Growth hormone therapy

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.

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 adult deficiency or for diseases as in exmple osteoporosis, AIDS, erectile disfunction, dementia, baldness, severe burns. 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.

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.

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

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 and IGF/I are life long important and they have 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.

GH increases bone mass, therefore is very efficient to cure osteoporosis.

GH decreases fat mass, therefore can be used as obesity treatment.

GH decreases ldlcolesterol and increases hdlcolesterol, therefore can be used against cardio/vascular diseases.

GH can also be useful against heart failure.

GH decreases SHBG levels and therefore increases free testosterone levels, for this reason GH treatment can reduce hypogonadism and erectile disfunction.

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

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 a child in overdoses 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.

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.

History

Perhaps the most famous person who exemplified the appearance of untreated congenital growth hormone deficiency was Charles Sherwood Stratton (1838-1883), who was exhibited by P.T. Barnum as General Tom Thumb, and married Lavinia Warren. Pictures of the couple show the typical adult features of untreated severe growth hormone deficiency. Despite the severe shortness, limbs and trunks are proportional.

Like many other nineteenth century medical terms which lost precise meaning as they gained wider currency, “midget” as a term for someone with extreme proportional shortness acquired pejorative connotations and is no longer used in medical contexts.

By the middle of the twentieth century endocrinologists understood the clinical features of growth hormone deficiency. GH is a protein hormone, like insulin.

Recombinant human growth hormone (rhGH)

Until 1981 GH was extracted from pituitary glands, In 1981, the new American corporation Genentech, after collaboration with Kabi, developed and started trials of recombinant human growth hormone (rhGH) made by a new technology (recombinant DNA) in which human genes were inserted into bacteria so that they could produce unlimited amounts of the protein. Because this was new technology, approval was deferred as lengthy safety trials continued over the next four years.

Within a few years, GH treatment had become “big business” in more than one sense. In the United States, Eli Lilly launched a competing natural sequence growth hormone, and in Europe, Pharmacia (formerly Kabi, now Pfizer), Novo Nordisk, and Serono marketed nearly identical recombinant human growth hormone products and competed with dozens of different marketing strategies (but without cutting price). Most children with severe deficiency in the developed world are now likely to have access to a pediatric endocrinologist and be diagnosed and offered treatment.

Pediatric endocrinology became a recognizable specialty in the 1950s, but did not reach board status in the U.S. until the late 1970s. Even 10 years later, as a cognitive, procedureless specialty dealing with mostly rare diseases, it was one of the smallest, lowest paid, and more obscure of the medical specialities. Pediatric endocrinologists were the only physicians interested in the arcana of GH metabolism and children’s growth, but their previously academic arguments took on new practical significance with major financial implications.

The major scientific arguments dated back to the days of GH scarcity:

• Everyone agrees on the nature and diagnosis of severe GH deficiency, but what are the edges and variations?
• How should marked constitutional delay be distinguished from partial GH deficiency?
• To what extent is “normal shortness” a matter of short children naturally making less growth hormone?
• Can a child make GH in response to a stimulation test but fail to make enough in “daily life” to grow normally?
• If a stimulation test is used to define deficiency, what GH cutoff should be used to define normal?

It was the ethical questions that were new. Is GH not a wise use of finite health care resources, or is the physician’s primary responsibility to the patient? If GH is given to most extremely short children to make them taller, will the definition of “extremely short” simply rise, negating the expected social benefit? If GH is given to short children whose parents can afford it, will shortness become a permanent mark of lower social origins? More of these issues are outlined in the ethics section. Whole meetings were devoted to these questions; pediatric endocrinology had become a specialty with its own bioethics issues.

Despite the price, the 1990s became an era of experimentation to see what else growth hormone could help. The medical literature of the decade contains hundreds of reports of small trials of GH use in nearly every type of growth failure and shortness imaginable. In most cases the growth responses were modest. For conditions with a large enough potential market, more rigorous trials were sponsored by pharmaceutical companies which making growth hormone to achieve approval to market for those specific indications. Turner syndrome and chronic renal failure were the first of these “non GH deficient causes of shortness” to receive FDA approval for GH treatment, and Prader-Willi syndrome and intrauterine growth retardation followed. Similar expansion of use occurred in Europe.

One obvious potential market was adult GH deficiency. By the mid-1990s, several GH companies had sponsored or publicized research into the quality of life of adults with severe GH deficiency. Most were people who had been treated with GH in childhood for severe deficiency. Although the injections are painless, many of them had been happy to leave injections behind as they reached final heights in the low normal range. However as adults in their 30s and 40s, these people who had been children with growth hormone deficiency were now adults with growth hormone deficiency and had more than their share of common adult problems: reduced physical, mental, and social energy, excess adipose and diminished muscle, diminished libido, poor bone density, higher cholesterol levels, and higher rates of cardiovascular disease. Research trials soon confirmed that a few months of GH could improve nearly all of these parameters. However, despite marketing efforts, most GH deficient adults remain untreated.

Though GH use was slow to be accepted among adults with GH deficiency, similar research to see if GH treatment could slow or reverse some of the similar effects of aging attracted much public interest. The most publicized trial was reported by Daniel Rudman in 1990. As with other types of hormone supplementation for aging (testosterone, estrogen, DHEA), confirmation of benefit and accurate understanding of risks has been only slowly evolving. There are always entrepreneurs who don't need much evidence to see a business opportunity. In 1997, Ronald Klatz of the American Academy of Anti-Aging Medicine published Grow Young With HGH: The Amazing Medically Proven Plan To Reverse the Effects Of Aging , an uncritical touting of GH as the answer to aging. This time the internet amplified the proposition and spawned a hundred frauds and scams. Fortunately, their adoption of the "HGH" term has provided an easy way to distinguish the hype from the evidence. For more, see HGH controversies.

In 2003, growth hormone hit the news again, when the US FDA granted Eli Lilly approval to market Humatrope for the treatment of idiopathic short stature. The indication was controversial for several reasons, the primary one being the difficulty in defining extreme shortness with normal test results as a disease rather than the extreme end of the normal height range; in fact, the definition offered by Lilly for ISS is a height in the shortest 1.2% of the population. While this is an extreme degree of shortness, critics suggested that the company could afford to be extremely restrictive to earn approval, yet be confident that the definition, as well as actual use, would be driven upward by parents and physicians. Meanwhile, pediatric endocrinologists are still arguing about whether ISS is a "pathologic" or a statistical condition.

As of 2004, GH use continues to rise, though it is no longer the most expensive prescription drug in the formulary. Recombinant growth hormone available in the U.S. (and their manufacturers) included Nutropin (Genentech), Humatrope (Eli Lilly and Company), Genotropin (Pfizer), Norditropin (Novo Nordisk), Tev-Tropin (Teva) and Saizen (Merck Serono). The products are nearly identical in composition, efficacy, and cost, varying primarily in the formulations and delivery devices.

Support organizations

• The Most Frequently Asked Questions when Beginning GH Treatment-The MAGIC Foundation for Children's Growth
• [1] Prader-Willi Syndrome Association (USA)

External links

• Human Growth Foundation
• Growth Section of The Hormone Foundation
• Magic Foundation for Children's Growth
• Other support groups
• Prader-Willi Syndrome Association (USA)
• General overview of GH use for physicians
• National Organization of Short Statured Adults
• Short Persons Support