Clinical Focus Box 321

Recombinant Human Growth Hormone and GH Deficiency

Growth hormone (GH) is species-specific, and humans do not respond to GH derived from animals. In the past, the only human GH available for treating children who were GH-deficient was a very limited amount made from human pituitaries obtained at autopsy, but there was never enough to meet the need. This problem was solved when the gene for human GH was cloned in 1979 and then expressed in bacteria. The production of large amounts of recombinant human GH, with all the activities of the natural substance, was now possible. During the 1980s, careful clinical trials established that recombinant human GH was safe to use in GH-deficient children to promote growth. The hormone was approved for clinical use and is now produced and sold worldwide.

Despite the availability of recombinant GH, the diagnosis of GH deficiency has remained controversial. GH is released in periodic bursts, the greatest of which occur in the early morning hours. Between pulses of secretion, the blood concentration of GH is nearly undetectable by most techniques. For these reasons, a random measure of GH in the blood is not useful for diagnosing GH deficiency. However, a random blood sample may be useful to detect GH resistance, a syndrome in which the patient exhibits symptoms of GH deficiency but presents with high GH levels in the blood.

An alternative means of diagnosing GH deficiency is to measure the levels of IGF-I, IGF-II, and the IGF-binding protein 3 (IGFBP3) in the blood. The IGFs mediate many of the mitogenic effects of GH on tissues in the body. IGF-I and IGF-II bind to IGFBP3 in the blood. IGFBP3 extends the halflife of the IGFs, transports them to target cells, and facilitates their interaction with IGF receptors. GH stimulates the production of all three molecules, which are present in the blood at fairly constant, readily detectable levels in normal individuals. In children with GH deficiency, the concentration of IGFs and IGFBP3 are low. Treatment with recombinant GH will increase IGF-I, IGF-II, and IGFBP3 in the blood, which will result in increased long bone growth. The epiphyseal growth plate in the bone becomes less responsive to GH and IGF-I several years after puberty, and long bone growth stops in adulthood (see Chapter 36).

GH is also thought to function as one of the counter-regulatory hormones that limit the actions of insulin on muscle, adipose tissue, and the liver. For example, GH inhibits glucose use by muscle and adipose tissue and increases glucose production by the liver. These effects are opposite those of insulin. Also, GH makes muscle and fat cells resistant to the action of insulin itself. Thus, GH normally has a tonic inhibitory effect on the actions of insulin, much like the glucocorticoid hormones (see Chapter 34).

The insulin-opposing actions of GH can produce serious metabolic disturbances in individuals who secrete excessive amounts of GH (people with acromegaly) or are given large amounts of GH for an extended time. They may develop insulin resistance and an elevated insulin level in the blood. They may also have hyperglycemia caused by the underutilization and overproduction of glucose. These disturbances are much like those in individuals with non-insulin-dependent (type 2) diabetes mellitus. For this reason, this metabolic response to excess GH is called its diabetogenic action.

In GH-deficient individuals, GH has a transitory insulin-like action. For example, intravenous injection of GH in a person who is GH-deficient produces hypoglycemia. The hypoglycemia is caused by the ability of GH to stimulate the uptake and use of glucose by muscle and adipose tissue and to inhibit glucose production by the liver. After about 1 hour, the blood glucose level returns to normal. If this person is given a second injection of GH, hypo-glycemia does not occur because the person has become insensitive or refractory to the insulin-like action of GH and remains so for some hours. Normal individuals do not respond to the insulin-like action of GH, presumably because they are always refractory from being exposed to their own endogenous GH. The actions of GH in humans are summarized in Table 32.3.

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