Growth hormone
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Growth hormone (GH) or somatotropin, also known as human growth hormone (hGH or HGH) in its human form, is a
A
In its role as an
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
The term growth hormone has been incorrectly applied to refer to
Biology
Gene
Genes for human growth hormone, known as
Structure
The major isoform of the human growth hormone is a protein of 191
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,[10] while recently an additional variant of ~ 23-24 kDa has also been reported in post-exercise states at higher proportions.[11] 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.[12] 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
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.[14] Maximal secretion of GH may occur within minutes of the onset of
A number of factors are known to affect GH secretion, such as age, sex, diet, exercise, stress, and other hormones.[3] 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.[20] Sleep deprivation generally suppresses GH release, particularly after early adulthood.[21]
Stimulators[quantify] of growth hormone (GH) secretion include:
- Peptide hormones
- Sex hormones[24]
- Clonidine and L-DOPA by stimulating GHRH release[25]
- α4β2 nicotinic agonists, including nicotine, which also act synergistically with clonidine.[26][27][28]
- Hypoglycemia, arginine,[29] pramipexole[30] and propranolol by inhibiting somatostatin release[25]
- Deep sleep[31]
- Glucagon
- Niacin as nicotinic acid (vitamin B3)[32]
- Fasting[33]
- Insulin[34]
- Vigorous exercise[35]
Inhibitors[quantify] of GH secretion include:
- GHIH (somatostatin) from the periventricular nucleus [36]
- circulating concentrations of GH and
- Hyperglycemia[25]
- Glucocorticoids[37]
- 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.[38]
Function
Effects of growth hormone on the tissues of the body can generally be described as anabolic (building up). Like most other peptide 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 cell membranes. Thus, GH exerts some of its effects by binding to receptors on target cells, where it activates the MAPK/ERK pathway.[39] Through this mechanism GH directly stimulates division and multiplication of chondrocytes of cartilage.
- GH also stimulates, through the paracrine hormone. IGF-1 also has stimulatory effects on osteoblast and chondrocyteactivity to promote bone growth.
In addition to increasing height in children and adolescents, growth hormone has many other effects on the body:
- Increases 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[42]
- Contributes to the maintenance and function of pancreatic islets
- Stimulates the immune system
- Increases deiodination of T4 to T3[43]
- Induces insulin resistance[44]
Biochemistry
GH has a short biological half-life of about 10 to 20 minutes.[45][46]
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 in heaviness of the jaw and increased size of digits, referred to as
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.[47]
Deficiency
The effects of
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".[49]
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.[50] 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.[50]
Cognitive function
GH has also been studied in the context of
Medical uses
Replacement therapy
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. Long acting growth hormone (LAGH) analogues are now available for treating growth hormone deficiency both in children and adults. These are once weekly injections as compared to conventional growth hormone which has to be taken as daily injections. LAGH injection 4 times a month has been found to be as safe and effective as daily growth hormone injections.[52]
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, Growth failure secondary to chronic kidney disease in children,[53] 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").[citation needed]
One version of rHGH has also been FDA approved for maintaining muscle mass in
Off-label use
Off-label prescription of HGH is controversial and may be illegal.[55]
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.[56] 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.[57][58][59] 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".[60]
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.[57] 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.[57] 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
In 1990, the US Congress passed an omnibus crime bill, the
The
Side effects
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.[69]
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.[70]
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.[71][72][73] 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.[74]
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.[75][76] Similarly, no chicken meat for sale in Australia is administered hormones.[77]
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.[78]
Drug development history
Genentech pioneered the use of recombinant human growth hormone for human therapy, which was approved by the FDA in 1985.
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.[79] 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.[80] 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."[80] 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.[81]
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.[20]
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 (
See also
References
- PMID 21584161.
- S2CID 1829264.
- ^ ISBN 978-1-55642-594-3.
- S2CID 46453790.
- PMID 16799101.
- S2CID 154707486.
- ^ "GH1 growth hormone 1 (Homo sapiens) - Gene". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "GH2 growth hormone 2 (Homo sapiens) - Gene". National Center for Biotechnology Information, U.S. National Library of Medicine.
- PMID 12082127.
- PMID 12217902.
- S2CID 22525768.
- PMID 19579232.
- ISBN 978-0-321-53910-6.
- ^ PMID 5675428.
- PMID 10984255.
- S2CID 23663131.
- PMID 808970.
- S2CID 16101442.
- PMID 8719443.
- ^ ISBN 978-0-07-144011-0.
- S2CID 3328167.
- S2CID 6263928.
- PMID 11089570.
- S2CID 20688016.
- ^ PMID 1901390.
- PMID 18042647.
- S2CID 37559511.
- PMID 6508989.
- S2CID 7488757.
- PMID 17578485.
- PMID 15135771.
- PMID 6345570.
- PMID 15809014.
- ^ "Greenspan's Basic & Clinical Endocrinology 10th Edition"
- PMID 9375348.
- PMID 779605.
- PMID 8879994.
- S2CID 40503492.
- ^ )
- ^ "Actions of Anterior Pituitary Hormones: Physiologic Actions of GH". Medical College of Georgia. 2007. Archived from the original on 2008-01-11. Retrieved 2008-01-16.
- PMID 12788900.
- ^ King MW (2006). "Structure and Function of Hormones: Growth Hormone". Indiana State University. Archived from the original on 2007-12-06. Retrieved 2008-01-16.
- ^ T.F. Davies (ed.), A Case-Based Guide to Clinical Endocrinology, 2008, pag.16
- PMID 32966863.
- ISBN 978-1-60456-438-9.
- ^ "Norditropin® (somatropin) injection, for subcutaneous use" (PDF). Novo Nordisk A/S. U.S. Food and Drug Administration.
- PMID 31244908.
- ^ ISBN 978-1455772551.
- ^ PMID 16636129.
- ^ PMID 23123585.
- ^ S2CID 33876345.
- S2CID 246689650.
- ^ "UpToDate". www.uptodate.com. Retrieved 2022-12-08.
- PMID 11367383.
- ^ a b DEA, US Department of Justice. DEA: Genotropin Archived 2015-04-04 at the Wayback Machine Quote: "The illicit distribution of hGH occurs as the result of physicians illegally prescribing it for off-label uses, and for the treatment of FDA-approved medical conditions without examination and supervision"
- PMID 2355952.
- ^ S2CID 27279712.
- ^ "No proof that growth hormone therapy makes you live longer, study finds". PhysOrg.com. 2007-01-16. Retrieved 2009-03-16.
- ^ Kreidler M (June 5, 2016). "Growth Hormone Schemes and Scams | Quackwatch".
- ^ Kuczynski A (1998-04-12). "Anti-Aging Potion or Poison?". New York Times.
- ISBN 9780415280341 p. 376
- ^ "21 U.S. Code § 333 – Penalties". LII / Legal Information Institute.
- ^ Barclay L, Lie D (October 28, 2005). "Growth Hormone Deemed Illegal for Off-Label Antiaging Use". Medscape.
- PMID 16249424.
- ^ a b Caruso D, Donn J (December 21, 2012). "Big Pharma Cashes in on HGH Abuse". AP Impact. Associated Press. Archived from the original on August 12, 2014. Retrieved August 10, 2014.
- ^ Edwards J (March 20, 2006). "Bad Medicine". BrandWeek. Archived from the original on 28 March 2006.
- ^ a b Zeman N (March 2012). "Hollywood's Vial Bodies". Vanity Fair.
- PMID 16284435.
- S2CID 16216532.
- PMID 19467612.
- PMID 18347346.
- ^ Randall T (2008-03-17). "Athletes Don't Benefit From Human Growth Hormone, Study Finds". Bloomberg. Retrieved 2011-08-28.
- ^ Gaffney G (2008-03-17). "Steroid Nation: Review from Stanford says HGH no benefit as PED". Steroid Nation. Retrieved 2011-08-28.
- ^ Singleton ER (2010-06-04). "Atlas Operations, Inc". Warning Letter. U.S. Food and Drug Administration. Retrieved 2011-08-28.
- ^ "Chicken from Farm to Table | USDA Food Safety and Inspection Service". Fsis.usda.gov. 2011-04-06. Archived from the original on 2011-09-03. Retrieved 2011-08-26.
- ^ "Poultry Industry Frequently Asked Questions". U.S. Poultry & Egg Association. Retrieved June 21, 2012.
- ^ "Hormones". Australian Chicken Meat Federation. Archived from the original on 1 July 2016. Retrieved 20 June 2016.
- ^ "Center for Veterinary Medicine Master" (PDF). www.fda.gov. 2011-04-06. Retrieved 2011-08-28.
- ISBN 978-0-8493-5542-4.
- ^ PMID 13421688.
- PMID 13595475.
- ^ "FDA Response to three Citizen Petitions against biosimilars" (PDF), FDA, 30 May 2006, retrieved 23 November 2015
- ^ In 2023, the FDA approved a different sustained-release form of growth hormone, Sogroya® (somapacitan-beco) (Novo) for both pediatric patients (2.5 years and older) and adult patients, whom have growth failure due to inadequate secretion of endogenous growth hormone (rHGH). Previously, the human growth hormone analog had only been approved for adult patients with growth hormone deficiency (AGHD). "Genentech and Alkermes Announce Decision to Discontinue Commercialization of Nutropin Depot". Press Release. Business Wire. 2004-06-01. Retrieved 2011-08-28.
External links
- Media related to Growth hormones at Wikimedia Commons