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Growth hormone treatment
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. GH is now produced by recombinant DNA technology, and prescribed 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 controversies, and growth hormone for cows.
Additional recommended knowledge
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, or sheep growth hormone, is abbreviated oGH). GH can refer either to the natural hormone produced by the pituitary (somatotropin), or biosynthetic GH for therapy.
HGH is an abbreviation sometimes used for counterfeit or fake "growth hormone" products. See HGH controversies for a fuller discussion of the origins and changing usages of HGH.
Cadaver growth hormone is the term for GH extracted from human pituitary glands between 1960 and 1985 for therapy of deficient children. In the U.S., cadaver GH, also referred to as NPA growth hormone, was provided by the (National Pituitary Agency), and by other national programs and commercial firms as well. In 1985 it was associated with the development of Creutzfeldt-Jakob Disease, and was withdrawn from use.
rhGH refers to recombinant human growth hormone (somatropin). It contains the identical amino acid sequence of human GH and is "natural sequence" GH. It is chemically identical to the growth hormone produced by the pituitary gland. A long-acting somatropin was previously available, but has recently (March 2007) been put on hold by the FDA. Human growth hormone is currently available through multiple pharmacutical companies in the US.
Coincidentally, rhGH also refers to rhesus monkey GH, using the accepted naming convention. Rhesus growth hormone was never used by physicians to treat human patients, but rhesus GH was part of the lore of the underground anabolic steroid community in those years and fraudulent versions may have been bought and sold in gyms.
met-GH refers to methionyl-growth hormone. This was the first recombinant GH product marketed (Protropin by Genentech). It had the same amino acid sequence as human GH with an extra methionine at the end of the chain to facilitate the manufacturing process. It was discontinued in the late 1990s.
rBST refers to recombinant bovine somatropin (cow growth hormone), or more properly, recombinant bovine GH (rbGH).
Treatment of GH deficiency in children
Growth hormone deficiency is treated by replacing GH. All GH prescribed in North America, Europe, and most of the rest of the world is a human GH, manufactured by recombinant DNA technology. As GH is a large 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. Other benefits may be noticed, such as increased strength, progress in motor development, and reduction of body fat. Side effects of this type of physiologic replacement are quite rare. Known risks and unsettled issues are discussed below, but GH deficient children receiving replacement doses are at the lowest risk for problems 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. 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, 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:
A variety of other causes of shortness is occasionally treated with growth hormone off-label.
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.
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.
The following effects are common, but of questionable harm.
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.
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.
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.
Questions and dilemmas arise from the previous facts.
See Synopsis of symposium on ethical aspects of GH treatment.
It is illegal to take growth hormone without a valid prescription from a doctor in many countries. In 2007, the actor Sylvester Stallone was prosecuted by Australian customs officials for bringing Jintropin into the country.
Perhaps the most famous person who exemplified the appearance of untreated congenital growth hormone deficiency was Charles Sherwood Stratton (1838-1883), who was exhibited by P.T. Barnum as General Tom Thumb, and married Lavinia Warren. Pictures of the couple show the typical adult features of untreated severe growth hormone deficiency. Despite the severe shortness, limbs and trunks are proportional.
Like many other nineteenth century medical terms which lost precise meaning as they gained wider currency, “midget” as a term for someone with extreme proportional shortness acquired pejorative connotations and is no longer used in medical contexts.
By the middle of the twentieth century endocrinologists understood the clinical features of growth hormone deficiency. GH is a protein hormone, like insulin, 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).
Extraction for treatment
In the late 1950s 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, UK, 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 four 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. 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$10,000–30,000 per year) was the highest 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 (National Cooperative Growth Study).
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 1950s, but did not reach board status in the U.S. until the late 1970s. Even 10 years later, as a cognitive, procedureless specialty dealing with mostly rare diseases, it was one of the smallest, lowest paid, and more obscure of the medical specialities. Pediatric endocrinologists were the only physicians interested in the arcana of GH metabolism and children’s growth, but their previously academic arguments took on new practical significance with major financial implications.
The major scientific arguments dated back to the days of GH scarcity:
It was the ethical questions that were new. Is GH not a wise use of finite health care resources, or is the physician’s primary responsibility to the patient? If GH is given to most extremely short children to make them taller, will the definition of “extremely short” simply rise, negating the expected social benefit? If GH is given to short children whose parents can afford it, will shortness become a permanent mark of lower social origins? More of these issues are outlined in the ethics section. Whole meetings were devoted to these questions; pediatric endocrinology had become a specialty with its own bioethics issues.
Despite the price, the 1990s became an era of experimentation to see what else growth hormone could help. The medical literature of the decade contains hundreds of reports of small trials of GH use in nearly every type of growth failure and shortness imaginable. In most cases the growth responses were modest. For conditions with a large enough potential market, more rigorous trials were sponsored by 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-1990s, several GH companies had sponsored or publicized research into the quality of life of adults with severe GH deficiency. Most were people who had been treated with GH in childhood for severe deficiency. 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 30s and 40s, 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.
Though GH use was slow to be accepted among adults with GH deficiency, similar research to see if GH treatment could slow or reverse some of the similar effects of aging attracted much public interest. The most publicized trial was reported by Daniel Rudman in 1990. As with other types of hormone supplementation for aging (testosterone, estrogen, DHEA), confirmation of benefit and accurate understanding of risks has been only slowly evolving. Use of GH for effects of aging is discussed in more detail in HGH controversies.
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, an uncritical touting of GH as the answer to aging. This time the internet amplified the proposition and spawned a hundred frauds and scams. Fortunately, their adoption of the "HGH" term has provided an easy way to distinguish the hype from the evidence. For more, see HGH controversies.
In 2003, growth hormone hit the news again, when the US FDA granted Eli Lilly approval to market Humatrope for the treatment of idiopathic short stature. The indication was controversial for several reasons, the primary one being the difficulty in defining extreme shortness with normal test results as a disease rather than the extreme end of the normal height range; in fact, the definition offered by Lilly for ISS is a height in the shortest 1.2% of the population. While this is an extreme degree of shortness, critics suggested that the company could afford to be extremely restrictive to earn approval, yet be confident that the definition, as well as actual use, would be driven upward by parents and physicians. Meanwhile, pediatric endocrinologists are still arguing about whether ISS is a "pathologic" or a statistical condition.
As of 2004, GH use continues to rise, though it is no longer the most expensive prescription drug in the formulary. Synthetic growth hormone available in the U.S. (and their manufacturers) included Nutropin (Genentech), Humatrope (Lilly), Genotropin (Pfizer), Norditropin (Novo), Tev-Tropin (Teva) and Saizen (Serono). The products are nearly identical in composition, efficacy, and cost, varying primarily in the formulations and delivery devices.
|This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Growth_hormone_treatment". A list of authors is available in Wikipedia.|