Intersubject responsiveness of high-affinity growth hormone (GH)-binding protein (GHBP) to long-term GH replacement therapy.

In adult growth hormone deficiency (GHD) syndrome responsiveness to GH replacement therapy is reported to vary considerably. The underlying mechanisms, however, are not well understood. The aim of this study was to investigate which baseline variables determine the reported variable intersubject responsiveness of high-affinity GH-binding protein (GHBP) to GH replacement therapy. In the setting of a double blind study over 12 months with placebo control over the first 6 months, we analyzed the interrelationship between a number of baseline variables, which vary considerably amongst subjects, and the GHBP response to GH replacement in 31 GHD adults (21 males and 10 females). The following variables were investigated: age, gender, duration of GHD, body composition, serum levels of high-affinity GHBP, insulin-like growth factor-1 (IGF-1), and IGF-binding protein-3 (IGFBP-3). The results showed that in the 6 months treated group of 16 patients (11 males, 5 females), serum IGF-1 increased from 87 ng/ml (range: 26 to 173) to 250 (range: 62 to 467) (p<0.01) and GHBP increased from 1,302 pmol/l (range: 845 to 1,m960) to 1418 (range: 941 to 2,025) (p=0.04). Both parameters showed a significant time effect (within-subjects) (p<0.001). In the 12 months treated group of 15 patients (10 males, 5 females), serum IGF-1 increased from 92 ng/ml (range: 20 to 180) to 272 (range: 45 to 491) (p<0.01), whereas GHBP did not show a significant change: from 1,186 pmol/l (range: 660 to 1,690) to 1,252 (range: 580 to 1,890) (p=0.87). Also no significant time effect (within-subjects) was observed for GHBP (p=0.06). Step-wise multiple regression analyses revealed that during the 6 months placebo period baseline GHBP explained 83% of the variance in post-placebo GHBP, whereas the variance in post-treatment GHBP could be accurately predicted (adjusted R2=0.93) from baseline GHBP and body fat mass, irrespective of the duration of GH treatment. No other baseline variables contributed independently to the GHBP response, with the exception of IGFBP-3, which showed a small, but significant contribution in females, but not in males. These findings indicate that the variable intersubject responsiveness of GHBP to GH replacement therapy is mainly due to differences in baseline body fat mass amongst adult GHD patients, and that in female patients a relatively low baseline IGFBP-3 contributes to a rise in serum GHBP after GH treatment. The clinical relevance of measuring GHBP in adult GHD patients is limited to the first screening step to diagnose GHD, because long-term GH therapy tends to restore serum GHBP to pretreatment levels.

High-affinity growth hormone (GH)-binding protein (GHBP), body fat mass, and insulin-like growth factor-binding protein-3 predict the GHBP response to GH therapy in adult GH deficiency syndrome.

The study objective was to investigate which baseline factors can accurately predict plasma high-affinity growth hormone (GH)-binding protein (GHBP) levels after GH replacement therapy in patients with GH deficiency (GHD). The study group consisted of 36 GHD patients (22 men and 14 women; mean age, 43.1 years; (range, 21 to 60) known to have adult-onset GHD for many years (range, 4 to 22). They were randomly divided into a GH-treated group (n = 19) and a placebo group (n = 17). Body composition (assessed by bioelectrical impendance analysis [BIA]), plasma GHBP (fast protein liquid chromatography [FPLC] size-exclusion gel chromatography), insulin-like growth factor-I (IGF-I), and IGF-binding protein-3 ([IGFBP-3] radioimmunoassays) were measured before and after 6 months. A stepwise multiple linear regression analysis with the plasma GHBP level after 6 months as the dependent variable was used to unravel significant explanatory (or predictor) variables. In contrast to placebo therapy, GH replacement therapy increased the mean plasma levels of IGF-I and IGFBP-3 to the normal range, whereas a small but statistically significant increase in plasma GHBP was observed. The combination of baseline plasma GHBP, body fat mass, and IGFBP-3 predicts posttreatment GHBP levels accurately (adjusted R2 = .97), indicating that baseline variables such as age, gender, fat-free mass, and IGF-I have no contribution. Furthermore, reliability analysis showed that the observed and predicted values for GHBP fit a strict parallel model. These findings indicate that the variations in body fat mass and IGFBP-3 among adult GHD subjects explain the reported variable response of GHBP to GH replacement therapy.

Visceral adipose tissue is associated with circulating high affinity growth hormone-binding protein.

Recent data show that body fat distribution, specifically visceral fat accumulation, is associated with the regulation of GH secretion. To our knowledge no studies have been performed with regard to the relationship between plasma high affinity GH-binding protein (GHBP) levels and fat distribution in humans. To address this question, we measured plasma GHBP and insulin-like growth factor I levels as well as visceral, sc abdominal, and hip adipose tissue (AT) areas by using magnetic resonance imaging scanning in 12 patients with GH deficiency (GHD) and in 12 age- and sex-matched healthy subjects. The GHD patients were subsequently treated with GH replacement therapy. Regardless of the GH status of the subjects, body mass index and visceral AT area were positively correlated to plasma GHBP (r = 0.70; P < 0.01 and r = 0.73; P < 0.01, respectively), whereas the sc AT areas at the abdominal level tended to correlate positively with GHBP levels, but did not reach significance (r = 0.44; P = 0.07). The sc AT areas at the hip level were not correlated with plasma GHBP levels. In the GHD patients the pretreatment visceral and abdominal sc AT areas were positively correlated with the change in GHBP levels after GH replacement (r = 0.82; P < 0.01 and r = 0.75; P < 0.01, respectively). The pretreatment sc AT area at the hip level was not associated with the therapy-induced changes in plasma GHBP (r = 0.28; P > 0.10). In summary, this study shows that visceral fat is associated with circulating GHBP levels, suggesting that visceral fat mass may be involved in the regulation of the plasma GHBP level. Further, the amount of abdominal fat in GHD patients may partially determine the plasma GHBP response to GH replacement therapy.

Deuterium and bromide dilution, and bioimpedance spectrometry independently show that growth hormone-deficient adults have an enlarged extracellular water compartment related to intracellular water.

GH has a strong influence on body composition. However, the effects of GH deficiency in adults on water compartments are not well understood. Therefore, extracellular water (ECW) and total body water were independently determined by deuterium and bromide dilution and by bioimpedance spectrometry in GH-deficient (GHD) adults and compared to those in controls, matched for age, sex, body weight, and height. The results show that the percent body fat was significantly (P < 0.05) higher, and total body water and intracellular water (ICW) were significantly lower in GHD adults for males, females, and both sexes combined. ECW was not significantly different between the two groups. ECW/ICW in GHD adults (0.42 +/- 0.03) was significantly (P < 0.01) higher than that in controls (0.39 +/- 0.02). There was a significant positive relation between the ECW/ICW ratio and the percent body fat. These results were confirmed by the bioimpedance spectrometry measurements.

High-affinity growth hormone binding protein, insulin-like growth factor I and insulin-like growth factor binding protein 3 in adults with growth hormone deficiency.

The high-affinity growth hormone binding protein (GHBP) circulates in human blood and represents the extracellular domain of the growth hormone (GH) receptor. The effects of GH deficiency on GHBP in adults are not clear. The aim of this study was to evaluate serum GHBP levels in adults with GH deficiency and to assess whether GHBP measurement may contribute to the diagnosis of adult GH deficiency, based on a two-step model. We measured insulin-like growth factor I (IGF-I), IGF binding protein 3 (IGFBP-3) and GHBP levels in serum samples of 36 patients with adult-onset GH deficiency. The GHBP levels were measured by FPLC size-exclusion chromatography; IGF-I and IGFBP-3 levels were measured by RIA. Serum GHBP levels were elevated above the upper limit of the 95% confidence interval in 26 patients, whereas IGF-I and IGFBP-3 levels were low in 10 patients and in 16 patients, respectively. The combination of low serum IGF-I and low IGFBP-3 levels was found in 10 patients. In nine patients, serum IGF-I levels were low, with elevated GHBP levels. Low serum IGF-I, low IGFBP-3 and elevated GHBP levels were found in five patients. Only four out of 36 patients had serum IGF-I, IGFBP-3 and GHBP levels that were within the 95% confidence interval of the control values. We conclude that adults with acquired GH deficiency have elevated GHBP levels in comparison to healthy subjects. We suggest that measurement of GHBP levels might contribute to the diagnosis of adult GH deficiency, though further research is required to study the additional value of GHBP measurements.

Resting metabolic rate, body composition and related hormonal parameters in growth hormone-deficient adults before and after growth hormone replacement therapy.

The resting metabolic rate (RMR), and body composition were assessed in 30 growth hormone-deficient (GHD) adults before and after 3 and 6 months of replacement therapy with recombinant human growth hormone (rhGH). In addition, insulin-like growth factor I (IGF-I), IGF binding proteins (IGFBPs) and plasma insulin were measured at baseline and at 6 months in relation to RMR. During 6 months of rhGH replacement therapy, body fat decreased from 18.2 +/- 1.5 (mean +/- SEM) to 14.3 +/- 1.6 kg (p < 0.0001), whereas fat-free mass (FFM) increased from 53.5 +/- 3.3 to 56.3 +/- 3.6 kg (p < 0.0001), RMR increased from 1246 +/- 92 to 1539 +/- 102 kcal/24 h (p < 0.0001) and RMR per kilogram of FFM increased from 23.2 +/- 0.6 to 27.4 +/- 0.5 (p < 0.0001). When RMR data were adjusted for the differences in FFM, it appeared that apart from the increase in FFM, other factors may play a role in the increase in RMR. During rhGH replacement therapy, IGF-I (p < 0.0001) and IGFBP-3 (p = 0.003) levels increased, whereas IGFBP-1 levels decreased significantly (p = 0.004). The FFM explained for about 80% of the variance in RMR. In addition, waist/hip ratio and plasma IGF-I contributed significantly to the explained variance of RMR. This study shows that in GHD adults FFM is the main determinant of RMR and that, next to the increase in FFM, changes in metabolic and hormonal parameters contribute to the increase in RMR during rhGH replacement therapy.

Magnetic resonance imaging-assessed adipose tissue and serum lipid and insulin concentrations in growth hormone-deficient adults. Effect of growth hormone replacement.

The visceral and subcutaneous abdominal adipose tissue (AT) areas and the subcutaneous hip AT area were assessed by magnetic resonance imaging (MRI) in relation to serum lipid and plasma insulin levels in 12 growth hormone-deficient (GHD) adults before and after 6 months of replacement therapy with recombinant human growth hormone (rhGH) and in 12 healthy control subjects. Compared with control subjects, GHD patients had a significantly increased amount of visceral AT, which was inversely related with plasma HDL cholesterol and positively correlated with plasma triglyceride levels. Visceral AT was not associated with plasma total and LDL cholesterol or plasma insulin concentrations. GHD patients also had elevated serum total cholesterol, LDL cholesterol, and triglyceride levels compared with control subjects. After 6 months of rhGH replacement therapy the mean visceral, subcutaneous abdominal, and subcutaneous hip AT areas and serum concentration of total cholesterol decreased significantly, whereas serum HDL cholesterol concentration increased significantly. No significant correlations were found between changes in the amount of AT and changes in serum lipid and plasma insulin levels.

Direct assessment of extracellular water volume by the bromide-dilution method in growth hormone-deficient adults.

Body composition and water content were assessed in 36 growth hormone deficient (GHD) patients (M:23, F:13) and 14 controls (M:7, F:7) using anthropometry, hydrodensitometry, bioelectrical impedance measurement and the bromide-dilution method, with which extracellular water volume can be measured directly. GHD patients, compared to controls, did not differ in extracellular water volume, in hydration state and water distribution. A higher BMI (P = 0.002) and a higher body fat mass (P < 0.0001) were found in the patients. Based on circumference measurements, the GHD patients had a higher waist/hip ratio (P = 0.0001). This study shows that GHD patients, in comparison with healthy controls, have a normal extracellular water volume. The finding that extracellular water volume is within the normal range in GHD patients may be clinically relevant as it is well known that in the first months after initiating GH-replacement therapy, most patients have signs and symptoms of excessive water retention.

Energy and macronutrient intake in growth hormone-deficient adults: the effect of growth hormone replacement.

OBJECTIVE: To assess the energy intake and the macronutrient composition of the diet in 25 growth hormone-deficient (GHD) patients before, and after 3 and 6 months replacement with recombinant human growth hormone (rhGH). DESIGN: The study had a randomised double-blind placebo-controlled design. Energy intake was assessed by the 4-day food record and 24-h urine total nitrogen excretion was used as a check on the validity. The energy and macronutrient intake of the GHD patients at baseline were compared with the data obtained in the Dutch Nutritional Survey. Fat-free mass (FFM) and body fat (BF) were assessed by bioelectrical impedance analysis (BIA). Plasma thyroid hormones and insulin-like growth factor-I (IGF-I) were studied in relation to energy and macronutrient intake. SETTING: Department of Endocrinology, University Hospital Utrecht, Utrecht, The Netherlands. SUBJECTS: 25 GHD patients, aged 21-60 years. RESULTS: GHD adults, compared to controls, have a lower energy intake. During the first 3 months of rhGH replacement therapy, there is a trend for energy intake to increase, no change in macronutrient intake, whereas plasma T3, IGF-1 and FFM increase and body weight does not change, hence BF decreases. The positive relationship between the increase in energy intake and the rise in plasma total T3 level during rhGH replacement therapy indicates that in addition to the GH-induced changes the increase in energy intake and specifically in carbohydrate intake might contribute to the enhanced conversion of thyroxine. Protein intake calculated from the 4-day food record was significantly correlated with protein intake calculated from 24-h urine nitrogen. CONCLUSION: GHD patients have a lower energy intake. Notwithstanding the fact that FFM and plasma T3 increase and body weight does not change, a significant increase in energy intake is not found with the use of the 4-day food record method.

Adipose tissue assessed by magnetic resonance imaging in growth hormone-deficient adults: the effect of growth hormone replacement and a comparison with control subjects.

The visceral and subcutaneous abdominal adipose tissue (AT) area and the subcutaneous hip AT area were assessed by magnetic resonance imaging (MRI) in 12 growth hormone-deficient adults before and after 6 mo of replacement with recombinant human growth hormone (rhGH) and in 12 healthy control subjects. The data obtained by MRI were compared with circumference measurements of waist and hip. Growth hormone-deficient patients compared with control subjects had a higher visceral AT area (P = 0.003) and subcutaneous AT area (P = 0.013); there was no significant difference in subcutaneous hip AT area. Six months of rhGH replacement reduced the subcutaneous hip AT area (19.8%), the subcutaneous abdominal AT area (15.6%), and particularly the visceral AT area (38.2%), resulting in fat areas that were not different from those of control subjects. Furthermore, this study shows that in contrast with control subjects, circumference measurements are not useful to predict AT areas in growth hormone-deficient patients and cannot be used to assess changes in AT areas during rhGH replacement.

Validation of extracellular water determination by bioelectrical impedance analysis in growth hormone-deficient adults.

We validated the determination of extracellular water (ECW) by the bioelectrical impedance method (BIA), using the RJL manufacturer-supplied equation and the equation of Lukaski in 34 growth hormone-deficient (GHD) patients before and after replacement with recombinant human growth hormone (rhGH), using the bromide-dilution (Br-) method as the reference method. At baseline, paired comparisons showed no significant differences between mean ECW assessed by the Br- method and by BIA using both equations in the placebo and rhGH group. At 6 months, no significant difference was found between ECW assessed by the Br- method and by BIA using the manufacturer-supplied equation, both in the placebo and rhGH group. High coefficients of reliability (0.88-0.98) and high correlations (0.79-0.98; p < 0.001) were found between ECW assessed by the Br- method and by BIA applying two different regression equations in the placebo and rhGH groups at baseline and after 6 months. Mean differences in ECW assessed by the Br- method and BIA were between 2.6 and 4.1% of the mean ECW determined by the Br- method at baseline and between 2.7 and 8.5% after 6 months. Multiple comparisons showed a significantly greater ECW assessed by the Br- method than by BIA using the equation of Lukaski (p < 0.0001). This difference was found in the placebo and rhGH replacement group. The difference changed with time (p = 0.005), indicating that the usefulness of the formula of Lukaski seems to be affected by rhGH replacement therapy. We conclude that the noninvasive BIA technique might be a useful method to predict ECW in GHD patients.(ABSTRACT TRUNCATED AT 250 WORDS)