19 months). Assessment of serum GH pulse characteristics was accomplished using the Cluster pulse detection algorithm. Characteristics of underlying pituitary GH secretory events were estimated by multiple parameter deconvolution analysis. Approximate entropy was used to quantify the serial regularity or orderliness of GH release over 24 h. Among the group data, mean 24-h GH concentrations spanned a range of more than 4-fold (1.6-7.0 micrograms/L). The intersubject coefficient of variation (CV) was 41%. In contrast, values from individuals exhibited much less variability, not only for mean 24-h GH level (CV = 25 +/- 4%; P =0.02), but also for all assessed component GH pulse properties (P0.01) vs. intersubject values). Similarly, the estimated daily GH production rate, the calculated GH half-lives, and all parameters of GH secretory events varied much less for intraindividual compared to interindividual values. The sizes of the serum GH pulses gave rise to the greatest differences in overall serum GH level among individuals, as demonstrated by the large within-subject CV (50%). The most constant pulse characteristic among subjects was that of 24-h GH pulse frequency (intersubject CV = 30%). Approximate entropy estimates disclosed high within-subject consistency (mean CV = 15%). Several aspects of GH secretion and serum concentrations varied inversely with the subject's mean age-adjusted body mass index, including the 24-h GH production rate (r = -0.67; P0.05), the GH secretory burst amplitude (r = -0.73; P = 0.026), the mean serum GH pulse amplitude (r = -0.79; P = 0.011), and the sum of the GH pulse amplitudes (r = -0.66; P = 0.05). By contrast, no consistent pattern of increase or decrease in serum GH concentrations with advancing age was detectable during the prepubertal period. These data suggest that during prepuberty, 1) individual boys regulate daily GH secretion within relatively confined limits characteristic for that individual, much narrower than the range present in the larger population; 2) differences in mean 24-h GH levels among normally growing prepubertal boys arise primarily from differences in GH pulse size; 3) differences in body composition, as indicated by the body mass index, may influence the GH secretion range characteristic of each individual; and 4) there is no consistent change in mean 24-h GH concentrations or the orderliness (approximate entropy) of the GH release process ever time during late prepuberty as the onset of puberty approaches.

The control of the onset of puberty involves the complex interaction of pituitary and gonadal hormones. At a preprogrammed time in a child’s life there is an increase in the amplitude of GnRH pulses which triggers a cascade of events including increases in the amplitude of FSH and LH pulses, followed by marked increases in gonadal sex steroidal output, which in turn increases growth hormone (GH) and insulin-like growth factor-1 (IGF-1) production. Evidence suggests that there is an integral interaction between the endogenous opiate system and the hypothalamic-pituitary-gonadal axis, at least in the later stages of puberty in the male. Both androgenic and estrogenic hormones markedly increase GH production rates as measured by deconvolution models in the prepubertal human, and compelling data strongly suggest that it is indeed the estrogen which controls the feedback amplification of GH production during puberty even in the male. It appears that the prepubertal gonad is actively producing sex hormones which might be important in the control of GH production since early childhood. The translation of these neuroendocrine rhythms into distal metabolic actions is also reviewed. Utilizing isotopic tracer infusions of the essential amino acid leucine, studies clearly show a selective stimulation of whole body protein synthesis by both GH and IGF-1. GH, IGF-1 and androgenic hormones all increase in puberty, stimulating whole body protein anabolism during that period. However, we observed no protein-anabolic effect in the hypogonadal female given increasing doses of estrogen. The latter suggests that at least as it pertains to whole body protein effects, the action of androgens is probably mediated via the androgen and not the estrogen receptor, in clear distinction from the estrogen-mediated effects of androgens on the neuroendocrine axis. Calcium absorption and retention are also positively affected by the androgens as shown by significant increases in calcium absorption and retention after the administration of testosterone to the prepubertal male. This suggests an important role of sex steroidal hormones in the mineralization of the skeleton. In conclusion: GH, IGF-1 and sex steroids all markedly increase during puberty and their actions are amplified mutually as they control growth, increase muscle mass and affect the mineralization of the skeleton. The dichotomy of androgen and estrogen effects in the male and female may regulate the differential timing of the onset of puberty and final height in the two sexes. The synergistic actions of these anabolic hormones appear to be most significant during the finite years of puberty.

To compare neurocognition and quality-of-life (QoL) in a group of children and adolescents with or without growth hormone deficiency (GHD) following moderate-to-severe traumatic brain injury (TBI).Thirty-two children and adolescents were recruited from the TBI clinic at a children's hospital. Growth hormone (GH) was measured by both spontaneous overnight testing and following arginine/glucagon stimulation administration. Twenty-nine subjects participated in extensive neuropsychological assessment.GHD as measured on overnight testing was significantly associated with a variety of neurocognitive and QoL measures. Specifically, subjects with GHD had significantly (p 0.05) lower scores on measures of visual memory and health-related quality-of-life. These scores were not explained by severity of injury or IQ (p 0.05). GHD noted in response to provocative testing was not associated with any neurocognitive or QoL measures.GHD following TBI is common in children and adolescents. Deficits in neurocognition and QoL impact recovery after TBI. It is important to assess potential neurocognitive and QoL changes that may occur as a result of GHD. It is also important to consider the potential added benefit of overnight GH testing as compared to stimulation testing in predicting changes in neurocognition or QoL.

Success in sports is often defined by winning, which drives athletes to use performance-enhancing drugs to gain an advantage over opponents. The use of doping agents in sports has a long history, especially over the last years, secondary to scandals and controversy. Athletes and the general public are now more aware and educated about this issue. The World Anti-Doping Agency’s (WADA) mission is to lead a collaborative worldwide campaign for doping-free sport. A list of doping substances and methods banned in sports is published yearly by WADA (http://www.wada-ama.org). A substance or method might be included in the list if it fulfills at least two of the following criteria: enhances sports performance, represents a risk to the athlete’s health, or violates the spirit of sports.

Growth and puberty are important aspects of adolescent development and serve as indicators of general health. Assessment of the stage of sexual maturity pinpoints where an adolescent is along the continuum of maturation. The hormonal control of puberty begins with an increase in gonadotropin-releasing hormone pulsatility, which stimulates secretion of gonadotropins and sex hormones, culminating in the establishment of the menstrual cycle in girls and adult maturation in boys. Disorders of pubertal development include delays and sexual precocity. Delayed puberty is common and most often is benign. However, it must be distinguished from disorders of the testes or ovaries and defects in hypothalamic or pituitary function such as hyperprolactinemia and the female athlete triad. Precocious puberty is more common in girls. Although it is often idiopathic, the presence of serious medical conditions, such as tumors of the central nervous system, must be excluded.

Proper groupings of children for physical activity and sport is important for injury prevention and competition. Several of the classification systems presently used are reviewed, as are the physiologic underpinnings of pubertal growth and development as they relate to the accrual of strength and power. It is during adolesence that the greatest physiologic differences exist, mainly because of the wide variations in the timing and tempo of the pubertal growth spurt in normally growing boys and girls. Maturity-based categorization, especially in contact and collision sports, would heighten the competition and may lessen rates of injury.

Congenital lipoid adrenal hyperplasia is an autosomal recessive disorder that is characterized by impaired synthesis of all adrenal and gonadal steroid hormones. In three unrelated individuals with this disorder, steroidogenic acute regulatory protein, which enhances the mitochondrial conversion of cholesterol into pregnenolone, was mutated and nonfunctional, providing genetic evidence that this protein is indispensable normal adrenal and gonadal steroidogenesis.

Purpose To assess the safety and clinical outcomes of 6-month treatment with testosterone gel 1% therapy in adolescent boys with primary hypogonadism resulting from Klinefelter syndrome (KS) or anorchia. Methods This was a subgroup analysis of a multicenter, open-label study of adolescent boys (N = 86) with delayed puberty who received .5–5.0 g testosterone gel 1% daily for ≤6 months. Adolescent boys 12–17 years of age with KS (n = 21) or anorchia (n = 8), bone age ≥10.5 years, and baseline growth data ≥6 months were included in this analysis. Serum hormone levels (total/free testosterone, luteinizing hormone, dihydrotestosterone, follicle-stimulating hormone, and estradiol) were measured using validated assays. Safety was assessed through adverse events (AEs). Results At baseline, patients with KS were taller, weighed more, and had higher total testosterone levels (mean 174 vs. 19 ng/dL) than patients with anorchia. At 6 months, total and free testosterone and dihydrotestosterone levels increased 1.8- to 2.3-fold in the KS group and eight- to 10-fold in anorchia patients. Estradiol levels increased 1.9-fold in the anorchia group and 1.4-fold in the KS group after treatment. No clinically significant changes were noted for luteinizing hormone, follicle-stimulating hormone, and sex hormone–binding globulin concentrations in either group. Cough was the most common AE (eight of 29), followed by acne and headache (both four of 29). One anorchia and two KS patients discontinued prematurely. Conclusions Once-daily testosterone gel application increased serum testosterone levels into the pubertal range and maintained pubertal testosterone levels during 6-month treatment. In this study, testosterone gel 1% raised testosterone levels and was associated with cough as the most common AE.

Purpose of review To provide up-to-date information on outcomes and adverse events associated with the use of recombinant human growth hormone (rhGH). We will focus on patients with Prader Willi Syndrome and Idiopathic Short Stature. We will also discuss recent reports on long-term adverse events from the European database. Recent findings Prader Willi Syndrome is associated with hypogonadism, which does not appear to be affected by treatment with rhGH. However, there is new evidence that treatment may improve cognition. For patients with Idiopathic Short Stature, the gain in near adult height with treatment with rhGH appears to be 3-4 cm. Although a recent analysis of this group shows that certain patient characteristics may help identify those most likely to have a good response to treatment. Additionally, the safety and appropriateness of growth hormone treatments in Europe study released preliminary data from patients treated in two separate locations that showed conflicting information on risk of mortality from treatment with rhGH. Summary Although we will continue to receive new information regarding the safety and effects of treatment with rhGH, it is important to discuss the risks and benefits with our patients. Additionally, it is incumbent on us to help guide the treatment to those most likely to benefit.

Complex mechanisms exist in the human to defend against adverse effects of negative energy balance. These include alterations of hormone secretion affecting the growth hormone/insulin-like growth factor system, the adrenal axis, and the reproductive system, particularly in females. Energy deficits are least partially offset by neuroendocrine mechanisms regulating appetite and satiety. The complex feedback mechanisms reporting peripheral fat and energy stores to the central nervous system involve secretion of the peptide hormones leptin and ghrelin, which act centrally on neurons in the arcuate nucleus and anteroventral periventricular area. In addition to appetite regulation, these hormones exert influences on spatially and functionally-related mechanisms regulating reproductive function, such as the kisspeptin-gonadotropin releasing hormone system. Negative energy balance often occurs partially as a result of strenuous and repetitive physical exercise. Exercise stress leads to increased cortisol secretion, but this action is mediated through the induced negative energy balance. In healthy adults with energy deficits, this exercise-induced stress appears to be more important than pure psychological stress in impairing reproductive function. Estrogen deficiency resulting from negative energy balance has important adverse effects on bone density as well as bone microarchitecture, and it may also adversely affect markers of cardiovascular disease.

Growth and pubertal maturation of youth athletes are overwhelmingly within the broad range of normal variability. These include many successful male athletes who mature earlier than average, and many successful female athletes, especially in the "aesthetic" sports (artistic gymnastics, ice-skating, ballet) and distance running, who mature later than average. Artistic gymnasts generally receive the most attention, but their growth and maturation characteristics fall largely within the physiologic range and are indistinguishable from short, late maturing girls. It is difficult to ascribe causality to intensive training for sport as a factor in the later pubertal maturation of heavily training athletes. The alterations in hypothalamic-pituitary function for the GH/IGF-I and gonadal axes are likely appropriate for the stage of adolescent maturation. The selection and sorting processes for elite sport, including ballet, need critical evaluation. If intensive training is a factor affecting growth and pubertal maturation, its effects must be partitioned from (a) other factors known to influence these biological processes, and (b) other components of the overall sport training environment before causality can be established. Other factors which play an indeterminate role include: genetics/epigenetics, stress, psychosocial interactions, family environment and caloric intake, among others. These factors together with the energy expenditure of intensive training may influence the growth and pubertal maturation of some adolescent athletes. The effect is not necessarily attributable to training per se; rather, it is likely embedded in the elite sport training environment which is essentially an adult dominated enterprise.

Growth hormone (GH) therapy has evolved rapidly since the introduction of recombinant human GH (rhGH). The increase in the availability and safety of GH therapy has also increased the number of US Food and Drug Administration (FDA) indications for use in both children and adults. FDA indications in children include GH deficiency (GHD), Turner syndrome, idiopathic short stature, small for gestational age with failure to attain normal growth percentiles, Prader-Willi syndrome (PWS), chronic renal insufficiency, Noonan syndrome, and short stature due to short stature homeobox gene haploinsufficiency. Children and adolescents with GHD have demonstrated the greatest response to GHD therapy. The primary objective of rhGH therapy in children is to increase height velocity; however, the therapy also has benefits related to improved body composition, especially in children with conditions like PWS. Treatment of adult GHD primarily targets improvements in body composition, quality of life, and surrogate markers for cardiovascular disease. The safety reports of rhGH in children are generally good, but there have been a small number of cases of raised intracranial pressure, scoliosis, and muscle and joint discomfort. In adults, many side effects can be managed with dose titration at the initiation of treatment and dose reduction if side effects occur.

SummaryObjective Weight-based GH dosing is the standard for treating children with short stature. The current study validates the usefulness of IGF-based GH dosing for GH therapy in nonGH-deficient (nonGHD) children and its relationship with pretreatment serum IGF-I concentration. Design and Patients In this twelve-month, open-label, randomized controlled study, 151 nonGHD (based on GH-stimulation tests), prepubertal children with short stature and IGF-I levels ≤ 33rd percentile [–0·44 standard deviation score (SDS)] were randomly assigned to receive GH (dose based on IGF-I titration algorithm; n = 114) or to observation (n = 37). GH dose (initially 40 μg/kg/d) was adjusted every 3 months to achieve an IGF-I SDS in the upper normal range (66–99th percentile). Measurements and Results In treated children, mean height SDS (HSDS) increased from −2·5 at baseline to −1·7 at 12 months and mean IGF-I SDS increased from −1·7 to 0·1. These parameters remained unchanged in untreated children. There was no relationship between change in HSDS (ΔHSDS) and degree of IGF-I deficiency at baseline. No safety problems were observed. Both groups had a similar advance in bone age. At the end of study, ΔHSDS in treated children showed a positive correlation with IGF-I SDS, but not with GH dose [mean 59 μg/kg/d (range 29–92)], basal IGF-I SDS or 1-month IGF parameters. Conclusions In nonGHD subjects with short stature and serum IGF-I concentrations within and below the lower third of normal, adjusting GH dose to achieve an IGF-I level in the upper normal range resulted in a significant increase in HSDS, regardless of basal IGF-I levels.

Diabetes mellitus complicated by mixed diabetic ketoacidosis and hyperglycemic hyperosmolar syndrome presents a special challenge to physicians. There is no standard protocol for the management of mixed hyperglycemic hyperosmolar syndrome and diabetic ketoacidosis in children. The commonest cause of neurological deterioration during an episode of diabetic ketoacidosis is cerebral edema, whereas hyperosmolality often leads to thrombosis. The risks for these complications are further increased in diseases associated with vasculopathies. We present the first case of complex cerebral arteriovenous thrombosis leading to stroke in a child with Adams-Oliver syndrome, a genetic condition that is associated with abnormal vasculogenesis. He presented with new-onset double diabetes complicated by a combination of diabetic ketoacidosis and hyperglycemic hyperosmolar syndrome. Magnetic resonance imaging, magnetic resonance angiography, and magnetic resonance venography provided evidence for an ischemic stroke. Children and adolescents who present with a combination of hyperglycemic hyperosmolar syndrome and diabetic ketoacidosis should be monitored for neurologic deficits and must be investigated for both stroke and cerebral edema in the event of neurological deterioration.

The adolescent growth spurt is associated with a sex steroid hormone-dependent rise in GH production; both androgens and estrogens are implicated as positive regulators of the somatotropic axis during puberty. The issue is complicated by the fact that testosterone may act both directly via the androgen receptor and indirectly, after its aromatization to 17beta-estradiol, through the estrogen receptor. Recently, a number of investigators have studied the effects of the administration of androgen and estrogen receptor antagonists, as well as nonaromatizable androgens, on GH secretion. These reports suggest that estrogen receptor-dependent processes play a facilitatory role in the pubertyassociated rise in GH secretion. If androgen receptor-mediated events are involved in the control of the somatotropic axis, their role is likely inhibitory. A hypothalamic site of action of the sex steroids is postulated.

Puberty is characterized by the onset and continued development of secondary sexual characteristics and an abrupt onset of linear growth. Growth in boys occurs due to the rising levels of androgens and also indirectly mediated by growth hormone (GH) and the insulin-like growth factors. Data are presented to show marked androgen-dependence of GH increases at puberty. The mode of this increase is through an augmentation in the amplitude of the pulses rather than in their frequency. Shortly after the maximal rate of growth, the pattern of GH release reverts toward that of the prepubertal child. To investigate the neuroendocrine mechanism through which androgens increase the mean circulating GH level, deconvolutional analysis has been applied. At mid-puberty the maximal rate of GH release per secretory burst and the total amount released per burst were increased. There were no significant alterations in the duration or frequency of the GH secretory burst or in the serum half-life reflecting the metabolic clearance of the hormone. Thus, the pubertal growth spurt in boys is likely subserved by the altered neurosecretory dynamics for GH. These altered hormone levels likely produce the equally profound changes in body composition, regional fat distribution, and muscular strength that occur during puberty in boys.