Growth Hormone Treatment

Growth hormone (GH) is a peptide hormone secreted by the pituitary gland that stimulates growth and cell reproduction. In the past growth hormone was extracted from human pituitary glands. GH is now produced by recombinant DNA technology and is prescribed for a variety of reasons. GH therapy has been a focus of social and ethical controversies for 50 years.

Terminology and glossary

Growth hormone (GH l) is also called somatotropin (British: somatotrophin). The human form of growth hormone is known as human growth hormone, or hGH (similarly ovine growth hormone, or sheep growth hormone, is abbreviated oGH). GH can refer either to the natural hormone produced by the pituitary (somatotropin), or biosynthetic GH for therapy.

Cadaver growth hormone is the term for GH extracted from human pituitary glands between 1960 and 1985 for therapy of deficient children. In the U.S., cadaver GH, also referred to as NPA growth hormone, was provided by the National Pituitary Agency, and by other national programs and commercial firms as well. In 1985 it was associated with the development of Creutzfeldt-Jakob Disease, and was withdrawn from use.

rhGH refers to recombinant human growth hormone (somatropin). It contains the identical amino acid sequence of human GH and is "natural sequence" GH. It is chemically identical to the growth hormone produced by the pituitary gland. A long-acting somatropin was previously available, but has recently (March 2007) been put on hold by the FDA. Human growth hormone is currently available through multiple pharmaceutical companies in the US.

Coincidentally, rhGH also refers to rhesus monkey GH, using the accepted naming convention. Rhesus growth hormone was never used by physicians to treat human patients, but rhesus GH was part of the lore of the underground anabolic steroid community in those years and fraudulent versions may have been bought and sold in gyms.

met-GH refers to methionyl-growth hormone. This 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.

rBST refers to recombinant bovine somatropin (cow growth hormone), or more properly, recombinant bovine GH (rbGH).

Treatment of GH deficiency in children

Growth hormone deficiency is treated by replacing GH. All GH prescribed in North America, Europe, and most of the rest of the world is a human GH, manufactured by recombinant DNA technology. As GH is a large peptide molecule, it must be injected into subcutaneous tissue or muscle to get it into the blood. Nearly painless insulin syringes make this less trying than is usually anticipated but perceived discomfort is a subjective value.

When a person has had a long-standing deficiency of GH, benefits of treatment are often obvious, and side effects of treatment are rare. When treated with GH, a deficient child will begin to grow faster within months. Other benefits may be noticed, such as increased strength, progress in motor development, and reduction of body fat. Side effects of this type of physiologic replacement are quite rare. Known risks and unsettled issues are discussed below, but GH deficient children receiving replacement doses are at the lowest risk for problems.

Still, costs of treatment in terms of money, effort, and perhaps quality of life, are substantial. Treatment of children usually involves daily injections of growth hormone, usually for as long as the child is growing. Lifelong continuation may be recommended for those most severely deficient as adults. Most pediatric endocrinologists monitor growth and adjust dose every 3–4 months. Assessing the psychological value of treatment is difficult but most children and families are enthusiastic once the physical benefits begin to be seen. Treatment costs vary by country and by size of child, but $US 10,000 to 30,000 a year is common.

Little except the cost of treating severely deficient children is controversial, and most children with severe growth hormone deficiency in the developed world are offered treatment. Most accept. The story is very different for adult deficiency.

Treatment of adult GH deficiency

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 at the expense of adipose tissue. Blood lipid levels improve, but long term mortality benefit has not yet been demonstrated. Treatment of healthy, normally aging individuals found the only benefit to be a slight increase in muscle mass, with frequent side-effects and no evidence that it is safe to use long-term.

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

Other GH uses and treatment indications

In the last two decades, GH has also been increasingly used for children and adults who are not severely deficient, either to enhance growth or for other reasons.

GH treatment for other conditions

Many conditions besides GH deficiency cause poor growth. GH therapy has been shown to improve short-term growth in many conditions, but long-term height gains are usually poorer than those achieved when GH deficiency is the cause of shortness. Higher ("pharmacologic") doses are typically required to achieve efficacy; side effects are uncommon and vary according to the condition being treated.

As of 2004, GH has been approved by the U.S. Food and Drug Administration for treatment of five other conditions that may involve short stature:

• Turner syndrome epitomizes the response of non-deficient shortness. At doses 20% higher than those used in GH deficiency, growth accelerates. With several years of treatment the median gain in adult height is about 2-3 inches (5-7.5 cm) on this dose. The gains appear to be dose-dependent.. It has been used successfully in toddlers with Turner syndrome, as well as in older girls.
• Chronic renal failure results in many problems, including growth failure. GH treatment for several years both before and after transplantation may prevent further deceleration of growth and may narrow the height deficit, though even with treatment net adult height loss may be about 4 inches (10 cm).
• Prader-Willi syndrome, a generally non-hereditary genetic condition, is a case where GH is prescribed for benefits in addition to height. GH is now standard care for children with PWS in the United States, when prescribed with appropriate precautions by an experienced endocrinologist. GH can help children with PWS in height, weight, body mass, strength, and agility.. Reports have indicated increase of growth rate (especially in the first year of treatment) and a variety of other positive effects, including improved body composition (higher muscle mass, lower fat mass); improved weight management; increased energy and physical activity; improved strength, agility, and endurance; and improved respiratory function. The Prader-Willi Syndrome Association (USA) recommends that a sleep study be conducted before initiating GH treatment in a child with PWS. At this time there is no direct evidence of a causative link between growth hormone and the respiratory problems seen in PWS (among both those receiving and those not receiving GH treatment), including sudden death. A follow-up sleep study after one year of GH treatment may also be indicated. GH (specifically Pfizer's version, Genotropin) is the only treatment that has received an FDA indication for children with PWS. The FDA indication only applies to children.
• Children 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 their heights remain below the third percentile by 2 or 3 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 are 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 3rd 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, those at least 2.25 standard deviations below mean (in the lowest 1.2 percent 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 4 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 IGF1 was low. Not surprisingly, approval for this extreme degree of shortness led to an increase in the number of parents seeking treatment to make otherwise healthy children a little taller.

A variety of other causes of shortness is occasionally treated with growth hormone off-label.

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 sometimes offered in these circumstances.

X-linked hypophosphatemic rickets is an inherited disorder of phosphorus metabolism that results in growth failure and rickets. GH has been shown to accelerate growth modestly.

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, but it is unknown if this actually leads to an increased adult height..

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

Small numbers of children with various forms of bone dysplasia (dwarfism in common parlance) have been treated with GH with modest increases in short-term height velocity. 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 amenable to GH treatment.

Coeliac Disease can prevent children from reaching their expected growth potential, if it begins before growth is complete. Stunted growth can be a result of Coeliac Disease damaging the intestines and preventing proper nutrient absorption. Treatment involves a gluten free diet. HGH treatment has been used in an attempt to recover lost growth due to this effect.

GH treatment for other benefits beyond height

GH has occasionally been used for other purposes than accelerating growth or replacing deficiency. Nearly every hormone available for administration has been given to non-deficient people in hope of obtaining improvement for 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. The following is not an exhaustive list.

Advanced acquired immunodeficiency syndrome (AIDS) is often accompanied by muscle wasting ("AIDS wasting"). GH has been shown to ameliorate this condition.

GH has been given to promote healing of large burns by reducing the amount of protein breakdown during the early post-injury period.

GH has been used as an adjunct to caloric restriction for obesity. GH promotes lipolysis and reduces proteolysis. It was hoped that GH would reduce muscle breakdown without interfering with use and reduction of fat as the body shifted to a near-starvation economy. Results showed benefit, but this has not been widely adopted for a variety of reasons (cost, injections, potential aggravation of insulin resistance, etc). Recent studies suggest that side-effects, particularly insulin resistance, may outweigh the potential benefits of such therapy.

Fibromyalgia and chronic fatigue syndrome are poorly understood and vaguely defined conditions with overlapping features. After demonstration of disorderd GH secretion and higher rates of tissue breakdown in patients with these conditions, a few people tried growth hormone treatment to see if energy or healing could be improved. Disturbances of GH secretion may be secondary phenomena and not causal. Despite anecdotal reports of improvement, no large, controlled trials have demonstrated significant, persistent improvement and GH is not a common or standard treatment for either condition.

GH has been used to slow or reverse some of the debilities of aging based on the following observations: (1) as adults get older, production and levels of GH and IGF1 decline, and (2) many of the effects of aging (diminished muscle strength and bone mass, reduced energy, reduced resilience) also occur with adult growth hormone deficiency and are improved with GH treatment. See HGH controversies for more on GH use to delay aging.

GH has been taken by athletes and to increase recovery, strength and power. Rumors of surreptitious athletic use date back to the days of cadaver GH. Since GH is a protein hormone, it is not detected by assays that screen for steroids and similar drugs—the primary laboratory clue would be elevated IGF1 levels. However, despite decades of rumors and presumably some amount of black market or surreptitious use, the magnitudes of both benefits and risks remain unestablished. See HGH controversies for more.

Risks of GH treatment

Known risks of GH are few and rare. 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.

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, nausea, and visual changes. Incidence is also perhaps 1 in 1000. All cases have been reversed, usually by temporary discontinuation or reduced dose of the GH.

Fluid retention and edema in 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 unlikely but possible.

Joint pains are 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 unless they have severe growth hormone deficiency. The following effects are common, but of questionable harm.

Altered body composition refers to the tendency of GH to build bone and muscle mass and reduce body fat.

GH treatment usually decreases insulin sensitivity. This effect does not seem to cause problems in most people but it is possible to envision factors which would make this an undesirable effect, such as obesity or pre-existing diabetes.

When GH is given to children and adults who are not deficient, IGF1 levels may be raised above normal. Though no effects are obvious, prolonged periods of extremely high IGF1 levels occur in acromegaly, and a small amount of evidence suggests that higher IGF1 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. It rarely is recognized as a change by patients and parents and even less often causes problems.

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's 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 counted since recombinant 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. 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 extra 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. This association has not been confirmed and even if it were, it would need to be established whether the GH treatment in childhood or the untreated GH deficient state in adult life represented the true association. Both obesity and elevated levels of IGF-1 have been associated with colon cancer.

Finally, in any discussion of side effects, our experience with Creutzfeldt-Jacob disease 20 years after cadaver GH treatment reminds us that side effects of an apparently safe treatment may be unforeseeable and long-delayed.