View source for Estramustine phosphate

{{Short description|Chemical compound}}
{{Distinguish|Estramustine}}
{{Drugbox
| Verifiedfields =
| Watchedfields =
| verifiedrevid =
| IUPAC_name = [(8''R'',9''S'',13''S'',14''S'',17''S'')-13-methyl-17-phosphonooxy-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[''a'']phenanthren-3-yl] ''N'',''N''-''bis''(2-chloroethyl)carbamate
| image = Estramustine phosphate.svg
| width = 250px
| image2 = Estramustine phosphate molecule ball.png
| width2 = 250px

<!--Clinical data-->
| tradename = Emcyt, Estracyt
| Drugs.com = {{drugs.com|monograph|emcyt}}
| MedlinePlus = a608046
| licence_US = Estramustine
| pregnancy_AU = D
| pregnancy_US = X
| legal_AU = S4
| legal_CA = Rx-only
| legal_US = Rx-only
| legal_UK = POM
| routes_of_administration = [[Oral administration|By mouth]], [[Intravenous therapy|IV]]
| class = [[Chemotherapeutic agent]]; [[Estrogen (medication)|Estrogen]]; [[Estrogen ester]]

<!--Pharmacokinetic data-->
| bioavailability = 44–75% (as estramustine and estromustine)<ref name="pmid9515186" />
| protein_bound = • Estradiol: 98%<ref name="pmid16112947" /><br />• Estrone: 96%<ref name="pmid16112947" />
| metabolism = [[Liver]], [[intestine]]s<ref name="pmid11240822" /><ref name="pmid9515186" /><ref name="MSR">{{cite web|title=Emcyt (estramustine) dosing, indications, interactions, adverse effects, and more|work=Medscape Reference|publisher=WebMD|access-date=8 February 2014|url=http://reference.medscape.com/drug/emcyt-estramustine-342085#showall}}</ref>
| metabolites = • [[Estramustine]]<ref name="pmid11240822" /><ref name="pmid9515186" /><br />• [[Estromustine]]<ref name="pmid11240822" /><ref name="pmid9515186" /><br />• [[Estradiol (medication)|Estradiol]]<ref name="pmid11240822" /><ref name="pmid9515186" /><br />• [[Estrone (medication)|Estrone]]<ref name="pmid11240822" /><ref name="pmid9515186" /><br />• [[Phosphoric acid]]<ref name="pmid11240822" /><ref name="pmid9515186" /><br />• [[Normustine]]<ref name="Inoue2018" />
| elimination_half-life = • EMP: 1.27&nbsp;hours<ref name="pmid7579781" /><br />{{Font|size=99%|• Estromustine: 10–14&nbsp;hrs<ref name="pmid9515186" />}}<br />• Estrone: 15–17&nbsp;hours<ref name="pmid9515186" />
| excretion = [[Bile]], [[fece]]s (2.9–4.8%)<ref name="pmid9515186" /><ref name="MSR" />

<!-- Identifiers -->
| CAS_number_Ref =
| CAS_number = 4891-15-0
| CAS_supplemental = <br />52205-73-9 ([[sodium]])<br />325726-21-4 ([[meglumine]])
| ATC_prefix = L01
| ATC_suffix = XX11
| ATC_supplemental =
| PubChem = 259329
| IUPHAR_ligand = 9076
| DrugBank_Ref =
| DrugBank = DB01196
| ChemSpiderID_Ref =
| ChemSpiderID = 227633
| UNII = MUZ9585Y7B
| KEGG = D02398+D06397
| ChEBI = 68643
| ChEMBL = 1756
| synonyms = EMP; Leo 299; NSC-89199; Ro 21-8837/001; Estradiol normustine phosphate; Estradiol 3-normustine 17β-phosphate; Estradiol 3-(bis(2-chloroethyl)carbamate) 17β-(dihydrogen phosphate)

<!--Chemical data-->
| C=23 | H=32 | Cl=2 | N=1 | O=6 | P=1
| SMILES = C[C@]12CC[C@H]3[C@H]([C@@H]1CC[C@@H]2OP(=O)(O)O)CCC4=C3C=CC(=C4)OC(=O)N(CCCl)CCCl
| StdInChI_Ref =
| StdInChI = 1S/C23H32Cl2NO6P/c1-23-9-8-18-17-5-3-16(31-22(27)26(12-10-24)13-11-25)14-15(17)2-4-19(18)20(23)6-7-21(23)32-33(28,29)30/h3,5,14,18-21H,2,4,6-13H2,1H3,(H2,28,29,30)/t18-,19-,20+,21+,23+/m1/s1
| StdInChIKey_Ref =
| StdInChIKey = ADFOJJHRTBFFOF-RBRWEJTLSA-N
}}
<!-- Definition and medical uses -->
'''Estramustine phosphate''' ('''EMP'''), also known as '''estradiol normustine phosphate''' and sold under the brand names '''Emcyt''' and '''Estracyt''', is a dual [[estrogen (medication)|estrogen]] and [[chemotherapy]] medication which is used in the treatment of [[prostate cancer]] in men.<ref name="EmcytLabel">{{cite web |title = Emcyt estramustine phosphate sodium capsules | url = https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/018045s023lbl.pdf |website=FDA |access-date=14 March 2022 }}</ref><ref name="Inoue2018">{{cite book| vauthors = Inoue T |title=Hormone Therapy and Castration Resistance of Prostate Cancer|chapter=Role of Estramustine Phosphate and Other Estrogens for Castration-Resistant Prostate Cancer|year=2018|pages=249–256|publisher=Springer |doi=10.1007/978-981-10-7013-6_26|isbn=978-981-10-7012-9}}</ref><ref name="pmid27684806">{{cite journal | vauthors = Qin Z, Li X, Zhang J, Tang J, Han P, Xu Z, Yu Y, Yang C, Wang C, Xu T, Xu Z, Zou Q | display-authors = 6 | title = Chemotherapy with or without estramustine for treatment of castration-resistant prostate cancer: A systematic review and meta-analysis | journal = Medicine | volume = 95 | issue = 39 | pages = e4801 | date = September 2016 | pmid = 27684806 | pmc = 5265899 | doi = 10.1097/MD.0000000000004801 }}</ref><ref name="pmid21756277">{{cite journal | vauthors = Ravery V, Fizazi K, Oudard S, Drouet L, Eymard JC, Culine S, Gravis G, Hennequin C, Zerbib M | display-authors = 6 | title = The use of estramustine phosphate in the modern management of advanced prostate cancer | journal = BJU International | volume = 108 | issue = 11 | pages = 1782–1786 | date = December 2011 | pmid = 21756277 | doi = 10.1111/j.1464-410X.2011.10201.x | s2cid = 33456591 | doi-access =  }}</ref><ref name="SimpsonWagstaff2003">{{cite journal | vauthors = Simpson D, Wagstaff AJ | title = Estramustine Phosphate Sodium | journal = American Journal of Cancer | year = 2003 | volume = 2 | issue = 5 | pages = 373–390 | doi = 10.2165/00024669-200302050-00013 | s2cid = 70507026 }}</ref><ref name="pmid11240822">{{cite journal | vauthors = Kitamura T | title = Necessity of re-evaluation of estramustine phosphate sodium (EMP) as a treatment option for first-line monotherapy in advanced prostate cancer | journal = International Journal of Urology | volume = 8 | issue = 2 | pages = 33–36 | date = February 2001 | pmid = 11240822 | doi = 10.1046/j.1442-2042.2001.00254.x | s2cid = 43384150 }}</ref><ref name="pmid9515186">{{cite journal | vauthors = Bergenheim AT, Henriksson R | title = Pharmacokinetics and pharmacodynamics of estramustine phosphate | journal = Clinical Pharmacokinetics | volume = 34 | issue = 2 | pages = 163–172 | date = February 1998 | pmid = 9515186 | doi = 10.2165/00003088-199834020-00004 | s2cid = 1943973 }}</ref><ref name="pmid9050135">{{cite journal | vauthors = Hudes G | title = Estramustine-based chemotherapy | journal = Seminars in Urologic Oncology | volume = 15 | issue = 1 | pages = 13–19 | date = February 1997 | pmid = 9050135 }}</ref><ref name="pmid7579781">{{cite journal | vauthors = Perry CM, McTavish D | title = Estramustine phosphate sodium. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in prostate cancer | journal = Drugs & Aging | volume = 7 | issue = 1 | pages = 49–74 | date = July 1995 | pmid = 7579781 | doi = 10.2165/00002512-199507010-00006 | s2cid = 36725810 }}</ref><ref name="pmid8595142">{{cite book | vauthors = Kreis W | title = Concepts, Mechanisms, and New Targets for Chemotherapy | chapter = Estramustine revisited | series = Cancer Treatment and Research | volume = 78 | pages = 163–184 | date = 1995 | publisher = Springer | pmid = 8595142 | doi = 10.1007/978-1-4615-2007-8_8 | isbn = 978-1-4613-5829-9 }}</ref> It is taken multiple times a day [[oral administration|by mouth]] or by [[intravenous injection|injection into a vein]].<ref name="EmcytLabel" /><ref name="pmid27684806" /><ref name="pmid11240822" /><ref name="pmid9515186" /><ref name="pmid7579781" /><ref name="pmid8595142" />

<!-- Side effects and mechanism -->
[[Side effect]]s of EMP include [[nausea]], [[vomiting]], [[gynecomastia]], [[feminization (biology)|feminization]], [[demasculinization]], [[sexual dysfunction]], [[thromboembolism|blood clot]]s, and [[cardiovascular]] complications.<ref name="pmid11240822" /><ref name="pmid21756277" /><ref name="pmid9274433" /> EMP is a dual [[cytostatic]] and hence [[chemotherapeutic agent]] and a [[hormonal therapy (oncology)|hormonal anticancer agent]] of the [[estrogen (medication)|estrogen]] type.<ref name="pmid9515186" /><ref name="pmid11240822" /><ref name="OettelSchillinger2012" /><ref name="pmid7579781" /> It is a [[prodrug]] of [[estramustine]] and [[estromustine]] in terms of its cytostatic effects and a prodrug of [[estradiol (medication)|estradiol]] in relation to its [[estrogen (medication)|estrogen]]ic effects.<ref name="pmid9515186" /><ref name="pmid11240822" /> EMP has strong estrogenic effects at typical clinical dosages, and consequently has marked [[antigonadotropic]] and functional [[antiandrogen]]ic effects.<ref name="Inoue2018" /><ref name="pmid9515186" /><ref name="pmid11240822" /><ref name="OettelSchillinger2012" />

<!-- History, society, and culture -->
EMP was introduced for medical use in the early 1970s.<ref name="pmid11240822" /> It is available in the [[United States]], [[Canada]], the [[United Kingdom]], other [[Europe]]an countries, and elsewhere in the world.<ref name="IndexNominum2000" /><ref name="Drugs.com" />

{{TOC limit|3}}

==Medical uses==
EMP is indicated, in the [[United States]], for the [[palliative care|palliative treatment]] of [[metastatic]] and/or progressive prostate cancer,<ref name="MSR" /> whereas in the [[United Kingdom]] it is indicated for the treatment of unresponsive or [[relapse|relapsing]] prostate cancer.<ref name="EMP-EMC">{{cite web|title=Estracyt Capsules - Summary of Product Characteristics (SPC)|work=electronic Medicines Compendium|publisher=Pfizer Limited|access-date=8 February 2014|date=12 August 2013|url=http://www.medicines.org.uk/emc/medicine/1511/SPC/Estracyt+Capsules/|archive-date=22 February 2014|archive-url=https://web.archive.org/web/20140222203824/http://www.medicines.org.uk/emc/medicine/1511/SPC/Estracyt+Capsules/|url-status=dead}}</ref><ref name="pmid7579781" /><ref name="pmid9515186" /><ref name="SimpsonWagstaff2003" /> The medication is usually reserved for use in hormone-refractory cases of prostate cancer, although it has been used as a first-line monotherapy as well.<ref name="pmid11240822" /> [[Response rate (medicine)|Response rate]]s with EMP in prostate cancer are said to be equivalent to conventional [[high-dose estrogen]] therapy.<ref name="Lupulescu1990">{{cite book| vauthors = Lupulescu A |title=Hormones and Vitamins in Cancer Treatment|url=https://books.google.com/books?id=VddUa-2cp-YC&pg=PA40|date=24 October 1990|publisher=CRC Press|isbn=978-0-8493-5973-6|pages=40–}}</ref>

Due to its relatively severe side effects and toxicity, EMP has rarely been used in the treatment of prostate cancer.<ref name="Inoue2018" /> This is especially true in [[Western world|Western countries]] today.<ref name="Inoue2018" /> As a result, and also due to the scarce side effects of [[gonadotropin-releasing hormone modulator]]s (GnRH modulators) like [[leuprorelin]], EMP was almost abandoned.<ref name="pmid11240822" /> However, encouraging clinical research findings resulted in renewed interest of EMP for the treatment of prostate cancer.<ref name="pmid11240822" />

EMP has been used at doses of 140 to 1,400&nbsp;mg/day orally in the treatment of prostate cancer.<ref name="StellaBorchardt2007">{{cite book| veditors = Stella V, Borchardt R, Hageman M, Oliyai R, Maag H, Tilley J |title=Prodrugs: Challenges and Rewards|url=https://books.google.com/books?id=qkjHxX5TgHEC&pg=PA174|date=12 March 2007|publisher=Springer Science & Business Media|isbn=978-0-387-49782-2|pages=174–}}</ref> However, oral EMP is most commonly used at a dose of 560 to 640&nbsp;mg/day (280–320&nbsp;mg twice daily).<ref name="pmid9515186" /> The recommended dosage of oral EMP in the [[Food and Drug Administration]] (FDA) label for Emcyt is 14&nbsp;mg per kg of body weight (i.e., one 140&nbsp;mg oral capsule for each 10&nbsp;kg or 22&nbsp;lbs of body weight) given in 3 or 4 divided doses per day.<ref name="EmcytLabel" /> The label states that most patients in studies of oral EMP in the United States have received 10 to 16&nbsp;mg per kg per day.<ref name="EmcytLabel" /> This would be about 900 to 1,440&nbsp;mg/day for a 90-kg or 200-lb man.<ref name="EmcytLabel" /> Lower doses of oral EMP, such as 280&nbsp;mg/day, have been found to have comparable effectiveness as higher doses but with improved [[tolerability]] and reduced toxicity.<ref name="Inoue2018" /> Doses of 140&nbsp;mg/day have been described as a very low dosage.<ref name="pmid20094950">{{cite journal | vauthors = Kitamura T, Suzuki M, Nishimatsu H, Kurosaki T, Enomoto Y, Fukuhara H, Kume H, Takeuchi T, Miao L, Jiangang H, Xiaoqiang L | display-authors = 6 | title = Final report on low-dose estramustine phosphate (EMP) monotherapy and very low-dose EMP therapy combined with LH-RH agonist for previously untreated advanced prostate cancer | journal = Aktuelle Urologie | volume = 41 | issue = Suppl 1 | pages = S34–S40 | date = January 2010 | pmid = 20094950 | doi = 10.1055/s-0029-1224657 | s2cid = 7710924 }}</ref> EMP has been used at doses of 240 to 450&nbsp;mg/day intravenously.<ref name="pmid9515186" />

EMP and other estrogens such as [[polyestradiol phosphate]] and [[ethinylestradiol]] are far less costly than newer therapies such as GnRH modulators, [[abiraterone acetate]], and [[enzalutamide]].<ref name="Inoue2018" /><ref name="pmid14644018">{{cite journal | vauthors = Sayed Y, Taxel P | title = The use of estrogen therapy in men | journal = Current Opinion in Pharmacology | volume = 3 | issue = 6 | pages = 650–654 | date = December 2003 | pmid = 14644018 | doi = 10.1016/j.coph.2003.07.004 }}</ref><ref name="pmid10699602">{{cite journal | vauthors = Hedlund PO, Henriksson P | title = Parenteral estrogen versus total androgen ablation in the treatment of advanced prostate carcinoma: effects on overall survival and cardiovascular mortality. The Scandinavian Prostatic Cancer Group (SPCG)-5 Trial Study | journal = Urology | volume = 55 | issue = 3 | pages = 328–333 | date = March 2000 | pmid = 10699602 | doi = 10.1016/s0090-4295(99)00580-4 }}</ref> In addition, estrogens may offer significant benefits over other means of [[androgen deprivation therapy]], for instance in terms of [[osteoporosis|bone loss]] and [[bone fracture|fracture]]s, [[hot flash]]es, [[cognition]], and [[metabolism|metabolic status]].<ref name="Inoue2018" /><ref name="pmid10699602" />

EMP has been used to prevent the [[testosterone]] flare at the start of [[GnRH agonist]] therapy in men with prostate cancer.<ref name="pmid7541359">{{cite journal | vauthors = Shimizu TS, Shibata Y, Jinbo H, Satoh J, Yamanaka H | title = Estramustine phosphate for preventing flare-up in luteinizing hormone-releasing hormone analogue depot therapy | journal = European Urology | volume = 27 | issue = 3 | pages = 192–195 | date = 1995 | pmid = 7541359 | doi = 10.1159/000475159 }}</ref>

{{Estrogen dosages for breast and prostate cancer}}

===Available forms===
EMP is or has been available in the form of both [[capsule (pharmacy)|capsule]]s (140&nbsp;mg, 280&nbsp;mg) for [[oral administration]] and [[aqueous solution]]s (300&nbsp;mg) for [[intravenous therapy|intravenous injection]].<ref name="StellaBorchardt2007" /><ref name="Muller1998">{{cite book| veditors = Muller NF, Dessing RP |title=European Drug Index: European Drug Registrations | edition = Fourth |url=https://books.google.com/books?id=2HBPHmclMWIC&pg=PA245|date=19 June 1998|publisher=CRC Press|isbn=978-3-7692-2114-5|pages=245, 454}}</ref><ref name="Becker2001">{{cite book| vauthors = Becker KL |title=Principles and Practice of Endocrinology and Metabolism|url=https://books.google.com/books?id=FVfzRvaucq8C&pg=PA2153|year=2001|publisher=Lippincott Williams & Wilkins|isbn=978-0-7817-1750-2|pages=2153–}}</ref><ref name="EmcytLabel" />

==Contraindications==
EMP is [[contraindication|contraindicated]] when used in children, patients [[hypersensitivity|hypersensitive]] to estrogens or [[nitrogen mustard]]s, those with [[peptic ulcer]] (an [[ulcer]] in the [[digestive tract]]), those with severely [[liver impairment|compromised liver function]], those with weak [[heart]] [[muscle]] (also known as [[cardiac insufficiency|myocardial insufficiency]]) and those with [[thromboembolism|thromboembolic disorder]]s or complications related to [[water retention (medicine)|fluid retention]].<ref name="EMP-EMC" />

==Side effects==
The [[side effect]]s of EMP overall have been described as relatively severe.<ref name="pmid11240822" /> The most common side effects of EMP have been reported to be [[gastrointestinal]] side effects like [[nausea]], [[vomiting]], and [[diarrhea]], with nausea and vomiting occurring in 40% of men.<ref name="pmid21756277" /><ref name="pmid9515186" /> They are usually mild or moderate in severity, and the nausea and vomiting can be managed with [[prophylactic]] [[antiemetic]] medications.<ref name="pmid21756277" /> Nonetheless, severe cases of gastrointestinal side effects with EMP may require dose reduction or [[medication discontinuation|discontinuation]] of therapy.<ref name="pmid9515186" /> Although nausea and vomiting have been reported to be the most common side effects of EMP, [[gynecomastia]] (male breast development) has been found to occur in as many as 83% of men treated with EMP, and the incidence of [[erectile dysfunction]] is possibly similar to or slightly less than the risk of gynecomastia.<ref name="pmid11240822" /> As a rule, [[feminization (biology)|feminization]], a [[gynoid fat distribution]], [[demasculinization]], and impotence are said to occur in virtually or nearly 100% of men treated with [[high-dose estrogen]] therapy.<ref name="pmid9274433">{{cite journal | vauthors = Galbraith SM, Duchesne GM | title = Androgens and prostate cancer: biology, pathology and hormonal therapy | journal = European Journal of Cancer | volume = 33 | issue = 4 | pages = 545–554 | date = April 1997 | pmid = 9274433 | doi = 10.1016/S0959-8049(96)00444-3 }}</ref><ref name="pmid15663992">{{cite journal | vauthors = Tammela T | title = Endocrine treatment of prostate cancer | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 92 | issue = 4 | pages = 287–295 | date = November 2004 | pmid = 15663992 | doi = 10.1016/j.jsbmb.2004.10.005 | s2cid = 25425351 }}</ref> Decreased [[human sexual activity|sexual activity]] has also been reported in men treated with EMP.<ref name="pmid9515186" /> These side effects are due to high [[estrogen (medication)|estrogen]] levels and low [[testosterone]] levels.<ref name="pmid9515186" /><ref name="pmid11240822" /> Prophylactic [[radiotherapy|irradiation]] of the [[breast]]s can be used to decrease the incidence and severity of gynecomastia with estrogens.<ref name="pmid9274433" />

Severe adverse effects of EMP are [[thromboembolic]] and [[cardiovascular]] complications including [[pulmonary embolism]], [[deep vein thrombosis]], [[stroke]], [[thrombophlebitis]], [[coronary artery disease]] (ischemic heart disease; e.g., [[myocardial infarction]]), [[thrombophlebitis]], and [[congestive heart failure]] with [[water retention (medicine)|fluid retention]].<ref name="pmid21756277" /><ref name="pmid9515186" /> EMP produces cardiovascular toxicity similarly to [[diethylstilbestrol]], but to a lesser extent in comparison at low doses (e.g., 280&nbsp;mg/day oral EMP vs. 1&nbsp;mg/day oral diethylstilbestrol).<ref name="pmid11240822" /><ref name="pmid7500443">{{cite journal | vauthors = Cox RL, Crawford ED | title = Estrogens in the treatment of prostate cancer | journal = The Journal of Urology | volume = 154 | issue = 6 | pages = 1991–1998 | date = December 1995 | pmid = 7500443 | doi = 10.1016/S0022-5347(01)66670-9 }}</ref> The prostate cancer disease state also increases the risk of thromboembolism, and combination with [[docetaxel]] may exacerbate the risk of thromboembolism as well.<ref name="pmid21756277" /> [[Meta-analysis|Meta-analyses]] of [[clinical trial]]s have found that the overall risk of thromboembolism with EMP is 4 to 7%, relative to 0.4% for chemotherapy regimens without EMP.<ref name="pmid21756277" /><ref name="pmid15536625" /> Thromboembolism is the major [[toxicity]]-related cause of [[medication discontinuation|discontinuation]] of EMP.<ref name="pmid17942366">{{cite journal | vauthors = Fizazi K, Le Maitre A, Hudes G, Berry WR, Kelly WK, Eymard JC, Logothetis CJ, Pignon JP, Michiels S | display-authors = 6 | title = Addition of estramustine to chemotherapy and survival of patients with castration-refractory prostate cancer: a meta-analysis of individual patient data | journal = The Lancet. Oncology | volume = 8 | issue = 11 | pages = 994–1000 | date = November 2007 | pmid = 17942366 | doi = 10.1016/S1470-2045(07)70284-X }}</ref> [[Anticoagulant]] therapy with medications such as [[aspirin]], [[warfarin]], unfractionated and low-[[molecular weight|molecular-weight]] [[heparin]], and [[vitamin K antagonist]]s can be useful for decreasing the risk of thromboembolism with EMP and other estrogens like [[diethylstilbestrol]] and [[ethinylestradiol]].<ref name="pmid21756277" /><ref name="pmid25920994">{{cite journal | vauthors = Petrioli R, Roviello G, Fiaschi AI, Laera L, Bianco V, Ponchietti R, Barbanti G, Francini E | display-authors = 6 | title = Low-Dose Estramustine Phosphate and Concomitant Low-Dose Acetylsalicylic Acid in Heavily Pretreated Patients With Advanced Castration-Resistant Prostate Cancer | journal = Clinical Genitourinary Cancer | volume = 13 | issue = 5 | pages = 441–446 | date = October 2015 | pmid = 25920994 | doi = 10.1016/j.clgc.2015.03.004 }}</ref><ref name="Inoue2018" />

Adverse [[liver function tests]] are commonly seen with EMP, but severe [[liver dysfunction]] is rare with the medication.<ref name="pmid9515186" /> [[Central nervous system]] side effects are rarely seen with EMP, although [[Ventricular system#Clinical significance|enlarged ventricles]] and [[neuron]]al [[pigmentation]] have been reported in monkeys treated with very high doses of EMP (20–140&nbsp;mg/kg/day) for 3 to 6&nbsp;months.<ref name="pmid9515186" /> EMP does not appear to have cytostatic effects in normal [[brain]] tissue.<ref name="pmid9515186" /> In women treated with EMP in clinical studies, a few instances of minor [[gynecological]] [[hemorrhage]]s have been observed.<ref name="pmid9515186" /> EMP is described as relatively well tolerated among cytostatic antineoplastic and nitrogen-mustard agents, rarely or not at all being associated with significant [[hematology|hematologic]] [[toxicity]] such as [[myelosuppression]] (bone marrow suppression), gastrointestinal toxicity, or other more marked toxicity associated with such agents.<ref name="pmid7579781" /><ref name="pmid9515186" /><ref name="pmid6375076" /> In contrast to most other cytostatic agents, which often cause myelosuppression, [[leukopenia]] (decreased [[white blood cell]] count), and [[neutropenia]] (decreased [[neutrophil]] count), EMP actually produces [[leukocytosis]] (increased white blood cell count) as a side effect.<ref name="pmid86404" /><ref name="pmid6349745" />

In a small low-dose study using 280&nbsp;mg/day oral EMP for 150&nbsp;days, tolerability was significantly improved, with gastrointestinal [[irritation]] occurring in only 15% of men, and there was no incidence of severe cardiovascular toxicity or deep vein thrombosis.<ref name="pmid11240822" /><ref name="Inoue2018" /> In addition, no other side effects besides slight transient [[elevated liver enzymes]] were observed.<ref name="pmid11240822" /> These findings suggest that lower doses of oral EMP may be a safer option than higher doses for the treatment of prostate cancer.<ref name="Inoue2018" /> However, a subsequent 2004 [[meta-analysis]] of 23&nbsp;studies of thromboembolic events with EMP found substantial incidence of thromboembolic events regardless of dosage and no association of EMP dose with risk of these complications.<ref name="pmid15536625">{{cite journal | vauthors = Lubiniecki GM, Berlin JA, Weinstein RB, Vaughn DJ | title = Thromboembolic events with estramustine phosphate-based chemotherapy in patients with hormone-refractory prostate carcinoma: results of a meta-analysis | journal = Cancer | volume = 101 | issue = 12 | pages = 2755–2759 | date = December 2004 | pmid = 15536625 | doi = 10.1002/cncr.20673 | s2cid = 21465413 }}</ref>

{{Side effects of estramustine phosphate (EMC)}}

{{Side effects of estramustine phosphate (FDA)}}

==Overdose==
There has been no clinical experience with [[overdose]] of EMP.<ref name="EmcytLabel" /> Overdose of EMP may result in pronounced manifestations of the known adverse effects of the medication.<ref name="EmcytLabel" /> There is no specific [[antidote]] for overdose of EMP.<ref name="EMP-EMC" /> In the event of overdose, [[gastric lavage]] should be used to evacuate gastric contents as necessary and treatment should be [[symptom]]-based and supportive.<ref name="EmcytLabel" /><ref name="EMP-EMC" /> In the case of dangerously low counts of [[red blood cell]]s, [[white blood cell]]s, or [[platelet]]s, [[whole blood]] may be given as needed.<ref name="EMP-EMC" /> [[Liver]] function should be monitored with EMP overdose.<ref name="EMP-EMC" /> After an overdose of EMP, [[hematological]] and [[liver|hepatic]] parameters should continue to be monitored for at least 6&nbsp;weeks.<ref name="EmcytLabel" />

EMP has been used at high doses of as much as 1,260&nbsp;mg/day by the [[oral administration|oral]] route and 240 to 450&nbsp;mg/day by [[intravenous injection]].<ref name="pmid11240822" /><ref name="pmid9515186" />

== Interactions ==

EMP has been reported to increase the [[efficacy]] and [[toxicity]] of [[tricyclic antidepressants]] like [[amitriptyline]] and [[imipramine]].<ref name="EMP-EMC" /> When products containing [[calcium]], [[aluminium]], and/or [[magnesium]], such as [[dairy product]]s like [[milk]], various [[food]]s [[dietary supplement]]s, and [[antacid]]s, are consumed concomitantly with EMP, an [[water solubility|insoluble]] [[chelate complex]]/[[phosphate]] [[salt (chemistry)|salt]] between EMP and these [[metal]]s can be formed, and this can markedly impair the [[absorption (pharmacokinetics)|absorption]] and hence [[oral administration|oral]] [[bioavailability]] of EMP.<ref name="pmid11240822" /><ref name="pmid9515186" /><ref name="EMP-EMC" /> There may be an increased risk of [[angioedema]] in those concurrently taking [[ACE inhibitor]]s.<ref name="EMP-EMC" />

==Pharmacology==

===Pharmacodynamics===
{{See also|Pharmacodynamics of estradiol}}

[[File:Estramustine.svg|thumb|right|250px|[[Estramustine]], the major active cytostatic form of estramustine phosphate.]]
[[File:Estradiol.svg|thumb|right|250px|[[Estradiol (medication)|Estradiol]], the major active estrogenic form of estramustine phosphate.]]

EMP, also known as estradiol normustine phosphate, is a combined [[estrogen ester]] and [[nitrogen mustard]] [[ester]].<ref name="pmid9515186" /><ref name="pmid11240822" /><ref name="OettelSchillinger2012" /> It consists of [[estradiol (medication)|estradiol]], an [[estrogen (medication)|estrogen]], linked with a [[phosphate]] ester as well as an ester of [[normustine]], a nitrogen mustard.<ref name="pmid9515186" /><ref name="pmid11240822" /><ref name="OettelSchillinger2012" /> In terms of its [[pharmacodynamic]] effects, EMP is a [[prodrug]] of [[estramustine]], [[estromustine]], and [[estradiol (medication)|estradiol]].<ref name="pmid9515186" /><ref name="pmid11240822" /> As a prodrug of estradiol, EMP is an estrogen and hence an [[agonist]] of the [[estrogen receptor]]s.<ref name="pmid9515186" /><ref name="pmid16112947">{{cite journal | vauthors = Kuhl H | title = Pharmacology of estrogens and progestogens: influence of different routes of administration | journal = Climacteric | volume = 8 | issue = Suppl 1 | pages = 3–63 | date = August 2005 | pmid = 16112947 | doi = 10.1080/13697130500148875 | s2cid = 24616324 }}</ref> EMP itself has only very weak [[affinity (pharmacology)|affinity]] for the estrogen receptors.<ref name="pmid9515186" /> The medication is of about 91% higher [[molecular weight]] than estradiol due to the presence of its C3 normustine and C17β phosphate esters.<ref name="Elks2014" /><ref name="IndexNominum2000" /> Because EMP is a prodrug of estradiol, it may be considered to be a [[natural product|natural]] and [[bioidentical hormone replacement therapy|bioidentical]] form of estrogen,<ref name="OettelSchillinger2012" /> although it does have additional cytostatic activity via estramustine and estromustine.<ref name="pmid9515186" /><ref name="pmid11240822" />

EMP acts by a dual [[mechanism of action]]: 1) direct cytostatic activity via a number of actions; and 2) as a form of [[high-dose estrogen]] therapy via estrogen receptor-mediated [[antigonadotropic]] and functional [[antiandrogen]]ic effects.<ref name="pmid9515186" /><ref name="pmid11240822" /><ref name="OettelSchillinger2012">{{cite book| vauthors = Oettel M, Schillinger E |title=Estrogens and Antiestrogens II: Pharmacology and Clinical Application of Estrogens and Antiestrogen|url=https://books.google.com/books?id=wBvyCAAAQBAJ&pg=PA540|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-60107-1|pages=540–}}</ref> The antigonadotropic and functional antiandrogenic effects of EMP consist of strong suppression of [[gonad]]al [[androgen]] [[biosynthesis|production]] and hence circulating levels of androgens such as [[testosterone]]; greatly increased levels of [[sex hormone-binding globulin]] and hence a decreased fraction of free androgens in the [[circulatory system|circulation]]; and direct antiandrogenic actions in prostate cells.<ref name="pmid6375076" /><ref name="pmid9515186" /><ref name="pmid11240822" /><ref name="Inoue2018" /><ref name="pmid10076535">{{cite journal | vauthors = Wang LG, Liu XM, Kreis W, Budman DR | title = Androgen antagonistic effect of estramustine phosphate (EMP) metabolites on wild-type and mutated androgen receptor | journal = Biochemical Pharmacology | volume = 55 | issue = 9 | pages = 1427–1433 | date = May 1998 | pmid = 10076535 | doi = 10.1016/S0006-2952(97)00657-6 | doi-access = free }}</ref><ref name="pmid2093302">{{cite journal | vauthors = Van Poppel H, Werbrouck PW, Baert L | title = Effect of estramustine phosphate on free androgens. A comparative study of the effect of orchiectomy and estramustine phosphate on free androgens in patients with prostatic cancer | journal = Acta Urologica Belgica | volume = 58 | issue = 4 | pages = 89–95 | date = 1990 | pmid = 2093302 }}</ref><ref name="pmid7190620">{{cite journal | vauthors = Karr JP, Wajsman Z, Kirdani RY, Murphy GP, Sandberg AA | title = Effects of diethylstilbestrol and estramustine phosphate on serum sex hormone binding globulin and testosterone levels in prostate cancer patients | journal = The Journal of Urology | volume = 124 | issue = 2 | pages = 232–236 | date = August 1980 | pmid = 7190620 | doi = 10.1016/S0022-5347(17)55383-5 }}</ref> The free androgen index with oral EMP has been found to be on average 4.6-fold lower than with [[orchiectomy]].<ref name="pmid2093302" /> As such, EMP therapy results in considerably stronger [[androgen deprivation therapy|androgen deprivation]] than orchiectomy.<ref name="pmid7190620" /> Metabolites of EMP, including estramustine, estromustine, estradiol, and [[estrone (medication)|estrone]], have been found to act as weak [[receptor antagonist|antagonist]]s of the [[androgen receptor]] ({{abbrlink|EC<sub>50</sub>|half-maximal effective concentration}} = 0.5–3.1&nbsp;μM), although the clinical significance of this is unknown.<ref name="pmid12084341">{{cite journal | vauthors = Olson KB, Pienta KJ | title = Recent advances in chemotherapy for advanced prostate cancer | journal = Current Urology Reports | volume = 1 | issue = 1 | pages = 48–56 | date = May 2000 | pmid = 12084341 | doi = 10.1007/s11934-000-0035-z | s2cid = 31084737 }}</ref><ref name="pmid10076535" /><ref name="pmid11240822" /><ref name="pmid9515186" />

Extremely high levels of estradiol and estrone occur during EMP therapy.<ref name="pmid11240822" /><ref name="Inoue2018" />  The estrogenic [[metabolite]]s of EMP are responsible for its most common adverse effects and its [[cardiovascular]] [[toxicity]].<ref name="pmid9515186" /> EMP has been described as having relatively weak estrogenic effects in some publications.<ref name="pmid7579781" /><ref name="pmid6375076" /> However, it has shown essentially the same rates and degrees of estrogenic effects, such as [[breast tenderness]], [[gynecomastia]], cardiovascular toxicity, changes in [[liver protein synthesis]], and testosterone suppression, as high-dose [[diethylstilbestrol]] and [[ethinylestradiol]] in clinical studies.<ref name="EmcytLabel" /><ref name="Inoue2018" /><ref name="pmid6375076" /><ref name="pmid7190620" /><ref name="pmid3092893">{{cite journal | vauthors = Daehlin L, Damber JE, von Schoultz B, Bergman B | title = The oestrogenic effects of ethinyl oestradiol/polyoestradiol phosphate and estramustine phosphate in patients with prostatic carcinoma. A comparative study of oestrogen sensitive liver proteins, gonadotrophins and prolactin | journal = British Journal of Urology | volume = 58 | issue = 4 | pages = 412–416 | date = August 1986 | pmid = 3092893 | doi = 10.1111/j.1464-410X.1986.tb09095.x }}</ref> The notion that EMP has relatively weak estrogen activity may have been based on [[animal research]], which found that EMP had 100-fold lower [[uterotrophic]] effects than estradiol in rats, and may also not have taken into account the very high doses of EMP used clinically in humans.<ref name="pmid3092893" /><ref name="Fredholm1974">Fredholm, B., Jensen, G., Lindskog, M., & Muntzing, J. (1974, January). Effects of estramustine phosphate (Estracyt) on growth of DMBA-induced mammary tumors in rats. In Acta Pharmacologica et Toxicologica (Vol. 35, pp. 28-28). 35 Norre Sogade, PO Box 2148, DK-1016 Copenhagen, Denmark: Munksgaard Int Publ Ltd.</ref>

The mechanism of action of the [[cytostatic]] effects of EMP is complex and only partially understood.<ref name="pmid9515186" /> EMP is considered to mainly be a [[mitotic inhibitor]], inhibiting mechanisms involved in the [[mitosis]] phase of the [[cell cycle]].<ref name="pmid9515186" /><ref name="Inoue2018" /> Specifically, it binds to [[microtubule-associated protein]]s and/or to [[tubulin]] and produces [[depolymerization]] of [[microtubule]]s (K<sub>d</sub> = 10–20&nbsp;μM for estramustine), resulting in the arrest of [[cell division]] in the [[G2 phase#G2/M Checkpoint|G<sub>2</sub>/M phase]] (specifically [[metaphase]]).<ref name="pmid9515186" /><ref name="Inoue2018" /><ref name="pmid1545778" /> EMP was originally thought to mediate its cytostatic effects as a prodrug of [[normustine]], a [[nitrogen mustard]], and hence was thought to be an [[alkylating antineoplastic agent]].<ref name="pmid11240822" /><ref name="SimpsonWagstaff2003" /><ref name="pmid7579781" /><ref name="OettelSchillinger2012" /> However, subsequent research has found that EMP is devoid of alkylating actions, and that the influence of EMP on microtubules is mediated by intact estramustine and estromustine, with normustine or estradiol alone having only minor or negligible effects.<ref name="pmid9515186" /><ref name="pmid11240822" /><ref name="pmid6373212" /> As such, the unique properties of the estramustine and estromustine [[chemical structure|structure]]s, containing a [[carbamate]]-[[ester]] [[chemical bond|bond]], appear to be responsible for the cytostatic effects of EMP.<ref name="pmid9515186" /> In addition to its antimitotic actions, EMP has also been found to produce other cytostatic effects, including induction of [[apoptosis]], interference with [[DNA synthesis]], [[nuclear matrix]] interaction, [[cell membrane]] alterations, induction of [[reactive oxygen species]] (free oxygen radicals), and possibly additional mechanisms.<ref name="pmid9515186" /><ref name="Inoue2018" /> EMP has been found to have a [[radiosensitizer|radiosensitizing]] effect in prostate cancer and [[glioma]] cells, improving sensitivity to [[radiation therapy]] as well.<ref name="pmid9515186" />

The cytostatic metabolites of EMP are accumulated in [[tissue (biology)|tissue]]s in a [[tissue selectivity|selective]] manner, for instance in [[prostate cancer]] [[cell (biology)|cell]]s.<ref name="pmid7579781" /><ref name="pmid9515186" /><ref name="Inoue2018" /> This may be due to the presence of a specific estramustine-binding protein (EMBP) (K<sub>d</sub> = 10–35&nbsp;nM for estramustine), also known as prostatin or prostatic secretion protein (PSP), which has been detected in prostate cancer, [[glioma]], [[melanoma]], and [[breast cancer]] cells.<ref name="pmid9515186" /><ref name="Inoue2018" /><ref name="pmid2682681">{{cite journal | vauthors = Tew KD, Stearns ME | title = Estramustine--a nitrogen mustard/steroid with antimicrotubule activity | journal = Pharmacology & Therapeutics | volume = 43 | issue = 3 | pages = 299–319 | date = 1989 | pmid = 2682681 | doi = 10.1016/0163-7258(89)90012-0 }}</ref> Because of its tissue selectivity, EMP is said to produce minimal cytostatic effects in healthy tissues, and its tissue selectivity may be responsible for its therapeutic cytostatic efficacy against prostate cancer cells.<ref name="pmid7579781" /><ref name="Inoue2018" /><ref name="pmid9515186" />

EMP was originally developed as a dual ester prodrug of an estrogen and normustine as a nitrogen mustard alkylating antineoplastic agent which, due to the affinity of the estrogen [[moiety (chemistry)|moiety]] for estrogen receptors, would be selectively accumulated in estrogen target tissues and hence estrogen receptor-positive [[tumor]] cells.<ref name="Inoue2018" /><ref name="OettelSchillinger2012" /><ref name="pmid16112947" /> Consequentially, it was thought that EMP would preferentially deliver the alkylating normustine moiety to these tissues, allowing for reduced cytostatic effects in healthy tissues and hence improved [[efficacy]] and [[tolerability]].<ref name="Inoue2018" /> However, subsequent research found that there is very limited and slow [[bond cleavage|cleavage]] of the normustine ester and that EMP is devoid of alkylating activity.<ref name="Inoue2018" /><ref name="pmid9515186" /><ref name="pmid11240822" /><ref name="pmid6375076" /> In addition, it appears that estramustine and estromustine may be preferentially accumulated in estrogen target tissues not due to affinity for the estrogen receptors, but instead due to affinity for the distinct EMBP.<ref name="pmid9515186" /><ref name="pmid11240822" />

Extremely high, [[pregnancy]]-like levels of estradiol may be responsible for the [[leukocytosis]] (increased [[white blood cell]] count) that is observed in individuals treated with EMP.<ref name="pmid86404">{{cite journal | vauthors = Alexander NC, Hancock AK, Masood MB, Peet BG, Price JJ, Turner RL, Stone J, Ward AJ | display-authors = 6 | title = Estracyt in advanced carcinoma of the breast: a phase II study | journal = Clinical Radiology | volume = 30 | issue = 2 | pages = 139–147 | date = March 1979 | pmid = 86404 | doi = 10.1016/S0009-9260(79)80133-6 }}</ref><ref name="pmid6349745">{{cite journal | vauthors = Daponte D, Sylvester R, De Pauw M, Fryszman A, Smith RM, Smith PH | title = Change in white cell count during treatment of advanced cancer of the prostate with estramustine phosphate and with stilboestrol | journal = British Journal of Urology | volume = 55 | issue = 4 | pages = 408–412 | date = August 1983 | pmid = 6349745 | doi = 10.1111/j.1464-410X.1983.tb03333.x }}</ref> This side effect is in contrast to most other cytotoxic agents, which instead cause [[myelosuppression]] ([[bone marrow]] suppression), [[leukopenia]] (decreased white blood cell count), and [[neutropenia]] (decreased [[neutrophil]] count).{{Citation needed|date=December 2019|reason=removed citation to predatory publisher content}}

====Antigonadotropic effects====
EMP at a dosage 280&nbsp;mg/day has been found to suppress testosterone levels in men into the [[castration|castrate]] range (to 30&nbsp;ng/dL) within 20&nbsp;days and to the low castrate range (to 10&nbsp;ng/dL) within 30&nbsp;days.<ref name="pmid11240822" /> Similarly, a dosage of 70&nbsp;mg/day EMP suppressed testosterone levels into the castrate range within 4&nbsp;weeks.<ref name="pmid11240822" />

===Pharmacokinetics===
{{See also|Pharmacokinetics of estradiol}}

[[File:Estradiol and testosterone levels with 280 mg per day oral estramustine phosphate in men with prostate cancer.png|thumb|right|450px|Estradiol and testosterone levels during therapy with 280&nbsp;mg/day oral EMP in men with prostate cancer (n = 11).<ref name="pmid11240822" />]]

{| class="wikitable floatright"
|+ Pharmacokinetics of estromustine after a single dose of EMP in men with prostate cancer (n = 5)
|-
! Parameter !! {{abbr|IV|intravenous injection}} 300&nbsp;mg !! Oral 420&nbsp;mg
|-
| [[Cmax (pharmacology)|{{abbr|C<sub>max</sub>|Peak levels}}]] || 506 ± 61&nbsp;ng/mL || 362 ± 38&nbsp;ng/mL
|-
| [[Tmax (pharmacology)|T<sub>max</sub>]] || 2.6 ± 0.4 hours || 2.2 ± 0.2 hours
|-
| [[Elimination half-life|{{abbr|t<sub>1/2</sub>|Elimination half-life}}]] || 10.3 ± 0.95 hours || 13.6 ± 3.09 hours
|-
| [[Area under the curve (pharmacokinetics)|{{abbr|AUC<sub>0–32</sub>|Area-under-the-curve levels (total exposure)}}]] || 4.82 ± 0.62 || 2.88 ± 0.34
|-
| [[Bioavailability]] || 100.0% || 43.7% ± 4.6%
|- class="sortbottom"
| colspan="3" style="width: 1px; background-color:#eaecf0; text-align: center;" | '''Sources:''' <ref name="pmid6375076" />
|}

{| class="wikitable floatright"
|+ <br />Levels of EMP metabolites during continuous therapy with 560&nbsp;mg/day oral EMP in men
|-
! Metabolite !! Plasma !! Ratio
|-
| [[Estramustine]] || 20,000–23,000 pg/mL || rowspan="2" | 1:9.6–9.8
|-
| [[Estromustine]] || 191,000–267,000 pg/mL
|-
| [[Estradiol (medication)|Estradiol]] || 4,900–9,000 pg/mL || rowspan="2" | 1:9.4–11.8
|-
| [[Estrone (medication)|Estrone]] || 71,000–85,000 pg/mL
|- class="sortbottom"
| colspan="3" style="width: 1px; background-color:#eaecf0; text-align: center;" | '''Sources:''' <ref name="pmid6375076" />
|}

Upon [[oral administration|oral ingestion]], EMP is rapidly and completely [[dephosphorylation|dephosphorylated]] by [[phosphatase]]s into [[estramustine]] during the [[first-pass metabolism|first pass]] in the [[gastrointestinal]] tract.<ref name="pmid9515186" /><ref name="Inoue2018" /><ref name="pmid7579781" /><ref name="CavalliKaye2009">{{cite book| veditors = Cavalli F, Kaye SB, Hansen HH, Armitage JO, Piccart-Gebhart M |title=Textbook of Medical Oncology | edition = Fourth |url=https://books.google.com/books?id=WdDKBQAAQBAJ&pg=PA442|date=12 September 2009|publisher=CRC Press|isbn=978-0-203-09289-7|pages=442–}}</ref> Estramustine is also partially but considerably [[oxidation|oxidized]] into [[estromustine]] by [[17β-hydroxysteroid dehydrogenase]]s during the first pass.<ref name="pmid7579781" /><ref name="pmid9515186" /><ref name="pmid8595142" /><ref name="pmid6673977">{{cite journal | vauthors = Gunnarsson O, Andersson SB, Johansson SA | title = The hydrolysis of estramustine phosphate; in vitro studies | journal = European Journal of Drug Metabolism and Pharmacokinetics | volume = 8 | issue = 4 | pages = 395–402 | date = 1983 | pmid = 6673977 | doi = 10.1007/BF03188772 | s2cid = 22105700 }}</ref> As such, EMP reaches the [[circulatory system|circulation]] as estramustine and estromustine, and the major [[metabolite]] of EMP is estromustine.<ref name="pmid9515186" /><ref name="pmid8595142" /> A limited quantity of approximately 10 to 15% of estramustine and estromustine is further slowly [[metabolism|metabolized]] via [[hydrolysis]] of the [[normustine]] [[ester]] into [[estradiol (medication)|estradiol]] and [[estrone (medication)|estrone]], respectively.<ref name="pmid9515186" /><ref name="Inoue2018" /><ref name="pmid6375076" /> This [[chemical reaction|reaction]] is believed to be [[catalysis|catalyzed]] by [[carbamidase]]s, although the [[gene]]s encoding the responsible enzymes have not been characterized.<ref name="pmid9515186" /><ref name="pmid19735314" /><ref name="pmid15733111" /> The circulating levels of normustine formed from EMP are insignificant.<ref name="pmid6373212">{{cite journal | vauthors = Hauser AR, Merryman R | title = Estramustine phosphate sodium | journal = Drug Intelligence & Clinical Pharmacy | volume = 18 | issue = 5 | pages = 368–374 | date = May 1984 | pmid = 6373212 | doi = 10.1177/106002808401800502 | s2cid = 25303747 }}</ref><ref name="GateTew2011">{{cite book| vauthors = Gate L, Tew KD |title=Cancer Management in Man: Chemotherapy, Biological Therapy, Hyperthermia and Supporting Measures|chapter=Alkylating Agents|series=Cancer Growth and Progression |year=2011|pages=61–85|publisher=Springer |doi=10.1007/978-90-481-9704-0_4|isbn=978-90-481-9703-3}}</ref> Release of [[nitrogen mustard]] [[gas]] from normustine via cleavage of the [[carboxylic acid]] [[functional group|group]] has not been demonstrated and does not seem to occur.<ref name="pmid1545778" /><ref name="pmid6375076" />

The oral [[bioavailability]] of EMP is low, which is due to profound first-pass metabolism; specifically, dephosphorylation of EMP.<ref name="pmid9515186" /> The oral bioavailability of EMP specifically as estramustine and estromustine is 44 to 75%, suggesting that [[absorption (pharmacokinetics)|absorption]] may be incomplete.<ref name="pmid9515186" /> In any case, there is a linear relationship between the oral dose of EMP and circulating levels of estramustine and estromustine.<ref name="pmid9515186" /> Consumption of [[calcium]], [[aluminium]], or [[magnesium]] with oral EMP can markedly impair its bioavailability due to diminished [[absorption (pharmacokinetics)|absorption]] from the intestines, and this may interfere with its therapeutic effectiveness at low doses.<ref name="pmid11240822" /><ref name="EMP-EMC" />

Following a single oral dose of 420&nbsp;mg EMP in men with prostate cancer, [[Cmax (pharmacology)|maximal]] levels of estromustine were 310 to 475&nbsp;ng/mL (475,000&nbsp;pg/mL) and occurred after 2 to 3&nbsp;hours.<ref name="pmid9515186" /> Estradiol levels with 280&nbsp;mg/day oral EMP have been found to increase to very high concentrations within one week of therapy.<ref name="pmid11240822" /> In one study, levels of estradiol were over 20,000&nbsp;pg/mL after 10&nbsp;days, were about 30,000&nbsp;pg/mL after 30&nbsp;days, and peaked at about 40,000&nbsp;pg/mL at 50&nbsp;days.<ref name="pmid11240822" /> Another study found lower estradiol levels of 4,900 to 9,000&nbsp;pg/mL during chronic therapy with 560&nbsp;mg/day oral EMP.<ref name="pmid6375076" /> An additional study found estradiol levels of about 17,000&nbsp;pg/mL with 140&nbsp;mg/day oral EMP and 38,000&nbsp;pg/mL with 280&nbsp;mg/day oral EMP.{{Citation needed|date=December 2019|reason=removed citation to predatory publisher content}}  The circulating levels of estradiol and estrone during EMP therapy have been reported to exceed normal levels in men by more than 100- and 1,000-fold, respectively.<ref name="Inoue2018" /><ref name="pmid6375076" /> Levels of estramustine and estradiol in the circulation are markedly lower than those of estromustine and estrone, respectively, with a ratio of about 1:10 in both cases.<ref name="pmid9515186" /><ref name="pmid6375076" /> Nonetheless, estradiol levels during EMP therapy appear to be similar to those that occur in mid-to-late [[pregnancy]], which range from 5,000 to 40,000&nbsp;pg/mL.<ref name="Abbott2009">{{cite web | title = Estradiol | date = November 2009 | url = http://www.ilexmedical.com/files/PDF/Estradiol_ARC.pdf | work = Abbott Laboratories | access-date = 2018-09-20 | archive-date = 2021-11-27 | archive-url = https://web.archive.org/web/20211127070253/https://www.ilexmedical.com/files/PDF/Estradiol_ARC.pdf | url-status = dead }}</ref> No unchanged EMP is seen in the circulation with oral administration.<ref name="pmid9515186" />

The [[pharmacokinetics]] of EMP are different with [[intravenous injection]].<ref name="pmid9515186" /> Following a single intravenous injection of 300&nbsp;mg EMP, levels of EMP were higher than those of its metabolites for the first 8&nbsp;hours.<ref name="pmid9515186" /> This is likely due to the bypassing of first-pass metabolism.<ref name="pmid9515186" /> However, by 24&nbsp;hours after the dose, unchanged EMP could no longer be detected in the circulation.<ref name="pmid9515186" /> The [[clearance (pharmacology)|clearance]] of EMP from [[blood plasma]] is 4.85 ± 0.684&nbsp;L/h.<ref name="pmid9515186" /> The [[volume of distribution|volumes of distribution]] of EMP with intravenous injection were small; under a two-compartment model, the volume of distribution for the central compartment was 0.043&nbsp;L/kg and for the peripheral compartment was 0.11&nbsp;L/kg.<ref name="pmid9515186" /> The [[plasma protein binding]] of EMP is high.<ref name="pmid9515186" /> Estramustine is accumulated in [[tumor]] tissue, for instance [[prostate cancer]] and [[glioma]] tissue, with estramustine levels much higher in these tissues than in plasma (e.g., 6.3- and 15.9-fold, respectively).<ref name="pmid9515186" /> Conversely, levels of estromustine in tumor versus plasma are similar (1.0- and 0.5-fold, respectively).<ref name="pmid9515186" /> Estramustine and estromustine appear to accumulate in [[adipose tissue]].<ref name="pmid9515186" />

The [[elimination half-life]] of estromustine with oral EMP was 13.6&nbsp;hours on average, with a range of 8.8 to 22.7&nbsp;hours.<ref name="pmid9515186" /> Conversely, the elimination half-life of estromustine with intravenous injection was 10.3&nbsp;hours, with a range of 7.36 to 12.3&nbsp;hours.<ref name="pmid9515186" /> For comparison, the corresponding elimination half-lives of estrone were 16.5 and 14.7 hours for oral and intravenous administration, respectively.<ref name="pmid9515186" /> Estramustine and estromustine are mainly [[excretion|excreted]] in [[bile]] and hence in [[feces]].<ref name="pmid9515186" /><ref name="pmid6375076" /> They are not believed to be excreted in [[urine]].<ref name="pmid9515186" />

[[File:Estramustine phosphate metabolism.png|thumb|center|900px|[[Metabolism]] of oral estramustine phosphate in humans.<ref name="pmid7579781" /><ref name="pmid9515186 "/><ref name="pmid6375076">{{cite journal | vauthors = Gunnarsson PO, Forshell GP | title = Clinical pharmacokinetics of estramustine phosphate | journal = Urology | volume = 23 | issue = 6 Suppl | pages = 22–27 | date = June 1984 | pmid = 6375076 | doi = 10.1016/S0090-4295(84)80093-X }}</ref><ref name="pmid19735314">{{cite journal | vauthors = Ozeki T, Takeuchi M, Suzuki M, Kitamura T, Takayanagi R, Yokoyama H, Yamada Y | title = Single nucleotide polymorphisms of 17beta-hydroxysteroid dehydrogenase type 7 gene: mechanism of estramustine-related adverse reactions? | journal = International Journal of Urology | volume = 16 | issue = 10 | pages = 836–841 | date = October 2009 | pmid = 19735314 | doi = 10.1111/j.1442-2042.2009.02374.x | s2cid = 38350076 }}</ref><ref name="pmid15733111">{{cite journal | vauthors = Suzuki M, Muto S, Hara K, Ozeki T, Yamada Y, Kadowaki T, Tomita K, Kameyama S, Kitamura T | display-authors = 6 | title = Single-nucleotide polymorphisms in the 17beta-hydroxysteroid dehydrogenase genes might predict the risk of side-effects of estramustine phosphate sodium in prostate cancer patients | journal = International Journal of Urology | volume = 12 | issue = 2 | pages = 166–172 | date = February 2005 | pmid = 15733111 | doi = 10.1111/j.1442-2042.2005.01004.x | s2cid = 71166897 | doi-access =  }}</ref>]]

==Chemistry==
{{See also|Estrogen ester|List of estrogen esters#Estradiol esters|List of hormonal cytostatic antineoplastic agents}}

EMP, also known as estradiol 3-normustine 17β-phosphate or as estradiol 3-(bis(2-chloroethyl)carbamate) 17β-(dihydrogen phosphate), is a [[synthetic compound|synthetic]] [[estrane]] [[steroid]] and a [[chemical derivative|derivative]] of [[estradiol (medication)|estradiol]].<ref name="Elks2014" /><ref name="IndexNominum2000" /> It is an [[estrogen ester]]; specifically, EMP is a [[ester|diester]] of estradiol with a C3 [[normustine]] ([[nitrogen mustard]]–[[carbamate]] [[moiety (chemistry)|moiety]]) ester and a C17β [[phosphate]] ester.<ref name="Elks2014" /><ref name="IndexNominum2000" /> EMP is provided as the [[sodium]] or [[meglumine]] [[salt (chemistry)|salt]].<ref name="Elks2014" /><ref name="IndexNominum2000" /><ref name="Muller1998" /> EMP is similar as a compound to other [[estradiol ester]]s such as [[estradiol sulfate]] and [[estradiol valerate]], but differs in the presence of its nitrogen mustard ester moiety.<ref name="Elks2014" /><ref name="IndexNominum2000" /> [[Antineoplastic agent]]s related to EMP, although none of them were marketed, include [[alestramustine]], [[atrimustine]], [[cytestrol acetate]], [[estradiol mustard]], [[ICI-85966]], and [[phenestrol]].<ref name="Elks2014" /><ref name="IndexNominum2000" />

Due to its [[hydrophilic]] phosphate ester moiety, EMP is a readily [[water solubility|water-soluble]] compound.<ref name="Loftsson2014">{{cite book| vauthors = Loftsson T |title=Drug Stability for Pharmaceutical Scientists|url=https://books.google.com/books?id=dUzyAQAAQBAJ&pg=PA77|date=25 January 2014|publisher=Academic Press|isbn=978-0-12-411562-0|pages=77–}}</ref><ref name="Bernal1997">{{cite book| vauthors = Bernal S |title=Drug Resistance in Oncology|url=https://books.google.com/books?id=x9rL5HiTFTUC&pg=PA287|date=21 August 1997|publisher=CRC Press|isbn=978-1-4200-0209-6|pages=287–}}</ref><ref name="Murff2012">{{cite book| vauthors = Murff SJ |title=Safety and Health Handbook for Cytotoxic Drugs|url=https://books.google.com/books?id=CqIPtcoUiMMC&pg=PA89|date=20 February 2012|publisher=Government Institutes|isbn=978-1-60590-705-5|pages=89–}}</ref> This is in contrast to most other estradiol esters, which are [[fatty acid]] esters and [[lipophilic]] compounds that are not particularly [[water solubility|soluble]] in [[water]].<ref name="pmid16112947" /> Unlike EMP, estramustine is highly lipophilic, practically insoluble in water, and non-[[ionization|ionizable]].<ref name="StellaBorchardt2007" /> The phosphate ester of EMP was incorporated into the molecule in order to increase its water solubility and allow for [[intravenous administration]].<ref name="EmcytLabel" />

The molecular weight of EMP sodium is 564.3&nbsp;g/mol, of EMP meglumine is 715.6&nbsp;g/mol, of EMP is 520.4&nbsp;g/mol, of estramustine is 440.4&nbsp;g/mol, and of estradiol is 272.4&nbsp;g/mol.<ref name="PubChem">{{cite web | title = Estramustine phosphate| url = https://pubchem.ncbi.nlm.nih.gov/compound/259329 | work = PubChem | publisher = U.S. National Library of Medicine }}</ref> As a result of these differences in molecular weights, EMP contains about 52%, EMP sodium about 48%, and EMP meglumine about 38% of the amount of estradiol within their structures as does an equal-mass quantity of estradiol.<ref name="PubChem" />

{{Structural properties of selected estradiol esters}}

==History==
EMP was first [[chemical synthesis|synthesized]] in the mid-1960s and was [[patent]]ed in 1967.<ref name="pmid1545778">{{cite journal | vauthors = Punzi JS, Duax WL, Strong P, Griffin JF, Flocco MM, Zacharias DE, Carrell HL, Tew KD, Glusker JP | display-authors = 6 | title = Molecular conformation of estramustine and two analogues | journal = Molecular Pharmacology | volume = 41 | issue = 3 | pages = 569–576 | date = March 1992 | doi = 10.1016/S0026-895X(25)08962-X | pmid = 1545778 | url = http://molpharm.aspetjournals.org/content/41/3/569 | url-access = subscription }}</ref> It was initially developed for the treatment of [[breast cancer]].<ref name="pmid9515186" /> The idea for EMP was inspired by the uptake and accumulation of [[radiolabel]]ed estrogens into breast cancer tissue.<ref name="pmid9515186" /> However, initial clinical findings of EMP in women with breast cancer were disappointing.<ref name="pmid9515186" /> Subsequently, radiolabeled EMP was found to be taken up into and accumulated rat [[prostate gland]], and this finding culminated in the medication being repurposed for the treatment of [[prostate cancer]].<ref name="pmid9515186" /><ref name="pmid11240822" /> EMP was introduced for medical use in the treatment of this condition in the early 1970s, and was approved in the [[United States]] for this indication in 1981.<ref name="pmid9515186" /><ref name="pmid11240822" /><ref name="FiggChau2010">{{cite book| vauthors = Figg WD, Chau CH, Small EJ | title = Drug Management of Prostate Cancer|url=https://books.google.com/books?id=4KDrjeWA5-UC&pg=PA402|date=14 September 2010|publisher=Springer Science & Business Media|isbn=978-1-60327-829-4|pages=402–}}</ref> EMP was originally introduced for use by intravenous injection.<ref name="pmid6375076" /> Subsequently, an oral formulation was introduced, and the intravenous preparation was almost abandoned in favor of the oral version.<ref name="pmid6375076" />

==Society and culture==

===Generic names===
EMP is provided as the [[sodium]] [[salt (chemistry)|salt]] for [[oral administration]], which has the [[generic term|generic name]]s ''estramustine phosphate sodium'' ({{abbrlink|USAN|United States Adopted Name}}) and ''estramustine sodium phosphate'' ({{abbrlink|BANM|British Approved Name}}, {{abbrlink|JAN|Japanese Accepted Name}}), and as the [[meglumine]] salt for [[intravenous administration]], which has the generic name ''estramustine phosphate meglumine''.<ref name="Muller1998" /><ref name="Elks2014">{{cite book| vauthors = Elks J |title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies|url=https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA502|date=14 November 2014|publisher=Springer|isbn=978-1-4757-2085-3|pages=502–503}}</ref><ref name="IndexNominum2000">{{cite book|title=Index Nominum 2000: International Drug Directory|url=https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA406|date=January 2000|publisher=Taylor & Francis|isbn=978-3-88763-075-1|pages=406–407}}</ref><ref name="MortonHall2012">{{cite book| vauthors = Morton IK, Hall JM |title=Concise Dictionary of Pharmacological Agents: Properties and Synonyms|url=https://books.google.com/books?id=tsjrCAAAQBAJ&pg=PA114|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-94-011-4439-1|pages=114–}}</ref><ref name="Drugs.com">{{Cite web|url=https://www.drugs.com/international/estramustine.html|title = Estramustine Uses, Side Effects & Warnings}}</ref> The {{abbrlink|INNM|International Nonproprietary Name}} is ''estramustine phosphate''.<ref name="Elks2014" /> The name ''estramustine phosphate'' is a contraction of ''estradiol normustine phosphate''.<ref name="Elks2014" /><ref name="Drugs.com" /> EMP is also known by its former developmental code names ''Leo 299'', ''Ro 21-8837'', and ''Ro 21-8837/001''.<ref name="Elks2014" /><ref name="IndexNominum2000" /><ref name="Drugs.com" />

===Brand names===
EMP is most commonly marketed under the brand names Estracyt and Emcyt, but has also been sold under a number of other brand names, including Amsupros, Biasetyl, Cellmustin, Estramustin HEXAL, Estramustina Filaxis, Estranovag, Multosin, Multosin Injekt, Proesta, Prostamustin, and Suloprost.<ref name="IndexNominum2000" /><ref name="Drugs.com" /><ref name="Muller1998" />

===Availability===
{{See also|List of estrogens available in the United States}}

EMP is marketed in the [[United States]],<ref name="Drugs@FDA">{{cite web | title = Drugs@FDA: FDA Approved Drug Products | publisher = United States Food and Drug Administration | access-date = 29 January 2017 | url = https://www.accessdata.fda.gov/scripts/cder/daf/}}</ref> [[Canada]], and [[Mexico]] under the brand name Emcyt, whereas the medication is marketed under the brand name Estracyt in the [[United Kingdom]] and elsewhere throughout [[Europe]] as well as in [[Argentina]], [[Chile]], and [[Hong Kong]].<ref name="IndexNominum2000" /> It has been discontinued in a number of countries, including [[Australia]], [[Brazil]], [[Ireland]], and [[Norway]].<ref name="Martindale">{{cite book|title=Martindale: The Complete Drug Reference|publisher=Pharmaceutical Press|date=12 February 2013|access-date=8 February 2014|url=http://www.medicinescomplete.com/mc/martindale/current/1832-c.htm|chapter=Estramustine Sodium Phosphate|editor=Sweetman, S|place=London, UK}}</ref>

==Research==
EMP has been studied in the treatment of other [[cancer]]s such as [[glioma]] and [[breast cancer]].<ref name="pmid9515186" /> It has been found to slightly improve [[quality of life]] in people with glioma during the first 3&nbsp;months of therapy.<ref name="pmid9515186" />

== References ==
{{Reflist}}

== Further reading ==
{{refbegin|30em}}
* {{cite journal | vauthors = Tew KD | title = The mechanism of action of estramustine | journal = Seminars in Oncology | volume = 10 | issue = 3 Suppl 3 | pages = 21–26 | date = September 1983 | pmid = 6364362 }}
* {{cite journal | vauthors = Hoisaeter PA, Bakke A | title = Estramustine phosphate (Estracyt): experimental and clinical studies in Europe | journal = Seminars in Oncology | volume = 10 | issue = 3 Suppl 3 | pages = 27–33 | date = September 1983 | pmid = 6364363 }}
* {{cite journal | vauthors = Sandberg AA | title = Metabolic aspects and actions unique to Estracyt | journal = Seminars in Oncology | volume = 10 | issue = 3 Suppl 3 | pages = 3–15 | date = September 1983 | pmid = 6364364 }}
* {{cite journal | vauthors = Haukaas SA | title = Immunological effects of diethylstilbestrol and estramustine phosphate | journal = Scandinavian Journal of Urology and Nephrology. Supplementum | volume = 83 | pages = 1–32 | date = 1984 | pmid = 6387896 }}
* {{cite journal | vauthors = Hauser AR, Merryman R | title = Estramustine phosphate sodium | journal = Drug Intelligence & Clinical Pharmacy | volume = 18 | issue = 5 | pages = 368–374 | date = May 1984 | pmid = 6373212 | doi = 10.1177/106002808401800502 | s2cid = 25303747 }}
* {{cite journal | vauthors = Sandberg AA | title = Metabolic parameters of Estracyt pertinent to its effects in prostatic cancer | journal = Urology | volume = 23 | issue = 6 Suppl | pages = 11–21 | date = June 1984 | pmid = 6375075 | doi = 10.1016/S0090-4295(84)80092-8 }}
* {{cite journal | vauthors = Gunnarsson PO, Forshell GP | title = Clinical pharmacokinetics of estramustine phosphate | journal = Urology | volume = 23 | issue = 6 Suppl | pages = 22–27 | date = June 1984 | pmid = 6375076 | doi = 10.1016/S0090-4295(84)80093-X }}
* {{cite journal | vauthors = Forsgren B, Björk P | title = Specific binding of estramustine to prostatic proteins | journal = Urology | volume = 23 | issue = 6 Suppl | pages = 34–38 | date = June 1984 | pmid = 6375077 | doi = 10.1016/S0090-4295(84)80095-3 }}
* {{cite journal | vauthors = Kalland T, Haukaas SA | title = Immunologic effects of estramustine phosphate | journal = Urology | volume = 23 | issue = 6 Suppl | pages = 39–45 | date = June 1984 | pmid = 6375078 | doi = 10.1016/S0090-4295(84)80096-5 }}
* {{cite journal | vauthors = Høisaeter PA | title = Mode of action of Emcyt | journal = Urology | volume = 23 | issue = 6 Suppl | pages = 46–48 | date = June 1984 | pmid = 6375079 | doi = 10.1016/S0090-4295(84)80097-7 }}
* {{cite journal | vauthors = Müntzing J, Gunnarsson K | title = Preclinical pharmacology and toxicology of estramustine phosphate | journal = Urology | volume = 23 | issue = 6 Suppl | pages = 6–10 | date = June 1984 | pmid = 6375082 | doi = 10.1016/S0090-4295(84)80091-6 }}
* {{cite journal | vauthors = Slack NH, Murphy GP | title = Clinical toxicity and long-term results of Emcyt therapy for prostate cancer | journal = Urology | volume = 23 | issue = 6 Suppl | pages = 73–77 | date = June 1984 | pmid = 6375085 | doi = 10.1016/S0090-4295(84)80103-X }}
* {{cite journal | vauthors = Hedlund PO | title = Mode of action of estramustine phosphate in hormone dependent and hormone non-dependent prostate cancer | journal = Progress in Clinical and Biological Research | volume = 185A | pages = 197–202 | date = 1985 | pmid = 3898129 }}
* {{cite journal | vauthors = Hedlund PO | title = Estracyt--mode of action and clinical experience | journal = Progress in Clinical and Biological Research | volume = 243B | pages = 215–219 | date = 1987 | pmid = 3309981 }}
* {{cite journal | vauthors = Murphy GP | title = A current review of the clinical experience with Estracyt | journal = Progress in Clinical and Biological Research | volume = 243B | pages = 221–225 | date = 1987 | pmid = 3309982 }}
* {{cite journal | vauthors = Forsgren B | title = Estramustine-binding protein in rat and human prostate | journal = Scandinavian Journal of Urology and Nephrology. Supplementum | volume = 107 | pages = 56–58 | date = 1988 | pmid = 3287598 }}
* {{cite journal | vauthors = Tew KD, Stearns ME | title = Intracellular effects of estramustine (Estracyt/Emcyt) | journal = Progress in Clinical and Biological Research | volume = 303 | pages = 169–175 | date = 1989 | pmid = 2674983 }}
* {{cite journal | vauthors = Tew KD, Stearns ME | title = Estramustine--a nitrogen mustard/steroid with antimicrotubule activity | journal = Pharmacology & Therapeutics | volume = 43 | issue = 3 | pages = 299–319 | date = 1989 | pmid = 2682681 | doi = 10.1016/0163-7258(89)90012-0 }}
* {{cite journal | vauthors = Könyves I | title = Estramustine phosphate (Estracyt) in the treatment of prostatic carcinoma | journal = International Urology and Nephrology | volume = 21 | issue = 4 | pages = 393–397 | date = 1989 | pmid = 2693392 | doi = 10.1007/BF02559635 | s2cid = 9727646 }}
* {{cite journal | vauthors = Benson R, Hartley-Asp B | title = Mechanisms of action and clinical uses of estramustine | journal = Cancer Investigation | volume = 8 | issue = 3–4 | pages = 375–380 | date = 1990 | pmid = 2207764 | doi = 10.3109/07357909009012056 }}
* {{cite journal | vauthors = Van Poppel H, Baert L | title = The present role of estramustine phosphate in advanced prostate cancer | journal = Progress in Clinical and Biological Research | volume = 370 | pages = 323–341 | date = 1991 | pmid = 1924466 }}
* {{cite journal | vauthors = Janknegt RA | title = Estramustine phosphate and other cytotoxic drugs in the treatment of poor prognostic advanced prostate cancer | journal = The Prostate. Supplement | volume = 4 | pages = 105–110 | date = 1992 | pmid = 1574449 | doi = 10.1002/pros.2990210516 | s2cid = 40562112 }}
* {{cite journal | vauthors = Tew KD, Glusker JP, Hartley-Asp B, Hudes G, Speicher LA | title = Preclinical and clinical perspectives on the use of estramustine as an antimitotic drug | journal = Pharmacology & Therapeutics | volume = 56 | issue = 3 | pages = 323–339 | date = December 1992 | pmid = 1301594 | doi = 10.1016/0163-7258(92)90023-S }}
* {{cite book | vauthors = Kreis W | title = Concepts, Mechanisms, and New Targets for Chemotherapy | chapter = Estramustine revisited | series = Cancer Treatment and Research | volume = 78 | pages = 163–184 | date = 1995 | publisher = Springer | pmid = 8595142 | doi = 10.1007/978-1-4615-2007-8_8 | isbn = 978-1-4613-5829-9 }}
* {{cite journal | vauthors = Perry CM, McTavish D | title = Estramustine phosphate sodium. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in prostate cancer | journal = Drugs & Aging | volume = 7 | issue = 1 | pages = 49–74 | date = July 1995 | pmid = 7579781 | doi = 10.2165/00002512-199507010-00006 | s2cid = 36725810 }}
* {{cite journal | vauthors = Hudes G | title = Estramustine-based chemotherapy | journal = Seminars in Urologic Oncology | volume = 15 | issue = 1 | pages = 13–19 | date = February 1997 | pmid = 9050135 }}
* {{cite journal | vauthors = Bergenheim AT, Henriksson R | title = Pharmacokinetics and pharmacodynamics of estramustine phosphate | journal = Clinical Pharmacokinetics | volume = 34 | issue = 2 | pages = 163–172 | date = February 1998 | pmid = 9515186 | doi = 10.2165/00003088-199834020-00004 | s2cid = 1943973 }}
* {{cite journal | vauthors = Kitamura T | title = Necessity of re-evaluation of estramustine phosphate sodium (EMP) as a treatment option for first-line monotherapy in advanced prostate cancer | journal = International Journal of Urology | volume = 8 | issue = 2 | pages = 33–36 | date = February 2001 | pmid = 11240822 | doi = 10.1046/j.1442-2042.2001.00254.x | s2cid = 43384150 }}
* {{cite journal | vauthors = Ravery V, Fizazi K, Oudard S, Drouet L, Eymard JC, Culine S, Gravis G, Hennequin C, Zerbib M | display-authors = 6 | title = The use of estramustine phosphate in the modern management of advanced prostate cancer | journal = BJU International | volume = 108 | issue = 11 | pages = 1782–1786 | date = December 2011 | pmid = 21756277 | doi = 10.1111/j.1464-410X.2011.10201.x | s2cid = 33456591 | doi-access =  }}
* {{cite journal | vauthors = Qin Z, Li X, Zhang J, Tang J, Han P, Xu Z, Yu Y, Yang C, Wang C, Xu T, Xu Z, Zou Q | display-authors = 6 | title = Chemotherapy with or without estramustine for treatment of castration-resistant prostate cancer: A systematic review and meta-analysis | journal = Medicine | volume = 95 | issue = 39 | pages = e4801 | date = September 2016 | pmid = 27684806 | pmc = 5265899 | doi = 10.1097/MD.0000000000004801 }}
{{refend}}

{{Estradiol}}
{{Chemotherapeutic agents}}
{{Estrogens and antiestrogens}}
{{Androgen receptor modulators}}
{{Estrogen receptor modulators}}

[[Category:Antiandrogens]]
[[Category:Antigonadotropins]]
[[Category:Carbamates]]
[[Category:Chloroethyl compounds]]
[[Category:DNA replication inhibitors]]
[[Category:Estradiol esters]]
[[Category:Estranes]]
[[Category:Estrogens]]
[[Category:Hormonal antineoplastic drugs]]
[[Category:Mitotic inhibitors]]
[[Category:Nitrogen mustards]]
[[Category:Phosphate esters]]
[[Category:Drugs developed by Pfizer]]
[[Category:Prodrugs]]
[[Category:Prostate cancer]]