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{{Short description|Chemical compound}}{{Use dmy dates|date=December 2023}}{{cs1 config|name-list-style=vanc}}{{Use PMID reference names|date=December 2023}} {{Drugbox | Verifiedfields = | Watchedfields = | verifiedrevid = | IUPAC_name = [(8''R'',9''S'',13''S'',14''S'',17''S'')-17-hydroxy-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[''a'']phenanthren-3-yl] benzoate | image = Estradiol benzoate.svg | width = 250px | image2 = Estradiol benzoate molecule ball.png | width2 = 250px <!--Clinical data--> | pronounce = {{IPAc-en|ˌ|ɛ|s|t|r|ə|ˈ|d|aɪ|oʊ|l|_|ˈ|b|ɛ|n|z|oʊ|eɪ|t}}<br />{{respell|ES|trə|DY|ohl|_|BEN|zoh|ayt}} | tradename = Agofollin Depot, Ben-Ovocylin, Benzofoline, Dimenformon, Ovocyclin M, Progynon-B, many others | pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --> | pregnancy_US = <!-- A / B / C / D / X --> | pregnancy_category = | legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 --> | legal_CA = | legal_UK = | legal_US = | legal_status = Rx-only | routes_of_administration = [[Intramuscular injection]], [[subcutaneous injection]], [[vaginal administration|vaginal]] | class = [[Estrogen (medication)|Estrogen]]; [[Estrogen ester]] <!--Pharmacokinetic data--> | bioavailability = {{abbr|IM|Intramuscular injection}}: High<ref name="pmid7169965">{{cite journal | vauthors = Düsterberg B, Nishino Y | title = Pharmacokinetic and pharmacological features of oestradiol valerate | journal = Maturitas | volume = 4 | issue = 4 | pages = 315–324 | date = December 1982 | pmid = 7169965 | doi = 10.1016/0378-5122(82)90064-0 }}</ref> | protein_bound = Estradiol: ~98% (to [[human serum albumin|albumin]] and {{abbrlink|SHBG|sex hormone-binding globulin}})<ref name="pmid23375353">{{cite journal | vauthors = Stanczyk FZ, Archer DF, Bhavnani BR | title = Ethinyl estradiol and 17β-estradiol in combined oral contraceptives: pharmacokinetics, pharmacodynamics and risk assessment | journal = Contraception | volume = 87 | issue = 6 | pages = 706–727 | date = June 2013 | pmid = 23375353 | doi = 10.1016/j.contraception.2012.12.011 }}</ref><ref name="Falcone-2007">{{Cite book | vauthors = Falcone T, Hurd WH |url=https://books.google.com/books?id=fOPtaEIKvcIC&pg=PA22 |title=Clinical Reproductive Medicine and Surgery |publisher=Elsevier Health Sciences |year=2007 |isbn=978-0-323-03309-1 |pages=22,362,388}}</ref> | metabolism = [[Bond cleavage|Cleavage]] via [[esterase]]s in the [[liver]], [[blood]], and [[tissue (biology)|tissue]]s<ref name="Oettel-2012" /><ref name="pmid16112947" /> | metabolites = [[Estradiol (medication)|Estradiol]], [[benzoic acid]], and [[metabolite]]s of estradiol<ref name="Oettel-2012" /><ref name="pmid16112947" /> | elimination_half-life = {{abbr|IM|Intramuscular injection}}: 48–120 hrs (2–5 days)<ref name="Runnebaum-2013">{{Cite book | vauthors = Runnebaum B, Rabe T |url=https://books.google.com/books?id=mBF9BwAAQBAJ&pg=PA86 |title=Gynäkologische Endokrinologie und Fortpflanzungsmedizin: Band 1: Gynäkologische Endokrinologie |date=17 April 2013 |publisher=Springer-Verlag |isbn=978-3-662-07635-4 |pages=86–}}</ref> | duration_of_action = {{abbr|IM|Intramuscular injection}} (0.3–1.7 mg): 2–3 days<ref name="Buchsbaum-2012" /><ref name="NNR1949e" /><br />{{abbr|IM|Intramuscular injection}} (5 mg): 4–6 days<ref name="pmid7389356" /><ref name="Knörr-2013">{{Cite book | vauthors = Knörr K, Knörr-Gärtner H, Beller FK, Lauritzen C |url=https://books.google.com/books?id=OjvMBgAAQBAJ&pg=PA508 |title=Lehrbuch der Geburtshilfe und Gynäkologie: Physiologie und Pathologie der Reproduktion |date=8 March 2013 |publisher=Springer-Verlag |isbn=978-3-662-00526-2 |pages=508–}}</ref><ref name="Labhart-2012" /> | excretion = [[Urine]] <!-- Identifiers --> | CAS_number_Ref = | CAS_number = 50-50-0 | CAS_supplemental = | ATC_prefix = G03 | ATC_suffix = CA03 | ATC_supplemental = | PubChem = 222757 | IUPHAR_ligand = | DrugBank_Ref = | DrugBank = DB13953 | ChemSpiderID_Ref = | ChemSpiderID = 193412 | UNII = 1S4CJB5ZGN | KEGG = D01953 | ChEBI = 77006 | ChEMBL = 282575 | synonyms = EB; E2B; Oestradiol benzoate; 17β-Estradiol-3-benzoate; NSC-9566; Benzhormovarine, Difollisterol, Follicormon, Follidimyl, Follidrinbensoat, Oestro-Vitis, Oestroform <!--Chemical data--> | C=25 | H=28 | O=3 | SMILES = C[C@]12CC[C@H]3[C@H]([C@@H]1CC[C@@H]2O)CCC4=C3C=CC(=C4)OC(=O)C5=CC=CC=C5 | StdInChI_Ref = | StdInChI = 1S/C25H28O3/c1-25-14-13-20-19-10-8-18(28-24(27)16-5-3-2-4-6-16)15-17(19)7-9-21(20)22(25)11-12-23(25)26/h2-6,8,10,15,20-23,26H,7,9,11-14H2,1H3/t20-,21-,22+,23+,25+/m1/s1 | StdInChIKey_Ref = | StdInChIKey = UYIFTLBWAOGQBI-BZDYCCQFSA-N }} <!-- Definition and medical uses --> '''Estradiol benzoate''' ('''EB'''), sold under the brand name '''Progynon-B''' among others, is an [[estrogen (medication)|estrogen]] medication which is used in [[hormone replacement therapy|hormone therapy]] for [[menopausal symptoms]] and [[hypoestrogenism|low estrogen levels]] in women, in [[transgender hormone therapy (male-to-female)|hormone therapy]] for [[transgender women]], and in the treatment of [[gynecological disorder]]s.<ref name="NNR1949e" /><ref name="pmid13638626" /><ref name="Israel-2001" /> It is also used in the treatment of [[prostate cancer]] in men.<ref name="NNR1949e" /> Estradiol benzoate is used in [[veterinary medicine]] as well.<ref name="Drugs.com-Estradiol" /><ref name="IndexNominum2000" /> When used clinically, the medication is given by [[intramuscular injection|injection into muscle]] usually two to three times per week.<ref name="NNR1949e" /><ref name="pmid13638626" /><ref name="HumansOrganization2007">{{Cite book | author1 = IARC Working Group on the Evaluation of Carcinogenic Risks to Humans |url=https://books.google.com/books?id=aGDU5xibtNgC&pg=PA388 |title=Combined Estrogen-progestogen Contraceptives and Combined Estrogen-progestogen Menopausal Therapy | author2 = World Health Organization | author3 = International Agency for Research on Cancer |publisher=World Health Organization |year=2007 |isbn=978-92-832-1291-1 |pages=388–}}</ref> <!-- Side effects and mechanism --> [[Side effect]]s of estradiol benzoate include [[breast tenderness]], [[breast enlargement]], [[nausea]], [[headache]], and [[water retention (medicine)|fluid retention]].<ref name="Ghosh-2010" /> Estradiol benzoate is an [[estrogen (medication)|estrogen]] and hence is an [[agonist]] of the [[estrogen receptor]], the [[biological target]] of [[estrogen]]s like [[estradiol]].<ref name="Oettel-2012" /><ref name="pmid16112947" /> It is an [[estrogen ester]] and a [[prodrug]] of [[estradiol (medication)|estradiol]] in the body.<ref name="Oettel-2012" /><ref name="pmid16112947" /> Because of this, it is considered to be a [[natural product|natural]] and [[bioidentical hormone replacement therapy|bioidentical]] form of estrogen.<ref name="Oettel-2012" /> <!-- History, society, and culture --> Estradiol benzoate was discovered in 1933 and was introduced for medical use that same year.<ref name="Oettel-2012" /><ref name="pmid16746750" /><ref name="Kaufman-1933" /><ref name="Buschbeck-1934" /><ref name="Biskind-1935" /><ref name="Novak-1935" /><ref name="Kleemann-2014" /> It was the first [[estradiol ester]] to be discovered or marketed, and was one of the first estrogens to be used in medicine.<ref name="Raviña-2011">{{Cite book | vauthors = Raviña E, Kubinyi H |url=https://books.google.com/books?id=iDNy0XxGqT8C&pg=PA175 |title=The Evolution of Drug Discovery: From Traditional Medicines to Modern Drugs |date=16 May 2011 |publisher=John Wiley & Sons |isbn=978-3-527-32669-3 |page=175 |access-date=20 May 2012}}</ref> Along with [[estradiol dipropionate]], estradiol benzoate was among the most widely used esters of estradiol for many years following its introduction.<ref name="pmid14388061" /> However, in the 1950s, longer-acting estradiol esters that necessitated less frequent injections, such as [[estradiol valerate]] and [[estradiol cypionate]], were developed, and have since largely superseded estradiol benzoate.<ref name="pmid7389356">{{Cite journal |vauthors=Oriowo MA, Landgren BM, Stenström B, Diczfalusy E |date=April 1980 |title=A comparison of the pharmacokinetic properties of three estradiol esters |journal=Contraception |volume=21 |issue=4 |pages=415–24 |doi=10.1016/S0010-7824(80)80018-7 |pmid=7389356}}</ref> Nonetheless, estradiol benzoate remains widely available throughout the world.<ref name="IndexNominum2000" /> It is not available for medical use in the [[United States]], but is available there for use in veterinary medicine.<ref name="Drugs@FDA" /><ref name="Witherspoon-1994" /> {{TOC limit|3}} ==Medical uses== {{Main|Estradiol (medication)#Medical uses|High-dose estrogen}} The [[medical use]]s of estradiol benzoate are the same as those of estradiol and other estrogens.<ref name="NNR1949e">{{Cite journal |year=1949 |title=NNR: Products Recently Accepted by the A. M. A. Council on Pharmacy and Chemistry |journal=Journal of the American Pharmaceutical Association (Practical Pharmacy Ed.) |volume=10 |issue=11 |pages=692–694 |doi=10.1016/S0095-9561(16)31995-8 |issn=0095-9561}}</ref><ref name="pmid13638626">{{Cite journal |vauthors=Swyer GI |date=April 1959 |title=The oestrogens |journal=Br Med J |volume=1 |issue=5128 |pages=1029–31 |doi=10.1136/bmj.1.5128.1029 |pmc=1993181 |pmid=13638626}}</ref> Estradiol benzoate is used in [[menopausal hormone therapy|hormone therapy]] for the treatment of [[menopausal symptoms]] such as [[hot flash]]es and [[vaginal atrophy]] and in the treatment of [[hypoestrogenism]] and [[delayed puberty]] due to [[hypogonadism]] or other causes in women.<ref name="NNR1949e" /><ref name="pmid13638626" /> It is also used in [[transgender hormone therapy (male-to-female)|hormone therapy]] for [[transgender women]].<ref name="Israel-2001">{{Cite book | vauthors = Israel GE |url=https://books.google.com/books?id=IlPX6E5glDEC&pg=PA64 |title=Transgender Care: Recommended Guidelines, Practical Information, and Personal Accounts |date=March 2001 |publisher=Temple University Press |isbn=978-1-56639-852-7 |pages=64–}}</ref><ref name="Fifková-2008">{{Cite book | vauthors = Fifková H, Weiss P, Procházka I, Cohen-Kettenis PT, Pfäfflin F, Jarolím L, Veselý J, Weiss V | display-authors = 6 |url=https://books.google.com/books?id=YG9aAgAAQBAJ&pg=PA95 |title=Transsexualita a jiné poruchy pohlavní identity | trans-title = Transsexuality and other gender identity disorders | language = Czech |date=4 August 2008 |publisher=Grada Publishing a.s. |isbn=978-80-247-6962-2 |pages=95– |quote=Injection of estradiol benzoate is supplied as Agofollin Depot inj. 10 mg, Biotika and as estradiol valerate Neofollin inj., 5 mg, Hoechst-Biotika. Depot estrogen injections are not recommended due to side effects. Possibility "overdose" of the patient is higher (in some individuals receiving doses "the higher the better," and parenteral drug administration may in some instances these cause serious side effects). While misuse of the drug with peroral administration also occurs, the problems are not so extreme.}}</ref><ref name="Weiss-2010">{{Cite book | vauthors = Weiss P |url=https://books.google.com/books?id=-oQJQWva5-4C&pg=PA452 |title=Sexuologie |date=1 January 2010 |publisher=Grada Publishing a.s. |isbn=978-80-247-2492-8 |pages=452–}}</ref> Aside from hormone therapy, estradiol benzoate is used in the treatment of [[gynecological disorder]]s such as [[menstrual disorder]]s, [[dysfunctional uterine bleeding]], and [[breast engorgement]].<ref name="NNR1949e" /><ref name="pmid13638626" /> In addition, it is used as a form of [[high-dose estrogen]] therapy in the [[palliation|palliative]] treatment of [[prostate cancer]] in men.<ref name="NNR1949e" /> Estradiol benzoate has a relatively short [[duration of action]], and is administered by [[intramuscular injection]] usually two to three times per week.<ref name="NNR1949e" /><ref name="pmid13638626" /> It is used in the treatment of menopausal symptoms at a dosage of 1 to 1.66 mg initially and 0.33 to 1 mg for maintenance two times per week, and in the treatment of hypoestrogenism and delayed puberty at a dosage of 1.66 mg two to three times per week.<ref name="NNR1949e" /><ref name="AMA1977">{{Cite book | author1 = American Medical Association. Dept. of Drugs |url=https://books.google.com/books?id=0h7s_rfEZgkC |title=AMA drug evaluations | author2 = Council on Drugs (American Medical Association) | author3 = American Society for Clinical Pharmacology and Therapeutics |date=1 February 1977 |publisher=Publishing Sciences Group |isbn=978-0-88416-175-2 |pages=540–572 |chapter=Estrogens, Progestagens, Oral Contraceptives, and Ovulatory Agents |quote=Intramuscular: For replacement therapy, (Estradiol, Estradiol Benzoate) 0.5 to 1.5 mg two or three times weekly; (Estradiol Cypionate) 1 to 5 mg weekly for two or three weeks; (Estradiol Dipropionate) 1 to 5 mg every one to two weeks; (Estradiol Valerate) 10 to 40 mg every one to four weeks.}}</ref> The dosage used in hormone therapy for transgender women is 0.5 to 1.5 mg two to three times per week.<ref name="Israel-2001" /> In the treatment of prostate cancer, estradiol benzoate is used at a dosage of 1.66 mg three times per week (for a total of 5 mg per week).<ref name="NNR1949e" /> {{Estrogen dosages for menopausal hormone therapy}} ===Available forms=== {{See also|List of marketed estradiol benzoate formulations|List of combined sex-hormonal preparations}} Estradiol benzoate is and has been available as an [[oil solution]] for intramuscular injection provided as [[vial]]s and [[ampoule]]s at concentrations of 0.167, 0.2, 0.33, 1, 1.67, 2, 5, 10, 20, and 25 mg/mL.<ref name="Kleemann-2014">{{Cite book | vauthors = Kleemann A, Engel J, Kutscher B, Reichert D |url=https://books.google.com/books?id=fO2IAwAAQBAJ&pg=PA1167 |title=Pharmaceutical Substances, 5th Edition, 2009: Syntheses, Patents and Applications of the most relevant APIs |date=14 May 2014 |publisher=Thieme |isbn=978-3-13-179525-0 |pages=1167–1174}}</ref><ref name="Muller1998e">{{Cite book | veditors = Muller NF, Dessign RP |url=https://books.google.com/books?id=2HBPHmclMWIC&pg=PA150 |title=European Drug Index: European Drug Registrations, Fourth Edition |date=19 June 1998 |publisher=CRC Press |isbn=978-3-7692-2114-5 |pages=150, 349, 370}}</ref><ref name="NNR1949e" /> It is also available as a [[microcrystalline]] [[aqueous suspension]] for intramuscular injection under the brand name Agofollin Depot.<ref name="Avicenum1973">{{Cite book |url=https://books.google.com/books?id=odA0AQAAIAAJ |title=Review of Czechoslovak Medicine |publisher=Avicenum - Czechoslovak Medical Press |year=1973 |page=5 |quote=Oestradiol benzoate, aqueous microcrystalline suspension (Agofollin Depot SPOFA).}}</ref><ref name="Agofollin-Depot-Label">{{Cite web |title=AGOFOLLIN Depot |url=http://www.sukl.cz/download/pil/PI16221.pdf |archive-url=https://web.archive.org/web/20190519104654/http://www.sukl.cz/download/pil/PI16221.pdf |archive-date=19 May 2019 |access-date=15 January 2022 |website=www.sukl.cz}}</ref><ref name="Marek-2010-Farmakoterapie">{{Cite book | vauthors = Marek J |url=https://books.google.com/books?id=Xc2OHeo0i0cC&pg=PA377 |title=Farmakoterapie vnitřních nemocí - 4. zcela přepracované a doplněné vydání |date=1 January 2010 |publisher=Grada Publishing a.s. |isbn=978-80-247-2639-7 |pages=377– |quote=Injection of estrogenic preparations - Injectable preparations are AGOFOLLIN, inj. 5 mg (estradiol dipropionate), AGOFOLLIN DEPOT, inj. 10 mg (estradiol benzoate), and NEOFOLLIN, inj. 5 mg (estradiol valerate). The producer of all these preparations is Biotika. Non-protracted AGOFOLLIN is used only for initiation of treatment, then it is continued with depot injections, which are administered three times: cycle day 4, 11 and 18. At the same time, [progesterone] (AGOLUTIN DEPOT, Biotika, amp. 2 ml / 50 mg, cycle day 18 and 25) is administered. Estrogen injection is not completely physiological - after application, the estrogen plasma concentration increases unnecessarily high and then decreases rapidly.}}</ref><ref name="Fifková-2008" /> [[Sistocyclin]] was the brand name of a product containing 10 mg microcrystalline estradiol benzoate and 200 mg microcrystalline [[progesterone (medication)|progesterone]] in an aqueous suspension.<ref name="Ufer-1968">{{Cite book | vauthors = Ufer J |url=https://books.google.com/books?id=t8GpBgAAQBAJ&pg=PA1058 |title=Die Gestagene |publisher=Springer-Verlag |year=1968 |isbn=978-3-642-99941-3 |pages=1026–1124 |trans-title=Progestogens |chapter=Die therapeutische Anwendung der Gestagene beim Menschen | series=Handbuch der experimentellen Pharmakologie / Handbook of Experimental Pharmacology |trans-chapter=Therapeutic Use of Progestagens in Humans |doi=10.1007/978-3-642-99941-3_7 |quote=C. Dysfunktionelle Uterusblutungen. [...] 1. Depotinjektionen. 1. Originalmethode nach KAUFMANN und OBER. Es wird 1 Amp. mit 200 mg Progesteron und 10 mg Oestradiol-Monobenzoat als Kristallsuspension (Sistocyclin) injiziert [676, 678, 679, 295, 482, 365, 434, 563, 400]. [...] Beispiele. KAUFMANN et al. [485]: 400 mg Progesteron + 20 mg Oestradiolmonobenzoat Kristallsuspension. ELERT [224] U. HERRMANN [363]: 200 mg Progesteron + 10 mg Oestradiolmono benzoat Kristallsuspension.}}</ref><ref name="Ciba1957a">{{Cite book |url=https://books.google.com/books?id=KwkbAQAAMAAJ |title=Ciba Symposium |publisher=Ciba |year=1957 |quote=CIBA's range of hormone preparations has been increased with the advent of "Sistocyclin", one ampoule of which contains 200 mg progesterone and 10 mg oestradiol monobenzoate in crystalline suspension; it thus meets the requirements—in line with the most recent findings of the KAUFMANN Clinic—of cases marked by deficiency of corpus luteum hormone, e. g. in functional bleeding such as metropathia haemorrhagica.}}</ref><ref name="Ciba1957b">{{Cite book |url=https://books.google.com/books?id=WgpOAQAAIAAJ |title=Ciba Zeitschrift |year=1957 |page=3001 |quote=Sistocyclin - a microcrystal suspension containing 200 mg progesterone and 10 mg oestradiol monobenzoate per ampoule - has become particularly useful in the treatment of so-called, functional [...]}}</ref><ref name="Pschyrembel-2011">{{Cite book | vauthors = Pschyrembel W |url=https://books.google.com/books?id=vVaTnHDFzZ0C&pg=PA601 |title=Praktische Gynäkologie: für Studierende und Ärzte |date=15 June 2011 |publisher=Walter de Gruyter |isbn=978-3-11-150424-7 |pages=601–}}</ref> [[Follivirin]] (and previously Femandren M) is the brand name of a product containing 2.5 mg microcrystalline estradiol benzoate and 25 to 50 mg microcrystalline [[testosterone isobutyrate]] in aqueous suspension.<ref name="www.sukl.cz-FOLIVIRIN" /><ref name="Kubíková-2014">{{Cite journal |vauthors = Kubíková D |date=2014 |title=Menopauzální symptomy a hormonální substituční terapie |trans-title=Menopausal symptoms and hormone replacement therapy |url=http://www.medvik.cz/link/bmc14059249 | journal=Praktické Lékárenství |language=cs |volume=10 |issue=2 |pages=68–73 |issn=1801-2434 <!-- |url2=http://www.solen.sk/pdf/95e898d92100a736e32110dd1b846a9e.pdf --> }}</ref><ref name="Marek-2010">{{Cite book | vauthors = Marek J |url=https://books.google.com/books?id=bUqECwAAQBAJ&pg=PA380 |title=Farmakoterapie vnitřních nemocí: 4., zcela přepracované a doplněné vydání |date=14 May 2010 |publisher=Grada Publishing a.s. |isbn=978-80-247-9524-9 |pages=380– |quote=In addition, testosterone isobutyrate in FOLIVIRIN, Biotika, an injection containing 25 mg testosterone isobutyrate and 2.5 mg estradiol benzoate is available. It is applied every 4-6 weeks depending on the effect.}}</ref><ref name="Ciba-1953">{{Cite book |url=https://books.google.com/books?id=yQgbAQAAMAAJ |title=Ciba Symposium: 1953/57:Index |publisher=Ciba |year=1953 |page=197 |quote=Femandren M. C'est le nom des nouvelles ampoules cristallines destinées au traitement associé œs- trogène-androgène. Elles renferment, sous forme de microcristaux, 2,5 mg de mono- benzoate d'œstradiol et 50 mg d'isobutyra- te de testostérone ; elles sont indiquées pour traiter les cas où il convient d'administrer simultanément de l'hormone femelle et de l'hormone mâle et où il importe aussi d'obtenir un effet prolongé, par exemple lors de symptômes d'insuffisance à la ménopause ou après castration. L'effet d'une injection se prolonge pendant 3-6 semaines.}}</ref> A [[vaginal administration|vaginal]] [[tablet (pharmacy)|tablet]] formulation containing 0.125 mg estradiol benzoate and 10 mg [[monalazone sodium]] (a vaginal [[disinfectant]] and [[spermicidal]] [[contraceptive]]) has been marketed under the brand name Malun 25.<ref name="Leidenberger-2013">{{Cite book | vauthors = Leidenberger FA |url=https://books.google.com/books?id=YTiuBgAAQBAJ&pg=PA527 |title=Klinische Endokrinologie für Frauenärzte |date=17 April 2013 |publisher=Springer-Verlag |isbn=978-3-662-08110-5 |pages=527–}}</ref> Estradiol benzoate was also formerly available as 50 and 100 mg [[subcutaneous pellet|pellet]]s for [[subcutaneous implantation]] and as a 2 mg/g ointment.<ref name="Martindale-1958">{{Cite book | vauthors = Martindale W |url=https://books.google.com/books?id=NM5QAAAAYAAJ |title=The Extra Pharmacopoeia |publisher=Pharmaceutical Press |year=1958 |page=960 |quote=PROPRIETARY PREPARATIONS CONTAINING OESTRADIOL MONOBENZOATE. Benztrone (Paines & Byrne). Oestradiol monobenzoate, available as an injection in 1-ml. Ampoules of 1, 2, and 5 mg., and in 2-ml. ampoules of 10 mg.; and as Implants of 50 and 100 mg. Dimenformon (Organon). [...] Also available as an Ointment containing 2 mg. per g. in a fatty basis.}}</ref> {{Available forms of estradiol}} ==Contraindications== {{Main|Estradiol (medication)#Contraindications}} [[Contraindication]]s of estrogens include [[coagulation]] problems, [[cardiovascular disease]]s, [[liver disease]], and certain [[hormone-sensitive cancer]]s such as [[breast cancer]] and [[endometrial cancer]], among others.<ref name="pmid2215269" /><ref name="Lauritzen-2005">{{Cite book | vauthors = Lauritzen C, Studd JW |url=https://books.google.com/books?id=WD7S7677xUUC&pg=PA95 |title=Current Management of the Menopause |date=22 June 2005 |publisher=CRC Press |isbn=978-0-203-48612-2 |pages=95–98,488}}</ref><ref name="Laurtizen-2001">{{Cite book | vauthors = Laurtizen C |title=Menopause – Andropause: Hormone Replacement Therapy Through the Ages |publisher=Krause & Pachernegg: Gablitz |year=2001 |isbn=978-3-901299-34-6 | veditors = Fisch FH |pages=67–88 |chapter=Hormone Substitution Before, During and After Menopause |chapter-url=https://www.kup.at/kup/pdf/4978.pdf}}</ref><ref name="Midwinter-1976">{{Cite book | vauthors = Midwinter A |title=The Management of the Menopause & Post-Menopausal Years: The Proceedings of the International Symposium held in London 24–26 November 1975 Arranged by the Institute of Obstetrics and Gynaecology, The University of London |publisher=MTP Press Limited |year=1976 |isbn=978-94-011-6167-1 | veditors = Campbell S |pages=377–382 |chapter=Contraindications to estrogen therapy and management of the menopausal syndrome in these cases |doi=10.1007/978-94-011-6165-7_33}}</ref> ==Side effects== {{Main|Estradiol (medication)#Side effects}} The [[side effect]]s of estradiol benzoate are the same as those of estradiol. Examples of such side effects include [[breast tenderness]] and [[breast enlargement|enlargement]], [[nausea]], [[bloating]], [[edema]], [[headache]], and [[melasma]].<ref name="Ghosh-2010">{{Cite book | vauthors = Ghosh AK |url=https://books.google.com/books?id=LS65jBzoD40C&pg=PA222 |title=Mayo Clinic Internal Medicine Board Review |date=23 September 2010 |publisher=OUP USA |isbn=978-0-19-975569-1 |pages=222–}}</ref> ==Overdose== {{See also|Estradiol (medication)#Overdose}} [[Symptom]]s of estrogen [[overdose|overdosage]] may include [[nausea]], [[vomiting]], [[bloating]], [[weight gain|increased weight]], [[water retention (medicine)|water retention]], [[breast tenderness]], [[vaginal discharge]], [[heavy legs]], and [[leg cramps]].<ref name="pmid2215269">{{Cite journal |vauthors=Lauritzen C |date=September 1990 |title=Clinical use of oestrogens and progestogens |journal=Maturitas |volume=12 |issue=3 |pages=199–214 |doi=10.1016/0378-5122(90)90004-P |pmid=2215269}}</ref> These side effects can be diminished by reducing the estrogen dosage.<ref name="pmid2215269" /> ==Interactions== {{See also|Estradiol (medication)#Interactions}} [[Enzyme inhibitor|Inhibitor]]s and [[enzyme inducer|inducer]]s of [[cytochrome P450]] may influence the [[metabolism]] of estradiol and by extension circulating estradiol levels.<ref name="pmid11741520">{{Cite journal |vauthors=Cheng ZN, Shu Y, Liu ZQ, Wang LS, Ou-Yang DS, Zhou HH |date=February 2001 |title=Role of cytochrome P450 in estradiol metabolism in vitro |journal=Acta Pharmacol. Sin. |volume=22 |issue=2 |pages=148–54 |pmid=11741520}}</ref> ==Pharmacology== [[File:Estradiol.svg|thumb|right|225px|[[Estradiol (medication)|Estradiol]], the [[active metabolite|active form]] of estradiol benzoate.]] ===Pharmacodynamics=== {{See also|Pharmacodynamics of estradiol}} Estradiol benzoate is an [[estradiol ester]], or a [[prodrug]] of [[estradiol (medication)|estradiol]].<ref name="Oettel-2012" /><ref name="pmid16112947">{{Cite journal |vauthors=Kuhl H |year=2005 |title=Pharmacology of estrogens and progestogens: influence of different routes of administration |url=http://hormonebalance.org/images/documents/Kuhl%2005%20%20Pharm%20Estro%20Progest%20Climacteric_1313155660.pdf |journal=Climacteric |volume=8 | issue = Suppl 1 |pages=3–63 |doi=10.1080/13697130500148875 |pmid=16112947 |s2cid=24616324}}</ref> As such, it is an [[estrogen (medication)|estrogen]], or an [[agonist]] of the [[estrogen receptor]]s.<ref name="Oettel-2012" /><ref name="pmid16112947" /> Estradiol benzoate has very low [[affinity (pharmacology)|affinity]] for the ERs, on the order of 100-fold less than that of estradiol.<ref name="pmid15276617">{{Cite journal |vauthors=Bovee TF, Helsdingen RJ, Rietjens IM, Keijer J, Hoogenboom RL |year=2004 |title=Rapid yeast estrogen bioassays stably expressing human estrogen receptors alpha and beta, and green fluorescent protein: a comparison of different compounds with both receptor types |journal=J. Steroid Biochem. Mol. Biol. |volume=91 |issue=3 |pages=99–109 |doi=10.1016/j.jsbmb.2004.03.118 |pmid=15276617 |s2cid=54320898}}</ref> As such, estradiol benzoate is regarded as essentially inactive in terms of estrogenic effect itself, acting solely as a [[prodrug]] to estradiol.<ref name="pmid16112947" /> Estradiol benzoate is of about 38% higher [[molecular weight]] than estradiol due to the presence of its C3 [[benzoic acid|benzoate]] ester.<ref name="Elks-2014" /><ref name="IndexNominum2000" /> Because estradiol benzoate is a prodrug of estradiol, it is considered to be a [[natural product|natural]] and [[bioidentical hormone replacement therapy|bioidentical]] form of estrogen.<ref name="Oettel-2012" /> {{Affinities and estrogenic potencies of estrogen esters and ethers at the estrogen receptors}} ====Estrogenic potency==== In the case of intramuscular injections of either estradiol benzoate or [[estradiol valerate]] in oil solution, the maturation dosage for the [[vagina]]l [[epithelium]] is 5 to 7 mg once per week and the [[endometrium|endometrial]] [[cell proliferation|proliferation]] dosage is 7 to 10 mg once per week.<ref name="pmid8370495" /> The total endometrial proliferation dosage of estradiol benzoate in oil solution by intramuscular injection over 14 days is 25 to 35 mg.<ref name="Lauritzen-1988">{{Cite book | vauthors = Lauritzen C |url=https://books.google.com/books?id=v4HvAQAACAAJ |title=Grundlagen und Klinik der Menschlichen Fortpflanzung |publisher=Walter de Gruyter |year=1988 |isbn=978-3110109689 | veditors = Schneider HP, Lauritzen C, Nieschlag E |pages=229–306 |language=de |trans-title=Foundations and Clinic of Human Reproduction |chapter=Natürliche und Synthetische Sexualhormone – Biologische Grundlagen und Behandlungsprinzipien |trans-chapter=Natural and Synthetic Sexual Hormones – Biological Basis and Medical Treatment Principles |oclc=35483492 }}</ref><ref name="Knörr-2013" /><ref name="Labhart-2012" /> The full [[endometrial transformation]] dosage of [[estradiol benzoate/progesterone]] in oil solution is 1 to 2 mg estradiol benzoate and 20 to 25 mg progesterone by intramuscular injection daily for 10 to 14 days, whereas the full endometrial transformation dosage of estradiol benzoate/progesterone in microcrystalline aqueous suspension is a single intramuscular injection of 10 mg estradiol benzoate and 200 mg progesterone.<ref name="pmid8370495" /> For comparison, the full endometrial transformation dosage of estradiol valerate and [[hydroxyprogesterone caproate]] in oil solution (brand name [[Gravibinon]]) is a single intramuscular injection of 10 mg estradiol valerate and 250 to 375 mg hydroxyprogesterone caproate.<ref name="pmid8370495" /> Endometrial transformation normally occurs during the [[luteal phase]] of the [[menstrual cycle]]; it is induced by [[endogenous]] progesterone following adequate priming by endogenous estradiol.<ref name="Patil-2014">{{Cite book | vauthors = Patil M, Mane SV |url=https://books.google.com/books?id=jOO4BwAAQBAJ&pg=PA66 |title=ECAB Luteal Phase Insufficiency - E-Book |date=11 December 2014 |publisher=Elsevier Health Sciences |isbn=978-81-312-3961-2 |pages=66–}}</ref> The [[decidua]] ([[pregnancy]]-type [[endometrium]]) induction dosage of estradiol benzoate/progesterone in oil solution is 2 to 5 mg estradiol benzoate and 20 to 100 mg progesterone by intramuscular injection daily for 5 to 7 weeks, whereas the decidua induction dosage of estradiol benzoate/progesterone in microcrystalline aqueous suspension is 10 to 20 mg estradiol benzoate and 200 to 250 mg progesterone in microcrystalline aqueous suspension by intramuscular injection once per week for about 6 weeks.<ref name="pmid8370495" /> For comparison, the decidua induction dosage of estradiol valerate and hydroxyprogesterone caproate in oil solution is about the same as that of microcrystalline estradiol benzoate/progesterone in aqueous suspension.<ref name="pmid8370495" /> The decidua induction dosages of estrogen and progestogen combinations are [[high-dose estrogen/pseudopregnancy|pseudopregnancy]] dosages.<ref name="pmid8370495" /> {{Parenteral potencies and durations of steroidal estrogens}} ====Antigonadotropic effects==== [[File:Hormone levels with twice-daily injectable estradiol benzoate in transgender women.png|thumb|right|400px|Levels of estradiol, [[testosterone]], and [[gonadotropin]]s with 4.5{{nbsp}}μg/kg injectable estradiol benzoate every 12{{nbsp}}hours (or ~0.63{{nbsp}}mg/day for a 70-kg [154-lb] person) in transgender women.<ref name="pmid6436856">{{cite journal | vauthors = Gooren LJ, Rao BR, van Kessel H, Harmsen-Louman W | title = Estrogen positive feedback on LH secretion in transsexuality | journal = Psychoneuroendocrinology | volume = 9 | issue = 3 | pages = 249–59 | date = 1984 | pmid = 6436856 | doi = 10.1016/0306-4530(84)90004-0 | s2cid = 45688010 | url = }}</ref>]] As with other estrogens and forms of estradiol,<ref name="pmid7500443">{{cite journal | vauthors = Cox RL, Crawford ED | title = Estrogens in the treatment of prostate cancer | journal = J Urol | volume = 154 | issue = 6 | pages = 1991–8 | date = December 1995 | pmid = 7500443 | doi = 10.1016/S0022-5347(01)66670-9| url = }}</ref><ref name="pmid17019433">{{cite journal | vauthors = Ockrim J, Lalani EN, Abel P | title = Therapy Insight: parenteral estrogen treatment for prostate cancer--a new dawn for an old therapy | journal = Nat Clin Pract Oncol | volume = 3 | issue = 10 | pages = 552–63 | date = October 2006 | pmid = 17019433 | doi = 10.1038/ncponc0602 | s2cid = 6847203 | url = }}</ref><ref name="pmid10386467">{{cite journal | vauthors = Henriksson P, Carlström K, Pousette A, Gunnarsson PO, Johansson CJ, Eriksson B, Altersgård-Brorsson AK, Nordle O, Stege R | title = Time for revival of estrogens in the treatment of advanced prostatic carcinoma? Pharmacokinetics, and endocrine and clinical effects, of a parenteral estrogen regimen | journal = Prostate | volume = 40 | issue = 2 | pages = 76–82 | date = July 1999 | pmid = 10386467 | doi = 10.1002/(sici)1097-0045(19990701)40:2<76::aid-pros2>3.0.co;2-q | s2cid = 12240276 | url = }}</ref> estradiol benzoate [[dose dependence|dose-dependently]] suppresses [[gonadotropin]] and [[testosterone]] levels in men and [[transgender women]].<ref name="pmid6436856" /> In a study that administered estradiol benzoate twice-daily to transgender women at a dose that resulted in measured estradiol levels of about 200 to 250{{nbsp}}pg/mL, testosterone levels decreased from around 530{{nbsp}}ng/dL at baseline to about 55{{nbsp}}ng/dL (–90%) within approximately 3{{nbsp}}days of treatment.<ref name="pmid6436856" /> ===Pharmacokinetics=== {{See also|Pharmacokinetics of estradiol}} Following administration, estradiol benzoate acts as a [[prodrug]] of estradiol via [[bond cleavage|cleavage]] by [[esterase]]s into estradiol and the natural [[fatty acid]] [[benzoic acid]].<ref name="pmid16112947" /> This cleavage occurs not only in the [[liver]], but also in the [[blood]] and in [[tissue (biology)|tissue]]s.<ref name="Oettel-2012" /><ref name="pmid16112947" /> Esters of estradiol like estradiol benzoate are readily [[hydrolysis|hydrolyzed]] to estradiol, but have an extended duration when administered in via [[intramuscular injection|intramuscular]] or [[subcutaneous injection]] due to a [[depot injection|depot]] effect afforded by their [[fatty acid]] ester [[moiety (chemistry)|moiety]] and consequent high [[lipophilicity]].<ref name="pmid16112947" /> A long-lasting local tissue depot is formed by the injection that slowly releases estradiol benzoate into the circulation.<ref name="pmid16112947" /> ====Intramuscular injection==== =====Oil solution===== The [[duration of action]] of estradiol benzoate in oil solution by intramuscular injection at typical clinical doses (e.g., 0.33–1.66 mg) is said to be 2 to 3 days.<ref name="Buchsbaum-2012">{{Cite book | vauthors = Buchsbaum HJ |url=https://books.google.com/books?id=z0LuBwAAQBAJ&pg=PA62 |title=The Menopause |date=6 December 2012 |publisher=Springer Science & Business Media |isbn=978-1-4612-5525-3 |pages=62–}}</ref><ref name="NNR1949e" /> A single dose of 2.5 mg estradiol benzoate in oil solution by intramuscular injection was found to produce plasma estradiol levels of greater than 400 pg/mL, measured 24 hours post-injection, in a group of patients with minimal baseline levels of estradiol (due to [[GnRH analogue]] therapy with [[triptorelin]]).<ref name="pmid8506068">{{Cite journal |vauthors=Vizziello G, D'Amato G, Trentadue R, Fanizza G |year=1993 |title=[Estradiol benzoate test in the study of pituitary block induced by triptorelin] |journal=Minerva Ginecol |language=it |volume=45 |issue=4 |pages=185–9 |pmid=8506068}}</ref> The [[elimination half-life]] of estradiol benzoate in oil solution by intramuscular injection has been reported to be 48 to 120 hours (2 to 5 days).<ref name="Runnebaum-2013"/> A single intramuscular injection of 5 mg estradiol benzoate in oil solution has been found to result in peak circulating concentrations of 940 pg/mL estradiol and 343 pg/mL estrone, which occurred at about 2 days post-injection.<ref name="pmid7389356" /> Compared to two other commonly used estradiol esters, estradiol benzoate had the shortest duration, at approximately 4 to 5 days, whereas [[estradiol valerate]] and [[estradiol cypionate]] were found to last for 7 to 8 days and 11 days, respectively.<ref name="pmid7389356" /> This is because estradiol benzoate has a shorter and less bulky [[fatty acid]] [[side chain|chain]], and in relation to this, is comparatively less [[lipophilicity|lipophilic]].<ref name="pmid16112947" /> For a given estradiol ester, the shorter or less bulky the fatty acid chain is, the less lipophilic, shorter-lasting, and less uniform/plateau-like the resultant levels of estradiol are as well as the higher (and hence more spike-like) the peak/maximal levels are.<ref name="pmid16112947" /> Daily intramuscular injections of 1 mg estradiol benzoate in oil solution have been found to produce estradiol [[excretion]] rates almost double those of the normal [[luteal phase]].<ref name="pmid8370495">{{cite journal | vauthors = Kaiser R | title = [Gestagen-estrogen combinations in gynecology. On the history, dosage and use of a hormone principle] | journal = Geburtshilfe und Frauenheilkunde | volume = 53 | issue = 7 | pages = 503–513 | date = July 1993 | pmid = 8370495 | doi = 10.1055/s-2007-1022924 | s2cid = 71261744 }}</ref><ref name="pmid13750804">{{cite journal | vauthors = Kaiser R | title = [Estrogen excretion during the cycle and after injection of estradiol esters. A contribution to therapy with depot estrogens] | language = de | journal = Geburtshilfe und Frauenheilkunde | volume = 21 | pages = 868–878 | date = September 1961 | pmid = 13750804 | trans-title = Estrogen excretion during the cycle and after injection of estradiol esters. A contribution to therapy with depot estrogens }}</ref><ref name="Kaiser-1962">{{Cite book | vauthors = Kaiser R |title=Gewebs-und Neurohormone: Physiologie des Melanophorenhormons |publisher=Springer, Berlin, Heidelberg |year=1962 |isbn=978-3-540-02909-0 |pages=227–232 |language=de |trans-title=Tissue and Neurohormones: Physiology of the Melanophore Hormone |chapter=Über die Oestrogenausscheidung nach Injektion von Oestradiolestern |series=Symposion der Deutschen Gesellschaft für Endokrinologie |trans-chapter=Estrogen excretion after injection of estradiol esters |doi=10.1007/978-3-642-86860-3_24}}</ref> This is in accordance with known production rates of estradiol in women (e.g., 300 μg/day in the luteal phase).<ref name="pmid8370495" /><ref name="pmid6717863">{{cite journal | vauthors = Nichols KC, Schenkel L, Benson H | title = 17 beta-estradiol for postmenopausal estrogen replacement therapy | journal = Obstetrical & Gynecological Survey | volume = 39 | issue = 4 | pages = 230–245 | date = April 1984 | pmid = 6717863 | doi = 10.1097/00006254-198404000-00022 }}</ref> {{Gallery | title=Hormone levels with estradiol benzoate by intramuscular injection | width=300 | height=200 | align=center | style="font-size:small;" | File:Estradiol levels after single intramuscular injections of different doses of estradiol benzoate in premenopausal women.png | Estradiol levels after single intramuscular injections of 0.5, 1.5, or 2.5 mg estradiol benzoate in oil in 5 premenopausal women each.<ref name="pmid1097136">{{Cite journal |vauthors=Shaw RW, Butt WR, London DR |date=May 1975 |title=The effect of oestrogen pretreatment on subsequent response to luteinizing hormone releasing hormone in normal women |journal=Clin. Endocrinol. (Oxf) |volume=4 |issue=3 |pages=297–304 |doi=10.1111/j.1365-2265.1975.tb01537.x |pmid=1097136 |s2cid=12139717}}</ref> Assays were performed using [[radioimmunoassay]].<ref name="pmid1097136" /> Source was Shaw et al. (1975).<ref name="pmid1097136" /> | File:Estradiol levels after a single 5 mg intramuscular injection of estradiol esters.png | Estradiol levels after single intramuscular injections of 5 mg of different estradiol esters in oil in about 10 premenopausal women each.<ref name="pmid7389356"/> Assays were performed using [[radioimmunoassay]] with [[chromatographic separation]].<ref name="pmid7389356" /> Source was Oriowo et al. (1980).<ref name="pmid7389356" /> | File:Estradiol levels after injections of estradiol, estradiol benzoate, estradiol valerate, and estradiol undecylate in women.png | Estradiol levels after a short intravenous infusion of 20 mg estradiol in aqueous solution or an intramuscular injection of equimolar doses of estradiol esters in oil solution in postmenopausal women.<ref name="Geppert-1975">{{Cite book | vauthors = Geppert G |url=https://books.google.com/books?id=cJ82vwEACAAJ |title=Untersuchungen zur Pharmakokinetik von Östradiol-17β, Östradiol-Benzoat, Östradiol-Valerianat und Östradiol-Undezylat bei der Frau: der Verlauf der Konzentrationen von Östradiol-17β, Östron, LH und FSH im Serum |year=1975 |pages=1–34 |trans-title=Studies on the pharmacokinetics of estradiol-17β, estradiol benzoate, estradiol valerate, and estradiol undecylate in women: the progression of serum estradiol-17β, estrone, LH, and FSH concentrations |oclc=632312599}}</ref><ref name="pmid1150068">{{Cite journal |vauthors=Leyendecker G, Geppert G, Nocke W, Ufer J |date=May 1975 |title=Untersuchungen zur Pharmakokinetik von Östradiol-17β, Östradiol-benzoat, Östradiol-Valerianat un Östradiol-Undezylat bei der Frau: Der Verlauf der Konzentration von Östradiol-17β, Östron, LH und FSH im Serum |trans-title=Estradiol 17β, estrone, LH and FSH in serum after administration of estradiol 17β, estradiol benzoate, estradiol valeriate and estradiol undecylate in the female |journal=Geburtshilfe Frauenheilkd |language=de |volume=35 |issue=5 |pages=370–374 |issn=0016-5751 |pmid=1150068}}</ref> Assays were performed using [[radioimmunoassay|RIA]] with [[chromatographic separation|CS]].<ref name="Geppert-1975" /><ref name="pmid1150068" /> Source was Geppert (1975).<ref name="Geppert-1975" /><ref name="pmid1150068" /> | File:Idealized curves of estradiol levels after injection of different estradiol esters in women.png | Simplified curves of estradiol levels after injection of different estradiol esters in women.<ref name="pmid8013219">{{Cite journal |vauthors=Garza-Flores J |date=April 1994 |title=Pharmacokinetics of once-a-month injectable contraceptives |journal=Contraception |volume=49 |issue=4 |pages=347–59 |doi=10.1016/0010-7824(94)90032-9 |pmid=8013219}}</ref> Source was Garza-Flores (1994).<ref name="pmid8013219" /> | File:Vaginal cornification with a single intramuscular injection of different estradiol esters in women.png | [[Vagina]]l [[cornification]] with a single intramuscular injection of different estradiol esters in oil solution in women.<ref name="pmid14388061">{{Cite journal |vauthors=Schwartz MM, Soule SD |date=July 1955 |title=Estradiol 17-beta-cyclopentylpropionate, a long-acting estrogen |journal=Am. J. Obstet. Gynecol. |volume=70 |issue=1 |pages=44–50 |doi=10.1016/0002-9378(55)90286-6 |pmid=14388061}}</ref> Source was Schwartz & Soule (1955).<ref name="pmid14388061" /> }} =====Aqueous suspension===== [[Microcrystalline]] estradiol benzoate in [[aqueous suspension]] (brand names Agofollin Depot and Ovocyclin M alone and [[Follivirin]] in combination with [[testosterone isobutyrate]])<ref name="Agofollin-Depot-Label" /><ref name="www.sukl.cz-FOLIVIRIN" /> has been found to have a longer [[duration of action]] than [[amorphous solid|amorphous]] estradiol benzoate in oil solution when administered via intramuscular injection.<ref name="vonWattenwyl1944">{{cite journal | vauthors = von Wattenwyl H |title=Über eine neue Anwendungsart oestrogener Substanzen |date=1944 |journal=Schweiz. Med. Wochenschr. |volume=74 |pages=159–161 |trans-title=A new type of application of estrogenic substances |language=de}}</ref><ref name="Toppozada-1950">{{Cite journal | vauthors = Toppozada HK |year=1950 |title=Oestrogenic Therapy with Prolonged Action |journal=Obstetrical & Gynecological Survey |volume=5 |issue=4 |pages=531 |doi=10.1097/00006254-195008000-00021 |issn=0029-7828}}</ref><ref name="pmid14907837">{{cite journal | vauthors = Ferin J | title = Relative duration of action of natural and synthetic estrogens administered parenterally in women with estrogen deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 12 | issue = 1 | pages = 28–35 | date = January 1952 | pmid = 14907837 | doi = 10.1210/jcem-12-1-28 }}</ref><ref name="pmid13198154">{{cite journal | vauthors = Ober KG, Klein I, Weber M | title = [The problem of progesterone therapy; experimental studies on the Hooker-Forbes test and clinical observations on crystalline suspensions] | journal = Archiv für Gynäkologie | volume = 184 | issue = 5 | pages = 543–616 | year = 1954 | pmid = 13198154 | doi = 10.1007/BF00976991 | trans-title = On the question of progesterone treatment: experimental studies with the Hooker-Forbes test and clinical observations with crystal suspensions | s2cid = 42832785 }}</ref><ref name="pmid14368390">{{cite journal | vauthors = Field-Richards S | title = A preliminary series of cases of uterine hypoplasia treated by local injection of an oestrogenic emulsion | journal = The Journal of Obstetrics and Gynaecology of the British Empire | volume = 62 | issue = 2 | pages = 205–213 | date = April 1955 | pmid = 14368390 | doi = 10.1111/j.1471-0528.1955.tb14121.x | quote = Oestradiol monobenzoate or oestradiol diproprionate are slowly absorbed from oily solution after intramuscular injection and for this purpose are to be preferred to the unesterified form. As an even slower absorption of oestradiol monobenzoate can be obtained from an aqueous emulsion of this hormone (Lens, Overbeek and Polderman, 1949). Such a preparation for parenteral use was made available for this experiment by Messrs. Organon Laboratories Limited. | s2cid = 41256797 }}</ref><ref name="pmid18140399">{{cite journal | vauthors = Lens J, Overbeek GA, Polderman J | title = The effect of sex hormones in some organic solvents; emulsified in water | journal = Acta Endocrinologica | volume = 2 | issue = 4 | pages = 396–404 | date = 1949 | pmid = 18140399 | doi = 10.1530/acta.0.0020396 }}</ref><ref name="Dorfman-2016">{{Cite book | vauthors = Dorfman RI |url=https://books.google.com/books?id=BbLfBAAAQBAJ&pg=PA40 |title=Steroidal Activity in Experimental Animals and Man |date=5 December 2016 |publisher=Elsevier Science |isbn=978-1-4832-7299-3 |pages=40– |quote=Ferin (1952) also studied duration of action in women with estrogen deficiency by recording the days of freedom from hot flushes. He rates estradiol-3-benzoate, estradiol-3-furoate, estradiol dipropionate, estradiol-17-caprylate, estradiol-3-benzoate-17-caprylate in oil, and finally estradiol-3-benzoate in emulsion or as microcrystals in that order of duration of action. After 10 mg. of each of the above preparations, a woman would typically remain free of symptoms for 10 days. This could, however, be as much as 50 days.}}</ref><ref name="Horský-1981">{{Cite book | vauthors = Horský J, Presl J |title=Ovarian Function and its Disorders: Diagnosis and Therapy |date=1981 |publisher=Springer Science & Business Media |isbn=978-94-009-8195-9 |pages=309–332 |chapter=Hormonal Treatment of Disorders of the Menstrual Cycle |series=Developments in Obstetrics and Gynecology |doi=10.1007/978-94-009-8195-9_11 |chapter-url=https://books.google.com/books?id=7IrpCAAAQBAJ&pg=PA310}}</ref>{{Rp|310}} Whereas the duration of a single intramuscular injection of estradiol benzoate in oil solution is 6 days, the duration of a single intramuscular injection of microcrystalline estradiol benzoate in aqueous suspension is 16 to 21 days.<ref name="Horský-1981" /><ref name="Toppozada-1950" /><ref name="pmid13750804" /><ref name="Kaiser-1962" /> Its duration also surpasses that of [[estradiol valerate]] and [[estradiol cypionate]].<ref name="Horský-1981" /> The duration of microcrystalline aqueous suspensions administered by intramuscular injection is dependent both on [[concentration]] and on [[particle size|crystal size]].<ref name="pmid1177432">{{cite journal | vauthors = Shearman RP | title = The development of depot contraceptives | journal = Journal of Steroid Biochemistry | volume = 6 | issue = 6 | pages = 899–902 | date = June 1975 | pmid = 1177432 | doi = 10.1016/0022-4731(75)90323-4 }}</ref><ref name="Edkins-1959">{{Cite journal | vauthors = Edkins RP |year=1959 |title=The Modification of the Duration of Drug Action |journal=Journal of Pharmacy and Pharmacology |volume=11 |issue=S1 |pages=54T–66T |doi=10.1111/j.2042-7158.1959.tb10412.x |issn=0022-3573 |s2cid=78850713}}</ref><ref name="pmid18140399" /><ref name="Herrmann-1958">{{Cite journal | vauthors = Herrmann U |year=1958 |title=Abhängigkeit der durch Oestrogen- und Progesteron-Kristalle induzierten Abbruchblutung von der Korngröße |journal=Gynecologic and Obstetric Investigation |volume=146 |issue=4 |pages=318–323 |doi=10.1159/000306607 |issn=1423-002X}}</ref> ====Other routes==== The [[duration of action|duration]] of estradiol benzoate is not prolonged if it is administered directly into the [[circulatory system|circulation]] via [[intravenous injection]], in contrast to intramuscular injection.<ref name="pmid20781252">{{Cite journal |vauthors=Parkes AS |date=February 1938 |title=Effective Absorption of Hormones |journal=Br Med J |volume=1 |issue=4024 |pages=371–3 |doi=10.1136/bmj.1.4024.371 |pmc=2085798 |pmid=20781252}}</ref><ref name="Dorfman1964">{{Cite book | vauthors = Dorfman RI |url=https://books.google.com/books?id=BbLfBAAAQBAJ&pg=PA4 |title=Steroidal Activity in Experimental Animals and Man |date=1964 |publisher=Elsevier Science |isbn=978-1-4832-7299-3 |pages=4–}}</ref><ref name="Emmens-2013">{{Cite book | vauthors = Emmens CW |url= https://books.google.com/books?id=cCzgBAAAQBAJ&pg=PA395 |title=Hormone Assay |date=22 October 2013 |publisher=Elsevier Science |isbn=978-1-4832-7286-3 |pages=395–}}</ref> Estradiol benzoate is active with [[oral administration|oral]] and [[sublingual administration]], similarly to [[estradiol valerate]] and [[estradiol acetate]].<ref name="Buchsbaum-2012" /><ref name="Horský-1981" />{{Rp|310}} However, it is not marketed in any formulation for use by these routes.<ref name="Kleemann-2014" /> Oral estradiol benzoate has been reported to possess about one-third to half the [[potency (pharmacology)|potency]] of intramuscular injection of estradiol benzoate.<ref name="Stanczyk-1998">{{Cite book | vauthors = Stanczyk FZ |url=https://books.google.com/books?id=eO5qAAAAMAAJ |title=Estrogens and Progestogens in Clinical Practice |publisher=Churchill Livingstone |year=1998 |isbn=978-0-443-04706-0 | veditors = Fraser IS, Jansen RP, Lobo RA, Whitehead MI |pages=27–39 |chapter=Structure-function relationships and metabolism of estrogens and progestogens }}</ref><ref name="Henzl-1978">{{Cite book | vauthors = Henzl MR |url=https://books.google.com/books?id=wPVqAAAAMAAJ |title=Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management |publisher=Saunders |year=1978 |isbn=978-0-7216-9625-6 | veditors = Yen SS, Jaffe RB |pages=421–468 |chapter=Natural and Synthetic Female Sex Hormones }}</ref><ref name="Dorfman1964b">{{Cite book | vauthors = Dorfman RI |url=https://books.google.com/books?id=BbLfBAAAQBAJ&pg=PA40 |title=Steroidal Activity in Experimental Animals and Man |date=1964 |publisher=Elsevier Science |isbn=978-1-4832-7299-3 |pages=40–}}</ref><ref name="Ferin-1941">{{Cite journal |vauthors=Ferin J |year=1941 |title=L'activité comparée de diverses substances oestrogènes naturelles et du stilboestrol administrés par voie orale, trans-hépatique, chez la femme ovariectomisée |trans-title=The comparative activity of various natural estrogen substances and stilboestrol administered by the oral, transhepatic route, in ovariectomized women |url=https://scholar.google.com/scholar?cluster=10302913900080981770 |journal=Revue Belge des Sciences Médicales |volume=13 |pages=177–198}}</ref> This level of oral potency has been described as remarkably high.<ref name="Henzl-1978" /> The sublingual potency of estradiol benzoate is similar to that of estradiol.<ref name="Horský-1981" />{{Rp|310}} A study found that the total dose of estradiol benzoate needed for [[endometrial proliferation]] in women was 60 to 140 mg, relative to 60 to 180 mg for estradiol.<ref name="Horský-1981" />{{Rp|310}} Both estradiol and estradiol benzoate has a persistence of estrogenic effect with single administration of one day.<ref name="Horský-1981" />{{Rp|310}} [[Subcutaneous implant]]ation of [[crystalline]] estradiol benzoate pellets has been studied, but no estradiol benzoate pellet implants have been marketed.<ref name="pmid14862159">{{Cite journal |vauthors=Bishop PM, Folley SJ |date=August 1951 |title=Absorption of hormone implants in man |journal=Lancet |volume=2 |issue=6676 |pages=229–32 |doi=10.1016/S0140-6736(51)93237-0 |pmid=14862159}}</ref> ==Chemistry== {{See also|Estrogen ester|List of estrogen esters#Estradiol esters}} Estradiol benzoate is a [[synthetic compound|synthetic]] [[estrane]] [[steroid]] and the C3 [[benzoic acid|benzoate]] (benzenecarboxylate) [[ester]] of [[estradiol (medication)|estradiol]].<ref name="IndexNominum2000" /><ref name="Elks-2014" /><ref name="Roberts-1991" /> It is also known as estradiol 3-benzoate or as estra-1,3,5(10)-triene-3,17β-diol 3-benzoate.<ref name="IndexNominum2000" /><ref name="Elks-2014" /><ref name="Roberts-1991" /> Two estradiol esters that are related to estradiol benzoate are [[estradiol dipropionate]], the C3,17β dipropionate ester of estradiol, and [[estradiol acetate]], the C3 acetate ester of estradiol. The experimental [[octanol/water partition coefficient]] (logP) of estradiol benzoate is 4.7.<ref name="ChemSpider">{{Cite web|url=http://www.chemspider.com/Chemical-Structure.193412.html|title=17β-estradiol 3-benzoate | C25H28O3 | ChemSpider|website=www.chemspider.com}}</ref> {{Structural properties of selected estradiol esters}} ==History== Estradiol benzoate was one of the first estrogens to be developed and marketed.<ref name="Biskind-1935" /> In 1932, [[Adolf Butenandt]] described [[estrone benzoate]] and reported that it had a prolonged [[duration of action]].<ref name="Labhart-2012">{{Cite book | vauthors = Labhart A |url=https://books.google.com/books?id=DAgJCAAAQBAJ&pg=PA512 |title=Clinical Endocrinology: Theory and Practice |date=6 December 2012 |publisher=Springer Science & Business Media |isbn=978-3-642-96158-8 |pages=512–}}</ref><ref name="Butenandt-1932">{{Cite journal | vauthors = Butenandt A, Störmer I |year=1932 |title=Über isomere Follikelhormone. Untersuchungen über das weibliche Sexualhormon, 7. Mitteilung. |trans-title=About isomeric follicle hormones. Studies on the female sex hormone, 7th communication. |journal=Hoppe-Seyler's Zeitschrift für physiologische Chemie |volume=208 |issue=4 |pages=129–148 |doi=10.1515/bchm2.1932.208.4.129 |issn=0018-4888}}</ref> Schwenk and Hildebrant at [[Schering AG|Schering]] discovered estradiol via [[redox|reduction]] of [[estrone (medication)|estrone]] in 1933, and they proceeded to synthesize estradiol benzoate from estradiol the same year.<ref name="Oettel-2012">{{Cite book | vauthors = Oettel M, Schillinger E |url=https://books.google.com/books?id=0BfrCAAAQBAJ&pg=PA8 |title=Estrogens and Antiestrogens I: Physiology and Mechanisms of Action of Estrogens and Antiestrogens |date=6 December 2012 |publisher=Springer Science & Business Media |isbn=978-3-642-58616-3 |pages=8–}}</ref><ref name="pmid16746750">{{cite journal | vauthors = Miescher K, Scholz C, Tschopp E | title = The activation of female sex hormones: Mono-esters of alpha-oestradiol | journal = The Biochemical Journal | volume = 32 | issue = 8 | pages = 1273–1280 | date = August 1938 | pmid = 16746750 | pmc = 1264184 | doi = 10.1042/bj0321273b }}</ref> Estradiol benzoate was [[patent]]ed by Schering in 1933 and was introduced in an [[oil solution]] for use by [[intramuscular injection]] under the brand name ''Progynon B'' that year as well.<ref name="Kaufman-1933">{{Cite journal | vauthors = Kaufman C |year=1933 |title=Die Behandlung der Amenorrhöe mit Hohen Dosen der Ovarialhormone |journal=Klinische Wochenschrift |volume=12 |issue=40 |pages=1557–1562 |doi=10.1007/BF01765673 |issn=0023-2173 |s2cid=25856898}}</ref><ref name="Buschbeck-1934">{{Cite journal | vauthors = Buschbeck H |year=1934 |title=Neue Wege der Hormontherapie in der Gynäkologie |trans-title=New ways of hormonal therapy in gynecology |journal=Deutsche Medizinische Wochenschrift |volume=60 |issue=11 |pages=389–393 |doi=10.1055/s-0028-1129842 |s2cid=72668930 |issn=0012-0472 }}</ref><ref name="Biskind-1935">{{Cite journal | vauthors = Biskind MS |year=1935 |title=Commercial Glandular Products |journal=Journal of the American Medical Association |volume=105 |issue=9 |pages=667 |doi=10.1001/jama.1935.92760350007009a |issn=0002-9955 |quote=Progynon-B, Schering Corporation: This is crystalline hydroxyestrin benzoate obtained by hydrogenation of theelin and subsequent conversion to the benzoate. [...] Progynon-B is marketed in ampules containing 1 cc. of a sesame oil solution of hydroxyestrin benzoate of either 2,500, 5,000, 10,000 or 50,000 international units.}}</ref><ref name="Novak-1935">{{Cite journal | vauthors = Novak E |year=1935 |title=The Therapeutic Use of Estrogenic Substances |journal=JAMA: The Journal of the American Medical Association |volume=104 |issue=20 |pages=1815 |doi=10.1001/jama.1935.92760200002012 |issn=0098-7484 |quote=Progynon B (Schering), in 1 cc. ampules, of 10,000 or 50,000 international units of hydroxyestrin benzoate in sesame oil.}}</ref><ref name="Kleemann-2014" /> By 1936, multiple formulations of estradiol benzoate in oil solution had been marketed, including under the brand names ''Progynon B'' by Schering, ''Dimenformon Benzoate'' by [[Hoffmann-La Roche|Roche]]-[[Organon International|Organon]], and ''Oestroform B'' by [[British Drug Houses]].<ref name="pmid29648134">{{cite journal | vauthors = Johnstone RW | title = Sex Hormone Therapy in Gynæcology | journal = Edinburgh Medical Journal | volume = 43 | issue = 11 | pages = 680–695 | date = November 1936 | pmid = 29648134 | pmc = 5303355 }}</ref><ref name="pmid18746057">{{cite journal | vauthors = Reilly WA | title = Estrogens: Their Use in Pediatrics | journal = California and Western Medicine | volume = 55 | issue = 5 | pages = 237–239 | date = November 1941 | pmid = 18746057 | pmc = 1634235 }}</ref><ref name="Greene-1941">{{Cite journal | vauthors = Greene RR |year=1941 |title=Endocrine Therapy for Gynecologic Disorders |journal=Medical Clinics of North America |volume=25 |issue=1 |pages=155–168 |doi=10.1016/S0025-7125(16)36624-X |issn=0025-7125}}</ref><ref name="Fluhmann-1944">{{Cite journal | vauthors = Fluhmann CF |year=1944 |title=Clinical Use of Extracts from the Ovaries |journal=Journal of the American Medical Association |volume=125 |issue=1 |pages=1 |doi=10.1001/jama.1944.02850190003001 |issn=0002-9955}}</ref><ref name="pmid19312076">{{cite journal | vauthors = Taylor HC | title = The Present Status of Gynecologic Endocrine Therapy | journal = Bulletin of the New York Academy of Medicine | volume = 14 | issue = 10 | pages = 608–634 | date = October 1938 | pmid = 19312076 | pmc = 1911308 }}</ref><ref name="pmid20320193">{{cite journal | vauthors = Watson MC | title = The Sex Hormones and Their Value as Therapeutic Agents | journal = Canadian Medical Association Journal | volume = 34 | issue = 3 | pages = 293–298 | date = March 1936 | pmid = 20320193 | pmc = 1561541 }}</ref><ref name="pmid20780598">{{cite journal | vauthors = Bishop PM | title = Hormones in the Treatment of Menstrual Disturbances | journal = British Medical Journal | volume = 1 | issue = 3979 | pages = 763–765 | date = April 1937 | pmid = 20780598 | pmc = 2088583 | doi = 10.1136/bmj.1.3979.763 }}</ref> By the early 1940s, ''Ben-Ovocylin'' had been introduced by [[Ciba Specialty Chemicals|Ciba]] as well.<ref name="pmid18746057" /><ref name="Greene-1941" /><ref name="Fluhmann-1944" /> In the late 1940s, the brand name ''Ben-Ovocylin'' was changed by Ciba to ''Ovocylin Benzoate''.<ref name="JAPA1949">{{Cite journal |year=1949 |title=New Prescription Products |journal=Journal of the American Pharmaceutical Association (Practical Pharmacy Ed.) |volume=10 |issue=4 |pages=198–206 |doi=10.1016/S0095-9561(16)31795-9 |issn=0095-9561}}</ref> Following their introduction, estradiol benzoate and [[estradiol dipropionate]] were the most widely used esters of estradiol for many years.<ref name="pmid14388061"/> However, [[estradiol valerate]] and [[estradiol cypionate]], which are longer-acting esters that require less frequent administration, were developed and introduced in the 1950s, and have since largely superseded estradiol benzoate and estradiol dipropionate.<ref name="pmid7389356" /> ==Society and culture== ===Generic names=== ''Estradiol benzoate'' is the [[generic term|generic name]] of the drug and its {{abbrlink|INN|International Nonproprietary Name}}, {{abbrlink|BANM|British Approved Name}}, and {{abbrlink|JAN|Japanese Accepted Name}}, while ''oestradiol benzoate'' was formerly its {{abbrlink|BANM|British Approved Name}}.<ref name="Drugs.com-Estradiol">{{Cite web|url=https://www.drugs.com/international/estradiol.html|title=Estradiol|website=Drugs.com}}</ref><ref name="IndexNominum2000">{{Cite book |url=https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA406 |title=Index Nominum 2000: International Drug Directory |publisher=Taylor & Francis US |year=2000 |isbn=978-3-88763-075-1 |page=406}}</ref><ref name="Elks-2014">{{Cite book |vauthors = Elks J |url=https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA897 |title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies |date=14 November 2014 |publisher=Springer |isbn=978-1-4757-2085-3 |pages=897–}}</ref><ref name="Roberts-1991">{{Cite book | vauthors = Roberts AD |url=https://books.google.com/books?id=qw5X0NK1A90C&pg=PA415 |title=Dictionary of Steroids: Chemical Data, Structures, and Bibliographies |publisher=CRC Press |year=1991 |isbn=978-0-412-27060-4 |page=415 |access-date=20 May 2012}}</ref> ===Brand names=== The major brand name of estradiol benzoate is Progynon-B.<ref name="IndexNominum2000" /><ref name="Elks-2014" /><ref name="Roberts-1991" /> It has also been sold under a variety of other brand names including Agofollin Depot, Ben-Ovocylin, Benzhormovarine, Benzoestrofol, Benzofoline, Benzo-Ginestryl, Benzo-Ginoestril, Benzo-Gynoestryl, Benzoate d'oestradiol P.A. Intervet, Benztrone, Benztrone Pabyrn, Diffollisterol, Di-Folliculine, Dimenformon, Dimenformon Benzoate, Dimenformone, Diogyn B, EBZ, Eston-B, Estradiolo Amsa, Femestrone, Follicormon, Follidrin, Graafina, Gynecormone, Gynecormone Gouttes, Gynformone, Metroval, Hidroestron, Hormogynon, Oestradiol Benzoat, Oestradiol-Benzoat Intervet, Oestradiol-K Streuli, Oestradiolium Benzoicum, Oestraform, Ostrin, Ovahormon Benzoate, Ovasterol-B, Ovex, Ovocyclin Benzoate, Ovocyclin M, Primogyn B, Primogyn B Oleosum, Primogyn I, Progynon Benzoate, Recthormone, Oestradiol, Reglovar, Solestro, and Unistradiol, among others.<ref name="IndexNominum2000" /><ref name="Elks-2014" /><ref name="Roberts-1991" /><ref name="Lewis-2008">{{Cite book | vauthors = Lewis RJ |url=https://books.google.com/books?id=WZeBDwAAQBAJ&pg=PA593 |title=Hazardous Chemicals Desk Reference |date=13 June 2008 |publisher=John Wiley & Sons |isbn=978-0-470-18024-2 |pages=593–}}</ref> ===Availability=== {{See also|List of marketed estradiol benzoate formulations|List of combined sex-hormonal preparations}} Estradiol benzoate is available in [[Europe]] and in other parts of the world.<ref name="IndexNominum2000" /><ref name="Kleemann-2014" /> It was previously available for medical use in the [[United States]], but is no longer marketed in this country.<ref name="IndexNominum2000" /><ref name="Witherspoon-1994">{{Cite book | vauthors = Witherspoon R |url=https://books.google.com/books?id=68n6f1Nw6EEC&pg=PA64 |title=Presidents List of Articles Which May Be Designated Or Modified As Eligible Articles for Purposes of the U.S. Generalized System of Preferences |date=1 June 1994 |publisher=DIANE Publishing |isbn=978-0-7881-1433-5 |pages=64–}}</ref><ref name="Kleemann-2014" /><ref name="Drugs@FDA">{{Cite web |title=Drugs@FDA: FDA Approved Drug Products |url=http://www.accessdata.fda.gov/scripts/cder/daf/ |access-date=26 July 2018 |publisher=United States Food and Drug Administration}}</ref> However, it is approved and marketed in the United States for [[veterinary use]] as a [[subdermal implant]] both alone and in combination with the [[androgen]]/[[anabolic steroid]] [[trenbolone acetate]] (brand names Celerin and Synovex, respectively).<ref name="Witherspoon-1994" /><ref name="FDACelerinLabel">{{Cite web |title=Microencapsulated Estradiol Benzoate Suspension Implant | work = SUPPLEMENTAL NEW ANIMAL DRUG APPLICATION |url=https://www.fda.gov/downloads/AnimalVeterinary/Products/ApprovedAnimalDrugProducts/FOIADrugSummaries/ucm116143.pdf |archive-url=https://web.archive.org/web/20170505225943/https://www.fda.gov/downloads/AnimalVeterinary/Products/ApprovedAnimalDrugProducts/FOIADrugSummaries/ucm116143.pdf |archive-date=5 May 2017 |access-date=16 December 2019 | publisher =[[Food and Drug Administration]]}}</ref><ref name="FDASynovexLabel">{{Cite web |title=SYNOVEXÒ Plus (Estradiol Benzoate and Trenbolone Acetate) | work = FREEDOM OF INFORMATION SUMMARY |url=https://www.fda.gov/downloads/AnimalVeterinary/Products/ApprovedAnimalDrugProducts/FOIADrugSummaries/UCM338208.pdf |archive-url=https://web.archive.org/web/20170505230004/https://www.fda.gov/downloads/AnimalVeterinary/Products/ApprovedAnimalDrugProducts/FOIADrugSummaries/UCM338208.pdf |archive-date=5 May 2017 |access-date=16 December 2019 | publisher = [[Food and Drug Administration]]}}</ref> Outside of the United States, estradiol benzoate is also marketed [[estradiol benzoate/progesterone|in combination with progesterone]] for use as an intramuscular injection.<ref name="Drugs.com-Estradiol" /><ref name="Drugs.com-Progesterone">{{Cite web |title=Progesterone |url=https://www.drugs.com/international/progesterone.html |access-date=31 July 2018 |website=Drugs.com}}</ref> [[Microcrystalline]] estradiol benzoate in [[aqueous suspension]] is available in the [[Czech Republic]] and [[Slovakia]] alone under the brand name Agofollin Depot and in combination with microcrystalline [[testosterone isobutyrate]] under the brand name Folivirin.<ref name="Agofollin-Depot-Label" /><ref name="www.sukl.cz-FOLIVIRIN">{{Cite web |title=FOLIVIRIN Injekční suspenze (Estradioli benzoas, testosteroni isobutyras)|url=http://www.sukl.cz/download/pil/PI15789.pdf |archive-url=https://web.archive.org/web/20190520031642/http://www.sukl.cz/download/pil/PI15789.pdf |archive-date=20 May 2019 |access-date=15 January 2022 |website=www.sukl.cz}}</ref><ref name="Drugs.com-Estradiol" /> ==Research== Estradiol benzoate has been studied in combination with [[norethisterone enanthate]] as a once-a-month [[combined injectable contraceptive]], but ultimately did not complete development for this indication.<ref name="GoldsmithToppozada1983">{{cite report | veditors = Toppozada M, Goldsmith A | title = Long-acting Contraception. | publisher = Program for Applied Research on Fertility Regulation, Northwestern University | date = 1983 | pages = 94–95 | url = https://www.popline.org/node/423289 | archive-url = https://web.archive.org/web/20190324131844/https://www.popline.org/node/423289 | archive-date = 24 March 2019}}</ref> ==References== {{Reflist}} {{Estradiol}} {{Estrogens and antiestrogens}} {{Estrogen receptor modulators}} [[Category:Antigonadotropins]] [[Category:Benzoate esters]] [[Category:Estradiol esters]] [[Category:Hormonal antineoplastic drugs]] [[Category:Hormonal contraception]] [[Category:Secondary alcohols]] [[Category:Synthetic estrogens]] [[Category:Veterinary drugs]]
Estradiol benzoate
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