| Growth hormone 1 (pituitary) | |
|---|---|
Growth hormone
| |
| Identifiers | |
| Symbol | GH1 |
| NCBI gene | 2688 |
| HGNC | 4261 |
| OMIM | 139250 |
| RefSeq | NM_022562 |
| UniProt | P01241 |
| Other data | |
| Locus | Chr. 17 q22-q24 |
| Growth hormone 2 (placental) | |
|---|---|
| Identifiers | |
| Symbol | GH2 |
| NCBI gene | 2689 |
| HGNC | 4262 |
| OMIM | 139240 |
| RefSeq | NM_002059 |
| UniProt | P01242 |
| Other data | |
| Locus | Chr. 17 q22-q24 |
Growth hormone (GH) or somatotropin, also known as human growth hormones (hGH or HGH) in its human form, is a peptide hormone that stimulates growth, cell reproduction, and cell regeneration in humans and other animals. It is thus important in human development. GH also stimulates production of IGF-1 and increases the concentration of glucose and free fatty acids. It is a type of mitogen which is specific only to the receptors on certain types of cells. GH is a 191-amino acid, single-chain polypeptide that is synthesized, stored and secreted by somatotropic cells within the lateral wings of the anterior pituitary gland.
A recombinant form of hGH called somatreopleopin (INN) is used as a prescription drug to treat children's growth disorders and adult growth hormone deficiency. In the United States, it is only available legally from pharmacies by prescription from a licensed health care provider. In recent years in the United States, some health care providers are prescribing growth hormone in the elderly to increase vitality. While legal, the efficacy and safety of this use for HGH has not been tested in a clinical trial. Many of the functions of hGH remain unknown.
In its role as an anabolic agent, HGH has been used by competitors in sports since at least 1982, and has been banned by the IOC and NCAA. Traditional urine analysis does not detect doping with HGH, so the ban was not enforced until the early 2000s, when blood tests that could distinguish between natural and artificial HGH were starting to be developed. Blood tests conducted by WADA at the 2004 Olympic Games in Athens, Greece targeted primarily HGH. Use of the drug for performance enhancement is not currently approved by the FDA.
GH has been studied for use in raising livestock more efficiently in industrial agriculture and several efforts have been made to obtain governmental approval to use GH in livestock production. These uses have been controversial. In the United States, the only FDA-approved use of GH for livestock is the use of a cow-specific form of GH called bovine somatotropin for increasing milk production in dairy cows. Retailers are permitted to label containers of milk as produced with or without bovine somatotropin.
Nomenclature
The names somatotropin (STH) or somatotropic hormone refer to the growth hormone produced naturally in animals and extracted from carcasses. Hormone extracted from human cadavers is abbreviated hGH. The main growth hormone produced by recombinant DNA technology has the approved generic name (INN) somatropin and the brand name Humatrope,
and is properly abbreviated rhGH in the scientific literature. Since
its introduction in 1992 Humatrope has been a banned sports doping
agent, and in this context is referred to as HGH.
Biology
Gene
Genes for human growth hormone, known as growth hormone 1 (somatotropin; pituitary growth hormone) and growth hormone 2 (placental growth hormone; growth hormone variant), are localized in the q22-24 region of chromosome 17 and are closely related to human chorionic somatomammotropin (also known as placental lactogen) genes. GH, human chorionic somatomammotropin, and prolactin belong to a group of homologous hormones with growth-promoting and lactogenic activity.
Structure
The major isoform of the human growth hormone is a protein of 191 amino acids and a molecular weight of 22,124 daltons.
The structure includes four helices necessary for functional
interaction with the GH receptor. It appears that, in structure, GH is
evolutionarily homologous to prolactin and chorionic somatomammotropin.
Despite marked structural similarities between growth hormone from
different species, only human and Old World monkey growth hormones have significant effects on the human growth hormone receptor.
Several molecular
isoforms of GH exist in the pituitary gland and are released to blood.
In particular, a variant of approximately 20 kDa originated by an
alternative splicing is present in a rather constant 1:9 ratio, while recently an additional variant of ~ 23-24 kDa has also been reported in post-exercise states at higher proportions.
This variant has not been identified, but it has been suggested to
coincide with a 22 kDa glycosylated variant of 23 kDa identified in the
pituitary gland. Furthermore, these variants circulate partially bound to a protein (growth hormone-binding protein, GHBP), which is the truncated part of the growth hormone receptor, and an acid-labile subunit (ALS).
Regulation
Secretion of growth hormone (GH) in the pituitary is regulated by the neurosecretory nuclei of the hypothalamus.
These cells release the peptides growth hormone-releasing hormone (GHRH or somatocrinin) and growth hormone-inhibiting hormone (GHIH or somatostatin) into the hypophyseal portal
venous blood surrounding the pituitary.
GH release in the pituitary is primarily determined by the balance of
these two peptides, which in turn is affected by many physiological
stimulators (e.g., exercise, nutrition, sleep) and inhibitors (e.g.,
free fatty acids) of GH secretion.
Somatotropic cells in the anterior pituitary
gland then synthesize and secrete GH in a pulsatile manner, in response
to these stimuli by the hypothalamus.
The largest and most predictable of these GH peaks occurs about an hour
after onset of sleep with plasma levels of 13 to 72 ng/mL.
Otherwise there is wide variation between days and individuals. Nearly
fifty percent of GH secretion occurs during the third and fourth NREM sleep stages.
Surges of secretion during the day occur at 3- to 5-hour intervals. The plasma concentration of GH during these peaks may range from 5 to even 45 ng/mL.
Between the peaks, basal GH levels are low, usually less than 5 ng/mL for most of the day and night.
Additional analysis of the pulsatile profile of GH described in all
cases less than 1 ng/ml for basal levels while maximum peaks were
situated around 10-20 ng/mL.
A number of factors are known to affect GH secretion, such as age, sex, diet, exercise, stress, and other hormones. Young adolescents secrete GH at the rate of about 700 μg/day, while healthy adults secrete GH at the rate of about 400 μg/day. Sleep deprivation generally suppresses GH release, particularly after early adulthood.
Stimulators of growth hormone (GH) secretion include:
- Peptide hormones
- Sex hormones
- Increased androgen secretion during puberty (in males from testes and in females from adrenal cortex)
- Testosterone and DHEA
- Estrogen
- Clonidine and L-DOPA by stimulating GHRH release
- α4β2 nicotinic agonists, including nicotine, which also act synergistically with clonidine.
- Hypoglycemia, arginine and propranolol by inhibiting somatostatin release.
- Deep sleep
- Insulin
- Glucagon
- Niacin as nicotinic acid (vitamin B3)
- Fasting
- Vigorous exercise
Inhibitors of GH secretion include:
- GHIH (somatostatin) from the periventricular nucleus
- circulating concentrations of GH and IGF-1 (negative feedback on the pituitary and hypothalamus)
- Hyperglycemia
- Glucocorticoids
- Dihydrotestosterone
- Phenothiazines
In addition to control by endogenous and stimulus processes, a number of foreign compounds (xenobiotics such as drugs and endocrine disruptors) are known to influence GH secretion and function.
Function
Main pathways in endocrine regulation of growth
Effects of growth hormone on the tissues of the body can generally be described as anabolic (building up). Like most other protein hormones, GH acts by interacting with a specific receptor on the surface of cells.
Increased height during childhood is the most widely known effect
of GH. Height appears to be stimulated by at least two mechanisms:
- Because polypeptide hormones are not fat-soluble, they cannot penetrate cell membranes. Thus, GH exerts some of its effects by binding to receptors on target cells, where it activates the MAPK/ERK pathway. Through this mechanism GH directly stimulates division and multiplication of chondrocytes of cartilage.
- GH also stimulates, through the JAK-STAT signaling pathway, the production of insulin-like growth factor 1 (IGF-1, formerly known as somatomedin C), a hormone homologous to proinsulin. The liver is a major target organ of GH for this process and is the principal site of IGF-1 production. IGF-1 has growth-stimulating effects on a wide variety of tissues. Additional IGF-1 is generated within target tissues, making it what appears to be both an endocrine and an autocrine/paracrine hormone. IGF-1 also has stimulatory effects on osteoblast and chondrocyte activity to promote bone growth.
In addition to increasing height in children and adolescents, growth hormone has many other effects on the body:
- Increases calcium retention, and strengthens and increases the mineralization of bone
- Increases muscle mass through sarcomere hypertrophy
- Promotes lipolysis
- Increases protein synthesis
- Stimulates the growth of all internal organs excluding the brain
- Plays a role in homeostasis
- Reduces liver uptake of glucose
- Promotes gluconeogenesis in the liver
- Contributes to the maintenance and function of pancreatic islets
- Stimulates the immune system
- Increases deiodination of T4 to T3
Biochemistry
GH has a short biological half-life of about 10 to 20 minutes.
Clinical significance
Excess
The
most common disease of GH excess is a pituitary tumor composed of
somatotroph cells of the anterior pituitary. These somatotroph adenomas
are benign and grow slowly, gradually producing more and more GH. For
years, the principal clinical problems are those of GH excess.
Eventually, the adenoma may become large enough to cause headaches,
impair vision by pressure on the optic nerves, or cause deficiency of
other pituitary hormones by displacement.
Prolonged GH excess thickens the bones of the jaw, fingers and
toes, resulting heaviness of the jaw and increased size of digits,
referred to as acromegaly. Accompanying problems can include sweating, pressure on nerves (e.g. carpal tunnel syndrome), muscle weakness, excess sex hormone-binding globulin (SHBG), insulin resistance or even a rare form of type 2 diabetes, and reduced sexual function.
GH-secreting tumors are typically recognized in the fifth decade
of life. It is extremely rare for such a tumor to occur in childhood,
but, when it does, the excessive GH can cause excessive growth,
traditionally referred to as pituitary gigantism.
Surgical removal is the usual treatment for GH-producing tumors.
In some circumstances, focused radiation or a GH antagonist such as pegvisomant may be employed to shrink the tumor or block function. Other drugs like octreotide (somatostatin agonist) and bromocriptine (dopamine agonist) can be used to block GH secretion because both somatostatin and dopamine negatively inhibit GHRH-mediated GH release from the anterior pituitary.
Deficiency
The effects of growth hormone (GH) deficiency vary depending on the age at which they occur. Alterations in somatomedin can result in growth hormone deficiency with two known mechanisms; failure of tissues to respond to somatomedin, or failure of the liver to produce somatomedin. Major manifestations of GH deficiency in children are growth failure, the development of a short stature, and delayed sexual maturity. In adults, somatomedin alteration contributes to increased osteoclast activity, resulting in weaker bones that are more prone to pathologic fracture and osteoporosis. However, deficiency is rare in adults, with the most common cause being a pituitary adenoma. Other adult causes include a continuation of a childhood problem, other structural lesions or trauma, and very rarely idiopathic GHD.
Adults with GHD "tend to have a relative increase in fat mass and
a relative decrease in muscle mass and, in many instances, decreased
energy and quality of life".
Diagnosis of GH deficiency involves a multiple-step diagnostic
process, usually culminating in GH stimulation tests to see if the
patient's pituitary gland will release a pulse of GH when provoked by
various stimuli.
Psychological effects
Quality of life
Several studies, primarily involving patients with GH deficiency,
have suggested a crucial role of GH in both mental and emotional
well-being and maintaining a high energy level. Adults with GH
deficiency often have higher rates of depression than those without. While GH replacement therapy has been proposed to treat depression as a result of GH deficiency, the long-term effects of such therapy are unknown.
Cognitive function
GH has also been studied in the context of cognitive function, including learning and memory.
GH in humans appears to improve cognitive function and may be useful in
the treatment of patients with cognitive impairment that is a result of
GH deficiency.
Medical uses
Replacement therapy
Treatment with exogenous GH is indicated only in limited circumstances, and needs regular monitoring due to the frequency and severity of side-effects.
GH is used as replacement therapy in adults with GH deficiency of
either childhood-onset or adult-onset (usually as a result of an
acquired pituitary tumor). In these patients, benefits have variably
included reduced fat mass, increased lean mass, increased bone density,
improved lipid profile, reduced cardiovascular risk factors, and
improved psychosocial well-being.
Other approved uses
GH
can be used to treat conditions that produce short stature but are not
related to deficiencies in GH. However, results are not as dramatic when
compared to short stature that is solely attributable to deficiency of
GH. Examples of other causes of shortness often treated with GH are Turner syndrome, chronic kidney failure, Prader–Willi syndrome, intrauterine growth restriction, and severe idiopathic short stature.
Higher ("pharmacologic") doses are required to produce significant
acceleration of growth in these conditions, producing blood levels well
above normal ("physiologic"). Despite the higher doses, side-effects
during treatment are rare, and vary little according to the condition
being treated.
Off-label use
Off-label prescription of HGH is controversial and may be illegal.
Claims for GH as an anti-aging treatment date back to 1990 when the New England Journal of Medicine published a study wherein GH was used to treat 12 men over 60.
At the conclusion of the study, all the men showed statistically
significant increases in lean body mass and bone mineral density, while
the control group did not. The authors of the study noted that these
improvements were the opposite of the changes that would normally occur
over a 10- to 20-year aging period. Despite the fact the authors at no
time claimed that GH had reversed the aging process itself, their
results were misinterpreted as indicating that GH is an effective
anti-aging agent. This has led to organizations such as the controversial American Academy of Anti-Aging Medicine promoting the use of this hormone as an "anti-aging agent".
A Stanford University School of Medicine meta-analysis
of clinical studies on the subject published in early 2007 showed that
the application of GH on healthy elderly patients increased muscle by
about 2 kg and decreased body fat by the same amount.
However, these were the only positive effects from taking GH. No other
critical factors were affected, such as bone density, cholesterol
levels, lipid measurements, maximal oxygen consumption, or any other
factor that would indicate increased fitness.
Researchers also did not discover any gain in muscle strength, which
led them to believe that GH merely let the body store more water in the
muscles rather than increase muscle growth. This would explain the
increase in lean body mass.
GH has also been used experimentally to treat multiple sclerosis, to enhance weight loss in obesity, as well as in fibromyalgia, heart failure, Crohn's disease and ulcerative colitis, and burns. GH has also been used experimentally in patients with short bowel syndrome to lessen the requirement for intravenous total parenteral nutrition.
In 1990, the US Congress passed an omnibus crime bill, the Crime Control Act of 1990, that amended the Federal Food, Drug, and Cosmetic Act, that classified anabolic steroids as controlled substances
and added a new section that stated that a person who "knowingly
distributes, or possesses with intent to distribute, human growth
hormone for any use in humans other than the treatment of a disease or
other recognized medical condition, where such use has been authorized
by the Secretary of Health and Human Services" has committed a felony.
The Drug Enforcement Administration
of the US Department of Justice considers off-label prescribing of HGH
to be illegal, and to be a key path for illicit distribution of HGH. This section has also been interpreted by some doctors, most notably the authors of a commentary article published in the Journal of the American Medical Association in 2005, as meaning that prescribing HGH off-label may be considered illegal.
And some articles in the popular press, such as those criticizing the
pharmaceutical industry for marketing drugs for off-label use (which is
clearly illegal) have made strong statements about whether doctors can
prescribe HGH off-label: "Unlike other prescription drugs, HGH may be
prescribed only for specific uses. U.S. sales are limited by law to
treat a rare growth defect in children and a handful of uncommon
conditions like short bowel syndrome or Prader-Willi syndrome, a
congenital disease that causes reduced muscle tone and a lack of
hormones in sex glands." At the same time, anti-aging clinics where doctors prescribe, administer, and sell HGH to people are big business. In a 2012 article in Vanity Fair,
when asked how HGH prescriptions far exceed the number of adult
patients estimated to have HGH-deficiency, Dragos Roman, who leads a
team at the FDA that reviews drugs in endocrinology, said "The F.D.A.
doesn't regulate off-label uses of H.G.H. Sometimes it's used
appropriately. Sometimes it's not."
Side effects
Injection-site reaction is common. More rarely, patients can experience joint swelling, joint pain, carpal tunnel syndrome, and an increased risk of diabetes. In some cases, the patient can produce an immune response against GH. GH may also be a risk factor for Hodgkin's lymphoma.
One survey of adults that had been treated with replacement
cadaver GH (which has not been used anywhere in the world since 1985)
during childhood showed a mildly increased incidence of colon cancer and
prostate cancer, but linkage with the GH treatment was not established.
Performance enhancement
The first description of the use of GH as a doping agent was Dan
Duchaine's "Underground Steroid handbook" which emerged from California
in 1982; it is not known where and when GH was first used this way.
Athletes in many sports have used human growth hormone in order
to attempt to enhance their athletic performance. Some recent studies
have not been able to support claims that human growth hormone can
improve the athletic performance of professional male athletes.
Many athletic societies ban the use of GH and will issue sanctions
against athletes who are caught using it. However, because GH is a
potent endogenous protein, it is very difficult to detect GH doping. In
the United States, GH is legally available only by prescription from a
medical doctor.
Dietary supplements
To capitalize on the idea that GH might be useful to combat aging, companies selling dietary supplements
have websites selling products linked to GH in the advertising text,
with medical-sounding names described as "HGH Releasers". Typical
ingredients include amino acids, minerals, vitamins, and/or herbal
extracts, the combination of which are described as causing the body to
make more GH with corresponding beneficial effects. In the United
States, because these products are marketed as dietary supplements, it
is illegal for them to contain GH, which is a drug. Also, under United
States law, products sold as dietary supplements cannot have claims that
the supplement treats or prevents any disease or condition, and the
advertising material must contain a statement that the health claims are
not approved by the FDA. The FTC and the FDA do enforce the law when
they become aware of violations.
Agricultural use
In
the United States, it is legal to give a bovine GH to dairy cows to
increase milk production, and is legal to use GH in raising cows for
beef; see article on Bovine somatotropin, cattle feeding, dairy farming and the beef hormone controversy.
The use of GH in poultry farming is illegal in the United States. Similarly, no chicken meat for sale in Australia is administered hormones.
Several companies have attempted to have a version of GH for use
in pigs (porcine somatotropin) approved by the FDA but all applications
have been withdrawn.
Drug development history
The identification, purification and later synthesis of growth hormone is associated with Choh Hao Li. Genentech pioneered the first use of recombinant human growth hormone for human therapy in 1981.
Prior to its production by recombinant DNA technology, growth hormone used to treat deficiencies was extracted from the pituitary glands of cadavers.
Attempts to create a wholly synthetic HGH failed. Limited supplies of
HGH resulted in the restriction of HGH therapy to the treatment of
idiopathic short stature. Very limited clinical studies of growth hormone derived from an Old World monkey, the rhesus macaque, were conducted by John C. Beck and colleagues in Montreal, in the late 1950s.
The study published in 1957, which was conducted on "a 13-year-old male
with well-documented hypopituitarism secondary to a
crainiophyaryngioma," found that: "Human and monkey growth hormone
resulted in a significant enhancement of nitrogen storage ... (and)
there was a retention of potassium, phosphorus, calcium, and sodium. ...
There was a gain in body weight during both periods. ... There was a
significant increase in urinary excretion of aldosterone during both
periods of administration of growth hormone. This was most marked with
the human growth hormone. ... Impairment of the glucose tolerance curve
was evident after 10 days of administration of the human growth hormone.
No change in glucose tolerance was demonstrable on the fifth day of
administration of monkey growth hormone."
The other study, published in 1958, was conducted on six people: the
same subject as the Science paper; an 18-year-old male with statural and
sexual retardation and a skeletal age of between 13 and 14 years; a
15-year-old female with well-documented hypopituitarism secondary to a
craniopharyngioma; a 53-year-old female with carcinoma of the breast and
widespread skeletal metastases; a 68-year-old female with advanced
postmenopausal osteoporosis; and a healthy 24-year-old medical student
without any clinical or laboratory evidence of systemic disease.
In 1985, unusual cases of Creutzfeldt–Jakob disease
were found in individuals that had received cadaver-derived HGH ten to
fifteen years previously. Based on the assumption that infectious
prions causing the disease were transferred along with the
cadaver-derived HGH, cadaver-derived HGH was removed from the market.
In 1985, biosynthetic human growth hormone replaced
pituitary-derived human growth hormone for therapeutic use in the U.S.
and elsewhere.
As of 2005, recombinant growth hormones available in the United States (and their manufacturers) included Nutropin (Genentech), Humatrope (Lilly), Genotropin (Pfizer), Norditropin (Novo), and Saizen (Merck Serono). In 2006, the U.S. Food and Drug Administration (FDA) approved a version of rHGH called Omnitrope (Sandoz).
A sustained-release form of growth hormone, Nutropin Depot (Genentech
and Alkermes) was approved by the FDA in 1999, allowing for fewer
injections (every 2 or 4 weeks instead of daily); however, the product
was discontinued by Genentech/Alkermes in 2004 for financial reasons
(Nutropin Depot required significantly more resources to produce than
the rest of the Nutropin line).
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