Adult growth hormone (GH)-deficient patients demonstrate heterogeneity between childhood onset and adult onset before and during human GH treatment. Adult Growth Hormone Deficiency Study Group.

The onset of adult GH deficiency may be during either adulthood (AO) or childhood (CO), but potential differences have not previously been examined. In this study the baseline and GH therapy (12.5 micrograms/kg per day) data from CO (n = 74; mean age 29 yr) and AO (n = 99; mean age 44 yr) GH-deficient adult patients have been compared. The first 6 months comprised randomized, double-blind treatment with GH or placebo, then all patients were GH-treated for a further 12 months. At baseline the height, body weight, body mass index, lean body mass, and waist/hip ratio of AO patients were significantly (P < 0.001) greater than in CO patients. Serum insulin-like growth factor-I (IGF-I) levels were below normal but were lower in CO than AO patients (P < 0.001), and the correlation with IGF binding protein-3 was stronger in CO than in AO patients. Osteocalcin concentration in CO patients was above the normal range and significantly greater than in AO patients. Both groups had significant psychosocial distress, but the deviation from normality was greater in AO patients. Throughout GH therapy there was a significant increase in lean body mass and significant decrease in percent body fat and sum of skinfolds in each group. Wais/hip ratio was decreased by long-term therapy in AO but not CO patients. Total and low density lipoprotein cholesterol levels were decreased from baseline at 6 months in AO but not CO patients and high density lipoprotein cholesterol was increased in both groups throughout therapy. IGF-I and IGF binding protein-3 were increased into the normal range by GH therapy in both groups. Mean osteocalcin level in AO patients was increased at 6 months with no further change with GH therapy, whereas in CO patients there was a steep increase up to 12 months but then a sharp decrease. Nottingham Health Profile scores showed significant improvements in physical mobility and energy at 18 months of therapy in AO patients but no consistent effects in CO patients. GH-induced side effects were mainly reported by AO patients; very few CO patients reported treatment-emergent adverse events. These results demonstrate significant differences in clinical and biochemical presentation and responses to therapy of the adult GH deficiency syndrome. This is consistent with the existence of two entities, developmental (CO) and metabolic (AO), and the different functions of GH at different periods of life.

Treatment of post-menopausal osteoporosis with a combination of growth hormone and pamidronate: a placebo controlled trial.

OBJECTIVE: It is known that growth hormone can induce accelerated bone turnover in GH deficient people as well as healthy elderly people. In this study we examined the effect of recombinant human GH (rhGH) on bone mineral mass and bone turnover in the presence of the bone resorption inhibiting agent, pamidronate. Effects on body composition were also studied. METHODS: Twenty-one post-menopausal osteoporotic women were treated with the bisphosphonate pamidronate during 12 months. During the initial 6 months rhGH (0.0675 IU/kg, 3 times/week) was administered in a placebo controlled fashion (10 vs 11 patients). MEASUREMENTS: Bone mineral content (BMC) of the lumbar spine and femoral neck was measured with dual-energy X-ray absorptiometry and BMC of the distal and proximal forearm with single-photon absorptiometry. Body composition was measured with bioelectrical impedance and total body dual-energy X-ray absorptiometry. Serum IGF-I and biochemical indices of bone turnover were also measured. RESULTS: The group treated with rhGH showed a two to three-fold increase in serum IGF-I levels. No effects on bone mineral mass were observed in the group treated with rhGH, either after the initial 6 months of treatment with rhGH or after the total period of 12 months. In women treated with pamidronate, however, a consistent increase of about 5% at the lumbar spine and somewhat less in the distal forearm was reached from 6 months onwards. In neither group was any change observed in BMC at the femoral neck or forearm. Compared to baseline, the biochemical measurements of bone turnover showed a decrease of about 50% in the pamidronate treated group, but this effect was blunted in the group additionally treated with rhGH. The body composition measurements showed clear effects of rhGH administration: a decrease in fat mass of about 5% and an increase in lean body mass of about 3%. However, these effects disappeared after the treatment with rhGH was stopped and both fat mass and lean body mass returned to initial values. CONCLUSIONS: The present study suggests that treatment with rhGH blunted both the pamidronate induced accumulation of bone mineral mass and the reduction of biochemical markers of bone turnover. Furthermore, the positive effect of rhGH on body composition disappears completely after cessation of treatment with rhGH.

Combined treatment of growth hormone and the bisphosphonate pamidronate, versus treatment with GH alone, in GH-deficient adults: the effects on renal phosphate handling, bone turnover and bone mineral mass.

OBJECTIVE: A potential drawback of GH replacement therapy in GH deficient (GHD) patients is the initial decrease in bone mass. The present study investigates the effects of the addition of pamidronate to GH replacement therapy in adult GHD subjects, on serum PTH and 1,25-dihydroxyvitamin D3 (1.25-(OH)2D3) levels, renal phosphate handling, bone turnover and bone mineral content (BMC). DESIGN: Six GHD adult patients were studied for two periods of 6 months with a wash-out period of 3 years. In the first period they were treated with conventional replacement therapy and GH. In the second study period GH treatment was identical, while after 2 weeks 150 mg pamidronate per day was added. RESULTS: In the first study period (GH only) there was a significant increase of phosphate reabsorption, without a change in serum PTH and 1.25-(OH)2D3 levels. This suggests a specific effect of GH or IGF-I on renal phosphate handling. This was supported by the close correlation between serum IGF-I levels and TmP/GFR (r = 0.75, P < 0.0001). When GH was administered together with pamidronate, this correlation was less, but remained significant (r = 0.44, P < 0.001). The increase in bone turnover and decrease in BMC, as initially observed during GH replacement therapy alone, were attenuated by simultaneous pamidronate administration. The decline in lumbar spine BMC (measured with dual-photon absorptiometry) at 6 months was -3.1 +/- 1.5% during GH replacement therapy alone vs an increase of +3.8 +/- 2.0% during the administration of the combination of GH and pamidronate (measured with dual-energy X-ray absorptiometry). At the distal and proximal forearm the changes amounted to -0.5 +/- 3.4% vs +4.5 +/- 1.8% and -1 +/- 1.2% vs +1.2 +/- 1.1% respectively. CONCLUSIONS: This study shows that the addition of a bisphosphonate to GH replacement therapy in GHD adults counteracts the GH (or IGF-I) induced increase in renal phosphate reabsorption. Furthermore, it reduces GH induced bone turnover and prevents the initial decrease in bone mineral content seen during GH treatment alone, resulting in a beneficial effect on bone mineral mass. Pamidronate might therefore be an important adjunct to GH replacement therapy in adults with GHD and severe osteopenia during the early phase of GH induced stimulation of bone turnover.

The effects of human growth hormone (GH) administration in GH-deficient adults: a 20-day metabolic ward study.

The early effects of human GH administration in GH-deficient (GHD) adults on protein, electrolyte homeostasis, and body composition were investigated in a metabolic ward study. Four patients were studied. In addition to a constant caloric and nitrogen (N)-sufficient diet, the patients received GH for 15 days in dosages of 12.5-25 micrograms/kg.day, with a maximum of 1.48 mg (4 IU)/day. GH replacement therapy was well tolerated by all patients. There was a slowly increasing effect on IGF-I levels, which reached a maximum after 8-12 days. The lowered IGFBP-3 levels normalized quicker, reaching maximum circulating concentrations 3 days after the start of GH treatment. Insulin concentrations maximally increased after 5 days, after which they leveled off. Insulin-like growth factor-binding protein-1 levels were maximally suppressed after 2 days of treatment. N balance became positive in all patients (mean, +2.8 +/- 0.2 g/day). Maximal N retention occurred after 2-5 days of GH administration, after which adaptation occurred. This degree of N retention represents a formation of 20 g muscle/day, which would mean an increase of 3.6 kg muscle over a period of 6 months of GH replacement therapy. A rapidly occurring positive sodium balance was observed within 24-72 h. Maximal sodium retention amounted to 61 mmol/day. It slowly decreased spontaneously over the subsequent 12 days. In parallel, rapid changes in bioelectrical impedance analysis (BIA) were observed. There was a close parallel between the net cumulative sodium retention and the decrease in BIA in these patients during the first 15 days of GH therapy. This suggests that the calculation of body composition compartments on the basis of BIA measurements during the initial phase of GH replacement does not represent actual changes in fat mass. This was substantiated with measurements of body composition using dual energy x-ray absorptiometry. In conclusion, measurements of early metabolic changes in GHD adults during the first 15 days after the start of GH replacement indicate that IGF-I values reach maximal levels only after 8-12 days, that the measurements of changes in IGFBP-1 and IGFBP-3 levels probably do not contribute to a determination of the optimal GH replacement dose, that maximal N-retaining effects occur within 2-5 days, after which adaptation occurs, that massive sodium retention occurs during this period, which spontaneously levels off, and that cumulative sodium retention closely correlates during this period with changes in BIA.(ABSTRACT TRUNCATED AT 400 WORDS)

Contrast echocardiography in pulmonary hypertension: observations explaining the early closure of the pulmonic valve.

We studied pulmonary artery flow patterns in 11 patients with pulmonary hypertension and 11 normal volunteers, by means of peripheral intravenous injections of 5% dextrose solution during M-mode echocardiography. Most of the patients had moderate to severe pulmonary hypertension. All normal subjects had antegrade flow throughout systole until just prior to pulmonic valve closure; none of the patients with pulmonary hypertension had continued antegrade flow throughout systole. The seven with early closure of the pulmonic valve showed abnormal retrograde flow of contrast in mid- to late systole; this was never observed in normal subjects. We conclude that early closure of the pulmonic value is seen in patients with early systolic retrograde flow in the pulmonary artery. A hypothesis for the pathogenesis of this flow is presented. Contrast M-mode echocardiography is a valuable new tool for the study of flow characteristics over the pulmonic valve. In patients with poor quality pulmonic valve echograms during systole, retrograde flow during midsystole imaged by contrast echocardiography may substitute for early closure as a sign of pulmonary hypertension.

Correlation between velocity measurements from Doppler echocardiography and from M-mode contrast echocardiography.

The slope of an individual contrast trajectory on M-mode contrast echocardiography represents a physiological variable similar to that measured by Doppler echocardiography: the projection of the intracardiac velocity vector in the direction of the sound beam. To test the hypothesis that M-mode contrast echocardiography slope measurement can yield information quantitatively similar to Doppler measurements, we performed both simultaneously in 11 normal volunteers. A pulsed Doppler unit capable of simultaneous M-mode and Doppler display was used. Contrast was obtained by intravenous injection of 5% dextrose. Two independent observers measured velocity simultaneously by both techniques at eight to 16 points per subject. One observer repeated the measurements a month later. All subjects had contrast, and 10 had sufficient quality tracings for simultaneous Doppler and contrast slope measurements. The correlation between velocity measurements by both techniques was good, though velocities by Doppler echocardiography were less than by M-mode contrast echocardiography. We conclude that the component of flow velocity towards or away from the transducer can be measured from M-mode contrast trajectory slopes as well as by Doppler echocardiography. M-mode contrast echocardiography may provide a practical method for verifying or calibrating Doppler measurements in vivo.