Growth hormone therapy

Growth hormone (GH) is a polypeptide hormone secreted by the pituitary gland which stimulates growth and cell reproduction. In the past growth hormone was extracted from human pituitary glands and given to deficient children. GH is now produced synthetically and given to both children and adults for a variety of reasons. GH therapy has been a focus of social and ethical controversies for 50 years.

This article describes the history of GH treatment, current uses, risks, and social controversies arising from GH use. Other articles describe GH physiology, diseases of GH excess (acromegaly and pituitary gigantism), deficiency, the recent phenomenon of HGH quackery, and growth hormone for cows.

Terminology and glossary

Growth hormone (GH) is also called somatropin (British: somatrophin) and somatotropin. The generic name of prescription growth hormone available for therapeutic use is also somatropin. GH can refer either to natural hormone produced by the pituitary, or synthetic GH for therapy.

HGH was the abbreviation used commonly in the 1960s—1980s for human growth hormone, whether measured in the blood or extracted from human pituitary glands for therapeutic use. When synthetic human-sequence GH became the primary GH in 1985, this was seldom used. In the mid-1990’s this older abbreviation began to develop paradoxical connotations. See HGH quackery for a fuller discussion of the origins and changing usages of HGH.

Cadaver growth hormone is the unappetizing term for human GH extracted from human pituitary glands between 1960 and 1985 for therapy of deficient children. In the U.S., cadaver GH is also referred to as NPA growth hormone (National Pituitary Agency).

rhGH currently refers to recombinant DNA human-sequence growth hormone (somatropin). It is a copy of the amino acid sequence of human GH and was for a time referred to as "natural sequence" GH. Since this is the only synthetic GH commercially available for human use today, the rhGH abbreviation is less commonly used.

rhGH was also used occasionally in the early 1980s to refer to rhesus growth hormone (GH extracted from pituitaries of rhesus monkeys). This 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-rhGH or met-GH refers to methionyl-growth hormone. This was the first synthetic GH 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, or cow growth hormone. Posilac is the brand name of Monsanto's rBST.

Treatment of GH deficiency in children

GH deficiency is treated by replacing GH. All GH prescribed in North America, Europe, and most of the rest of the world, is a synthetic copy of human GH, manufactured by recombinant DNA technology. As GH is a large protein 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 discomfort is a subjective value.

When the patient has had a long-standing deficiency of GH, benefits of treatment are often obvious and gratifying and side effects of treatment are rare. See growth hormone deficiency for details of treatment of this condition with GH.

When treated with GH, a deficient child will begin to grow faster within months. Parents may notice other benefits such as increased strength, progress in motor development, and reduction of adipose. There are almost no side effects of this type of physiologic replacement. Rare risks and unsettled issues are discussed below, but GH deficient children receiving replacement doses are at the lowest risk for problems and receive the greatest benefit.

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 quite enthusiastic once the benefits begin to be seen. However, no one except the stockholders of the pharmaceutical companies is enthusiastic at the cost. 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

It has been shown repeatedly in research studies that GH treatment can confer 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.

GH for severe adult deficiency is usually prescribed as three injections per week at a weekly dose about 25% of childrens' doses and comparably lower cost. Despite the demonstrated 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, unacceptibility of injections, inadequate insurance coverage (in the U.S.), and significantly lower rates of diagnosis and treatment offer 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 types of shortness

Many other conditions besides GH deficiency cause poor growth. GH therapy has been shown to improve growth in many of the conditions listed, but growth benefits (height gains) are often poorer than when GH deficiency is treated. Higher ("pharmacologic") doses are typically used, producing blood levels well above physiologic, so that even though side effects are uncommon, these patients are at higher risk.

Other causes of shortness often treated with growth hormone

• Turner syndrome epitomizes the response of non-deficient shortness. At doses up to 50% high than replacement doses, growth accelerates. With several years of treatment the median gain is about 2 inches (5 cm).

• 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 represents a unique combination both encouraging and discouraging GH treatment. Many of the children seem to have at least partial deficiency, so that the adipose reduction and muscle strength benefits are amplified, and these are exactly the two benefits that are specifically helpful in this syndrome. On the other hand, these children are intellectually and socially limited by their condition such that it is difficult to imagine that 2 or 3 more height inches would make any difference to quality of life; furthermore, a handfull of sudden deaths during treatment of older children may end up restricting use to early childhood.

• 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 occure 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 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 3rd percentile. In the late 1990's, the pharmaceutical manufacturer Eli Lilly sponsored trials of Humatrope 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. The controversies revolve around the percentage of these children who were not truly "short" normal children, since the average IGF1 was low. A cynical view might suggest that the company could afford to be extremely restrictive to earn approval, yet be confident that the definition would creep upwards, as there are no specific criteria other than statistical.

A wide variety of other causes of shortness are occasionally treated with growth hormone.

• Chronic glucocorticoid use (in high doses) 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, however, GH cannot completely prevent or reverse them and use of GH for this purpose remains rare.

• Post-transplant growth failure sometimes will improve 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 needed to protect the transplanted organ may continue to interfere with growth. Growth hormone sometimes helps offset these effects and is often 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) often impairs growth even before producing obvious bowel symptoms. Several 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 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 height.

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 at best, and side effect risk is higher. Experience with GH has yielded the same results. The following is not an exhaustive list.

• In children with Prader-Willi syndrome, GH treatment has been shown to improve muscle strength and slightly reduce body fat, benefits more important to these children than increased height. The risk:benefit ratio is currently being reassessed after a small number of deaths related to sleep apnea while children with this syndrome were being treated with growth hormone.

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

• 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 severe calorie restriction for obesity. GH tend to promote lipolysis and reduce proteolysis. The intention was to 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).

• 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. Despite anecdotal reports of improvement, no large, controlled trials have demonstrated significant, persistent improvement and GH is not considered a common or standard treatment for either condition.

• GH has been used to slow or reverse some of the debilities of aging.

• GH has been taken by athletes and muscle builders to increase either strength or bulk.

Risks of GH treatment

Known risks of GH are few and rare. Few reasonable parents or physicians would incur a high risk of harm to a child to add a few inches to height. Most of the complications have been reported in children over 10 years of age or in adults. Children who are not truly GH deficient and are therefore being treated with higher doses seem more likely to suffer side effects.

Though rare, the following harmful side effects have been reported during GH treatment often enough to assume some sort of noncoincidental association.

• 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 headaches. Incidence is also perhaps 1 in 1000. All cases have been reversed by temporary discontinuation of the GH.

• Fluid retention in early months of treatment is rare and mild 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 couple of instances.

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

• 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 moderately higher mortality rate for the patients who received GH. The mechanism is unknown, but GH is now rarely used in ICU patients without severe deficiency.

The following effects are common, but of questionable harm.

• Altered body composition refers to the tendency of GH to build bone and muscle at the cost of 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 a combination of factors which would make this a more significant effect.

• When GH is given to children and adults who are not deficient, the IGF1 levels may be raised above normal. The only reasons for concern are that 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. The difficulty in determining whether it is a causal association is that 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 in in 40,000 children each year. Because leukocytes have GH receptors, leukemia has been carefully watched for 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. 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 are became GH deficient as a result of treatment for leukemia or a brain tumor. The 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. As children all had been treated for several years with cadaver GH but few had received GH as adults. 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.

Finally, in any discussion of side effects, our experience with Jacob-Creutzfeldt disease 20 years after cadaver GH treatment should remind us that unforeseen or long-delayed side effects may be unforeseeable and long-delayed.

Ethical issues

• Is GH a wise use of finite health care resources? Does a physician have a responsibility to society to decline to spend US$ 100 000 or more to make an otherwise healthy child a few inches taller?
• Or is the physician’s primary responsibility to the patient? If the family thinks GH treatment is worth the cost and trouble (especially if insurance or the government pays), and the treatment is safe, does the physician have the standing to forbid it?
• whose values govern treatment: family, physician, others (paternalism)
• If GH is given to short children whose parents can afford it, will shortness become a permanent mark of lower social origins, like crooked teeth?
• If we treat to protect from heightism, is that like lightening skin to protect from racism?
• If the treatment has the same benefit, is a deficient child as deserving as a non-deficient child? Is the dx morally relevant?
• to what extent is iss a medical condition worthy of treatment
• what is the diffeerence between enhancement and therapy
• gh rx of handicapped children
• Do we define gh defic as response to gh
• how do we measure qol harm: being short is so bad well give you shots for it

oregon criteria ranks hypopit & TS in cutoff but not otehr conditions what is proper endpoint of rx: genetic potential, finishing growth, or arbitrary minimalcutoff What do we know about qol improvement from treatment Registries & professional closeness to industry Are some causes of shortness more deserving Baby Doe Does cost change ethics of treatment? Cf T for delay

Lifelong responsibility after a trial Government role in vaccines like gh Ethics of body part use http://www.gghjournal.com/pdf/volume_16/16-1/ethical.pdf

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 Tom Thumb, and married Lavinia Warren. Pictures of the couple appear to show the typical adult features of untreated severe growth hormone deficiency. Despite the severe shortness, limbs and trunk are proportional.

Like many other 19th 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 a medical context.

By the middle of the twentieth century endocrinologists understood the clinical features of 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 1920's. However pig and cow GH did not work as well in humans, due to greater species-to-species variation of molecular structure (i.e., insulin is considered more "evolutionarily conserved" than GH).

In the late 1950’s Maurice Raben purified enough GH from collected human pituitary glands to successfully treat a GH-deficient boy. Over the next few years, endocrinologists began to encourage parents of severely GH deficient children to collect human pituitary glands (after removal at autopsy) from local pathologists. Parents would then contract with a biochemist to purify enough growth hormone to treat their child. This was an arduous and complicated undertaking that few families could manage.

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 when autopsies were performed, arrange for large scale extraction and purification of GH, and distribute it to a limited number of pediatric endocrinologists for treating GH-deficient children under research protocols. Canada, U.K., Australia, New Zealand, France, Israel, and other countries establish similar government-sponsored agencies to collect pituitaries, purify GH, and distribute it for treatment of severely GH deficient children.

Supplies of this “cadaver growth hormone” were limited and only the most severely deficient children were treated. From 1963 to 1985 about 7700 children in the U.S. and 27,000 children worldwide were given GH extracted from human pituitary glands to treat severe GH deficiency. Physicians trained in the relatively new specialty of pediatric endocrinology provided most of this care, but in the late 1960’s there were only a hundred of these physicians in a few dozen of the largest university medical centers around the world.

In 1976 physicians became aware that Creutzfeldt-Jacob disease could be transmitted by neurosurgical procedures and cornea transplantation. CJD is a rapidly fatal dementing disease of the brain also known as spongiform encephalopathy, a form of “mad cow disease”.

In 1977 the NPA GH extraction and purification procedure was refined and improved.

The 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. Often treatment would be stopped when a child reached an arbitrary minimal height, such as 5 feet (152 cm). Children who were short for reasons other than severe GH deficiency were told that they would not benefit from treatment. Only those pediatric endocrinologists who remained at university medical centers with departments able to support a research program had access to NPA growth hormone.

In the late 1970’s a Swedish pharmaceutical company, Kabi, contracted with a number of hospitals in Europe to buy pituitary glands for the first commercial GH product, Crescormon. Although an additional source of GH was welcomed, Crescormon was greeted with ambivalence by pediatric endocrinologists in the United States. The first concern was that Kabi would begin to purchase pituitaries in the U.S., which would quickly undermine the NPA, which relied on a donation system like blood transfusion. As the number of autopsies continued to shrink, would pathologists sell pituitaries to a higher bidder? The second offense was Kabi-Pharmacia’s marketing campaign, which was directed at primary care physicians under the slogan, “Now, you determine the need,” implying that the services of a specialist were not needed for growth hormone treatment anymore and that any short child might be a candidate for treatment. Although the Crescormon controversy in the U.S. is long forgotten, Kabi’s pituitary purchase program continued to generate scandal in Europe as recently as 2000.

In 1981, the new American corporation Genentech, after collaboration with Kabi, developed and started trials of synthetic human growth hormone made by a new technology (recombinant DNA) in which human genes were inserted into bacteria so that huge vats of bacteria could produce unlimited amounts of the protein. Because this was new technology, lengthy safety trials continued over the next 4 years, delaying approval.

In 1985 four young adults in the U.S. who had received NPA growth hormone in the 1960’s developed CJD. The connection was recognized within a few months and use of human pituitary GH rapidly ceased. Between 1985 and 2003, a total of 26 cases of CJD occurred in adults who had received NPA GH before 1977 (out of 7700). Comparable numbers of cases occurred around the world. Nevertheless, by 2003 there had been no cases in people who received only GH purified by the improved 1977 methods.

Discontinuation of human cadaver growth hormone led to rapid Food and Drug Administration approval of Genentech’s synthetic methionyl growth hormone, which was introduced in 1985 as Protropin in the United States. Although this previously scarce commodity was suddenly available in “bucketfuls,” the price of treatment (US$ 10,000 to 30,000 per year) was uniquely astronomical at the time. Genentech justified it by the prolonged research and development investment, orphan drug status, and a pioneering post-marketing surveillance registry for tracking safety and effectiveness.

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, and Serono marketed nearly identical synthetic human growth hormone products and competed with dozens of different marketing strategies-- except cutting price. Most children with severe deficiency in the western 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 1950’s, but did not reach board status in the U.S. until the late 1970’s. Even 10 years later, as a cognitive, procedureless specialty dealing with mostly rare diseases, it was still 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 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” will simply rise, negating the social benefit?
• If GH is given to short children whose parents can afford it, will shortness become a permanent mark of lower social origins, like crooked teeth?

More of these issues are outlined in the ethics section. Whole meetings were devoted to these questions and for the first time, pediatric endocrinology was a specialty with its own bioethics issues.

Despite the price, the 1990’s 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 growth hormone companies 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. Parallel expansion of use occurred in Europe.

One obvious potential market was adult GH deficiency. By the mid-1990’s, 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. Nearly all of them had been happy to leave the injections behind as they reached final heights in the low normal range. However as adults in their 30’s and 40’s, these people 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, as outlined above, despite marketing efforts, most GH deficient adults remain untreated.

HGH

ISS

As of 2004, synthetic growth hormones available in the U.S. (and their manufacturers) 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.

External links

• Human Growth Foundation

http://www.gghjournal.com/pdf/volume_14/14-1/14_1_related_ab2.pdf gen gh use support groups: http://www.gghjournal.com/pdf/volume_7/3/feature_3.pdf

''This article is in process of expansion