Treatment of hypophyseal dwarfism with biosynthetic growth hormone

17 prepubertal children (12 male, 5 female) with growth hormone deficiency (GHD) were treated with a total of 12 IU/m2/week biosynthetic human growth hormone for at least three years. Growth hormone was administered daily by the subcutaneous route. Growth velocity (GV) increased from -2.75 SDS +/- 1.06 (3.58 cm +/- 0.87) to +2.91 SDS +/- 1.73 (8.6 +/- 1.3 cm) after one year of treatment. GV decreased subsequently, but remained above the pretherapeutic values. Height for chronological age increased from -2.68 SDS +/- 0.44 (pretreatment value) to -2.22 SDS +/- 0.49 SDS after one year and to -1.67 +/- 0.6 SDS after 3 years of GH therapy. Analysis of the height of each individual patient after each of the three years of treatment shows a positive correlation to the pretreatment height. Our data stress the need for early diagnosis and treatment of GHD patients because GV remains elevated for three years under therapy with 12 IU GH/m2/week in this group of GHD patients. This results in a height gain in the second and third year of treatment after catch up growth in the first year of therapy. Nevertheless, pretreatment height seems to be an important factor influencing the therapeutic results of GH administration in the individual GHD patient, stressing the need for improving the treatment schedule in patients with the most severe growth retardation.     

Suppression of growth hormone (GH) secretion by a selective GH-releasing hormone (GHRH) antagonist. Direct evidence for involvement of endogenous GHRH in the generation of GH pulses.

To study the potential involvement of growth hormone-releasing hormone (GHRH) in the generation of growth hormone (GH) pulses in humans we have used a competitive antagonist to the GHRH receptor, (N-Ac-Tyr1,D-Arg2)GHRH(1-29)NH2(GHRH-Ant). Six healthy young men were given a bolus injection of GHRH-Ant 400 micrograms/kg body wt or vehicle at 2200 h and nocturnal GH concentrations were assessed by every 10-min blood sampling until 0800 h. Integrated total and pulsatile GH secretion were suppressed during GHRH-Ant treatment by 40 +/- 6 (SE) % and 75 +/- 5%, respectively. GHRH-Ant suppressed maximum (7.6 +/- 2.2 vs 1.8 +/- 0.5 micrograms/liter; P < 0.001) and mean (3.3 +/- 1.0 vs 1.1 +/- 0.2 micrograms/liter; P = 0.02) GH pulse amplitudes. There was no change in integrated nonpulsatile GH levels, pulse frequency, or interpulse GH concentration. GHRH-Ant 400 micrograms/kg also suppressed the GH responses to intravenous boluses of GHRH 0.33 micrograms/kg given 1, 6, 12, and 24 h later by 95, 81, 59, and 4%, respectively. In five healthy men, the responses to 10-fold larger GHRH boluses (3.3 micrograms/kg) were suppressed by 82 and 0%, 1 and 6 h after GHRH-Ant 400 micrograms/kg, respectively. These studies provide the first direct evidence that endogenous GHRH participates in the generation of spontaneous GH pulses in humans.     

Increased prolactin concentration and thyrotropic insufficiency in patients with growth hormone deficiency

An increase in TSH secretion in patients with growth hormone deficiency (GHD) indicates hypothalamic thyrotropic dysfunction. A simultaneous increase in prolactin (PRL) response to TRH is often observed in these patients. In order to find out whether these patients need additional thyroxine treatment, we investigated thyrotropic function in 15 patients with GHD and increased PRL secretion. 3 groups of patients emerged: 1. Four patients were clinically hypothyroid (T42.9 +/- 1.3 micrograms/dl); 2. Four patients developed low T4 levels during growth hormone therapy (T43.5 +/- 0.1 micrograms/dl), although their T4 levels were normal before growth hormone treatment was initiated (T45.7 +/- 0.5 micrograms/dl). 3. Seven patients had T4 levels in the lower normal range (7.0 +/- 0.8 micrograms/dl). The growth velocity of these patients was monitored when thyroxine treatment was given in addition to hGH. Thyroxine administration resulted in suppression of TSH secretion in all patients while PRL concentrations remained elevated. Growth velocity was improved with additional T4 therapy in groups 2 and 3 without undue acceleration of bone age. All patients with GHD and elevated PRL levels should be carefully monitored for thyrotropic dysfunction.     

Recombinant human growth hormone (rhGH) treatment of children undergoing peritoneal dialysis

The authors studied the effect of recombinant growth hormone (rhGH) treatment on 5 growth retarded children, age 2 2/12 to 17 8/12 years, who had end-stage renal disease (ESRD) and were undergoing continuous cycling peritoneal dialysis (CCPD). Patients received 0.125 mg/kg of subcutaneous rhGH 3 times weekly. Accelerated height velocity compared to the previous year of CCPD was noted in 2 patients and improvement in the standard deviation score (SDS) as a parameter of improved growth velocity was noted in a third patient. This was associated with an increase in weight and improvement in the midarm muscle circumference (MAMC) suggesting an anabolic effect of rhGH treatment. Bone age advancement was consistent with the period of observation; no advancement greater than that expected for the increase in chronological age was observed. No significant side effects were attributable to rhGH therapy. These preliminary results indicate some growth retarded children without growth hormone deficiency with ESRD undergoing CCPD may respond to exogenous rhGH therapy with an acceleration in growth velocity: However, the failure to achieve uniform acceleration of height velocity indicates the need for controlled studies before rhGH can be recommended for all growth retarded children with ESRD undergoing peritoneal dialysis.     

An evaluation of human chorionic gonadotrophin (HCG) therapy in boys with delayed puberty

Fifty male patients with delayed pubertal development (chronological age 13.3-17.6 years; bone age 9.5-14 years) were treated with human chorionic gonadotrophin (HCG) 1500-2000 units twice weekly for six months to promote pubertal development and accelerate growth. Response was compared with an untreated control group of 28 patients (chronological age 12.5-17.5 years; bone age 7.0-13.0 years). Forty-four of 46 patients in the treatment group achieved genital stage 3 or 4 by the end of therapy; untreated patients either remained unchanged or advanced only one genital stage during this period. Testicular volumes increased from a median 4.5 ml (range 1-12 ml) to 9 ml (range 3.5-15 ml) in the treated patients. In untreated patients testicular volume increased from 6.0 ml (range 2-10 ml) to 9.5 ml (range 4-20 ml) over the same period. In patients initially growing at less than 7.0 cm/year height velocity increased from 3.9 cm/year (range 0-6.6 cm/year) to 12.7 cm/year (range 8.9-16.8 cm/year) during therapy, falling to 6.0 cm/year (range 0-12 cm/year) in the three-month period immediately following treatment. Patients initially growing at greater than 7.0 cm/year showed variable responses to treatment. Prepubertal patients showed the greatest acceleration in annual growth compared with controls. Treated patients with an initial skeletal age less than 12.0 years showed either a final height (when known) which was less than initially predicted or a significant reduction in predicted height following treatment. Skeletal age greater than 12.0 years was not associated with excess osseous maturation. In conclusion, pre-pubertal children growing at less than 7 cm/year show the greatest benefit from HCG therapy, but final height may be prejudiced if initial bone age is less than 12 years.     

Radioimmunoassay of growth hormone-releasing hormone (GHRH) with a polyclonal antibody against synthetic GHRH(1-29)-Gly4-Cys-NH2: method and clinical studies.

A radioimmunoassay (RIA) for growth hormone-releasing hormone (GHRH) using a polyclonal antibody against synthetic GHRH(1-29)-Gly4-Cys-NH2 has been developed. The antiserum (RBM105) showed full cross-reactivity with GHRH-(1-44)NH2, GHRH-(1-40)OH, GHRH-(1-37)OH and GHRH-(3-44)NH2, and probably recognized the region of Ala4 to Lys12 of GHRH. Since the sensitivity of the GHRH RIA was 1.5 pg/tube, the lowest detectable plasma level was 5 ng/l when an extract of 0.3 ml of plasma per tube was used. On gelfiltration chromatography, the GHRH immunoreactivity of normal plasma was eluted in the same position as synthetic GHRH. The plasma GHRH concentration in healthy subjects was 20.5 +/- 6.5 ng/l (mean +/- SD), and in patients with hypothalamic disorders was 17.4 +/- 2.0 ng/l. In contrast, the plasma GHRH level in hemodialysis-dependent, chronic renal failure (CRF-HD) patients (38.7 +/- 13.1 ng/l) was significantly higher than normal. The acromegalic patients were 24.3 +/- 11.9 ng/l, except for one patient with ectopic GHRH syndrome (990 ng/l): his plasma GHRH level reached 7,100 ng/l during operation, and then decreased logarithmically to 70 ng/l after 6 h. Somatostatin at concentrations of 10 and 1,000 nmol/l significantly suppressed (GHRH release) from primary culture cells of the GHRH-producing tumor from 17.3 +/- 0.92 ng/2 x 10(5) cells to 9.98 +/- 3.61 and 4.32 +/- 1.01 ng/2 x 10(5) cells, respectively after 48 h. These data indicate that this GHRH RIA is useful for determining the plasma GHRH concentration in normal and diseased states and also for in vitro studies of GHRH release.     

Exercise-induced changes in insulin-like growth factors and their low molecular weight binding protein in healthy subjects and patients with growth hormone deficiency

Serum concentrations of insulin-like growth factors 1 and 2 (IGF-1 and IGF-2), the low molecular weight form of IGF binding protein (IGFBP-1), insulin, C-peptide and GH were determined in six healthy subjects and four patients with GH deficiency during 30 min of moderate physical exercise on the cycle ergometer. The load corresponded to 60% of individual maximal oxygen uptake. IGF-1 and IGF-2 were determined by radioimmunoassays developed with antibodies isolated from immunized hens eggyolk after separation by automated acid gel filtration of serum samples prior to assay. Significant increases in the serum concentrations (mean +/- SEM) of IGF-1 (157 +/- 24 to 196 +/- 29 micrograms l-1, P less than 0.05) and IGF-2 (451 +/- 37 to 678 +/- 85 micrograms l-1, P less than 0.01) were seen in the healthy subjects after 10 min of exercise. The mean percentage increase was 26 +/- 5% for IGF-1 and 50 +/- 11% for IGF-2. No relation to the GH release was found. In GH-deficient patients the mean IGF-2 concentration rose 48 +/- 17% from basal 216 +/- 63 micrograms l-1 to a peak concentration of 324 +/- 115 micrograms l-1 (P less than 0.01) after 30 min, while the 38 +/- 20% rise of IGF-1 from basal 36 +/- 13 micrograms l-1 to a peak concentration of 55 +/- 27 micrograms l-1 was not significant. The serum IGFBP-1 concentration did not change during exercise, while insulin and C-peptide concentrations, as well as blood glucose, decreased in both healthy subjects and GH-deficient patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

Six-month, prospective, longitudinal, open-label caffeine and dextromethorphan phenotyping study in children with growth hormone deficiency receiving recombinant human growth hormone replacement

BACKGROUND: Recombinant human growth hormone (r-hGH) is increasingly being used in children. Although growth hormone (GH) may alter the clearance of concomitantly administered medications, its effects on individual drug-metabolizing enzymes in children have not been characterized. OBJECTIVE: The goal of this study was to assess the activities of cytochrome P450 (CYP) 1A2, N-acetyltransferase 2, xanthine oxidase, and CYP2D6 in children with isolated idiopathic GH deficiency before and 3 and 6 months after initiation of r-hGH treatment. METHODS: This 6-month, prospective, longitudinal, open-label phenotyping study was conducted at 4 academic tertiary care centers within the Pediatric Pharmacology Research Unit network. Prepubertal or early pubertal children (4-14 years) with short stature and isolated idiopathic GH deficiency were enrolled. Patients were given 4 ounces of a cola beverage and 0.5 mg/kg of dextromethorphan (DM) before and 3 and 6 months after initiation of r-hGH treatment. Urine was collected for 8 hours after probe substrate administration, and enzyme activity was assessed using validatedcaffeine/metaboliteandDM/metabolitemolar ratios. Patients with a DM/dextrorphan molar ratio > or =0.3 were classified as poor metabolizers, and those with a ratio <0.3 were classified as extensive metabolizers. Anthropometric and biochemical responses were assessed at each visit. Blood was also obtained for determination of serum insulinlike growth factor-1 (IGF-1) levels and CYP2D6 genotype. RESULTS: Fourteen patients (mean [SD] age, 11.5 [2.6] years [age range, 4.5-14.6 years]; 11 males, 3 females; 100% white; median height and weight, 131.8 cm and 29.2 kg, respectively) completed the 3 study visits. However, data from 2 patients were excluded from analysis due to procedural violations. In all patients, growth velocity and serum IGF-1 concentrations were significantly higher (P < 0.001) after r-hGH treatment (mean doses, 0.32 and 0.33 mg/kg per week at 3 and 6 months, respectively). However, molar ratio values did not significantly change after initiation of r-hGH. CONCLUSIONS: In this study population of children with isolated idiopathic GH deficiency, no significant differences in caffeine/metabolite and DM/metabolite molar ratios were observed after initiation of r-hGH treatment.     

Growth hormone by daily injection in patients previously treated for growth hormone deficiency

When recombinant-DNA-derived methionyl growth hormone (met-GH) became available for patients resuming treatment, we were able to compare dose intervals in 47 prepubertal children with growth hormone deficiency. Patients were randomly assigned to one or three doses weekly or to daily injections for a total dosage of 0.3 mg/kg weekly. If the patient's annual growth failed to increase more than 2 cm above baseline, the dose interval was changed from weekly to three times a week or from three times a week to daily. In the second year of the study, all patients received daily injections. Despite a mean duration of previous treatment with growth hormone of more than 3 years, daily injections in 16 patients throughout the first year of the study resulted in a mean growth velocity (9.6 +/- 2.4 cm) comparable to that in newly treated patients given met-GH three times weekly in other trials. Administration by daily injection was more effective than injection three times per week (P less than .05) in 13 patients (7.9 +/- 2.1 cm) or once a week in four patients (7.7 +/- 1.2 cm). Second year growth velocities in 21 patients who had received once-a-week or three-times-a-week injections the first year of the study, increased significantly with a change to daily injection (7.7 +/- 2.2 vs 8.8 +/- 1.9 cm) (P less than .05).     

Growth hormone and cortisol secretion in patients with burn injury.

A prospective study of growth hormone, insulin-like growth factor (IGF-1), and cortisol secretion was undertaken in six adults with burn injury. Serum concentrations of growth hormone and IGF-1 were low in all patients during the first 2 weeks of hospitalization. The mean growth hormone level was 4.35 +/- 0.83 micrograms/L on day 1 and 1.70 +/- 0.50 micrograms/L on day 13. The mean serum concentration of IGF-1, which reflects overall growth hormone secretion, was 0.43 +/- 0.09 U/ml on day 1 and 0.61 +/- 0.11 U/ml on day 13; these values are distinctly low. After 3 to 4 weeks, IGF-1 concentrations increased to the mid-normal range, whereas growth hormone values did not change. Morning plasma cortisol concentrations were modestly elevated; however, urine free cortisol concentrations, which reflect total cortisol secretion, were elevated 2 to 28 times above normal values at the time of admission (mean, 443.5 +/- 323.7 nmol/L). Urinary free cortisol concentrations remained elevated after 2 weeks (mean, 230.5 +/- 94.5 nmol/L). Patients with burn injury have inappropriately low growth hormone secretion and IGF-1 production in spite of the stress of the injury and more than adequate nutritional therapy.