Serum leptin levels correlate with growth hormone secretion and body fat in children.

The aim of this study was to investigate the relationship among GH secretion, leptin concentrations, and body composition measured with x-ray absorptiometry (DXA) in children. In total, 71 children were investigated, 51 males and 20 females. Their mean chronological age was 10.8 yr (range, 6.2-17.7 ys), and their mean height (SD) was -2.1 (0.63) SD scores. Their mean weight for height SD scores (WH(SDS)) was 0.2 (1.18). Body composition was investigated using DXA. Blood samples were taken for analysis of leptin, insulin-like growth factor I (IGF-I), IGF-binding protein-3, and 24-h GH secretion. A positive correlation was found between leptin and total body fat (r = 0.83; P < 0.0001) and when fat was expressed as a percentage of body weight (r = 0.86; P < 0.0001). There were significant (P < 0.0001) relationships between leptin and WH(SDS) (r = 0.45) and between leptin and body mass index (r = 0.69). A significant gender difference in leptin levels was found, but this disappeared after adjustment for body fat, as measured by DXA. There were significant (P < 0.001) inverse correlations between leptin and the AUCb for GH (r = -0.41), leptin, and GHmax (r = -0.38), where AUCb is the area under the curve above the calculated baseline, and GHmax is the maximum peak during the 24-h GH profile (percent fat and AUCb for GH, r = -0.43; percent fat and GHmax, r = -0.39). In a multiple stepwise forward regression analysis with leptin as the dependent variable, the percent trunk fat accounted for 77.7% of the leptin variation. With AUCb for GH as the dependent variable, the percent trunk fat accounted for 20.3% of the variation. With GHmax as the dependent variable, the percent trunk fat accounted for 18.8% of the variation, IGF-binding protein-3 for another 8.5%, and the percentage of fat from arms and legs for another 4.4%. We demonstrated a strong positive correlation between leptin levels and body fat, a significant negative correlation between leptin levels and GH secretion, and a significant negative correlation between body fat and GH secretion. We have also shown that specific regional fat depots have different relationships with leptin and particular markers of GH secretion.     

Long-term effects of growth hormone (GH) treatment on body composition and bone mineral density in short children born small-for-gestational-age: six-year follow-up of a randomized controlled GH trial

Context Alterations in the GH-IGF-I axis in short small-for-gestational-age (SGA) children might be associated with abnormalities in bone mineral density (BMD) and body composition. In addition, birth weight has been inversely associated with diabetes and cardiovascular disease in adult life. Data on detailed body composition in short SGA children and long-term effects of GH treatment are very scarce. OBJECTIVE: To investigate effects of long-term GH treatment on body composition and BMD by dual energy X-ray absorptiometry (DXA) in short SGA children. DESIGN: Longitudinal 6-year GH study with a randomized controlled part for 3 years. RESULTS: At baseline, fat percentage standard deviation score (SDS) and lumbar spine BMD SDS corrected for height (BMAD(LS) SDS) were significantly lower than zero. Lean body mass (LBM) SDS adjusted for age was also reduced, but LBM adjusted for height (LBM SDS(height)) was not decreased. GH treatment induced a decrease in fat percentage SDS and an increase in BMAD(LS) SDS. LBM SDS(height) remained similar in GH-treated children, but deteriorated in untreated controls. When these untreated controls subsequently started GH treatment, their LBM SDS(height) rapidly normalized to values comparable with zero. CONCLUSION: During long-term GH treatment in short SGA children, fat percentage SDS decreased and BMAD(LS) SDS increased. These effects of GH treatment were most prominent in children who started treatment at a younger age and in those with greater height gain during GH treatment. LBM SDS(height )remained around 0 SDS in GH-treated children, but declined to low normal values in untreated controls.     

Effects of growth hormone (GH) on ghrelin, leptin, and adiponectin in GH-deficient patients

Ghrelin is a recently discovered gastric peptide that increases appetite, glucose oxidation, and lipogenesis and stimulates the secretion of GH. In contrast to ghrelin, GH promotes lipolysis, glucose production, and insulin secretion. Both ghrelin and GH are suppressed by intake of nutrients, especially glucose. The role of GH in the regulation of ghrelin has not yet been established. We investigated the effect of GH on circulating levels of ghrelin in relation to its effects on glucose, insulin, body composition, and the adipocyte-derived peptides leptin and adiponectin. Thirty-six patients with adult-onset GH deficiency received recombinant human GH for 9 months in a placebo-controlled study. Body composition and fasting serum analytes were assessed at baseline and at the end of the study. The GH treatment was accompanied by increased serum levels of IGF-I, reduced body weight (-2%) and body fat (-27%), and increased serum concentrations of glucose (+10%) and insulin (+48%). Ghrelin levels decreased in 30 of 36 subjects by a mean of -29%, and leptin decreased by a mean of -24%. Adiponectin increased in the women only. The decreases in ghrelin and leptin correlated with changes in fat mass, fat-free mass, and IGF-I. The reductions in ghrelin were predicted independently of the changes in IGF-I and fat mass. It is likely that the reductions in ghrelin and leptin reflect the metabolic effects of GH on lipid mobilization and glucose production. Possibly, a suppression of ghrelin promotes loss of body fat in GH-deficient patients receiving treatment. The observed correlation between the changes in ghrelin and IGF-I may suggest that the GH/IGF-I axis has a negative feedback on ghrelin secretion.     

Circadian and ultradian rhythm and leptin pulsatility in adult GH deficiency: effects of GH replacement

Leptin contributes to the regulation of body weight in healthy individuals and is secreted by adipocytes in a diurnal pattern, with superimposed pulsatility. The circulating leptin concentration is increased in both normally obese and untreated adult GH deficiency, a syndrome characterized by increased adiposity. Leptin circadian rhythm is preserved in adult GH deficiency patients; however, an ultradian rhythm and pulsatility has previously not been reported. Alterations in plasma leptin concentration in obese individuals and adult GH deficiency patients after GH replacement have been attributed to changes in body fat mass. In our present study leptin circadian and ultradian rhythm, leptin pulsatility and its relationship with body fat mass were examined in 12 adult GH deficiency patients (6 men) before and 1 month after GH replacement. All subjects with adult GH deficiency had hypopituitarism subsequent to pituitary surgery and were stabilized on conventional pituitary hormone replacement. Plasma leptin was measured over 24 h at 30-min intervals, and changes in body composition were recorded using bioelectrical impedance. The 24-h mean leptin concentration decreased from 2.04 +/- 0.04 nmol/liter in untreated adult GH deficiency patients to 1.64 +/- 0.03 nmol/liter after 1 month of GH replacement (P < 0.0001). Before GH replacement, patients demonstrated a significant mean leptin circadian rhythm (P < 0.001), with a mesor of 2.05 +/- 0.03 nmol/liter and a superimposed ultradian frequency of 2.0 +/- 0.1 cycles/d. After GH replacement, the circadian rhythm was preserved (P < 0.001), but mesor decreased to 1.65 +/- 0.01 nmol/liter (P < 0.0001), and leptin ultradian frequency increased to 16.0 +/-0.2 cycles/d (P < 0.0001). Pulse analysis (ULTRA) revealed 3.1 +/- 0.9 pulses/24 h in untreated adult GH deficiency patients, which significantly increased to 9.9 +/- 2.2 pulses/24 h after 1 month of GH replacement (P < 0.001). There was no significant change in body mass index or body fat mass after 1 month of GH replacement. The body fat percentage significantly reduced from 36.5 +/- 2.8% to 35.5 +/- 2.7% after 1 month of GH replacement (P < 0.05). This change in body fat percentage was explained by a significant increase in lean body mass, from 56.2 +/- 2.8 kg at baseline to 57.4 +/- 2.7 kg after 1 month (P < 0.05). A significant correlation was observed between plasma leptin and body fat percentage at baseline and 1 month after GH replacement (both, r = 0.7; P < 0.01) in the absence of a significant correlation between leptin and body fat mass before and after GH replacement (P = 0.13 and P = 0.11, respectively). Thus, untreated adult GH deficiency is associated with elevated 24-h leptin concentration, preserved circadian rhythm, and decreased pulsatility. The secretory pattern is restored after GH replacement, with a significant reduction in the 24-h mean leptin concentration, maintenance of circadian rhythm, and increased pulsatility. This GH-induced change in the leptin secretory pattern precedes significant changes in body fat mass and may therefore be independent of changes in adipose tissue. Restoration of leptin pulsatility may be of clinical benefit, and our data could lead to novel approaches for leptin manipulation in the future.     

Serum leptin and body composition in children with familial GH deficiency (GHD) due to a mutation in the growth hormone-releasing hormone (GHRH) receptor

OBJECTIVE: The relationship between GH, body composition and leptin in children remains ill-defined. We have therefore examined the impact of severe GH deficiency (GHD) due to a mutation in the GHRH receptor on serum leptin concentrations and body composition in childhood. PATIENTS: 12 affected children and young people (GHD) (4 M:8F, age 5.4-20.1 years, 8 Tanner stage (TS) 1-2, 4 TS 3-5) and 40 healthy controls (C) from the same region (13 M:27F, age 5.3-18.4 years, 20 TS 1-2, 20 TS 3-5). METHODS: Percent body fat was determined by infra-red interactance, from which the amounts of fat mass (FM, kg) and fat free mass (FFM, kg) were derived. Serum leptin concentrations were measured in a single fasted, morning serum sample and results expressed as a concentration and as leptin per unit fat mass (L/FM, ng/ml/kg). To control for differences in sex and pubertal maturation, leptin standard deviation scores (leptin SDS) were calculated using normative data from UK children. RESULTS: FFM was significantly lower in GHD children than in controls (TS 1-2 P < 0.05, TS 3-5 P < 0.001). FM did not differ significantly between the two groups. Serum leptin concentrations, leptin per unit fat mass and leptin SDS were significantly elevated in GHD children both peripubertal and pubertal compared with controls. Using all subjects, stepwise multiple linear regression with FM, FFM, age, puberty and sex as explanatory variables and leptin concentration as the dependent variable indicated that 59% of the variability in leptin could be accounted for by FM (+, 45%), FFM (-, 9%) and sex (+, 5%) (P < 0.001). However on inclusion of GH deficiency (coded GHD = 1, control = 2) as an explanatory variable 73% of the variability in leptin was explained by FM (+, 45%), GHD (-, 22%) and sex (+, 6%) (P < 0.001). CONCLUSIONS: These data indicate that severe GH deficiency in children is associated with elevated leptin concentrations, irrespective of sex or pubertal stage. This increase is not associated with differences in fat mass but is related to reduced fat free mass in GH deficiency. Furthermore in this population there may be an additional effect of GH deficiency on leptin, independent of the influences of sex and body composition.     

Serum leptin levels are not influenced by arginine and insulin infusion and by acute changes of GH

The aim of this study was to evaluate the relationship between GH and leptin in a group of short children and adolescents. Leptin and GH serum levels were measured before and during pharmacological stimulation tests (arginine and insulin) in a group of 45 children (30 male, 15 female), mean age 8.6+/-3.9 yr, affected by idiopathic isolated GH deficiency (GHD), and in a group of 27 children (15 male, 12 female), age 10.9+/-3.3 yr, with constitutional growth delay. Results showed that basal and peak leptin levels as well as the AUC were significantly higher in GHD patients compared to controls (p<0.05) and correlated with BMI SDS (p<0.0001) in GHD patients. No change in leptin serum levels was observed during either stimulation test. No correlation was found, however, between basal leptin serum levels and basal, peak and the AUC of GH during the tests. Moreover, no correlation was found between the acute changes of serum GH concentration during both stimulation tests and leptin serum levels. The results suggest that leptin and GH secretion is not correlated and that leptin serum levels mainly reflect the amount of fat tissue, which is higher in GHD patients.     

Growth hormone binding protein correlates strongly with leptin and percentage body fat in GH-deficient adults, is increased by GH replacement but does not predict IGF-I response.

GH-binding protein (GHBP) corresponds to the extracellular domain of the GH receptor (GHR) and has been shown to be closely related to body fat. This study aimed to examine the inter-relationship between GHBP, leptin and body fat, and to test the hypothesis that GHBP is modified by GH replacement in GH-deficient adults and predicts IGF-I response. Twenty adults, mean age 47 years (range 20-69) with proven GH deficiency were randomly allocated to either GH (up to 0.25 U/kg/week in daily doses) or placebo for 3 months before cross-over to the opposite treatment. Plasma GHBP and leptin were measured at baseline and 2, 4, 8 and 12 weeks after each treatment. Whole body composition was measured at baseline by dual-energy X-ray absorptiometry (DEXA). There was a strong correlation between baseline leptin and GHBP (r = 0.88, P < 0.0001) and between baseline GHBP and percentage body fat, (r = 0.83, P < 0.0001). Mean GHBP levels were higher on GH compared with placebo, 1.53 +/- 0.28 vs 1.41 +/- 0.25nM, P = 0.049. There was no correlation between baseline IGF-I and GHBP (r = -0.049, P = 0.84), and GHBP did not predict IGF-I response to GH replacement. The close inter-relationship between GHBP, leptin and body fat suggests a possible role for GHBP in the regulation of body composition. GHBP is increased by GH replacement in GH-deficient adults, but does not predict biochemical response to GH replacement.     

ORIGINAL ARTICLE: Metabolic outcome of GH treatment in prepubertal short children with and without classical GH deficiency

Context Few studies have evaluated the metabolic outcomes of growth hormone (GH) treatment in idiopathic short stature (ISS). Moreover, children with ISS appear to need higher GH doses than children with GH deficiency (GHD) to achieve the same amount of growth and may therefore be at increased risk of adverse events during treatment. The individualized approach using prediction models for estimation of GH responsiveness, on the other hand, has the advantage of narrowing the range of growth response, avoiding too low or high GH doses. Design Short prepubertal children with either isolated GHD (39) or ISS (89) participated in a 2‐year randomized trial of either individualized GH treatment with six different GH doses (range, 17–100 μg/kg/day) or a standard dose (43 μg/kg/day). Objective To evaluate if individualized GH treatment reduced the variance of the metabolic measures as shown for growth response and to compare changes in metabolic variables in children with ISS and GHD. Hypothesis Individualized GH dose reduces the range of metabolic outcomes, and metabolic outcomes are similar in children with ISS and GHD. Results We observed a narrower variation for fasting insulin (?34·2%) and for homoeostasis model assessment (HOMA) (?38·9%) after 2 years of individualized GH treatment in comparison with standard GH dose treatment. Similar metabolic changes were seen in ISS and GHD. Delta (Δ) height SDS correlated with Δinsulin‐like growth factor I (IGF‐I), Δleptin and Δbody composition. Principal component analysis identified an anabolic and a lipolytic component. Anabolic variables [Δlean body mass (LBM) SDS and ΔIGF‐I SDS] clustered together and correlated strongly with Δheight SDS and GH dose, whereas lipolytic variables [Δfat mass (FM) SDS and Δleptin] were clustered separately from anabolic variables. Regression analysis showed GH dose dependency in ISS, and to a lesser degree in GHD, for ΔLBM SDS and Δheight SDS, but not for changes in FM. Conclusions Individualized GH dosing during catch‐up growth reduces the variance in insulin and HOMA and results in equal metabolic responses irrespective of the diagnosis of GHD or ISS.     

Serum leptin response to the acute and chronic administration of growth hormone (GH) to elderly subjects with GH deficiency

In human studies, the principal determinant of serum leptin concentrations is fat mass (FM), but lean mass (LM) also has a significant negative influence. GH treatment in GH deficiency (GHD) alters body composition, increasing LM and decreasing FM, and thus would be expected to alter leptin concentrations. We have therefore examined the acute and chronic effects of GH on serum leptin in 12 elderly GHD subjects (ages 62-85 yr; 3 women and 9 men). FM (kilograms) and LM (kilograms) were determined by dual energy x-ray absortiometry. Leptin, insulin, insulin-like growth factor I (IGF-I), IGF-II, IGF-binding protein-1 (IGFBP-1), IGFBP-2, and IGFBP-3 were measured by specific immunoassays. Leptin, insulin, and IGFBP-1 concentrations were log10 transformed, and data were expressed as the geometric mean (-1, +1 tolerance factor). All other data are presented as the mean +/- SD. In the acute study, patients received a single bolus dose of GH (0.1 mg/kg BW) at time zero, with blood samples drawn at 0, 12, 24, 48, and 72 h and 1 and 2 weeks. There was a significant rise in leptin, insulin, and IGF-I at a median time of 24 h, followed by a significant fall, and nadir concentrations were reached at a median time of 1.5 weeks (leptin) or 2 weeks (insulin and IGF-I). IGFBP-3 concentrations were also significantly increased, but peak concentrations were not achieved until 48 h. IGF-II, IGFBP-1, and IGFBP-2 exhibited transient decreases before returning to baseline levels. There was no relationship between increased leptin concentrations and either insulin or IGF-I concentrations. In the chronic study, patients received daily GH treatment at doses of 0.17, 0.33, and 0.5 mg/day, each for 3 months (total time on GH, 9 months), and were then followed off GH for a further 3 months. Dual energy x-ray absortiometry was undertaken at 0, 3, 6, 9, and 12 months, and blood samples were drawn at these time points. Over 9 months on GH there was a significant fall in FM and a significant rise in LM, but no change in leptin. There were also significant increments in insulin, IGF-I, and IGFBP-3, whereas IGF-II, IGFBP-1, and IGFBP-2 did not change over 9 months of GH treatment. After 3 months off GH, there was a significant rise in FM and leptin. High dose single bolus GH led to an increase in serum leptin within 24 h apparently independent of changes in insulin or IGF-I. Despite the changes in body composition during chronic GH treatment, there was no change in leptin. However, discontinuation of GH led to a rapid reversal of the favorable body composition and a rise in serum leptin.     

Body composition during GH replacement in adults - methodological variations with respect to gender

OBJECTIVE: Men with growth hormone deficiency (GHD) may be more sensitive to GH treatment than women in terms of changes in body composition. We have studied whether age, body-mass index (BMI) and the different types of methodology used to assess body composition may explain these differences. DESIGN: Forty-four men and forty-four women with GHD, closely matched for age and BMI, were studied before and after 6 months of GH replacement. The dose of GH was individually adjusted. Body composition was assessed by measurements of potassium-40, total body nitrogen (TBN), tritiated water dilution, dual-energy X-ray absorptiometry (DXA) and bioelectrical impedance analysis (BIA). Four- and five-compartment models for body composition were also calculated. RESULTS: The total daily dose of GH was similar in men and women at 6 months. Serum insulin-like growth factor-I (IGF-I) was higher in men than women at baseline and after 6 months of treatment (P = 0.01, paired t-test). The increment was, however, similar. In women, GH treatment reduced body weight and increased TBN. In both men and women, total body water and body cell mass increased, while total body fat (BF) mass decreased. At baseline, mean total BF varied considerably depending on the methodology used, with the highest value obtained from DXA. The changes in BF were, however, less dependent on the methodology, but DXA and BIA demonstrated the largest inconsistency between men and women. CONCLUSIONS: These results suggest that gender differences in body composition in response to GH treatment are small, if adjustments are made for baseline factors such as age, BMI and dose of GH. Different methods of body composition measurements produce different results, but changes in response to GH administration are less inconsistent.     

Low-dose growth hormone replacement lowers plasma leptin and fat stores without affecting body mass index in adults with growth hormone deficiency

OBJECTIVE  The ob gene product, leptin, is considered to be a marker of adipose tissue mass and a possible homeostatic regulator of body mass. Our objective was to examine the effect of GH replacement on adipose tissue stores and leptin in adult hypopituitarism.
SUBJECTS  Twenty adults, mean age 47 years (range 20–69) with proven GH deficiency were randomly allocated to either GH (up to 0.25 U/kg/week in daily doses) or placebo for 3 months before cross-over to the opposite treatment.
MEASUREMENTS  Body composition was measured by dual-energy X-ray absorptiometry (DEXA) in the whole body, trunk and limbs. Plasma leptin was measured by radioimmunoassay at baseline and +2, +4, +8 and +12 weeks in each treatment arm.
RESULTS  Total body tissue fat (mean±SE) was 30.1±2.2% after GH compared with 31.9±2.2% after placebo, P <0.001 (ANOVA). There were no significant changes in BMI (kg/m²), 29.1±1.3 after placebo vs 28.8±1.2 after GH; or waist to hip ratio (WHR), 0.91±0.01 after both placebo and GH. Baseline plasma leptin showed a significant correlation with baseline BMI, r =0.67, P <0.005 and baseline percentage total body fat, R =0.89, P <0.001. Plasma leptin (adjusted by using baseline percentage total body fat as a covariate) showed a significant linear decrease with time on GH compared with placebo ( P =0.03 ANOVA).
CONCLUSIONS  Plasma leptin and total body fat fall promptly in response to low-dose replacement of GH in GH-deficient subjects. Hormone-induced changes in leptin can occur in humans in the absence of change in body mass index.     

Thyroid function in short children born small-for-gestational age (SGA) before and during GH treatment

Context  Disturbances in thyroid function have been described in small-for-gestational age (SGA) children but the influence of prematurity is unclear. In addition, the effect of GH treatment on thyroid function has not been studied in short SGA children.
Objectives  To determine whether short SGA children have higher TSH levels compared to age-matched controls and evaluate the influence of gestational age. To investigate whether GH treatment alters thyroid function.
Patients  A total of 264 short SGA children (116 preterm), prepubertal and non-GH deficient.
Measurements  Serum FT4 and TSH at baseline and after 6, 12 and 24 months of GH treatment.
Results  Baseline mean TSH was higher in preterm short SGA children than in age-matched controls ( P <  0·05). Mean FT4 was not significantly different between short SGA children and controls. Baseline FT4 or TSH did not correlate with gestational age, or SDS for birth weight, birth length, height, body mass index, IGF-I or IGFBP-3. Mean FT4 decreased significantly during the first 6 months of GH treatment, but remained within the normal range. TSH did not change during treatment. The change in FT4 did not correlate with the change in height SDS during 24 months of GH treatment.
Conclusion  Preterm short SGA children have higher, although within the normal range, TSH levels than controls. The level of TSH does not correlate with gestational age, birth weight SDS or birth length SDS. FT4 decreases during GH treatment, but is neither associated with an increase in TSH nor does it affect the response to GH treatment. As these mild alterations in thyroid function do not appear clinically relevant, frequent monitoring of thyroid function during GH therapy is not warranted in short SGA children.     

Survivors of childhood acute lymphoblastic leukaemia, with radiation-induced GH deficiency, exhibit hyperleptinaemia and impaired insulin sensitivity, unaffected by 12 months of GH treatment

OBJECTIVE: Adult survivors of childhood acute lymphoblastic leukaemia (ALL) often exhibit GH deficiency (GHD), due to prophylactic cranial radiotherapy (CRT). It is not known whether the observed risk for adiposity in these patients is associated with impaired insulin sensitivity and whether the insulin sensitivity is affected by GH replacement therapy. SUBJECTS AND DESIGN: Eleven patients with GHD (median age 29 years), previously given prophylactic CRT for ALL, and 11 sex-, age- and body mass index (BMI)-matched controls were investigated with bioimpedance analysis (BIA) and analysis of serum leptin, serum free fatty acids (FFA) and serum insulin. Insulin sensitivity was measured by a euglycaemic-hyperinsulinaemic clamp technique (IS-clamp). Moreover, the effects of 12 months of individually titrated GH treatment (median dose 0.5 mg/day) on these parameters were investigated. RESULTS: At baseline, the patients had lower fat free mass (FFM) (P = 0.003), higher percentage fat mass (FM) (P = 0.05), serum insulin (P = 0.02) and serum leptin/kg FM (P = 0.01) than controls. The patients had a tendency towards impaired IS-clamp (P = 0.06), which disappeared after correction for body composition (IS-clamp/kg FFM; P > 0.5). In the patients, time since CRT was positively correlated with percentage FM (r = 0.70, P = 0.02), and there was an independent negative association between serum FFA and IS-clamp (P = 0.05). Twelve months of GH treatment increased serum IGF-I (P = 0.003) and FFM (P = 0.02) and decreased percentage FM (P = 0.03), but no significant changes were seen in serum leptin/kg FM, serum FFA, FFA-clamp, serum insulin or IS-clamp (all, P > or = 0.2). CONCLUSIONS: Young adult survivors of childhood ALL with GHD had increased fat mass, hyperleptinaemia and impaired insulin sensitivity, which could be a consequence of radiation-induced impairment of GH secretion or mediated by other hypothalamic dysfunctions, such as leptin resistance or other unknown factors, affected by CRT. Twelve months of individualized GH replacement therapy led to positive effects on body composition, but the hyperleptinaemia, hyperinsulinaemia and the impaired insulin sensitivity remained unchanged.     

Differential effects of GH replacement on the components of the leptin system in GH-deficient individuals

GH therapy is associated with a reduction in fat mass and an increase in lean mass in subjects with GH deficiency (GHD). Leptin, like GH, plays an important role in the regulation of body composition. GH treatment has been shown to reduce serum leptin; however, the physiological interactions between the leptin system (free leptin, bound leptin, and soluble leptin receptor) and the GH/IGF-I system largely remain unknown. Twenty-five patients with childhood (n = 10) and adult-onset (n = 15) GHD were studied. GH status had previously been determined using an insulin tolerance test and/or an arginine stimulation test. The following parameters were recorded at baseline (V1) and then after 3 months (V2) and 6 months (V3) on GH treatment: fat mass, body mass index (BMI), and waist/hip ratio (WHR); blood samples were taken after an overnight fast for free leptin, bound leptin, soluble leptin receptor, insulin, and IGF-I. At V2 and V3, respectively, a fall in free leptin (P < 0.001 for each), and at V3 a fall in in percent fat mass (P < 0.001) were observed. There were no significant changes in BMI or WHR. Simultaneously, there was a rise in insulin (P = 0.068 and P < 0.001), IGF-I (P < 0.001 and P < 0.001), bound leptin (P = 0.005 and P < 0.001), and soluble leptin receptor (P = 0.61 and P < 0.001). A positive relationship was noted between free leptin and BMI (P < 0.001) and between free leptin and fat mass (P < 0.001), and a negative relationship was found between free leptin and IGF-I (P < 0.001) and, within patient, between free leptin and insulin (P < 0.001). There was no significant correlation between free leptin and WHR. Bound leptin had a positive association with IGF-I (P < 0.001) and insulin (P = 0.002) and a negative relationship with percent fat mass (P = 0.023). Soluble leptin receptor was also positively related to IGF-I (P < 0.001). In conclusion, our data suggest that the reduction in serum leptin with GH treatment, as noted by others, is mediated through a fall in free leptin. The fall in free leptin and in part the rise in bound leptin are most likely through a reduction in percent fat mass. However, the observed changes in free leptin and bound leptin and, more importantly, the rise in soluble leptin receptor, are not explained entirely by modifications in body composition and may be a direct result of GH/IGF-I.     

Leptin concentrations in GH deficiency: the effect of GH insensitivity

Disorders of GH secretion are known to impair the physiological lipostat and to affect the secretion of leptin, a sensitive marker of regional fat accumulation and total body composition. In both children and adults with GH deficiency (GHD), leptin levels are increased proportionately with enhanced adiposity. In GHI, mutations of the GH receptor gene result in a phenotype similar to GHD, with increased adiposity and unfavorable lipid profiles. To examine the impact of different forms of growth disorders on leptin production, we measured leptin levels in 22 GHI patients homozygous for the E180 splice mutation (15 females and 7 males, aged 8-37 yr) and compared results with those obtained in 20 subjects heterozygous for the mutation (11 females and 9 males, aged 7-54), 17 idiopathic GHD patients (6 females and 11 males, aged 3-34), and 44 normal subjects (25 females and 19 males, aged 7-45). After the baseline evaluation, all subjects received two 7-d GH treatments at doses of 0.025 and 0.050 mg/kg x d in random order. Leptin, IGF-I, and IGF-binding protein-3 (IGFBP-3) were assayed by specific immunoassays. IGF-I and IGFBP-3 levels were significantly lower (P < 0.0001) in homozygous GHI and GHD patients compared with either controls or GHI heterozygotes. Circulating leptin levels were significantly higher in homozygous GHI patients than in normal controls (20.7 +/- 4.2 vs. 8.7 +/- 1.4 microg/liter) as well as when compared with heterozygous GHI subjects (14.4 +/- 3.4 microg/liter) and GHD patients (9.8 +/- 1.6 microg/liter; P < 0.01). Similar results were obtained when leptin was normalized for body mass index. When subjects were subgrouped by gender, leptin levels were significantly higher (P < 0.05) in GHI females than in females of all other groups and were significantly increased in GHD males (P < 0.01 vs. control males). Within the study groups, females had significantly higher leptin levels than males in controls (12.7 +/- 2 vs. 3.3 +/- 1 microg/liter; P < 0.001) and homozygous GHI patients (28.7 +/- 5.3 vs. 6.9 +/- 2.3 microg/liter; P < 0.05), but not in heterozygous GHI (20.1 +/- 5.4 vs. 7.3 +/- 2.4 microg/liter; P < 0.06) and GHD (10.9 +/- 2.6 vs. 9.2 +/- 2.1 microg/liter) patients. By multivariate analysis, log-normalized leptin levels were best predicted by gender and body mass index in homozygous GHI patients as well as in normal subjects. During the 1-wk courses of GH therapy, serum IGF-I and IGFBP-3 levels significantly increased (P < 0.0001) in GHD patients, heterozygous GHI patients, and control subjects at both GH doses. Inversely, leptin levels did not change significantly during either course of GH administration in the groups examined. These data demonstrate that leptin is increased in patients affected with long-standing homozygous GHI, probably reflecting abnormalities of body composition and metabolism typical of this condition.     

Metabolic parameters and adipokine profile during GH replacement therapy in children with GH deficiency

OBJECTIVE: GH replacement therapy in children with GH deficiency (GHD) mainly promotes linear growth. Not only have very few studies fully analyzed the metabolic consequences of GH therapy, but also the question as to whether GH may affect adipokine secretion has been insufficiently investigated. Our aim was to study the effects of GH replacement therapy on auxological data, lipid and glycemic profiles, insulin homeostasis (HOMA-IR) and serum adipokines in children. METHODS: This was a 1-year prospective study. Thirty-four GHD children (11.6 +/- 2.6 years) and thirty healthy matched controls were enrolled. Children affected by GHD were studied both before beginning continuous GH replacement therapy and again at 12 months. RESULTS: At the beginning of the study, total and LDL cholesterol were higher in GHD children than in controls (P<0.001), whereas HDL cholesterol, triglycerides, insulin, HOMA-IR, leptin, and adiponectin were similar. At 12 months of continuous GH replacement therapy in the GHD group, there was a significant increase in both auxological data and IGF-I (P<0.001); total cholesterol (P<0.001), LDL (P<0.001), triglycerides (P<0.005), and leptin (P<0.001) decreased significantly; HDL (P<0.003), insulin (P<0.001), HOMA-IR (P<0.001) increased while adiponectin was unmodified. Furthermore, IGF-IDelta showed an inverse correlation with leptin Delta (rho = -0.398, P = 0.02). CONCLUSIONS: In GHD children, the evaluation of metabolic parameters proves to be a useful tool for the evaluation of auxological parameters during GH replacement therapy. In our study, GH replacement therapy in GHD children improved final height, restored IGF-I levels, reduced leptin levels, and improved the lipid profile, without producing any unfavorable effects on glucose metabolism.     

The acute leptin response to GH

The effect of an acute bolus of GH on serum leptin in normal individuals and the factors affecting this response have not previously been studied. Seventeen healthy volunteers with normal body mass index, with ages ranging from 20.5-78.2 yr were studied. Each subject received three single doses of GH in random order at least 4 wk apart. Bioimpedence analysis was performed to provide estimates of fat and lean masses. Serum samples for leptin, insulin, and IGF-I were taken 0, 18, 24, 48, 72, and 120 h after each dose of GH. Leptin levels changed significantly after the 0.67- and 7-mg doses of GH, but not after the 0.27-mg dose. Compared with baseline, there was a significant elevation (P < 0.001) in serum leptin levels at 24 h, followed by a significant decrease (P < 0.01) at 72 h. Baseline and peak leptin levels were significantly determined by gender, fat mass, and log(10) insulin. Nadir leptin levels were significantly determined by gender and fat mass. In contrast, the increment in leptin levels was significantly determined by age, although this only accounted for 24% of the variability in the increment in leptin levels. We have demonstrated that administration of a single bolus dose of GH significantly increases serum leptin levels, followed by a significant nadir. This occurs not only after a supraphysiological dose of GH, but also after 0.67 mg, a dose within the physiological replacement range. The increment in leptin increases with advancing age, suggesting that at the level of the adipocyte, aging increases responsiveness to GH. However, this only partially explains the changes seen, and it is likely that another factor(s) is involved in the acute impact of GH on circulating leptin levels. The presence of a significant nadir after the peak in leptin levels supports the existence of a negative feedback loop, linking circulating leptin to its own biosynthesis in adipose tissue, mediated by peripheral leptin receptors. These data provide unequivocal evidence that GH can affect serum leptin levels in the absence of a change in body composition.     

Growth hormone (GH) effects on central fat accumulation in adult Japanese GH deficient patients: 6-month fixed-dose effects persist during second 6-month individualized-dose phase

Both Japanese and Caucasian adults with GH deficiency (GHD) have pronounced abdominal obesity, which is associated with increased risk of cardiovascular complications. We investigated the effects of GH treatment in 27 adult Japanese GHD patients, 15 with adult onset (AO) and 12 with childhood onset (CO) GHD. Patients initially received GH titrated to 0.012 mg/kg/day for 24 weeks in a double-blind design and the dose was then individualized for each patient according to IGF-I for a further 24 weeks. Dual-energy x-ray absorptiometry (DXA) data were evaluated for percentages of trunk fat, total body fat and lean body mass. Serum IGF-I and lipid concentrations were determined at a central laboratory. There were 25 patients who completed 48 weeks of treatment, with 7, 6 and 12 patients then receiving GH at 0.003, 0.006 and 0.012 mg/kg/day, respectively. With the reductions in dose when individualized between weeks 24 and 48, mean serum IGF-I level was reduced and excessively high values, observed in AO patients on the fixed GH dose, were no longer seen. The decrease from baseline in trunk fat was similar at week 24 (-3.8 +/- 3.3%, p<0.001) and week 48 (-3.1 +/- 3.7%, p<0.001), and the difference between changes was not significant. Total cholesterol was decreased from baseline by -24 +/- 28 mg/dl (p<0.001) at week 24 and -17 +/- 28 mg/dl (p = 0.007) at week 48. Two patients had elevated HbA1c levels: one continued GH treatment after a dose reduction and the other discontinued due to persistent impaired glucose tolerance. Therefore, excessively high IGF-I levels can be avoided by individualized dosing during long-term GH treatment. Individualized dosing maintains the decrease in abdominal fat in adult Japanese GHD patients and should reduce the cardiovascular risk.     

Benefits of long-term GH therapy in Prader-Willi syndrome: a 4-year study

Obesity, poor growth, and hypotonia in children with Prader-Willi syndrome (PWS) are accompanied by abnormal body composition resembling a GH-deficient state. Hypothalamic dysfunction in PWS includes decreased GH secretion, suggesting a possible therapeutic role for GH treatment. While short-term benefits of treatment with GH have been shown, whether these beneficial effects are dose dependent and persist or wane with prolonged therapy remains uncertain. Effects of 24 additional months of GH treatment at varying doses (0.3, 1.0, and 1.5 mg/m(2).d) on growth, body composition, strength and agility, pulmonary function, resting energy expenditure (REE), and fat utilization were assessed in 46 children with PWS, who had previously been treated with GH therapy (1 mg/m(2).d) for 12-24 months. Percent body fat, lean muscle mass, and bone mineral density (BMD) were measured by dual x-ray absorptiometry. Indirect calorimetry was used to determine REE and to calculate respiratory quotient. A modified Bruininks-Oseretski test of physical performance evaluated strength and agility. During months 24-48 of GH therapy, continued beneficial effects on body composition (decrease in fat mass and increase in lean body mass), growth velocity, and REE occurred with GH therapy doses of 1.0 and 1.5 mg/m(2).d (P < 0.05), but not with 0.3 mg/m(2).d. BMD continued to improve at all doses of GH (P < 0.05). Prior improvements in strength and agility that occurred during the initial 24 months were sustained but did not improve further during the additional 24 months regardless of dose. Salutary and sustained GH-induced changes in growth, body composition, BMD, and physical function in children with PWS can be achieved with daily administration of GH doses > or =1 mg/m(2). Lower doses of GH, (0.3 mg/m(2).d) effective in improving body composition in GHD adults, do not appear to be effective in children with PWS at sustaining improvement in body composition.     

Body mass index (BMI) in Turner Syndrome before and during growth hormone (GH) therapy

OBJECTIVE: To study whether body mass index (BMI) is different in girls with Turner syndrome (TS) compared to normal girls, and whether BMI in TS is affected by growth hormone (GH) treatment. DESIGN: A retrospective cross-sectional study. SUBJECTS: 2468 girls with TS enrolled in the National Cooperative Group Study (NCGS), a collaborative surveillance study for assessing GH-treated children. MEASUREMENTS: BMI and BMI standard deviation score (BMI SDS) at baseline and during GH treatment were computed from height and weight data. RESULTS: BMI in TS patients increases with age as expected. However, BMI SDS increased starting at about age 9 y. A similar pattern of increase in BMI SDS was observed after each year of GH treatment for up to 4 y, but GH treatment did not change the magnitude of increase. BMI and BMI SDS curves before and during GH treatment were essentially superimposable. CONCLUSION: These findings suggest that mechanisms specific for TS are responsible for the age-related increase in BMI SDS. This increase was unaffected by GH treatment.