Human growth hormone from cadaveric sources to recombinant DNA production

Human Growth Hormone in Biotechnology

Human growth hormone (GH), also known as somatotrophin, is a protein consisting of 191 amino acids with a molecular weight of ~22,000. Growth hormone is secreted by the pituitary gland, which stimulates growth and cell reproduction. The structure is made up of four helices, which are necessary for functional interaction with the GH receptor. Despite remarkable structural similarities between GH from different species, only human and primate GH may be active in humans.

History of Human Growth Hormone

Growth hormone was first purified from pig and cow pancreas for treatment of type 1 diabetes since the 1920's. However, these types of GH did not function as well in humans, due to greater variation of molecular structure compared to human GH. In 1958, Maurice Raben purified enough GH from human pituitary glands to successfully treat a GH-deficient boy (Raben). In 1960, the National Pituitary Agency was formed as a branch of the U.S. National Institutes of Health. The purpose of this agency was to supervise the collection of human pituitary glands after autopsy, arrange for large scale extraction and purification of GH, and distribute GH to a limited number of pediatric endocrinologists for treating GH-deficient children under research protocols.

Supplies of cadaveric GH were limited and only the most severely GH-deficient children were treated. From 1963 to 1985, ~7700 children in the U.S. And ~27,000 children worldwide were given GH extracted from human pituitary glands to treat severe GH deficiency. In 1976, physicians became aware that Creutzfeldt-Jacob disease may be transmitted by neurosurgical procedures and cornea transplantation. This disease is a rapidly fatal dementing disease of the brain also known as spongiform encephalopathy, related to "mad cow disease."

A shortage of available cadaver GH worsened in the late 1970's as the autopsy rate in the U.S. declined, while the number of pediatric endocrinologists able to diagnose and treat GH deficiency increased. However, in 1981, Genentech started trials of synthetic human GH made by recombinant DNA, in which human genes were inserted into bacteria so that bacteria could produce unlimited amounts of the protein.

In 1985, four young adults in the U.S. who had received growth hormone in the 1960's developed Creutzfeldt-Jacob disease (Frasier). The connection was recognized quickly and use of human pituitary GH ceased. Discontinuation of human cadaver growth hormone led to rapid Food and Drug Administration approval of Genentech's synthetic GH, which was introduced to the United States in 1985.

As of 2004, GH use continues to increase. Synthetic growth hormones available in the U.S. included Nutropin (Genentech), Humatrope (Lilly), Genotropin (Pfizer), Norditropin (Novo), and Saizen (Serono). The products are nearly identical in composition, efficacy, and cost, varying primarily in the formulations and delivery devices.

Functions of Human Growth Hormone

Growth hormone has an anabolic effect on the tissues of the body. One of the primary functions attributed to GH is height growth in childhood. This process is stimulated by two mechanisms. First, GH directly stimulates division and multiplication of chondrocytes of cartilage, which are the primary cells in the epiphyses of children's long bones. Second, GH stimulates production of insulin-like growth factor 1 (IGF1). The liver is a major target organ of GH for this process and is the principal site of IGF1 production. Insulin-like growth factor 1 has growth-stimulating effects on a wide variety of tissues.

In addition to height growth in childhood, GH serves many other metabolic functions. Growth hormone increases calcium retention, increases the mineralization of bone (Vestergaard and Mosekilde), increases muscle mass, induces protein synthesis and growth of many different organ systems of the body, resulting in a positive nitrogen balance.

Growth hormone also plays a role in metabolic homeostasis (Jorgensen et al.). Growth hormone reduces liver uptake of glucose, an effect that opposes that of insulin. Growth hormone also promotes lipolysis, which results in reduction of adipose tissue and free fatty acids and glycerol concentrations in the circulation.

Sources of Human Growth Hormone

From 1963 to 1985, the National Hormone and Pituitary Program supplied human GH to individuals with certain disorders such as GH deficiency. The sole means to obtain GH during this period was to extract the hormone from the pituitary glands of cadavers. However, in 1985, researchers discovered that cadaver-derived GH may transmit Creutzfeldt-Jakob Disease, which is a fatal brain disorder. Cadaver-derived GH distribution was immediately halted. In October 1985, synthetic GH was approved by the FDA. Today, all distributed GH is manufactured synthetically, which poses no risk of Creutzfeldt-Jakob Disease.

Uses of Synthetic Human Growth Hormone

Before the discovery of synthetic GH, the hormone was purified from human cadavers, which resulted in two drawbacks: risk of developing Creutzfeldt-Jakob Disease and limited supply. Due to the limited supply, GH was primarily distributed to treat children with severe growth retardation. However, after GH was able to be synthetically derived, the virtually unlimited supply of recombinant GH has lead to several other applications in human and animal populations.

Synthetically-derived human GH is still used to treat children of pathologically short stature. Examples of causes of shortness that are often treated with GH are Turner syndrome, chronic renal failure, Prader-Willi syndrome, intrauterine growth retardation, and severe idiopathic short stature. Growth hormone has been shown to improve muscle strength and slightly reduce body fat in Prader-Willi syndrome, benefits that are more important to these children than increased height. Growth hormone has also been shown to help maintain muscle mass in AIDS wasting.

Growth hormone has multiple applications in the animal science field. Growth hormone is currently approved and marketed for enhancing milk production in dairy cattle. Administration of bovine GH to lactating cows results in increased milk yield and can be an economically-viable therapy. Drinking milk from cattle treated with bovine GH does not pose a risk to human health. Another application of GH in animal agriculture is treatment of growing pigs with porcine GH, which has been demonstrated to significantly stimulate muscle growth and reduce deposition of fat.

Risks of Human Growth Hormone Use

Patients who are not GH-deficient are more likely to experience side effects of GH administration. Nonetheless, side effects for both healthy adults and growth-hormone-deficient adults taking growth hormone are similar and may include:

Slipped capital femoral epiphysis causes hip pain due to separation of the head of the femur from the shaft. The incidence of this disorder in GH-treated children is about 1 in 1000.

Benign intracranial hypertension occurs in 1 in 1000 patients and results in severe headaches..

Edema in the early months of GH treatment is rare in children, but more common and occasionally more severe in adults.

Joint pains are occasionally experienced by adults being treated with GH, but are rare in children.

Carpal tunnel syndrome may occur in adults treated with GH, likely due to a combination of tissue growth and fluid retention causing pressure on the nerves and tendons of the wrists.

Most of these signs and symptoms ease or disappear when doses of growth hormone are reduced.

Chronic excess GH concentrations in the circulation may lead to a condition called acromegaly. Increased and unregulated GH production, usually caused by a GH-secreting pituitary tumor, characterizes acromegaly. Other causes of increased and unregulated GH production include increased growth hormone -- releasing hormone (GHRH) from hypothalamic tumors, ectopic GHRH release from nonendocrine tumors, and ectopic GH secretion by nonendocrine tumors. The development of symptoms is takes years to decades to become apparent. Acromegaly results in many signs and symptoms and significantly increases morbidity and mortality rates. Common signs of acromegaly include a protruding brow or lower jaw and enlarged hands or feet. Additionally, the increased mass of the pituitary tumor itself can cause symptoms. Acromegaly incidence is estimated to be 3-4 cases per million population per year (Orme et al.).

Ethical Considerations Associated with Growth Hormone Use

For several decades, GH treatment has been a rich source of social controversy. The primary controversies arise from the intersection of two factors: high cost and the difficulty of defining a boundary between disease and normal. For example, if GH treatment were inexpensive, the degree of controversy would likely diminish. Furthermore, if potential benefit was limited to only several specific conditions, controversy surrounding GH use would likely decrease. However, neither of statements are true.

Growth hormone is one of the most expensive treatments in medicine. The cost of adult GH replacement for deficiency is ~$2,000 per year. The cost of treatment for a non-GH-deficient child, e.g. Turner syndrome or idiopathic short stature, is ~$25,000 per year. A typical treatment course of 5 years, which may yield ~2 inches of extra adult height costs ~$125,000. The highest cost, for treatment from infancy to age 70 of severe, congenital GH deficiency, may exceed $300,000. Assessing the value of treatment to offset the cost is problematic due to the range of severity of conditions treated and the difficulty of clearly distinguishing disease from normal human variation.

Human Growth Hormone Conclusions

In summary, human GH is a widely administered hormone that is used for a multitude of reasons. Some uses are approved by the FDA and are generally considered very safe. However, GH is also used for performance enhancement in athletes and "anti-aging" in the elderly, both of which are practices that are sharply criticized. The risk-to-benefit ratio for these latter applications is questionable, especially in regards to cost, potential for physical enhancement, and risk of side effects.