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Recombinant human GH (rhGH) has been in use for 30 years, and over that time its safety and efficacy in children and adults has been subject to considerable scrutiny. In 2001, a statement from the GH Research Society (GRS) concluded that 'for approved indications, GH is safe'; however, the statement highlighted a number of areas for on-going surveillance of long-term safety, including cancer risk, impact on glucose homeostasis, and use of high dose pharmacological rhGH treatment. Over the intervening years, there have been a number of publications addressing the safety of rhGH with regard to mortality, cancer and cardiovascular risk, and the need for long-term surveillance of the increasing number of adults who were treated with rhGH in childhood. Against this backdrop of interest in safety, the European Society of Paediatric Endocrinology (ESPE), the GRS, and the Pediatric Endocrine Society (PES) convened a meeting to reappraise the safety of rhGH. The ouput of the meeting is a concise position statement., (© 2016 The authors.)

Background: Diurnal variation in serum growth hormone (s-GH) levels after exogenous GH delivery has previously been reported in patients with no endogenous GH secretion. Changes in postural position or physical activity, leading to changes in blood flow and/or lymphatic drainage may be underlying explanations., Primary Objectives: The primary aim of this study is to study a possible impact of exercise and supine rest on pharmacokinetics (PK) and day-to-day variation of subcutaneously (s.c.) administered GH in adult GH deficient (AGHD) patients., Secondary Objective: The secondary aim of this study is to compare s-IGF-I, s-insulin, and plasma (p)-glucose profiles after a carbohydrate rich breakfast following s.c. GH injection vs. continuous infusion., Design and Methods: During supine rest eight AGHD males (59.8±8 years, BMI 29.7±4.9 kg/m(2)) were treated with one daily s.c. GH injections of 3 mg/24 h for 48 h (treatment sessions A, B) or a continuous s.c. GH infusion of 3 mg/24 h for 60 h (treatment sessions C, D). Exercise comprised 1 h bicycling with 50 W load on two consecutive days during treatment sessions B and D., Results: Administration of GH as a bolus injection, but not as a continuous GH infusion, resulted in about 32% higher s-GH levels during exercise (60 min) as well as 30 min after (s-GH logAUC(B-A) difference was 0.28; 95% CI: 0.14-0.4; p<0.001). However, the total s-GH(AUC 0-24 h) (p=0.75) and s-IGF-I(AUC0-48 h) levels (p=0.51) remained unchanged between the two occasions. P-glucose and insulin profiles were significantly higher after carbohydrate rich breakfast before first and second dosing both following s.c. GH injection and continuous infusion (p<0.05)., Conclusions: Moderate exercise intermittently increased s-GH levels. These changes seem to have no clinical short-term relevance, since total s-GH(24 h) and s-IGF-I(48 h) levels were unaffected., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Previous studies in growth hormone (GH)-deficient (GHD) patients have indicated a possible diurnal variation in the pharmacokinetics (PK) of GH after subcutaneous (sc) GH administration. Thus, higher GH levels were observed during the night with continuous sc infusion, and increased GH bioavailability was reported following daily sc injections in the evening compared to morning., Objective: The aim was to study whether diurnal variability in the PK of sc administered exogenous GH can be reproduced under standard conditions for all study participants, e.g. supine rest., Design and Methods: Eight male GHD patients (59.8 ± 8 years, body mass index 29.7 ± 4.9 kg/m(2)) received a continuous sc infusion of GH (3mg/24h) for 60 h on two different occasions. Diurnal variation in PK of GH was studied during steady state in the last 24h of the infusion period., Results: Median GH levels were higher at night time (23:00 h-07:00 h) than during the day (10:00 h-18:00 h) for visit 1 [5.1 (4.5-7.2 ng/ml/0.5h) vs. 4.6 (3.7-5.7 ng/ml/0.5h); p<0.05], and reproducible results of diurnal GH variation were obtained during visit 2 [5.7 (4.6-7.4) ng/ml/0.5h vs. 4.6 (3.8-6.0) ng/ml/0.5h, p<0.05]. Reproducible results between days 1 and 2 were also obtained during 08:30 h-20:30 h and 20:30 h-08:30 h, respectively., Conclusions: Previous findings of higher nocturnal GH levels were confirmed during steady state continuous sc GH infusion under standard conditions. The underlying mechanisms, e.g. whether GH absorption, distribution or elimination is primarily affected need to be further elucidated., (© 2013.)

Prader-Willi syndrome is a genetic disorder that is associated with short stature, partial growth hormone deficiency, small hands and feet, learning and behavioural problems, and hyperphagia leading to severe, often morbid, obesity. Growth hormone therapy is associated with an improvement in height and body composition. We evaluated the efficacy and safety of long-term growth hormone treatment in a retrospective observational multinational study of 41 prepubertal children (mean age 3.8±3.0 years) with genetically diagnosed Prader-Willi syndrome treated with growth hormone (0.03-0.06 mg/kg/day) for >12 months [mean duration 4.1 (range 0.9-9.5) years]. Height, weight, and body composition measurements were recorded at baseline and at 6 month intervals until last observation. Mean (SD) gain in height at 12 months was 0.9 (0.2) SD score (p<0.0001). At last observation (after approximately 6 years) mean gain in height was 1.3 (0.3) (p=0.0001) with 85% of children achieving height>- 2 SD score. Body composition improved during treatment with an estimated 9.1% increase in lean body mass and 9.1% decrease in fat mass at last observation (p=0.019). Scoliosis was reported in 3 patients at baseline and 8 patients at last observation. Sleep apnoea was recorded in 3 (7.3%) patients. There were no other severe adverse events reported. Long-term growth hormone treatment of prepubertal children with Prader-Willi syndrome was associated with significant improvements in height and body composition. Treatment was well tolerated. The development of scoliosis warrants monitoring by an orthopaedic specialist., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Bone mineral density (BMD) in adult patients with Prader-Willi syndrome (PWS) might be low due to high bone turnover., Objectives: The objective of the study was to investigate bone mass in a group of adult PWS subjects and study the effects of GH treatment on BMD and markers of bone turnover., Design: Forty-six adults with genetically verified PWS were randomized to GH or placebo for 12 months, followed by open prospective GH for 24 additional months. BMD at the lumbar spine (LS) L1-4, the total hip, and the total body was assessed by dual-energy x-ray absorptiometry at baseline and every 12th month thereafter. Markers of bone turnover were measured at baseline and at the end of the controlled study., Results: In this cohort of adult subjects with PWS, baseline BMD was reduced in all compartments compared with the reference (Z-scores). Men had lower Z-scores BMD than women in LS and total body (P < .05). With 12 months of GH, LS-BMD was significantly reduced compared with placebo. No changes in BMD were observed with continuous GH treatment for 24 months. The bone formation markers increased with GH therapy compared with placebo, whereas the resorption marker did not change., Conclusions: Adult PWS subjects, especially the men, have low bone mass that was not improved with GH treatment for 2 years. Because PWS subjects are short, BMD might be underestimated and should be adjusted for. Further studies, with adequate GH and sex hormone replacement throughout puberty and early adult life, are needed to better characterize PWS.

Context: It is clinically relevant and of physiological interest to investigate whether GH-induced insulin resistance depends on the timing of GH exposure relative to when insulin sensitivity is assessed., Hypothesis: GH-induced insulin resistance is rapidly reversible., Design and Participants: Eight male GH-deficient patients underwent a 6-h euglycemic-hyperinsulinemic glucose clamp thrice in a randomized crossover design receiving either no GH (study 0), a 7-h GH infusion (0.2-0.3 mg in total) that terminated 5 h before the clamp (study 1), or a similar GH infusion timed to continue during the first hour of the clamp (study 2). A muscle biopsy was obtained 30 min into the clamp. The patients were compared with eight healthy untreated control subjects (study c)., Main Outcome Measures: The glucose infusion rate, indirect calorimetry, and free fatty acid metabolism were assessed. In muscle biopsies, protein phosphorylation of signal transducer and activator of transcription 5, Akt, and Akt substrate 160 (phospho-Akt substrate signal) and gene expression of IGF-I and SOCS1-3 were assessed., Results: Insulin sensitivity differed significantly between the GH-deficiency studies (P = 0.005) with distinct insulin resistance in study 2 and increased insulin sensitivity in study 0 [area under the glucose infusion rate curve (mg/kg · min): 1663 ± 151 (study 0) vs. 1482 ± 166 (study 1) vs. 1123 ± 136 (study 2) vs. 1492 ± 229 (control group)]. Free fatty acid levels and lipid oxidation were elevated in response to GH exposure but became suppressed during the clamp. IGF-I and SOCS3 gene expression was increased in study 2., Conclusions: Very-low-dose GH exposure evokes acute insulin resistance that subsides after 5 h. This time-dependent reversibility should be considered when assessing the impact of GH on glucose homeostasis.

Spontaneous rupture of tendons is rare, and typically occurs in large weight bearing tendons such as the quadriceps, Achilles and patellar tendon, in the context of various chronic diseases including end-stage renal disease. In general, tendon rupture in dialysis patients is associated with hyperparathyroidism, long duration of dialysis, steroid and quinolone use. We present a case of a young man on chronic dialysis who presented with sequential rupture of triceps and quadriceps tendons requiring surgical repair, several months after initiating use of multiple hormone supplements including human growth hormone and androgens. The supplements were obtained over the internet with the aim of improving his kidney function. Although this patient did have hyperparathyroidism, it is likely his PTH elevation was exacerbated by use of human growth hormone, and tendon rupture risk increased by concurrent use of an androgen supplement. This case highlights the fact that dialysis patients do utilize alternative remedies and that there may be unexpected, dialysis-specific complications associated with their use.

The adult growth hormone deficiency (GHD) syndrome is a well-defined clinical entity. Although the symptoms of GHD are not age specific, their relative importance differs depending on the patient's age, and the impact of GHD varies throughout adult life. Ceasing growth hormone (GH) therapy soon after final height in patients with severe GHD potentially limits somatic development by reducing accrual of bone and muscle mass. It is now recognized that the continuation of GH therapy in the transition years is required to achieve adult levels of somatic development. In middle age, the most worrying feature of GHD is the increase in cardiovascular risk, an important component of which is GHD-related dyslipidemia. One of the most profound effects of GH therapy in this age group is the durable reduction in cholesterol levels. Elderly GH-deficient patients experience the symptoms of GHD over and above the signs of normal aging. Perhaps most importantly, these patients have impaired quality of life, with fatigue as a major component. Evidence is growing for improved quality of life with GH therapy in the elderly. This review describes the diagnosis, symptoms and treatment of GHD specific to the different age groups.

Context: GH and other stress hormones stimulate lipolysis, which may result in free fatty acid (FFA)-mediated insulin resistance. However, there are also indications that FFAs in the very low physiological range have the same effect., Objective: The objective of the study was to address systematically the dose-response relations between FFAs and insulin sensitivity., Design: We therefore examined eight healthy men for 8 h (6 h basal and 2 h glucose clamp) on four occasions., Intervention: Intralipid was infused at varying rates (0, 3, 6, 12 microl.kg(-1).min(-1)); lipolysis was blocked by acipimox; and endogenous GH, insulin, and glucagon secretion was blocked by somatostatin and subsequently replaced at fixed rates., Results: This resulted in four different FFA levels between 50 and 2000 micromol/liter, with comparable levels of insulin and counterregulatory hormones. Both in the basal state and during insulin stimulation, we saw progressively decreased glucose disposal, nonoxidative glucose disposal, and forearm muscle glucose uptake at FFA levels above 500 micromol/liter. Apart from forearm glucose uptake, the very same parameters were decreased at low FFA levels (approximately 50 micromol/liter). FFA rate of disposal was linearly related to the level of FFAs, whereas lipid oxidation reached a maximum at FFA levels approximately 1000 micromol/liter., Conclusion: In the presence of comparable levels of all major metabolic hormones, insulin sensitivity peaks at physiological levels of FFAs with a gradual decrease at elevated as well as suppressed FFA concentrations. These data constitute comprehensive dose-response curves for FFAs in the full physiological range from close to zero to above 2000 micromol/liter.

Background: Data regarding the mortality rates of patients with growth hormone deficiency (GHD), whether or not treated with growth hormone (GH), are limited, but an increased mortality rate among hypopituitary patients compared with the general population has been documented. Cardiovascular disease has been suggested as a primary cause of death, whereas cancer statistics might be influenced by the number of malignancies causing the pituitary disease. Furthermore, differences in mortality rates in females and males have been reported., Methods: Epidemiological studies of mortality in hypopituitary and GHD patients were identified and reviewed., Results: Most studies showed an increased mortality rate in hypopituitary and GHD patients and an increased mortality among female compared with male patients. There is a possibility that differences between patients with adult-onset and childhood-onset GHD might also exist. Two studies showed a normal mortality rate in GHD patients treated with GH compared with the general population., Conclusions: Although an increased mortality rate in hypopituitary patients is well documented, further research is needed to provide more reliable estimates of the actual causes. Caution should be taken in the interpretation of results regarding mortality and GH treatment due to the limited amount of data and the limitations of the study designs., (Copyright (c) 2007 S. Karger AG, Basel.)

Objective: The regulation and function of systemic ghrelin levels appear to be associated with food intake and energy balance rather than GH. Since GH, in turn, acutely induces lipolysis and insulin resistance in skeletal muscle, we aimed to study the isolated and combined effects of GH, free fatty acids (FFAs) and insulin sensitivity on circulating ghrelin levels in human subjects., Design: Seven GH-deficient patients (aged 37 +/- 4 years (mean +/- s.e.)) were studied on four occasions in a 2 x 2 factorial design with and without GH substitution and with and without administration of acipimox, which lowers FFA levels by inhibition of the hormone-sensitive lipase, in the basal state and during a hyperinsulinemic euglycemic clamp., Results: Serum FFA levels decreased with acipimox administration irrespective of GH status. The GH-induced reduction in insulin sensitivity was countered by acipimox. Fasting ghrelin levels decreased insignificantly during GH administration alone, but were reduced by 33% during co-administration of GH and acipimox (Aci) (in ng/l): 860 +/- 120 (-GH - Aci), 711 +/- 130 (-GH + Aci), 806 +/- 130 (+GH - Aci), 574 +/- 129 (+GH + Aci), P < 0.01. The clamp was associated with a further, moderate lowering of ghrelin. GH and acipimox induced a reciprocal 25% increase in serum leptin levels (microg/l): 11.2 +/- 4.4 (-GH - Aci), 11.7 +/- 4.4 (-GH + Aci), 11.5 +/- 4.4 (+GH - Aci), 13.9 +/- 4.2 (+GH + Aci), P = 0.005., Conclusion: Our data suggest that antilipolysis via suppression of the hormone-sensitive lipase in combination with GH administration is associated with significant and reciprocal changes in ghrelin and leptin.

Objective: Growth hormone (GH) increases during exercise, but the response of the insulin-like growth factor (IGF) system has not been as definitive. Therefore, we investigated the effect of the exercise-induced GH response on the circulating IGF-system in GH-deficient (GHD) and intact adults., Design: Eight GHD adults were studied on 2 occasions, with (+GH) and without (-GH) GH administered (0.4 IU) during exercise (45 min of cycle ergometer exercise at the lactate threshold). Eight age-matched controls were only studied on one occasion. Blood samples were drawn at baseline, during and post-exercise. IGFBP-3 proteolysis was measured by an in vitro proteolytic activity assay, IGF-I bioactivity by novel IGF-I kinase receptor activation assay (KIRA) and other hormones by immunoassay., Results: GH administration to GHD adults resulted in a serum GH peak similar to the exercise-stimulated GH response in GH intact controls, but exercise had only a small impact on the IGF system. IGF-I concentration was lower in controls but was only significantly lower than the +GH day. Neither IGF-I nor -II levels changed over time. IGFBP-1 demonstrated a time effect (P<0.01) in all groups, and a time x group interaction (P<0.01) with a rise at 75 min post-exercise, which was greater in the GHD subjects than controls. IGFBP-2 and -3 increased significantly (P<0.01) over time in the GHD subjects, but not in the controls. No change in IGFBP-3 proteolysis or IGF-I bioactivity was found during exercise or recovery in either group., Conclusion: Submaximal exercise induced minor changes in IGFBP-1, -2 and -3, without affecting IGFBP-3 proteolysis and IGF-I bioavailability. Thus the metabolic status during submaximal exercise does not require a change in plasma IGF-I bioavailability. Administration of GH to GHD adults does not result in changes in proteolysis or bioavailability.

Pituitary GH secretion is feedback regulated by circulating IGF-I. However, it remains to be determined whether the feedback control is mediated through circulating free or total IGF-I. To study this, we compared the temporal changes in circulating levels of GH vs. free and total IGF-I during fasting. Seventeen healthy normal-weight subjects (body mass index 23.4 +/- 0.6 kg/m(2)) were studied during 80 h of fasting. Serum was assayed for GH every 3 h; total, free, and bioactive IGF-I, IGF binding protein (IGFBP)-1, -2, and -3 as well as IGFBP-1 bound IGF-I were assayed every morning. During fasting, mean 24-h GH levels increased from 1.41 +/- 0.20 to 3.01 +/- 0.46 and 2.09 +/- 0.30 microg/liter (d 1 vs. d 2 and 3; P < 0.03). After 24 h of fasting, free and bioactive IGF-I had decreased by 40 +/- 5 and 17 +/- 5%, respectively (P < 0.02), and both concentrations remained suppressed for the rest of the study. In contrast, total IGF-I remained unchanged until the end of d 3, at which levels were slightly reduced (P < 0.007). IGFBP-1 increased from 38 +/- 2 to 137 +/- 24, 212 +/- 32, and 214 +/- 22 microg/liter (d 1 vs. d 2, d 3, and end of d 3; P < 0.0001), and these changes closely paralleled those of IGFBP-1-bound IGF-I (P < 0.0001). IGFBP-2 increased only transiently at d 2 (P < 0.05), and IGFBP-3 remained unchanged. The increase in mean 24-h GH levels from d 1 to d 2 correlated inversely with the relative reduction in free IGF-I from d 1 to d 2 (r = -0.51; P = 0.04), i.e. the larger the reduction in free IGF-I, the larger the increase in GH. None of the other IGF-related parameters correlated with GH. In conclusion, the temporal relationship between the increase in GH and the reduction in free IGF-I supports the hypothesis that circulating free IGF-I mediates the feedback regulation of GH secretion.

Patients with active acromegaly are insulin resistant and glucose intolerant, whereas children with GH deficiency are insulin sensitive and may develop fasting hypoglycemia. Surprisingly, however, hypopituitary adults with unsubstituted GH deficiency tend to be insulin resistant which may worsen during GH substitution. A unifying mechanism explaining insulin resistance in both conditions could be increased flux of free fatty acids (FFA) caused by visceral obesity (untrated GHDA) and enhanced lipid oxidation (GH substitution), respectively. During fasting, which may be considered the natural domain for the metabolic effects of GH, the induction of insulin resistance by GH is associated with enhanced lipid oxidation and protein conservation. In this particular context, insulin resistance appears to constitute a favorable metabolic adaptation. The problem is that GH substitution results in elevated circadian GH levels in non-fasting patients. The best way to address this challenge is to employ evening administration of GH and to tailor the dose. Insulin therapy may cause hypoglycemia, and GH substitution may cause hyperglycemia. Such untoward effects should be minimised by carefully monitoring the individual patient. It is also plausible that the long-term beneficial effects of GH on body composition will balance the insulin antagonistic effects on glucose metabolism.

Unlabelled: That physical exercise stimulates pituitary GH secretion has been known for forty years, but the underlying mechanisms as well as the physiological significance remain elusive. We have previously shown that the concomitant increase in core temperature is essential for the exercise-induced GH release, inasmuch as exercise performed at 4 C results in a suppression of GH secretion, whereas passive heating constitutes a potent stimulus for GH release. Moreover, studies in normal subjects show that GH stimulates sweat production and evaporative heat loss during heat exposure with and without exercise, whereas GH-deficiency is associated with reduced sweat secretion and increased heat storage during similar conditions. The neurotransmitters involved in GH secretion during exercise remain uncertain; we therefore investigated the putative role of ghrelin, which is a gut-derived endogenous ligand for the GHS receptor. We measured circulating ghrelin levels before during and after submaximal aerobic exercise in healthy subjects and GH-deficient patients. The circulating ghrelin levels were unchanged during and after exercise in all subjects. Growth hormone stimulates lipolysis and lipid oxidation during basal and fasting conditions and we recently investigated whether GH also regulates substrate metabolism during exercise. The design involved GH-deficient patients studied during exercise with and without GH administration as compared to untreated healthy subjects. Growth hormone predominantly stimulated the turnover of free fatty acids in the recovery phase after exercise., Conclusions: 1) the increase in GH release during exercise is associated with the concomitant increase in body temperature, 2) GH stimulates sweat secretion and heat evaporation during exercise, which seems to be of distinct physiological significance, 3) ghrelin is not involved in exercise-induced GH release, 4) the impact of GH on substrate metabolism during exercise includes increased FFA turnover.

The aim of the GH-2000 project is to develop a method for detecting GH doping among athletes. Previous papers in the GH-2000 project have proposed that a forthcoming method to detect GH doping will need specific components from the GH/IGF-I axis and bone markers because these specific variables seem more sensitive to exogenous GH than to exercise. The present study examined the responses of the serum concentrations of these specific variables to a maximum exercise test in elite athletes from selected sports. A total of 117 elite athletes (84 males and 33 females; mean age, 25 yr; range, 18-53 yr) from Denmark, the United Kingdom, Italy, and Sweden participated in the study. The serum concentrations of total GH, GH22 kDa, IGF-I, IGF binding protein (IGFBP)-2, IGFBP-3, acid-labile subunit, procollagen type III (P-III-P), and the bone markers osteocalcin, carboxy-terminal cross-linked telopeptide of type I collagen (ICTP), and carboxy-terminal propeptide of type I procollagen were measured. The maximum exercise test showed, in both genders, a peak concentration of total GH (P < 0.001) and GH22 kDa (P < 0.001) by the time exercise ended compared with baseline, and a subsequent decrease to baseline levels within 30-60 min after exercise. The mean time to peak value for total GH and GH22 kDa was significantly shorter in males than females (P < 0.001). The components of the IGF-I axis showed a similar pattern, with a peak value after exercise compared with baseline for IGF-I (P < 0.001, males and females); IGFBP-3 (P < 0.001, males and females); acid-labile subunit [P < 0.001, males; not significant (NS), females], and IGFBP-2 (P < 0.05, females; NS, males). The serum concentrations of the bone markers ICTP (P < 0.001, males; P < 0.05, females) and P-III-P (P < 0.001, males and females) increased in both genders, with a peak value in the direct post-exercise phase and a subsequent decrease to baseline levels or below within 120 min. The osteocalcin and propeptide of type I procollagen values did not change during the exercise test. Specific reference ranges for each variable in the GH/IGF-I axis and bone markers at specific time points are presented. Most of the variables correlated negatively with age. In summary, the maximum exercise test showed a rather uniform pattern, with peak concentrations of the GH/IGF-I axis hormones and the bone markers ICTP and P-III-P immediately after exercise, followed by a subsequent decrease to baseline levels. The time to peak value for total GH and GH22 kDa was significantly shorter for females compared with males. This paper presents reference ranges for each marker in each gender at specific time points in connection to a maximum exercise test to be used in the development of a test for detection of GH abuse in sports.

Studies in animals and humans indicate that GH and IGF-I modulate immune function. Recently, it was reported that GH therapy increased the mortality in critically ill patients. The excessive mortality was almost entirely attributable to septic shock or multiorgan failure, suggesting that a GH-induced modulation of immune function was involved. In the present study, we examined whether GH or IGF-I influences the serum concentrations of mannan-binding lectin (MBL). MBL is a plasma protein of the innate immune system that initiates the complement cascade and activates inflammation after binding to carbohydrate structures on microbial surfaces. We performed a cross-over study of 16 healthy men examined during a control period, and during treatment with either GH or IGF-I for 6 d. The levels of MBL were more than doubled during GH treatment, whereas no changes were observed in the IGF-I group or during the control period (P < 0.001). IGF-I levels were elevated similarly during treatment with GH and IGF-I. Subsequently, we studied 30 healthy persons and 25 GH-deficient (GHD) patients randomized to treatment with GH or placebo in a double-blinded manner, and further included samples from 23 patients with active acromegaly examined before and after treatment with octreotide or the GH-receptor antagonist pegvisomant for 3 months. Baseline concentrations of MBL were lower in GHD patients and higher in acromegalic patients than in healthy subjects (P < 0.02). Treatment with GH doubled the MBL concentrations in healthy subjects and almost quadrupled the concentrations in GHD patients; whereas in acromegalic patients, the levels of MBL were reduced to approximately two thirds of the initial values during treatment with octreotide or pegvisomant. Our results demonstrate that treatment with GH, but not IGF-I, significantly increases MBL concentrations. The clinical consequences of this new link between the endocrine and the immune system remain to be elucidated.

Objective: To evaluate the histomorphology of skin and its appendages, especially eccrine sweat glands, in patients with GH disorders, because reduced sweating ability in patients with growth hormone deficiency (GHD) is associated with increased risk of hyperthermia under stressed conditions., Design and Methods: A skin biopsy was obtained from 17 patients with GHD treated with GH, five patients with untreated GHD, 10 patients with active acromegaly and 13 healthy controls., Results: The sweat secretion rate (SSR) was significantly decreased in both the untreated (median 41 mg/30 min, range 9-79 mg/30 min) and the GH-treated (median 98 mg/30 min, range 28-147 mg/30 min) patients with GHD compared with that in controls (median 119 mg/30 min, range 90-189 mg/30 min; P=0.001 and 0.01 respectively). Epidermal thickness was significantly decreased in both untreated (median 39 microm, range 28-55 microm) and GH-treated patients with GHD (median 53 microm, range 37-100 microm), compared with that in controls (median 66 microm, range 40-111 microm; P<0.02). A statistically non-significant tendency towards thinner epidermis (median 59 microm, range 33-83 microm) was recorded in acromegalic patients (P=0.08) compared with controls. There was no significant difference in the area of the sebaceous glands in the biopsies between the three groups and the controls. The area of eccrine sweat gland glomeruli was significantly decreased in the untreated patients with GHD (median 16407 microm2, range 12758-43976 microm2) compared with that in controls (median 29446 microm2, range 13511-128661 microm2; P=0.03), but there was no significant difference between the GH-treated patients with GHD and controls., Conclusions: We conclude that GH, either directly or via IGF-I, may have both a structural and a functional effect on human skin and its appendages, and that patients with GHD have histomorphological changes in skin compared with controls. Importantly, these changes are not fully reversed despite long-term and adequate GH treatment in patients with childhood onset GHD.

The consequences of GH deficiency during conditions in which endogenous GH release is acutely stimulated are largely unknown. Short-term fasting constitutes a robust GH stimulus, but the metabolic significance of GH during fasting is uncertain. To address both of these issues, we therefore evaluated the effect of GH on substrate metabolism during fasting in adults with GH deficiency. Seven hypopituitary GH-deficient patients were each studied twice during a 40-h fast: once with GH replacement continued and once with GH discontinued during the fast. After 40 h of fasting, protein synthesis and turnover were higher with than without GH replacement [phenylalanine incorporation (micromol/kg fat free mass/h): 36.6 +/- 1.2 (GH) vs. 32.8 +/- 1.4, P < 0.05; phenylalanine flux (micromol/kg fat free mass/h): 41.3 +/- 1.0 (GH) vs. 38.0 +/- 1.8, P < 0.05]. During continued GH replacement, urea excretion decreased during nighttime [urea excretion (mmol/24 h): 269 +/- 51 (GH) vs. 390 +/- 69, P < 0.05], and a significant decline in urea-N synthesis rate was found [urea-N synthesis rate (mmol/h): 14.7 +/- 1.6 (GH) vs. 21.1 +/- 2.2, P < 0.01]. GH replacement was associated with increased lipid oxidation [lipid oxidation (mg/kg per min): 0.91 +/- 0.07 (GH) vs. 0.70 +/- 0.03, P < 0.05]. Finally, continuation of GH induced moderate elevations in plasma glucose levels without significant changes in total glucose turnover or oxidation. In summary, continued GH substitution during fasting conserves nitrogen, which involves stimulation or maintenance of protein synthesis. Our data support the importance of GH replacement in hypopituitary adults.

The importance of growth hormone (GH) deficiency in adults became evident 10 to 15 years ago, when the first clinical studies on GH replacement therapy in adults were published. Since then, a number of studies have been reported showing that GH replacement therapy can improve this condition. Adult GH deficiency (GHD) is now recognized as a specific clinical syndrome and the first reports of long-term use of GH (up to 10 years) are now being published. The aim of this paper was to review the accumulated data on the various clinical aspects of adult GHD., (Copyright 2001 Academic Press.)

The importance of growth hormone (GH) deficiency in adults became evident at the end of the 1980s, when the first clinical studies on GH replacement therapy in adults were published. Since then, accumulated experience has shown a great individual variability in the response to GH replacement, including a potential difference in responsiveness between genders. The aim of this paper is to review the data regarding the effects of gender differences on GH pharmacokinetics, pharmacodynamics, and efficacy of replacement. In addition, we start with a short review of the possible role of GH in sexual development and sexual life.

It remains uncertain whether close imitation of the physiological pulsatile GH pattern determines the effects of GH treatment in humans. However, human studies have reported comparable metabolic responses to short-term constant and intermittent GH exposure. The aim of the study was to compare the metabolic effects of GH after continuous and intermittent sc delivery. In a parallel design, 14 GH-treated GH-deficient patients (mean age, 37 yr; mean body mass index, 27.4 kg/m(2)) were studied during steady state at the start of the study and after 6 months. Seven patients received daily injections (inj) in the evening as usual, and 7 received a continuous infusion (inf) of GH by means of a portable pump. The GH dose was kept unchanged before and during the study. Serum levels of insulin-like growth factor I (IGF-I) tended to increase in the patients switched to constant infusion (from 175 +/- 36 to 209 +/- 50 microg/L), but the differences obtained during the two regimens [+34.3 (inf) vs. -11.9 (inj)] were not significant (P = 0.34). Serum levels of IGF-II (P = 0.71) and IGF-binding protein (IGFBP)-3 (P = 0.75) were identical during the two modes of treatment. Serum levels of IGFBP-1 (P = 0.72), IGFBP-2 (P = 0.34), and GH-binding protein (P = 0.75) were unaffected by treatment regimen. Serum levels of free fatty acids, reflecting lipolysis, decreased significantly (16%) in the group switched to GH infusion (difference, -99.8 vs. +5 micromol/L; P < 0.03). The GH pattern did not influence insulin sensitivity (P = 0.71) or glucose effectiveness (P = 0.15) derived from Bergman's minimal model. Similarly, the two treatment regimens had no differential impact on lipoprotein levels, bone metabolism, or body composition. In conclusion, continuous and intermittent administrations of GH for 6 months are comparable with respect to the IGF-IGFBP axis, whereas intermittent exposure may be of importance for the lipolytic effect of GH. The data on insulin sensitivity and lipoproteins suggest that constant GH exposure is as safe as intermittent GH administration.

The aim of the present study was to examine the GH/insulin-like growth factor (IGF) axis, post exercise, with emphasis on IGF-binding protein (IGFBP)-3 proteolysis. Sixteen elite rowers (8 female/8 male) performed a stepwise submaximal rowing test followed by a 6- to 7-min-long maximal test. Blood samples were drawn at baseline, t = 0 (end of exercise) and t = 15, 30, 60, 90, and 120 min. GH and IGFBP-1 levels increased post exercise (P < 0.0005). Total IGF-I and IGF-II increased significantly post exercise (P < 0.0005) but not after albumin correction. Free IGF-I decreased after exercise with nadir coincidently with the IGFBP-1 peak, and free IGF-II decreased post exercise coincidently with the IGFBP-6 peak. IGFBP-3, measured by immunoradiometric assay, increased after exercise (P < 0.0005) but not after albumin adjustment. IGFBP-3 proteolysis (%) (measured by a specific in vitro proteolytic activity assay) and IGFBP-3 (measured by Western ligand blotting) were unchanged post exercise. Albumin-adjusted levels of IGFBP-6 increased by 18% (P < 0.0005), whereas IGFBP-2 and IGFBP-4 did not change significantly post exercise. Our findings do not support the hypothesis that short-term strenuous exercise induces major acute changes in the GH/IGF axis. To what degree the protein anabolic effects of regular exercise are associated with acute alterations in the GH/IGF axis remains unclear.

In humans at least two GH receptors are significantly expressed. One is the full-length receptor (GHR); the other is a truncated form (GHRtr), that lacks most of the intracellular domain. This receptor may inhibit the action of the full-length receptor. Circulating GH-binding protein (GHBP) is a proteolytically cleaved product from both of these receptors. The clinical relevance of the different receptor types is unknown. We examined the gene expression of GHR and GHRtr in human adipose tissue and skeletal muscle and the influence of GH treatment on this expression. Furthermore, we studied the relationship of circulating GHBP and body composition to GHR and GHRtr gene expression. Eleven adult GH-deficient patients were studied before and after 4 months of GH substitution therapy. Abdominal fat obtained by liposuction and femoral muscle biopsies were taken at baseline and after 4 months. Gene expression of GHR and GHRtr in adipose tissue and skeletal muscle was determined and expressed relative to the expression of beta-actin. Gene expression of GHR in abdominal sc adipose tissue was not altered, whereas the expression of GHRtr increased significantly. In skeletal muscle inverse changes were seen in the expression of messenger ribonucleic acid (mRNA) levels for the two GH receptor forms: expression of GHR increased significantly, whereas mRNA levels for GHRtr decreased. As expected, body composition changed with reduction of body fat mass after 4 months of GH treatment. Levels of circulating GHBP decreased significantly. We conclude that GH treatment in GH-deficient adults changes the expression of mRNA for GHR and GHRtr in adipose tissue and skeletal muscle. Whether these changes are responsible for the observed changes in body composition in response to GH treatment and the observed changes in levels of circulating GHBP, however, needs further elucidation.

The metabolic response to fasting involves a series of hormonal and metabolic adaptations leading to protein conservation. An increase in the serum level of growth hormone (GH) during fasting has been well substantiated. The present study was designed to test the hypothesis that GH may be a principal mediator of protein conservation during fasting and to assess the underlying mechanisms. Eight normal subjects were examined on four occasions: 1) in the basal postabsorptive state (basal), 2) after 40 h of fasting (fast), 3) after 40 h of fasting with somatostatin suppression of GH (fast-GH), and 4) after 40 h of fasting with suppression of GH and exogenous GH replacement (fast+GH). The two somatostatin experiments were identical in terms of hormone replacement (except for GH), meaning that somatostatin, insulin, glucagon and GH were administered for 28 h; during the last 4 h, substrate metabolism was investigated. Compared with the GH administration protocol, IGF-I and free IGF-I decreased 35 and 70%, respectively, during fasting without GH. Urinary urea excretion and serum urea increased when participants fasted without GH (urea excretion: basal 392 +/- 44, fast 440 +/- 32, fast-GH 609 +/- 76, and fast+GH 408 +/- 36 mmol/24 h, P < 0.05; serum urea: basal 4.6 +/- 0.1, fast 6.2 +/- 0.1, fast-GH 7.0 +/- 0.2, and fast+GH 4.3 +/- 0.2 mmol/1, P < 0.01). There was a net release of phenylalanine across the forearm, and the negative phenylalanine balance was higher during fasting with GH suppression (balance: basal 9 +/- 3, fast 15 +/- 6, fast-GH 17 +/- 4, and fast+GH 11 +/- 5 nmol/min, P < 0.05). Muscle-protein breakdown was increased among participants who fasted without GH (phenylalanine rate of appearance: basal 17 +/- 4, fast 26 +/- 9, fast-GH 33 +/- 7, fast+GH 25 +/- 6 nmol/min, P < 0.05). Levels of free fatty acids and oxidation of lipid decreased during fasting without GH (P < 0.01). In summary, we find that suppression of GH during fasting leads to a 50% increase in urea-nitrogen excretion, together with an increased net release and appearance rate of phenylalanine across the forearm. These results demonstrate that GH-possibly by maintenance of circulating concentrations of free IGF-I--is a decisive component of protein conservation during fasting and provide evidence that the underlying mechanism involves a decrease in muscle protein breakdown.

Aims: The impact of growth hormone (GH) and prednisolone on the GH/insulin-like growth factor (IGF) axis with special emphasis on IGF binding protein-3 (IGFBP-3) proteolysis was studied in 8 healthy adults in a double-blind cross-over study with four periods: (1) placebo; (2) s.c. GH 0.1 IU/kg/day; (3) oral prednisolone 50 mg/day, and (4) co-administration of GH and prednisolone., Methods: Each treatment period lasted for 4 days followed by a washout period of 10 days. We measured IGF-I, IGF-II, IGFBP-1, IGFBP-2, IGFBP-3 by immunoassays, IGFBP-3 by Western ligand blotting (WLB) and finally in vitro IGFBP-3 proteolysis by a (125)I-IGFBP-3 degradation assay., Results: IGF-I levels increased by 99% during GH administration and 67% during co-administration of GH and prednisolone (p < 0.0005), whereas no significant change was seen during prednisolone alone. IGFBP-1 levels decreased 55% during the prednisolone period (p < 0.002), but the between period changes were not significant (p < 0.1). IGFBP-2 decreased 33% during co-administration of GH and prednisolone (p < 0.002). IGFBP-3 increased 12% during GH and 7% during co-administration of GH and prednisolone (p < 0.003 and p < 0.03 compared to placebo, respectively), whereas prednisolone alone induced no significant changes. IGFBP-3 measured by WLB did not change significantly, neither did IGFBP-3 proteolysis., Conclusions: Prednisolone administration induces only minimal changes in circulating components of the IGF axis and is not accompanied by alterations in IGFBP-3 proteolysis. This indicates that the metabolic effects of glucocorticoids do not depend on serum IGF-I., (Copyright 2001 S. Karger AG, Basel)

The aim of the present study was to evaluate the long-term (30 months) metabolic effects of recombinant human GH (rhGH) given in a mean dose of 6.7 microg/kg x day (= 1.6 IU/day), in 11 patients with adult GH deficiency. Glucose metabolism was evaluated by an oral glucose tolerance test and an iv (frequently sampled iv glucose tolerance test) glucose tolerance test, and body composition was estimated by dual-energy x-ray absorptiometry. Treatment with rhGH induced persistent favorable changes in body composition, with a 10% increase in lean body mass (P < 0.001) and a 12% reduction of fat mass (P < 0.002); however, the glucose tolerance deteriorated significantly, and three patients developed impaired glucose tolerance. Fasting insulin level (P < 0.003) and the homeostasis model assessment insulin resistance score increased significantly, indicating a deterioration in insulin sensitivity; whereas the insulin sensitivity index, calculated from the frequently sampled iv glucose tolerance test, only decreased slightly. The clearance of C-peptide and insulin increased 100% and 60%, respectively, and the prehepatic insulin secretion was tripled during rhGH treatment; but related to the impairment in glucose tolerance, beta-cell response was still inappropriate. Our conclusion is that long-term rhGH-replacement therapy in GH deficiency adults induced a significant deterioration in glucose tolerance, profound changes in kinetics of C-peptide, and insulin and prehepatic insulin secretion, despite an increase in lean body mass and a reduction of fat mass. Therefore, rhGH treatment may precipitate diabetes in some patients already susceptible to the disorder.

Objective: Hyperinsulinemia in association with GH excess is considered a compensatory response to insulin resistance, but the possibility of alternative insulinotropic mechanisms has not been investigated in vivo. It is also unknown how GH influences the secretion from pancreatic beta-cells of amylin, a peptide which regulates prandial glucose homeostasis and may be linked to development of beta-cell dysfunction. We therefore measured plasma concentrations of two gut insulinotropic hormones, glucagon-like peptide 1 (GLP-1) and glucose-dependent insulin-releasing peptide (GIP), and total as well as non-glycosylated amylin, in 24 GH-deficient adults before and after 4 months of GH replacement (daily evening injections of 2 IU GH/m)., Design: Double-blind, placebo-controlled, parallel study., Methods: All participants underwent an oral glucose tolerance test (OGTT) at 0 and 4 months., Results: A 33% suppression of fasting GLP-1 concentrations was measured in the GH group at 4 months (P=0.02), whereas a non-significant increase occurred in the placebo group (P=0.08). Fasting levels of GIP and amylin did not change significantly after 4 months in either group. The incremental response in GLP-1 during the OGTT was significantly lower after GH treatment as compared with both baseline (P=0.02) and the response in the placebo group (P=0. 03). The stimulation of GIP secretion following OGTT was similar on all occasions. The OGTT-induced incremental response in non-glycosylated amylin was moderately elevated after GH treatment as compared with placebo (P=0.05). Plasma concentrations of glucose and insulin, both in the fasting state and after the OGTT, were higher after GH treatment, but the ratio between amylin and insulin remained unchanged., Conclusions: GH-induced hyperinsulinemia is accompanied by proportionate elevations in amylin concentrations and a blunting of gut GLP-1 secretion. The mechanisms underlying the suppression of GLP-1 remain to be elucidated.

In the circulation insulin-like growth factor I (IGF-I), IGF-binding protein 3 (IGFBP-3), and the acid-labile subunit (ALS) form a 150-kDa ternary complex that is of importance for the regulation of IGF-I bioactivity. GH administration is known to increase each of the single components of the ternary complex, and in GH-deficient rats formation of the 150-kDa complex is induced more by continuous than by pulsatile GH patterns. The aim of the present studies was to study the effects of the GH administration pattern on the formation of the 150-kDa ternary complex in humans. A fixed total GH dose (2 IU/m2-24 h) was administered iv randomly as 1) continuous infusion or 2) eight bolus injections to five GH-deficient patients over a period of 24 h. GH administration significantly increased serum IGF-I and IGFBP-3 levels and the IGF-I/IGFBP-3 ratio. IGF-I levels increased most pronouncedly after continuous administration (P < 0.01). Serum ALS levels increased significantly (both P < 0.005) from 94+/-21 to 180+/-29 (infusion) and from 85+/-17 to 155+/-17 nmol/L (pulses). Employment of neutral size exclusion chromatography enabled separation of IGFBP-3 in ternary complex and noncomplex-bound fractions. IGFBP-3 in the ternary complex increased significantly after GH administration [by 44% (P = 0.048) during infusion and by 62% (P = 0.004) during bolus]. The noncomplex-associated IGFBP-3 fraction, however, did not increase significantly after GH administration (P = NS). Finally, formation of the ternary complex was unaffected by the pattern of GH delivery. In conclusion, short-term GH administration increased all components of the 150-kDa ternary complex. Higher levels of IGF-I after constant GH exposure could indicate an increased bound fraction. However, the GH pattern did not influence the induction of the ternary complex itself. Continuous and intermittent GH patterns may be clinically equally effective during long-term GH therapy, as judged by levels of the components of the ternary complex.

Measurements of serum insulin-like growth factor I (IGF-I) and related markers are routinely used in the diagnosis and treatment of GH deficiency and excess. The validity of these markers for assessment of exogenous GH exposure in healthy adults is, however, unknown. We therefore conducted a double blind, placebo-controlled GH treatment trial in 99 healthy subjects [49 women and 50 men; mean +/- SE age, 25.6+/-0.6 (women)/25.7+/-0.6 yr (men)]. Blood was collected weekly during a 4-week treatment period (days 1-28), and the subjects were subsequently followed for additional 8 weeks (days 29-84). The treatment arms included: I) 0.1 IU/kg x day GH (n = 30; GH 0.1), II) 0.2 IU/kg x day GH (n = 29; GH 0.2), and III) placebo (n = 40). At baseline no gender-specific differences existed, except that the acid-labile subunit (ALS) levels were higher in females. Serum insulin-like growth factor I (IGF-I) levels in males receiving GH increased significantly through day 42 with no significant difference between the 2 doses. The absolute IGF-I response was significantly lower in females, and there was a clear dose-response relationship. ALS levels in males increased through day 30 (P < 0.001). In females ALS levels were only modestly increased on day 28 compared with those in the placebo group (P < 0.02). IGF-binding protein-3 (IGFBP-3) levels in males increased significantly in the GH 0.1 and the GH 0.2 groups on day 30 (P < 0.03), whereas no solid IGFBP-3 increase was detected in females. IGFBP-2 levels decreased insignificantly during GH exposure in both genders. A gender-specific upper normal range for each analyte was arbitrarily defined as 4 SD above the mean level at baseline. On the basis of IGF-I levels alone, GH exposure in the GH 0.2 group was detected in 86% of the males and in 50% of the females on day 21. On day 42 GH exposure was only weakly detectable in males and was not detectable in females. We conclude that 1) males are significantly more responsive than females to exogenous GH; 2) the increase in IGF-I is more robust compared with those in IGFBP-3 and ALS; 3) IGFBP-2 changes very little during GH treatment; and 4) among IGF-related substances, IGF-I is the most specific marker of supraphysiological GH exposure.

It is well known that growth hormone (GH) treatment reduces fat mass (FM), which presumably is mediated through stimulation of triglyceride breakdown and inhibition of adipose tissue lipoprotein lipase activity (AT-LPL). However, it is unknown which of the 2 GH-regulated pathways are of most importance for the reduction in FM. We investigated the effect of weight loss together with GH treatment on the activity and gene expression of LPL and hormone-sensitive lipase (HSL) in AT and muscle tissue. A very-low-calorie diet ([VLCD] 740 kcal/d) was given to 18 obese women (body mass index [BMI] > 35 kg/m2) and half of them were treated with GH (0.04 IU/kg) for 4 weeks in a randomized double-blind placebo-controlled study. Subcutaneous fat and muscle biopsies were taken before and after 4 weeks. Weight loss after 4 weeks was similar in the 2 groups, with a reduction of 4.5% (placebo) and 4.6% (GH) and a reduction of FM by 7.4% and 9.0% ([NS] nonsignificant). The weight loss resulted in a small and NS reduction of AT-LPL activity by 20% +/- 12% in the placebo group, but in the GH group, AT-LPL was significantly reduced by 65% +/- 8% (P < .01). Muscle LPL (M-LPL) activity was not affected by the weight loss alone, but a significant reduction was observed in the GH group (20.4% +/- 10%, P < .05). AT-HSL activity was significantly enhanced after weight loss, but GH had no additional effect on this minor increment. This is in accordance with the finding that the increment in free fatty acid (FFA) after weight loss was similar in the 2 groups. GH treatment was associated with a significant reduction of high-density lipoprotein (HDL) cholesterol (P < .05). In conclusion, GH significantly inhibited AT-LPL activity but had no additional effect on the hypocaloric-induced loss of FM, indicating that under such circumstances, AT-LPL does not directly regulate adipose tissue mass. GH was not found to have opposite effects on the activity of LPL in adipose tissue and muscle, since GH treatment reduced them both (by 65% and 20%, respectively). The VLCD-induced weight loss was associated with a minor enhanced activity of AT-HSL with no independent effect of GH. Thus, concerning body weight, FM, and lipolytic activity, treatment with GH offers no extra benefits during a VLCD for 4 weeks.

Cardiac muscle is characterized by insulin resistance in specific heart diseases such as coronary artery disease and congestive heart failure, but not in generalized disorders like diabetes mellitus and essential hypertension when cardiac manifestations are absent. To examine whether the insulin antagonistic effect of growth hormone (GH) acts upon the heart, we compared insulin-stimulated whole body and myocardial glucose uptake with and without GH administration during a 3.5-h euglycemic-hyperinsulinemic clamp in eight healthy males. Myocardial 2-deoxy-2-[(18)F]fluoro-D-glucose uptake was measured with positron emission tomography. The data were converted to myocardial glucose uptake by tracer kinetic analysis. GH did not change the rate-pressure product. GH decreased whole body insulin-stimulated glucose disposal by 26% (48.0 +/- 12.1 vs. control 62.8 +/- 6.1 micromol. kg(-1). min(-1), P < 0.02). Free fatty acids were suppressed to a similar extent with and without GH during the insulin clamp. Insulin-stimulated myocardial glucose uptake was similar in the presence and in the absence of GH (0.34 +/- 0.05 and 0.31 +/- 0.03 micromol. g(-1). min(-1), P = 0.18). In conclusion, GH does not impair insulin-stimulated myocardial glucose uptake despite a considerable whole body insulin antagonistic effect. Myocardial insulin resistance is not an inherent consequence of whole body insulin resistance.

The appropriate management of GH-deficient patients during transition from childhood to adulthood has not been reported in controlled trials, even though there is evidence to suggest that this phase is associated with specific problems in relation to GH sensitivity. An issue of particular interest is the impact of GH substitution on insulin sensitivity, which normally declines during puberty. We, therefore, evaluated insulin sensitivity (euglycemic glucose clamp) and substrate metabolism in 18 GH-deficient patients (6 females and 12 males; age, 20 +/- 1 yr; body mass index, 25 +/- 1 kg/m2) in a placebo-controlled, parallel study. Measurements were made at baseline, where all patients were on their regular GH replacement, after 12 months of either continued GH (0.018 +/- 0.001 mg/kg day) or placebo, and finally after 12 months of open phase GH therapy (0.016 mg/kg x day). Before study entry GH deficiency was reconfirmed by a stimulation test. During the double-blind phase, insulin sensitivity and fat mass tended to increase in the placebo group [deltaM-value (mg/kg x min), -0.7 +/- 1.1 (GH) vs. 1.3 +/- 0.8 (placebo), P = 0.18; deltaTBF (kg), 0.9 +/- 1.2 (GH) vs. 4.4 +/- 1.6 (placebo), P = 0.1]. Rates of lipid oxidation decreased [delta lipid oxidation (mg/kg x min), 0.02 +/- 0.14 (GH) vs. -0.32 +/- 0.13 (placebo), P < 0.05], whereas glucose oxidation increased in the placebo-treated group (P < 0.05). In the open phase, a decrease in insulin sensitivity was found in the former placebo group, although they lost body fat and increased fat-free mass [M-value (mg/kg x min), 5.1 +/- 0.7 (placebo) vs. 3.4 +/- 1.0 (open), P = 0.09]. In the group randomized to continued GH treatment almost all hormonal and metabolic parameters remained unchanged during the study. In conclusion, 1) discontinuation of GH therapy for 1 yr in adolescent patients induces fat accumulation without compromising insulin sensitivity; and 2) the beneficial effects of continued GH treatment on body composition in terms of decrease in fat mass and increase in fat-free mass does not fully balance the direct insulin antagonistic effects.

Previous studies have demonstrated beneficial effects of GH replacement, in adults with GH deficiency (GHD), on body composition, physical fitness, and quality of life. These studies, however, concern patients with adult-onset GHD or childhood-onset (CO) patients enrolled several years after withdrawal of initial therapy. So far, the effects of continuation of GH-administration in patients with CO-GHD have not been examined. We studied a group of nineteen young adults (13 males + 6 females; 16-26 yr old; mean age, 20.2 +/- 0.65 yr) with CO-GHD, in a randomized, parallel, double-blind, placebo-controlled trial for 1 yr, followed by an open phase with GH for 1 yr. All patients received GH therapy at the start of study, and trial medication (GH/placebo) was given in a similar dose. Patients randomized to continued GH treatment exhibited no significant changes in any parameters tested, but intra- and interindividual variations in insulin-like growth factor (IGF)-I levels could suggest compliance problems. Discontinuation of GH for 1 yr resulted in a decrease in serum IGF-I, from 422.0 +/- 56.8 to 147.8 +/- 33.4 microg/L, in the placebo group (P = 0.003). After discontinuation of GH for 1 yr, an increase in total body fat (TBF, kg), measured by dual-energy x-ray absorptiometry scan, was seen [placebo: 22.7 +/- 2.7 to 26.5 +/- 2.5 (P = 0.01); GH: 16.2 +/- 2.1 to 17.2 +/- 2.1 (not significant)]. Resumption of GH after placebo was followed by increments in serum IGF-I (microg/L) [from 147.8 +/- 33.4 to 452 +/- 76 (P = 0.001)] and IGF-binding protein 3, as well as in fasting glucose (mmol/L) [4.9 +/- 0.2 vs. 5.3 +/- 0.2 (P = 0.03)]. After resumption of GH lean body mass (kg) increased [52.4 +/- 4.9 vs. 60.7 +/- 5.6 (P = 0.006)]. Likewise, resumption of GH therapy increased thigh muscle volume and thigh muscle/fat ratio, as assessed by computed tomography [muscle volume (cm2/10 mm): 118.2 +/- 11.7 vs. 130.0 +/- 10.9 (P = 0.002); muscle/fat ratio: 1.33 +/- 0.24 vs. 1.69 +/- 0.36 (P = 0.02)]. In conclusion, discontinuation of GH treatment in GHD patients, during the transition from childhood to adulthood, induces significant and potentially unfavorable changes in IGF-I and body composition, both of which are reversed after resumption of GH treatment. By contrast, continuation of GH therapy results in unaltered IGF-I and body composition. We recommend continuation of GH therapy in these patients, to be undertaken in collaboration between pediatricians and adult endocrinologists.

Objective: Treatment of obesity with very low calorie diet (VLCD) is complicated by protein loss. We evaluated the effects of coadministration of GH on protein turnover, substrate metabolism, and body composition in VLCD treated obesity., Design and Patients: Fifteen obese women underwent 4 weeks of very low calorie diet (VLCD) in parallel with GH treatment (n = 7) or placebo (n = 8)., Measurements: Protein metabolism and total glucose turnover were isotopically assayed. Plasma concentrations of amino acids were determined by an HPLC system. Estimated rates of lipid and glucose oxidation were obtained by indirect calorimetry. Fat free mass was determined by DEXA-scan., Results: Protein breakdown decreased in both groups (tyrosine flux micromol/h): -12% +/- 3 (GH) vs. - 9% +/- 3 (placebo)). Phenylalanine degradation in relation to phenylalanine concentration decreased by 9% in the GH group, whereas an increase of 8% was observed in the placebo group (P = 0.1). Plasma concentrations of several amino acids were significantly decreased in the placebo group, while urea excretion decreased in the GH group. A decrease in FFM was found in placebo treated patients (2.14% +/- 1.9 (GH) vs. - 3.54% +/- 1.6 (placebo), P < 0.05). Rates of lipid oxidation tended to be increased by GH treatment (lipid oxidation (mg/minutes): 79.7 +/- 5.9 (GH) vs. 64.6 +/- 5.9 (placebo), P = 0.1)., Conclusion: During dietary restriction GH primarily seems to conserve protein by a reduced hepatic degradation of amino acids.

Background: Many adult patients in chronic hemodialysis exhibit malnourishment and muscle wasting, which in some may be due partly to blockage of the biological action of growth hormone and the somatomedines. Growth hormone (GH) promotes protein synthesis, and long-term treatment with growth hormone has induced an augmentation in lean body-mass (LBM) in normal elderly persons, in persons with GH deficiency as well as growth improvement in uremic children. The purpose of this study was to evaluate the effect of long-term GH treatment on soft tissues in hemodialyzed patients by dual-energy X-ray absorptiometry (DXA) with special regard to the improvement in lean body mass and fat mass (FM)., Design: The study was double-blinded, randomized, and placebo-controlled. Twenty enfeebled patients in chronic hemodialysis were treated by subcutaneous injections of biosynthetic human GH (4 IU/m2 per day) or placebo, given every evening for 6 months. Soft tissues as LBM and FM, were measured by DXA scan, and height, and weight were recorded before, and after 6 months treatment. Serum concentration of insulin-like growth factor (IGF-I) and type III collagen N-terminal propeptide (PIIINP) were analyzed at baseline and after 2, 4 and 6 months., Results: Six months of GH therapy induced a total FM reduction of 3.05 +/- 0.75 kg (mean +/- SEM) (p < 0.001) (n = 9) corresponding to 25% of the total fat mass. The reduction in fat was most marked at the trunk, i.e. 1.39 +/- 0.41 kg (p < 0.001) corresponding to 40% of the total FM reduction. Total LBM increased by 3.14 +/-0.41 kg (p < 0.001) in the GH group. Regional changes for arm, truncus and leg in GH group amounted to 0.22 +/- 0.06 kg (p < 0.001), 1.64 +/- 0.37 kg (p < 0.001) and 0.51 +/- 0.06 kg (p < 0.001), respectively. In contrast, total body weight remained unchanged. Serum IGF-I increased from 199 +/- 14.8 microg/l to 527 +/- 111 microg/l (p < 0.0001) at month 6, and the serum PIIINP from 7.8 +/- 1.3/microg/l to 14.3 +/- 2.1 microg/l (p < 0.001) in the GH-treated group. In the placebo group (n = 11) there were no significant changes in FM, LBM or PIIINP while serum IGF-I decreased from 285 +/- 36 microg/l to 219 +/- 35 microg/l (p < 0.01) after 6 months treatment., Conclusions: Six months of GH therapy to patients with chronic renal failure resulted in marked changes of the soft tissue with an increase in LBM, and reduction of FM particularly at the trunk. The data imply that GH-induced changes in body composition are maintained with long-term therapy. Very few side-effects of GH treatment were observed, and no serious ones were encountered, though the dosage were 2 to 3 times higher than the one given to GH-insufficient, non-uremic persons, and the serum IGF-I concentrations during treatment equalized those seen in acromegalia. This indicates the existence of a reduced biological effect of GH and IGF-I in uremic persons.

The effects of growth hormone (GH) substitution on bone metabolism were evaluated by dynamic histomorphometry on iliac crest bone biopsies. Twenty-nine patients, aged 21-61 years (mean 45.5 years), with adult-onset GH deficiency (GHD) were randomized to receive subcutaneous injections with GH (2 IU/m2/day = 0.67 mg/m2/day) or placebo for 12 months. Serum insulin-like growth factor I (IGF-I) levels increased 263 +/- 98% (mean +/- SD) during GH treatment (p < 0.0001). In the GH group, osteoid surface increased during treatment from 11% (3-15%) (median [25-75 percentiles]) to 21% (10-27%) (p = 0.01) and mineralizing surface from 4% (1-8%) to 11%(7-16%) (p = 0.04). Moreover, erosion surface tended to increase in the GH group from 2% (1-3%) to 4% (3-5%) (p = 0.07). The quiescent surface decreased in the GH group from 87% (83-96%) to 74% (68-87%) (p = 0.01). The adjusted appositional rate, mineral apposition rate, bone formation rate, bone erosion rate, mineralization lag time, and osteoid thickness remained unchanged during treatment. Erosion depth showed a trend toward increase in the GH group (p = 0.09), whereas wall thickness was unchanged. Bone balance at the remodeling unit level and activation frequency were unchanged. At the tissue level, bone erosion rate increased significantly from 26% (17-36%)/year to 39% (23-72%)/year (p = 0.03). Similarly, the bone formation rate at the tissue level tended to increase, from 24% (15-31%)/year to 36% (17%-63%)%/year (p = 0.06). Finally, bone balance at the tissue level decreased significantly from 1% (-2-2%)/year to -5% (-13-1%)/year (p = 0.01). No significant difference in change was seen in the cancellous bone volume. We conclude that 12 months of GH substitution therapy increases trabecular bone turnover. Moreover, our data suggest that bone balance at the bone multicellular unit level is not changed to positive.

Objective: It is generally accepted that there is no clinically significant circadian variation in total insulin-like growth factor (IGF)-I or total IGF-II in healthy subjects. In contrast there is a significant nocturnal decrease in free IGF-I in healthy subjects, corresponding to the nocturnal increase in IGF binding protein-1. In this study we have investigated the circadian variation in circulating free IGF-I and IGF-II in patients with acromegaly and patients with adult onset growth hormone deficiency., Patients: Seven acromegalic patients were studied with and without treatment with a slow-release formulation of octreotide. Seven GH-deficient patients were studied without GH replacement. In addition 5 of the GH-deficient patients were studied during GH replacement., Design: Serum samples were obtained every hour for 24 h. Free IGF-I and IGF-II were measured every 2nd hour. Total IGF-I and IGF-II were measured every 2nd hour (acromegalic patients) or every 4th hour (GH deficient patients). IGF binding protein (IGFBP)-1 was measured every 2nd hour (acromegalic patients) or every hour (GH deficient patients)., Results: In the untreated acromegalic patients there was a significant nocturnal decrease in free IGF-I, but not free IGF-II, before treatment. During treatment there was a significant nocturnal decrease in both free IGF-I and free IGF-II. Peak values of free IGF-I were 112% and 75% above trough (treatment and withdrawal, respectively). In the GH-deficient patients there were no significant circadian variations in free IGF-I or free IGF-II in either of the two occasions. In contrast, there was a significant circadian variation of total IGF-I after adjustment for changes in plasma volume in both treated and untreated acromegaly and GH deficiency in all cases with a peak between 0300 h and 0400 h. The nocturnal increase in total IGF-I ranged from 20% to 35%., Conclusions: A significant circadian variation in free IGF-I and IGF-II was demonstrated in acromegalic patients. In contrast no significant circadian variation in free IGF-I and IGF-II was found in GH-deficient patients. Part of the variations may be due to poorly understood variations in IGF-I release. It is not clear whether and to what extent the observed circadian changes in free and total IGF-I are involved in circadian changes in IGF-I bioactivity.

To examine the interactions between acute exercise and GH on markers of bone and collagen turnover and to assess the potential for detecting GH abuse in athletes using these markers, we studied 17 aerobically trained males (age, 26.9+/-1.5 yr). Sequential studies of exercise, GH administration, and GH withdrawal were undertaken. A randomized, controlled study of rest vs. exercise showed that exercise did not change serum osteocalcin; other markers of formation increased transiently (each P<0.001): bone-specific alkaline phosphatase (+16.1%), carboxyterminal propeptide of type I procollagen (+14.1%), and procollagen III N-terminal extension peptide (+5.0%). The carboxyterminal cross-linked telopeptide of type I collagen, a bone resorption marker, increased 9.7% (P = 0.018) in response to exercise. A randomized, double blind, placebo-controlled, parallel study of recombinant human GH treatment (0.15 IU/kg x day) for 1 week increased serum osteocalcin (net increase preexercise, +/-10.0%; P = 0.017), carboxyterminal propeptide of type I procollagen (+17.6%; P = 0.002), procollagen III N-terminal extension peptide (+48.4%; P = 0.001), and carboxyterminal cross-linked telopeptide of type I collagen (53.3%; P = 0.009). Disappearance half-times after cessation of recombinant human GH for pre- and postexercise markers ranged from 248-770 h. We conclude 1) endurance exercise transiently activates bone and collagen turnover; 2) brief GH administration results in similar but quantitatively greater augmentation; and 3) these data will assist in designing a GH detection strategy.

In the past decade, a large number of controlled clinical trials have reported positive effects of growth hormone (GH) replacement therapy in GH-deficient adults. The majority of these studies have been carried out in accordance with the guidelines for Good Clinical Practice. The data thus accumulated offer a solid baseline for practicing evidence-based medicine within this area of endocrinology.

In patients with acromegaly, clinical improvement has been reported after octreotide (OCT) treatment, even in cases of only a moderate suppression of growth hormone (GH) levels. In rats, OCT suppresses IGF-I mRNA expression and generation of serum and tissue IGF-I levels. A direct effect of OCT on the IGF system could have therapeutical implications in diabetes mellitus, cardiovascular disease, and certain malignancies in which IGF-I might be involved. The aim of this study was to examine possible GH-independent effects of OCT on IGF components in humans. Six GH-deficient (GHD) patients were studied for 24 h after each of the following treatment regimens (each of 1 weeks duration): (a) daily s.c. GH injection (2 IU/m(2)); (b) as (a) + continuous s.c. infusion of OCT (200 microg/24 h) by means of a portable pump (Nordic Infuser); (c) no treatment. Serum GH binding protein (GHBP) levels tended to be lower after GH and OCT than after GH alone (P =0.10). OCT reduced the GH induced increase in serum IGF-I levels (P<0.05, ANOVA). Mean integrated levels (microg/l) were 359.1+/-49.6 (GH), and 301.6+/-58.9 (GH+OCT). OCT did not significantly reduce serum IGFBP-3 levels (microg/l) [3460+/-270 (GH), and 3112+/-435 (GH+/-OCT);P =0.14]. Serum levels of free IGF-I (P =0.39), IGF-II (P =0.54), and of the acid-labile subunit (ALS) of the ternary complex (P =0.50) were similar during GH+/-OCT as compared with GH alone. After 1 week off GH treatment, significantly lower levels of IGF-I, IGF-II, IGFBP-3, and ALS were recorded (P<0.001). Serum IGFBP-1 levels were significantly higher after GH+OCT than after GH alone (P<0.0001), and levels were even higher without GH. Serum insulin levels (pmol/l) were significantly higher after GH alone as compared with no GH (P<0.05, ANOVA), whereas OCT partly suppressed the insulinotropic effect of GH (P<0. 05) [mean: 114.5+/-33.0 (GH), 91.3+/-29.6 (GH+OCT), 65.9+/-22.5 (no GH)]. This was also reflected in higher blood glucose levels during GH+OCT. Finally, GH+OCT reduced glucagon levels significantly as compared with GH alone (P =0.02). In conclusion, 7 days' administration of OCT to GH-treated GHD patients slightly attenuated serum IGF-I generation, and tended to decrease levels of the other components of the 150 kDa ternary complex. Whether these effects are mediated directly by OCT or indirectly via the accompanying changes in insulin levels remains to be investigated., (Copyright 1999 Harcourt Publishers Ltd.)

Objective: The regulation of IGF-I levels is complex and not only dependent on GH status, as the diagnostic sensitivity of serum IGF-I levels for GH deficiency (GHD) in adults is low. Other GH-related parameters have so far not proven to be of additional diagnostic value in GHD adults. In the present study we evaluated the impact of gender and androgen status on IGF-I levels and the diagnostic value of IGF-I and GH-related parameters in a population of adult hypopituitary patients and age- and gender-matched healthy subjects., Design: A cross-sectional study., Subjects: Fifty-nine GHD patients (40 males, mean age 39.3+/-1.7 (s.e.m.) years, and 19 females, mean age 41.9+/-2.6 years) and 69 healthy subjects (42 males, mean age 36. 7+/-1.5 years, and 27 females, mean age 38.9+/-2.1 years)., Results: IGF-I levels were low in the GHD patients (91+/-7 vs 173+/-7 microgram/l, P<0.001), and lower in female patients than in male (68+/-10 vs 100+/-8 microgram/l, P=0.03). In the control group there was no gender-related difference in IGF-I levels (males: 178+/-8, females: 164+/-12 microgram/l, P=0.23). IGF-II and IGF-binding protein-3 (IGFBP-3) were also decreased in GHD without any gender-related differences. GH-binding protein (GHBP) levels were increased in the patient group. The diagnostic sensitivity (%) of IGF-I, IGF-I/GHBP, IGF-I/IGFBP-3, and of the combination of IGF-I plus IGF-II (both low or one normal and one low), was higher in female patients than in male (IGF-I: 57.8 vs 22.0, P<0.0001; IGF-I/GHBP: 84.2 vs 48.8, P=0. 002; IGF-I/IGFBP-3: 36.8 vs 7.3 P=0.001; IGF-I+IGF-II: 77.8 vs 52.6, P=0.01). Testosterone levels were reduced in the female patients compared with female controls (0.5+/-0.3 vs 2.1+/-0.2nmol/l, P<0.001). Forward regression analyses revealed that IGFBP-3 was a significant predictor of IGF-I levels in both patients and healthy subjects. In a combined analysis of both patients and controls, sex hormone-binding globulin (SHBG) level was the main contributor as an explanatory variable. Gender and prolactin also predicted IGF-I in patients, whereas SHBG and estradiol were significant predictors only in the control group., Conclusion: (i) Levels of IGF-I, and of IGF-I/IGFBP-3 and IGF-I/GHBP ratios are lower in females compared with male adult GHD patients. (ii) IGF-I/GHBP has a high diagnostic sensitivity of adult GHD, in particular in women. (iii) We hypothesize that the gender difference in IGF-I levels among adult GHD patients are causally related to the very low androgen levels observed among females.

The newly described uncoupling proteins, UCP2 and UCP3, may play a role in regulating energy expenditure (EE) in humans. GH deficiency (GHD) is associated with decreased lean body mass, increased adiposity, and reduced EE, which are reversed by GH treatment. In the present study we investigated whether GH treatment for 4 months influenced the expression of UCPs in skeletal muscle and adipose tissue in 22 GHD patients who were investigated before and after GH (n = 11) or placebo (n = 11) treatment. GH treatment increased the amount of lean body mass by 4.5% (P < 0.05) and decreased body fat mass by 12% (P < 0.05), whereas no changes in these parameters were observed after placebo treatment. The level of UCP3 messenger ribonucleic acid (mRNA) increased 3-fold (P < 0.005) in skeletal muscle and almost 2-fold (P < 0.05) in adipose tissue after GH treatment, with no changes observed after placebo treatment. Skeletal muscle UCP2 mRNA was slightly (25%), but significantly (P < 0.05), decreased, whereas the level of UCP2 mRNA in adipose tissue was unaffected after GH treatment. The T4 level was positively correlated with skeletal muscle UCP2 and UCP3 expression (r = 0.518; P < 0.05 and r = 0.463; P < 0.05, respectively). Furthermore, plasma free fatty acids were positively correlated with the expression of UCP2 (r = 0.573; P < 0.01) and UCP3 (r = 0.518; P < 0.05) in skeletal muscle. The marked increase in UCP3 expression after GH treatment indicates that the UCPs might play a role in the effects of GH on EE in GHD patients. Finally, the strong association between thyroid hormone and skeletal muscle UCP and the correlation between plasma free fatty acids and UCP expression in skeletal muscle indicate that these hormones/metabolites might influence UCP expression in humans as previously demonstrated in rodents.

Physiologically, growth hormone (GH) is secreted in pulses with episodic bursts shortly after the onset of sleep and postprandially. Such pulses increase circulating levels of free fatty acid and glycerol. We tested whether small GH pulses have detectable effects on intercellular glycerol concentrations in adipose tissue, and whether there would be regional differences between femoral and abdominal subcutaneous fat, by employing microdialysis for 6 h after administration of GH (200 microgram) or saline intravenously. Subcutaneous adipose tissue blood flow (ATBF) was measured by the local Xenon washout method. Baseline of interstitial glycerol was higher in adipose tissue than in blood [220 +/- 12 (abdominal) vs. 38 +/- 2 (blood) micromol/l, P < 0.0005; 149 +/- 9 (femoral) vs. 38 +/- 2 (blood) micromol/l, P < 0.0005] and higher in abdominal adipose tissue compared with femoral adipose tissue (P < 0.0005). Administration of GH induced an increase in interstitial glycerol in both abdominal and femoral adipose tissue (ANOVA: abdominal, P = 0. 04; femoral, P = 0.03). There was no overall difference in the response to GH in the two regions during the study period as a whole (ANOVA: P = 0.5), but during peak stimulation of lipolysis abdominal adipose tissue was, in absolute but not in relative terms, stimulated more markedly than femoral adipose tissue (ANOVA: P = 0. 03 from 45 to 225 min). Peak interstitial glycerol values of 253 +/- 37 and 336 +/- 74 micromol/l were seen after 135 and 165 min in femoral and abdominal adipose tissue, respectively. ATBF was not statistically different in the two situations (ANOVA: P = 0.7). In conclusion, we have shown that a physiological pulse of GH increases interstitial glycerol concentrations in both femoral and abdominal adipose tissue, indicating activated lipolysis. The peak glycerol increments after GH were higher in abdominal adipose tissue, perhaps due to a higher basal rate of lipolysis in this region.

GH abuse by elite athletes is currently undetectable. To define suitable markers of GH doping, we assessed the effects of acute exercise, GH administration, and GH withdrawal on the GH/insulin-like growth factor (IGF) axis in athletic adult males. Acute endurance-type exercise increased serum GH, GH-binding protein (GHBP), total IGF-I, IGF-binding protein (IGFBP)-3, and acid-labile subunit (ALS), each peaking at the end of exercise. IGFBP-1 increased after exercise was completed. Free IGF-I did not change with exercise. Recombinant human GH treatment (0.15 IU/kg x day) for 1 week increased serum total IGF-I, IGFBP-3, and ALS, exaggerating the responses to exercise. IGFBP-2 and IGFBP-1 were trivially suppressed. After GH withdrawal, the GH response to identical exercise was suppressed. Total IGF-I, IGFBP-3, and ALS returned to baseline over 3-4 days. In summary, 1) acute exercise transiently increased all components of the IGF-I ternary complex, possibly due to mobilization of preformed intact complexes; 2) GH pretreatment augmented the exercise-induced changes in ternary complexes; 3) postexercise IGFBP-1 increments may protect against delayed onset hypoglycemia; 4) serum total IGF-I, IGFBP-3, and ALS may be suitable markers of GH abuse; and 5) differences in disappearance times altered the sensitivity of each marker for detecting GH abuse.

Background: Growth deficiency and malnutrition in uremic children are often caused by malfunction of the growth hormone (GH)/insulin-like growth factor I (IGF-I) axis and can be corrected by treatment with GH. The purpose of this study was to evaluate the levels of GH, IGF-I and II and their binding proteins compared to changes in body composition in adult, enfeebled, uremic patients in chronic hemodialysis (HD), treated for 6 months with recombinant human growth hormone (rhGH)., Methods: 31 patients were included in a controlled, randomized, double-blinded study using either 4 IU/m2/day of rhGH or placebo injected subcutaneously every evening for 6 months., Results: Fasting levels of GH were normal at start and increased significantly from 2.2 to 13.5 microg/l (p = 0.01) within the first 4 months of rhGH treatment. Before treatment IGF-I was at the upper limit of normal range (130 to 220 microg/l) in both groups, and it increased significantly from 213 to 348 microg/l (p = 0.01) during rhGH treatment. IGF-II was above the normal range in both groups, and remained unchanged throughout. IGFBP-1 decreased in the rhGH-treated group from 53.1 to 24.7 microg/l (p = 0.004), while IGFBP-3 increased from 5620 to 7100 microg/l (p = 0.004). The molar ratio of IGF-I/IGFBP-3 increased significantly from 14 to 25% (p = 0.01), while the ratio decreased in the placebo group (p = 0.01). During the treatment with rhGH the patients increased their lean body mass (= muscle mass) by a median of 3.18 kg (range 0.82 to 5.12 kg) (p = 0.0001) while their fat mass decreased by a median of 3.33 kg (range 0.18 to 5.82 kg) (p = 0.004). Total body mass (= weight) remained stable. No significant changes were observed in the placebo group., Conclusion: The baseline GH and IGF-I concentrations were normal in malnourished HD patients. When treated with rhGH in a dosage as used in growth-retarded uremic children, IGF-I increased to the levels seen in acromegalic persons. IGF-I increased more than IGFBP-3 whereby its biological activity obviously improved. This was reflected in an increased muscle mass and a decreased fat mass. The rhGH treatment was well tolerated.

The purpose of the present study was to evaluate the combined effect of GH treatment on body composition and glucose metabolism, with special focus on beta-cell function in adult GHD patients. In a double-blind placebo-controlled design, 24 GHD adults (18M/6F), were randomized to 4 months treatment with biosynthetic GH 2 IU/m2s.c. daily (n =13) or placebo (n =11). At inclusion and 4 months later an oral glucose tolerance test (OGTT), a frequently sampled intravenous glucose tolerance test (FSIGT) and dual-energy X-ray absorptiometry (DXA) whole-body scanning were performed. During the study period, body weight decreased 1.6 kg from 94.0 +/- 18.7 to 92.4 +/- 19.4 kg (mean +/- SD) (P<0.05) in the GH-treated group, but remained unchanged in the placebo group. Fat mass decreased from 32.4 +/- 9.6 to 28.1 +/- 10.5 kg (P<0.001), whereas lean body mass increased from 58.3 +/- 11.5 to 61.0 +/- 11.7 kg (P<0.01) in the GH-treated group. Treatment with GH for 4 months resulted in a significant increase in fasting blood glucose (before GH 5.0 +/- 0.3 and after 5.4 +/- 0.6 mmol/l, P<0.05), fasting plasma insulin (before GH 38.4 +/- 30.2 and after 55.3 +/- 34.7 pmol/l, P<0.02) and fasting proinsulin (before 8. 1 +/- 6.7 and after 14.6 +/- 16.1 pmol/l, P<0.05). The insulin sensitivity index SI, estimated by Bergmans Minimal Model, decreased significantly [before GH 1.1 +/- 0.7 and after 0.4 +/- 0.2 10(-4)(min x pmol/l), P<0.003]. The non-insulin-dependent glucose uptake (glucose effectiveness SG did not change (before GH 0.017 +/- 0.005 and after 0.015 +/- 0.006 min-1, NS). Insulin secretion was enhanced during GH therapy, but insufficiently to match the changes in SI, resulting in a higher blood glucose level during an OGTT. Blood glucose at 120 min was 5.5 and 6.3 mmol/l before and after GH treatment, respectively (P = 0.07). One patient developed impaired glucose tolerance. Short-term GH replacement therapy in a dose of about 2 IU/m2 daily in GHD adults induces a reduction in insulin sensitivity, despite favourable changes in body composition, and an inadequate enhancement of insulin secretion., (Copyright 1999 Harcourt Publishers Ltd.)

It has occasionally been suggested that GH directly suppresses circulating IGFBP-1 levels, although it is generally believed that such an effect is secondary to a GH-induced increase in insulin levels. We present data from several experiments in which the effects of GH on IGFBP-1 could be studied more extensively. In normal subjects (n = 36), an i.v. GH bolus caused a small but significant decrease in plasma IGFBP-1 concentrations without changes in insulin [IGFBP-1 (microgram/l): 2.6 +/- 0.3 (GH) vs 3.2 +/- 0.4 (placebo), P < 0.05]. Conversely, a 28-h somatostatin infusion with and without GH administration during fasting in normal subjects yielded higher IGFBP-1 levels in the non-GH substituted study [50.5 +/- 5.3 (GH-suppression) vs 22.6 +/- 5.6 (GH-substitution), P < 0.01], comparable with an increased concentration of IGFBP-1 during fasting in GH-deficient patients without usual GH substitution [23.4 +/- 7.6 (GH pause) vs 14.1 +/- 4.9 (GH substitution), P < 0.01]. In both fasting studies insulin levels remained stable. During a hypocaloric diet, long-term GH treatment in obesity lead to a significant decline in IGFBP-1 level (2.3 +/- 0.6 vs 1.2 +/- 0.2, P < 0.01), while no changes were found in the placebo group. Again, insulin levels remained equally low in both studies. Finally, a significant rebound increase in IGFBP-1 level in response to insulin induced hypoglycemia was only observed among GH-deficient patients, but not in control subjects, the latter of whom responded to hypoglycemia with a significant increase in serum GH levels [23.2 +/- 7.2 (GHDA) vs 2.5 +/- 0.3 (controls), P < 0.01]. In conclusion, a suppressive effect of GH on IGFBP-1 appears to be unmasked in the presence of low or suppressed insulin levels, making GH a potential regulator of IGF-1 bioactivity in a hitherto unrecognized way.

In animals, it has been demonstrated that nitric oxide (NO) is a potent neuroregulatory substance. By intravenous infusion, L-arginine is converted to NO and citrulline, but it is unknown whether NO is responsible for the GH stimulating effect of L-arginine in humans. We investigated whether intravenous infusion of the NO synthase inhibitor N-monomethyl-L-arginine (L-NMMA) influenced L-arginine stimulated GH secretion. Ten healthy men, aged 28.6 +/- 1.9 (mean +/- SEM) years were examined twice. L-arginine was infused intravenously in a dose of 0.5 g/kg, max 35 g, from 0 to 30 min, accompanied by either: (1) L-NMMA from -5 to 0 min, in a dose of 3 mg/kg, max 250 mg, and in a dose of 3.5 mg/kg, max 250 mg from 0 to 60 min; or (2) a saline infusion. Heart rate increased (P = 0.032), and diastolic blood pressure decreased (P < 0.001) in the two situations. Plasma cGMP was unchanged and identical in the two situations (P = 0.679). Urine cGMP/creatinine ratio increased during both examinations (P = 0.041). Growth hormone secretion increased significantly during L-arginine infusion (P = < 0.001) without any effect of L-NMMA (P = 0.848). We did not find evidence that NO influences GH secretion. It remains to be tested, however, whether a higher dose of L-NMMA may influence L-arginine stimulated GH secretion.