Short and long-term cardiovascular effects of growth hormone therapy in growth hormone deficient adults

OBJECTIVE: Since GH substitution therapy is now available for adult GH deficient patients, information on the cardiovascular effects of GH substitution has assumed major clinical interest. We have therefore assessed cardiovascular effects of short and long-term growth hormone substitution therapy in these patients. PATIENTS AND MEASUREMENTS: Doppler echocardiography was performed in 21 GH deficient patients after 4 months placebo and 4 months GH therapy, in a double blind cross-over study. In an open design study, 13 patients were reinvestigated following 16 months and 9 patients following 38 months of GH therapy. Twenty-one age and sex-matched normal control subjects were also investigated. RESULTS: Heart rate was increased in placebo treated patients as compared to controls. After 4 months of GH treatment, heart rate showed a further increase (10%, P < 0.01) and seemed to remain elevated after 16 months of GH therapy. Systolic and diastolic blood pressures were significantly lower in placebo treated patients than in controls, and did not change significantly after GH treatment. The left ventricular diastolic diameter was reduced in patients as compared to controls, but increased after 4 months GH therapy (P > 0.05) and seemed to increase further during prolonged GH treatment. Cardiac index was at the same level in controls and in placebo-treated patients, but increased by 20% following GH therapy and remained elevated after 16 and 38 months (P < 0.05) of GH substitution. CONCLUSION: Following GH substitution in GH deficient adult patients, left ventricular diastolic dimensions increased and seemed to normalize, while heart rate and cardiac output were found to be increased to supranormal levels.     

Complications of growth hormone therapy in children

The introduction of human growth hormone (GH) prepared by recombinant DNA technology has resulted in increased numbers of children and adults receiving treatment. This trend has led to questions concerning the safety of GH, particularly when used for indications other than GH deficiency. This review discusses the effects of GH on fluid, lipid, and carbohydrate metabolism; the risk of intracranial hypertension or pseudotumor cerebri; the effects on the skeletal system; the risk of malignancy; and the effects on the immune system. At present, GH treatment appears to be safe, although long-term follow-up of GH-treated patients is necessary.     

Effect of growth hormone therapy in children with achondroplasia: growth pattern, hypothalamic-pituitary function, and genotype

PURPOSE: To evaluate the success rates of the implantation of stent grafts in the treatment of peripheral aneurysms. MATERIALS AND METHODS: In 13 patients with 15 aneurysms at the common iliac artery (n = 6), external iliac artery (n = 1), hypogastric artery (n = 2), femoral artery (n = 2) or popliteal artery (n = 4), implantation of dacron-covered nitinol stents was performed. The patients were followed up for three to 20 months (mean, 8.8 months) with intravenous digital subtraction angiography, CT or colour-coded Doppler sonography. RESULTS: In all cases, the aneurysm was successfully occluded after stent implantation. In one case with a popliteal aneurysm, kinking of the vessel caused thrombosis of the stent. The stent was successfully reopened. The aneurysm however, had to be surgically treated 9 months later. The primary and secondary patency rates at 6 months were 93% and 100%, respectively. CONCLUSION: The method described might be an alternative therapy to surgery. There are some limitations in respect of treatment of popliteal aneurysms.     

Effect of asthma treatment on urinary growth hormone excretion in children

We present a case report of extensive wear that occurred on the surface of the titanium-alloy head of a shoulder prosthesis after only 2 years' service. Such wear warrants discontinuing the use of titanium-alloy articulating surfaces even in nonweight-bearing joints.     

Renal reserve filtration capacity in growth hormone deficient subjects

In normal subjects, the glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) acutely increase in response to infusion of amino acids and to low doses of dopamine. It is uncertain whether circulatory growth hormone (GH) is a permissive factor for these stimulatory effects. GFR and ERPF (constant infusion technique using 125I-iothalamate and 131I-hippuran, respectively) were measured before and during the infusion of dopamine and amino acids in 8 GH deficient subjects. The clearance study was repeated during concomitant administration of octreotide to investigate whether this somatostatin analogue would modify the amino acid and dopamine-induced renal haemodynamic changes. Dopamine increased baseline GFR from 89 +/- 3 (mean +/- SEM, n = 8) to 102 +/- 4 ml min-1 1.73 m-2 and ERPF from 352 +/- 19 to 476 +/- 26 ml min-1 1.73 m-2, P less than 0.001 for both. During amino acid infusion GFR and ERPF increased to 108 +/- 3 and 415 +/- 23 ml min-1 1.73 m-2, respectively, P less than 0.001 for both. Octreotide did not significantly decrease baseline and dopamine-stimulated renal haemodynamics but lowered the amino acid-stimulated GFR (98 +/- 4 ml min-1 1.73 m-2, P less than 0.05) and ERPF (381 +/- 18 ml min-1 1.73 m-2, P less than 0.05). Basal plasma glucagon concentrations were not suppressed by octreotide, whereas the amino acid-induced increments in plasma glucagon were partially inhibited. It is concluded that GH is not a necessary factor for the stimulatory effects of amino acids and dopamine on renal haemodynamics.(ABSTRACT TRUNCATED AT 250 WORDS)     

Moral assessment of growth hormone therapy for children with idiopathic short stature

Subjects ranging in age from 50 to 89 years old, either with or without dementia were studied by both ELISA for anti-human T-cell lymphotropic virus type I (HTLV-I) gag 100-130 antibody and by cranial CT in order to clarify the relationship between HTLV-I infection and dementia. The frequency of anti-HTLV-I antibody was found to be significantly higher in the patients with dementia (24/130, 18.5%) than in those without dementia (11/139, 7.9%) (P=0.0169). Among the various types of dementia, HTLV-I seropositivity was found to be significantly associated with vascular dementia (11/48, 23%) (P=0.0087), but not with Alzheimer type dementia. In addition, HTLV-I seropositivity was also associated with Babinski sign, and the severity of cerebral infarction, ventricular dilatation and periventricular lucency on CT. The presence of HTLV-I therefore appears to be one of the risk factors for vascular dementia in HTLV-I endemic areas.     

Cognitive impairments and mood disturbances in growth hormone deficient men

PURPOSE: Physicians lack objective outcome data to define the medically appropriate length of stay (LOS) for patients hospitalized with acute upper gastrointestinal hemorrhage (UGIH), resulting in wide variations in resource utilization and quality of care. A clinical practice guideline with the ability to assign relative risk for adverse events is proposed. METHODS: A comprehensive scoring system was derived from the literature by using four variables; hemodynamics, time from bleeding, comorbidity, and esophagoduodenoscopy findings. The discriminatory ability, potential safety, and impact on resource utilization of the clinical practice guideline was measured in a retrospective, observational study. RESULTS: Seventy percent of UGIH patients (349 of 500) achieved low-risk status according to the guideline, and, were therefore potentially suitable for early discharge from the hospital. If low-risk patients were discharged based upon the guideline, mean (+/- SD) hospital LOS would have been decreased from 4.8 +/- 2.4 days to 2.7 +/- 1.4 days; mean reduction was 2.1 bed-days per patient (95% CI 1.8 to 2.3, P <0.001). LOS would have increased in 4% of cases. Adopting the guideline's recommendation of early discharge would have resulted in a 0.6% (95% CI 0.07 to 2.1) complication rate, with no worsening of quality of care, as judged by implicit review. CONCLUSIONS: The proposed clinical practice guideline may safely reduce hospital LOS for selected low-risk patients with acute UGIH. Moreover, it also may reduce premature discharge of high-risk patients prone to life-threatening events.     

Effect of thyroid hormone on bone and mineral metabolism in rat: evaluation by biochemical markers

We evaluated the effects of the thyroid hormone on bone and mineral metabolism in rats using biochemical markers [pyridinoline (Pyr), deoxypyridinoline (Dpyr), Osteocalcin (OC), alkaline phosphatase (Alp)] and the measuring of bone mineral density (BMD). First, the rats were divided into three groups: 1) control group 2) The fifty micrograms group (T3-50) [It was given 50 micrograms/kg ip/day of triiod-l-thyronine (T3) for 2 weeks.] 3)The hundred micrograms group (T3-100) [It was given 100 micrograms/kg ip/day of T3 for 2 weeks.] Next, the rats were divided into two groups: 1)control group and 2)T3 group. The latter was given 100 micrograms/kg of T3 ip/day for 4 weeks. In experiment 1, Pyr and Dpyr levels in the T3 groups were significantly higher or well tended to be higher than those in the control group. OC levels in the T3 groups were significantly higher than in the control group until day 7. The Z-score of Pyr and Dpyr in T3-100 were two to thirteen times higher than those of OC and Alp. In experiment 2, Pyr and Dpyr levels in the T3 group were significantly higher or well tended to be higher than those in the control group. OC levels in the T3 group were significantly higher than those in the control group only on day 3. In the present study, the administering of T3 100 micrograms decreased both cortical (tibia) and trabecular (lumbar spine) BMDs in the rats. Bone resorption continued to increase after increased bone formation was reduced by T3 administration. Furthermore, bone resorption exceeded bone formation throughout T3 administration.     

Effect of timing of growth hormone administration on plasma growth-hormone-binding activity, insulin-like growth factor-I and growth in children with a subnormal spontaneous secretion of growth hormone

Since normal pulsatile growth-hormone (GH) secretion displays a major and consistent surge during sleep, we studied the effect of timing of GH supplementation on plasma GH-binding protein activity (GH-BP), insulin-like growth factor-I (IGF-I) and growth. 34 prepubertal subjects (28 boys, 6 girls) aged 8-11 years, of short stature (< 2 SD for age), with a GH response to provocative test > 10 micrograms/l and a subnormal 24-hour GH secretion (< 3 micrograms/l), were randomly allocated to receive Bio-Tropin (recombinant GH, Bio-Technology, Israel) 0.81 IU/kg/week in 3 equally divided doses. GH was administered either at 8.00-10.00 h (M group), 14.00-16.00 h (AN group) or 19.00-21.00 h (NT group). Height velocity, IGF-I and GH-BP were determined prior to and after 6 and 12 months on GH therapy in the three groups. There was no significant difference between the three groups in the growth response, IGF-I and GH-BP increase, all of which increased significantly during GH therapy. Although GH levels after the injection decline to preinjection levels after 10 h, the changes induced by GH therapy, as reflected in IGF-I and GH-BP, last in the circulation long enough to prevent fluctuations in its action. The similarity of IGF-I and of GH-BP levels in the three treatment groups might explain the similar growth effects of the 3 protocols.     

Weight relative to height before and during growth hormone therapy in prepubertal children

We used the Genentech National Cooperative Growth Study database to examine differences in weight relative to height (weight for height standard deviation score or WTHTZ) in 3460 patients at enrollment and after one year of therapy with recombinant human growth hormone (rhGH), and in a subset of 450 patients treated for three years with rhGH. The major diagnostic categories were idiopathic growth hormone deficiency (IGHD), organic GH deficiency (OGHD), and idiopathic short stature (ISS). Children with IGHD and ISS were underweight for height at baseline but had a progressive increase in WTHTZ during three years of rhGH therapy. The same pattern applied to children with IGHD associated with septo-optic dysplasia and CNS trauma or infection. However, children with OGHD associated with craniopharyngiomas, other CNS tumors, leukemia, or CNS irradiation were overweight when starting rhGH and showed a decrease in WTHTZ during the first year of rhGH therapy. The increase in WTHTZ during rhGH treatment in children with ISS and OGHD suggests that the GH-induced increase in muscle mass exceeded loss of fat mass. Because children with neoplasm-related OGHD were overweight at baseline, the decline in WTHTZ during the first year of rhGH therapy suggests that loss of fat mass is the predominant effect in this subgroup.     

Normal growth hormone secretion in growth hormone insufficient children retested after completion of linear growth

Tuberculosis of the cervical spine is rare, comprising 3-5% of cases of tuberculosis of the spine. Eight patients with tuberculosis of the cervical spine seen during 1989-1992 were reviewed. They all presented with neck pain. The 4 children presented with a kyphotic deformity. In all the children the disease was extensive, with a large prevertebral abscess formation, while in the adults it was localised to one or two motion segments. Cord compression was present in 4 of the 8 patients. All the patients were treated with antituberculosis drugs and 6 underwent surgery. There was full neurological recovery in all patients. The kyphosis was improved though not fully corrected. There was a problem in stabilisation of severe involvement of the body and dens of C2. Surgery seems to play a major role in the treatment of tuberculosis of the cervical spine.     

Acute growth hormone effects on amino acid and lipid metabolism

The anabolic actions of GH are well known, although specific tissue responses and the mechanism of nitrogen conservation are less well understood. This study was designed to examine the acute metabolic effects of GH on whole body and regional protein metabolism, using an experimental protocol which controlled for confounding perturbations in other hormones by a simultaneous infusion of somatostatin. Control subjects received replacement doses of insulin, glucagon, and GH for the entire 7-h study period, whereas GH subjects received an identical protocol, except for an increased dose of GH sufficient to increase serum concentrations into the high-physiological range (12-20 ng/mL) for the final 3.5 h of the study (P < 0.001). Thirteen young, healthy male subjects were studied in the postabsorptive period; five served as control subjects and eight as treatment (GH) subjects. Each received continuous iv infusions of somatostatin, L-[13-C]leucine, and L-[2H5]phenylalanine throughout the study. Femoral arterial and venous sampling allowed for simultaneous measurements across the leg and in the whole body. C-Peptide levels were suppressed throughout the infusion; insulin, glucagon, insulin-like growth factor I, cortisol, epinephrine, norepinephrine, and glucose concentrations were not different between groups. Glycerol concentrations increased 3-fold in GH subjects during the final 3.5-h period (P = 0.04). Concentrations of several amino acids declined through the study, but no differences were observed between treatment groups. Leucine oxidation was reduced in GH compared to control subjects (P = 0.04). No changes in CO2 production or whole body leucine or phenylalanine flux were observed, whereas nonoxidative disposal of leucine was marginally higher in GH compared to control subjects (P = 0.07). By contrast, rates of appearance and disappearance of both leucine and phenylalanine across the leg all were relatively lower in GH compared to control subjects; leucine balance across the leg was reduced by GH (P = 0.03), whereas phenylalanine balance was not influenced by GH. Our data thus demonstrate an acute stimulatory effect of GH on lipolysis, a decrease in leucine oxidation, and no stimulation of muscle protein synthesis in spite of enhanced protein synthesis in nonmuscle tissue.     

The influence of growth hormone (rhGH) therapy on tooth formation in idiopathic short statured children

The purpose of this preliminary study was to evaluate tooth formation in children with idiopathic short stature, before and during treatment with recombinant growth hormone (rhGH). Twenty-nine short-statured children ages 6 to 13 years were assigned into two treatment groups, an "experimental" group (n = 18), which received rhGH, and a "control" group (n = 11), which was observed for 1 year before commencing rhGH treatment. Clinical and radiographic records were obtained at the initial, year 1, and year 2 visits. Tooth formation and stature were assessed by calculating Z-scores, appropriate for the age and gender of each child. Delta-Z scores, which measure the change in Z-score over time, were also calculated between annual visits. Height was measured and recorded every 3 months, and Z-score statural norms for age and gender were derived from the 1977 National Center for Health Services national probability sampling. Tooth formation standards were derived from Moorrees et al. A matched control sample for tooth development was derived from untreated children. Tooth formation was initially delayed although the degree of reduction in stature exceeded the initial degree of delay in tooth formation. During this 2-year study, rhGH therapy had a significant influence on acceleration or gain in stature, but did not have a significant influence on tooth formation.     

Changes in bone mineral density, body composition, and lipid metabolism during growth hormone (GH) treatment in children with GH deficiency

Adults with childhood onset GH deficiency (GHD) have reduced bone mass, increased fat mass, and disorders of lipid metabolism. The aim of the present study was to evaluate bone mineral density (BMD), bone metabolism, body composition, and lipid metabolism in GHD children before and during 2-3 yr of GH treatment (GHRx). Forty children with GHD, mean age 7.9 yr, participated in the study of bone metabolism and body composition; and an additional group of 17 GHD children, in the study of lipid metabolism. Lumbar spine BMD, total body BMD, and body composition were measured with dual-energy x-ray absorptiometry. Volumetric BMD (bone mineral apparent density, BMAD) was calculated to correct for bone size. BMD, BMAD, lean tissue mass, bone mineral content, fat mass, and percentage body fat were expressed as SD scores (SDS), in comparison with normative data of the same population. Lumbar spine BMD and BMAD and total body BMD were all decreased at baseline. All BMD variables increased significantly during GHRx, lumbar spine BMD SDS, already after 6 months of treatment. Lean tissue mass SDS increased continuously. Bone mineral content SDS started to increase after 6 months GHRx. Fat mass SDS decreased during the first 6 months of GHRx and remained stable thereafter. Biochemical parameters of bone formation and bone resorption did not differ from normal at baseline and increased during the first 6 months of GHRx. Serum 1,25 dihydroxyvitamin D increased continuously during GHRx, whereas PTH and serum calcium remained stable. Lipid profile was normal at baseline: Atherogenic index had decreased and apolipoprotein A1(Apo-A1) had increased after 3 yr of treatment. In conclusion, children with GHD have decreased bone mass. BMD, together with height and lean tissue mass, increased during GHRx. GHRx had a beneficial effect on lipid metabolism.     

Historical perspective on growth hormone treatment in children]

The history of growth hormone treatment can be divided into two episodes. Between 1958 and 1985 growth hormone was extracted from human pituitaries. Because of the scarcity little scientific research was carried out and efficacy was not optimal. In 1985 biosynthetic growth hormone became available, which facilitated research on the use of growth hormone for various indications. In the future further research is needed on the pathophysiology of growth disturbances, on methods to improve efficacy, and on possible side-effects of pharmacological dosages.     

Oral administration of arginine enhances the growth hormone response to growth hormone releasing hormone in short children

We have evaluated the effect of oral administration of arginine chlorhydrate on the growth hormone response to growth hormone releasing hormone in a group of nine short prepubertal children (six boys and four girls). Arginine chlorhydrate 10 g, administered orally 60 min before an i.v. bolus injection of growth hormone releasing hormone 1-29, 1 microgram/kg, significantly enhanced the growth hormone response to the neuropeptide, confirming the results of previous studies which used the i.v. route. Furthermore, our data strengthen the view that the effects of arginine chlorhydrate on growth hormone secretion are mediated by inhibition of endogenous somatostatin release.     

Body composition in growth hormone deficient adults over the age of 60 years

OBJECTIVE: Elderly patients with hypothalamic-pituitary disease exhibit a reduction in GH secretion distinct from the decline in GH secretion related to age. GH deficiency in young adults causes a change in body composition, with increased fat mass (FM) and reduced fat free mass (FFM), similar to that seen as a result of the normal ageing process. The aim of this study was to determine whether organic GH deficiency in elderly patients may cause changes in body composition beyond those due to ageing. SUBJECTS: Twenty-one patients (15 male) with documented pituitary disease and 24 controls (17 male) matched for age, height, weight and BMI, all over the age of 60, in whom GH status had been defined by a 24-hour GH profile and an arginine stimulation test. MEASUREMENTS: Serum was taken for fasting IGF-l and IGFBP-1 estimations. Total and regional FM and FFM were determined using dual-energy X-ray absorptiometry. RESULTS: FM (median (range)) was increased in the patients, 27.76 (19.25-50.24) vs 21.23 (8.81-49.15) kg in the controls (P < 0.005). FM was significantly increased in the arms, legs and trunk in the patients compared with the controls. The proportion of fat deposited centrally did not differ significantly between the two groups (57.0% (47.6-65.1) in the patients vs 55.3% (44.1-63.8) in the controls, P = 0.25). There was an inverse relation between total FM and serum IGFBP-1 present in the patients, p = -0.632, P < 0.005, and in the controls p = -0.467, P < 0.05, but the relation between total FM and area under the GH profile was significant only in the controls (p = -0.651, P < 0.001) and not in the patients. FFM (51.19 (26.96-69.18) kg in the patients vs 51.55 (32.35-60.53) kg in the controls, P = 0.99) and serum IGFBP-1 levels did not differ significantly between the two groups. CONCLUSION: Organic growth hormone deficiency causes changes in body composition beyond the changes associated with the ageing process. These changes differ from those seen in younger GH deficient adults in that they are limited to an increase in FM with no change in FFM. These findings indicate that even in the elderly, in whom GH secretion is normally very low, the additional imposition of GH deficiency due to organic disease has significant biological impact.     

An early rise in urine N-telopeptide predicts the growth response of normal prepubertal short children to growth hormone therapy

The effects of growth hormone (GH) therapy on biochemical markers of bone turnover were investigated in 11 short prepubertal children without GH deficiency by measuring serum osteocalcin, a marker for bone formation, and urinary concentrations of pyridinium cross-linked amino acids of collagen (PCL), and the peptide-bound pyridinoline residue N-telopeptide (NT), which are specific markers for bone resorption. GH treatment for three months increased bone turnover in this group of children: urinary PCL concentrations increased from 69 +/- 6.2 to 114 +/- 9.3 nmol/mmol Cr (p < 0.01), and urinary NT levels increased from 512 +/- 65 to 766 +/- 74 pmol BCE/mumol Cr (p = 0.058). Serum osteocalcin concentrations increased from 13.64 +/- 2.57 ng/ml to 26.45 +/- 1.39 ng/ml (p < 0.01). The increment in 12-hour urinary concentrations of PCL was highly correlated with the increment in 12-hour urinary NT levels (r = 0.92, p < 0.01). Stepwise multiple regression analysis revealed that the urinary concentrations of NT after 3 months of GH therapy were the best predictor of growth after 12 months of treatment (r = 0.78, F = 7.9, p = 0.037).