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.     

Effect of acute pharmacological reduction of plasma free fatty acids on growth hormone (GH) releasing hormone-induced GH secretion in obese adults with and without hypopituitarism

In obesity, there is a markedly decreased GH secretion. The diagnosis of GH deficiency (GHD) in adults is based on peak GH responses to stimulation tests. In the severely obese, peak GH levels after pharmacological stimulation are often in the range that is observed in hypopituitary patients. To distinguish obese subjects from GHD patients, it will be necessary to demonstrate that reduced GH responsiveness to a given test is reversible in the former, but not in the latter, group. Recent studies have shown that reduction of plasma free fatty acids (FFA) with acipimox in obese patients restores their somatotrope responsiveness. There are no data evaluating GH responsiveness to acipimox plus GHRH in obese adults with hypopituitarism. The aim of the present study was to evaluate the effect of acute pharmacological reduction of plasma FFA on GHRH-mediated GH secretion in obese normal subjects and obese adults with hypopituitarism. Eight obese patients with a body mass index of 34.2+/-1.2; eight obese adults with hypopituitarism, with a body mass index of 35.5+/-1.9; and six control subjects were studied. All the patients showed an impaired response to an insulin-tolerance test (0.15 U/kg, i.v.), with a peak GH secretion of less than 3 microg/L. Two tests were carried out. On one day, they were given GHRH (100 microg, i.v., 0 min), preceded by placebo; and blood samples were taken every 15 min for 60 min. On the second day, they were given GHRH (100 microg, i.v., 0 min), preceded by acipimox (250 mg, orally, at -270 min and -60 min); and blood samples were taken every 15 min for 60 min. The administration of acipimox induced a FFA reduction during the entire test. Normal control subjects had a mean peak (microg/L) of 23.8+/-4.8 after GHRH-induced GH secretion; previous acipimox administration increased GHRH-induced GH secretion, with a mean peak of 54.7+/-14.5. In obese patients, GHRH-induced GH secretion was markedly reduced, with a mean peak (microg/L) of 3.9+/-1; previous administration of acipimox markedly increased GHRH-mediated GH secretion, with a mean peak of 16.0+/-3.2 (P < 0.05). In obese adults with hypopituitarism, GHRH-induced GH secretion was markedly reduced, with a mean peak (microg/L) of 2+/-0.7; previous acipimox administration did not significantly modify GHRH-mediated GH secretion, with a mean peak of 3.3+/-1.1 (P < 0.05). The GH response of obese patients and obese adults with hypopituitarism was similar after GHRH alone. In contrast, the GH response after GHRH plus acipimox, was markedly decreased in obese adults with hypopituitarism (mean peak, 3.3+/-1.1), compared with obese patients (mean peak, 16.0+/-3.2) (P < 0.05) and control subjects (mean peak, 54.7+/-14.5) (P < 0.01). In conclusion, GH secretion, after GHRH-plus-acipimox administration, is reduced in obese adults with hypopituitarism patients, when compared with obese normal patients. Testing with GHRH plus acipimox is safe and is free from side effects and could be used for the diagnosis of GHD in adults.     

Lack of effects of recombinant growth hormone on muscle function in patients requiring prolonged mechanical ventilation: a prospective, randomized, controlled study

OBJECTIVE: To evaluate the benefit of recombinant human growth hormone administration on muscle strength and duration of weaning in critically ill patients undergoing prolonged mechanical ventilation. DESIGN: Prospective, randomized, controlled, single-blind study. SETTING: Intensive care unit. Patients: Twenty patients requiring > or = 7 days of mechanical ventilation for acute respiratory failure. INTERVENTION: Random assignment to receive either 0.43 IU (approximately 0.14 mg) recombinant growth hormone/kg body weight/day (treated group), or saline (nontreated group) for 12 days. MEASUREMENTS AND MAIN RESULTS: Nutritional support was guided by indirect calorimetry. Cumulative nitrogen balance was positive throughout the study period in the treated group 17.3 (44.9 +/- 17.3[SEM] g/12 days) vs. the nontreated group (-65.8 +/- 11.8 g/12 days) (p<.0001). Despite similar initial plasma concentrations, recombinant growth hormone supplementation resulted in marked increases in growth hormone, insulin like growth factor-1, and insulin concentrations (p<.05, .02, and .0001, respectively, vs. nontreated group). Body impedance determined net fat-free mass increased in the treated group (0.8 +/- 0.6 kg) vs. the nontreated group (-1.1 +/- O.5 kg) (p<.03). Initial peripheral muscle function, assessed by computer-controlled electrical stimulation of the adductor pollicis, was similarly lower in treated and nontreated groups than sex and age-matched normal controls, and decreased further during the study period. Arterial blood gases, cumulative total mechanical ventilation time, and number of hrs/day of mechanical ventilation during weaning were similar in both patient groups. Only three of the ten patients in each group were weaned from mechanical ventilation by day 12. CONCLUSIONS: Daily administration of recombinant growth hormone in mechanically ventilated patients with acute respiratory failure promotes a marked nitrogen retention. However, this reaction is accompanied neither by an improvement in muscle strength nor by a shorter duration of ventilatory supports.     

The importance of growth hormone in the regulation of erythropoiesis, red cell mass, and plasma volume in adults with growth hormone deficiency

Total body water (TBW) is reduced in adult GH deficiency (GHD) largely due to a reduction of extracellular water. It is unknown whether total blood volume (TBV) contributes to the reduced extracellular water in GHD. GH and insulin-like growth factor I (IGF-I) have been demonstrated to stimulate erythropoiesis in vitro, in animal models, and in growing children. Whether GH has a regulatory effect on red cell mass (RCM) in adults is not known. We analyzed body composition by bioelectrical impedance and used standard radionuclide dilution methods to measure RCM and plasma volume (PV) along with measuring full blood count, ferritin, vitamin B12, red cell folate, IGF-I, IGF-binding protein-3, and erythropoietin in 13 adult patients with GHD as part of a 3-month, double blind, placebo-controlled trial of GH (0.036 U/kg.day). TBW and lean body mass significantly increased by 2.5 +/- 0.53 kg (mean +/- SEM; P < 0.004) and 3.4 +/- 0.73 kg (P < 0.004), respectively, and fat mass significantly decreased by 2.4 +/- 0.32 kg (P < 0.001) in the GH-treated group. The baseline RCM of all patients with GHD was lower than the predicted normal values (1635 +/- 108 vs. 1850 +/- 104 mL; P < 0.002). GH significantly increased RCM, PV, and TBV by 183 +/- 43 (P < 0.006), 350 +/- 117 (P < 0.03), and 515 +/- 109 (P < 0.004) mL, respectively. The red cell count increased by 0.36 +/- 0.116 x 10(12)/L (P < 0.03) with a decrease in ferritin levels by 39.1 +/- 4.84 micrograms/L (P < 0.001) after GH treatment. Serum IGF-I and IGF-binding protein-3 concentrations increased by 3.0 +/- 0.43 (P < 0.001) and 1.3 +/- 0.15 (P < 0.001) SD, respectively, but the erythropoietin concentration was unchanged after GH treatment. No significant changes in body composition or blood volume were recorded in the placebo group. Significant positive correlations could be established between changes in TBW and TBV, lean body mass and TBV (r = 0.78; P < 0.04 and r = 0.77; P < 0.04, respectively), and a significant negative correlation existed between changes in fat mass and changes in TBV in the GH-treated group (r = -0.95; P < 0.02). We conclude that 1) erythropoiesis is impaired in GHD; 2) GH stimulates erythropoiesis in adult GHD; and 3) GH increases PV and TBV, which may contribute to the increased exercise performance seen in these patients.     

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.     

The effects of growth hormone in children with a GH deficiency: a report of 5 cases

The authors describe 5 cases, 3 boys and 2 girls, with idiopathic growth hormone deficiency in prepubertal age, treated with human growth hormone. In four of five cases the response to treatment with GH was relevant. Only in one case (F1) the response was negative. The results of this study confirm that rhGH is a safe and effective therapy in children with GHD.     

Reduced growth hormone (GH) responsiveness to combined GH-releasing hormone and pyridostigmine administration in the Prader-Willi syndrome

Pea aphid (Acyrthosiphon pisum) clones have been shown to be adapted to particular host plant species but it is unknown whether there are host races. A 1101 base pair region of the mitochondrial cytochrome oxidase I gene (COI) was sequenced for 21 pea aphid clones that had been collected from different host plants in Canada and the U.S.A. Only five closely related mitochondrial haplotypes were found. A maximum likelihood phylogeny was estimated for these five haplotypes and four related aphid species: Acyrthosiphon macrosiphum, A. kondoi, Fimbriaphis fimbriata, and Macrosiphum creelii. Pea aphids from the same host plant species were no more likely to have the same mitochondrial haplotype than aphids from different host plant species. In addition, aphids from the same geographical regions were no more likely to have the same mitochondrial haplotype than aphids from different geographic regions. I therefore reject the hypothesis that there are monophyletic host races of the pea aphid.     

Neuroendocrinology of prolonged critical illness: effects of exogenous thyrotropin-releasing hormone and its combination with growth hormone secretagogues

CENP-B is a constitutive centromere DNA-binding protein that is conserved in a number of mammalian species and in yeast. Despite this conservation, earlier cytological and indirect experimental studies have provided conflicting evidence concerning the role of this protein in mitosis. The requirement of this protein in meiosis has also not previously been described. To resolve these uncertainties, we used targeted disruption of the Cenpb gene in mouse to study the functional significance of this protein in mitosis and meiosis. Male and female Cenpb null mice have normal body weights at birth and at weaning, but these subsequently lag behind those of the heterozygous and wild-type animals. The weight and sperm content of the testes of Cenpb null mice are also significantly decreased. Otherwise, the animals appear developmentally and reproductively normal. Cytogenetic fluorescence-activated cell sorting and histological analyses of somatic and germline tissues revealed no abnormality. These results indicate that Cenpb is not essential for mitosis or meiosis, although the observed weight reduction raises the possibility that Cenpb deficiency may subtly affect some aspects of centromere assembly and function, and result in reduced rate of cell cycle progression, efficiency of microtubule capture, and/or chromosome movement. A model for a functional redundancy of this protein is presented.     

Growth hormone versus placebo treatment for one year in growth hormone deficient adults: increase in exercise capacity and normalization of body composition

OBJECTIVE: Studies with GH substitution in GH-deficient (GHD) adults lasting more than 6 months have so far been uncontrolled. End-points such as physical fitness and body composition may be subject to a considerable placebo effect which weakens the validity of open studies. We therefore tested GH (2 IU/m2 per day) versus placebo treatment for 12 months. DESIGN: Twenty-nine patients (mean age 45.5 +/- 2.0 years) with adult-onset GHD were studied in a double-blind, parallel design. Measurements of body composition by means of conventional anthropometry, bioelectrical impedance (BIA), CT scan and DEXA scan, exercise capacity, and isometric muscle strength were performed at baseline and after 12 months treatment. For body composition measurements a control group of 39 healthy, age and sex-matched subjects was included. RESULTS: Sum of skinfolds (SKF) at 4 sites decreased significantly after GH treatment. Total body fat (TBF) as assessed by DEXA and BIA was elevated at baseline but normalized after GH. TBF assessed by SKF revealed significantly higher levels compared to DEXA and BIA, although all estimates intercorrelated closely. Visceral and subcutaneous abdominal fat decreased by 25 and 17%, respectively after GH (P < 0.01) to levels no longer different from the control group. CT of the mid thigh revealed a significant reduction in fat tissue and a significant increase in muscle volume after GH treatment, both of which resulted in a normalization of the muscle: fat ratio (%) (placebo: 58:42 (baseline) vs 58:42 (12 months); GH: 66:34 (baseline) vs 72:28 (12 months) (P = 0.002); normal subjects: 67:33 (P < 0.05 when compared to 12 months placebo data)). Total body resistance and resistance relative to muscle volume decreased significantly after GH treatment suggesting over-hydration as compared to normal subjects. Exercise capacity (kJ) increased significantly after GH treatment (placebo: 54.7 +/- 9.8 (baseline) vs 51.6 +/- 8.2 (12 months); GH: 64.9 +/- 13.3 (baseline) vs 73.5 +/- 13.6 (12 months) (P < 0.05)). Isometric quadriceps strength increased after GH but no treatment effect could be detected owing to a small increase in the placebo group. Serum IGF-I levels (microgram/l) were low baseline and increased markedly after GH treatment to a level exceeding that of normal subjects (270 +/- 31 (12 months GH) vs 156 +/- 8 (normal subjects (P < 0.01)). The levels of serum electrolytes and HbA1c remained unchanged. The number of adverse effects were higher in the GH group after 3 months, but not after 6 and 12 months. CONCLUSIONS: (1) The reduction in excess visceral fat during GH substitution is pronounced and sustained; (2) beneficial effects on total body fat, muscle volume and physical fitness can be reproduced during prolonged placebo-controlled conditions; (3) uncontrolled data on muscle strength must be interpreted with caution; (4) a daily GH substitution dose of 2 IU/m2 seems too high in many adult patients.     

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.     

Decreased expression of transforming growth factor beta 1 in blood plasma of guinea pigs fed vitamin C deficient diet

Liposarcoma is a malignant neoplasm of soft tissue. Its occurrence in the head and neck region is extremely rare. The case of a 26-year-old woman with neck liposarcoma is presented. The clinical manifestation, histopathology, possibility and results of the tumor treatment are described according to the literature.     

Effects of luteinizing hormone-releasing hormone analog-induced pubertal delay in growth hormone (GH)-deficient children treated with GH: preliminary results

To study the effect of delaying epiphyseal fusion on the growth of GH-deficient children, we studied 14 pubertal, treatment naive, GH-deficient patients (6 girls and 8 boys) in a prospective, randomized, placebo-controlled trial. Chronological age was 14.5 +/- 0.5 yr, and bone age was 11.6 +/- 0.3 yr (mean +/- SEM) at the beginning of the study. Patients were assigned randomly to receive GH and LH-releasing hormone (LHRH) analog (n = 8) or GH and placebo (n = 6) during 3 yr, with planned continuation of GH treatment until epiphyseal fusion. Patients were measured with a stadiometer and had serum LHRH tests, serum testosterone (boys), serum estradiol (girls), and bone age performed every 6 months. Patients treated with GH and LHRH analog showed a clear suppression of their pituitary-gonadal axis and a marked delay in bone age progression. We observed a greater gain in height prediction in these patients than in the patients treated with GH and placebo after 3 yr of treatment (mean +/- SEM, 14.0 +/- 1.6 vs. 8.0 +/- 2.4 cm; P < 0.05). These preliminary findings suggest that delaying epiphyseal fusion with LHRH analog in pubertal GH-deficient children treated with GH increases height prediction and may increase final height compared to treatment with GH alone.     

Co-expression of bovine growth hormone (GH) and human GH antagonist genes in transgenic mice

Bovine growth hormone (bGH) transgenic (Tg) mice have been shown to possess enhanced growth phenotypes and exhibit severe glomerulosclerosis. One amino acid substitution in GH, i.e. G119R in bGH or G120R in human (h) GH, results in GH antagonists (GHAs). GHA-Tg mice exhibit dwarf phenotypes and normal kidneys. In order to investigate the possibility of GHAs as pharmaceutical agents for the treatment of human diseases with excessive GH levels, we cross bred mice that express bGH with those that express hGHA. Double positive Tg mice were identified that express both genes although at different levels. Kidney histological studies revealed that the double positive Tg mice with high GHA/GH expression ratios possessed normal or near normal kidneys, whereas those with low GHA/GH ratios exhibited glomerulosclerosis similar to GH-Tg mice. Thus, co-expression of GH and GHA genes in vivo results in animal phenotypes and kidney histopathologies which are a reflection of the relative expression levels of each gene.     

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.     

Free and total insulin-like growth factors and insulin-like growth factor binding proteins during 14 days of growth hormone administration in healthy adults

The objective was to investigate the effect of growth hormone (GH) administration on circulating levels of free insulin-like growth factors (IGFs) in healthy adults. Eight healthy male subjects were given placebo and two doses of GH (3 and 6 IU/m2 per day) for 14 days in a double-blind crossover study. Fasting blood samples were obtained every second day. Free IGF-I and IGF-II were determined by ultrafiltration of serum. Total IGF-I and IGF-II were measured after acid-ethanol extraction. In addition, GH, insulin, IGF binding protein 1 (IGFBP-1) and IGFBP-3 were measured. Serum-free and total IGF-I increased in a dose-dependent manner during the 14 days of GH administration. After 14 days, serum-free IGF-I values were 610 +/- 100 ng/l (mean +/- SEM) (placebo), 2760 +/- 190 ng/l (3 IU/ m2) and 3720 +/- 240 ng/l (6 IU/m2) (p = 0.0001 for 3 and 6 IU/m2 vs placebo; p = 0.004 for 3 IU/m2 vs 6 IU/m2). Total IGF-I values were 190 +/- 10 micrograms/l (placebo), 525 +/- 10 (3 IU/m2), and 655 +/- 40 micrograms/l (6 IU/m2) (p < 0.0001 for 3 and 6 IU/m2 vs placebo; p = 0.04 for 3 IU/m2). There were no differences in the levels of free or total IGF-II during the three study periods. Insulin-like growth factor binding protein 1 was decreased during GH administration (p = 0.04 for placebo vs 3 IU/m2; p = 0.006 for placebo vs 6 IU/m2). In conclusion, fasting serum free IGF-I increased dose dependently during GH administration and free IGF-I increased relatively more than total IGF-I. This may partly be due to the decrease in IGFBP-1.     

Novel compound heterozygous mutations of growth hormone (GH) receptor gene in a patient with GH insensitivity syndrome

A girl with severe growth retardation had the clinical features of Laron syndrome. Her serum insulin-like growth factor-I level was completely unresponsive to exogenous GH administration. The serum GH-binding protein (GHBP) level was below the detectable limit in the patient, but it was normal in her parents and brother. Her parents and brother were normal in their height. Amplification with PCR and direct sequencing of her GH receptor gene revealed compound heterozygous mutations. The allele from her mother contained a transversion of G to T in exon 7 that could introduce a stop codon in place of a glutamic acid at amino acid 224. Another mutation was found in the allele in her father and also identified in her brother. It was a C deletion at position 981 in exon 10 that could introduce a frame shift, thereby causing the production of 20 novel amino acids (310-329) instead of the wild-type sequence, the premature termination at codon 330, and the subsequent deletion of the C terminal portion of the intracellular domain. RT-PCR of her father's lymphocytes and sequencing of its complementary DNA revealed that only the wild-type GH receptor messenger RNA was expressed in his lymphocytes, though the mechanism remains unclear. These results suggest that neither of the mutant alleles could generate a functional GH receptor, which would be consistent with the patient's severe growth retardation and undetectable serum GHBP.     

Effects of growth hormone (GH) replacement on bone metabolism and mineral density in adult onset of GH deficiency: results of a double-blind placebo-controlled study with open follow-up

It is known that GH stimulates bone turnover and that GH-deficient adults have a lower bone mass than healthy controls. In order to evaluate the influences of GH replacement therapy on markers of bone turnover and on bone mineral density (BMD) in patients with adult onset GH deficiency, a double-blind placebo-controlled study of treatment with recombinant human GH (rhGH; mean dose 2.4 IU daily) in 20 patients for 6 months and an extended open study of 6 to 12 months were conducted. Eighteen patients, fourteen men and four women, with a mean age of 44 years with adult onset GH deficiency were evaluated in the study. Compared with placebo, after 6 months serum calcium (2.39 +/- 0.02 vs 2.32 +/- 0.02 mmol/l, P = 0.037) and phosphate (0.97 +/- 0.06 vs 0.75 +/- 0.05 mmol/l, P = 0.011) increased and the index of phosphate excretion (0.03 +/- 0.03 vs 0.19 +/- 0.02, P < 0.001) decreased significantly, and there was a significant increase in the markers of bone formation (osteocalcin, 64.8 +/- 11.8 vs 17.4 +/- 1.8 ng/ml, P < 0.001; procollagen type I carboxyterminal propeptide (PICP), 195.3 +/- 26.4 vs 124.0 +/- 15.5 ng/ml, P = 0.026) as well as those of bone resorption (type I collagen carboxyterminal telopeptide (ICTP), 8.9 +/- 1.2 vs 3.3 +/- 0.5 ng/ml, P < 0.001; urinary hydroxyproline, 0.035 +/- 0.006 vs 0.018 +/- 0.002 mg/100 ml glomerular filtration rate, P = 0.009). BMD did not change during this period of time. IGF-I was significantly higher in treated patients (306 +/- 45.3 vs 88.7 +/- 22.5 ng/ml, P < 0.001). An analysis of the data compiled from 18 patients treated with rhGH for 12 months revealed similar significant increases in serum calcium and phosphate, and the markers of bone turnover (osteocalcin, PICP, ICTP, urinary hydroxyproline). Dual energy x-ray absorptiometry (DXA)-measured BMD in the lumbar spine (1.194 +/- 0.058 vs 1.133 +/- 0.046 g/cm2, P = 0.015), femoral neck (1.009 +/- 0.051 vs 0.936 +/- 0.034 g/cm2, P = 0.004), Ward's triangle (0.881 +/- 0.055 vs 0.816 +/- 0.04 g/cm2, P = 0.019) and the trochanteric region (0.869 +/- 0.046 vs 0.801 +/- 0.033 g/cm2, P = 0.005) increased significantly linearly (compared with the individual baseline values). At 12 months, BMD in patients with low bone mass (T-score < -1.0 S.D.) increased more than in those with normal bone mass (lumbar spine 11.5 vs 2.1%, P = 0.030, and femoral neck 9.7 vs 4.2%, P = 0.055). IGF-I increased significantly in all treated patients. In conclusion, treatment of GH-deficient adults with rhGH increases bone turnover for at least 12 months. BMD in the lumbar spine and the proximal femur increases continuously in this time (open study) and the benefit is greater in patients with low bone mass. Therefore, GH-deficient patients exhibiting osteopenia or osteoporosis should be considered candidates for GH supplementation. However, long-term studies are needed to establish that the positive effects on BMD are persistent and are associated with a reduction in fracture risk.