Download (direct link):
Eli Lilly Genentech
Schwartz Pharma AG Biotechnology General Pharmacia and Upjohn Serono Laboratories Serono Laboratories
hGH deficiency in children hGH deficiency in children Growth failure, Turner’s syndrome hGH deficiency in children hGH deficiency in children hGH deficiency in children Treatment of AIDS-associated catabolism/wasting Treatment of growth failure in children due to inadequate growth hormone secretion
administered on a weekly basis by i.m. or s.c. injection. Duration of treatment typically varies from 6 months to 2 years, although on occasion administration has continued for up to 4 years.
Increased growth rates are generally observed, although the extent varies with, for example, the recipient’s age at onset of treatment, sex and baseline growth rates. rhGH-induced growth
Figure 8.14. Production of recombinant human growth hormone (rhGH) in E. coli (as an intracellular protein). Subsequent to fermentation, the cells are collected by centrifugation or filtration. After homogenization, nucleic acids and some membrane constituents are precipitated by the addition of polyethyleneimine. Ammonium sulphate precipitation of the supernatant concentrates the crude rhGH preparation. Chromatographic purification follows, as illustrated
acceleration is most notable during the initial stages of treatment, with relative effect decreasing with time. In most cases, growth hormone treatment ensures a final body height several centimetres greater than would otherwise be attained in recipients.
Idiopathic short stature and Turner’s syndrome
In many cases, a root cause for slower than normal growth rate in children of short stature is not immediately obvious (idiopathic short stature). Endogenous GH levels are often considered to be within a normal range (although there may be changes in its pusatile secretion patterns). A host of clinical trials have shown, however, that rhGH administration can increase the growth rate of many children with idiopathic short stature. Several trials lasting up to 3 years showed that, although the response was most dramatic during the first year, even during year three, mean growth rates were over 3 cm/year greater than expected.
Turner’s syndrome is a genetic defect that affects females (sufferers carry only one of the usual two X chromosomes). These individuals are infertile, often show developmental defects, mental retardation and short stature. Virtually all clinical trials involving Turner’s syndrome patients confirm that administration of GH significantly increases growth velocity, indicating its therapeutic usefulness in these cases.
Metabolic effects of hGH
The twin metabolic effects of hGH in promoting increased body protein synthesis and increased lipolytic activity suggest a role for the hormone in influencing body lean mass/fat composition. Attention in this regard has focused upon treating obesity and burns, as well as counteracting some of the effects of old age. Clinical studies in dieting obese people suggest that GH treatment (typically for 3-12 weeks) did not promote reduction of body fat levels any faster than in persons’ dieting, but without treatment. A lipolytic effect was, however, observed in obese people who were not subject to caloric restriction during rhGH treatment. A future role for this hormone in treating obesity is, therefore, far from certain.
Clinical trials have also revealed a role for rhGH in the treatment of severe burns, particularly in children. The fear and emotional trauma (as well as physical damage) associated with receiving a severe burn triggers a neurological and immune-mediated response termed the stress response. This is characterized by:
• protein catabolism;
• loss of lean body mass;
• increased metabolic rate;
• futile substrate cycling and lipolysis;
• elevated body temperature.
rhGH treatment is aimed largely at slowing/preventing elevated protein catabolism. Initial trials in burn patients showed that GH administration reduced protein loss by 50% compared to (untreated) controls. Subsequent GH studies in children with massive burning (over 50% of total body surface), revealed accelerated wound healing, particularly at the skin graft donor site. This, in turn, facilitated further skin grafting within shorter time periods, thus reducing the time to close the burn wound. On the basis of such results, GH may well play a future expanding role in burn care management.
HORMONES OF THERAPEUTIC INTEREST 331
The production of GH is age-modulated. The highest production levels are recorded immediately after birth, with a second increase noted at puberty. GH secretion decreases steadily after age 40, and this decline is likely linked to age-associated decreased muscle, bone and skin mass, all of which contribute to age-associated frailty.
In recent years, several pilot clinical trials, assessing the effects of GH administration to ageing adults, have been carried out. Typically, trial duration is 4-6 months. A 7% increase in lean body mass and skin thickness, along with a 14% drop in body fat, was observed in one trial, although results recorded in other trials were less striking. More detailed clinical trials and cost:benefit analysis must be carried out in order to fully assess the potential of GH to counteract some of the effects of ageing in the elderly population.