Impact of growth hormone status on body composition and the skeleton

Severe growth hormone (GH) deficiency (GHD) induces a well-defined clinical entity encompassing, amongst the most reported features, abnormalities of body composition, in particular increased fat mass, especially truncal, and reduced lean body mass. The results from virtually all treatment studies are in agreement that GH replacement improves the body composition profile of GHD patients by increasing lean body mass and reducing fat mass. More recently, the observations have been extended to adults with partial GHD, defined by a peak GH response to insulin-induced hypoglycaemia of 3-7 microg/l. These patients exhibit abnormalities of body composition similar in nature to those described in adults with severe GHD; these include an increase in total fat mass of around 3.5 kg and a reduction of lean body mass of around 5.5 kg. The increase in fat mass is predominantly distributed within the trunk. The degree of abnormality of body composition is intermediate between that of healthy subjects and that of adults with GHD. The impact of GH replacement on body composition in adults with GH insufficiency, although predictable, has not been formally documented. The skeleton is another biological endpoint affected by GH status: in adults with severe GHD, low bone mass has been reported using dual energy x-ray absorptiometry (DEXA) and other quantitative methodologies. The importance of low bone mass, in any clinical setting, is as a surrogate marker for the future risk of fracture. Several retrospective studies have documented an increased prevalence of fractures in untreated GHD adults. Hypopituitary adults with severe GHD have reduced markers of bone turnover which normalize with GH replacement, indicating that GH, directly or via induction of insulin-like growth factor-I, is intimately involved in skeletal modelling. Whilst the evidence that GH plays an important role in the acquisition of bone mass during adolescence and early adult life is impressive, the impact of GHD acquired later in adulthood is less clear. Recently we examined the relationship between bone mineral density (BMD) and age in 125 untreated adults with severe GHD using DEXA. A significant positive correlation was observed between BMD (z-scores) and age at all skeletal sites studied. Overall, few patients, except those aged less than 30 years, had significantly reduced bone mass (i.e. a BMD z-score of less than -2); correction of BMD to provide a pseudo-volumetric measure of BMD suggested that reduced stature of the younger patients may explain, at least in part, this higher frequency of subnormal BMD z-scores. Despite normal BMD, however, an increase in fracture prevalence may still be observed in elderly GHD adults as a consequence of increased falls related to muscle weakness and visual field defects.     

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

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

Growth hormone and bone health

Growth hormone (GH) and insulin-like growth factor-I have major effects on growth plate chondrocytes and all bone cells. Untreated childhood-onset GH deficiency (GHD) markedly impairs linear growth as well as three-dimensional bone size. Adult peak bone mass is therefore about 50% that of adults with normal height. This is mainly an effect on bone volume, whereas true bone mineral density (BMD; g/cm(3)) is virtually normal, as demonstrated in a large cohort of untreated Russian adults with childhood-onset GHD. The prevalence of fractures in these untreated childhood-onset GHD adults was, however, markedly and significantly increased in comparison with normal Russian adults. This clearly indicates that bone mass and bone size matter more than true bone density. Adequate treatment with GH can largely correct bone size and in several studies also bone mass, but it usually requires more than 5 years of continuous treatment. Adult-onset GHD decreases bone turnover and results in a mild deficit, generally between -0.5 and -1.0 z-score, in bone mineral content and BMD of the lumbar spine, radius and femoral neck. Cross-sectional surveys and the KIMS data suggest an increased incidence of fractures. GH replacement therapy increases bone turnover. The three controlled studies with follow-up periods of 18 and 24 months demonstrated a modest increase in BMD of the lumbar spine and femoral neck in male adults with adult-onset GHD, whereas no significant changes in BMD were observed in women. GHD, whether childhood- or adult-onset, impairs bone mass and strength. Appropriate substitution therapy can largely correct these deficiencies if given over a prolonged period. GH therapy for other bone disorders not associated with primary GHD needs further study but may well be beneficial because of its positive effects on the bone remodelling cycle.     

Influence of growth hormone on accretion of bone mass

Growth hormone (GH) exerts important influences on bone metabolism during lifespan. During childhood, GH is a major determinant of acquisition of bone mass and in adult life, GH partly determines the rate of bone remodelling and therefore influences maintenance of bone mineral density (BMD). Insights into the importance of GH in these respects may be obtained by studies of BMD and indices of bone remodelling in GH deficiency (GHD) of adult-onset and childhood-onset. Adult-onset GHD, usually accompanied by other features of hypopituitarism, may be associated with osteopenia and an increased fracture risk. Postulated mechanisms include GHD and gonadal steroid deficiency of unknown duration; glucocorticoid and thyroxine replacement do not appear to exert a major role. GH replacement in adult-onset GHD results in an early increment in indices of bone remodelling which persists for up to 5 years; BMD increases by 0.5-1.0 SD in males and stabilizes in females over this time period. In adolescents with GHD who traditionally discontinue GH at completion of linear growth, BMD is substantially lower than peak bone mass for a young adult population. Studies addressing the effects of continuation of GH after achievement of final height are currently underway and will provide insights into the possible need to continue GH into adult life. Such studies may confirm a role for GH in promoting continued accrual of bone mass and thereby demonstrate that cessation of GH at achievement of final height, by limiting peak bone mass, may predispose to clinically significant osteoporosis in later life. In addition to the potential importance of GH for achievement of peak bone mass, there may be a superimposed accelerated loss of BMD with advancing age similar to the situation observed in adult-onset GHD. To date, this has been difficult to assess in adult GHD of childhood-onset because the relative contributions of low peak bone mass and increased loss of bone in later life could not be distinguished.     

Long-term challenges in growth hormone treatment

Growth hormone deficiency (GHD) is defined biochemically as a response to hypoglycaemia with a peak GH concentration of less than 5 microg/l. The 'GHD syndrome' is a range of psychological and physical symptoms that are associated with GHD, which include increased central adiposity, decreased bone mineral density, abnormal lipid profiles, decreased cardiovascular performance, reduced lean body mass (LBM), social isolation, depressed mood and increased anxiety. Importantly, the combination of physical and psychological problems can often result in a reduced quality of life. A number of trials have shown that GH replacement therapy can lead to a substantial improvement in GHD associated symptoms. Following up to 12 months of treatment with GH, LBM increased, left ventricular systolic function improved and the mean volume of adipose tissue fell. After only 4 months of treatment, a rise in exercise capacity was recorded, and after 2 years' treatment, isokinetic and isometric muscle strength had normalized in proximal muscle groups. Feelings of well-being and vitality also improved significantly. However, studies on the effects of treatment on insulin sensitivity in GH-deficient patients have had conflicting results. In this paper, we will discuss the long-term consequences of GHD and the effects of GH replacement therapy.     

Bone densitometry: assessing the effects of growth hormone treatment in adults

Dual-energy X-ray absorptiometry (DXA) is the reference method for the measurement of bone mineral mass at different skeletal sites. It has been widely used in recent years to assess the effects of growth hormone (GH) treatment on bone metabolism. In normal individuals, bone mineral content (BMC) and density (BMD), as assessed using DXA, correlate with body size. Therefore, using DXA in patients with congenital GH deficiency (GHD), who have a smaller body frame, would be expected to result in lower bone mass. Thus, comparisons with reference data derived from populations of normal body size are invalid. The evaluation of the effects of GH administration should take into account the possible effects of GH on bone size, not only in children, but also in adults. The enlargement of bone, due to stimulation of the periosteal apposition, may partially mask an increase in BMC, resulting in little or no change in BMD. The ability of GH to affect bone area therefore requires analysis of the possible changes in bone area and BMC, as well as BMD. This issue has been poorly handled in the studies published to date. Lastly, the acceleration of bone turnover induced by GH leads to an increase in bone remodelling space, which in turn is associated with a reduction in BMC and BMD, independent of the net balance between breakdown and formation in each metabolic unit. This bone loss is completely reversible when the remodelling space returns to previous levels. This phenomenon must be taken into account when analysing the effects of GH treatment on bone mass, because a net gain in bone mass may be found in long-term GH treatment or after GH discontinuation, even if bone loss was evident during the first 6 months of treatment. In conclusion, the interpretation of bone density data in patients with GHD, and after GH administration, should take into account some of the methodological aspects of bone densitometry, as well as the specific actions of GH on bone metabolism and body composition.     

The effects of growth hormone on cortical and cancellous bone

Growth hormone (GH) has profound effects on linear bone growth, bone metabolism and bone mass. The GH receptor is found on the cell surface of osteoblasts and osteoclasts, but not on mature osteocytes. In vitro, GH stimulates proliferation, differentiation and extracellular matrix production in osteoblast-like cell lines. GH also stimulates recruitment and bone resorption activity in osteoclast-like cells. GH promotes autocrine/paracrine insulin-like growth factor 1 (IGF-I) production and endocrine (liver-derived) IGF-I production. Some of the GH-induced effects on bone cells can be blocked by IGF-I antibodies, while others cannot. In animal experiments, GH administration increases bone formation and resorption, and enhances cortical bone mass and mechanical strength. When GH induces linear growth, increased cancellous bone volume is seen, but an unaffected cancellous bone volume is found in the absence of linear growth. Patients with acromegaly have increased bone formation and resorption markers. Bone mass results are conflicting because many acromegalics have hypogonadism, but in acromegalics without hypogonadism, increased bone mineral density (BMD) is seen in predominantly cortical bone, and normal BMD in predominantly cancellous bone. Adult patients with growth hormone deficiency have decreased bone mineral content and BMD. GH therapy rapidly increases bone formation and resorption markers. During the first 6-12 months of therapy, declined or unchanged BMD is found in the femoral neck and lumbar spine. All GH trials with a duration of two years or more show enhanced femoral neck and lumbar spine BMD. In osteoporotic patients, GH treatment quickly increases markers for bone formation and resorption. During the first year of treatment, unchanged or decreased BMD values are found, whereas longer treatment periods report enhanced or unchanged BMD values. However, existing trials comprising relatively few patients and limited treatment periods do not allow final conclusions to be drawn regarding the effects of GH on osteoporosis during long-term treatment.     

Bone markers and bone mineral density during growth hormone treatment in children with growth hormone deficiency

Growth hormone (GH) has a positive impact on muscle mass, growth and bone formation. It is known to interact with the bone-forming unit, with well-documented increases in markers of bone formation and bone resorption within weeks of the start of GH therapy. These changes relate significantly to short-term growth rate, but it is not evident that they predict long-term response to GH therapy. The consequences of GH deficiency (GHD) and GH replacement therapy on bone mineral density (BMD) have been difficult to interpret in children because of the dependency of areal BMD on height and weight. Some studies have tried to overcome this problem by calculating volumetric BMD, but results are conflicting. The attainment of a normal peak bone mass in an individual is considered important for the future prevention of osteoporosis. From the limited data available, it appears difficult to normalize bone mass totally in GH-deficient individuals, despite GH treatment for long periods. Studies to date examining the interaction between GH and bone have included only small numbers of individuals, making it difficult to interpret the study findings. It is hoped that these issues can be clarified in future research by the direct measurement of bone density (using quantitative computer tomography). Mineralization is only one facet of bone strength, however; other important components (e.g. bone structure and geometry) should be addressed in future paediatric studies. Future studies could also address the importance of the degree of GHD in childhood; how GH dose and insulin-like growth factor-I levels achieved during therapy relate to the final outcome; whether or not the continuation of GH therapy after the attainment of final height may further enhance bone mass; whether the timing and dose of other treatments (e.g. sex hormone replacement therapy) are critical to the outcome; and whether GHD in childhood is associated with an increased risk of fracture.     

Trabecular Bone Score Change Differs with Regard to 25(OH)D Levels in Patients Treated for Adult-Onset Growth Hormone Deficiency

Objective: Vitamin D is important in bone health. However, potential relationships of concomitant vitamin D deficiency with growth hormone deficiency (GHD) and the possibility that vitamin D inadequacy may alter the skeletal effects of growth hormone (GH) replacement therapy have not been adequately evaluated.Methods: A prospective study was conducted in adult-onset GHD patients treated with recombinant human GH (rhGH) for 2 years. Trabecular bone score (TBS), lumbar spine (LS) bone mineral density (BMD), total hip (TH) BMD, and 25-hydroxyvitamin D (25(OH)D) levels were assessed at baseline and 24 months. The study cohort was divided based on 25(OH)D levels into 2 groups with the cutoff defined as the 50^th percentile at each follow-up time point.Results: Fifty-seven patients (29 males/28 females, mean age 34.4 years) were studied. After 24 months of GH replacement, LS BMD increased by 7.6% and TH BMD increased by 4.5% (both P<.05), with no difference according to 25(OH)D levels. TBS increased (+1.39 ± 3.6%) in those whose 25(OH)D was above the 50^th percentile but decreased (-1.36 ± 5.6%, P<.05) in the cohort below the 50^th percentile of 25(OH)D. Positive correlations were observed between baseline levels of IGF-1 and 25(OH)D (R = 0.37, P<.001) and between 24-month 25(OH)D and TBS (R = 0.25, P<.05).Conclusion: A differential effect of GH on TBS change was observed; TBS increased only in the cohort with 25(OH)D above the 50^th percentile. Vitamin D sufficiency may be required to obtain optimal effects of GH treatment on bone quality, as assessed by TBS, in GHD adults.Abbreviations:AO-GHD = adult-onset GHDBMD = bone mineral densityBMI = body mass indexCa = calciumCTx = carboxyterminal collagen crosslinksCV = coefficient of variationDXA = dual energy X-ray absorptiometryECLIA = enzyme-labeled chemiluminescent immunometric assayGH = growth hormoneGHD = growth hormone deficiencyIGF-1 = insulin-like growth factor 1LS BMD = lumbar spine BMDOC = osteocalcin25(OH)D = 25-hydroxyvitamin DP = phosphorusPTH = parathyroid hormonerhGH = recombinant human GHTBS = trabecular bone scoreTH BMD = total hip BMD     

Growth hormone deficiency and replacement in patients with treated Cushing's Disease, prolactinomas and non-functioning pituitary adenomas: effects on body composition, glucose metabolism, lipid status and bone mineral density

BACKGROUND/AIMS: This study was designed to determine whether previous Cushing's disease (CD) or prolactinoma (PRL) could exert adverse effects additional to those of growth hormone (GH) deficiency as a consequence of variable degrees of prior hypogonadism or hypercatabolism. We report the effects of 5 years GH treatment in 124 GH deficiency adults; 42 patients with non-functioning pituitary adenomas (NFPA), 43 with treated PRL and 39 with treated CD. METHODS: Fasting plasma glucose, HbA(1c), lipoprotein profile, anthropometry and bone mineral density (BMD) were measured at baseline, 6 months and annually up to 5 years. RESULTS: Mean body mass index remained unchanged in the PRL group and tended to increase in the NFPA group. In contrast, body mass index decreased in the CD group. Decreases in waist and waist/hip ratio were seen in all groups at 6 months. Decreases in total cholesterol and low-density lipoprotein cholesterol were seen in all groups and remained sustained at 5 years. Plasma glucose and HbA(1c) increased at 6 months. Subsequently, plasma glucose returned to baseline values at 5 years; in contrast, HbA(1c )remained unchanged at the end of the study. Baseline lumbar spine and hip BMD were lower in the PRL and CD groups than in the NFPA group, decreased over 1 year in all groups and subsequently increased by 2 years in NFPA with a subsequent increase in lumbar spine BMD in PRL and CD groups delayed to 3-5 years. CONCLUSIONS: Baseline characteristics and response to GH replacement are qualitatively similar in NFPA, PRL and CD patients. Because improvements in BMD occur later in PRL and CD patients, an extended trial of GH therapy may be indicated in those patients who were commenced on GH therapy as an additional treatment for reduced BMD.     

Physical Activity and Bone Mineral Accrual in Boys with Different Body Mass Parameters during Puberty: A Longitudinal Study

The aim of our longitudinal study was to investigate the relationships between physical activity and bone mass in boys with different body mass status during the years surrounding pubertal growth spurt. Two hundred and six boys entering puberty took part in this study. The subjects were divided into underweight (), normal weight (), overweight () and obese () groups at baseline according to age related categories. Whole-body DXA scans were performed at baseline, after 12 and 24 months to assess body composition (lean body mass, fat mass), and total body (TB), lumbar spine (LS) and femoral neck (FN) bone mineral density (BMD) parameters. Physical activity was measured by 7- day accelerometry. For longitudinal analysis, multilevel fixed effects regression models were constructed. Biological age, height and lean body mass had an effect for explanation of TB BMD, FN BMD and LS BMD. Moderate to vigorous physical activity (MVPA), vigorous physical activity (VPA) and sedentary time (SED) had the significant effect only on FN BMD. Being an underweight boy at the baseline indicated greater chance (p<0.01) to have lower TB BMD in the future (2 years at follow up) development, compared to normal weight (estimates = −0.038), overweight (estimates = −0.061) and obese boys (estimates = −0.106).     

Effect of growth hormone-releasing factor on plasma growth hormone, prolactin and somatomedin C in hypopituitary and short normal children

We studied the effect of a single intravenous bolus of 0.5 microgram/kg of growth hormone-releasing factor (GRF) on plasma GH, prolactin (PRL) and somatomedin C (SMC) in 12 short normal children and 24 patients with severe GH deficiency (GHD), i.e. GH less than 5 ng/ml after insulin and glucagon tolerance tests. GRF elicited an increase in plasma GH in both short normal and GHD children. The mean GH peak was lower in the GHD than in the short normal children (8.2 +/- 2.5 vs. 39.2 +/- 5.1 ng/ml, p less than 0.001). In the GHD patients (but not in the short normals) there was a negative correlation between bone age and peak GH after GRF (r = -0.58, p less than 0.005); GH peaks within the normal range were seen in 5 out of 8 GHD children with a bone age less than 5 years. In the short normal children, GRF had no effect on plasma PRL, which decreased continuously between 8.30 and 11 a.m. (from 206 +/- 22 to 86 +/- 10 microU/ml, p less than 0.005), a reflection of its circadian rhythm. In the majority of the GHD patients, PRL levels were higher than in the short normal children but had the same circadian rhythm, except that a slight increase in PRL was observed 15 min after GRF; this increase in PRL was seen both in children with isolated GHD and in those with multiple hormone deficiencies; it did occur in some GHD patients who had no GH response to GRF. Serum SMC did not change 24 h after GRF in the short normal children. We conclude that: (1) in short normal children: (a) the mean GH response to a single intravenous bolus of 0.5 microgram/kg of GRF is similar to that reported in young adults and (b) GRF has no effect on PRL secretion; (2) in GHD patients: (a) normal GH responses to GRF are seen in patients with a bone age less than 5 years and establish the integrity of the somatotrophs in those cases; (b) the GH responsiveness to GRF decreases with age, which probably reflects the duration of endogenous GRF deficiency, and (c) although the PRL response to GRF is heterogeneous, it does in some patients provide additional evidence of responsive pituitary tissue.     

Effect of neonatal hypoxia on leptin, insulin, growth hormone and body composition in the rat.

The purpose of the present study was to evaluate the effect of exposure to hypoxia from birth to 7 days of age on leptin, insulin, growth hormone (GH), insulin-like growth factor-1 (IGF-1), glucose, corticosterone, body weight, and body composition in rats studied at 7 days of age and then after return to normoxia. Hypoxia for the first 7 days of life resulted in a significant decrease in plasma leptin, body weight, and an increase in corticosterone and insulin with no change in plasma glucose, GH or IGF-1. There was no significant effect of hypoxia on % lean body mass, but a small but significant increase in % body fat. Bone mineral density (BMD) was lower in 7-day-old hypoxic rats as compared to normoxic controls. All hormonal variables and BMD had normalized by 7 days after return to normoxia. However, body weight remained lower even 5 weeks after return to normoxia. We conclude that leptin is decreased during neonatal hypoxia despite no change in adiposity. Furthermore, insulin is increased probably to overcome the effects of increased counterregulatory hormones (such as corticosterone).     

Leptin expression and leptin receptor gene polymorphisms in growth hormone deficiency patients

Growth hormone deficiency (GHD) patients have lower weight, height, bone age, insulin-like growth factor 1 (IGF-1) levels, GH levels, fat metabolism and skeletal growth. The association of leptin with GHD characteristics and the effect of gene variants of leptin on GHD are unknown. Our aim was to examine the association of circulating leptin levels and common genetic variants in leptin (LEP) and leptin receptor (LEPR) genes with anthropometric measures, circulating hormone concentrations and GHD. A case control study of 125 GHD cases and 159 control subjects were characterized for bone age, body mass index (BMI), height, weight, leptin, IGF-1, GH and their genotype at the leptin promoter G-2548A, and LEPR variants, K109R and Q223R, at Chung Shan Medical University Hospital. Leptin levels were significantly associated with lower bone age, weight and BMI in GHD patients. Leptin levels were also significantly associated with reduced IGF-1 levels in girls but not boys in both groups. The frequency of LEPR223 [A/G or A/A] genotype was significantly higher than the LEPR223 G/G genotype in the GHD group. The LEPR223 [A/G or A/A] genotype was significantly associated with increased weight and BMI in the control group, but not in the GHD group. In conclusion, the GHD group carried a significantly higher frequency of the LEPR [G/A or A/A] genotype and of the A allele (LEPR223R). The LEPR223R polymorphism affected weight and BMI in control, but not in GHD patients, suggesting that the effect of LEPR223 [A/G or A/A] genotype was counteracted by other factor(s) in GHD patients.     

Volumetric bone mineral density in young women with Turner's syndrome treated with estrogens or estrogens plus growth hormone

To explore the effects of estrogen replacement therapy (ERT) and recombinant growth hormone (GH) treatment on bone mineral density (BMD) in Turner's syndrome, we assessed volumetric BMD (vBMD), which is less dependent on body and bone sizes, in these patients at final height. The areal BMD (aBMD) was measured in 26 young women with Turner's syndrome (age range 17.5-25.0 years) by dual-energy X-ray absorptiometry, and vBMD was calculated. Patients were subdivided as group 1 (n = 12; ERT alone) and group 2 (n = 14; GH + ERT). Years of estrogen exposure were not different between the groups (group 1: 6. 4 +/- 1.5 years; group 2: 5.3 +/- 1.7 years); in group 2, GH therapy was 5.3 +/- 1.4 years. Final heights were significantly higher in group 2 than in group 1 (148.1 +/- 3.0 vs. 142.0 +/- 2.8 cm; p < 0. 0001) as well as aBMD (1.073 +/- 0.118 vs. 0.968 +/- 0.122 g/cm(2); p < 0.04). vBMD was higher in group 2 but not significantly different from group 1 (0.374 +/- 0.030 vs. 0.358 +/- 0.027 g/cm(3); p = 0.169). aBMD was reduced with respect to the normative values in both groups (group 1: -1.97 +/- 1.04 SDS, p < 0.0001 vs. 0; group 2: -0.93 +/- 1.01 SDS, p < 0.005 vs. 0), whereas vBMD was not (group 1: -0.07 +/- 0.79 SDS; group 2: 0.42 +/- 0.82 SDS). Our data suggest that: in Turner's syndrome GH administration improves final height and aBMD, but it does not significantly increase vBMD; aBMD reduction in Turner's syndrome is likely due to the impaired growth and reduced bone size; Turner's patients on ERT from adolescence show vBMD values in the normal range in young adulthood.     

The phenotype of adults with partial growth hormone deficiency

The concept of partial growth hormone (GH) deficiency (GHD) is well established within the paediatric setting having been validated against height velocity. In hypopituitary adults, GHD is defined by a peak GH response <3 microg/l to stimulation. This cut-off is arbitrary due to the lack of a biological marker equivalent of height velocity. The majority of normal adults achieve peak GH levels several fold higher than this cut off during stimulation. It can be argued, therefore, that there is a cohort of hypopituitary adults with intermediate peak GH values (3-7 microg/l), who have relatively impaired GH secretion, and for whom the impact of this partial GHD (GH insufficiency, GHI) on biological endpoints is not known. Studies of GHI adults have demonstrated an abnormal body composition, adverse lipid profile, impaired cardiac performance, reduced exercise tolerance and insulin resistance. The severity of these abnormalities lies between GHD adults and normal subjects. Whether these anomalies translate into increased mortality, as observed in GHD hypopituitary adults, is not yet known. Given the presence of similar sequelae in GHI and GHD adults, and the improvements during GH replacement in GHD adults, a randomized placebo-controlled study of GH replacement in GHI patients is warranted.     

European audit of current practice in diagnosis and treatment of childhood growth hormone deficiency

BACKGROUND: The present survey among members of the ESPE on current practice in diagnosis and treatment of growth hormone (GH) deficiency (GHD) is of great clinical relevance and importance in the light of the recently published guidelines for diagnosis and treatment of GHD by the Growth Hormone Research Society. We have found much conformity but also numerous discrepancies between the recommendations of the Growth Hormone Research Society and the current practice in Europe. RESULTS: We found that 80% of the pediatric endocrinologists included insulin-like growth factor I (IGF-I) in their initial evaluation of a short child suspected of having GHD, whereas only 22% used GH provocative testing alone in the initial evaluation of a short child. Sixty-eight percent confirmed the diagnosis of GHD using two separate provocative tests. In the present survey cutoff values for GH provocative testing clustered around two values; 10 ng/ml and 20 mU/l. Interestingly, these two values, differing by a factor of 2, were also the most prevalent cutoff values among those who reported their assay to be calibrated against the WHO International Reference Preparation 80/505 where the conversion factor between milligrams and milliunits is 2.6. This suggests that the selection of cutoff values is based on tradition rather than on specific GH assay characteristics. In addition, only 63% of the respondents actually knew what GH assay they were using, and only 57% knew how their GH assay was calibrated. Dosing of GH at the start of treatment was reported according to body surface by 39%, whereas 59% were dosing according to body weight. GH dose adjustment was primarily based on growth response and height during auxological assessment every 3-4 months (height velocity, change in height velocity or change in height standard deviation scores) as indicated by almost 70% of the respondents. However, dose adjustment according to body surface (38%) and body weight (44%) was also quite common. Sixty-five percent measures IGF-I regularly (at least once a year) during GH therapy in children, and to our surprise 17% reported that they adjust the GH dose according to the IGF-I levels. SUMMARY: In summary, we have found large heterogeneity in the current practice of diagnosis and treatment of childhood GHD among European pediatric endocrinologists. Especially standardizations of GH assays and cutoff values are urgently required to ensure a uniform and correct diagnosis and therapy of GHD in the future.     

Calcium supplementation increases bone mass in GH-deficient prepubertal children during GH replacement

BACKGROUND/AIMS: Since GH plays an important role in bone mineralization, and several studies demonstrated the positive influence of a higher calcium intake on bone mass, we studied the effect of calcium supplementation in GHD children during GH therapy. METHODS: 28 prepubertal GHD children, 5.0-9.9 years old, were assigned to two groups: group A (n = 14; 7 females) treated with GH, and group B (n = 14; 7 females) treated with GH + calcium gluconolactate and carbonate (1 g calcium/day per os). Auxological parameters, total bone mineral content (TBMC) and density (TBMD), leg BMC and BMD, lumbar BMD, fat mass (FM) and lean tissue mass (LTM), blood 25-hydroxyvitamin D (25-OHD), parathyroid hormone (PTH), osteocalcin (OC) and urinary N-terminal telopeptide of type I collagen (NTx) were determined at the start of therapy and after 1 and 2 years of treatment. RESULTS: During the 2 years of the study, TBMC, TBMD, leg BMC and BMD (but not lumbar BMD) increased in both groups of patients, however after 2 years of treatment they were significantly higher in the calcium-supplemented group B than in group A (p < 0.05, for all parameters). At the start of therapy, in both groups of patients percentage FM was higher and total and leg LTM lower than in controls (p < 0.05 for each parameter). Thereafter, FM decreased and LTM increased and after 2 years they were both different from baseline (p < 0.05). After 2 years of treatment, leg BMC and BMD were more positively correlated with regional leg LTM in patients of group B (r = 0.834 and r = 0.827, respectively; p < 0.001) than in patients of group A (r = 0.617 and r = 0.637, respectively; p < 0.05). 25-OHD and PTH levels were in the normal range in all patients at the start and during treatment. OC levels were lower and urinary NTx levels higher in patients than in controls (p < 0.05 for both parameters), either at the start and after 1 year of treatment. After 2 years of treatment, OC levels were significantly higher than at the start of the study (p < 0.05) in both groups of patients, but they were higher in group B than in group A (p < 0.05); on the contrary, urinary Ntx levels were lower in group B than in group A (p < 0.05). CONCLUSION: In GHD children, treated with GH, calcium supplementation improved bone mass; it may aid in reaching better peak bone mass and in protecting weight-bearing bones, usually completed in childhood to maximum levels, from risk of osteoporosis and fractures later in life.     

The effects of growth hormone deficiency and growth hormone replacement therapy on bone. A meeting report

Recently, several reports have described the effects of growth hormone (GH) deficiency (GHD) on bone and the associated potential benefits of GH therapy. Not all of these reports have, however, been consistent and the results are debated. Some of the contention surrounding this issue reflects disagreement about which bone parameters are the best indicators of bone strength and fracture risk. In November 1999, a meeting was held in Taormina, Italy, to discuss the assessment of bone in patients with GHD and the effects of GH therapy on the skeleton. The participants included endocrinologists, orthopaedists and biophysicists from around the world. During the meeting, the advantages and disadvantages of the various indicators of bone strength were defined. In considering GH therapy, the delegates agreed that it had beneficial effects on bone in adults with GHD, but that further studies were needed in GH-deficient children. Finally, the participants stressed the need for more data to clarify which indicator of bone strength is the most appropriate to use in adults and children with GHD, and to define fully the role of GH therapy in bone metabolism. It was recognized that pharmacoepidemiological surveys, such as KIGS (Pharmacia International Growth Database) and KIMS (Pharmacia International Metabolic Database), are valuable sources of such data, and are, therefore, important in the development of evidence-based medicine.     

Effects of one-year low-dose growth hormone (GH) therapy on body composition, lipid profile and carbohydrate metabolism in young adults with childhood-onset severe GH deficiency confirmed after completion of growth promotion

Introduction: The symptoms of GH deficiency (GHD) in adults include: abnormalities in body composition, unfavourable lipid profile, early atherosclerosis and impaired quality of life. The aim of the study was the selection of patients with confirmed severe GHD from among all the children treated due to GHD, who could benefit from GH therapy continuation in adulthood and the optimization of GH dosage in young adults with severe GHD. Material and methods: The study group consisted of 54 young adults (38 male), age 17.6 +/- 1.5 years, with childhood-onset GHD, who had reached final height. At least 1 month after the GH therapy withdrawal, the second evaluation of GH secretion was performed in all the patients. In 24% of patients, permanent severe GHD (PSGHD) was confirmed, but a group of 9 patients (4 male) was involved in renewed GH therapy. Results: The renewed GH therapy gave positive effects, including a significant increase in fat-free mass and a decrease in fat mass, and a significant decrease in LDL-cholesterol, but connected with an insignificant decrease of HDL-cholesterol serum concentration and improved results of quality of life (QoL) assessment. During the therapy, an insignificant increase of fasting insulin was observed, with no change in fasting glucose and only a slight increase in HbA(1c) percentage. A decrease of insulin sensitivity was also observed, but both insulin secretion and the values of insulin resistance indices still remained within the reference range. Conclusions: The observed positive effects on body composition, lipid metabolism and QoL, together with the absence of adverse events, confirm the indications for GH therapy in young adults with severe GHD.