Polyestradiol phosphate

Polyestradiol phosphate (PEP), sold under the brand name Estradurin, is an estrogen medication which is used primarily in the treatment of prostate cancer in men.[5][2] The safety profile of parenteral estradiol esters like PEP is greatly improved relative to synthetic oral estrogens like ethinylestradiol and diethylstilbestrol.[20][7] PEP has been compared to combined androgen blockade (CAB; castration plus flutamide) for the treatment of prostate cancer in a large randomized clinical trial of 915 patients.[21][22] These findings suggest that parenteral forms of estradiol may have similar effectiveness and safety relative to androgen deprivation therapy (ADT) in the treatment of prostate cancer.[21][22] In addition, estrogens may have significant advantages relative to ADT in terms of bone loss and fractures, hot flashes, sexual function, and quality of life, as well as considerable cost savings with parenteral forms of estradiol compared to GnRH analogue therapy.[24] At a dosage of 160 mg/month, PEP incompletely suppresses testosterone levels, failing to reach the castrate range, and is significantly inferior to orchiectomy in slowing disease progression.[11][19][25][5] PEP is provided in the form of powder or an aqueous solution in vials and ampoules alone or in combination with mepivacaine and/or nicotinamide (vitamin B3) for administration via intramuscular injection.[1] Common or frequent (>10%) side effects are considered to include headache, abdominal pain, nausea, rash, pruritus, loss of libido, erectile dysfunction, breast tenderness, gynecomastia, feminization, demasculinization, infertility, and vaginal bleeding or spotting.[1][32] Side effects that occur occasionally or uncommonly (0.1–1%) include sodium and water retention, edema, hypersensitivity, breast tension, depression, dizziness, visual disturbances, palpitations, dyspepsia, erythema nodosum, urticaria, and chest pain.[1] The rare (<0.1%) side effects of PEP are considered to include weight gain, impaired glucose tolerance, mood changes (elation or depression), nervousness, tiredness, headache, migraine, intolerance of contact lenses, hypertension, thrombosis, thrombophlebitis, thromboembolism, heart failure, myocardial infarction, vomiting, bloating, cholestatic jaundice, cholelithiasis, transient increases in transaminases and bilirubin, erythema multiforme, hyperpigmentation, muscle cramps, dysmenorrhea, vaginal discharge, premenstrual-like symptoms, breast enlargement, testicular atrophy, allergic reactions (e.g., urticaria, bronchial asthma, anaphylactic shock) due to mepivacaine, and injection site reactions (e.g., pain, sterile abscesses, inflammatory infiltrates).[33][34][6] The difference between the two types of therapies is due to the bioidentical and parenteral nature of PEP and its minimal influence on liver protein synthesis.[2] However, PEP at a higher dosage of 240 mg/month has subsequently been found in large studies to significantly increase cardiovascular morbidity relative to GnRH modulators and orchiectomy in men treated with it for prostate cancer.[46] A single intramuscular injection of 320 mg PEP in men has been found to suppress testosterone levels to within the castrate range (< 50 ng/dL) within 3 weeks.[47] Studies have found a markedly increased 5-year risk of cardiovascular mortality of 14 to 26% in men treated with oral synthetic estrogens like ethinylestradiol and diethylstilbestrol for prostate cancer.[7] Another study found no change in levels of coagulation factor VII, a protein of particular importance in the cardiovascular side effects of estrogens, with 240 mg/month intramuscular PEP.[7] Originally, PEP was typically used at a dosage of 80 mg per month in combination with 150 μg per day oral ethinylestradiol in the treatment of prostate cancer.[1] Early studies found that a dosage of 80 mg PEP every 4 weeks rapidly produced relatively high mean estradiol levels of about 400 to 800 pg/mL.[15][69][46][70] It has been determined via ultracentrifugation that the mean molecular weight of PEP corresponds to a chain length of approximately 13 repeat units of estradiol 17β-phosphate.[72] PEP is of very low solubility in water, acetone, chloroform, dioxane, and ethanol, but dissolves readily in bases, especially in aqueous pyridine.[63] When the same scientists wanted to synthesize simple phosphates of phloretin, a compound found in apple tree leaves,[74] they accidentally created a polymer instead.[15][26][1][76][77][14] It is no longer available in the United States, Switzerland, and certain other countries however,[13][16] but is still known to be marketed in Austria, Belgium, Denmark, Finland, the Netherlands, Norway, and Sweden.
SHBG levels with 1) i.m. injection of 320 mg PEP every 4 weeks; 2) i.m. injection of 320 mg PEP every 4 weeks plus 150 μg/day oral ethinylestradiol ; 3) orchiectomy . [ 35 ]
Availability of polyestradiol phosphate in countries throughout the world as of March 2018. Blue is currently marketed, green is formerly marketed.
Polyestriol phosphateEstradiol phosphateSkeletal structureball-and-stick modelmonomerDrugs.comPregnancycategoryRoutes ofadministrationIntramuscular injectionDrug classEstrogenEstrogen esterATC codeL02AA02Legal statusPharmacokineticBioavailabilityProtein bindingalbuminMetabolismkidneysgonadsmusclephosphatasesMetabolitesEstradiolphosphoric acidElimination half-lifeExcretionconjugatesIUPAC nameCAS NumberDrugBankChemSpiderChEMBLFormulaMolar massPolymerRepeat unitMelting pointprostate cancerbreast cancerhormone therapylow estrogen levelsmenopausalsymptomsfeminizing hormone therapytransgender womeninjection into muscleside effectsheadachebreast tendernessbreast developmentfeminizationsexual dysfunctioninfertilityvaginal bleedingagonistestrogen receptorbiological targetestrogensprodrugbiological half-lifenaturalbioidenticalsafetyparenteralsyntheticethinylestradioldiethylstilbestrolUnited Statesestradiol undecylateestradiol valerateEuropeestrogen therapypostmenopausalhormone replacement 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gravisPregnancylactationbreastfeedingSystematic studiesestradiol estersabdominal painnauseapruritusloss of libidoerectile dysfunctiondemasculinizationvaginal bleeding or spottingsodiumwater retentionbreast tensiondepressiondizzinessvisual disturbancespalpitationsdyspepsiaerythema nodosumurticariachest painweight gainimpaired glucose toleranceelationnervousnesstirednessmigrainecontact lensesthromboembolismheart failurevomitingbloatingcholestatic jaundicecholelithiasistransaminasesbilirubinerythema multiformehyperpigmentationmuscle crampsdysmenorrheavaginal dischargepremenstrual-like symptomsbreast enlargementtesticular atrophyallergic reactionsbronchial asthmaanaphylactic shockinjection site reactionssterile abscessesinflammatory infiltratesthromboemboliccardiovascularcoagulation factorsblood clotsliver protein synthesisantithrombin IIIHDL cholesterolLDL cholesterolcoronary artery diseasehemostasismorbidityGnRH modulatorsischemic heart diseaseheart decompensationmortalityvenoustransient 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phosphatasehyaluronidasein vitroEstradiol benzoateEstradiol dipropionateEstradiol benz. butyrateEstradiol cypionateEstradiol enanthateEstradiol dienanthateEstroneEstriolaqueous suspensionsmicrocrystallineparticle sizemenstrual cyclevaginalepitheliumovulation-inhibiting dosedihydrotestosteronecastration-resistantdepriving it of androgensnegative feedbackhypothalamic–pituitary–gonadal axissecretionluteinizing hormoneproductionLeydig cellstestessex hormone-binding globulincytotoxicityFactor VIIFactor VIIIProthrombin fragment 1+2Activated protein C resistanceFibrinogensynthesisplasma proteinslipoproteinstriglyceridescoagulation factor VIIgrowth hormoneinsulin-like growth factor 1Pharmacokinetics of estradioldurationbloodstreamreticuloendothelial systemcleavedsteady-stateexcretedestranesteroidestradiol 17β-phosphateultracentrifugationrepeat unitspolytestosterone phloretin phosphatetestosterone esterspolymerspolydiethylstilbestrol phosphatediethylstilbestrol esterEstradiol acetateEthanoic acidBenzoic acidPropanoic acidPentanoic acidEstradiol benzoate butyratebutyric acidCyclopentylpropanoic acidHeptanoic acidUndecanoic acidEstradiol stearateOctadecanoic acidEstradiol distearateEstradiol sulfateSulfuric acidEstradiol glucuronideGlucuronic acidEstramustine phosphateNormustinecarbonstraight-chain fatty acidsaromaticcyclicestrogenicoctanol/water partition coefficientlipophilicityhydrophobicityPubChemsolubilityacetonechloroformdioxaneethanolaqueouspyridinepolyphenolsphosphoryl chloridehydroxylaliphaticmolecular massestradiol phosphatesphloretingeneric nameList of estrogens available in the United StatesAustriaBelgiumCzech RepublicDenmarkFinlandGermanyNetherlandsNorwayRussiaSwedenSwitzerlandUkraineUnited Kingdommedroxyprogesterone acetatecombined injectable contraceptivePolyestradiol phosphate/medroxyprogesterone acetateBibcodeHOE2OHvariousHOE2O4PH2HSO4E2OHHSO4E2O4SHEstradiol (as a hormone)Estradiol (as a medication)Estrogen (as a hormone)Estrogen (as a medication)Menopausal 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diacetatetiboloneClomestroneCloxestradiol acetateConjugated estriolEpiestriolEpimestrolestradiol ester mixturesClimacteronestriol succinateEstrogenic substancesEthinylestradiol sulfonateHydroxyestrone diacetateMestranolMethylestradiolMoxestrolNilestriolPrasterone (dehydroepiandrosterone; DHEA)Prasterone enanthatePrasterone sulfatePromestrieneQuinestradolQuinestrolBenzestrolBifluranolChlorotrianiseneDienestrolDienestrol diacetateDiethylstilbestrol (stilbestrol)Dimestrol (diethylstilbestrol dimethyl ether)Fosfestrol (diethylstilbestrol diphosphate)Mestilbol (diethylstilbestrol monomethyl ether)Doisynoestrol (fenocycline)HexestrolMethallenestrilMethestrol (promethestrol)Methestrol dipropionate (promethestrol dipropionate)ParoxypropioneQuadrosilanTriphenylbromoethyleneTriphenylchloroethyleneZeranolProgonadotropinsAntiandrogensbicalutamideGnRH agonistsGnRH 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(methandrostenolone)nandroloneAtrimustineBolandiolBolandiol dipropionateButolameCloxestradiolCyclodiolCyclotriolDHEA-Sent-EstradiolEpiestriol (16β-epiestriol, 16β-hydroxy-17β-estradiol)EquileninEquilinERA-63 (ORG-37663)Lipoidal estradiolEstramustineEstrapronicateEstrazinolEstrofurateEstromustineEstrone methyl etherEstropipateEtamestrol (eptamestrol)EthinylandrostenediolEthandrostateEthinylestradiol 3-benzoateEthinylestriolEthylestradiolEtynodiolHexolameHippulinLynestrenolLynestrenol phenylpropionateMytatrienediolOrestratePentolameProdiameProlameRU-16117(R,R)-THC(S,S)-THC2,8-DHHHCβ-LGND2 (GTx-878)AllenestrolAllenolic acidBisdehydrodoisynolic acidButestrolCarbestrolD-15414DCW234DiarylpropionitrileDimestrol (dianisylhexene)DimethylstilbestrolDoisynolic acidERB-196 (WAY-202196)Erteberel (SERBA-1, LY-500307)Estrobin (DBE)FenestrelFERb 033Furostilbestrol (diethylstilbestrol difuroate)GTx-758ICI-85966 (Stilbostat)meso-Butestrolmeso-HexestrolMestilbolMethestrolMethestrol dipropionatePentafluranolPhenestrolPrinaberel (ERB-041, WAY-202041)PropylpyrazoletriolSC-4289SERBA-2SKF-82,958TerfluranolTriphenyliodoethyleneTriphenylmethylethylene (triphenylpropene)WAY-166818WAY-200070WAY-204688 (SIM-688)WAY-214156ERB-26ERA-45ERB-79ZK-283197anetholedianetholedianolphotoanetholeChalconoidsisoliquiritigeninphlorizin (phloridzin)wedelolactoneCoumestanscoumestrolpsoralidinFlavonoids7,8-DHF8-prenylnaringeninapigeninbaicaleinbaicalinbiochanin AcalycosincatechindaidzeindaidzinepicatechinformononetinglabreneglabridingenisteingenistinglyciteinkaempferolliquiritigeninmirificinmyricetinnaringeninpinocembrinprunetinpuerarinquercetintectoridintectorigeninLavender oilLignansenterodiolenterolactonenyasol (cis-hinokiresinol)MetalloestrogenscadmiumPesticidesalternarioldieldrinendosulfanfenarimolmethiocarbmethoxychlortriclocarbantriclosanPhytosteroidsdigitoxindigitalisdiosgeninguggulsteronePhytosterolsβ-sitosterolcampesterolstigmasterolResorcylic acid lactoneszearalanoneα-zearalenolβ-zearalenolzearalenonezeranol (α-zearalanol)taleranol (teranol, β-zearalanol)deoxymiroestrolmiroestrolStilbenoidsresveratrolrhaponticinSynthetic xenoestrogensalkylphenolsbisphenolsparabensphthalatesagnuside2-Phenylbenzofuran4'-Hydroxynorendoxifen27-HydroxycholesterolAcefluranolAfimoxifeneAnordiolArzoxifeneBrilanestrantCamizestrantClomifenoxideDesmethylchlorotrianiseneDroloxifeneEndoxifenEtacstil (GW-5638, DPC-974)Ethamoxytriphetol (MER-25)FemarelleFispemifeneICI-55548IdoxifeneLevormeloxifeneLN-1643LN-2299MenerbaMiproxifeneMiproxifene phosphateNafoxidineNitromifeneNNC 45-0095PanomifenePipendoxifeneRimostil (P-081)SpironolactoneTAS-108 (SR-16234)TrioxifeneZindoxifeneZuclomifene7β-Hydroxy-DHEACytestrol acetateFulvestrant (ICI-182780)GlyceollinsICI-164384MethylepitiostanolMethylpiperidinopyrazoleProchlorazERX-112-MethoxyestradiolAfimoxifene (4-hydroxytamoxifen)AldosteroneAtrazineBisphenol Ap,p'-DDTHydroxytyrosolKeponeNicotinic acidNonylphenolOleuropein