The effect of gender and age on growth hormone replacement in growth hormone-deficient patients.

We analyzed the effect of growth hormone replacement therapy (36 months) analyzed at a dose adjusted to maintain serum insulin-like growth factor-I level between the median and the upper end of the age-related reference range on bone mineral density, body composition, and carbohydrate metabolism with respect to gender and age in 20 adult patients (9 women, 11 men, mean age: 43 years, range: 21-61 years). The lumbar and femoral T-score was increased after 12 and after 18 months of therapy respectively in men (p < 0.001 and p = 0.002), but did not changed significantly in women. The increase of femoral T-score was greater in young men (< or = 45 years, n = 6) than old men (> 45 years, n = 5, p < 0.001). Body fat was lower in men than in women after 6 months (p = 0.002). The waist/hip ratio only decreased in women (p = 0.044). The waist circumference decreased in both genders after 6 months of therapy (p < 0.001), but more markedly in females than in males (p < 0.05). The sum of skinfold thicknesses was reduced in males after 6 months of therapy (p < 0.001). Changes in body composition parameters measured were independent of age. The glycosylated hemoglobin increased without sex or age difference after 12 months of initiation of therapy (p < 0.001), but fasting glucose and insulin levels did not change during the therapy. Our results indicate that the effect of growth hormone replacement on bone mineral content in adults is age- and gender-dependent, gender dependent on body composition, but independent of age and gender on carbohydrate metabolism.     

Growth hormone receptors in lymphocytes of growth hormone-deficient children

Human growth hormone was injected intravenously into 18 growth hormone-deficient children and growth hormone binding sites in lymphocytes were investigated. Fresh circulating lymphocytes had a low initial value for the binding of growth hormone to solubilized receptors (3.45 +/- 1.46%) but after growth hormone injection, the binding rapidly increased to 14.8 +/- 4.2% at 2 1/2 h and 8.7 +/- 1.8% at 5 h. The sharp increase in binding is due to increase in the number of binding sites. Two control children who received chorionic gonadotropin had no change in lymphocyte growth hormone receptors. The methodological differences between the present study and previous attempts to identify human growth receptors in lymphocytes were (1) lymphocytes were separated and disrupted with Triton X-100 as quickly as possible (to avoid error from receptor leaking out of the cell) and (2) the receptors were assayed at 2 1/2 h after growth hormone administration (previous studies were 12-24 h later). One possible explanation for the data is that growth hormone receptor from liver is taken up by lymphocytes and rapidly released again, thus, contributing to the hormonal receptor economy in humans.     

Effect of growth hormone therapy on the proinflammatory cytokine profile in growth hormone-deficient children

The aim of the present study was to establish whether growth hormone (GH) treatment in vivo affects pro-inflammatory cytokine production by resting or in vitro, activated, cultured, peripheral blood mononuclear cells (PBMC) from children with complete growth hormone deficiency (GHD). We evaluated 11, pre-pubertal children (6 males and 5 females) with GHD, aged between 6 and 14 years, and 9, age- and sex-matched healthy subjects were studied as controls (CTRLs). Freshly isolated PBMC were cultured for 4 or 24 h in X-VIVO medium in the presence or absence of 0.01 microg/mL lipopolysaccharide for the determination of TNF-alpha and IL-6 production; alternatively, cells were incubated 24 h in X-VIVO medium with or without 25 microg/mL Concanavalin A for IFN-gamma production. Cytokines were measured in the cell supernatants by enzyme-linked immunosorbent assay kits. The results of the present study provide evidence that spontaneous and/or mitogen-induced, in vitro PBMC production of pro-inflammatory cytokines is lower in GHD children than in healthy, age-matched individuals (p<0.05 by the Mann-Whitney U-test). After 3 months of GH therapy, cytokine production was significantly (p<0.05 by the Wilcoxon test) increased, but was still lower than in healthy controls. It is reasonable to speculate that severe GH deficiency can cause alterations in the pro-inflammatory cytokine-induced immune response in humans, and that GH treatment can ameliorate this important immunological function.     

Medium-term cardiovascular effects of high-dose growth hormone treatment in growth hormone-deficient children

AIM: To investigate the possible cardiac morphofunctional alterations inducd by prolonged and high-dose GH therapy in a group of 14 children with isolated GH deficiency. PATIENTS AND METHODS: Patients were evaluated at phase 1, after 1.1 +/- 0.6 years of treatment with GH 0.93 +/- 0.13 U/kg/week, and at phase 2, after 5.5 +/- 2.1 years of therapy 0.89 +/- 0.11 U/kg/week. At each phase left ventricular volume, mass and systolic function were evaluated by two-dimensional guided M-mode echocardiography; left ventricular diastolic function was assessed by PW-Doppler sampling of transmitral flow. RESULTS: Phase 1: diastolic blood pressure was lower (p < 0.05) and fractional shortening was not adequate for the level of afterload (stress shortening index p < 0.05) in patients compared to controls. Phase 2: diastolic blood pressure was lower (p < 0.01) and mass and mass/volume ratio were increased (mass index p < 0.05, mass/ volume ratio p < 0.05) in patients compared to controls. The increased mass/volume ratio, together with the normal systolic blood pressure, explains the reduction in peak systolic stress (p < 0.005). Among the parameters of left ventricular diastolic function, the peak E velocity/total area under mitral valve tracing and the area under E velocity/total area under mitral value tracing ratios were significantly decreased (p < 0.05). CONCLUSION: After a mean period of 5 years on high-dose GH treatment in GH-deficient children, subclinical morphofunctional alterations in the left ventricle were found.     

The effect of portacaval shunt on plasma lipids and lipoproteins in swine.

Plasma lipids and lipoprotein composition and distribution were studied in fasted miniature swine prior to and at 5 and 19 weeks following portacaval shunt surgery or a sham operation. Plasma triacylglycerol and cholesterol levels were significantly reduced in the portacaval shunt swine at 5 weeks. These reductions were accompanied by significant decreases in the plasma very low density lipoprotein (d less than 1.006), low density lipoprotein (d = 1.02-1.07) and high density lipoprotein (d = 1.09-1.21) levels. The very low density lipoprotein were shown depleted in lipids and the low density lipoprotein was a cholesterol-depleted, triacylglycerol-enriched particle. No changes in the composition of the high density lipoprotein were observed. These reductions and changes in composition were maintained until killing at 19 weeks post-surgery.     

Growth hormone receptor structure in adipocytes from normal and growth hormone-deficient rats

Using cross-linking techniques, we compared the properties of the growth hormone (GH) receptor in freshly isolated adipocytes from normal rats, from GH deficient rats, and in preincubated adipocytes from normal rats. Bound [125I]iodo-hGH was cross-linked to adipocytes with disuccinimidyl suberate, and membrane proteins labelled with [125I]iodo-hGH were visualized using sodium dodecyl sulfate polyacrylamide gel electrophoresis and autoradiography. All of the adipocytes tested exhibited a prominent Mr = 134,000 band and additional less intense bands in the presence of reductant. No significant differences in the overall banding pattern of membrane proteins were evident in reducing or nonreducing gels, using adipocytes from rats made GH deficient by hypophysectomy or by treatment with antibodies against rat GH, or in fresh and preincubated cells from normal rats. Taken together with binding studies, these findings suggest that differences in the ability of GH to stimulate glucose oxidation in rat adipose tissue probably involve differences distal to the GH receptor.     

Effects of growth hormone replacement therapy on bone markers and bone mineral density in growth hormone-deficient adults

During the 1990s, interest in the effects of growth hormone deficiency (GHD) in adults increased, and several studies were performed to evaluate the effects of growth hormone (GH) substitution therapy in these patients. Because adults with GHD have reduced bone mineral density (BMD) and an increased risk of fractures, the effects of GH replacement therapy on bone metabolism have been evaluated in long-term studies. A universal finding is that the serum and urinary levels of biochemical bone markers increase during GH substitution therapy, and these increases are dose dependent. After years of GH substitution therapy, the levels of biochemical bone markers remain elevated, according to some studies, whereas other studies report that these levels return to baseline. BMD of the spine, hip and forearm increase after 18-24 months of treatment. Bone mineral content (BMC) increases to a greater extent than BMD, because the areal projection of bone also increases. This difference could be caused by increased periosteal bone formation, but a measurement artefact resulting from the use of dual-energy X-ray absorptiometry cannot be excluded as a possible explanation. One study of GH-deficient adults found that, after 33 months of GH treatment, BMD and BMC increased to a greater extent in men with GHD than in women. There is also a gender difference in the increases in serum levels of insulin-like growth factor I and biochemical bone markers during GH treatment. The reason for these findings is unknown, and the role of sex steroids in determining the response to GH therapy remains to be fully elucidated.     

The effect of cyclosporine administration on growth hormone release and serum concentrations of insulin-like growth factor-I in male rats.

The aim of this work was to study the effect of cyclosporine on the somatotropic axis. Accordingly, growth hormone (GH) secretion, circulating insulin-like growth factor I (IGF-I) and IGF binding proteins (IGFBPs) in response to cyclosporin A (CsA) treatment were examined in adult male Wistar rats. Cyclosporine administration (5, 10 or 20 mg/Kg daily) over 8 days did not modify the body weight, but it did decrease serum concentration of corticosterone and increased serum IGF-I and GH levels. Rats treated with 5 and 10 mg/Kg of cyclosporine had similar levels of serum IGFBPs to control rats, but there was an increase in circulating IGFBP-3 and IGFPB-1,2 in the group treated with 20 mg/Kg of CsA. The increase in circulating GH correlates with a decrease in pituitary GH content in CsA treated rats, with no modification in hypothalamic somatostatin content, suggesting an increase in pituitary GH release. In order to test this hypothesis, anterior pituitary cell cultures were exposed to different CsA concentrations during a 4 h incubation period. Cyclosporine increased GH secretion in cultured pituitary cells (p<0.05). These data suggest that cyclosporine increases circulating IGF-I and GH by stimulating pituitary GH release.     

Chronic growth hormone administration does not suppress endogenous growth hormone secretion in patients with neurosecretory growth hormone dysfunction.

Short children who respond normally to growth hormone (GH) stimulation, but have a subnormal spontaneous secretion of GH (neurosecretory GH dysfunction, NSD) are treated with exogenous GH which might suppress their endogenous GH secretion. The effect of chronic administration of GH (8-24 months) on plasma GH responses to GHRH, clonidine and spontaneous GH secretion were studied in 17 NSD patients. The diagnosis of NSD was based on a normal GH response to clonidine (greater than 10 micrograms/l) and an integrated concentration of (IC-GH) GH less than 3.2 micrograms/l. The GH dose used in this study was 0.25 IU/kg three times a week in 10 patients and 0.05 IU/kg daily in 7 patients. Insulin-like growth factor I levels (nmol) increased significantly on therapy from 9.3 +/- 3.8 to 24.4 +/- 22.4 (p less than 0.001). The GH response (microgram/l) to GHRH was 20.4 +/- 5.5 before treatment and 22.4 +/- 6.2 on GH. Peak GH after clonidine was 22.4 +/- 8.9 and 22.8 +/- 8.1, respectively. There was no significant decrease in the number of GH spontaneous peaks (1.8 +/- 0.7 vs. 2.0 +/- 0.7, respectively) or in the area under the curve. A subcutaneous GH bolus of 0.25 IU/kg in 4 patients resulted in a GH peak of 55-82 micrograms/l at 3-5 h and a gradual return to basal levels at 15-20 h after GH administration. The first spontaneous GH peak appeared 26-28 h after GH injection, peak amplitude was 10-15 micrograms/l.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of growth hormone administration on wool growth in merino sheep

The effects of daily administration of 10 mg of highly purified ovine growth hormone (GH) for a period of 4 weeks on wool growth have been measured in 12 Merino ewes fed either a calculated maintenance energy intake or 1.6 times this amount (six on each ration). Concentrations of hormones, glucose, urea, alpha-amino N and amino acids in the blood were monitored and faeces and urine collected for measurement of nitrogen balance. Wool growth rate decreased by 20% during the 4 weeks of GH treatment in sheep fed the high energy diet, largely because of reduced wool fibre diameter. This was followed by restoration of normal growth and then an increase of up to 20% above control levels, a response which persisted for 12 weeks following cessation of GH administration, and which was due to increases in both fibre length and diameter. GH administration caused marked increases in plasma concentrations of GH, insulin and somatomedin C, glucose and free fatty acids, all of which returned to basal levels following cessation of GH administration. No consistent changes in plasma concentration of T3, T4, cortisol, prolactin or alpha amino N were detected. Plasma urea and methionine levels decreased during GH treatment and returned to, or were raised above, basal levels after the GH treatment period. GH injection also resulted in a net retention of N during treatment, followed by a transient period of net N loss. The GH-induced changes in wool growth may be caused by a change in the partitioning of amino acids between the muscle mass and the skin. No other contributing factor(s) were identified.     

The effect of the frequency of subcutaneous insulin-like growth factor-1 administration on weight gain in growth hormone deficient mice.

To ascertain the frequency of subcutaneous IGF-1 administration necessary to promote growth we examined the weight gain of male homozygous lit/lit mice in response to either sc. IGF-1 or bovine GH administration. Lit/lit mice showed a dose dependent response to treatment with GH. Bovine GH induced a response in body weight gain within 3 days of the start of treatment. Following a single subcutaneous injection of IGF-1, plasma IGF-1 levels were elevated for 4-6 hours. Three treatment schedules for IGF-1 were used (once daily, twice daily and four times daily), each employing the same total daily dose of IGF-1 (30 micrograms). With IGF-1 treatment, a significant effect on body weight gain was obtained when administered four times daily. The growth rate with IGF-1 treatment 6 hourly was similar to that observed following treatment with bGH (10 micrograms sc daily). Twelve hourly IGF-1 administration only had a significant effect on body weight gain when weight was measured in the evening. Lit/lit mice treated once daily with 30 micrograms IGF-1 had no weight gain response and became severely hypoglycaemic. Frequent subcutaneous IGF-1 administration is one approach to growth enhancement in GH deficiency; higher doses administered less frequently do not promote growth and may cause hypoglycaemia.     

Effect of growth hormone replacement therapy on plasma lecithin:cholesterol acyltransferase and lipid transfer protein activities in growth hormone-deficient adults

The effects of growth hormone (GH) replacement on plasma lecithin:cholesterol acyltransferase (LCAT), cholesteryl ester transfer protein (CETP), and phospholipid transfer protein (PLTP), factors involved in high density lipoprotein (HDL) metabolism, are unknown. We carried out a 6 months study in 24 GH-deficient adults who were randomized to placebo (n = 8), low dose GH (1 U daily, n = 8), and high dose GH (2 U daily, n = 8), followed by a 6 months open extension study with high dose GH (1 drop-out). No significant changes in plasma lipoproteins, LCAT, CETP, and PLTP activities, cholesterol esterification (EST) and cholesteryl ester transfer (CET) were observed after placebo. After 6 months of GH (combined data, n = 24), very low + low density lipoprotein (VLDL + LDL) cholesterol (P < 0.05) and apolipoprotein B (P < 0.05) decreased, whereas HDL cholesterol and HDL cholesteryl ester increased (P < 0. 05). Prolonged treatment showed comparable effects. Plasma apolipoprotein A-I and Lp[a] remained unchanged. Plasma LCAT (P < 0. 01) and CETP activities (P < 0.01), as well as EST (P < 0.01) and CET decreased (P < 0.01) after 12 months of GH (n = 15), but PLTP activity did not significantly change. Changes in EST and CET after 12 months of treatment were independently related to changes in plasma LCAT (P = 0.001 and CETP activity (P = 0.01). In conclusion, GH replacement therapy improves the lipoprotein profile in GH-deficient adults. Chronic GH replacement lowers plasma LCAT and CETP activities, contributing to a decrease in cholesterol esterification and cholesteryl ester transfer. These effects may have consequences for HDL metabolism and reverse cholesterol transport.     

Impact of growth hormone on central nervous activity, vigilance, and tiredness after short-term therapy in growth hormone-deficient adults.

Impairment of well-being and cognitive function has been reported in growth hormone-deficient adults, as well as an improvement of these parameters after GH substitution, albeit inconsistently. The effect of growth hormone on central nervous activity, vigilance and sleepiness was studied prospectively in 16 growth hormone-deficient adults (7 females, 9 males, mean age: 36.8 yrs) with multiple pituitary hormone deficiencies before and 3 months after the start of growth hormone substitution using two objective methods of measurement, pupillographic sleepiness test and a choice reaction time test. Significant differences were found for neither pupillary unrest index nor for reaction time, false or missing reactions in 12 evaluable patients (7 females, 5 males, mean age 37.8 years). Because of the known interrelationships between growth hormone, sleep and mood, the visual analogue scale for tiredness and standardized retrospective questionnaires regarding sleep and mood (Pittsburgh sleep quality index, Epworth sleepiness scale, Depression scale) were used as additional methods. After GH substitution, there was no difference in sleep efficiency and daytime sleepiness, but some of the subjective sleep parameters (sleep quality and sleep latency) improved significantly. There was a tendency for mood improvement, too. Although results must be interpreted cautiously due to the small sample size, we conclude that the improved sleep and mood parameters might be caused by other indices of general well-being in our study.