Growth hormone therapy refers to the use of growth hormone (GH) as a prescription medication—it is one form of hormone therapy. Growth hormone is a peptide hormone secreted by the pituitary gland that stimulates growth and cell reproduction. In the past, growth hormone was extracted from human pituitary glands. Growth hormone is now produced by recombinant DNA
technology and is prescribed for a variety of reasons. GH therapy has
been a focus of social and ethical controversies for 50 years.
This article describes the history of GH treatment and the current uses and risks arising from GH use. Other articles describe GH physiology, diseases of GH excess (acromegaly and pituitary gigantism), deficiency, the recent phenomenon of HGH controversies, growth hormone in sports, and growth hormone for cows.
This article describes the history of GH treatment and the current uses and risks arising from GH use. Other articles describe GH physiology, diseases of GH excess (acromegaly and pituitary gigantism), deficiency, the recent phenomenon of HGH controversies, growth hormone in sports, and growth hormone for cows.
Medical uses
HGH deficiency in children
Growth hormone deficiency is treated by replacing GH. All GH prescribed in North America, Europe, and most of the rest of the world is a human GH, manufactured by recombinant DNA technology.
As GH is a large peptide molecule, it must be injected into
subcutaneous tissue or muscle to get it into the blood. Nearly painless
insulin syringes make this less trying than is usually anticipated, but perceived discomfort is a subjective value.
When 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.
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, although most accept.
HGH deficiency in adults
The Endocrine Society
has recommended that adult patients diagnosed with growth hormone
deficiency (GHd) be administered an individualized GH treatment regimen.
With respect to diagnosis, their guidelines state that "adults
patients with structural hypothalamic/pituitary disease, surgery or
irradiation in these areas, head trauma, or evidence of other pituitary
hormone deficiencies be considered for evaluation for acquired GHd" and
that "idiopathic GHd in adults is very rare, and stringent criteria are
necessary to make this diagnosis. Because in the absence of suggestive
clinical circumstances there is a significant false-positive error rate
in the response to a single GH stimulation test, we suggest the use of
two tests before making this diagnosis."
GH replacement therapy can provide a number of measurable benefits to GH-deficient adults. These include improved bone density, increased muscle mass, decrease of adipose tissue, faster hair and nail growth, strengthened immune system, increased circulatory system, and improved blood lipid levels, but long term mortality benefit has not yet been demonstrated.
A peer-reviewed article published in 2010 indicates that "Growth
hormone (GH) replacement unequivocally benefits growth, body
composition, cardiovascular risk factors and quality of life. Less is
known about the effects of GH on learning and memory."
Other
As of 2004, GH has been approved by the U.S. Food and Drug Administration for treatment of other conditions:
- In adults, wasting (or cachexia) caused by AIDS.
- 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 in (5.1–7.6 cm) on this dose. The gains appear to be dose-dependent. It has been used successfully in toddlers with Turner syndrome, as well as in older girls.
- Short-stature homeobox gene deficiency
- Chronic kidney 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 in (10 cm)
- Prader–Willi syndrome, a generally non-hereditary genetic condition, is a case where GH is prescribed for benefits in addition to height. GH is one of the treatment options an experienced endocrinologist may use when treating a child with PWS. GH can help children with PWS in height, weight, body mass, strength, and agility. Reports have indicated increase of growth rate (especially in the first year of treatment) and a variety of other positive effects, including improved body composition (higher muscle mass, lower fat mass); improved weight management; increased energy and physical activity; improved strength, agility, and endurance; and improved respiratory function. The Prader-Willi Syndrome Association (USA) recommends that a sleep study be conducted before initiating GH treatment in a child with PWS. At this time there is no direct evidence of a causative link between growth hormone and the respiratory problems seen in PWS (among both those receiving and those not receiving GH treatment), including sudden death. A follow-up sleep study after one year of GH treatment may also be indicated. GH (specifically Pfizer's version, Genotropin) is the only treatment that has received an FDA indication for children with PWS. The FDA indication only applies to children.
- Children short because of intrauterine growth retardation are small for gestational age at birth for a variety of reasons. If early catch-up growth does not occur and their heights remain below the third percentile by 2 or 3 years of age, adult height is likely to be similarly low. High-dose GH treatment has been shown to accelerate growth, but data on long term benefits and risks are limited.
- Idiopathic short stature (ISS) is one of the most controversial indications for GH as pediatric endocrinologists do not agree on its definition, diagnostic criteria, or limits. The term has been applied to children with severe unexplained shortness that will result in an adult height below the 3rd percentile. In the late 1990s, the pharmaceutical manufacturer Eli Lilly and Company sponsored trials of their brand of rHGH (Humatrope) in children with extreme ISS, those at least 2.25 standard deviations below mean (in the lowest 1.2 percent of the population). These boys and girls appeared to be headed toward heights of less than 63" (160 cm) and 59" (150 cm) respectively. They were treated for about 4 years and gained 1.5–3 in (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. Approval of HGH for the treatment of this extreme degree of shortness led to an increase in the number of parents seeking its use to make otherwise normal children a little taller.
Adverse effects
The New England Journal of Medicine published two editorials in 2003 expressing concern about off-label uses
of HGH and the proliferation of advertisements for "HGH-Releasing"
dietary supplements, and emphasized that there is no evidence that use
of HGH in healthy adults or in geriatric patients is safe and effective -
and especially emphasized that risks of long-term HGH treatment are
unknown. One editorial was by Jeffrey M. Drazen, M.D., the
editor-in-chief of the journal; the other one
was by Dr. Mary Lee Vance, who provided the NEJM's editorial original,
cautious comment on a much cited 1990 study on the use of HGH in
geriatric patients with low growth hormone levels.
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 having received GH. The reason is unknown, but GH is now rarely used in ICU patients unless they have severe growth hormone deficiency.
GH treatment usually decreases insulin sensitivity, but some studies showed no evidence for increased diabetes incidence in GH-treated adult hypopituitary patients.
In past it was believed that GH treatment could increase the cancer
risk; a large study recently concluded that "With relatively short
follow-up, the overall primary cancer risk in 6840 patients receiving GH
as adults was not increased. Elevated SIRs (which is risk of getting
cancer) were found for subgroups in the USA cohort defined by age <35 childhood="" deficiency.="" gh="" onset="" or="" p="" years="">
The FDA issued a Safety Alert in August 2011, communicating the
fact that a French study found that persons with certain kinds of short
stature (idiopathic growth hormone deficiency and idiopathic or gestational short stature)
treated with recombinant human growth hormone during childhood and who
were followed over a long period of time, were at a small increased risk
of death when compared to individuals in the general population of
France.
History
Perhaps the most famous person who exemplified the appearance of untreated congenital growth hormone deficiency was Charles Sherwood Stratton (1838–1883), who was exhibited by P. T. Barnum as General Tom Thumb,
and married Lavinia Warren. Pictures of the couple show the typical
adult features of untreated severe growth hormone deficiency. Despite
the severe shortness, limbs and trunks are proportional.
Like many other nineteenth-century medical terms that 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 1920s. However, pig and cow
GH did not work at all 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
Extracted growth hormone was used since the late 1950s until the late 1980s when its use was replaced by recombinant GH.
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 1960s 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–Jakob 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 1970s 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 ft 0 in (1.52 m). Children who
were short for reasons other than severe GH deficiency were lied to and
told that they would not benefit from treatment. Only those pediatric
endocrinologists that remained at university medical centers with
departments able to support a research program had access to NPA growth
hormone.
In the late 1970s, 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.
Recombinant human growth hormone (rHGH)
In
1981, the new American corporation Genentech, after collaboration with
Kabi, developed and started trials of recombinant human growth hormone
(rHGH) made by a new technology (recombinant DNA) in which human genes
were inserted into bacteria so that they could produce unlimited
amounts of the protein. Because this was new technology, approval was
deferred as lengthy safety trials continued over the next four years.
In 1985, four young adults in the U.S. having received NPA growth hormone in the 1960s developed CJD (Creutzfeldt–Jakob disease).
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 having 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 recombinant human
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 more common and competitors entered the market. Eli Lilly launched a competing natural sequence growth hormone (Humatrope). Pharmacia (formerly Kabi, now Pfizer) introduced Genotropin. Novo Nordisk introduced Norditropin. Serono
(now EMD Serono) introduced Saizen and Serostim. Ferring has introduced
Zomacton. Genentech eventually introduced another HGH product,
Nutropin, and stopped making Protropin in 2004. Price competition had
begun. Teva, which is primarily a generics company, has introduced
Tev-tropin. Chinese companies have entered the market as well and have
introduced more pricing competition: NeoGenica BioScience Ltd.
introduced Hypertropin, GeneScience introduced Jintropin, Anhui Anke
Biotechnology introduced Ansomone, Shanghai United Kefei Biotechnology
introduced Kefei HGH,
and Hygene BioPharm introduced Hygetropin. These are all recombinant
human growth hormone products and they have competed with various
marketing strategies. Most children with severe deficiency in the
developed world are now likely to have access to a pediatric
endocrinologist and be diagnosed and offered treatment.
Pediatric endocrinology
became a recognizable specialty in the 1950s, but did not reach board
status in the U.S. until the late 1970s. Even 10 years later, as a
cognitive, procedureless specialty dealing with mostly rare diseases, it
was one of the smallest, lowest-paid, and more obscure of the medical
specialities. Pediatric endocrinologists were the only physicians interested in the arcana of GH metabolism and children’s growth, but their previously academic arguments took on new practical significance with major financial implications.
The major scientific arguments dated back to the days of GH scarcity:
- Everyone agrees on the nature and diagnosis of severe GH deficiency, but what are the edges and variations?
- How should marked constitutional delay be distinguished from partial GH deficiency?
- To what extent is "normal shortness" a matter of short children naturally making less growth hormone?
- Can a child make GH in response to a stimulation test but fail to make enough in "daily life" to grow normally?
- If a stimulation test is used to define deficiency, what GH cutoff should be used to define normal?
It was the ethical
questions that were new. Is GH not a wise use of finite healthcare
resources, or is the physician’s primary responsibility to the patient?
If GH is given to most extremely short children to make them taller,
will the definition of “extremely short” simply rise, negating the
expected social benefit? If GH is given to short children whose parents
can afford it, will shortness become a permanent mark of lower social
origins? More of these issues are outlined in the ethics section. Whole
meetings were devoted to these questions; pediatric endocrinology had
become a specialty with its own bioethics issues.
Despite the price, the 1990s became an era of experimentation to
see what else growth hormone could help. The medical literature of the
decade contains hundreds of reports of small trials of GH use in nearly
every type of growth failure and shortness imaginable. In most cases,
the growth responses were modest.
For conditions with a large enough potential market, more rigorous
trials were sponsored by pharmaceutical companies that were making
growth hormone to achieve approval to market for those specific
indications. Turner syndrome and chronic kidney failure were the first of these “nonGH-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 having been treated with GH in childhood for severe deficiency.
Although the injections are painless, many of them had been happy to
leave injections behind as they reached final heights in the low-normal
range.
However, as adults in their 30s and 40s, these people, who had been
children with growth hormone deficiency, were now adults with growth
hormone deficiency and had more than their share of common adult
problems: reduced physical, mental, and social energy, excess adipose
and diminished muscle, diminished libido, poor bone density, higher
cholesterol levels, and higher rates of cardiovascular disease. Research
trials soon confirmed that a few months of GH could improve nearly all
of these parameters. However, despite marketing efforts, most
GH-deficient adults remain untreated.
Though GH use was slow to be accepted among adults with GH
deficiency, similar research to see if GH treatment could slow or
reverse some of the similar effects of aging attracted much public
interest. The most publicized trial was reported by Daniel Rudman in
1990. As with other types of hormone supplementation for aging (testosterone, estrogen, DHEA), confirmation of benefit and accurate understanding of risks has been only slowly evolving.
In 1997, Ronald Klatz of the American Academy of Anti-Aging Medicine published Grow Young With HGH: The Amazing Medically Proven Plan To Reverse the Effects Of Aging, an uncritical touting of GH as the answer to aging.
This time, the internet amplified the proposition and spawned a hundred
frauds and scams. However, their adoption of the "HGH" term has
provided an easy way to distinguish the hype from the evidence. 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.
Recombinant growth hormone available in the U.S. (and their manufacturers) included Nutropin (Genentech), Humatrope (Eli Lilly and Company), Genotropin (Pfizer), Norditropin (Novo Nordisk), Tev-Tropin (Teva) and Saizen (Merck Serono).
The products are nearly identical in composition, efficacy, and cost,
varying primarily in the formulations and delivery devices.
Terminology
Growth hormone
(GH l) is also called somatotropin (British: somatotrophin). The human
form of growth hormone is known as human growth hormone, or hGH (ovine
growth hormone, or sheep growth hormone, is abbreviated oGH). GH can
refer either to the natural hormone produced by the pituitary
(somatotropin), or biosynthetic GH for therapy.
Cadaver growth hormone is the term for GH extracted from the pituitary glands of human cadavers 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 (rHGH, rhGH) refers to recombinant human growth hormone, that is, somatropin (INN). Its amino acid sequence is identical with that of endogenous human GH.
It is coincidental that RHGH also refers to rhesus monkey GH (RhGH), using the accepted naming convention of Rh for rhesus. 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, that is, somatrem (INN). This was the first recombinant GH product marketed (trade name 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 2004.
rBST refers to recombinant bovine somatotropin (cow growth hormone), or recombinant bovine GH (rbGH, RBGH).
