Array ( [0] => {{Short description|Protein that stimulates red blood cell production}} [1] => {{Use dmy dates|date=April 2022}} [2] => {{Infobox_gene}} [3] => '''Erythropoietin''' ({{IPAc-en|ɪ|ˌ|r|ɪ|θ|r|oʊ|ˈ|p|ɔɪ|.|ᵻ|t|ɪ|n|,_|-|r|ə|-|,_|-|p|ɔɪ|ˈ|ɛ|t|ɪ|n|,_|-|ˈ|iː|t|ɪ|n}};{{refn|{{MerriamWebsterDictionary|Erythropoietin}}}}{{refn|{{Dictionary.com|Erythropoietin}}}}{{refn|{{cite web |url=https://www.oxforddictionaries.com/definition/english/erythropoietin |archive-url=https://web.archive.org/web/20120927080345/http://oxforddictionaries.com/definition/english/erythropoietin |url-status=dead |archive-date=27 September 2012 |title=erythropoietin – definition of erythropoietin in English from the Oxford dictionary |publisher=[[OxfordDictionaries.com]] |access-date=20 January 2016 }} }} '''EPO'''), also known as '''erythropoetin''', '''haematopoietin''', or '''haemopoietin''', is a [[glycoprotein]] [[cytokine]] secreted mainly by the [[kidney]]s in response to cellular [[Hypoxia (medical)|hypoxia]]; it stimulates [[red blood cell]] production ([[erythropoiesis]]) in the [[bone marrow]]. Low levels of EPO (around 10 [[Enzyme unit|mU]]/mL) are constantly secreted in sufficient quantities to compensate for normal red blood cell turnover. Common causes of cellular hypoxia resulting in elevated levels of EPO (up to 10 000 mU/mL) include any [[anemia]], and [[hypoxemia]] due to chronic lung disease and mouth disease. [4] => [5] => Erythropoietin is produced by interstitial [[fibroblast]]s in the kidney in close association with the [[peritubular capillary]] and [[proximal convoluted tubule]]. It is also produced in [[Perisinusoidal space|perisinusoidal]] cells in the [[liver]]. Liver production predominates in the fetal and perinatal period; renal production predominates in adulthood. It is homologous with [[thrombopoietin]]. [6] => [7] => [[Exogeny|Exogenous]] erythropoietin, recombinant human erythropoietin (rhEPO), is produced by [[recombinant DNA technology]] in [[cell culture]] and are collectively called [[erythropoiesis-stimulating agent]]s (ESA): two examples are [[epoetin alfa]] and [[epoetin beta]]. ESAs are used in the treatment of [[anemia]] in [[chronic kidney disease]], anemia in [[myelodysplasia]], and in anemia from [[cancer]] [[chemotherapy]]. Risks of therapy include death, [[myocardial infarction]], [[stroke]], [[venous thromboembolism]], and tumor recurrence. Risk increases when EPO treatment raises hemoglobin levels over 11 g/dL to 12 g/dL: this is to be avoided. [8] => [9] => rhEPO has been used illicitly as a [[performance-enhancing drug]].{{cite journal | vauthors = Momaya A, Fawal M, Estes R | title = Performance-enhancing substances in sports: a review of the literature | journal = Sports Medicine | volume = 45 | issue = 4 | pages = 517–31 | date = April 2015 | pmid = 25663250 | doi = 10.1007/s40279-015-0308-9 | s2cid = 45124293 }} It can often be detected in blood, due to slight differences from the endogenous protein; for example, in features of [[posttranslational modification]]. [10] => [11] => ==Pharmacology== [12] => EPO is highly [[glycosylation|glycosylated]] (40% of total molecular weight), with half-life in blood around 5 h. EPO's half-life may vary between endogenous and various recombinant versions. Additional glycosylation or other alterations of EPO via recombinant technology have led to the increase of EPO's stability in blood (thus requiring less frequent injections). [13] => [14] => == Function == [15] => [16] => === Red blood cell production === [17] => Erythropoietin is an essential hormone for red blood cell production. Without it, definitive [[erythropoiesis]] does not take place. Under [[hypoxia (medical)|hypoxic]] conditions, the kidney will produce and secrete erythropoietin to increase the production of red blood cells by targeting [[CFU-E]], pro[[erythroblast]] and basophilic erythroblast subsets in the differentiation. Erythropoietin has its primary effect on red blood cell progenitors and precursors (which are found in the bone marrow in humans) by promoting their survival through protecting these cells from [[apoptosis]], or cell death. [18] => [19] => Erythropoietin is the primary erythropoietic factor that cooperates with various other growth factors (e.g., [[interleukin 3|IL-3]], [[Interleukin 6|IL-6]], [[glucocorticoid]]s, and [[stem cell factor|SCF]]) involved in the development of [[erythroid]] lineage from [[stem cell|multipotent progenitors]]. The burst-forming unit-erythroid ([[BFU-E]]) cells start [[erythropoietin receptor]] expression and are sensitive to erythropoietin. Subsequent stage, the colony-forming unit-erythroid ([[CFU-E]]), expresses maximal erythropoietin receptor density and is completely dependent on erythropoietin for further differentiation. Precursors of red cells, the proerythroblasts and basophilic erythroblasts also express erythropoietin receptor and are therefore affected by it. [20] => [21] => === Nonhematopoietic roles === [22] => Erythropoietin was reported to have a range of actions beyond stimulation of erythropoiesis including [[vasoconstriction]]-dependent [[hypertension]], stimulating [[angiogenesis]], and promoting cell survival via activation of EPO receptors resulting in anti-apoptotic effects on ischemic tissues. However this proposal is controversial with numerous studies showing no effect.{{cite journal | vauthors = Elliott S, Sinclair AM | title = The effect of erythropoietin on normal and neoplastic cells | journal = Biologics: Targets and Therapy | volume = 6 | pages = 163–89 | year = 2012 | pmid = 22848149 | pmc = 3402043 | doi = 10.2147/BTT.S32281 | doi-access = free }} It is also inconsistent with the low levels of EPO receptors on those cells. Clinical trials in humans with ischemic heart, neural and renal tissues have not demonstrated the same benefits seen in animals. In addition some research studies have shown its neuroprotective effect on diabetic neuropathy, however these data were not confirmed in clinical trials that have been conducted on the deep peroneal, superficial peroneal, tibial and sural nerves.{{cite journal | vauthors = Hosseini-Zare MS, Dashti-Khavidaki S, Mahdavi-Mazdeh M, Ahmadi F, Akrami S | title = Peripheral neuropathy response to erythropoietin in type 2 diabetic patients with mild to moderate renal failure | journal = Clinical Neurology and Neurosurgery | volume = 114 | issue = 6 | pages = 663–7 | date = July 2012 | pmid = 22296650 | doi = 10.1016/j.clineuro.2012.01.007 | s2cid = 19516031 }} [23] => [24] => == Mechanism of action == [25] => Erythropoietin has been shown to exert its effects by [[protein-protein interaction|binding]] to the [[erythropoietin receptor]] (EpoR).{{cite journal | vauthors = Middleton SA, Barbone FP, Johnson DL, Thurmond RL, You Y, McMahon FJ, Jin R, Livnah O, Tullai J, Farrell FX, Goldsmith MA, Wilson IA, Jolliffe LK | title = Shared and unique determinants of the erythropoietin (EPO) receptor are important for binding EPO and EPO mimetic peptide | journal = The Journal of Biological Chemistry | volume = 274 | issue = 20 | pages = 14163–9 | date = May 1999 | pmid = 10318834 | doi = 10.1074/jbc.274.20.14163 | doi-access = free }}{{cite journal | vauthors = Livnah O, Johnson DL, Stura EA, Farrell FX, Barbone FP, You Y, Liu KD, Goldsmith MA, He W, Krause CD, Pestka S, Jolliffe LK, Wilson IA | title = An antagonist peptide-EPO receptor complex suggests that receptor dimerization is not sufficient for activation | journal = Nature Structural Biology | volume = 5 | issue = 11 | pages = 993–1004 | date = November 1998 | pmid = 9808045 | doi = 10.1038/2965 | s2cid = 24052881 }} EPO binds to the erythropoietin receptor on the red cell progenitor surface and activates a [[janus kinase 2|JAK2]] signalling cascade. This initiates the [[STAT5]], [[Phosphoinositide 3-kinase|PIK3]] and [[MAPK/ERK pathway|Ras MAPK]] pathways. This results in differentiation, survival and proliferation of the erythroid cell.{{cite book |doi=10.1016/B978-012689663-3/50011-9 |chapter=Erythropoietin |title=The Cytokine Handbook |year=2003 |last1=Kasper |first1=C. |pages=149–166 |isbn=978-0-12-689663-3 }} SOCS1, SOCS3 and CIS are also expressed which act as negative regulators of the cytokine signal.{{cite journal | vauthors = Hodges VM, Rainey S, Lappin TR, Maxwell AP | title = Pathophysiology of anemia and erythrocytosis | journal = Critical Reviews in Oncology/Hematology | volume = 64 | issue = 2 | pages = 139–58 | date = November 2007 | pmid = 17656101 | doi = 10.1016/j.critrevonc.2007.06.006 }} [26] => [27] => High level erythropoietin receptor expression is localized to erythroid progenitor cells. While there are reports that EPO receptors are found in a number of other tissues, such as heart, muscle, kidney and peripheral/central nervous tissue, those results are confounded by nonspecificity of reagents such as anti-EpoR antibodies.{{cite journal | vauthors = Elliott S, Busse L, Bass MB, Lu H, Sarosi I, Sinclair AM, Spahr C, Um M, Van G, Begley CG | display-authors = 6 | title = Anti-Epo receptor antibodies do not predict Epo receptor expression | journal = Blood | volume = 107 | issue = 5 | pages = 1892–5 | date = March 2006 | pmid = 16249375 | doi = 10.1182/blood-2005-10-4066 | doi-access = free }} In controlled experiments, a functional EPO receptor is not detected in those tissues.{{cite journal | vauthors = Sinclair AM, Coxon A, McCaffery I, Kaufman S, Paweletz K, Liu L, Busse L, Swift S, Elliott S, Begley CG | display-authors = 6 | title = Functional erythropoietin receptor is undetectable in endothelial, cardiac, neuronal, and renal cells | journal = Blood | volume = 115 | issue = 21 | pages = 4264–72 | date = May 2010 | pmid = 20124513 | doi = 10.1182/blood-2009-10-248666 | doi-access = free }} In the bloodstream, red cells themselves do not express erythropoietin receptor, so cannot respond to EPO. However, indirect dependence of red cell longevity in the blood on plasma erythropoietin levels has been reported, a process termed neocytolysis.{{cite journal | vauthors = Risso A, Ciana A, Achilli C, Antonutto G, Minetti G | title = Neocytolysis: none, one or many? A reappraisal and future perspectives | journal = Frontiers in Physiology | volume = 5 | pages = 54 | date = 2014 | pmid = 24592241 | doi = 10.3389/fphys.2014.00054 | pmc = 3924315 | doi-access = free }} In addition, there is conclusive evidence that EPO receptor expression is upregulated in brain injury.{{cite journal | vauthors = Ott C, Martens H, Hassouna I, Oliveira B, Erck C, Zafeiriou MP, Peteri UK, Hesse D, Gerhart S, Altas B, Kolbow T, Stadler H, Kawabe H, Zimmermann WH, Nave KA, Schulz-Schaeffer W, Jahn O, Ehrenreich H | display-authors = 6 | title = Widespread Expression of Erythropoietin Receptor in Brain and Its Induction by Injury | journal = Molecular Medicine | volume = 21 | issue = 1 | pages = 803–815 | date = December 2015 | pmid = 26349059 | doi = 10.2119/molmed.2015.00192 | pmc = 4818269 }} [28] => [29] => == Synthesis and regulation == [30] => Erythropoietin levels in blood are quite low in the absence of anemia, at around 10 mU/mL. However, in hypoxic stress, EPO production may increase up to 1000-fold, reaching 10 000 mU/mL of blood. In adults, EPO is synthesized mainly by interstitial cells in the peritubular capillary bed of the [[renal cortex]], with additional amounts being produced in the liver,{{cite journal | vauthors = Jacobson LO, Goldwasser E, Fried W, Plzak L | title = Role of the kidney in erythropoiesis | journal = Nature | volume = 179 | issue = 4560 | pages = 633–4 | date = March 1957 | pmid = 13418752 | doi = 10.1038/179633a0 | bibcode = 1957Natur.179..633J | s2cid = 4162940 }}{{cite journal | vauthors = Fisher JW, Koury S, Ducey T, Mendel S | title = Erythropoietin production by interstitial cells of hypoxic monkey kidneys | journal = British Journal of Haematology | volume = 95 | issue = 1 | pages = 27–32 | date = October 1996 | pmid = 8857934 | doi = 10.1046/j.1365-2141.1996.d01-1864.x | s2cid = 38309595 }}{{cite book |editor1-first=Kim E. |editor1-last=Barrett |editor2-first=Susan M. |editor2-last=Barman |editor3-first=Scott |editor3-last=Boitano |editor4-first=Heddwen |editor4-last=Brooks | name-list-style = vanc |title=Ganong's review of Medical Physiology |edition=24th |publisher=McGraw Hill |isbn=978-1-25-902753-6 |page=709 }} and the [[pericytes]] in the [[brain]].{{cite journal | vauthors = Ji P | title = Pericytes: new EPO-producing cells in the brain | journal = Blood | volume = 128 | issue = 21 | pages = 2483–2485 | date = November 2016 | pmid = 27884833 | doi = 10.1182/blood-2016-10-743880 | doi-access = free }} Regulation is believed to rely on a feedback mechanism measuring blood oxygenation and iron availability.{{cite journal | vauthors = Jelkmann W | title = Erythropoietin after a century of research: younger than ever | journal = European Journal of Haematology | volume = 78 | issue = 3 | pages = 183–205 | date = March 2007 | pmid = 17253966 | doi = 10.1111/j.1600-0609.2007.00818.x | s2cid = 37331032 | doi-access = }} Constitutively synthesized transcription factors for EPO, known as [[hypoxia-inducible factors]], are hydroxylated and proteosomally digested in the presence of oxygen and iron. During normoxia [[GATA2]] inhibits the promoter region for EPO. [[GATA2]] levels decrease during hypoxia and allow the promotion of EPO production.{{cite journal | vauthors = Jelkmann W | title = Regulation of erythropoietin production | journal = The Journal of Physiology | volume = 589 | issue = Pt 6 | pages = 1251–8 | date = March 2011 | pmid = 21078592 | pmc = 3082088 | doi = 10.1113/jphysiol.2010.195057 }} [31] => [32] => Erythropoietin production can be induced by [[EPAS1|HIF-2α]] as well as by [[PPARGC1A|PGC-1α]].{{cite journal | author=Packer M | title=Sodium-Glucose Cotransporter-2 Inhibitor (SGLT2i) as a Primary Preventative Agent in the Healthy Individual: A Need of a Future Randomised Clinical Trial? | journal=[[Circulation: Heart Failure]] | volume=13 |issue=9 | pages=e007197 | year=2020 | doi = 10.1161/CIRCHEARTFAILURE.120.007197 | pmid=32894987 | s2cid=221540765 | doi-access=free }} Erythropoietin also activates these factors, resulting in a [[Feedback|positive feedback loop]]. [33] => [34] => == Medical use == [35] => [36] => {{anchor|epoetin}} [37] => {{main|Erythropoiesis-stimulating agent}} [38] => Erythropoietins available for use as [[Biologic medical product|therapeutic agents]] are produced by [[recombinant DNA technology]] in [[cell culture]], and include Epogen/Procrit ([[epoetin alfa]]) and Aranesp ([[darbepoetin alfa]]); they are used in treating [[anemia]] resulting from [[chronic kidney disease]],{{Cite web|url=http://www.hematology.org/About/History/50-Years/1532.aspx|title=The Story of Erythropoietin|date=16 February 2018|website=www.hematology.org|language=en-US|access-date=18 February 2019|archive-date=18 February 2019|archive-url=https://web.archive.org/web/20190218141735/http://www.hematology.org/About/History/50-Years/1532.aspx|url-status=live}} chemotherapy induced anemia in patients with cancer, [[inflammatory bowel disease]] ([[Crohn's disease]] and [[ulcerative colitis]]){{cite journal | vauthors = Liu S, Ren J, Hong Z, Yan D, Gu G, Han G, Wang G, Ren H, Chen J, Li J | title = Efficacy of erythropoietin combined with enteral nutrition for the treatment of anemia in Crohn's disease: a prospective cohort study | journal = Nutrition in Clinical Practice | volume = 28 | issue = 1 | pages = 120–7 | date = February 2013 | pmid = 23064018 | doi = 10.1177/0884533612462744 }} and [[Myelodysplastic syndrome|myelodysplasia]] from the treatment of [[cancer]] ([[chemotherapy]] and [[radiation]]). The [[package insert]]s include [[boxed warning]]s of increased risk of death, [[myocardial infarction]], [[stroke]], [[Venous thrombosis|venous thromboembolism]], and tumor recurrence, particularly when used to increase the hemoglobin levels to more than 11 g/dL to 12 g/dL.{{cite web |url=https://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm267698.htm |title=Safety Labeling Changes: Epogen/Procrit (epoetin alfa) and Aranesp (darbepoetin alfa) |work=MedWatch: The FDA Safety Information and Adverse Event Reporting Program |date=11 August 2011 |publisher=United States Food and Drug Administration |access-date=16 December 2019 |archive-date=12 January 2017 |archive-url=https://web.archive.org/web/20170112174940/http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm267698.htm |url-status=live }} [39] => [40] => == History == [41] => In 1905, [[Paul Carnot]] proposed the idea that a hormone regulates the production of red blood cells. After conducting experiments on rabbits subject to [[bloodletting]], Carnot and his graduate student [[Clotilde-Camille Deflandre]]{{cite journal| vauthors = Carnot P, Deflandre C |title=Sur l'activite hematopoietique du serum au cours de la regeneration du sang|journal=Compt. Rend. Acad. Sci.|date=1906|volume=143|pages=384–386}} attributed an increase in red blood cells in rabbit subjects to a hemotropic factor called hemopoietin. Eva Bonsdorff and [[Eeva Jalavisto]] called the hemopoietic substance 'erythropoietin'. K.R. Reissman and Allan J. Erslev demonstrated that a certain substance, circulated in the blood, is able to stimulate red blood cell production and increase [[hematocrit]]. This substance was purified and confirmed as erythropoietin.{{cite book |first=Ahmet |last=Höke |name-list-style=vanc |title=Erythropoietin and the Nervous System |publisher=Springer |location=Berlin |year=2005 |isbn=978-0-387-30010-8 |oclc=64571745 }}{{page needed|date=April 2016}} [42] => [43] => In 1977, Goldwasser and Kung purified EPO.{{cite journal | vauthors = Miyake T, Kung CK, Goldwasser E | title = Purification of human erythropoietin | journal = The Journal of Biological Chemistry | volume = 252 | issue = 15 | pages = 5558–64 | date = August 1977 | doi = 10.1016/S0021-9258(19)63387-9 | pmid = 18467 | doi-access = free | title-link = doi }} Pure EPO allowed the amino acid sequence to be partially identified and the gene to be isolated. Synthetic EPO was first successfully used to correct anemia in 1987.{{cite journal | vauthors = Eschbach JW, Egrie JC, Downing MR, Browne JK, Adamson JW | title = Correction of the anemia of end-stage renal disease with recombinant human erythropoietin. Results of a combined phase I and II clinical trial | journal = The New England Journal of Medicine | volume = 316 | issue = 2 | pages = 73–8 | date = January 1987 | pmid = 3537801 | doi = 10.1056/NEJM198701083160203 }} In 1985, Lin ''et al'' isolated the human erythropoietin gene from a genomic phage library and used it to produce EPO.{{cite journal | vauthors = Lin FK, Suggs S, Lin CH, Browne JK, Smalling R, Egrie JC, Chen KK, Fox GM, Martin F, Stabinsky Z | title = Cloning and expression of the human erythropoietin gene | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 82 | issue = 22 | pages = 7580–4 | date = November 1985 | pmid = 3865178 | pmc = 391376 | doi = 10.1073/pnas.82.22.7580 | bibcode = 1985PNAS...82.7580L | doi-access = free }} In 1989, the US [[Food and Drug Administration]] (FDA) approved the hormone [[Epogen]] for use in certain anemias.{{cite web | title=Epogen- epoetin alfa solution | website=DailyMed | date=25 July 2018 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1f2d0b28-9cc5-4523-80b8-637fdaf3f7a5 | access-date=20 April 2022}}{{cite web | title=Epogen: FDA-Approved Drugs | website=U.S. [[Food and Drug Administration]] (FDA) | date=13 January 2017 | url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=103234 | access-date=20 April 2022}} [44] => [45] => [[Gregg L. Semenza]] and [[Peter J. Ratcliffe]] studied the EPO gene and its oxygen-dependent regulation. Along with [[William Kaelin Jr.]], they were awarded the 2019 [[Nobel Prize in Physiology or Medicine]] for their discovery of [[hypoxia-inducible factor]] (HIF), which regulates the EPO gene, as well as other genes, in response to hypoxia.{{cite web |title=The Nobel Prize in Physiology or Medicine 2019 |url=https://www.nobelprize.org/prizes/medicine/2019/press-release/ |website=NobelPrize.org |access-date=30 October 2019 |date=7 October 2019 |archive-date=31 October 2021 |archive-url=https://web.archive.org/web/20211031222947/https://www.nobelprize.org/prizes/medicine/2019/press-release/ |url-status=live }} [46] => [47] => ===Biosimilars=== [48] => {{see also|Biosimilars}} [49] => [50] => In December 2007, Retacrit and Silapo (both [[epoetin zeta]]) were approved for use in the European Union.{{cite web | title=Retacrit EPAR | website=[[European Medicines Agency]] (EMA) | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/retacrit | access-date=2 April 2020 | archive-date=30 December 2019 | archive-url=https://web.archive.org/web/20191230161825/https://www.ema.europa.eu/en/medicines/human/EPAR/retacrit | url-status=live }}{{cite web | title=Silapo EPAR | website=[[European Medicines Agency]] (EMA) | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/silapo | access-date=2 April 2020 | archive-date=22 October 2020 | archive-url=https://web.archive.org/web/20201022043818/https://www.ema.europa.eu/en/medicines/human/EPAR/silapo | url-status=live }} [51] => [52] => ==Usage as doping product== [53] => As a [[Performance-enhancing substance|performance-enhancing drug]], EPO has been banned since the early 1990s, but a first test was not available until the [[2000 Summer Olympics]].{{cite web|url=https://www.wada-ama.org/en/questions-answers/epo-detection|title=EPO DETECTION|publisher=[[World Anti-Doping Agency]]|date=December 2014|access-date=17 December 2017|archive-date=7 September 2017|archive-url=https://web.archive.org/web/20170907215023/https://www.wada-ama.org/en/questions-answers/epo-detection|url-status=live}} Before this test was available, some athletes were sanctioned after confessing to having used EPO, for example in the [[Festina affair]], when a car with doping products for the Festina cycling team was found. [54] => [55] => The first doping test in cycling was used in the [[2001 La Flèche Wallonne]]. The first rider to test positive in that race was [[Bo Hamburger]], although he was later acquitted because his B-sample was not conclusive.{{Cite news|url=http://news.bbc.co.uk/sport2/hi/other_sports/1483975.stm|publisher=BBC|date=10 August 2001|title=Hamburger cleared of EPO use|access-date=17 December 2017|archive-date=16 April 2016|archive-url=https://web.archive.org/web/20160416103453/http://news.bbc.co.uk/sport2/hi/other_sports/1483975.stm|url-status=live}} [56] => [57] => The [[U.S. Postal Service Pro Cycling Team]], under the leadership of [[Lance Armstrong]] and [[Johan Bruyneel]], ran a sophisticated doping program that lasted for many years during the late 1990s and early 2000s. Erythropoietin was a common substance used by the cyclists.{{Cite web|last=Perishable|title=Statement From USADA CEO Travis T. Tygart Regarding The U.S. Postal Service Pro Cycling Team Doping Conspiracy {{!}} U.S. Anti-Doping Agency (USADA)|url=https://www.usada.org/statement/statement-from-usada-ceo-travis-t-tygart-regarding-the-u-s-postal-service-pro-cycling-team-doping-conspiracy/|access-date=26 August 2021|website=www.usada.org|date=10 October 2012|language=en-US|archive-date=26 August 2021|archive-url=https://web.archive.org/web/20210826135347/https://www.usada.org/statement/statement-from-usada-ceo-travis-t-tygart-regarding-the-u-s-postal-service-pro-cycling-team-doping-conspiracy/|url-status=live}} [58] => [59] => A 2007 study showed that EPO has a {{clarify span|text=significant effect on exercise performance.|reason=In this context this cited claim needs expansion (as with the study which follows): what ''kind'' of "significant effect", under what conditions, with what qualificatins, if any.|date=September 2023}}{{cite journal | vauthors = Thomsen JJ, Rentsch RL, Robach P, Calbet JA, Boushel R, Rasmussen P, Juel C, Lundby C | title = Prolonged administration of recombinant human erythropoietin increases submaximal performance more than maximal aerobic capacity | journal = European Journal of Applied Physiology | volume = 101 | issue = 4 | pages = 481–6 | date = November 2007 | pmid = 17668232 | doi = 10.1007/s00421-007-0522-8 | s2cid = 6492432 }} A 2017 study showed at ''submaximal'' exertion the effects of EPO were not distinguishable from a placebo. Stating "[At] Submaximal [exertion]...[mean power] did not differ between groups." Nevertheless, at "maximal [exertion power output was] higher in the rHuEPO group compared with the placebo group." So, even though there was no difference at lower levels of exertion at ''maximal'' exertion the EPO group ''still'' performed better than the placebo group.{{cite journal | vauthors = Heuberger JA, Rotmans JI, Gal P, Stuurman FE, van 't Westende J, Post TE, Daniels JM, Moerland M, van Veldhoven PL, de Kam ML, Ram H, de Hon O, Posthuma JJ, Burggraaf J, Cohen AF | title = Effects of erythropoietin on cycling performance of well trained cyclists: a double-blind, randomised, placebo-controlled trial | journal = The Lancet. Haematology | volume = 4 | issue = 8 | pages = e374–e386 | date = August 2017 | pmid = 28669689 | doi = 10.1016/S2352-3026(17)30105-9 }} [60] => [61] => In March 2019, American mixed martial artist and former [[Ultimate Fighting Championship|UFC]] [[UFC Bantamweight Championship|Bantamweight Champion]] [[T.J. Dillashaw]] tested positive for EPO in a drug test administered by [[USADA]], and was stripped of the UFC bantamweight title and suspended for 2 years.{{cite web|url=http://www.espn.com/mma/story/_/id/26479192/usada-suspends-dillashaw-2-years-epo-use|title=USADA suspends Dillashaw 2 years for EPO use|work=ESPN.com|date=9 April 2019|access-date=9 April 2019|archive-date=10 April 2019|archive-url=https://web.archive.org/web/20190410145325/http://www.espn.com/mma/story/_/id/26479192/usada-suspends-dillashaw-2-years-epo-use|url-status=live}} In September 2023 two-time tennis major champion [[Simona Halep]] received a 4-year suspension by the [[International Tennis Integrity Agency]] for two separate violations, one concerning the level of EPO in a blood sample collected in August 2022; Halep maintained her innocence, and indicated she would appeal the ban.[https://www.espn.com/tennis/story/_/id/38385896/simona-halep-banned-4-years-separate-doping-violations "Simona Halep: Will appeal 4-year ban over doping violations"], ESPN, September 12, 2023 [62] => [63] => EPO has been used as a performance enhancing agent in [[horse racing]] since at least 2019.{{cite web|url=https://www.timesunion.com/news/article/horse-racing-doping-new-york-16771265.php?IPID=Times-Union-HP-CP-spotlight|title=N.Y. lab losing battle of doping in horse racing's 'cat and mouse game'|first=Emilie|last=Munson|work=www.timesunion.com|date=6 February 2022|accessdate=7 February 2022|archive-date=6 February 2022|archive-url=https://web.archive.org/web/20220206130818/https://www.timesunion.com/news/article/horse-racing-doping-new-york-16771265.php?IPID=Times-Union-HP-CP-spotlight|url-status=live}} [64] => [65] => == References == [66] => {{reflist}} [67] => [68] => == Further reading == [69] => {{refbegin|35em}} [70] => * {{cite journal | vauthors = Liu C, Huang C, Xie J, Li H, Hong M, Chen X, Wang J, Wang J, Li Z, Wang J, Wang W | title = Potential Efficacy of Erythropoietin on Reducing the Risk of Mortality in Patients with Traumatic Brain Injury: A Systematic Review and Meta-Analysis | journal = Biomed Res Int | volume = 2020 | pages = 7563868 | date = October 2020 | pmid = 33178833 | doi = 10.1155/2020/7563868 | pmc = 7644316 | doi-access = free }} [71] => * {{cite journal | vauthors = Takeuchi M, Kobata A | title = Structures and functional roles of the sugar chains of human erythropoietins | journal = Glycobiology | volume = 1 | issue = 4 | pages = 337–46 | date = September 1991 | pmid = 1820196 | doi = 10.1093/glycob/1.4.337 }} [72] => * {{cite journal | vauthors = Semba RD, Juul SE | title = Erythropoietin in human milk: physiology and role in infant health | journal = Journal of Human Lactation | volume = 18 | issue = 3 | pages = 252–61 | date = August 2002 | pmid = 12192960 | doi = 10.1177/089033440201800307 | s2cid = 13546958 }} [73] => * {{cite journal | vauthors = Ratcliffe PJ | title = From erythropoietin to oxygen: hypoxia-inducible factor hydroxylases and the hypoxia signal pathway | journal = Blood Purification | volume = 20 | issue = 5 | pages = 445–50 | year = 2002 | pmid = 12207089 | doi = 10.1159/000065201 | s2cid = 46866485 | doi-access = free }} [74] => * {{cite journal | vauthors = Westenfelder C | title = Unexpected renal actions of erythropoietin | journal = Experimental Nephrology | volume = 10 | issue = 5–6 | pages = 294–8 | year = 2002 | pmid = 12381912 | doi = 10.1159/000065304 | s2cid = 33343853 }} [75] => * {{cite journal | vauthors = Becerra SP, Amaral J | title = Erythropoietin--an endogenous retinal survival factor | journal = The New England Journal of Medicine | volume = 347 | issue = 24 | pages = 1968–70 | date = December 2002 | pmid = 12477950 | doi = 10.1056/NEJMcibr022629 }} [76] => * {{cite journal | vauthors = Genc S, Koroglu TF, Genc K | title = Erythropoietin and the nervous system | journal = Brain Research | volume = 1000 | issue = 1–2 | pages = 19–31 | date = March 2004 | pmid = 15053948 | doi = 10.1016/j.brainres.2003.12.037 | s2cid = 46246546 }} [77] => * {{cite journal | vauthors = Fandrey J | s2cid = 697196 | title = Oxygen-dependent and tissue-specific regulation of erythropoietin gene expression | journal = American Journal of Physiology. Regulatory, Integrative and Comparative Physiology | volume = 286 | issue = 6 | pages = R977–88 | date = June 2004 | pmid = 15142852 | doi = 10.1152/ajpregu.00577.2003 }} [78] => * {{cite journal | vauthors = Juul S | title = Recombinant erythropoietin as a neuroprotective treatment: in vitro and in vivo models | journal = Clinics in Perinatology | volume = 31 | issue = 1 | pages = 129–42 | date = March 2004 | pmid = 15183662 | doi = 10.1016/j.clp.2004.03.004 }} [79] => * {{cite journal | vauthors = Buemi M, Caccamo C, Nostro L, Cavallaro E, Floccari F, Grasso G | title = Brain and cancer: the protective role of erythropoietin | journal = Medicinal Research Reviews | volume = 25 | issue = 2 | pages = 245–59 | date = March 2005 | pmid = 15389732 | doi = 10.1002/med.20012 | s2cid = 46380760 }} [80] => * {{cite journal | vauthors = Sytkowski AJ | title = Does erythropoietin have a dark side? Epo signaling and cancer cells | journal = Science's STKE | volume = 2007 | issue = 395 | pages = pe38 | date = July 2007 | pmid = 17636183 | doi = 10.1126/stke.3952007pe38 | s2cid = 43566459 }} [81] => {{refend}} [82] => [83] => == External links == [84] => * {{cite web | url = https://druginfo.nlm.nih.gov/drugportal/name/erythropoietin | publisher = U.S. National Library of Medicine | work = Drug Information Portal | title = Erythropoietin }} [85] => * {{PDBe-KB2|P01588|Erythropoietin}} [86] => [87] => {{Navboxes [88] => |title=Articles and topics related to Erythropoietin [89] => |state=collapsed [90] => |list1= [91] => {{PDB Gallery|geneid=2056}} [92] => {{Hormones}} [93] => {{Renal physiology}} [94] => {{Colony-stimulating factors}} [95] => {{Antianemic preparations}} [96] => {{Growth factor receptor modulators}} [97] => {{Cytokine receptor modulators}} [98] => }} [99] => {{Portal bar | Medicine}} [100] => {{Authority control}} [101] => [102] => [[Category:Cytokines]] [103] => [[Category:Growth factors]] [104] => [[Category:Hormones of the kidneys]] [105] => [[Category:Nephrology procedures]] [] => )
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Erythropoietin

Erythropoietin (EPO) is a hormone produced mainly by the kidneys that regulates the production of red blood cells in the body. It plays a crucial role in maintaining the oxygen-carrying capacity of the blood.

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It plays a crucial role in maintaining the oxygen-carrying capacity of the blood. The Wikipedia page on Erythropoietin provides a comprehensive overview of this hormone, including its history, structure, function, regulation, and medical applications. The page begins by tracing the discovery of EPO and its isolation as a glycoprotein hormone that stimulates the production of red blood cells. It then describes the physiological role of EPO, explaining how it interacts with the bone marrow to promote the generation, differentiation, and maturation of erythrocytes. The regulation of EPO synthesis is discussed in detail, focusing on the factors that stimulate or inhibit its production, such as oxygen levels, anemia, and hypoxia-inducible factors. The page also delves into the signaling pathways involved in EPO production and the mechanisms by which it exerts its effects on target cells. In addition to its natural role, the page explores the various medical applications of EPO. Erythropoietin therapy, which involves the administration of recombinant EPO, is widely used to treat anemia associated with chronic kidney disease, cancer, and certain other conditions. The page discusses the dosing, adverse effects, and potential risks associated with EPO therapy. It also touches upon the controversies surrounding the use of EPO in sports, particularly in enhancing athletic performance. The Wikipedia page on Erythropoietin concludes with a section on ongoing research and future directions. It highlights recent advances in understanding the role of EPO in conditions like ischemic stroke, heart disease, and neurodegenerative disorders. The page also touches upon new approaches to EPO therapy, including modified EPO variants and alternative delivery methods. Overall, the Wikipedia page provides a comprehensive and informative overview of Erythropoietin, covering its discovery, structure, function, regulation, medical applications, and ongoing research. It serves as a valuable resource for anyone seeking in-depth information on this essential hormone.

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