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.     

Ciaglia's percutaneous dilatative tracheostomy in intensive care. Perioperative complications and long-term results

BACKGROUND AND AIM: The introduction of percutaneous tracheostomic techniques using dilatation (PDT) has led to the gradual disuse of conventional methods of surgery. The aim of this study was to evaluate ventilatory function in critical patients during the execution of PDT using Ciaglia's method as well as, in the postoperative phase, the long-term results, namely endotracheal lesions and cosmetic deformities of the stoma. EXPERIMENTAL DESIGN: A prospective study was carried out on a consecutive series of adult patients. SETTING: The intensive care ward of a 600-bed teaching hospital. PATIENTS: A group of 50 critical patients undergoing PDT from 1993 to 1996. Valuations of ventilatory function: expiratory volume (EV), PaO2 and PaCO2, were calculated in 40 patients undergoing PDT. Endoscopic controls of the trachea were performed in 21 surviving patients 60 days after the removal of the tracheostomic tube and a cosmetic evaluation of the tube insertion site was also made in the same patients. RESULTS: During PDT a mean reduction of EV was observed of 1.41/min and PaO2 values also diminished 15% accompanied by a 14.2% increase in PaCO2. The endoscopic control performed after 60 days in 21 out of 50 patients revealed a subglottal stenosis in 1 patient, the presence of nonstenosing cicatricial granuloma in 2 patients, edema in 2 patients and dysepithelisation of the tracheal mucosa in a further 2 patients. The remaining 66% showed flattening of the mucosa and complete restitutium ad integrum. No usurpations and cicatricial tractions of the tube insertion site were observed. CONCLUSIONS: This prospective study of intraoperative ventilatory function and the final outcome of PDT according to Ciaglia confirms that this is a reliable technique for the ventilatory management of critical patients with a low percentage of long-term complications.     

Effects of short- and long-term dexamethasone treatment on growth and growth hormone (GH)-releasing hormone (GRH)-GH-insulin-like growth factor-I axis in conscious rats

Although the inhibitory effects of a chronic excess of glucocorticoids (GC) on body growth and GH secretion are well established, the mechanisms involved remain unclear. In this study, we examined the chronic effects of a high dose of dexamethasone (DEX) on spontaneous GH secretion and insulin-like growth factor (IGF)-I in conscious rats. The animals were given daily i.p. injections of DEX (200 microg/day) for either one or four weeks. Body growth assessed by tibia length and serum IGF-I levels was significantly inhibited 1 week after treatment. By contrast, spontaneous GH secretion was not altered 1 week after the treatment. Neither hypothalamic GRH and somtatostain mRNA levels nor GH responses to GRH from single somatotropes were affected 1 week after the treatment. Four weeks after DEX treatment, body growth of the rats was noticeably suppressed. Interestingly, spontaneous GH secretion, hypothalamic GRH mRNA levels and GH responses to GRH were all inhibited 4 weeks after treatment. Pituitary GRH receptor mRNA levels were not altered 1 week after treatment, but increased after 4 weeks. These results indicate that a high dose of DEX initially impairs IGF-I production and subsequently inhibits spontaneous GH secretion in rats. Inhibition of spontaneous GH secretion resulting from chronic GC excess is due, at least in part, to the impairment of hypothalamic GRH synthesis and pituitary GH responsiveness. An increase in the pituitary GRH receptor may be caused by decreased GRH secretion.     

Metabolic clearance and secretion rates of porcine growth hormone in genetically lean and obese swine

The metabolic clearance rate (MCR) and the secretion rate (SR) of porcine growth hormone (pGH) have been examined in swine rendered genetically either lean or obese after 18 generations of selection for or against backfat thickness. At 15 weeks of age (when the muscle:fat ratio was greater than 1) the mean half-life (t1/2), MCR, and SR, for the obese, control, and lean swine were: t1/2 = 7.4, 8.9, and 9.8 min; MCR = 341, 279, and 158 ml/min; SR = 907, 802, and 520 ng/min, respectively. At 90 kg body weight (when muscle:fat ratio was less than 1, and the age was about 30 weeks) the data for obese, control, and lean swine were: t1/2 = 11.3, 12.0, and 11.7 min; MCR =305, 280, and 336 ml/min; SR= 535, 626, and 932 ng/min, respectively. The t1/2, MCR, and SR were not significantly different among the obese, control, and lean swine at either 15 weeks or 90 kg body weight. Comparing the two stages of development, the younger swine (15 weeks of age) had a shorter t1/2 (P less than .01), and secreted and cleared more pGH on a per kg body weight basis (P less than .05) than the older swine (90 kg bodyweight, about 30 weeks of age). However, the results suggest that the selection of swine for either leanness or fatness for 18 generations did not alter the MCR and SR of pGH. In addition, the differences observed between the younger and older swine suggest that GH is cleared at a more rapid rate and more GH is available per unit of mass in the younger animals.     

Treatment with human growth hormone in patients with Prader-Labhart-Willi syndrome reduces body fat and increases muscle mass and physical performance

Using a monoclonal antibody based ELISA, 600 pAN7-1 plasmid-tagged mutants of Penicillium paxilli were screened for paxilline accumulation and one paxilline-negative mutant, YI-20, was identified. A molecular analysis of this mutant showed that pAN7-1 was inserted at a single site but was present as 4-6 copies arranged in a head-to-tail tandem array. Rescue of flanking sequences and analysis of the corresponding genomic region revealed that YI-20 has an extensive deletion at the site of pAN7-1 integration. Probing of a CHEF gel with the same sequences showed that associated with the deletion is a rearrangement of chromosome Va. Targeted gene disruption of wild-type sequences adjacent to the site where pAN7-1 inserted, resulted in the generation of two additional paxilline-negative mutants; both were single crossovers with deletions extending outside the region mapped. Neither of these new mutants had a rearrangement of chromosome Va, suggesting that deletion of genes on this chromosome is responsible for the paxilline-negative phenotype. Telomeric fingerprinting of genomic digests of P. paxilli, combined with pulsed-field gel electrophoresis of chromosomal DNA, established that there are a minimum of eight chromosomes in this fungus.     

Recombinant human growth hormone decreases lung and liver tissue lipid peroxidation and increases antioxidant activity after thermal injury in rats

The effects of pulsed direct current (dc) electric fields on the frequency of spontaneous bursting in a model epileptic focus were studied. The high potassium hippocampal slice model was used to generate spontaneous burst firing activity similar to interictal spikes in the pyramidal cell layer of CA3. Electric fields were generated from platinum subdural electrodes placed in the perfusion bath. Three hundred and seventy-eight experimental trials were performed on 10 hippocampal slices from 10 rats and the effects of field polarity, field strength and duration of stimuli on firing frequency was examined. Hippocampal slices were oriented horizontally with the CA3 layer towards the positive electrode, the average interburst interval did not correlate significantly with polarity of the delivering pulses (one-way ANOVA, p = 0.96). Average interburst interval showed a significant correlation with pulse duration of 200 and 400 msec (p = 0.030 and p = 0.004, respectively). As a function of field strength, there were significant average interval changes for fields of 33, 46, and 73 mV/mm (p = 0.024, p = 0.001 and p = 0.001, respectively). In conclusion, CA3 burst firing activity in high potassium concentration can therefore be altered by electric fields.     

Effect of short-term hormone replacement therapy on left ventricular mass and contractile function

This study examined the effects of neonatal cocaine exposure on the rewarding properties of play in a modified T-maze. Animals were artificially reared from postnatal day (PND) 4-9 with drug concentrated in four daily feeds. There were four treatment groups, 40 mg/kg/day cocaine, 20 mg/kg/day cocaine, an artificially reared control and a surgery control. From PND 38-42, subjects were tested with a food reward (EXP 1) or a play reward (EXP 2). No deficits in learning were seen when the reward was food. The 20 mg/kg/day cocaine group, however, showed impaired learning and altered play behavior when the reward was access to a play partner. Neonatal cocaine exposure thus appears to differentially affect learning based on the type of reward presented.     

The importance of the lumpectomy surgical margin status in long-term results of breast conservation

BACKGROUND: The impact of the surgical margin status on long-term local control rates for breast cancer in women treated with lumpectomy and radiation therapy is unclear. METHODS: The records of 289 women with 303 invasive breast cancers who were treated with lumpectomy and radiation therapy from 1972 to 1992 were reviewed. The surgical margin was classified as positive (transecting the inked margin), close (less than or equal to 2 mm from the margin), negative, or indeterminate, based on the initial biopsy findings and reexcision specimens, as appropriate. Various clinical and pathologic factors were analyzed as potential prognostic factors for local recurrence in addition to the margin status, including T classification, N classification, age, histologic features, and use of adjuvant therapy. The mean follow-up was 6.25 years. RESULTS: The actuarial probability of freedom from local recurrence for the entire group of patients at 5 and 10 years was 94% and 87%, respectively. The actuarial probability of local control at 10 years was 98% for those patients with negative surgical margins versus 82% for all others (P = 0.007). The local control rate at 10 years was 97% for patients who underwent reexcision and 84% for those who did not. Reexcision appears to convey a local control benefit for those patients with close, indeterminate, or positive initial margins, when negative final margins are attained (P = 0.0001). Final margin status was the most significant determinant of local recurrence rates in univariate analysis. By multivariate analysis, the final margin status and use of adjuvant chemotherapy were significant prognostic factors. CONCLUSIONS: The attainment of negative surgical margins, initially or at the time of reexcision, is the most significant predictor of local control after breast-conserving treatment with lumpectomy and radiation therapy.     

Parenteral glycyl-L-tyrosine maintains tyrosine pools and supports growth and nitrogen balance in phenylalanine-deficient rats

Poor solubility hampers the addition of sufficient amounts of free tyrosine to parenteral amino solutions. We investigated the use of a highly soluble synthetic dipeptide, glycyl-L-tyrosine, as a parenteral tyrosine source in 18 male Wistar rats (body weight 180-200 g). The animals were randomized into three equal groups and catheterized to facilitate isoenergetic (1.2 MJ.kg-1.d-1) and isonitrogenous (1.25 g nitrogen.kg-1.d-1) total parenteral nutrition for 7 d. Controls (Group 1) received a complete amino acid solution, Group 2 received the same solution deficient in phenylalanine (nitrogen replaced with glycine), and group 3 received the phenylalanine-deficient solution supplemented with glycyl-L-tyrosine. Between d 4 and 7, weight gain and nitrogen retention were lower in Group 2 and in Group 1 or 3. In plasma and organ samples obtained at the end of the study, amino acids and dipeptides were analyzed by means of reversed phase-HPLC. In Group 2, phenylalanine and tyrosine concentrations were lower than in controls in plasma, muscle and kidney; in liver, only the tyrosine concentration was lower compared with controls. With glycyl-L-tyrosine supplementation, plasma, liver and kidney tyrosine concentrations and the phenylalanine:tyrosine ratio were normal. Intact glycyl-L-tyrosine was not detectable, suggesting a virtually quantitative elimination or utilization of the infused dipeptide. The results indicate that in phenylalanine-deficient rats, parenteral glycyl-L-tyrosine rapidly provides free tyrosine to facilitate normal growth, promote nitrogen metabolism and maintain intra- and extracellular tyrosine pools.     

Responses of IGF-I to endogenous increases in growth hormone after heavy-resistance exercise

The purpose of this study was to examine the effects of a heavy-resistance exercise protocol known to dramatically elevate immunoreactive growth hormone (GH) on circulating insulin-like growth factor I (IGF-I) after the exercise stimulus. Seven men (23.1 +/- 2.4 yr) volunteered to participate in this study. Each subject was asked to perform an eight-station heavy-resistance exercise protocol consisting of 3 sets of 10 repetition maximum resistances with 1-min rest between sets and exercises followed by a recovery day. In addition, a control day followed a nonexercise day to provide baseline data. Pre- and postexercise (0, 15, and 30 min) blood samples were obtained and analyzed for lactate, creatinine kinase, GH, and IGF-I. Postexercise values for lactate and GH were significantly (P < 0.05) elevated above preexercise and resting baseline values. The highest mean GH concentration after the heavy-resistance exercise protocol was 23.8 +/- 11.8 micrograms/l, observed at the immediate postexercise time point. Significant increases in creatine kinase were observed after the exercise protocol and during the recovery day. No significant relationships were observed between creatine kinase and IGF-I concentrations. No significant changes in serum IGF-I concentrations were observed with acute exercise or between the recovery and control days. Thus, these data demonstrate that a high-intensity bout of heavy-resistance exercise that increases circulating GH did not appear to affect IGF-I concentrations over a 24-h recovery period in recreationally strength-trained and healthy young men.     

Human growth hormone treatment of short-stature children born small for gestational age: effect on muscle and adipose tissue mass during a 3-year treatment period and after 1 year's withdrawal

In addition to its growth promoting effect, GH has profound metabolic effects that have not always been evaluated in longitudinal studies. We have recently shown that the effect of GH on body composition can be evaluated by magnetic resonance imaging measurement of adipose and muscle tissue cross-sectional (cs) areas in the thigh. The aim of this study was to evaluate the long-term effects of human GH (hGH) (0.2 IU/kg day) on muscle and adipose tissue mass during a 3-yr treatment period and after 1 year's withdrawal in short SGA (small for gestational age) children. Measurement of muscle and fat tissue mass by magnetic resonance imaging of the thighs was used to study the metabolic effect of hGH in 14 prepubertal short children born SGA. Results were compared with those of a control group of 7 normal children followed longitudinally. An increase of muscle tissue cs area was observed during the 3 yr of hGH treatment, an increase which was significantly different during the first 2 yr of treatment from that seen in controls (+31.2+/-2.6% and +18.1+/-1.8% during the 1st and 2nd year, respectively, vs. +9.1+/-2.6% change during 1 yr in controls). After a significant decrease in adipose tissue cs area during the first year of therapy (-16.4+/-3.4% vs. baseline values), an increase in adipose tissue cs area occurred during the second and third years. At the end of the third year, the muscle tissue cs area change was significantly greater in SGA-treated children, as compared with controls (+71.6+/-4.6% vs. 22.1+/-4.6%; P < 0.001), whereas the adipose tissue cs area change was similar in the two groups (+12.6+/-9.5% vs. +19.9+/-4.2%). After hGH withdrawal, the effects were opposite after 3 months, as compared with those observed after the first 3 months of hGH administration, whereas no additional significant change was seen after 1 yr off treatment, indicating the maintenance of muscle and adipose tissue mass. In conclusion, hGH administered to SGA children is effective in improving growth velocity and has long-term effects on muscle and adipose tissue mass. These effects may lead to speculation about the sensitivity of these tissues to GH. The physiological consequences of such effects must be evaluated.     

Effects of long-term growth hormone therapy on adrenal steroidogenesis in Turner syndrome

Nature's most potent molecules are produced by enzyme-catalysed reactions, coupled with the natural selection of those products that possess optimal biological activity. Combinatorial biocatalysis harnesses the natural diversity of enzymatic reactions for the iterative synthesis of organic libraries. Iterative reactions can be performed using isolated enzymes or whole cells, in natural and unnatural environments, and on substrates in solution or on a solid phase. Combinatorial biocatalysis is a powerful addition to the expanding array of combinatorial methods for the generation and optimization of lead compounds in drug discovery and development.     

Water and sodium retention during short-term administration of growth hormone to short normal children

OBJECTIVE: To find out whether leptin can attenuate hypometabolic torpor-like states of metabolic rate (MR) in adult lean animals, as it attenuates the morning suppression of thermoregulatory thermogenesis in suckling-age rat pups. DESIGN: Leptin effects on MR and food intake were studied in mice aged 4-7 months, in which a high incidence of exaggerated circadian reductions of MR had been induced by chronic food-restriction and, for comparison, in free-feeding mice. PROTOCOL: Continuous recordings of MR, for a group of seven mice maintained at an ambient temperature of 24 degrees C, while they were repeatedly-with pauses of at least six days-treated for three consecutive days with either recombinant murine leptin (20, 200 or 600 pmol x g(-1) x d[-1]) or saline. RESULTS: Leptin treatment caused dose-dependent 5-15% increases in energy expenditure by moderating the decreases in MR during the circadian minima, without affecting either the MR during the circadian maxima or food intake. Similar treatment of free-feeding mice caused dose-dependent decreases of food intake without changing MR. CONCLUSION: Leptin controls thermoregulatory energy expenditure when food supplies are scarce and changes food intake, rather than energy expenditure, when food is abundant.     

Surgical treatment of choledochal cyst in adults: results and long-term follow-up

BACKGROUND/AIMS: Results of the surgical management of 60 adults with choledochal cysts at Chang Gung Memorial Hospital Taipei are presented. PATIENTS AND METHODS: All patients were diagnosed and surgically managed during the period between March 1979 and December 1992. There were 47 females and 13 males, with ages ranging from 16 to 81 years (mean age = 31.9 years). Of the total, there were 41 Type I, one Type II, 14 Type IV, and four Type V choledochal cysts classified according to Todani's classification system. The definite surgical procedures were cyst excision and hepatico-jejunostomy in 43 cases in type I and IV diseases, one cyst excision in type II disease, two hepatectomy for type V disease, cyst enterostomy in seven cases, and T-tube choledochocystostomy in seven cases. RESULTS: The operative mortality rate was 3.3% and the complication rate related to the surgical procedure was 20%. Early postoperative complications include wound infection, leakage of anastomosis, acute pancreatitis, septic shock, left pleural effusion, and intra-abdominal abscessing. Reoperations were needed in the early postoperative days in two cases due to hepatico-jejunostomy leakage and intraabdominal abscess formation. Long-term surgical outcome, concerning recurrence of symptoms, was related to the following factors, excluding the factors of surgery: presence of bile duct lithiasis, common channel less than 22 mm, presence of preoperative pancreatitis and acute angle type pancreaticobiliary unions. Only common channel less than 22 mm is statistically significant. The percentage of recurrence of the symptoms after resectional surgery was 32.5% in the long term follow-up period. Most of the cases responded well to an antibiotics treatment. Three of the cases required a second operation or PTCD as well as dilatation to treat the recurrent cholangitis. CONCLUSION: Although the recurrence of symptoms is not uncommon and satisfactory explanation of the analysed factors is still the treatment of choice for adult patients with choledochal cysts.     

Feeding colostrum increases circulating insulin-like growth factor I in newborn pigs independent of endogenous growth hormone secretion

Our objective was to examine the influence of feeding and endogenous GH secretion on circulating IGF-I in colostrum-deprived newborn pigs fed colostrum (n = 4), formula (control, n = 4), or water (n = 4). In another four formula-fed pigs, GH was ablated (GRF-A) with two intravenous injections of a GH releasing-factor antagonist (N-Ac-Tyr1,D-Arg2)-GRF(1-29)-NH2. Blood was serially sampled in all pigs to measure plasma IGF-I and GH profiles. Feeding increased plasma IGF-I concentration two- to fourfold and decreased GH secretion. Despite a more than 80% decrease in the plasma GH in GRF-A pigs, the circulating IGF-I concentration was similar to that in control pigs. In colostrum-fed pigs, plasma IGF-I was higher than that in control pigs, despite equal nutrient intake and lower circulating GH. There were no differences in plasma IGF binding protein (IGFBP)-3 levels among the treatment groups. However, the relative abundance of plasma IGFBP-4 was lower, and that of IGFBP-1 higher, in unfed pigs than in any of the three fed groups. The plasma insulin concentration was not different among fed pigs, but it was lower in unfed pigs. Our results indicate that the circulating IGF-I concentration is more dependent on nutrient intake than on GH in newborn pigs, despite relatively high GH concentrations. However, because the nutrient content in the formula was designed to match that of colostrum, a factor other than nutrient intake and GH was responsible for the maximal increase in circulating IGF-I concentration observed in colostrum-fed pigs.     

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.     

Immediate and long-term results of the treatment in cancer of the large intestine

Operative treatment of 200 patients with carcinoma of the rectum is analysed. Planned operations were conducted on 101 patients, postoperative mortality was 7.8%. Surgery was undertaken in 93 patients with acute intestinal obstruction, postoperative mortality was 15.05%. Changes of the policy of treatment of patients with acute intestinal obstruction reduced postoperative mortality. Five-year survival was 67.1%.     

Strength and its relationship to changes in fat-free mass, total body potassium, total body water and IGF-1 in adults with growth hormone deficiency: effect of treatment with growth hormone

The present investigation examined changes in strength in growth hormone deficient (GHD) adults following treatment with recombinant human growth hormone (rhGH), and assessed their relationship to changes in fat-free mass (FFM), total body potassium (TBK), total body water (TBW), the concentration of TBK and TBW per kg FFM, and insulin like growth factor-1 (IGF-1). The investigation was double-blind and placebo-controlled for a period of 6 months; this was followed by a period of open treatment for a further 6 months. Patients were assigned randomly to experimental (E) and control (C) groups. In the first 6 months group E received rhGH and group C placebo; in the second 6 months both groups received rhGH. Serial data were analysed for 23 males (11 group E, 12 group C) and 20 females (10 group E, 10 group C). Body composition was assessed by dual energy X-ray absorptiometry, TBK and TBW. Muscle strength was recorded for arm flexion, leg extension and hand grip. Significant increases in FFM occurred in the first 6 months in group E (2.3 kg males, 1.4 kg females) and in the second 6 months in group C (2.4 kg males, 1.4 kg females). There was a modest increase in absolute strength with time, although only three increments were significant (knee extension in group E males and arm flexion in groups E and C females), all of which occurred during the 6-12 month period. Allometric scaling did not improve the identification of significant increments of strength. The mean concentrations of TBK (males 57.0-58.6, females 51.4-53.9 mmol) and TBW (males 0.65-0.69, females 0.65-0.68 l) per kg FFM, were significantly smaller at all stages of the trial than the reference values, suggesting that treatment had not fully normalized these variables. Likewise, the relationship between most of the increments of regional and total strength, and the corresponding increments of FFM, were generally poor and not significant. It was concluded that the reduced concentrations of TBK and TBW per kg FFM, which may be the effect of an inappropriate dose regime or mode of delivery, may, in part, contribute to the anomaly between increases in strength and FFM.