Wayne V. Moore

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.

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.

Ambulatory Blood Pressure in Type I Diabetes Mellitus: Comparison to Presence of Incipient Nephropathy in Adolescents and Young Adults

AMBP measurements were obtained at 20-min intervals during the day and at 60-min intervals during the night in 38 adolescents and young adults (12–25 yr old) with type I diabetes, and in 36 healthy, nondiabetic control subjects of comparable age. The group of patients with elevated AER (>15 μg/min) had higher mean 24-h sBP, dBP, and BPB (defined as the prevalence of systolic readings >130 mm Hg or diastolic readings >85 mm Hg) compared with both the group of patients with type I diabetes and AER<15, and the control group. The normal diurnal variation in BP and BPB was observed in the control group and the group with type I diabetes and AER<15, whereas the nocturnal decrease observed in the group with type I diabetes and AER>15 was not statistically significant. Elevations in AMBP of the patient group with AER>15 were reflected in random BP measurements. Even though the mean random BP measurements of all groups were within the normal range for age, the mean random sBP and dBP of the type I diabetes patients with AER>15 was higher than both the control group and the group with type I diabetes and AER<15. The GFR, determined by the clearance of 99Tc-DTPA, was associated negatively with measures of AMBP and AER in the group with AER>15. The mean 24-h sAMBP, dAMBP, and BPB of the type I diabetes patients with AER<15 were elevated compared with the control group. The mean random sBP of the type I patients with AER<15 was not significantly different from the control group, whereas the mean random dBP of this group was significantly greater than the control group. Significant overlap in the BPs and BPBs occurred among the groups, but the mean 24-h sBP and BPBs were above the 90th percentile for control subjects in most type I diabetes patients with AER<15 and in ∼50% of type I diabetes patients with AER<15. The three groups separated across the age range (12–25 yr old) for the different measures of AMBP. We conclude that AMBP measurement is useful in detecting abnormalities in BP that are not apparent in random BP measurement in patients with onset of type I diabetes before puberty and no evidence of early diabetic nephropathy. These findings may be important in identifying individuals who either are susceptible to the development of diabetic nephropathy or have early renovascular dysfunction not apparent in AER>15. AMBP measurement may be useful in monitoring interventions designed to prevent or delay the development of diabetic nephropathy.

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.

Growth hormone secretory profiles: Variation on consecutive nights*

To evaluate the reproducibility of overnight growth hormone (GH) testing and the effect of daytime administration of levodopa and clonidine on overnight GH secretion, we examined consecutive 12-hour overnight GH profiles of 48 short subjects, ages 5 to 16 years, who had GH stimulation testing with levodopa and clonidine. In six subjects (12%) the overnight pool GH concentration on the second night increased by greater than 100% from the first-night result (night-to-night changes of +1.2 to +5.2 ng/ml). In the remaining subjects, night-to-night changes in pool GH concentrations ranged from -1.2 to +1.8 ng/ml (-60% to +88% changes from the first night value). Night-to-night changes were less than 25% of the first-night value in 17 subjects (35%), 25% to 50% in 18 subjects (38%), and 50% to 100% in 7 subjects (15%). Night-to-night changes in pool GH concentrations correlated with differences in peak nighttime GH concentrations but not with differences in duration of observed sleep. There was no discernible effect of daytime levodopa-clonidine administration on overnight pool GH concentrations. These results demonstrate the potential for night-to-night variation in overnight GH profiles and suggest the need for some means of confirming that overnight GH testing reflects normal physiologic GH secretion. Without such confirmation, the results from a single overnight GH profile should be interpreted with caution.

Short-term treatment of short stature and subnormal growth rate with human growth hormone

Forty-eight children with short stature, growth rate less than 4 cm/yr, and normal growth hormone response to secretagogues were given exogenous human growth hormone (hGH) for 6 months to determine its effect on the short-term growth rate in these children. All except three had an increase in growth rate with hGH therapy. The mean +/- SD pretreatment growth rate (3.4 +/- 0.8 cm/yr) was significantly less than either the growth rate during 6 months of hGH therapy (6.9 +/- 2.6 cm/yr) or after therapy (4.1 +/- 1.8 cm/yr). Several patterns of response were observed after treatment was stopped: the mean growth rate in 22 children decreased after treatment but remained above basal rates, the mean growth rate in seven children was similar to the rates during treatment, and the mean growth rate in 16 children was less than basal rates. Twenty children received therapy for an additional 6 months and had a mean increase in growth rate from 3.6 +/- 1.3 to 6.7 +/- 2.4 cm/yr. The decreased growth rate after discontinuation of treatment and increased rate with resumption of therapy indicates that maintenance of the increased growth rate might be dependent on continuation of hGH therapy.

Clinical diagnoses of children with extremely short stature and their response to growth hormone

This study was undertaken to determine the prevalence of clinical diagnoses in a group of children with extremely short stature (standard deviation score for height, < -2.5) and to determine whether the classification might help in predicting response to human growth hormone (hGH) treatment. We classified 49 children referred consecutively to our outpatient clinic for evaluation of short stature with heights < -2.5 standard deviation score and bone ages < 9 years for girls or < 10 years for boys (to avoid an effect of puberty on the response to hGH). The diagnostic categories were growth hormone (GH) deficiency, constitutional delay, familial short stature, and primordial short stature. After referral, Turner syndrome was diagnosed in two children. The remaining 47 children were classified according to primary criteria, considered essential for the diagnosis, and secondary criteria, considered necessary but of lesser importance. There were five children, four children, no children, and one child classified, respectively, with GH deficiency, constitutional delay, familial short stature, and primordial short stature by using the most rigorous definitions of the diagnoses. There was significant overlap in the diagnoses other than GH deficiency. Growth hormone deficiency defined by the primary criterion of peak stimulated GH values < 5 micrograms/L was the most definitive. Of the 47 children, 7 were classified as GH deficient by this criterion and 5 were classified as GH deficient by the primary and secondary criteria. The mean pretreatment growth rate (3.1 +/- 1.9 cm/yr) of the group with stimulated GH values < 5 micrograms/L was significantly less than that in the other groups (4.2 +/- 1.5 cm/yr). The mean growth rate of the children with GH deficiency during treatment with hGH was greater than that in the other groups and was 3.4 times greater than the pretreatment growth rate. The mean growth rate of children in the other groups during hGH treatment was twofold greater than the pretreatment growth rate. We conclude that except for GH deficiency, children with an extreme degree of short stature are not easily classified by standard diagnostic criteria, and that most short children have a positive response to hGH therapy regardless of the diagnosis; therefore a specific clinical diagnosis should not be used to exclude children from hGH therapy.

Binding of bovine growth hormone to bovine liver membranes

The binding of [125I]bGH and [125I]hGH to bovine liver membranes is compared to characterize the somatotrophic hormone-receptor interaction. [125I]bGH binding exhibits higher nonspecific binding than [125I]hGH while the time-course of binding and displacement with unlabeled GH are similar. Divalent and monovalent cations enhance [125I]hGH binding with well-defined peaks of binding at specific cation concentrations. Monovalent cations do not enhance [125I]bGH binding at concentrations of 100 mM while divalent cations enhance binding over a range of cation concentration (4-80 mM). The binding of [125I]bGH is dependent upon the presence of divalent cations, with minimal effect of pH upon binding in the absence of calcium. Scatchard plots of bGH and hGH binding data indicate at least two binding sites. We conclude that somatotrophic GH exhibits unique and distinguishing characteristics of binding. The characteristics of hGH binding to the bovine liver membranes suggest that its binding may differ from bGH binding to its homologous receptor.

Comparison of dose frequency of human growth hormone in treatment of organic and idiopathic hypopituitarism

Two weekly (biw) injections of pituitary human growth hormone (hGH) were compared with three weekly (tiw) injections of hGH (0.24 IU hGH/kg body weight/wk for both groups) for effect on growth rate in children with idiopathic and organic hypopituitarism. Both dosage schedules resulted in increased growth rate during the first 12 months of therapy; the tiw dosage was more effective in the first 6 months in patients with organic hypopituitarism, and in the second 6 months in patients with idiopathic hypopituitarism. There was no advantage to tiw therapy during the second year of therapy in either group. The additional increment in height after 1 year of therapy using tiw compared with biw therapy was 2 cm and 1 cm for the patients with organic and idiopathic hypopituitarism, respectively. This increment should be weighed against the cost, pain, and inconvenience of tiw versus biw doses of hGH in the treatment of hGH deficiency. With the dosages used in this study, tiw therapy was more effective during the first year, when patients are more responsive, and should be recommended. Twice weekly therapy could be considered for the second and possibly subsequent years of therapy. Other schedules of treatment may be more effective than either of these schedules.

Species Variation in the Binding of hGH to Hepatic Membranes

The binding of 125I-labeled human growth hormone (hGH) to liver membranes from several different species was studied to determine the lactogenic or somatotropic hormone nature of the receptors. Liver membranes from several species of the class of Mammalia bound significant quantities of 125I-hGH. Goat, sheep, rat, mouse, and rabbit liver membranes exhibited the highest binding with cow, pig, human, and hamster liver membranes exhibiting severalfold less binding. The binding of the dog and cat liver membranes exhibited relatively high nonspecific binding. Fish and chicken liver membranes did not bind appreciable quantities of 125I-hGH. In all species except for dog and cat in which 125I-hGH bound to the membranes, hGH was the most effective competitor for binding. The mean ID50 for hGH and all membranes was 2.4 X 10(-9) M. Human liver membranes exhibited the smallest ID50, 4.9 X 10(-10) M. In sheep liver membranes, bovine growth hormone (bGH) was equipotent to hGH in competing for 125I-hGH binding. bGH also demonstrated significant competition for 125I-hGH binding in pig and cow membranes. Ovine prolactin (oPrl) exhibited significant competition for 125I-hGH only in rodent membranes. The ID50 for oPrl was 3- to 10-fold greater than for hGH in the rat, hamster, and mouse liver membranes. The ID50 for oPrl in the sheep liver membranes was 13-fold greater than that of hGH. We conclude the following: (1) There appears to be a species specificity of hGH binding that may be phylogenetically significant and may result from variations in the structure of the hormone or the receptor. (2) The competitive binding properties of hGH are fairly consistent within phylogenetic orders. (3) The simple designation of lactogenic or somatotropic for hormones and receptors is insufficient to characterize the binding properties of this group of hormones.