Growth hormone
Encyclopedia
Growth hormone is a peptide hormone
that stimulates growth
, cell
reproduction and regeneration in humans and other animals. Growth hormone is a 191-amino acid, single-chain polypeptide that is synthesized, stored, and secreted by the somatotroph cells within the lateral wings of the anterior pituitary
gland. Somatotropin (STH) refers to the growth hormone 1
produced naturally in animals, whereas the term somatropin refers to growth hormone produced by recombinant DNA technology, and is abbreviated "HGH" in humans.
Growth hormone is used as a prescription drug
in medicine 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 doctor. In recent years in the United States, some doctors have started to prescribe growth hormone in GH-deficient older patients (but not on healthy people) to increase vitality. While legal, the efficacy and safety of this use for HGH has not been tested in a clinical trial. At this time, HGH is still considered a very complex hormone, and many of its functions are still unknown.
In its role as an anabolic agent, HGH has been abused by competitors in sports since the 1970s, and it has been banned by the IOC and NCAA. Traditional urine
analysis could not detect doping with HGH, so the ban was unenforceable until the early 2000s when blood test
s 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. This use for the drug is not approved by the FDA; GH is legally available only by prescription in the United States.
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. Now retailers are permitted to label containers of milk as produced with or without bovine somatotropin.
(somatotropin) and growth hormone 2, 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.
s 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 primate
growth hormones have significant effects in humans.
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 glycosilated 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).
(Growth hormone-releasing hormone/somatocrinin and Growth hormone-inhibiting hormone/somatostatin) into the hypophyseal portal
venous blood surrounding the pituitary are the major controllers of GH secretion by the somatotropes. However, although the balance of these stimulating and inhibiting peptides determines GH release, this balance is affected by many physiological stimulators (e.g., exercise, nutrition, sleep) and inhibitors of GH secretion (e.g., Free fatty acids)
Stimulators of HGH secretion include:
Inhibitors of GH secretion include:
In addition to control by endogenous and stimulus processes, a number of foreign compounds (xenobiotics such as drugs and endocrine disruptor
s) are known to influence GH secretion and function.
HGH is synthesized and secreted from the anterior pituitary
gland in a pulsatile manner throughout the day; surges of secretion occur at 3- to 5-hour intervals. The plasma concentration of GH during these peaks may range from 5 to even 45 ng/mL. The largest and most predictable of these GH peaks occurs about an hour after onset of sleep. Otherwise there is wide variation between days and individuals. Nearly fifty percent of HGH secretion occurs during the third and fourth NREM sleep stages. 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 HGH secretion, such as age, gender, diet, exercise, stress, and other hormones. Young adolescents secrete HGH at the rate of about 700 μg/day, while healthy adults secrete HGH at the rate of about 400 μg/day.
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:
In addition to increasing height in children and adolescents, growth hormone has many other effects on the body:
s 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 is 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.
vary depending on the age at which they occur. In children, growth failure and short stature
are the major manifestations of GH deficiency, with common causes including genetic conditions and congenital malformations. It can also cause delayed sexual maturity. In adults, deficiency is rare, with the most common cause a pituitary adenoma, and others including a continuation of a childhood problem, other structural lesions or trauma, and very rarely idiopathic GHD.
Adults with GHD present with non-specific problems including truncal obesity with 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.
, chronic renal failure
, Prader–Willi syndrome, intrauterine growth retardation, 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.
.
In recent years in the United States, some doctors have started to prescribe growth hormone in GH-deficient older patients (but not on healthy people) to increase vitality. While legal, the efficacy and safety of this use for HGH has not been tested in a clinical trial. At this time, hGH is still considered a very complex hormone, and many of its functions are still unknown.
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, 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 survey 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 in maintaining muscle mass in wasting
due to AIDS
and in patients with short bowel syndrome
to lessen the requirement for intravenous total parenteral nutrition
.
, 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.
and cattle feeding
and dairy farming
and Beef hormone controversy
.
Use in poultry farming
is illegal in the United States as per the poultry farming article.
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.
. 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 gland
s of cadaver
s. 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. Furthermore, growth hormone from other primates was found to be inactive in humans.
In 1985, unusual cases of Creutzfeldt-Jacob 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).
Peptide hormone
Peptide hormones are a class of peptides that are secreted into the blood stream and have endocrine functions in living animals.Like other proteins, peptide hormones are synthesized in cells from amino acids according to an mRNA template, which is itself synthesized from a DNA template inside the...
that stimulates growth
Human development (biology)
Human development is the process of growing to maturity. In biological terms, this entails growth from a one-celled zygote to an adult human being.- Biological development:...
, cell
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
reproduction and regeneration in humans and other animals. Growth hormone is a 191-amino acid, single-chain polypeptide that is synthesized, stored, and secreted by the somatotroph cells within the lateral wings of the anterior pituitary
Anterior pituitary
A major organ of the endocrine system, the anterior pituitary, also called the adenohypophysis, is the glandular, anterior lobe of the pituitary gland...
gland. Somatotropin (STH) refers to the growth hormone 1
Growth hormone 1
Somatotropin is a protein that in humans is encoded by the GH1 gene.-Further reading:...
produced naturally in animals, whereas the term somatropin refers to growth hormone produced by recombinant DNA technology, and is abbreviated "HGH" in humans.
Growth hormone is used as a prescription drug
Prescription drug
A prescription medication is a licensed medicine that is regulated by legislation to require a medical prescription before it can be obtained. The term is used to distinguish it from over-the-counter drugs which can be obtained without a prescription...
in medicine 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 doctor. In recent years in the United States, some doctors have started to prescribe growth hormone in GH-deficient older patients (but not on healthy people) to increase vitality. While legal, the efficacy and safety of this use for HGH has not been tested in a clinical trial. At this time, HGH is still considered a very complex hormone, and many of its functions are still unknown.
In its role as an anabolic agent, HGH has been abused by competitors in sports since the 1970s, and it has been banned by the IOC and NCAA. Traditional urine
Urine
Urine is a typically sterile liquid by-product of the body that is secreted by the kidneys through a process called urination and excreted through the urethra. Cellular metabolism generates numerous by-products, many rich in nitrogen, that require elimination from the bloodstream...
analysis could not detect doping with HGH, so the ban was unenforceable until the early 2000s when blood test
Blood test
A blood test is a laboratory analysis performed on a blood sample that is usually extracted from a vein in the arm using a needle, or via fingerprick....
s that could distinguish between natural and artificial HGH were starting to be developed. Blood tests conducted by WADA
World Anti-Doping Agency
The World Anti-Doping Agency , , is an independent foundation created through a collective initiative led by the International Olympic Committee . It was set up on November 10, 1999 in Lausanne, Switzerland, as a result of what was called the "Declaration of Lausanne", to promote, coordinate and...
at the 2004 Olympic Games in Athens, Greece targeted primarily HGH. This use for the drug is not approved by the FDA; GH is legally available only by prescription in the United States.
GH has been studied for use in raising livestock more efficiently in industrial agriculture
Industrial agriculture
Industrial farming is a form of modern farming that refers to the industrialized production of livestock, poultry, fish, and crops. The methods of industrial agriculture are technoscientific, economic, and political...
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
Bovine somatotropin
Bovine somatotropin , or BGH, is a chain of amino acids produced by the cow's pituitary gland. Like other hormones, it is produced in small quantities and is used in regulating metabolic processes...
for increasing milk production in dairy cows. Now retailers are permitted to label containers of milk as produced with or without bovine somatotropin.
Gene locus
Genes for human growth hormone, known as growth hormone 1Growth hormone 1
Somatotropin is a protein that in humans is encoded by the GH1 gene.-Further reading:...
(somatotropin) and growth hormone 2, are localized in the q22-24 region of chromosome 17 and are closely related to human chorionic somatomammotropin (also known as placental lactogen
Placental lactogen
Placental lactogen is a polypeptide placental hormone. Its structure and function is similar to that of growth hormone. It modifies the metabolic state of the mother during pregnancy to facilitate the energy supply of the fetus....
) genes. GH, human chorionic somatomammotropin, and prolactin
Prolactin
Prolactin also known as luteotropic hormone is a protein that in humans is encoded by the PRL gene.Prolactin is a peptide hormone discovered by Henry Friesen...
belong to a group of homologous hormones
Somatotropin family
Somatotropin is a hormone that plays an important role in growth control. It belongs to a family that includes choriomammotropin , its placental analogue; prolactin, which promotes lactation in the mammary gland, and placental prolactin-related proteins; proliferin and proliferin related protein;...
with growth-promoting and lactogenic activity.
Structure
The major isoform of the human growth hormone is a protein of 191 amino acidAmino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
s and a molecular weight of 22,124 daltons
Atomic mass unit
The unified atomic mass unit or dalton is a unit that is used for indicating mass on an atomic or molecular scale. It is defined as one twelfth of the rest mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state, and has a value of...
. 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
Species
In biology, a species is one of the basic units of biological classification and a taxonomic rank. A species is often defined as a group of organisms capable of interbreeding and producing fertile offspring. While in many cases this definition is adequate, more precise or differing measures are...
, only human and primate
Primate
A primate is a mammal of the order Primates , which contains prosimians and simians. Primates arose from ancestors that lived in the trees of tropical forests; many primate characteristics represent adaptations to life in this challenging three-dimensional environment...
growth hormones have significant effects in humans.
Several molecular
Molecule
A molecule is an electrically neutral group of at least two atoms held together by covalent chemical bonds. Molecules are distinguished from ions by their electrical charge...
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 glycosilated 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
Growth hormone receptor
Growth hormone receptor is a protein that in humans is encoded by the GHR gene. GHR orthologs have been identified in most mammals.-Interactions:...
, and an acid-labile subunit (ALS).
Biological regulation
Peptides released by neurosecretory nuclei of the hypothalamusHypothalamus
The Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...
(Growth hormone-releasing hormone/somatocrinin and Growth hormone-inhibiting hormone/somatostatin) into the hypophyseal portal
Hypophyseal portal system
The hypophyseal portal system is the system of blood vessels that link the hypothalamus and the anterior pituitary in the brain.It allows endocrine communication between the two structures. It is part of the hypothalamic-pituitary-adrenal axis. The anterior pituitary receives releasing and...
venous blood surrounding the pituitary are the major controllers of GH secretion by the somatotropes. However, although the balance of these stimulating and inhibiting peptides determines GH release, this balance is affected by many physiological stimulators (e.g., exercise, nutrition, sleep) and inhibitors of GH secretion (e.g., Free fatty acids)
Stimulators of HGH secretion include:
- peptide hormones
- Growth hormone-releasing hormone (GHRH) through binding to the growth hormone-releasing hormone receptor (GHRHRGrowth hormone releasing hormone receptorThe growth-hormone-releasing hormone receptor is a G-protein-coupled receptor that binds growth hormone-releasing hormone. The GHRHR activates a Gs protein that causes a cascade of cAMP via Adenylate cyclase.-External links:*...
) - ghrelinGhrelinGhrelin is a 28 amino acid peptide and hormone that is produced mainly by P/D1 cells lining the fundus of the human stomach and epsilon cells of the pancreas that stimulates hunger. Ghrelin levels increase before meals and decrease after meals. It is considered the counterpart of the hormone...
through binding to growth hormone secretagogue receptors (GHSRGrowth hormone secretagogue receptorGrowth hormone secretagogue receptor is a G protein-coupled receptor that binds ghrelin and plays a role in energy homeostasis and regulation of body weight.-Function:...
)
- Growth hormone-releasing hormone (GHRH) through binding to the growth hormone-releasing hormone receptor (GHRHR
- sex hormones
- increased androgenAndrogenAndrogen, also called androgenic hormone or testoid, is the generic term for any natural or synthetic compound, usually a steroid hormone, that stimulates or controls the development and maintenance of male characteristics in vertebrates by binding to androgen receptors...
secretion during puberty (in males from testis and in females from adrenal cortex) - estrogenEstrogenEstrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
- increased androgen
- clonidineClonidineClonidine is a sympatholytic medication used to treat medical conditions, such as high blood pressure, some pain conditions, ADHD and anxiety/panic disorder...
and L-DOPA by stimulating GHRH release - hypoglycemiaHypoglycemiaHypoglycemia or hypoglycæmia is the medical term for a state produced by a lower than normal level of blood glucose. The term literally means "under-sweet blood"...
, arginineArginineArginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...
and propranolol by inhibiting somatostatinSomatostatinSomatostatin is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with G-protein-coupled somatostatin receptors and inhibition of the release of numerous secondary hormones.Somatostatin...
release
- deep sleep
- niacinNiacin"Niacin" redirects here. For the neo-fusion band, see Niacin .Niacin is an organic compound with the formula and, depending on the definition used, one of the forty to eighty essential human nutrients.Niacin is one of five vitamins associated with a pandemic deficiency disease: niacin deficiency...
as nicotinic acid - fastingFastingFasting is primarily the act of willingly abstaining from some or all food, drink, or both, for a period of time. An absolute fast is normally defined as abstinence from all food and liquid for a defined period, usually a single day , or several days. Other fasts may be only partially restrictive,...
- vigorous exercise
Inhibitors of GH secretion include:
- somatostatinSomatostatinSomatostatin is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with G-protein-coupled somatostatin receptors and inhibition of the release of numerous secondary hormones.Somatostatin...
from the periventricular nucleusPeriventricular nucleusThe Periventricular nucleus is a thin sheet of small neurons located in the wall of the third ventricle, a composite structure of the hypothalamus. Functions in analgesia.... - circulating concentrations of GH and IGF-1 (negative feedbackNegative feedbackNegative feedback occurs when the output of a system acts to oppose changes to the input of the system, with the result that the changes are attenuated. If the overall feedback of the system is negative, then the system will tend to be stable.- Overview :...
on the pituitary and hypothalamusHypothalamusThe Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...
) - hyperglycemiaHyperglycemiaHyperglycemia or Hyperglycæmia, or high blood sugar, is a condition in which an excessive amount of glucose circulates in the blood plasma. This is generally a glucose level higher than 13.5mmol/l , but symptoms may not start to become noticeable until even higher values such as 15-20 mmol/l...
- glucocorticoidGlucocorticoidGlucocorticoids are a class of steroid hormones that bind to the glucocorticoid receptor , which is present in almost every vertebrate animal cell...
s - dihydrotestosteroneDihydrotestosteroneDihydrotestosterone is an androgen or male sex hormone. The enzyme 5α-reductase synthesises DHT in the prostate, testes, hair follicles, and adrenal glands...
In addition to control by endogenous and stimulus processes, a number of foreign compounds (xenobiotics such as drugs and endocrine disruptor
Endocrine disruptor
Endocrine disruptors are chemicals that interfere with endocrine in animals, including humans. These disruptions can cause cancerous tumors, birth defects, and other developmental disorders...
s) are known to influence GH secretion and function.
HGH is synthesized and secreted from the anterior pituitary
Anterior pituitary
A major organ of the endocrine system, the anterior pituitary, also called the adenohypophysis, is the glandular, anterior lobe of the pituitary gland...
gland in a pulsatile manner throughout the day; surges of secretion occur at 3- to 5-hour intervals. The plasma concentration of GH during these peaks may range from 5 to even 45 ng/mL. The largest and most predictable of these GH peaks occurs about an hour after onset of sleep. Otherwise there is wide variation between days and individuals. Nearly fifty percent of HGH secretion occurs during the third and fourth NREM sleep stages. 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 HGH secretion, such as age, gender, diet, exercise, stress, and other hormones. Young adolescents secrete HGH at the rate of about 700 μg/day, while healthy adults secrete HGH at the rate of about 400 μg/day.
Normal functions of GH produced by the body
Anabolism
Anabolism is the set of metabolic pathways that construct molecules from smaller units. These reactions require energy. One way of categorizing metabolic processes, whether at the cellular, organ or organism level is as 'anabolic' or as 'catabolic', which is the opposite...
(building up). Like most other protein hormones, GH acts by interacting with a specific receptor
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
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 sarcolemmaSarcolemmaThe sarcolemma is the cell membrane of a muscle cell . It consists of a true cell membrane, called the plasma membrane, and an outer coat made up of a thin layer of polysaccharide material that contains numerous thin collagen fibrils...
. Thus, GH exerts some of its effects by binding to receptors on target cells, where it activates the MAPK/ERK pathwayMAPK/ERK pathwayThe MAPK/ERK pathway is a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell. The signal starts when a growth factor binds to the receptor on the cell surface and ends when the DNA in the nucleus expresses a...
. Through this mechanism GH directly stimulates division and multiplication of chondrocytes of cartilageCartilageCartilage is a flexible connective tissue found in many areas in the bodies of humans and other animals, including the joints between bones, the rib cage, the ear, the nose, the elbow, the knee, the ankle, the bronchial tubes and the intervertebral discs...
. - GH also stimulates, through the JAK-STAT signaling pathwayJAK-STAT signaling pathwayThe JAK-STAT signaling pathway transmits information from chemical signals outside the cell, through the cell membrane, and into gene promoters on the DNA in the cell nucleus, which causes DNA transcription and activity in the cell. The JAK-STAT system is a major signaling alternative to the second...
, the production of insulin-like growth factor 1Insulin-like growth factor 1Insulin-like growth factor 1 also known as somatomedin C is a protein that in humans is encoded by the IGF1 gene. IGF-1 has also been referred to as a "sulfation factor" and its effects were termed "nonsuppressible insulin-like activity" in the 1970s.IGF-1 is a hormone similar in molecular...
(IGF-1, formerly known as somatomedin C), a hormone homologous to proinsulinProinsulinProinsulin is the prohormone precursor to insulin made in the beta cells of the islets of Langerhans, specialized regions of the pancreas. In humans, proinsulin is encoded by the INS gene.- Synthesis and post-translational modification :...
. The liverLiverThe liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
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 calciumCalciumCalcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
retention, and strengthens and increases the mineralization of bone - Increases muscleMuscleMuscle is a contractile tissue of animals and is derived from the mesodermal layer of embryonic germ cells. Muscle cells contain contractile filaments that move past each other and change the size of the cell. They are classified as skeletal, cardiac, or smooth muscles. Their function is to...
mass through sarcomereSarcomereA sarcomere is the basic unit of a muscle. Muscles are composed of tubular muscle cells . Muscle cells are composed of tubular myofibrils. Myofibrils are composed of repeating sections of sarcomeres, which appear under the microscope as dark and light bands...
hyperplasiaHyperplasiaHyperplasia means increase in number of cells/proliferation of cells. It may result in the gross enlargement of an organ and the term is sometimes mixed with benign neoplasia/ benign tumor.... - Promotes lipolysisLipolysisLipolysis is the breakdown of lipids and involves the hydrolysis of triglycerides into free fatty acids followed by further degradation into acetyl units by beta oxidation. The process produces Ketones, which are found in large quantities in ketosis, a metabolic state that occurs when the liver...
- Increases protein synthesis
- Stimulates the growth of all internal organs excluding the brainBrainThe brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
- Plays a role in homeostasisHomeostasisHomeostasis is the property of a system that regulates its internal environment and tends to maintain a stable, constant condition of properties like temperature or pH...
- Reduces liverLiverThe liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
uptake of glucoseGlucoseGlucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate... - Promotes gluconeogenesisGluconeogenesisGluconeogenesis is a metabolic pathway that results in the generation of glucose from non-carbohydrate carbon substrates such as lactate, glycerol, and glucogenic amino acids....
in the liver - Contributes to the maintenance and function of pancreatic islets
- Stimulates the immune systemImmune systemAn immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
Problems caused when the body produces too much GH
The most common disease of GH excess is a pituitary tumor composed of somatotroph cells of the anterior pituitary. These somatotroph adenomaAdenoma
An adenoma is a benign tumor of glandular origin. Adenomas can grow from many organs including the colon, adrenal glands, pituitary gland, thyroid, prostate, etc. Although these growths are benign, over time they may progress to become malignant, at which point they are called adenocarcinomas...
s 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 is referred to as acromegaly
Acromegaly
Acromegaly is a syndrome that results when the anterior pituitary gland produces excess growth hormone after epiphyseal plate closure at puberty...
. Accompanying problems can include sweating, pressure on nerves (e.g., carpal tunnel syndrome
Carpal tunnel syndrome
Carpal Tunnel Syndrome is an entrapment idiopathic median neuropathy, causing paresthesia, pain, and other symptoms in the distribution of the median nerve due to its compression at the wrist in the carpal tunnel. The pathophysiology is not completely understood but can be considered compression...
), muscle weakness, excess sex hormone-binding globulin (SHBG), insulin resistance or even a rare form of type 2 diabetes
Diabetes mellitus type 2
Diabetes mellitus type 2formerly non-insulin-dependent diabetes mellitus or adult-onset diabetesis a metabolic disorder that is characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency. Diabetes is often initially managed by increasing exercise and...
, 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
Gigantism
Gigantism, also known as giantism , is a condition characterized by excessive growth and height significantly above average...
.
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.
Problems caused when the body produces too little GH
The effects of growth hormone deficiencyGrowth hormone deficiency
Growth hormone deficiency is a medical condition in which the body does not produce enough growth hormone . Growth hormone, also called somatotropin, is a polypeptide hormone which stimulates growth and cell reproduction...
vary depending on the age at which they occur. In children, growth failure and short stature
Short stature
Short stature refers to a height of a human being which is below expected. Shortness is a vague term without a precise definition and with significant relativity to context...
are the major manifestations of GH deficiency, with common causes including genetic conditions and congenital malformations. It can also cause delayed sexual maturity. In adults, deficiency is rare, with the most common cause a pituitary adenoma, and others including a continuation of a childhood problem, other structural lesions or trauma, and very rarely idiopathic GHD.
Adults with GHD present with non-specific problems including truncal obesity with 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.
GH in human medicine
See sections above for problems caused when the body produces too much GH or too little GH.FDA-approved treatments with GH related to deficiency of GH
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 (after completing growth phase) 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.FDA-approved treatments with GH unrelated to deficiency of GH
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 syndromeTurner syndrome
Turner syndrome or Ullrich-Turner syndrome encompasses several conditions in human females, of which monosomy X is most common. It is a chromosomal abnormality in which all or part of one of the sex chromosomes is absent...
, chronic renal failure
Chronic renal failure
Chronic kidney disease , also known as chronic renal disease, is a progressive loss in renal function over a period of months or years. The symptoms of worsening kidney function are unspecific, and might include feeling generally unwell and experiencing a reduced appetite...
, Prader–Willi syndrome, intrauterine growth retardation, and severe idiopathic short stature
Idiopathic short stature
Idiopathic short stature refers to extreme short stature that does not have a diagnostic explanation after an ordinary growth evaluation...
. 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.
Experimental uses
The following discussion describes experimental uses of GH, that are legal when the GH is prescribed by a doctor. However, the efficacy and safety of use of GH as anti-aging agent are unknown as this use has not been tested in a double-blinded clinical trialClinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
.
In recent years in the United States, some doctors have started to prescribe growth hormone in GH-deficient older patients (but not on healthy people) to increase vitality. While legal, the efficacy and safety of this use for HGH has not been tested in a clinical trial. At this time, hGH is still considered a very complex hormone, and many of its functions are still unknown.
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, 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
American Academy of Anti-Aging Medicine
The American Academy of Anti-Aging Medicine is a United States registered 501 nonprofit organization that promotes the field of anti-aging medicine and trains and certifies physicians in this specialty. As of 2011, approximately 26,000 practitioners had been given certificates...
promoting the use of this hormone as an "anti-aging agent".
A Stanford University School of Medicine survey 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
Multiple sclerosis
Multiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...
, to enhance weight loss
Weight loss
Weight loss, in the context of medicine, health or physical fitness, is a reduction of the total body mass, due to a mean loss of fluid, body fat or adipose tissue and/or lean mass, namely bone mineral deposits, muscle, tendon and other connective tissue...
in obesity
Obesity
Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems...
, as well as in fibromyalgia
Fibromyalgia
Fibromyalgia is a medical disorder characterized by chronic widespread pain and allodynia, a heightened and painful response to pressure. It is an example of a diagnosis of exclusion...
, heart failure, Crohn's disease
Crohn's disease
Crohn's disease, also known as regional enteritis, is a type of inflammatory bowel disease that may affect any part of the gastrointestinal tract from mouth to anus, causing a wide variety of symptoms...
and ulcerative colitis
Ulcerative colitis
Ulcerative colitis is a form of inflammatory bowel disease . Ulcerative colitis is a form of colitis, a disease of the colon , that includes characteristic ulcers, or open sores. The main symptom of active disease is usually constant diarrhea mixed with blood, of gradual onset...
, and burns. GH has also been used in maintaining muscle mass in wasting
Wasting
In medicine, wasting refers to the process by which a debilitating disease causes muscle and fat tissue to "waste" away. Wasting is sometimes referred to as "acute malnutrition" because it is believed that episodes of wasting have a short duration, in contrast to stunting, which is regarded as...
due to AIDS
AIDS
Acquired immune deficiency syndrome or acquired immunodeficiency syndrome is a disease of the human immune system caused by the human immunodeficiency virus...
and in patients with short bowel syndrome
Short bowel syndrome
Short bowel syndrome is a malabsorption disorder caused by the surgical removal of the small intestine, or rarely due to the complete dysfunction of a large segment of bowel. Most cases are acquired, although some children are born with a congenital short bowel...
to lessen the requirement for intravenous total parenteral nutrition
Total parenteral nutrition
Parenteral nutrition is feeding a person intravenously, bypassing the usual process of eating and digestion. The person receives nutritional formulae that contain nutrients such as glucose, amino acids, lipids and added vitamins and dietary minerals...
.
Side-effects
Use of GH as a drug has been approved by the FDA for several indications. This means that the drug has acceptable safety in light of its benefits when used in the approved way. Like every drug, there are several side effects caused by GH, some common, some rare. Injection-site reaction is common. More rarely, patients can experience joint swelling, joint pain, carpal tunnel syndromeCarpal tunnel syndrome
Carpal Tunnel Syndrome is an entrapment idiopathic median neuropathy, causing paresthesia, pain, and other symptoms in the distribution of the median nerve due to its compression at the wrist in the carpal tunnel. The pathophysiology is not completely understood but can be considered compression...
, 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
Hodgkin's lymphoma
Hodgkin's lymphoma, previously known as Hodgkin's disease, is a type of lymphoma, which is a cancer originating from white blood cells called lymphocytes...
.
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.
Non-medical use in athletic enhancement
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. In the United States, GH is legally available only by prescription from a medical doctor.Use of GH in production of meat and milk
In the United States, it is legal to give a bovine GH to dairy cows to increase milk production, but it is not legal to use GH in raising cows for beef; see articles on Bovine somatotropinBovine somatotropin
Bovine somatotropin , or BGH, is a chain of amino acids produced by the cow's pituitary gland. Like other hormones, it is produced in small quantities and is used in regulating metabolic processes...
and cattle feeding
Cattle feeding
Different cattle feeding production systems have separate advantages and disadvantages. Most cows have a diet that is composed of at least some forage . In fact most beef cattle are raised on pasture from birth in the spring until autumn...
and dairy farming
Dairy farming
Dairy farming is a class of agricultural, or an animal husbandry, enterprise, for long-term production of milk, usually from dairy cows but also from goats and sheep, which may be either processed on-site or transported to a dairy factory for processing and eventual retail sale.Most dairy farms...
and Beef hormone controversy
Beef hormone controversy
The Beef Hormone Dispute is one of the two most intractable transatlantic agricultural disputes since the establishment of the World Trade Organization, the other being the Banana War....
.
Use in poultry farming
Poultry farming
Poultry farming is the raising of domesticated birds such as chickens, turkeys, ducks, and geese, for the purpose of farming meat or eggs for food. According to the Worldwatch Institute, 74 percent of the world's poultry meat, and 68 percent of eggs are produced in ways that are described as...
is illegal in the United States as per the poultry farming article.
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.
History of use and manufacture of GH as a drug
The identification, purification and later synthesis of growth hormone is associated with Choh Hao LiChoh Hao Li
Choh Hao Li was a Chinese-born U.S. biochemist who discovered, in 1966, that human pituitary growth hormone consists of a chain of 256 amino acids...
. Genentech
Genentech
Genentech Inc., or Genetic Engineering Technology, Inc., is a biotechnology corporation, founded in 1976 by venture capitalist Robert A. Swanson and biochemist Dr. Herbert Boyer. Trailing the founding of Cetus by five years, it was an important step in the evolution of the biotechnology industry...
pioneered the first use of recombinant
Recombinant DNA
Recombinant DNA molecules are DNA sequences that result from the use of laboratory methods to bring together genetic material from multiple sources, creating sequences that would not otherwise be found in biological organisms...
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 gland
Pituitary gland
In vertebrate anatomy the pituitary gland, or hypophysis, is an endocrine gland about the size of a pea and weighing 0.5 g , in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain, and rests in a small, bony cavity covered by a dural fold...
s of cadaver
Cadaver
A cadaver is a dead human body.Cadaver may also refer to:* Cadaver tomb, tomb featuring an effigy in the form of a decomposing body* Cadaver , a video game* cadaver A command-line WebDAV client for Unix....
s. 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. Furthermore, growth hormone from other primates was found to be inactive in humans.
In 1985, unusual cases of Creutzfeldt-Jacob 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
Genentech
Genentech Inc., or Genetic Engineering Technology, Inc., is a biotechnology corporation, founded in 1976 by venture capitalist Robert A. Swanson and biochemist Dr. Herbert Boyer. Trailing the founding of Cetus by five years, it was an important step in the evolution of the biotechnology industry...
), Humatrope (Lilly
Eli Lilly and Company
Eli Lilly and Company is a global pharmaceutical company. Eli Lilly's global headquarters is located in Indianapolis, Indiana, in the United States...
), Genotropin (Pfizer
Pfizer
Pfizer, Inc. is an American multinational pharmaceutical corporation. The company is based in New York City, New York with its research headquarters in Groton, Connecticut, United States...
), Norditropin (Novo
Novo Nordisk
Novo Nordisk manufactures and markets pharmaceutical products and services. Created in 1989 through a merger of two Danish companies dating back to the 1920s, it has become one of the world's leading companies in diabetes care, where Novo Nordisk pursues research into pulmonary delivery systems;...
), and Saizen (Merck Serono
Merck Serono
Merck Serono is a pharmaceutical company headquartered in Geneva, Switzerland. In September 2006, Merck KGaA announced its intent to purchase the majority of Serono shares from Ernesto Bertarelli and the Bertarelli family. The Merck-Serono merger was announced on September 21, 2006...
). 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).