Related Terms

• Acromegaly, Genotropin®, GH, GHRH, growth hormone, growth hormone deficiency, growth hormone-releasing hormone, HGH, Humatrope, natural sequence GH, Norditropin®, Nutropin®, recombinant growth hormone, rhGH, Saizen®, somatotropin, somatropin, Turner syndrome.

Background

• Human growth hormone (HGH or GH), also known as somatotropin, is a protein hormone naturally synthesized and secreted by the anterior pituitary gland, which stimulates growth and cell reproduction. During adolescence production of HGH is generally high. HGH levels peak somewhere between the ages of 21 and 30 and then decline when a person is in his or her 40s.

• The identification, purification, and later synthesis of growth hormone are associated with Choh Hao Li, a Chinese biologist and biochemist living from 1913-1987.

• By the middle of the 20th Century, endocrinologists gained a better understanding of the clinical features that define growth hormone deficiency. GH is a protein hormone, like insulin, which had been purified from pig and cow pancreases for treatment of type 1 diabetes since the 1920s. However, similar attempts to use pig and cow sources of GH did not work as well in humans due to greater species-to-species variation of molecular structure.

• From 1960 to 1985, growth hormone was extracted from human pituitary glands and given to children who did not naturally produce enough of the hormone. In 1985 the use of growth hormone from human cadavers was associated with the development of Creutzfeldt - Jakob disease (a rare, usually fatal disease of the brain, characterized by progressive dementia and gradual loss of muscle control, that occurs most often in middle age and is caused by a slow virus), and was withdrawn from use.

• GH is now produced synthetically and given to both children and adults for a variety of reasons, most often involving deficiencies of the hormone. In the last two decades, GH has also been used to enhance growth in children and adults for reasons besides growth hormone deficiency, such as HIV-associated muscle wasting or organ transplant.

• As of 2004, GH has been approved by the United States (US) Food and Drug Administration for treatment of many types of short stature. As of 2005, synthetic growth hormones available in the United States 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. In 2005 an Israeli company, Teva, offered Tev-Tropin in the US at a lower price. Lilly and Alkermes are developing an inhalable version that is in phase III clinical trials as of 2006.

• Currently, some adults are turning to shots of growth hormone in hopes to stop aging, even as its effectiveness and safety remain unproven. Growth hormone has also been occasionally misused by athletes hoping to increase strength or muscle mass.

Technique

• Early manufacturing of growth hormone used tissue harvested from the pituitary glands of cadavers. This method of production was stopped in 1985 due to the associated risk of developing Creutzfeldt - Jakob disease.

• A synthetic form of human growth hormone was then developed using recombinant DNA technology. Recombinant human growth hormone (also known as rhGH or somatropin), contains the identical amino acid sequence of human GH and was for a time referred to as "natural sequence" GH. It is the only synthetic GH commercially available for human use today. Methionyl-growth hormone (met-GH) was the first recombinant GH product marketed (Protropin® by Genentech). It had the same amino acid sequence as human GH with an extra methionine at the end of the chain to facilitate the manufacturing process. It was discontinued in the late 1990s.

• Growth hormone is available by prescription, and is approved to treat children with short stature, kidney disease, Prader-Willi syndrome, and Turner's syndrome, and patients with HIV/AIDS related muscle wasting or growth hormone deficiency.

• Because GH is a large protein molecule, it must be injected to get it into the bloodstream, either subcutaneously using an insulin syringe, or intramuscularly.

• Some medications given by injection may be given at home to patients who do not need to be in the hospital. A health care professional can teach the patient how to prepare and inject the medicine. It is important to understand exactly how the medicine is to be prepared and injected and read the patient information and instructions for use.

• It is also important to follow any instructions from a doctor about the selection and rotation of injection sites on the body. This may help to prevent skin problems associated with the injection.

• Used needles and syringes should be put in a puncture-resistant disposable container or disposed of as directed by a health care professional. Do not reuse needles or syringes.

• Treatment of GH deficient children usually involves daily injections of growth hormone, often required for as long as the child is growing and possibly into adulthood. Dosing of GH is weight based and must be determined by a doctor. Often, the dosage of 0.3mg/kg per week is used initially and reevaluated by a pediatric endocrinologist every three to four months. Treatment costs vary by country and by size of the patient, but the typical cost in the US ranges from $10,000 to $30,000 a year. However, the cost may be completely or partially covered by health insurance depending on the individual insurance company and the reason for use of GH.

• GH for severe adult deficiency is usually prescribed as daily injections at a weekly dose about 25% of the pediatric dose and has a comparably lower cost. Lifelong continuation may be necessary for adults with severe deficiency. Despite the potential benefits, most adults with GH deficiency are not being treated due to a combination of factors such as unwillingness of young adults to seek medical care, unacceptability of injections, inadequate insurance coverage, and significantly lower rates of diagnosis and treatment offered by internist endocrinologists.

Theory/Evidence

• Height growth in childhood is the best-known effect of GH action, and appears to be stimulated by at least two mechanisms: GH directly stimulates division and multiplication of chondrocytes of cartilage. These are the primary cells in the growing ends (epiphyses) of children's long bones (arms, legs, fingers and toes); GH also 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 IGF-1 production. IGF-1 has growth-stimulating effects on a wide variety of tissues including muscle, cartilage, bone, liver, kidney, nerves, skin, and lungs.

• Although height growth is the best-known effect of GH, it serves many other metabolic functions as well. GH increases calcium retention, strengthens and increases the mineralization of bone, increases muscle mass, induces protein synthesis and promotes growth of many different organ systems of the body.

• GH may also stimulate the immune system, affect homeostasis, and reduce liver uptake of glucose, an effect that opposes that of insulin. GH may also contribute to the maintenance and function of pancreatic islets, groups of cells in the pancreas that secrete insulin and glucagon. GH tends to promote lipolysis, which results in some reduction of adipose tissue (body fat) and rising amounts of free fatty acids and glycerol in the blood.

• When a person has had a long-standing deficiency of GH, benefits of treatment are often obvious, and side effects of treatment are generally rare. When treated with GH, a deficient child may begin to grow faster within months. Other benefits such as increased strength, progress in motor development, and reduction of body fat may also occur.

• Research has shown that GH treatment can provide a number of measurable benefits to severely GH-deficient adults, such as enhanced energy and strength, and improved bone density. Muscle mass may increase while adipose tissue may decrease. Blood lipid levels often improve, but long term mortality benefit has not yet been demonstrated.

• In patients with Turner syndrome (a genetically determined condition that is typically associated with the presence of only one complete X chromosome and no Y chromosome), growth often accelerates when doses 20% higher than those used in GH deficiency are administered. With several years of treatment the median gain in adult height is about 2-3 inches (5-7.5 cm) with this treatment dose. The gains appear to only occur with this high dose.

• Chronic renal failure may result in many problems, including growth failure. GH treatment for several years both before and after kidney transplantation may prevent further deceleration of growth and may narrow the height deficit; though even with GH treatment net adult height loss may be about 4 inches (10 cm).

• Post-transplant growth failure sometimes improves with GH. Many children who suffer from chronic renal, liver, and heart disease grow poorly for years before a transplant is required (or available). While growth may improve after correction of organ function by successful transplantation, the immunosuppressive drugs taken to protect the transplanted organ may continue to interfere with growth. Growth hormone may help offset these effects and is often offered in these circumstances.

• Children who are short because of intrauterine growth retardation are small for gestational age at birth for a variety of reasons. If early catch-up growth does not occur and height remains below the third percentile by two or three years of age, adult height is likely to be similarly low. High-dose GH treatment has been shown to accelerate growth, but data on long-term benefits and risks is limited.

• Idiopathic short stature (ISS) is one of the most controversial indications for GH as pediatric endocrinologists do not agree on its definition, diagnostic criteria, or limits. The term has been applied to children with severe unexplained shortness that will result in an adult height below the third percentile. In the late 1990s, the pharmaceutical manufacturer Eli Lilly and Company sponsored trials of Humatrope (their brand of rhGH) in children with extreme ISS, at least 2.25 standard deviations below mean (in the lowest 1.2% of the population). These boys and girls appeared to be headed toward heights of less than 63" (160 cm) and 59" (150 cm) respectively. They were treated for about four years and gained 1.5 to 3 inches (3.8-7.6 cm) in adult height. Controversy has arisen as to whether all of these children were truly "short normal" children, since the average IGF-1 was low.

• Chronic high dose glucocorticoid use may result in growth failure, diminished bone density, reduced muscle mass and strength, increased fat, skin fragility, and poor healing. Growth hormone supplementation may reduce many of these complications without interfering with the anti-inflammatory benefits of the steroid. However GH cannot completely prevent or reverse these adverse effects. GH is currently used for only a small percentage of people with this problem.

• X-linked hypophosphatemic rickets is an inherited disorder of phosphorus metabolism that results in growth failure and rickets, a deficiency disease resulting from a lack of vitamin D or calcium and from insufficient exposure to sunlight, characterized by defective bone growth and occurring chiefly in children. GH has been shown to modestly accelerate growth in patients with this disorder.

• Inflammatory bowel disease (ulcerative colitis and Crohn's disease) can impair growth before producing obvious bowel symptoms. Trials of GH have shown at least modest acceleration of growth.

• Poor growth is a part of Noonan syndrome and many other genetic syndromes. Many short children with various syndromes have been treated with GH. Generally, GH treatment for several years usually produces faster growth and about 1-2 inches (2.5-5 cm) of extra adult height.

• Small numbers of children with various forms of bone dysplasia have been treated with GH with modest increases in short-term height. No long-term studies have demonstrated increased adult height, and dwarfism due to bone dysplasia remains the prime example of extreme shortness considered not very responsive to GH treatment.

• GH has occasionally been used for purposes other than accelerating growth or replacing deficiency. Nearly every hormone available for administration has been given to non-deficient people in hope of obtaining improvement in various conditions for which other treatments are unsatisfactory. With a few exceptions, benefits are modest and side effect risk is higher. Experience with GH has yielded the same results.

• Advanced acquired immunodeficiency syndrome is often accompanied by muscle wasting ("AIDS wasting"). GH may improve muscle loss in these patients.

• GH has also been given to promote healing of large burns, treat fibromyalgia, treat chronic fatigue syndrome, and prevent the effects of aging (diminished muscle strength and bone mass, reduced energy, reduced resilience). However, these uses are often very controversial.

• Effects of growth hormone on the tissues of the body can generally be described as anabolic (building up). Like most other protein hormones, GH acts by interacting with a specific receptor on the surface of cells. Thus, GH has been taken by athletes and muscle builders to increase either strength or bulk. However, the magnitude of both benefits and risks remain not well-established.

Safety

• Most of the complications have been reported in children over 10 years of age or in adults. Though rare, the following harmful side effects have been reported during GH treatment often enough to be assumed noncoincidental. A qualified healthcare provider should be consulted before making decisions about therapies and/or health conditions.

• Slipped capital femoral epiphysis (SCFE) causes hip pain due to separation of the head of the femur from the shaft. Incidence in GH-treated children may be about 1 in 1000. SCFE usually requires casting or surgical pinning to reverse.

• Pseudotumor cerebri (also known as benign intracranial hypertension) is manifested by severe headache, papilledema (swelling and protrusion of the blind spot of the eye), nausea, and visual changes. Incidence is also perhaps 1 in 1000. All known cases have been reversed, usually by temporary discontinuation or reducing the dose of GH.

• Fluid retention and edema in the early months of treatment is rare in children but more common and occasionally more severe in adults. It typically disappears with temporary interruption of treatment.

• Pancreatitis has been reported in a few patients receiving GH, but a causal relationship seemed plausible in only a few cases.

• Joint pain is occasionally experienced by children or adults being treated with GH.

• Carpal tunnel syndrome has also occurred in adults being treated with GH, presumably due to a combination of tissue growth and fluid retention causing pressure on the tightly confined nerves and tendons of the wrists.

• A small but controlled study of GH given to severely ill adults in an intensive care unit setting for the purpose of increasing strength and reducing the muscle wasting of critical illness showed a higher mortality rate for the patients who received GH. The reason is unknown, but GH is now rarely used in ICU patients without severe deficiency.

• GH tends to build bone and muscle mass and reduce body fat, thus altering body composition.

• GH treatment may decrease insulin sensitivity, mainly affecting patients with diabetes.

• When GH is given to children and adults who are not deficient, IGF-1 levels may be raised above normal. Though no effects are obvious, prolonged periods of extremely high IGF-1 levels occur in acromegaly, a chronic disease marked by enlargement of the bones of the head and soft tissue of the hands and feet, due to excessive secretion of GH by the pituitary gland. Additionally, a small amount of evidence suggests that higher IGF-1 levels in older adults (not receiving GH) are associated with a slightly higher risk of certain cancers; a causal relationship has not been established.

• When GH is given to a child in high doses for many years, it can subtly affect the facial bone structure.

• The following serious problems have been linked by one or two small reports but a true risk has not been confirmed by larger surveillance studies:

• Type 2 diabetes has been reported in a few adolescents treated with GH. It is uncertain whether this is a causal association, because the incidence of adolescent type 2 diabetes is rising so rapidly in most countries that we no longer have reliable incidence statistics for diabetes in the untreated adolescent population.

• Leukemia is the most common childhood cancer, occurring in about 1 in 40,000 children each year. Because leukocytes have GH receptors, leukemia cases have been carefully recorded since synthetic GH was introduced. Although a few children with no risk factors treated with GH have developed leukemia, the numbers have been no more than would be expected in a similarly sized group not taking GH. For a variety of reasons, it has been harder to achieve the same level of reassurance for children who do have a higher leukemia risk. These are primarily children who became GH deficient as a result of treatment for leukemia or a brain tumor. Available statistics are reassuring, but numbers are not large enough to exclude any amplification of risk.

• Several cases of colon cancer were found in a study of lifelong health and mortality of a group of middle-aged British adults with severe GH deficiency from childhood. All had been treated as children with cadaver GH. A causal relationship has not been confirmed and even if it were, it would be unclear whether the GH treatment in childhood or the untreated GH deficient state in adult life was associated with the increase incidence of colon cancer.

Author Information

• This information has been edited and peer-reviewed by contributors to the Natural Standard Research Collaboration (www.naturalstandard.com).

Bibliography

Natural Standard developed the above evidence-based information based on a thorough systematic review of the available scientific articles. For comprehensive information about alternative and complementary therapies on the professional level, go to www.naturalstandard.com. Selected references are listed below.

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3. Growth Hormone.19 July 2006. www.nlm.nih.gov

4. Human Growth Foundation. 19 July 2006. www.hgfound.org

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6. SchwenkIi WF, et al. Links Growth hormone therapy-established uses in short children Acta Paediatr Suppl. 2006 Jul;95(452):6-8. View Abstract

7. Simon D, et al. Intermittent Recombinant Growth Hormone Treatment in Short Children Born Small for Gestational Age: Four-Year Results of a Randomized Trial of Two Different Treatment Regimens. Horm Res. 2006 Jun 12;66(3):118-123. View Abstract