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Clinical pharmacological aspects of growth hormone administration

2004

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For many years the preferred administration regimen for GH therapy has been daily sc GH injections in the evening, which is superior to less frequent im injections in terms of e.g. growth promotion and compliance. The sc route provides an acceptable bioavailability of 50-70% without an appreciable ... ( view more )reduction in bioactivity. As concerns the site of sc GH injections, the faster absorption from the abdominal as compared with the femoral site is not accompanied by different levels of any effect parameter, and both sites can therefore be used safely. The physiological pulsatile GH secretion pattern is presumed to be essential for induction of growth and development. Consequently, it is assumed that an optimal therapeutic efficacy can be obtained by GH administration regimens which aim to mimick endogenous pulsatile GH release. Studies in animals - most often rats - seem to support that view, as pulsatile GH administration is superior to continuous delivery in terms of increasing serum IGF-I levels. A main issue of the present thesis was to illustrate the impact in man of intermittent and continuous exposure to GH on levels of metabolic determinants such as IGF-I, IGF binding proteins, GH binding protein, insulin, glucose, FFA and lipoprotein metabolism. Among these serum IGF-I and glucose homeostasis are used for clinical monitoring of GH therapy. By studying the effect of GH administration in GHD patients the interference of endogenous GH in the evaluation is almost eliminated. Overall, approximated pulsatile GH schedules were not superior to continuous GH delivery. A single iv GH bolus injection was incapable of increasing serum IGF-I, and even two iv bolus injections increased IGF-I levels less efficiently than more frequent injections or a continuous infusion of the same total GH dose. Increased serum GH levels are obtained for up to 60 min after an iv bolus injection, but induction of IGF-I generation apparently requires a more sustained period of GH exposure. An increased frequency of injections extend the period with GH in the circulation, which might explain why more pronounced increases in serum IGF-I have been achieved in parallel to more frequent administration of smaller GH doses. Even constant exposure to GH as achieved with a continuous iv infusion, increased serum IGF-I levels more effectively than frequent iv injections. Surprisingly, a combination of pulsatile and continuous GH exposure as obtained by concomitant administration of frequent injections and a constant infusion of GH, was unable to increase serum IGF-I levels more effeciently than frequent pulses or constant infusion alone. Increased serum levels of IGFBP-3, ALS, and formation of the 150 kDa ternary complex of IGF-I, IGFBP-3 and ALS were induced by GH, but unlike IGF-I, this occurred independently of the mode of delivery during short-term iv exposure to GH. Thus, the importance of pulsatile GH administration reported in animal studies could not be confirmed in human studies. No obvious explanation for these species discrepancies can be given. It is unknown whether induction of the generation of extrahepatic IGF-I, which is also involved in the mediation of the effects of GH, depends on GH pulsatilily in humans. Apart from the experimentally relevant iv route an approximation to physiology might be obtained by nasal delivery, which provides increased GH levels for 3-4 h. With addition of an absorption enhancer in appropriate concentrations, GH is absorbed rapidly from the nasal mucosa, but the bioavailability remains below 10%. As no concomitant increase in serum IGF-I or other metabolic response parameters could be observed, employment of the nasal route would, however, require more than once daily GH administration. Contemporary animal studies have questioned the safety of nasal GH delivery, so this route is presently not a clinical option. Returning to the clinical situation, employing the sc route, a schedule of twice daily injections giving 2/3 of the total GH dose at bedtime and 1/3 in the morning was compared with once daily injections in the evening. The twice daily injections regimen provided an additional 'pulse', and sustained the daily interval of GH exposure. Higher levels of serum IGF-I and concomitantly lower levels of the inhibitory IGFBP-1 were obtained with this twice daily injection. The impact of constant GH exposure was further examined by comparing daily sc injections with continuous sc infusion. Higher or similar serum IGF-I levels could be obtained after 4 weeks and 6 months of continuous sc infusion as compared with daily sc injections. Serum GHBP levels were unaffected by mode of GH delivery, which again is in contrast to the findings in animal studies. However, the present studies provided no information on the regulation of tissue levels of the GH receptor. Glucose homeostasis, including insulin sensitivity, was unaffected by the mode of GH administration. During constant exposure to GH it is advisable, however, to consider a potential risk of daytime hyperinsulinaemia, glucose intolerance or diabetes in particular when supraphysiological GH doses are employed, or when insulin resistant patients are treated. When the 24 h GH dose is distributed as more than one daily sc injection it still seems rational to administer the main proportion of the dose in the evening. In particular, this applies to the effects of the GH pattern on lipolysis, as the increase in circulating levels of FFA was attenuated when the GH dose was distributed on two daily sc injections, or administered as a continuous sc infusion for four weeks or six months. The overall beneficial effects of GH on lipoprotein metabolism were not significantly diminished during more constant exposure to GH as compared with daily injections. The present studies of up to six months duration revealed no impact of the mode of GH delivery on measures of body composition or bone metabolism. Daily sc injections in the evening still represent an approximated physiological GH administration regimen. A more detailed imitation of the endogenous GH pattern by e.g. patterned iv delivery might improve the therapeutic effects of GH. However, long-term exposure would be mandatory to assure significant clinical pharmacological effects, and this would be unrealistic in clinical practice. Alternatively, continuous delivery of GH as attained by a sustained-release GH preparation could be a future and more convenient, albeit also less physiological, alternative to some patients, but further data on efficacy and safety are obviously needed

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