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HORMONES OF THERAPEUTIC INTEREST 327
GH bound to GH binding proteins
Figure 8.13. Growth hormone found in the circulation is generally bound to GH-binding proteins. Binding to the cell surface receptor promotes receptor dimerization and phosphorylation and hence activation. This leads to the phosphorylation of various cystolic protein substrates, which mediate intracellular effects of the hormone
Biological effects of GH
GH primarily displays an anabolic activity. It partially stimulates the growth of bone, muscle and cartilage cells directly. Binding of GH to its hepatic receptor results in the synthesis and release of insulin-like growth factor (IGF-1), which mediates most of GH’s growth-promoting activity on, for example, bone and skeletal muscle (Chapter 7). The major effects mediated by hGH are summarized in Table 8.6.
A deficiency in the secretion of hGH during the years of active body growth results in pituitary dwarfism (a condition responsive to exogenous hGH administration). On the other hand, overproduction of hGH during active body growth results in gigantism. hGH overproduction after primary body growth has occurred results in acromegaly, a condition characterized by enlarged hands and feet, as well as coarse features.
Table 8.6. Some of the major biological effects promoted by growth hormone. While many of these are direct, other effects are mediated via IGF-1 (Chapter 7)
Increased body growth (particularly bone and skeletal muscle) Stimulation of protein synthesis in many tissues Mobilization of depot lipids from adipose tissue (lipolytic effect) Elevation of blood glucose levels (anti-insulin effect)
Increase of muscle and cardiac glycogen stores
Increased kidney size and enhanced renal function
Reticulocytosis (increased reticulocyte production in the bone marrow)
Table 8.7. Some actual or likely therapeutic uses for hGH. Refer to text for details
Treatment of short stature caused by GH deficiency
Treatment of defective growth caused by various diseases/medical conditions
Induction of lactation
Treatment of obesity
Induction of ovulation
Therapeutic uses of GH
GH has a potentially wide range of therapeutic uses (Table 8.7). To date, however, its major application has been for the treatment of short stature. hGH extracted from human pituitary glands was first used to treat pituitary dwarfism (i.e. caused by sub-optimal pituitary GH secretion), in 1958. It has subsequently proved effective in the treatment of short stature caused by a variety of other conditions, including:
• Turner’s syndrome;
• idiopathic short stature;
• chronic renal failure.
The use of hGH extracted from the pituitaries of deceased human donors came to an abrupt end in 1985, when a link between treatment and Creutzfeldt-Jakob disease (CJD, a rare, but fatal, neurological disorder) was discovered. In this year, a young man who had received hGH therapy some 15 years previously died from CJD, which, investigators concluded, he had contracted from infected pituitary extract (CJD appears to be caused by a prion). At least an additional 12 CJD cases suspected of being caused in the same way have subsequently been documented. Fortunately, several recombinant hGH (rhGH) preparations were coming on-stream at that time (Table 8.8), and now all hGH preparations used clinically are derived from recombinant sources. Currently, in excess of 20 000 people are in receipt of rhGH therapy.
rhGH was first produced in E. coli in the early 1980s. The initial recombinant preparations differed from the native human hormone only in that they contained an extra methionine residue (due to the AUG start codon inserted at the beginning of the gene). Subsequently, a different cloning strategy allowed production in E. coli of products devoid of this terminal methionine.
In vitro analysis, including tryptic peptide mapping, amino acid analysis and comparative immunoassays, show the native and recombinant form of the molecule to be identical. Clinical trials in humans have also confirmed that the recombinant version promotes identical biological responses to the native hormone. rhGH was first purified (on a lab scale) by Genentech scientists using the strategy outlined in Figure 8.14. A somewhat similar strategy is likely used in its process-scale purification.
Recombinant hGH (rhGH) and pituitary dwarfism
Various studies have confirmed that rhGH promotes increased linear growth rates in children suffering from pituitary dwarfism (classical growth hormone deficiency). Dosages are generally
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Table 8.8. Recombinant human growth hormone (rhGH) preparations approved for general medical use
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