GH-deficient Subjects Research Articles

EXERCISE TOLERANCE IN ADULTS WITH GROWTH HORMONE DEFICIENCY 1601

Aim of the study was to investigate the exercise tolerance in subjects with adult onset of growth hormone deficiency (GHD) for at least 24 months, who received optimal conventional pituitary hormone replacement therapy. Ten male(M) and 9 female (F) GHD subjects (mean (range)) age 45.9 (24-68)yrs, height 172 (160-185)cm, body weight 72.2 (56.8-98.6)kg, BMI 24.4(19.9-36.7)kg/m2, FFM 51.3 (36.3-64.1)kg, underwent an incremental cycle ergometer test up to exhaustion for assessing (mean±SD) maximal power output (F: 120±23, M: 170±24 Watt),˙VO2max (F: 1656±294, M: 2396±312 ml/min), maximal heart rate (F: 172±19, M: 174±14 bpm) and maximal blood lactate (F: 6.8±2.1, M: 8.3±2.9 mmol/l).˙VO2max was compared with values from predictive equations, used for healthy, sedentary men and women separately. Assuming that˙VO2max declines proportionally with age, and varies exponentially with height (Jones 1988), the predicted˙VO2max (F: 1740±199, M: 2562±436 ml/min) was higher than measured (p=0.06, pooled data, Wilcoxon test). However, the prediction of ˙VO2max from height and age only in overweight(F: n=6, M: n=2), and otherwise from weight and age (Wasserman et al., 1987), showed no significant differences between predicted ˙VO2max(F: 1643±150, M: 2336±370 ml/min) and measured values (p=0.18, pooled data). It is concluded that the exercise tolerance for leg cycling in female GHD adults is 70% of that of male GHD subjects. Furthermore, GHD adults showed a reduced maximal blood lactate level and exercise tolerance is not impaired when predictive equations are used, taking into account the fact that not all GHD subjects are overweight, in spite of their disturbed body composition.

Increased Arterial Intima-Media Thickness in Childhood-Onset Growth Hormone Deficiency

Very little is known about the atherosclerotic risk in patients with childhood-onset growth hormone deficiency (GHD). Such data may be relevant to reconstructing the natural course of the cardiovascular abnormalities associated with GHD. To this end, the intima-media thickness (IMT) of the carotid arteries and the vascular risk factors were evaluated in 14 childhood-onset GHD patients (age 25 +/- 1 yr, BMI 22 +/- 0.6 Kg/m2) and in 14 age-, sex-, and BMI-matched control subjects. IMT was greater in GHD patients (0.83 +/- 0.06 and 0.81 +/- 0.06 mmol/L for the right and left carotid artery) than in controls (0.64 +/- 0.03 and 0.64 +/- 0.04 mmol/L, P < 0.01 and P < 0.02, respectively). Serum total and lipoprotein cholesterol, and serum total triglycerides did not differ between the two groups. However, a significant increase in low density lipid triglycerides was present in GHD patients (0.27 +/- 0.02 mmol/L) compared with controls (0.19 +/- 0.01; P = 0.007). No difference was found in plasma fibrinogen and serum Lp(a) levels. Plasma glucose and insulin concentrations were similar in GHD and control subjects both in the fasted state and after an oral glucose load. In conclusion, young patients with childhood-onset GHD show an increased IMT in the absence of clear-cut abnormalities of the classic vascular risk factors. This suggests a role for GH deficiency per se in increasing the atherosclerotic risk.

Growth hormone and heart performance. A novel mechanism of cardiac wall stress regulation in humans.

This study was designed to assess systolic wall stress and ventricular function in patients with deranged growth hormone secretion, in an attempt to elucidate the mechanisms of growth hormone interaction with heart performance. A case-control study. Thirty patients with active acromegaly, free of diabetes mellitus and coronary artery disease, and 25 subjects with congenital growth hormone deficiency were studied. Twelve growth hormone-deficient subjects were reevaluated after 12 months of recombinant human growth hormone therapy. Two groups of 30 normal subjects each were used as controls for the acromegalic and growth hormone-deficient patients, respectively. In the acromegalics, end-systolic wall stress was reduced (-20%; P < 0.01) due to ventricular wall thickening (+ 26%; P < 0.001), whereas cardiac output was significantly increased (+ 20%; P < 0.01). The velocity of fibre shortening was unchanged. In growth hormone-deficient subjects, end-systolic wall stress was markedly increased (+ 38%; P < 0.001) due to a significant reduction of ventricular wall thickness (- 28%; P < 0.001), whereas cardiac output was significantly decreased (-44%; P < 0.001). Replacement therapy with recombinant human growth hormone produced a partial correction of wall thickness and stress. Consequently, systolic performance and cardiac output improved significantly. This study demonstrates that growth hormone plays a role in the control of cardiac wall stress and performance through a mechanism mediated by the effect of growth hormone on myocardial tissue growth. The data may have therapeutic implications in cardiac diseases that lead to heart failure.

Short Stature, Growth Hormone Deficiency, and Social Anxiety

We have reported high rates of social phobia in growth hormone-deficient (GHD) adults who had been treated with growth hormone during childhood. This follow-up study was conducted to determine whether the increased social phobia observed in GHD subjects was secondary to the effects of short stature. Twenty-one age- and sex-matched non-GHD short adults were evaluated for social anxiety and compared with the previously studied 21 GHD subjects. Thirty-eight percent (8 of 21) of GHD and 10% (2 of 21) of short subjects met DSM-III-R criteria for social phobia. GHD subjected scored significantly higher than short subjects on the following self-report questionnaires: Fear of Negative Evaluation (p = .03), Fear Questionnaire (p = .01), Social Avoidance and Distress Scale (p = .01), Beck Depression Inventory (p = .007), and the Tridimensional Personality Questionnaire-harm avoidance subscale (p = .0004). These data suggest that the high prevalence of social phobia in GHD adults is not explained by short stature alone.

Insulin-like growth factor I alters peripheral thyroid hormone metabolism in humans: comparison with growth hormone

Insulin-like growth factor I (IGF-I) is considered to mediate some of the growth-promoting and metabolic effects of growth hormone (GH). Growth hormone treatment of healthy and GH-deficient subjects is accompanied by increased conversion of thyroxine (T4) to triiodothyronine (T3) in peripheral tissues. Whether these effects are mediated by IGF-I is unknown. To assess the respective roles of these hormones on thyroid hormone metabolism we have treated two groups of subjects. The first group consisted of eight healthy subjects who were treated with IGF-I (10 micrograms.kg-1.h-1 sc for 5 days). The second group consisted of eight subjects with combined GH and thyrotropin (TSH) deficiency due to acquired pituitary disease. They were treated with IGF-I (10 micrograms.kg-1.h-1 sc for 7 days), GH (2 IU m-2 sc q.i.d.) or both hormones together. The IGF-I treatment in healthy subjects led to an increase in free T3 (FT3) and a reduction in TSH levels, whereas FT4 and total T4 (TT4) levels remained unchanged. In the second group-in which all subjects were substituted with oral L-thyroxine-treatment with IGF-I led to an elevation of FT3 in the face of unchanged T4 levels. Growth hormone alone and GH plus IGF-I resulted in a more pronounced elevation in T3 level. The results suggest that IGF-I partially mediates the well-known effects of GH on peripheral conversion of T4 to T3. However, GH has more pronounced effects on thyroid hormones that apparently are not mediated by IGF-I.

Two weeks of daily injections and continuous infusion of recombinant human growth hormone (GH) in GH-deficient adults. II. Effects on serum lipoproteins and lipoprotein and hepatic lipase activity

Recombinant human growth hormone (GH) administered as daily subcutaneous (SC) injections has been shown to affect serum lipoproteins in GH-deficient subjects. However, the effects of continuous infusion of GH on serum lipoproteins have not been investigated in GH-deficient adults. The aim of the present study was to compare effects of daily injections and continuous infusion of GH on lipoprotein metabolism. Recombinant human GH (0.25 U/kg/wk) was administered to nine GH-deficient adult men during a period of 14 days in two different ways, ie, as a daily SC injection at 8:00 pm and as a continuous SC infusion, with 1 month of washout between the treatments. Blood samples and tests were performed in the morning after an overnight fast before the start of GH treatment (day 0) and on day 2 and day 14 of treatment. Abdominal SC adipose tissue lipoprotein lipase (LPL), postheparin plasma LPL, and hepatic lipase (HL) activity were measured 120 minutes after the intake of 100 g glucose. Adipose tissue LPL activity decreased and postheparin plasma HL activity increased after 14 days of GH treatment irrespective of the mode of GH administration, whreas GH treatment had no effect on postheparin plasma LPL activity. Serum triglyceride and very-low-density lipoprotein (VLDL) triglyceride concentrations increased during GH treatment. However, VLDL triglyceride concentrations increased to a greater degree during treatment with daily GH injections than during continuous infusion of GH. Serum apolipoprotein (apo) B and low-density lipoprotein (LDL) cholesterol concentrations decreased during treatment with daily GH injections, but were not significantly affected by continuous GH infusion. Thus, apo B and LDL cholesterol concentrations were lower after daily GH injections versus continuous GH infusion. Serum lipoprotein(a) [Lp(a)] and apo E concentrations increased during both modes of GH treatment. However, continuous infusion of GH resulted in a more marked increase in Lp(a) and apo E concentrations than daily GH injections. Minor effects were observed on serum apo A-I concentrations, but high-density lipoprotein (HDL) cholesterol concentrations were not affected. In conclusion, GH treatment of GH-deficient men influenced adipose tissue LPL and postheparin plasma HL activity, as well as serum lipoprotein concentrations. Moreover, continuous GH infusion and daily GH injections differed with respect to the magnitude of effects on several lipoprotein fractions including VLDL triglycerides, LDL cholesterol, apo B, apo E, and Lp(a) concentrations.

Evidence for social phobia and other psychiatric disorders in adults who were growth hormone deficient during childhood.

We assessed the psychiatric status of 21 growth hormone deficient (GHD) adults who had been treated with growth hormone (GH) for short stature during childhood. Eight individuals (38%) were found to have undiagnosed social phobia. On a psychometric battery, the scores of GHD subjects with social phobia corresponded closely to those of a matched group of psychiatric patients with social phobia. Because these psychiatric symptoms have deleterious effects on quality of life, social function, and productivity, the physician should be alert to obtain psychiatric assessment of patients with GHD.

Effects of 1 Year of Growth Hormone Therapy on Serum Lipoprotein Levels in Growth Hormone–Deficient Adults

We investigated the influence of gender and apoE and apo(a) phenotypes as well as the effect of the metabolic effects of growth hormone (GH) on the effect of GH therapy on serum lipoprotein concentrations in GH-deficient (GHD) adults. Forty-four consecutive patients, 30 men and 14 women aged 46.5 (range, 19 to 76) years with GHD due mainly to pituitary tumors, were treated with recombinant human GH for 12 months. Serum concentrations of lipoproteins, insulin, thyroxine, and insulin-like growth factor-I were determined, body composition was assessed by bioelectrical impedance, and apo(a) and apoE phenotypes were analyzed. Lipoprotein(a) [Lp(a)] concentrations in the GHD subjects were compared with a gender- and apo(a) phenotype-matched control group. After 12 months of GH treatment, the total cholesterol, LDL cholesterol, and apoB concentrations decreased, the HDL cholesterol and apoE concentrations increased, and the apoA-I and triglyceride concentrations were unchanged. Before treatment, the Lp(a) concentration was similar to that in the control group. However, after 12 months of treatment, the Lp(a) concentration had increased by 44% and 101% above baseline and the control group, respectively. Men and women responded differently to GH, with a more marked increase in Lp(a) concentration and fat-free mass and a more pronounced decrease in body-fat mass in men. Apo(a) phenotypes had no major influence on the effect of GH therapy. The only significant difference between apoE phenotypes was a higher baseline Lp(a) concentration among apoE4 heterozygotes.(ABSTRACT TRUNCATED AT 250 WORDS)

Defining growth hormone deficiency in adults

The absence of a distinct clinical syndrome calls for a strategy to reliably identify patients with hyposomatotropism. However, there is no consensus as to the most appropriate method of defining growth hormone (GH) deficiency in adults. Since GH secretion falls with senescence and is also reduced by obesity, both of these factors must be controlled for in such an evaluation. We have investigated the relative diagnostic merits of measuring (1) peak GH response to insulin-induced hypoglycemia (ITT), (2) mean 24-hour GH concentration derived from 20-minute sampling (IGHC), (3) serum IGF-I levels, and (4) serum insulin-like growth factor (IGF)-binding protein-3 (IGFBP-3) levels. These tests were undertaken in 23 patients considered GH-deficient from extensive organic pituitary disease and in 35-sex-matched normal subjects of similar age and body mass index. The ITT was the only test capable of distinguishing patients with organic GH deficiency from matched normal subjects. The sensitivity of the GH radioimmunoassay (0.2 ng/mL) limited the utility of IGHC measurements, since many subjects from both groups had undetectable values. Using a GH assay with a 100-fold greater sensitivity, we found a better but still incomplete separation of values between the two groups. There was a significant overlap of IGF-I and IGFBP-3 values, with only a third of GH-deficient subjects having low IGF-I values. The limitation of IGF-I has been confirmed by others, although its sensitivity as a diagnostic test is greater in young adults. We conclude that organic GH deficiency in adults can be reliably diagnosed by the ITT. IGF-I and IGFBP-3 measurements are unreliable, because these levels may be normal in GH deficiency.

Growth hormone-deficient adults are insulin-resistant

Patients with growth hormone deficiency (GHD) have traditionally been described as having increased insulin sensitivity with a tendency toward fasting hypoglycemia, at least in children. In other studies, impaired glucose tolerance has been found. To evaluate basal insulin sensitivity, a hyperinsulinemic, normoglycemic clamp was performed with an insulin infusion rate of 40 mU/m 2/min after an overnight fast. Fifteen patients (four women and 11 men aged 20 to 62 years) with GHD for at least 1 year were compared with 15 healthy controls matched for sex, age, and body mass index (BMI). Thirteen patients had complete pituitary deficiency and were being treated with conventional hormone replacement therapy. Two men had isolated GHD since childhood. Four men were being treated with bromocriptin. There were no significant differences between fasting blood glucose (4.4 ± 0.1 v 4.7 ± 0.2 [mean ± SEM] mmol/L) or fasting plasma insulin (9.5 ± 1.4 v 8.8 ± 1.1 mU/L) in patients and controls, respectively. Fasting free fatty acid (FFA) levels were lower in patients (444 ± 35 v 796 ± 94 μmol/L, P < .01). Blood glucose levels during the clamp were similar (4.6 ± 0.1 v 4.9 ± 0.1 mmol/L), as were insulin levels (81 ± 4 v 93 ± 4 mU/L). A decrease in glucose infusion rate (GIR) was seen during the clamp in GHD subjects (3.9± 0.5 v 9.9 ± 0.7 mg/kg body weight/min) as compared with controls ( P = .001). Even if corrections were made for body fat, there was a significant difference (GIR corrected per lean body mass, 5.8 ± 0.8 v 13.9 ± 0.9 mg/kg lean body mass/min, P < .001). The results suggest that adults with GHD are insulin-resistant. Despite this finding, normal fasting plasma insulin levels were seen.

Adults with growth hormone deficiency have abnormal body composition but normal energy metabolism.

We compared body composition and energy metabolism in a cross-sectional study involving 21 GH-deficient (GHD) and 29 normal adults. Fifteen subjects from each group were pair-matched for age, sex, height, and weight. Comparison of body composition by dual energy x-ray absorptiometry in the 15 pairs showed that GHD subjects had a significantly greater fat mass (23.9 +/- 1.8 vs. 19.8 +/- 2.6 kg; P = 0.02), lower bone mineral content (2.6 +/- 0.1 vs. 2.9 +/- 0.1 kg; P = 0.06), and lower fat-free soft tissue mass (FFSTM; 45.8 +/- 2.5 vs. 48.9 +/- 2.6 kg; P = 0.02). To determine which subcompartment changes were responsible for the reduced FFSTM in GH deficiency, extracellular water (ECW) was measured by 24Na dilution in 11 of the subject pairs, and body cell mass (BCM) was derived by subtracting ECW from FFSTM. The GHD subjects had lower ECW (19.4 +/- 1.0 vs. 21.0 +/- 1.0 kg; P = 0.05) and BCM (26.6 +/- 1.9 vs. 28.6 +/- 2.1 kg; P = 0.08) than their normal counterparts, with the difference approaching statistical significance. When the relationship between ECW and FFSTM was compared in the larger group of 18 GHD and 27 normal subjects, no statistically significant difference was found between the 2 regression lines, indicating that ECW and BCM were proportionately reduced in GH deficiency. Energy expenditure and fuel utilization before and after a standardized mixed meal were measured by indirect calorimetry in 12 matched pairs of GHD and normal subjects. Comparison of energy expenditure and fuel utilization showed no significant difference in fasting or postprandial energy expenditure, or carbohydrate or fat oxidation rates between the two groups. We conclude that GHD adults have an increased FM, a reduced FFSTM due to a proportionate reduction in ECW and BCM, and no detectable disturbance in energy metabolism.

Growth hormone (GH) treatment in GH‐deficient adults: effects on muscle size, strength and neural activation

The effects of 6 months of recombinant growth hormone (GH) treatment (0.5 IU kg-1 per week) on muscle size, strength and neural activation (EMG) was studied in eight adults with childhood onset GH deficiency (GHD). Before treatment, height, body mass (BM) and lean body mass (LBM) of the GHD subjects were significantly lower (P < 0.01) from those recorded in eight healthy controls, while no significant differences were found between the body mass index (BMI) of the two populations. Thigh muscle + bone cross-sectional area (CSAM+B) and lower limb muscle plus bone volume (LLVM+B) of the GHD patients were 66.1 +/- 13.7% and 47.6 +/- 6.8% of those recorded in the controls (P < 0.01), whereas no difference in CSA/height2 was found between the two groups. By contrast, LLVM+B/height3 was 82.0 +/- 19.0% that of the controls (P < 0.05). Similarly, quadriceps muscle strength (MVC) of the GHD patients was 63.2 +/- 12.4% that of controls (P < 0.01), while no significant differences in the force per unit area (F/CSA) and per body mass (F/BM) were found. After 6 months of GH treatment LBM increased by 6.0 +/- 4.2% (P < 0.02), CSAM+B by 14.5 +/- 12.7% (P < 0.01) and LLVM+B by 10.1 +/- 7.3% (P < 0.01), absolute differences from the normals still persisting. However, the LLVM+B/height3 of the GHD patients after treatment was no longer significantly different from that of the controls. Quadriceps MVC increased by 9.8 +/- 12.0% (P < 0.02), differences from the controls being still significant, whereas the F/CSA and F/BM did not change. A right shift of the integrated EMG/Force relation, with no change in the maximal integrated EMG (iEMG) activity, was observed in the patients after treatment. In conclusion, the current study shows that adults with childhood onset GHD have a reduced skeletal muscle mass and strength which seem to be positively influenced by 6 months of GH treatment.

Direct quantitation of growth hormone binding protein in human serum by a ligand immunofunctional assay: comparison with immunoprecipitation and chromatographic methods.

Current methods for measuring GH-binding protein (GHBP) are laborious, require separation of GHBP complex, and may be affected by endogenous GH content of the sample. Such methods estimate binding activity and GHBP concentration can only be obtained by Scatchard analysis. We have developed and validated a 2-site immunofunctional assay for the direct quantitation of GHBP in human serum employing a capture monoclonal antibody against GHBP and a polyclonal antibody against hGH. Results were compared with binding activity data and Scatchard-derived capacity estimates obtained by immunoprecipitation and gel chromatography procedures. Serum samples were obtained from 21 subjects with GH deficiency, 24 patients with acromegaly, and 56 normal subjects; 12 of whom were postmenopausal women who were studied before and during oral estrogen treatment. Using the immunofunctional assay, serum GHBP concentrations in normal subjects ranged from 0.14-3.28 nmol/L, was positively related to body mass index (BMI, P = 0.0004) and negatively related to age (P = 0.015). Women had significantly higher levels (0.99 +/- 0.12 vs. 0.63 +/- 0.09 nmol/L; P = 0.0191) than age and BMI-matched men. GHBP levels were not different between normal, acromegalic, or GH-deficient subjects. Oral estrogen therapy in postmenopausal women increased serum GHBP concentrations up to 5-fold. There was a significant nonlinear relationship between the immunofunctional assay measurements and binding activity by either immunoprecipitation (r = 0.84) or chromatographic (r = 0.73) methods; increase in GHBP concentrations was not reflected in proportionate increase in both activity assays. Estrogen-induced changes in circulating GHBP levels were greatest with the immunofunctional assay followed by Scatchard-derived values from immunoprecipitation and chromatographic methods. We conclude that ligand immunofunctional assay measurements of GHBP are higher but show good agreement with binding activity or Scatchard derived estimates from immunoprecipitation and chromatographic methods. This assay provides a direct and practical tool for rapid, accurate and sensitive estimation of GHBP concentration in serum.

High fibrinogen and plasminogen activator inhibitor activity in growth hormone-deficient adults.

Hypopituitary patients on routine replacement therapy except growth hormone (GH) have an increased risk of death from cardiovascular diseases compared with healthy subjects. Untreated GH deficiency might explain the premature death from vascular disease. Plasminogen activator inhibitor (PAI-1) activity, fibrinogen, insulin, blood lipid, and blood pressure levels were studied in 20 GH-deficient adults (10 men, 10 women) 50 +/- 11 years old with routine hormone replacement therapy (except GH) and compared with 20 healthy control subjects matched for sex, age, and body mass index. GH-deficient subjects had a higher waist-to-hip circumference ratio (P < .001), serum triglycerides (P < .02), PAI-1 activity (13.2 +/- 10.6 versus 6.8 +/- 4.8 U/mL [P < .05]), and fibrinogen (3.2 +/- 0.7 versus 2.4 +/- 0.6 g/L [P < .001]) and lower blood glucose (P < .05) compared with control subjects. Blood pressure, insulin, and cholesterol levels were similar. The aberrations found in this study might contribute to an increased atherothrombotic propensity and play a role in the pathogenesis of cardiovascular disease.

Circulating immunoreactive growth hormone releasing hormone concentrations and growth hormone response to growth hormone releasing hormone in short children.

To study the role of peripheral immunoreactive growth hormone releasing hormone (ir-GHRH) concentrations and the GHRH test in the evaluation of growth hormone (GH) secretion in short stature, 46 children with a mean age of 9.4 years (range 1.6-16.3 years) and a mean relative height score of -3.2 SD (range -5.0-2.1 SD) were investigated. The children were divided into prepubertal (n = 35) and pubertal (n = 11) and the prepubertal children further into three groups based on their maximal GH responses to insulin-induced hypoglycaemia (IIH) and clonidine: (1) GH deficient subjects (maximal GH < 10 micrograms/l in both tests); (2) discordant responders (maximal GH < 10 micrograms/l in one test and > or = 10 micrograms/l in the other); and (3) normal responders (maximal GH > or = 10 micrograms/l in both tests). Peripheral ir-GHRH concentrations were measured during the IIH test by radioimmunoassay after purification of plasma samples on Sep-pak cartridges. Among the prepubertal children 10 fell into group 1, 16 into group 2 and 9 into group 3. Children in group 1 were older than those in group 3. There were no significant differences in relative heights and weights or absolute and relative growth velocities between the groups. Subjects in groups 1 and 2 had lower maximal GH responses to GHRH than those in group 3. There were no significant differences in the basal plasma ir-GHRH concentrations between the groups. Nine children (19.6%) had somatotrophs with a poor response to a single dose of exogenous GHRH (maximal GH < 10 micrograms/l).(ABSTRACT TRUNCATED AT 250 WORDS)

Marked effects of sustained low growth hormone (GH) levels on day-to-day fuel metabolism: studies in GH-deficient patients and healthy untreated subjects.

The metabolic effects of circadian GH levels in the very low physiological range are unknown. Therefore, we studied 1) GH-deficient patients on receiving GH replacement therapy in whom the last GH injection was replaced with a constant iv infusion starting at 24 h of either GH (35 micrograms/h) or saline (SAL), and 2) an untreated healthy control group. Glucose turnover, indirect calorimetry, and forearm exchange of metabolites were investigated the following day in the basal state (8-11 h) and during a euglycemic (11-13 H) and a hypoglycemic (13-14 h) glucose clamp. During infusion, steady state GH levels increased by 1.9 micrograms/L. Basal and insulin-stimulated energy expenditures (EE) were lower in the patients during SAL than during GH infusion, and the basal respiratory exchange ratio was also lower during GH treatment. Protein EE was elevated during SAL compared to GH infusion (P < 0.05). During the clamp, forearm glucose uptake decreased in the GH study compared to that in the SAL study ((P < 0.05). The patients in the SAL study were more sensitive to insulin during the clamp in terms of suppression of endogenous glucose production (EGP; P < 0.05) and infusion rate of glucose necessary to maintain euglycemia (M value; P < 0.01). Lipid oxidation, in particular in the basal state, was decreased during SAL compared to GH infusion (P < 0.01). The SAL-treated compared with the control group was characterized by decreased basal and insulin-stimulated EE (P < 0.01), increased protein EE (P < 0.01), and hypersensitivity to insulin in terms of suppression of EGP (P < 0.05) and M value (P < 0.01). During the hypoglycemic clamp, the patients in the SAL study were hypersensitive to the hypoglycemic actions of insulin in terms of increased M-value and suppression of EGP, and lipolysis was impaired, as judged by the inhibition of net forearm uptake of FFA. In conclusion, very low GH levels exert powerful actions on day-to-day metabolism, resulting in protein and glucose sparing at the expense of lipids.

Marked effects of sustained low growth hormone (GH) levels on day-to- day fuel metabolism: studies in GH-deficient patients and healthy untreated subjects

Marked effects of sustained low growth hormone (GH) levels on day-to- day fuel metabolism: studies in GH-deficient patients and healthy untreated subjects

THE EFFECT OF SIX WEEKS GROWTH HORMONE TREATMENT ON BODY COMPOSITION AND RESTING ENERGY EXPENDITURE IN PRADER-LABHART-WILLI SYNDROME (PWS)

Growth hormone deficiency (GHD) is suggested as part of the hypothalamic disorder considered to be the basis for PWS - short stature, gross obesity, hypotonia. We are measuring the effect of treatment with biosynthetic growth hormone (rhGH one year duration) on body composition, resting energy expenditure (REE) and total daily energy expenditure in 12 PWS children. We report here the changes observed at 6 weeks on 7 children (4F; age range 5.1-16.7 yr.; BMI 13.8-43.4) compared with children treated with rhGH for GHD. Fat free mass (FFM, kg) and fat mass (FM, kg) were obtained from H2 18O dilution, REE (kj/24hr) was measured by indirect calorimetry. All results are expressed as mean(SE) and variance analysed by Wilcoxon rank test. All subjects gained weight. However, all 7 subjects significantly increased their FFM and in 6 there was a decrease in FM.: (* p<0.05)The mean change in FFM in PWS was significantly greater than in GHD subjects (14.4 v. 6.9%., p<0.01) One subject (14.2 yr., weight 78.2kg, BMI 33.9) developed diabetes mellitus after 3 wks of therapy (pre-treatment glycosylated haemoglobin 7.2%). Following 6 weeks of rhGH treatment, PWS children show a greater change in FFM than children with short stature. Growth hormone therapy may be appropriate for long term use in PWS as a means of increasing FFM with possible beneficial sequelae. However, it should be recognised that there is some risk of diabetes occurring.

Discontinuation of growth hormone therapy in growth-hormone-deficient patients: assessment of body fat mass using bioelectrical impedance.

The changes in body composition evaluated by the mean of bioelectrical impedance analysis (BIA) have been observed in a group of 16 male adolescents at the time of discontinuation of growth hormone (GH) therapy as well as at 6 and 12 weeks later. After reevaluation of their endocrine function, 6 patients (3 craniopharyngioma, 1 irradiation, 1 malformative, 1 idiopathic) had a profound persistent GH deficiency (maximum peak of GH under provocative tests < 5 ng/ml and low IGF-1 levels), while 10 patients had a normal somatotropic function. Both groups were comparable as far as age, weight and body mass index are concerned. Fat weight is significantly higher in the GH-deficient patients (9.9 +/- 2.6 kg) than in boys with a normal somatotropic function (6.0 +/- 1.1 kg) at the time of the discontinuation of GH therapy (p < 0.01). 3 months later, the increase in fat weight is significant only in the group of patients with severe GH deficiency (+4.1 +/- 2.2 kg; p < 0.05), the difference between the 2 groups (14.0 +/- 3.5 and 7.3 +/- 1.0 kg) becoming highly significant (p < 0.001). Lean body mass is lower in the GH-deficient patients and decreases slightly after GH discontinuation, while no significant variation is observed in the group of non GH-deficient boys. Although BIA assessment of body composition may be discussed when applied to GH-deficient subjects, these results show that such patients should be reevaluated after the discontinuation of GH therapy, including examination of the possible metabolic consequences of GH deficiency.

Effect of long-term rhGH administration in GH-deficient adults on fat cell epinephrine response

Besides exerting its own lipolytic effect, growth hormone (GH) has been reported to potentiate the lipolytic response of adipose tissue to epinephrine. It was thought interesting to find out whether long-term recombinant human growth hormone (rhGH) administration modifies epinephrine-induced lipolysis in isolated adipocytes of GH-deficient adults. In a double-blind protocol, GH-deficient subjects received either 6 mo placebo (controls, n = 5) or 6 mo rhGH (treated, n = 5). Biopsies of fat were obtained from the periumbilical region before and after placebo or rhGH administration. The response of the collagenase-isolated fat cells to various concentrations of epinephrine was assessed by glycerol release, measured by bioluminescence. Epinephrine-induced lipolysis was not altered by 6 mo placebo, while it was significantly increased by 6 mo rhGH. A similar response was obtained with isoproterenol, but no significant differences occurred in either group with UK 14304, an alpha 2-adrenoreceptor agonist. Thus, in GH-deficient adults, long-term rhGH administration improves the lipolytic response of isolated adipocytes to epinephrine, essentially by increasing the efficiency of the beta-adrenergic pathway.