Jo Anne Brasel

Six-year results of a randomized, prospective trial of human growth hormone and oxandrolone in Turner syndrome

Seventy girls with Turner syndrome, verified by karyotype, were randomly assigned to observation or treatment with human growth hormone (hGH), oxandrolone, or a combination of hGH plus oxandrolone for a period of 12 to 24 months, to assess the effect of treatment on growth velocity and adult height. Subsequently, all subjects received either hGH alone or hGH plus oxandrolone. Data are presented for 62 subjects treated for a period of 3 to 6 years. When compared with the anticipated growth rate in untreated patients, the growth rate after treatment with hGH, both alone and in combination with oxandrolone, showed a sustained increase for at least 6 years. Treatment is continuing in over half of the subjects; at present, 14 (82%) of 17 girls receiving hGH alone and 41 (91%) of 45 girls receiving combination therapy exceeded their expected adult heights. Thirty girls have completed treatment; mean height for these 30 patients is 151.9 cm, compared with their mean original projected adult height of 143.8 cm. We conclude that therapy with hGH, alone and in combination with oxandrolone, can result in a sustained increase in growth rate and a significant increase in adult height for most prepubertal girls with Turner syndrome.

Increased physical activity and the growth hormone-IGF-I axis in adolescent males.

Insulin-like growth factor-I (IGF-I) is associated with muscle hypertrophy, and circulating IGF-I levels are correlated with fitness. To test the hypothesis that IGF-I increases with increased physical activity in adolescent males, 38 subjects (16 +/- 0.7 yr old) were randomized to control (n = 18) or increased physical activity groups for 5 wk. Before and after the intervention, we measured thigh muscle volume using magnetic resonance imaging and serum levels of mean growth hormone (GH) by overnight multiple sampling, GH binding protein (GHBP), IGF-I, and IGFBPs 1-5 by standard assays. Energy expenditure was assessed with the doubly labeled water technique toward the end of the study. In the training subjects there was 1) a significant increase in thigh muscle volume (+3.6 +/- 1%), 2) 15.5 +/- 3.3% greater energy expenditure than in controls, and 3) no evidence of weight loss (+1.44 +/- 0.4%). In contrast to our hypothesis, but similar to our recent observations in adolescent females, training decreased IGF-I (-12 +/- 4%, P < 0. 005). Moreover, training substantially reduced GHBP (-21 +/- 4%, P < 0.00002) and increased IGFBP-2 (+40 +/- 16%, P < 0.008). Brief training increased muscle volume in weight-stable adolescent males and, surprisingly, influenced not only IGF-I but GHBP and IGFBP-2 as well in a manner typically found in energy-deficient states.

Three-year results of a randomized prospective trial of methionyl human growth hormone and oxandrolone in Turner syndrome

Seventy girls with Turner syndrome, 4 to 12 years of age, participated in a prospective, randomized study to determine the effects on growth of methionyl human growth hormone (met-hGH) or oxandrolone. Subjects were randomly assigned to receive either no treatment (control) or met-hGH (0.125 mg/kg three times per week), oxandrolone (0.125 mg/kg/day), or combination met-hGH plus oxandrolone. At the end of an initial period of 12 to 20 months, patients in the original control and oxandrolone groups were given combination met-hGH plus oxandrolone. At that time the dosage of oxandrolone was lowered to 0.0625 mg/kg/day. Sixty-five subjects have now completed the first 3 years of the study. Compared with the control growth rate for year 1 (3.8 cm/yr), significant increases in growth rate were seen in all 3 years of combination therapy (9.8, 7.4, and 6.1 cm/yr, respectively) and in the first 2 years of treatment with met-hGH alone (6.6, 5.4, and 4.6 cm/yr). When growth velocity was expressed as standard deviation for age in girls with Turner syndrome, significant increases relative to the control group for year 1 (-0.1 SD) were seen in all three years of both combination therapy and met-hGH alone (combination, +6.6, +4.3, +3.0 SD; met-hGH, +3.1, +2.0, +1.4 SD). After 3 years of treatment, predicted adult height by the method of Bayley-Pinneau increased 4.5 cm in the met-hGH group and 8.2 cm in the combination group.

Anogenital ratio: Measure of fetal virilization in premature and full-term newborn infants

To provide normative data, we measured anogenital distances in 115 infants of 25 to 42 weeks gestational age and 10 pregnant women, including anus to fourchette (AF), anus to base of the clitoris (AC), and fourchette to base of the clitoris (FC). All infant measurements showed positive and significant correlations with body surface area, weight, length, and gestational age (P less than 0.001). However, the anogenital ratio (AF/AC) followed a normal distribution and did not correlate with any of the anthropometric variables or age. Mean (+/- SD) value in infants was 0.37 +/- 0.07, and in adults, 0.36 +/- 0.07. An anogenital ratio greater than 0.50 falls outside the 95% confidence limits, suggests labioscrotal fusion, and indicates a need for further evaluation. Because it is independent of body size and gestational age, the anogenital ratio should be useful in diagnosing androgen-induced labioscrotal fusion in both premature and full-term female infants.

Methionyl human growth hormone and oxandrolone in Turner syndrome: Preliminary results of a prospective randomized trial

Seventy girls with Turner syndrome, 4 to 12 years of age, were randomly assigned to receive either no treatment (control) or methionyl human growth hormone (0.125 mg/kg three times per week), oxandrolone (0.125 mg/kg/day), or combination hGH plus oxandrolone therapy. Baseline growth rates averaged 4.3 cm/yr, and all were within 2 SD of mean growth velocity for age in girls with Turner syndrome. Sixty-seven girls remained in the study for a minimum of 1 year. Growth rates and growth velocity (in standard deviations for age in girls with Turner syndrome) were control 3.8 cm/yr (-0.1 SD), hGH 6.6 cm/yr (+2.3 SD), oxandrolone 7.9 cm/yr (+3.7 SD), and combination therapy 9.8 cm/yr (+5.4 SD). Mean bone ages advanced 1.0 years (hGH), 1.3 years (oxandrolone), and 1.6 years (combination). However, median increments in height age/bone age (delta HA/delta BA) ratios ranged from 1.0 to 1.1 for treatment groups, compared with 0.8 for the controls. Predicted adult height by the method of Bayley-Pinneau increased 2.5 cm for hGH or oxandrolone alone, and 3.2 cm for combination treatment. These data indicate that both hGH and oxandrolone can significantly stimulate short-term skeletal growth in patients with Turner syndrome, and potentially increase final adult height.

Increase in muscle IGF-I protein but not IGF-I mRNA after 5 days of endurance training in young rats

Five days of treadmill training in rats leads to increased muscle size and running time. This was used to examine the effect of exercise on circulating insulin-like growth factor I [IGF-I; radioimmunoassay (RIA)], local muscle (hindlimb) IGF-I (by RIA), and muscle IGF-I mRNA (by ribonuclease protection assay). Eight-week-old female Sprague-Dawley rats were divided into three groups: control ( n = 10); single-exercise test ( n = 10), untrained but with one maximal exercise test at the end of the study; and training ( n = 16), trained for 5 days and one maximal exercise test on day 6. There were no differences among the groups with respect to circulating IGF-I. Muscle IGF-I protein in trained rats (4.2 ± 1.5 ng/g of muscle tissue) was significantly greater than both control (0.27 ± 0.1 ng/g) and single-exercise test (0.62 ± 0.19 ng/g, P < 0.05 by analysis of variance). There was no difference among the groups in IGF-I mRNA gene expression. These data suggest that there is an early, marked, local muscle increase in IGF-I protein in response to exercise. This increase, however, may not be related to increased muscle IGF-I gene expression. Moreover, the IGF-I response was probably local in nature since it was not matched by any increase in circulating IGF-I.

Effect of exercise training on energy expenditure, muscle volume, and maximal oxygen uptake in female adolescents

OBJECTIVES American female adolescents are at high risk of a physically inactive lifestyle that likely leads to health problems later in life. We hypothesized that a brief program of endurance exercise training in female adolescents would result in increased energy expenditure and quantifiable structural and functional adaptations. STUDY DESIGN Forty-four high school girls (aged 15 to 17 years, none were elite athletes) enrolled in a 5-day per week anatomy class for 5 weeks and were randomly assigned to control (n = 22) and training groups. All subjects participated in a 2-hour daily teaching program. During the remaining time (2 hours), the training group members underwent endurance-type training and control group subjects participated in a computer workshop. The intervention was assessed by (1) comparison of total energy expenditure between groups with the doubly labeled water technique, (2) determination of changes in thigh muscle volume by magnetic resonance imaging, and (3) determination of changes in maximal oxygen uptake by use of respiratory gas exchange responses. RESULTS Total energy expenditure was significantly greater (15.3%) in the training group compared with the control subjects (p < 0.003). Five weeks of training led to a 4.3% +/- 1% increase in thigh muscle volume (p < 0.0002) and a 12.1% +/- 3.7% increase in maximal oxygen uptake (p < 0.004); there were no changes in the control group. The training effect was most pronounced in the least fit subjects. CONCLUSIONS Exercise training programs for female adolescents can be successfully integrated into a high school summer curriculum. Quantifiable, substantial structural and functional responses occur with relatively short periods of training. Approximately 60% of the training response was related to factors independent of muscle size per se. These data may serve to better design physical activity programs for female adolescents.

Training, muscle volume, and energy expenditure in nonobese American girls

Little is known about the relationship among training, energy expenditure, muscle volume, and fitness in prepubertal girls. Because physical activity is high in prepubertal children, we hypothesized that there would be no effect of training. Forty pre- and early pubertal (mean age 9.1 +/- 0.1 yr) nonobese girls enrolled in a 5 day/wk summer school program for 5 wk and were randomized to control (n = 20) or training groups (n = 20; 1.5 h/day, endurance-type exercise). Total energy expenditure (TEE) was measured using doubly labeled water, thigh muscle volume using magnetic resonance imaging, and peak O(2) uptake (VO(2 peak)) using cycle ergometry. TEE was significantly greater (17%, P < 0.02) in the training girls. Training increased thigh muscle volume (+4.3 +/- 0.9%, P < 0.005) and VO(2 peak) (+9.5 +/- 6%, P < 0.05), effects surprisingly similar to those observed in adolescent girls using the same protocol (Eliakim A, Barstow TJ, Brasel JA, Ajie H, Lee W-NP, Renslo R, Berman N, and Cooper DM, J Pediatr 129: 537-543, 1996). We further compared these two sample populations: thigh muscle volume per weight was much lower in adolescent compared with prepubertal girls (17.0 +/- 0.3 vs. 27.8 +/- 0.6 ml/kg body mass; P < 0.001), and allometric analysis revealed remarkably low scaling factors relating muscle volume (0.34 +/- 0.05, P < 0.0001), TEE (0.24 +/- 0. 06, P < 0.0004), and VO(2 peak) (0.28 +/- 0.07, P < 0.0001) to body mass in all subjects. Muscle and cardiorespiratory functions were quite responsive to brief training in prepubertal girls. Moreover, a retrospective, cross-sectional analysis suggests that increases in muscle mass and VO(2 peak) may be depressed in nonobese American girls as they mature.

Peak oxygen uptake, muscle volume, and the growth hormone-insulin-like growth factor-I axis in adolescent males

PURPOSE The growth effects of exercise appear to be mediated in part by central neuroendocrine control reflected in circulating levels of growth hormone (GH), insulin-like growth factor-I (IGF-I), and their binding proteins (BP). In previous studies positive correlations between peak VO2 and circulating IGF-I have been demonstrated. The relationship between peak oxygen uptake and these potential regulating factors has not been examined in adolescent males where patterns of GH pulsatility and levels of IGF-I are rapidly changing. METHODS Forty-three healthy adolescent males (age 16 +/- 0.7 yr, 70% at Tanner V) performed cycle ergometry to determine p oxygen uptake (peak VO2), and magnetic resonance images to determine the thigh muscle volume. Baseline blood samples were collected for GHBP, the extracellular portion of the GH tissue receptor (by ligand mediated immunofunctional assay), IGF-I (by RIA), and IGFBPs 1-5 (by RIA). Mean GH was determined from samples obtained every 20 min overnight. RESULTS Peak VO2/kg was positively correlated with mean overnight GH levels (r = 0.41, P < 0.005). Both peak VO2/kg and thigh muscle volume/kg were negatively correlated with GHBP (r = -0.33, P < 0.02) and IGFBP-4 (r = -0.52, P < 0.005). There were no correlations between peak VO2/kg and IGF-I or IGFBPs 1-3, and 5. CONCLUSIONS GH pulsatility is increased adolescent males who have higher peak VO2, but this did not translate into increases in IGF-I. We speculate that in the fitter males, lower GHBP levels may reduce hepatic sensitivity to GH. Thus, circulating IGF-I was unchanged despite higher mean GH in subjects with higher peak VO2. IGFBP-4 which is known to inhibit IGF-I was negatively correlated with peak VO2 leading, possibly, to increased IGF-I bioactivity. Fitness (as assessed by muscle mass and peak VO2) does modulate the GH-IGF-I axis, but not solely through circulating IGF-I; both GHBP and IGFBPs play important roles.

The source of urinary epidermal growth factor in humans.

SummaryTo clarify the source of human urine EGF, we studied EGF renal clearance in 20 healthy, young adult subjects. Immunoreactive EGF was measured hourly in EDTA plasma, heparin plasma, serum and urine of 12 males and 8 females during a 3 h study period. Plasma and urine creatinine and creatinine clearance were measured and calculated hourly. Mean (and SEM) creatinine clearance was similar in males and females (118±12 vs 105±6 ml/min). EGF was not detectable in plasma, whereas relatively high levels were measured in serum (2.5±0.25 vs 1.5±0.18 ng/ml in males and females respectivelyp<0.05). Urine EGF excretion averaged 1641±233 ng/h in males and 1507±191 ng/h in females (p>0.05). A significant correlation was observed between urine creatinine and urine EGF concentrations in both male (r = 0.98,p<0.01) and female (r=0.94,p< 0.01) subjects. EGF immunoreactivity in urine and serum eluted from G-75 sephadex columns similarly to recombinant 6000 Mr hEGF. Urine excretion of EGF approximated 1.5 μg/h or 25 ng/mg creatine. The high concentrations of EGF found in urine in the face of non-detectable levels of EGF in plasma favor the hypothesis that EGF in urine is derived from kidney synthesis and secretion. The significant positive correlation between urine creatinine and urine EGF suggests a functional correlation between glomerular filtration and the process of tubular EGF excretion.