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Date Posted: 09:31:48 12/12/05 Mon
Author: Colonel Angus
Subject:

Growth Hormone (GH)
In reply to: Colonel Angus 's message, "Deuterium Oxide and Mitosis (Heavy Water)" on 09:26:07 12/12/05 Mon

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

HGH is an abbreviation sometimes used for counterfeit or fake "growth hormone" products. See HGH quackery for a fuller discussion of the origins and changing usages of HGH.

Cadaver growth hormone is the unappetizing term for 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). In 1985 it was associated with the development of Creutzfeldt-Jakob Disease, and was withdrawn from use.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 was for a time referred to as "natural sequence" GH. It is the only synthetic GH commercially available for human use today.

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 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 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. Parents may notice other benefits 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 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 enthusiastic once the physical 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

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.

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 young adults to seek medical care, unacceptability of injections, inadequate insurance coverage (in the U.S.), and significantly lower rates of diagnosis and treatment offer by internist endocrinologists.

See growth hormone deficiency for further details of treatment for this specific condition.

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 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 types of 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.

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 have at least partial deficiency, so that the adipose reduction and muscle strength benefits are amplified. These two benefits 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 much difference to quality of life. Furthermore, a handful of sudden deaths during treatment of older children has raised questions about safety and an official warning.

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 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 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. 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 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) 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. 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.

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 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 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).

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 quackery for more on GH use to retard aging.

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

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. 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 plausible in only a couple.

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 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 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 a combination of factors which would make this a more significant effect.

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 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 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. 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.

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.

Ethical issues

Hormone treatment seems an unlikely source of social controversy, but for four decades, growth hormone has been second only to estrogens and progestins (diethylstilbestrol, contraception, abortifacients, and post-menopausal replacement) in its ability to engender challenging ethical issues. The principal controversies of the last two decades arise from the intersection of two factors: high cost and the difficulty of defining a boundary between disease and variation of normal. In other words, if GH were inexpensive, it would be no more controversial than orthodontics. If there were zero potential benefit to all but the most easily defined, severely deficient persons, GH would be one more expensive treatment for a rare disease. But neither condition is true.

Growth hormone is one of the most expensive treatments in all of medicine. The cost of adult GH replacement for deficiency (or for “aging”) is about US$2000 per year, or about US$20,000 per decade. The cost of treatment for a non-deficient child (e.g., with Turner syndrome or idiopathic short stature) is about US$25,000 per year. A typical treatment course of 5 years yielding about 2 inches (5 cm) of extra adult height would cost approximately US$125,000. The highest cost, for treatment from infancy to age 70 of severe, congenital GH deficiency, could exceed US$300,000.

The high cost has been a subject of criticism of the pharmaceutical companies. A high cost was originally justified by the new technology and unusually extensive clinical trials. Orphan drug status in the United States (which blocks competing products for several years) was granted to the first two recombinant products (Genentech's Protropin and Lilly's Humatrope) introduced in the mid-1980s. Continuing production costs have been much lower than the drug price. When orphan drug status expired in the early 1990s it was hoped that introduction of additional brands into the market would result in a lower price. Instead, the 5 major companies offering synthetic GH have competed on other grounds than price. While the dollar price has not been increased to keep up with inflation over 2 decades, it hasn't been reduced as net manufacturing costs have fallen. Despite a similar manufacturing process, pricing of synthetic GH for use in cattle (see Bovine somatotropin), turkeys, and chickens is inexpensive compared to the human product since the price is constrained by market prices for the meat and milk products enhanced by the animal GH.

Assessing the value of treatment to balance against the cost is made difficult by the range of severity of conditions treated and the difficulty of cleanly distinguishing disease from human variability. The most expensive treatment cost cited above for lifetime replacement of severe deficiency purchases for that person a 12"; (30 cm) height difference, enough to prevent shortness severe enough to be a physical handicap, enhanced marriage and employment prospects (compared with those under 56”). It also enhances bone and muscle strength, and perhaps even psychological resilience. It can prevent obesity, and may even prolong employability and life span. These are substantial benefits in return for the high cost, but less than 1 in 5000 children is born with this type of severe deficiency. At the other extreme is a child whose only diagnosable disease is a height in the lowest 2% of the population, who may gain 1 inch from 2 years of treatment. In between these extremes is a continuum of more or less severe shortness, greater or lesser response to treatment, and greater or smaller abnormalities to testing.

Questions and dilemmas arise from the previous facts.

Is GH a wise use of finite health care resources? Is there anything wrong with an insurer or government health program declining to spend US$ 100 000 or more to make an otherwise healthy child a few inches taller?

A physician usually assumes the responsibility of advocating for a patient to get coverage for a treatment. If the family of a normal but slightly short child thinks GH treatment is worth the cost and trouble, does the physician have a duty to support it? If the physician declines, is she being “paternalistic” rather than “respecting the patient’s autonomy”.

If the cost of GH drops, and is given to short children whose parents can afford it, will shortness become a lifelong mark of lower social origins, like crooked teeth?

If we treat a child to protect him from the disadvantages of social heightism, is that like lightening skin or straightening hair to protect from racism?

If two children of the same height might gain the same benefit from treatment, is the reason for the shortness (diagnosis) an ethically relevant consideration? Does the child who tests more abnormally have a better claim to treatment?

Is “idiopathic short stature” a medical condition worthy of treatment if it is defined simply as the shortest 1% of the population? Would it make a difference if many or most of this lowest 1% could be shown to have a defect of IGF1 production or responsiveness? If ISS were defined as the shortest 3%, 5%...?

What is the difference between enhancement and therapy?

Should mentally handicapped children be as eligible for GH treatment as those with more “normal” social prospects? Are parents the best judges of potential benefits?

See Synopsis of symposium on ethical aspects of GH treatment.

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 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 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, 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 human pituitary glands to successfully treat a GH-deficient boy. A few endocrinologists began to help parents of severely GH deficient children to make arrangements with local pathologists to collect human pituitary glands after removal at autopsy. Parents would then contract with a biochemist to purify enough growth hormone to treat their child. Few families could manage such a complicated undertaking.

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, related to “mad cow disease”.

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

A shortage of available cadaver GH worsened in the late 1970’s as the autopsy rate in the U.S. declined, while the number of pediatric endocrinologists able to diagnose and treat GH deficiency increased. GH was "rationed." 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, approval was deferred as lengthy safety trials continued over the next 4 years.

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. Fortunately, 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 (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 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 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 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 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. Similar 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, despite marketing efforts, most GH deficient adults remain untreated.

Ironically, 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 (Rudman D, Feller AG, Nagraj HS et al; Effect of human growth hormone in men over 60 years old; New Engl J Med 323:1-6). 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. Use of GH for effects of aging is discussed in more detail in HGH quackery.

There are always entrepreneurs who don't need much evidence to see a business opportunity. In 1997, Ronald Klatz published Grow Young With HGH: The Amazing Medically Proven Plan To Reverse the Effects Of Aging (New York:Harper-Collins), 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 quackery.

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. 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.

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Winstrol -- Colonel Angus, 09:34:24 12/12/05 Mon

Stanozolol, sold under the name Winstrol, was developed by Winthrop Laboratories in 1962. It is a synthetic anabolic steroid derived from testosterone, and has been approved by the FDA for human use.

Unlike most injectable anabolic steroids, Stanozolol is not esterified and is sold as an aqueous suspension. The drug has a large oral bioavailability, due to a C17 á-alkylation which allows the hormone to survive first pass liver metabolism when ingested. Because of this, Stanozolol is also sold in tablet form

Stanozolol has been used on both animal and human patients for a number of conditions. In humans, it has been demonstrated to be successful in treating anaemia and hereditary angioedema. Veterinarians may prescribe the drug to improve muscle growth, red blood cell production, increase bone density and stimulate the appetite of debilitated or weakened animals. It is also illegally used in bodybuilding, typically "stacked" with other testosterone-based anabolic steroids.

The drug has been known to cause masculinising side-effects in women with doses as low as 2 mg per day, and liver damage has been known to occur with extended usage of larger doses.

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>Growth hormone (GH) is a protein 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 somatotropin >(British: somatotrophin). The human form of growth >hormone is known as human growth hormone, or hGH >(similarly ovine growth hormone is abbreviated oGH). >GH can refer either to the natural hormone produced by >the pituitary (somatotropin), or biosynthetic GH for >therapy (somatropin). > >HGH is an abbreviation sometimes used for counterfeit >or fake "growth hormone" products. See HGH quackery >for a fuller discussion of the origins and changing >usages of HGH. > >Cadaver growth hormone is the unappetizing term for 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). 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 was for a time referred to as >"natural sequence" GH. It is the only synthetic GH >commercially available for human use today. > >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 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 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. Parents may notice other benefits 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 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 enthusiastic once the >physical 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 > >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. > >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 young adults to seek medical >care, unacceptability of injections, inadequate >insurance coverage (in the U.S.), and significantly >lower rates of diagnosis and treatment offer by >internist endocrinologists. > >See growth hormone deficiency for further details of >treatment for this specific condition. > >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 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 types >of 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. > >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 have at least partial deficiency, so >that the adipose reduction and muscle strength >benefits are amplified. These two benefits 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 >much difference to quality of life. Furthermore, a >handful of sudden deaths during treatment of older >children has raised questions about safety and an >official warning. > >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 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 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. 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 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) 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. 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. > >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 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 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). > >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 quackery for more on GH use >to retard aging. > >GH has been taken by athletes and muscle builders to >increase either strength or bulk. 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 quackery for more. > >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. 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 >plausible in only a couple. > >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 >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 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 a combination of >factors which would make this a more significant >effect. > >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 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 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. 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. > >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. > >Ethical issues > >Hormone treatment seems an unlikely source of social >controversy, but for four decades, growth hormone has >been second only to estrogens and progestins >(diethylstilbestrol, contraception, abortifacients, >and post-menopausal replacement) in its ability to >engender challenging ethical issues. The principal >controversies of the last two decades arise from the >intersection of two factors: high cost and the >difficulty of defining a boundary between disease and >variation of normal. In other words, if GH were >inexpensive, it would be no more controversial than >orthodontics. If there were zero potential benefit to >all but the most easily defined, severely deficient >persons, GH would be one more expensive treatment for >a rare disease. But neither condition is true. > >Growth hormone is one of the most expensive treatments >in all of medicine. The cost of adult GH replacement >for deficiency (or for “aging”) is about US$2000 per >year, or about US$20,000 per decade. The cost of >treatment for a non-deficient child (e.g., with Turner >syndrome or idiopathic short stature) is about >US$25,000 per year. A typical treatment course of 5 >years yielding about 2 inches (5 cm) of extra adult >height would cost approximately US$125,000. The >highest cost, for treatment from infancy to age 70 of >severe, congenital GH deficiency, could exceed >US$300,000. > >The high cost has been a subject of criticism of the >pharmaceutical companies. A high cost was originally >justified by the new technology and unusually >extensive clinical trials. Orphan drug status in the >United States (which blocks competing products for >several years) was granted to the first two >recombinant products (Genentech's Protropin and >Lilly's Humatrope) introduced in the mid-1980s. >Continuing production costs have been much lower than >the drug price. When orphan drug status expired in the >early 1990s it was hoped that introduction of >additional brands into the market would result in a >lower price. Instead, the 5 major companies offering >synthetic GH have competed on other grounds than >price. While the dollar price has not been increased >to keep up with inflation over 2 decades, it hasn't >been reduced as net manufacturing costs have fallen. >Despite a similar manufacturing process, pricing of >synthetic GH for use in cattle (see Bovine >somatotropin), turkeys, and chickens is inexpensive >compared to the human product since the price is >constrained by market prices for the meat and milk >products enhanced by the animal GH. > >Assessing the value of treatment to balance against >the cost is made difficult by the range of severity of >conditions treated and the difficulty of cleanly >distinguishing disease from human variability. The >most expensive treatment cost cited above for lifetime >replacement of severe deficiency purchases for that >person a 12"; (30 cm) height difference, enough to >prevent shortness severe enough to be a physical >handicap, enhanced marriage and employment prospects >(compared with those under 56”). It also enhances bone >and muscle strength, and perhaps even psychological >resilience. It can prevent obesity, and may even >prolong employability and life span. These are >substantial benefits in return for the high cost, but >less than 1 in 5000 children is born with this type of >severe deficiency. At the other extreme is a child >whose only diagnosable disease is a height in the >lowest 2% of the population, who may gain 1 inch from >2 years of treatment. In between these extremes is a >continuum of more or less severe shortness, greater or >lesser response to treatment, and greater or smaller >abnormalities to testing. > >Questions and dilemmas arise from the previous facts. > >Is GH a wise use of finite health care resources? Is >there anything wrong with an insurer or government >health program declining to spend US$ 100 000 or more >to make an otherwise healthy child a few inches >taller? > >A physician usually assumes the responsibility of >advocating for a patient to get coverage for a >treatment. If the family of a normal but slightly >short child thinks GH treatment is worth the cost and >trouble, does the physician have a duty to support it? >If the physician declines, is she being >“paternalistic” rather than “respecting the patient’s >autonomy”. > >If the cost of GH drops, and is given to short >children whose parents can afford it, will shortness >become a lifelong mark of lower social origins, like >crooked teeth? > >If we treat a child to protect him from the >disadvantages of social heightism, is that like >lightening skin or straightening hair to protect from >racism? > >If two children of the same height might gain the same >benefit from treatment, is the reason for the >shortness (diagnosis) an ethically relevant >consideration? Does the child who tests more >abnormally have a better claim to treatment? > >Is “idiopathic short stature” a medical condition >worthy of treatment if it is defined simply as the >shortest 1% of the population? Would it make a >difference if many or most of this lowest 1% could be >shown to have a defect of IGF1 production or >responsiveness? If ISS were defined as the shortest >3%, 5%...? > >What is the difference between enhancement and >therapy? > >Should mentally handicapped children be as eligible >for GH treatment as those with more “normal” social >prospects? Are parents the best judges of potential >benefits? > >See Synopsis of symposium on ethical aspects of GH >treatment. > >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 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 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, 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 human pituitary glands to successfully treat a >GH-deficient boy. A few endocrinologists began to help >parents of severely GH deficient children to make >arrangements with local pathologists to collect human >pituitary glands after removal at autopsy. Parents >would then contract with a biochemist to purify enough >growth hormone to treat their child. Few families >could manage such a complicated undertaking. > >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, related to “mad >cow disease”. > >In 1977 the NPA GH extraction and purification >procedure was refined and improved. > >A shortage of available cadaver GH worsened in the >late 1970’s as the autopsy rate in the U.S. declined, >while the number of pediatric endocrinologists able to >diagnose and treat GH deficiency increased. GH was >"rationed." 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, approval was deferred >as lengthy safety trials continued over the next 4 >years. > >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. >Fortunately, 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 (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 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 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 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 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. Similar >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, despite marketing efforts, most >GH deficient adults remain untreated. > >Ironically, 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 (Rudman D, Feller AG, Nagraj HS >et al; Effect of human growth hormone in men over 60 >years old; New Engl J Med 323:1-6). 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. Use of GH for effects of aging >is discussed in more detail in HGH quackery. > >There are always entrepreneurs who don't need much >evidence to see a business opportunity. In 1997, >Ronald Klatz published Grow Young With HGH: The >Amazing Medically Proven Plan To Reverse the Effects >Of Aging (New York:Harper-Collins), 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 quackery. > >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. 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.
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