Human Growth Hormone Therapy Research Articles

Serum levels of carboxyterminal propeptide of type I procollagen and pyridinoline crosslinked telopeptide of type I collagen in normal children and children with growth hormone (GH) deiciency during GH therapy

In this study, we investigated age-related changes in serum levels of both the carboxyterminal propeptide of type I procollagen (PICP) and the pyridinoline crosslinked telopeptide of type I collagen (ICTP) to elucidate bone formation and resorption, respectively, in 200 normal Japanese children (141 males and 59 females, age range 0–16 years). Furthermore, to clarify the effect of GH on bone turnover, we measured serum PICP and ICTP in 26 growth hormone (GH)-deficient children (20 males and 6 females, age range 4–15 years) who showed significant bone growth during recombinant human GH therapy. In the normal children, the curves for age-related changes in both serum PICP and ICTP levels almost paralleled that of the standard height velocity curve in both sexes. The serum levels of both peptides were higher than those in adults, and the peak increases corresponded with the timing of the adolescent growth spurt. Furthermore, the serum levels of PICP and ICTP were significantly correlated with the height velocity. In the GH-deficient patients, the serum ICTP levels before GH therapy were lower than those in age- and sex-matched controls. Both PICP and ICTP levels in serum increased significantly at the beginning of GH therapy. Furthermore, the percent increase in PICP after 1 month of GH treatment was positively correlated with the percent increase in height velocity during 1 year of GH treatment. These results suggest that bone turnover is high in normal children, particularly during infancy and puberty, and that GH could affect bone resorption as well as formation. The serum level of PICP is a potential marker for predicting the growth response to long-term GH therapy. ( Bone 17:397-401; 1995)

Hypercalcemia associated with the use of human growth hormone in an adult surgical intensive care unit.

The anabolic properties of human growth hormone (HGH) may prove beneficial in critically ill surgical patients. Potential effects of hypercalcemia with HGH therapy have not been addressed for adult patients in the intensive care unit. We performed a retrospective review of the past 100 patients treated with HGH in a surgical intensive care unit. Laboratory data, including serum calcium levels, were recorded at baseline and during HGH therapy. Additionally, calcium levels in 27 burn patients receiving HGH were compared with calcium levels in a well-matched group of 27 burn patients not receiving HGH. The incidence and severity of hypercalcemia were recorded, with attention to contributing factors and overall outcome. There was a statistically significant increase in the mean +/- SD serum calcium level with the institution of HGH therapy (2.50 +/- 0.20 mmol/L [10.0 +/- 0.8 mg/dL] before HGH vs 2.74 +/- 0.27 mmol/L [11.0 +/- 1.1 mg/dL] during HGH, P < .05). Before HGH, 14% of the patients had hypercalcemia, defined as a calcium level greater than 2.74 mmol/L (11.0 mg/dL). During HGH, 43% of the patients developed hypercalcemia. Before HGH, no patient exhibited severe hypercalcemia, defined as a calcium level greater than 3.12 mmol/L (12.5 mg/dL). However, during HGH, 10% of the patients developed severe hypercalcemia. Elevations in serum calcium levels were correlated with the duration of HGH therapy and renal dysfunction. Burn patients receiving HGH exhibited significantly higher mean +/- SD calcium levels than controls (2.87 +/- 0.32 mmol/L [11.5 +/- 1.3 mg/dL] vs 2.50 +/- 0.17 mmol/L [10.0 +/- 0.7 mg/dL], P < .001). Studies performed in selected patients demonstrated that alterations in parathyroid function, vitamin D metabolism, and thyroid function did not appear to contribute to this effect. Prolonged HGH therapy in critically ill surgical patients may result in severe hypercalcemia, particularly in patients with altered renal function. Possible mechanisms for HGH-induced hypercalcemia include increased intestinal absorption and decreased urinary excretion. Outcome was not adversely affected by this biochemical alteration, but careful monitoring of calcium levels should be undertaken in this population receiving HGH.

Long-Term Effects of Growth Hormone Treatment on Height in Turner Syndrome: Results of a 6-Year Multicentre Study in Japan

Patients with Turner syndrome have many somatic characteristics, including short stature. We report the results of a 6-year multicentre clinical trial of recombinant human growth hormone (GH) therapy in 63 patients with Turner syndrome. Twenty-six patients received GH at a dose of 0.5 IU/kg/week, while 37 received GH, 1.0 IU/kg/week, by daily subcutaneous injection. At the start of GH treatment, there was no significant difference between the two groups in chronological age, bone age, height or growth rate. Both treatment groups showed a significant growth increase during treatment. The current mean height of the 12 patients over the age of 16 treated with GH, 0.5 IU/kg/week, is 145.1 +/- 4.7 cm, and in the 16 patients treated with GH, 1.0 IU/kg/week, is 144.0 +/- 2.2 cm. In conclusion, treatment with GH does increase final height in patients with Turner syndrome. However, further studies are needed to determine the optimum age for the initiation of GH therapy, the best dose regimen and the optimal time and manner of sex and anabolic steroid use.

Final Height and Long-Term Outcome after Growth Hormone Therapy in Turner Syndrome: Results of a German Multicentre Trial

Final height was investigated in 85 patients from a German multicentre trial of human growth hormone (GH) therapy in Turner syndrome. Six patients (mean age, 15.4 +/- 1.0 years; mean duration of therapy, 4.4 +/- 1.0 years) fulfilled the criteria for having reached final height (i.e. a height velocity < 0.5 cm/year). Four subjects had stopped therapy and two were still receiving GH. The mean final height of patients was 150.9 +/- 4.7 cm (range, 143.3-154.9 cm). In 3 subjects, projected final height was exceeded by 1.4, 6.5 and 10.8 cm, 1 patient just failed to reach projected final height by -1.7 cm and the 2 remaining patients did not attain projected final height by -3.2 and -12.1 cm. In the latter case, lack of height gain was associated with early onset and rapid progress of spontaneous puberty. The changes in height SDS were analysed in the other patients still receiving GH therapy over a period of 6 years, and it appeared that 2 IU/m2/day was less effective than 3 or 4 IU/m2/day, but that 4 IU/m2/day was no more effective than 3 IU/m2/day. These limited, non-controlled results indicate that GH therapy may be effective in increasing final height in Turner syndrome, though some patients may not benefit.

The effect of 3 months of recombinant human growth hormone (GH) therapy on insulin and glucose-mediated glucose disposal and insulin secretion in GH-deficient adults: a minimal model analysis.

The effect of 3 months of low dose (120 micrograms/kg.week or 0.24 IU/kg.week) recombinant human GH (rhGH) treatment on glucose tolerance, insulin secretion, and insulin- and glucose-mediated glucose disposal was examined in 10 GH-deficient adults. The frequently sampled iv glucose tolerance test was performed at baseline and after 1 week and 3 months of rhGH therapy and analyzed by the minimal model method of Bergman to provide estimates of the glucose decay rate, first and second phase insulin secretion (phi 1 and phi 2), fractional clearance of insulin, and glucose-mediated and insulin-mediated glucose disposal. Fasting glucose, insulin, C-peptide, nonesterified fatty acids (NEFA), and serum cholesterol and triglycerides were also measured. When the 1 week data were compared to baseline, there was a small but significant rise in mean (+/- SE) fasting glucose (4.62 +/- 0.17 vs. 5.1 +/- 0.15 mmol/L; P < 0.01), NEFA (0.70 +/- 0.09 vs. 1.1 +/- 0.12 mmol/L; P < 0.005), insulin (93.6 +/- 8.9 vs. 238.9 +/- 9.2 pmol/L; P < 0.0001), C-peptide (0.32 +/- 0.13 vs. 0.66 +/- 0.13 nmol/L; P < 0.005), and phi 1 (11.9 +/- 1.3 vs. 16.2 +/- 1.8 pmol/L.min/mmol.L x 10(2)) and phi 2 (1.43 +/- 0.17 vs. 3.15 +/- 0.25 pmol/L.min/mmol.L x 10(3); P < 0.05). Conversely, there were associated decreases in glucose decay rate (1.83 +/- 0.26 vs. 1.28 +/- 0.12 min-1; P < 0.05) and insulin-mediated glucose disposal (0.36 +/- 0.08 vs. 0.18 +/- 0.06 min/pmol.L x 10(-4); P < 0.005). There was no change in glucose-mediated glucose disposal or the fractional clearance of insulin. By 3 months, fasting insulin and C-peptide levels remained significantly elevated, whereas other parameters had returned to baseline. There was a minor reduction in serum cholesterol at 1 week (5.1 +/- 0.15 vs. 4.62 +/- 0.17 mmol/L; P < 0.01), which was not maintained at 3 months. Serum triglycerides remained unchanged throughout the study. We conclude that short term low dose rhGH treatment of GH-deficient adults induces a temporary state of mild glucose intolerance, hyperinsulinemia, insulin resistance, and raised NEFA levels at 1 week. By 3 months, these metabolic disturbances had returned to baseline for a persisting modest hyperinsulinemia. Whether this hyperinsulinemia will last over the longer term and/or has distant detrimental metabolic consequences in the individual must await further studies.

The effect of 3 months of recombinant human growth hormone (GH) therapy on insulin and glucose-mediated glucose disposal and insulin secretion in GH-deficient adults: a minimal model analysis

The effect of 3 months of recombinant human growth hormone (GH) therapy on insulin and glucose-mediated glucose disposal and insulin secretion in GH-deficient adults: a minimal model analysis

Altered lipid kinetics in adjuvant recombinant human growth hormone-treated multiple-trauma patients

Adjuvant recombinant human growth hormone therapy during the postinjury period may improve the efficiency of utilization of body energy stores. In a group of 20 severely injured highly catabolic hypermetabolic adult multiple-trauma victims, we have investigated the basic lipid kinetics of trauma (study I) and its modification after 7 days of intravenous feeding (total parenteral nutrition) with (group H, n = 10) or without (group C, n = 10) daily rhGH (0.15 mg somatotropin.kg-1.day-1) intramuscular injections (study II). Whole body lipolysis rate (2-stage primed constant infusion of 10% glycerol), substrate net oxidation rates (indirect calorimetry), and plasma levels of hormones were determined. Compared with the control group (group C) the treatment group (group H) showed significantly (P = 0.006) enhanced rates of lipolysis and free fatty acid reesterification (10 +/- 2 to 18 +/- 2 kcal.kg-1.day-1, P = 0.05). As a function of resting energy expenditure (REE), a trend of increased net glucose oxidation [32 +/- 10 vs. 56 +/- 7% REE, not significant (NS)] and decreased fat (40 +/- 8 vs. 25 +/- 5% REE, NS) and protein oxidation rates (28 +/- 2 vs. 19 +/- 2% REE, P = 0.007) were also indicated. The simultaneous operation of increased lipolytic and reesterification processes may allow the adipocyte to respond rapidly to changes in peripheral metabolic fuel requirements in injury.

Effect of Human Growth Hormone (GH) Therapy on Non-Endocrine Short Stature (NESS) Compared with GH Deficient Children and Factors which Predict the Response to GH Therapy

The effect of human growth hormone treatment was studied on 11 prepubertal NESS children compared with six GH deficient (GHD) children (3 partial GHD, 3 GH neurosecretory dysfunction (GHNSD)). All patients were evaluated after 6 months to 1 year of treatment. Height velocity (HV), height SD (HSD) and height velocity SD score for chronological age (HV SDSCA) increased statistically significantly (p<0.05) in both groups. Predicted adult height did not change significantly in both groups (NESS: 154.6cm vs. 156.5cm, n=7, GHD: 154.8cm vs. 157.1cm, n=3). δHV SDSCA correlated significantly with HV (r=0.67, p=0.03) and HV SDSCA (r=0.72, p=0.001) but not with nocturnal GH secretion, urinary GH secretion and stimulated peak serum GH level. δBA/δCA and δHA/δCA of NESS and GHD were 0.88±0.49 and 1.84±1.36, n=7, 1.84±1.36 and 0.89±0.5, n=3, respectively.NESS children responded equally well to GH treatment as GHD children did; auxological parameters affect the response to GH treatment.

Similar genetic susceptibility in iatrogenic and sporadic Creutzfeldt-Jakob disease.

Creutzfeldt-Jakob disease (CJD) is one of the transmissible spongiform encephalopathies (TSEs). In all TSEs host susceptibility is an important factor in the development of clinical disease. The prion protein (PrP) gene appears to confer the main component of this susceptibility. The appearance of spontaneous neurodegeneration in PrP transgenic mice carrying a human mutation has raised the possibility that the origin of sporadic CJD is solely genetic. We studied PrP codon 129 polymorphism in 23 of the 25 CJD cases in France related to human growth hormone (hGH) therapy. They constitute the largest and most homogeneous hGH-related iatrogenic CJD population yet analysed. All these CJD cases were homozygous at codon 129, compared with only 50% in the healthy control group (P < 0.00002). These iatrogenic cases also displayed a genotype frequency distribution similar to that observed in sporadic CJD. These results underline the importance of the PrP gene and especially the homozygous codon 129 genotype in determining the risk of developing CJD after contamination by a TSE agent. They also suggest that highly susceptible individuals may exist and raise the possibility that sporadic CJD may have an environmental origin.

Growth Hormone Therapy for the Elderly: The Fountain of Youth Proves Toxic

<h3>To the Editor.</h3> —We¹and others^2,3have proposed the use of recombinant human growth hormone (GH) therapy for the elderly in an attempt to retard the undesirable changes in muscle mass and function, body fat, and bone mineral content associated with advancing age, and the subsequent impact these have on health care costs. Our initial enthusiasm for this idea has declined as the result of an unexpectedly high incidence of side effects of GH therapy in this population. In 12 healthy older men (63 to 76 years of age) and two women (68 and 73 years of age) who received daily GH (12.5 γg/kg per day, n=12) or placebo injections (n=2) for 4 months to assess the effects of GH therapy on body composition and muscle strength, we have experienced a notable subject attrition rate related to symptoms of carpal tunnel compression, fluid retention, and arthralgia—complications not frequently

Human Growth Hormone Therapy May Stimulate Growth of Melanocytic Nevi

On the basis of an observation that melanocytic nevi were stimulated in a patient with Turner's syndrome receiving human growth hormone (HGH) therapy,

Effects of human growth hormone therapy on melanocytic naevi

Melanocytic naevi may grow more rapidly during human growth hormone (hGH) therapy. With standardised skin photographs, the growth rate of the naevi was two-fold greater in 14 hypopituitary and 5 Turner's syndrome girls treated with hG H than in untreated patients or controls. HMB-45 immunoreactivity, a marker of stimulated melanocytes, was absent in naevi from 18 of 19 individuals not treated with hGH, including 5 Turner's syndrome patients studied 2-43 months after stopping hGH. In naevi from 39 hGH-treated patients, 22 showed unusual HMB-45 reactivity in dermal naevocytes. During administration of hGH, melanocytic naevi grow faster and there is reversible stimulation of naevocytes.

Increased chromosome fragility in lymphocytes of short normal children treated with recombinant human growth hormone.

A few years ago it was reported that some growth-hormone-deficient children had developed leukemia following therapy with human growth hormone. This raised concern that this therapy may stimulate tumor development. Since it is known that the tendency to develop cancer is closely related to chromosome breakage, we decided to investigate whether recombinant human growth hormone (rhGH) therapy can increase chromosome fragility. Ten short normal children were studied during their first year of treatment. Lymphocytes were collected at 0, 6 and 12 months of rhGH therapy, and we assessed the rate of spontaneous chromosome aberrations, the frequency of sister chromatid exchanges, the proliferative rate indices, the expression of common fragile sites induced by aphidicolin, and the sensitivity towards the radiomimetic action of bleomycin. At 6 months of therapy, there was a significant increase in bleomycin-induced chromosome aberrations, which remained unchanged after 1 year of treatment. An increase in spontaneous chromosome rearrangements at 6 and 12 months of therapy was also observed. These findings are further supported by data obtained from the analysis of 16 short normal children already on rhGH therapy.

INCREASED CHROMOSOME FRAGILITY IN LYMPHOCYTES OF SHORT NORMAL CHILDREN TREATED WITH RECOMBINANT HUMAN GROWTH HORMONE

The report, few years ago, of some growth hormone-deficient children having developed leukemia following therapy with human growth hormone, raised concern about a possible stimulatory effect of this therapy on tumor development. Since it is known that proneness to cancer is related to chromosome breakage, we decided to investigate whether recombinant human growth hormone (rhGH) therapy might increase chromosome fragility. Ten short-normal children (age: 6-11 yrs. mean height: −2.5 SD; mean growth rate: 4.1 cm/yr; mean bone age: −2.5 SD) were studied. Lymphocytes were collected at 0, 6 and 12 months of therapy, and the rate of spontaneous chromosome aberrations, the frequency of sister chromatid exchanges, the proiterative rate indices, the expression of common fragile sites induced by aphidicolin, and the sensitivity towards the radiomimetic action of bleomicin (BLM) were assessed. The mean frequency of BLM-induced chromosome aberrations increased from the pretherapy 0.11 breaks/cell (b/c) value to 0.23 b/c at 6 months of therapy (p<0.01), and remained at the same level (0.22 b/c) at 12 months. The frequency of damaged cells, showed a significative difference (p<0.05) between the pretherapy value (0.09) and the value found in the cultures performed at 6 and 12 months of therapy (0.14). An increase in spontaneous chromosome rearrangements at 6 and 12 months of therapy was also observed. These findings are supported by data obtained from the analysis of 16 short normal children already on rhGH therapy. Our data point out the need for rhGH to be given only in the strictest of indications. The opportunity of starting rhGH therapy should be carefully questioned when short stature is associated with conditions at risk for the development of tumours, for an increased chromosomal radiosensitivity, e.g. Down syndrome, or tor increased chromosomal breakage, e.g. Fanconi anemia and Bloom syndrome.

Increased bone density after recombinant human growth hormone (GH) therapy in adults with isolated GH deficiency

Increased bone density after recombinant human growth hormone (GH) therapy in adults with isolated GH deficiency

Effects of 1,25-dihydroxyvitamin D 3 and growth hormone therapy on serum osteocalcin levels in children with growth hormone deficiency

In order to investigate the influence on bone metabolism of growth hormone (GH), we evaluated the response to an acute load of 1,25(OH)2D3 (Rocaltrol) (1.5 micrograms/day for 4 days) in 16 growth hormone-deficient prepubertal children (11 boys and 5 girls, aged from 6.2 to 9.6 years) both before and after 1 month of human GH (hGH) therapy (0.1 IU/kg/day, 6 times per week). Before and after the 1,25(OH)2D3 load, serum IGF-I, osteocalcin, Ca, P, alkaline phosphatase (ALP) and urinary excretion of Ca and P were measured. The serum levels of osteocalcin rose significantly after the first 1,25(OH)2D3 load, without an increase in IGF-I values and with a slight non-significant increase in serum Ca and P. Almost superimposable increases of osteocalcin, Ca and P were observed after 1 month of hGH therapy, with a significant increase of IGF-I, but they did not rise further after the second 1,25(OH)2D3 load. On the basis of our results, 1,25(OH)2D3 seems to have a stimulatory action on osteoblastic activity even in the absence of normal levels of GH. However, there is no apparent additional stimulatory activity after administration of hGH. Osteocalcin level behaviour during our study might suggest that GH and 1,25(OH)2D3 have a common and easily saturable stimulatory pathway on osteoblastic function.

CARDIAC MRI IN R-HGH TREATED CHILDREN

To evaluate side effects of a human growth hormone therapy (r-hGH) we performed standard ECG-gated MRI (multiple slice echo sequence, 1.5 T). We investigated 12 girls with Turner's syndrome (TS, chronological age 3.5 to 19.1 years, r-hGH dosis 13-24 IU/m2/Week, period of treatment 24 to 35 months) and 14 children (normotonic) with chronic renal failure (CRF, chron. age 4.1 to 15.6 years, r-hGH dosis 23-32 IU/m2/w, treatment period 3 to 11 months). There were no pathological findings in the group of TS patients whereas in 3 of 14 cases suffering from CRF we have seen circumscriptal thickness of the central and basal part of the septum of the heart without any evidence of left ventricular hypertrophy. The signal intensity of these suspected areas were identical to normal myocardium. These abnormalities were found to be unchanged (e.g. without any progression) under further treatment of 6 months. Although the etiology of this regional myocardial hypertrophy of the intraventricular septum of the heart is still unknown, such myocardial changes may be related to metabolic disturbances in uremic children and/or to the higher r-hGH dosis used in tne group of CSF in comparison to TS.

No beneficial effects of human growth hormone therapy in normal ovulatory patients with a poor ovarian response to gonadotropins.

We studied the effects of human growth hormone (hGH) in 7 in vitro fertilization (IVF) patients with normal ovulatory menstrual cycles who showed a low response to ovarian stimulation with follicle-stimulating hormone (FSH) and human menopausal gonadotropin (hMG). Human growth hormone therapy had no significant effect on the number of days of gonadotropic stimulation, on the total amount of hMG administered, on the serum estradiol level on the day of human chorionic gonadotropin injection, or on the IVF outcome. Our preliminary results do not encourage the routine use of hGH to improve IVF outcome in normogonadotropic ovulatory patients who respond poorly to the standard FSH/hMG protocol.

Hyperthyroidism without Clinical Symptoms Found in Turner Syndrome During Human Growth Hormone Therapy

A nine-year-old Japanese girl with Turner syndrome (45, X/46, Xr (X)) showed poor GH secretion, normal response of TSH, and slightly increased secretion of LH and FSH with increased basic levels, after injection of insulin, TRH, and LH-RH respectively. Since then, r-hGH at 0.5 IU/kg/W has been given for five years under the diagnosis of pituitary dwarfism with Turner syndrome, and an increase of 26 cm in height has been obtained, though menstruation has not been observed till now. Autoimmune diseases such as diabetes mellitus, Addison's disease or thyroid dysfunction have not been observed, up to the age of 14 years. At 15 years, however, regular examination for side-effects of r-hGH revealed hyperthyroidism with 0.1 μU /ml of TSH, 15.7 μg/dl of T4, 4.22 ng/dl of free T4, positive thyroid test, positive microsome test, increased TSAb (1.4 μU/ml) and +32% of BMR, though she has not complained of any kind of clinical symptoms for six months.

Commentary to the ESPE Statements on the Safety of Human Growth Hormone Therapy

Commentary to the ESPE Statements on the Safety of Human Growth Hormone Therapy