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08-SEPTEMBER-2008 07:42:01 - Growth hormone Redirected from Human Growth Hormone January 2008 Growth hormone growth hormone 1 Identifiers Symbol GH1 Entrez 2688 HUGO 4261 OMIM 139250 RefSeq NM_022562 UniProt P01241 Other data Locus Chr. 17 q22-q24 HGH redirects here. For other uses, see HGH disambiguation. Growth hormone GH is a peptide hormone that stimulates growth and cell reproduction in humans and other animals. It is a 191-amino acid, single chain polypeptide hormone which is synthesized, stored, and secreted by the somatotroph cells within the lateral wings of the anterior pituitary gland. Somatotrophin refers to the growth hormone produced natively in animals, the term somatropin refers to growth hormone produced by recombinant DNA technology1, and is abbreviated rhGH in human. Growth hormone has a variety of functions in the body, the most noticeable of which is the increase of height throughout childhood, and there are several diseases which can be treated through the therapeutic use of GH. Contents 1 Gene locus 2 Molecular structures 3 Secretion 3.1 Regulation 3.2 Secretion patterns 4 Functions of GH 4.1 Excesses 4.2 Deficiencies 5 Therapeutic use 5.1 Treatments unrelated to deficiency 5.2 Anti-aging agent 5.3 Side effects 6 History 7 References Gene locus Main article: Growth hormone 1 The genes for human growth hormone, known as Growth hormone 1, 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 PRL are a group of homologous hormones with growth-promoting and lactogenic activity. Molecular structures 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. GH is structurally and apparently 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. Secretion Several molecular isoforms of GH circulate in the plasma. Much of the growth hormone in the circulation is bound to a protein growth hormone binding protein, GHBP which is derived from the growth hormone receptor, and an acid label sub unit ALS. Regulation Peptides released by neurosecretory nuclei of the hypothalamus Growth hormone releasing hormone and somatostatin into the 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. 2 Stimulators of GH secretion include: growth hormone releasing hormone GHRH from the arcuate nucleus ghrelin sleep exercise low levels of blood sugar hypoglycemia dietary protein increased androgen secretion during puberty in males from testis and in females from adrenal cortex arginine3 Inhibitors of GH secretion include: somatostatin from the periventricular nucleus circulating concentrations of GH and IGF-1 negative feedback hyperglycemia glucocorticoids estradiol In addition to control by endogenous processes, a number of foreign compounds xenobiotics are now known to influence GH secretion and function 4, highlighting the fact that the GH-IGF axis is an emerging target for certain endocrine disrupting chemicals see endocrine disruptor. Secretion patterns Most of the physiologically important secretion occurs as several large pulses or peaks of GH release each daycitation needed. The plasma concentration of GH during these peaks may range from 5 to even 45 ng/mL Stokes, 2003citation needed. Peaks typically last from 10 to 30 minutes before returning to basal levels see a complete review, Laursen, 2003citation needed. The largest and most predictable of these GH peaks occurs about an hour after onset of sleep.5 Otherwise there is wide variation between days and individuals. Between the peaks, basal GH levels are low, usually less than 5 ng/mL for most of the day and night5. Additional analysis of the pulsatile profile of GH described in all cases less than 1 ng/ml for basal levels while maximum peaks where situated around 10-20 ng/ml Nindl et al, 2001, Juul et Jorgensen, 1996. The amount and pattern of GH secretion change throughout lifecitation needed. Basal levels are highest in early childhoodcitation needed. The amplitude and frequency of peaks is greatest during the pubertal growth spurtcitation needed. Healthy children and adolescents average about 8 peaks per 24 hourscitation needed. Adults average about 5 peakscitation needed. Basal levels and the frequency and amplitude of peaks decline throughout adult lifecitation needed. Functions of GH Effects of growth hormone on the tissues of the body can generally be described as anabolic building up as well as people with short stature, grow taller. Like most other protein hormones GH acts by interacting with a specific receptor on the surface of cells. Stimulating the increase in height in childhood is the most widely known effect of GH, and appears to be stimulated by at least two mechanisms. GH directly stimulates division and multiplication of chondrocytes of cartilage. These are the primary cells in the growing ends epiphyses of children's long bones arms, legs, digits. GH also stimulates production of insulin-like growth factor 1 IGF-1, formerly known as somatomedin C, a hormone homologous to proinsulin.6 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 apparently 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 the sarcomere hyperplasia Promotes lipolysis Increases protein synthesis Stimulating the growth of all internal organs excluding the brain Plays a role in fuel homeostasis Reduces liver uptake of glucose Promotes gluconeogenesis in the liver7 It contributes to the maintenance and function of pancreatic islets It stimulates the immune system Excesses 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 thickness of digits is referred to as acromegaly. Accompanying problems can include pressure on nerves e.g., carpal tunnel syndrome, muscle weakness, 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 bromocriptine or octreotide may be employed to shrink the tumor or block function. Deficiencies Main article: Growth hormone deficiency The effects of growth hormone deficiency 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 rare8, 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 life8. 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. Treatment with external GH is only indicated in limited circumstances8, 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. Therapeutic use Treatments unrelated to deficiency GH can be used to treat conditions which produce short stature but are not related to deficiencies in GH, though results are not as dramatic when compared to short stature solely due to deficiency of GH. Examples of other causes of shortness often treated with GH are Turner syndrome, 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 physiologic. Despite the higher doses, side effects during treatment are rare, and vary little according to the condition being treated. GH treatment improves muscle strength and slightly reduces body fat in Prader-Willi syndrome, which are significant concerns beyond the need to increase height. GH is also useful in maintaining muscle mass in wasting due to AIDS. GH can also be used in patients with short bowel syndrome to lessen the requirement for intravenous total parenteral nutrition. Uses that are controversial include GH treatment for remission of Multiple sclerosis GH treatment to reverse effects of aging in older adults see below GH treatment to enhance weight loss in obesity GH treatment for fibromyalgia GH treatment for Crohn's disease and ulcerative colitis GH treatment for idiopathic short stature GH treatment for bodybuilding or athletic enhancement The use of bovine somatotropin to increase milk production in cattle Anti-aging agent Claims for GH as an anti-aging treatment date back to 1990 when the New England Journal of Medicine published a study where 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 GH was an effective anti-aging agent. 9 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.9 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.9 Researchers also didn't 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. Regular application of GH did show several negative side effects such as joint swelling, joint pain, carpal tunnel syndrome, and an increased risk of diabetes.9 Side effects Main article: HGH controversies There is theoretical concern that GH treatment may increase the risks of diabetes, especially in those with other predispositions treated with higher doses. One survey of adults who 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, but linkage with the GH treatment was not established.10 History Main article: Growth hormone treatment#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. In 1985, biosynthetic human growth hormone replaced pituitary-derived human growth hormone for therapeutic use in the U.S. and elsewhere. GH is also known to increase chances of breast cancer and lung cancer. 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 Association 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 in 2004. References ^ e.g., Daniels, M.E. 1992. Lilly's Humatrope Experience. Nature Biotechnology 10: 812. ^ Actions of Anterior Pituitary Hormones: Growth Hormone GH. Medical College of Georgia. 2007. ^ Alba-Roth J, Müller O, Schopohl J, von Werder K 1988. Arginine stimulates growth hormone secretion by suppressing endogenous somatostatin secretion. J Clin Endocrinol Metab 67 6: 1186-9. doi:10.1126/science.2237411.br inactive 2008-06-26. PMID 2903866. ^ Scarth J. Modulation of the growth hormone-insulin-like growth factor GH-IGF axis by pharmaceutical, nutraceutical and environmental xenobiotics: an emerging role for xenobiotic-metabolizing enzymes and the transcription factors regulating their expression. A review. Xenobiotica 36 2-3: 119-218. PMID 16702112. ^ a b Takahashi Y, Kipnis D, Daughaday W 1968. Growth hormone secretion during sleep. J Clin Invest 47 9: 2079-90. doi:10.1172/JCI105893. PMID 5675428. ^ Actions of Anterior Pituitary Hormones: Physiologic Actions of GH. Medical College of Georgia 2007. Retrieved on 2008-01-16. ^ King, MW 2006. Structure and Function of Hormones: Growth Hormone. Indiana State University. Retrieved on 2008-01-16. ^ a b c Molitch ME, Clemmons DR, Malozowski S, et al May 2006. Evaluation and treatment of adult growth hormone deficiency: an Endocrine Society Clinical Practice Guideline. J. Clin. Endocrinol. Metab. 91 5: 1621-34. doi:10.1210/jc.2005-2227. PMID 16636129. Retrieved on 2008-07-23. ^ a b c d Liu H, Bravata DM, Olkin I, et al 2007. Systematic review: the safety and efficacy of growth hormone in the healthy elderly. Ann. Intern. Med. 146 2: 104-15. PMID 17227934. ; news report ^ Swerdlow AJ, Higgins CD, Adlard P, Preece MA 2002. Risk of cancer in patients treated with human pituitary growth hormone in the UK, 1959-85: a cohort study. Lancet 360 9329: 273-7. doi:10.1016/S0140-67360209519-3. PMID 12147369. Retrieved from http://en..org/wiki/Growth_hormone Categories: Genes on chromosome 17Hidden categories: Pages with DOIs broken since 2008 | Articles needing additional references from January 2008 | All articles with statements | Articles with statements since August 2008 Views Article Discussion this page History Personal tools Log in / create account Navigation Main page Contents Featured content Current events Random article Search Go Search Interaction Community portal Recent changes Contact Donate to Help Toolbox What links here Related changes Upload file Special pages Printable version Permanent link Cite this page Languages العربية БългарÑ?ки Català Česky Deutsch Þ‹Þ¨ÞˆÞ¬Þ€Þ¨Þ„Þ¦Þ?Þ° Español Français Bahasa Indonesia Italiano עברית Lietuvių МакедонÑ?ки Nederlands 日本語 ‪Norsk bokmÃ¥l‬ Polski Português РуÑ?Ñ?кий Shqip SlovenÄ?ina SlovenÅ¡Ä?ina СрпÑ?ки / Srpski Suomi Svenska This page was last modified on 28 August 2008, at 09:0
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