摘要:

Growth hormone (GH) is a powerful anabolic hormone with a broad spectrum of action that has been assessed with three general parameters: auxological to assess the growth response; biochemical to measure anabolic effects; and body composition. In childhood, linear growth response is assessed with height, short-term changes in height velocity (HV), and attainment of final adult height, which may not be concordant. In both children and adults, the biochemical indices utilized to predict and/or monitor response to GH therapy have included: (1) nonspecific indices: glucose, insulin, urea, protein synthesis, lipid metabolism, and lipoproteins; (2) more specific indices of the GH-IGF axis: GH binding protein, IGF-I, IGFBP-3, and acid-labile subunit; or (3) indices of bone and mineral metabolism: calcium, phosphate, bone alkaline phosphatase, osteocalcin, propeptides of procollagen type I and III, and bone mineral content. For body composition, body mass index, total body % fat, total body or extracellular water, and bone mineral density have been addressed most frequently. Modest changes with wide variability have been observed with most measurements. GH dose is a very significant positive factor for all parameters. Few of the currently available tests can reliably predict and/or monitor response to GH therapy. Of these, serum IGF-I appears to offer the best integrated indicator of the action of GH throughout all age groups.

ISSN:1663-2818    

DOI:10.1159/000191321

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

Over 12 years’ experience with recombinant human growth hormone (rhGH) treatment has created a powerful and safe therapeutic tool. However, to fully optimize the potential of GH therapy and to provide a guide for future GH research, several key issues must be addressed. These are the identification of specific patients or conditions for whom rhGH provides proven long-term benefit; an understanding of when treatment should be started and stopped; a determination of the best dose and regimen; establishment of the most accurate parameter in measuring success of the treatment plan; and recognition of the therapy’s potential adverse effects and their relation to dosing. To date, approved pediatric indications for GH therapy are GH deficiency, chronic renal insufficiency and Turner syndrome. Long-term benefits for other indications have yet to be clearly demonstrated. Although starting GH therapy at the youngest possible age yields better results, the treatment endpoint remains controversial. Data so far has shown that daily injections are superior to thrice weekly dosing. Bedtime administration provides more physiologic GH profiles than morning injections. Subcutaneous administration of GH is as efficacious as intramuscular GH and better tolerated. Published pilot studies and large ongoing pediatric trials suggest that the growth response is dose-dependent between 0.025 and 0.1 mg/kg per day. Studies in adults, however, show efficacy at lower doses. It appears that both auxologic and biochemical parameters are useful in assessing treatment efficacy, but which marker is best suited for indicating appropriate dose adjustments remains unclear. The normalization of serum GH-dependent growth factors may have a role in individualizing the GH dose in a similar way to the approach used in managing other endocrine deficienc

ISSN:1663-2818    

DOI:10.1159/000191323

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

During puberty, growth hormone (GH)-deficient children may experience difficulties achieving an appropriate pubertal growth spurt. We review the complex hormonal interactions which occur during puberty. At least two therapeutic strategies have been developed to optimize GH therapy during puberty. In the first strategy, the GH dose administered per kilogram of body weight is increased during puberty, in an attempt to mimic the physiological increase of GH which occurs during puberty. In the second strategy, luteinizing hormone-releasing hormone (LHRH) analogs are administered concomitantly with GH with the aim of delaying epiphyseal fusion. The efficacy of these strategies to increase final height has not previously been clearly demonstrated.

ISSN:1663-2818    

DOI:10.1159/000191324

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

To minimize the rate of side-effects, a retrospective analysis of 28 studies of GH replacement therapy in adults indicates that the maintenance dose should usually not exceed 1.0 IU/m2/day (about 1.5-2.0 IU/day) in GHD patients 40-60 years old, or 1.5 IU/m2/day (about 2.5-3.0 IU/day) in GHD patients 20-40 years old. GHD women may tolerate, and in fact may need, higher replacement doses, though this issue requires further investigation. GH treatment should be started at a low dose, i.e. about 1.0 IU/day, and increased gradually, by about 0.5 IU per month, until the target dose is reached. In the absence of side-effects, the GH dose may be either too low, adequate, or too high. Measurement of GH-dependent serum markers provides the most promising approach to detect both GH depletion and excess, with serum IGF-I concentration the current method of choice. Clinical awareness of symptoms of GH excess remains important, however, particularly in patients with IGF-I levels in the high normal range.

ISSN:1663-2818    

DOI:10.1159/000191325

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

Growth hormone (GH) is registered for children with Turner syndrome (TS) in several countries. Improving the final heights (FH) is certainly the most worthy goal of therapy, but evaluation of treatment effect is complicated by methodological difficulties. Several series of FH results have now been published, with estimated benefits ranging from 0-9.3 cm, as compared to predicted height before treatment. The majority of studies report height gains of less than 5 cm, but in these studies, GH was started at a relatively late age and used at low doses. Several approaches can be utilized to improve FH results in TS, including early initiation of GH therapy, increased or optimized GH dose regimens, or optimization of sexual steroid utilization.

ISSN:1663-2818    

DOI:10.1159/000191326

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

The effect of growth hormone (GH) on short-to-medium-term growth in girls with Turner syndrome is well-established. However, it is only relatively recently that final height data have become available. This paper reviews 10 reports from Europe (including Sweden, Austria, France, Holland, Belgium and Scotland), Canada, USA and Japan, on final height and near-final height in girls with Turner syndrome receiving GH therapy. An improvement in final height outcome versus projected adult height was found in all the studies, except for the Scottish study, in which the median final height was only 142.6 cm, and the Canadian study, in which the projected adult height was unexpectedly high at 148.2 cm. Although the mean final height was 150 cm or greater in six studies, all 10 showed considerable individual variation in final height with minimum values ranging between 131.5 and 145 cm.These results must be interpreted cautiously since the mean age of starting treatment was relatively late at 9.1-13.1 years. However, the overall modesty and interpatient variability of response to GH in Turner syndrome, and continuing uncertainty as to the role of oxandrolone and the timing of estrogen therapy, emphasizes the need for further research. National and international collaboration in both retrospective and prospective studies are necessary to achieve sufficient data to offset the large number of variables to be analysed.In the UK, the British Society for Paediatric Endocrinology and Diabetes hopes to do a retrospective meta-analysis of final/near-final height outcome, comparing this with midparental and maternal height, as well as projected height and control data. A prospective study with GH dose standardized at 30 IU/m2 per week in the form of daily injections, with randomization to receive oxandrolone or not at 9 years, and estrogen at either 12 or 14 years, is also planned.

ISSN:1663-2818    

DOI:10.1159/000191327

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

Bone remodelling is a cyclical phenomenon consisting of osteoclastic bone resoφtion followed by osteoblastic bone formation. Although recent evidence suggests that GH participates in bone remodelling, the exact mechanism remains unclear. The present series of in vitro studies aimed to clarify how GH affects bone formation and resorption. GH binding sites were found to be present in osteoblastic MC3T3-E1 cells. Bovine GH (bGH) increased DNA synthesis, stimulated alkaline phosphatase activity and enhanced both type I procollagen mRNA expression and collagen synthesis. GH also increased the expression of both IGF-I and IGF-binding protein-5 mRNA as well as the release of IGF-I from these cells. The addition of IGF-I or recombinant IGFBP-5 alone significantly increased ALP activity and type I procollagen mRNA expression. These findings indicate that GH acts directly on osteoblasts to stimulate bone formation and that IGF-I and IGFBP-5 are involved in GH-stimulated bone formation. GH also stimulated pit formation on dentine slices and osteoclast differentiation in stromal cell-containing mouse bone cell cultures, whereas it did not affect the bone-resorbing activity of isolated rabbit osteoclasts. The addition of IGF-I or rIGFBP-5 alone exhibited similar effects. These stimulatory effects of GH on pit formation and osteoclast differentiation were significantly blocked in the presence of neutralizing anti-IGF-I antibody. PCR products corresponding in size to the mouse GH receptor were detected in osteoclast precursor cells. GH stimulated osteoclast-like cell formation from these cells in the absence of stromal cells, and these osteoclast-like cells formed pits on dentine slices in the presence of MC3T3-G2/PA-6 stromal cells. These findings indicate that GH stimulates osteoclastic bone resoφtion through both its direct and indirect action on the maturation of osteoclast precursor cells and through its indirect activation of mature osteoclasts, possibly via stromal cells. In conclusion, GH stimulates osteoclastic bone resorption as well as osteoblastic bone formation in vitro, and locally produced IGF-I and/or IGFBP-5 are involved in the stimulation of bone remodelling by G

ISSN:1663-2818    

DOI:10.1159/000191328

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

This paper gives a short overview of the physiology of biochemical indices of bone metabolism, their origins, the problems of interpretation of their activities and the most important clinical applications in childhood and adolescence. Markers of bone formation are all osteoblast products that enter the circulation; alkaline phosphatase (bone isoform), osteocalcin and type I pro-collagen peptides. Most of the traditional and new markers for bone resorption analyse the matrix (collagen) degradation products in urine from osteoclast activity. These include urinary hydroxyproline, hydroxylysine glycosides, total or free pyridinoline cross-links and cross-linked N- or C-telopeptides. Many studies have shown that both the old and new markers of bone metabolism are useful tools for basic bone biology research, for defining physiological phenomena in clinical studies, or drug trials of growth modifying therapies (e.g. growth hormone), and for following up individual patients. For the exact interpretation of bone markers it is necessary to define the factors which may influence measurement of the markers, such as age, sex, puberty, height velocity, circadian rhythms, diet, liver function and kidney clearance rates.

ISSN:1663-2818    

DOI:10.1159/000191329

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

Three processes occur in the skeleton; modelling during growth, fracture repair and remodelling. Remodelling is bone resorption coupled to bone formation, and alterations in the remodelling balance are the final pathway to bone loss. Therapeutic agents are now available to minimize the normal phenomenon of age- related bone loss and protect against osteoporotic fracture. These agents reduce the rate of bone resorption, have positive effects on bone mass and some reduce fracture rates. None, however, restore bone mineral to normal levels. GH has been considered for this role due to its positive effects in vitro and in vivo. GH-deficient adults have low BMD compared to healthy controls, and the reasons for this finding are discussed. A neglected factor is a measurement artefact from the use of DXA. Long-term GH therapy can lead to clinically important increases in BMD in GH-deficient adults. The results from studies of GH administration to healthy elderly populations are also presented. The small rise of lumbar BMD or maintenance of BMD at the hip seen in these studies are no better than results achieved with cheaper, easier to administer therapies. Investigation of other agents in the somatotrophic axis, are, however, potentially promising and warrant further investigation.

ISSN:1663-2818    

DOI:10.1159/000191330

出版商:S. Karger AG    

年代:1997

数据来源: Karger

摘要:

Bone mineralization increases with age, height and weight through childhood, with a significant gain during pubertal development. Approximately 37% of bone mass is accumulated between pubertal stages 2-5. The factors driving the pubertal increase of bone mass is not fully known, but a crucial role is played by the sex steroids. Patients with central precocious puberty show an increased bone mineral density (BMD) for their chronological age, but appropriate for their bone age and pubertal stage. In girls and boys with hypogonadism, as well as in constitutional delay of puberty, the ‘tempo’ of puberty seems to be another important determinant of peak bone mass. Hypogonadal patients increase their BMD when treated in adulthood with sex steroid substitutive therapy, but normal adult BMD values are not reached. If these patients start sex steroid therapy at the appropriate age for the onset of pubertal development, however, a greater increase in BMD occurs. Both oestrogen and androgen receptors have been demonstrated in bone cells. Patients with oestrogen resistance or aromatase deficiency had a severely undermineralized skeleton. Reduced area and volume BMD are also present in patients with complete androgen resistant syndrome compared to normal. The pubertal increase of BMD may be the result of the coordinated activation of oestrogen and androgen receptors at the bone level in both sexes. In conclusion, the gonadal secretion of sex steroids, the tempo of puberty, and the normal function of both oestrogen and androgen receptors seem to be important factors in the acquisition of bone m

ISSN:1663-2818    

DOI:10.1159/000191331

出版商:S. Karger AG    

年代:1997

数据来源: Karger