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| legal_US =
| legal_US =
| legal_status = Rx-only
| legal_status = Rx-only
| routes_of_administration = [[Intramuscular injection]]
| routes_of_administration = [[Intramuscular injection]], [[subcutaneous injection]], [[vaginal administration|vaginal]]
| class = [[Estrogen (medication)|Estrogen]]; [[Estrogen ester]]
| class = [[Estrogen (medication)|Estrogen]]; [[Estrogen ester]]


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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&nbsp;mg/mL.<ref name="KleemannEngel2014">{{cite book|author1=A. Kleemann|author2=J. Engel|author3=B. Kutscher|author4=D. Reichert|title=Pharmaceutical Substances, 5th Edition, 2009: Syntheses, Patents and Applications of the most relevant APIs|url=https://books.google.com/books?id=fO2IAwAAQBAJ&pg=PA1167|date=14 May 2014|publisher=Thieme|isbn=978-3-13-179525-0|pages=1167–1174}}</ref><ref name="Muller1998">{{cite book|author=Muller|title=European Drug Index: European Drug Registrations, Fourth Edition|url=https://books.google.com/books?id=2HBPHmclMWIC&pg=PA150|date=19 June 1998|publisher=CRC Press|isbn=978-3-7692-2114-5|pages=150,349,370}}</ref><ref name="NNR1949" /> It is also available as a [[microcrystalline]] [[aqueous suspension]] for intramuscular injection under the brand name Agofollin Depot.<ref name="Avicenum1973">{{cite book|title=Review of Czechoslovak Medicine|url=https://books.google.com/books?id=odA0AQAAIAAJ|year=1973|publisher=Avicenum - Czechoslovak Medical Press|quote=Oestradiol benzoate, aqueous microcrystalline suspension (Agofollin Depot SPOFA).|page=5}}</ref><ref name="Agofollin-Depot-Label">https://web.archive.org/web/20190519104654/http://www.sukl.cz/download/pil/PI16221.pdf</ref><ref name="MarekJosef2010">{{cite book|author=Marek Josef a kolektiv|title=Farmakoterapie vnitřních nemocí - 4. zcela přepracované a doplněné vydání|url=https://books.google.com/books?id=Xc2OHeo0i0cC&pg=PA377|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="HankaPetr2008" /> [[Sistocyclin]] was the brand name of a product containing 10&nbsp;mg microcrystalline estradiol benzoate and 200&nbsp;mg microcrystalline [[progesterone (medication)|progesterone]] in an aqueous suspension.<ref name="Ufer1968">{{cite book | last1 = Ufer | first1 = Joachim | chapter = Die therapeutische Anwendung der Gestagene beim Menschen | trans-chapter = Therapeutic Use of Progestagens in Humans | pages = 1026–1124 | doi = 10.1007/978-3-642-99941-3_7 | title = Die Gestagene | trans-title = Progestogens | year = 1968 | publisher = Springer-Verlag | isbn = 978-3-642-99941-3 | url = https://books.google.com/books?id=t8GpBgAAQBAJ&pg=PA1058 | 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 | title = Ciba Symposium | url = https://books.google.com/books?id=KwkbAQAAMAAJ | year = 1957 | publisher = Ciba | 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 | title = Ciba Zeitschrift | url = https://books.google.com/books?id=WgpOAQAAIAAJ | 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="Pschyrembel2011">{{cite book|author=Willibald Pschyrembel|title=Praktische Gynäkologie: für Studierende und Ärzte|url=https://books.google.com/books?id=vVaTnHDFzZ0C&pg=PA601|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&nbsp;mg microcrystalline estradiol benzoate and 25 to 50&nbsp;mg microcrystalline [[testosterone isobutyrate]] in aqueous suspension.<ref name="Folivirin-Label" /><ref name="Kubíková2014">{{cite journal | last1 = Kubíková | first1 = Drahomíra | title = Menopauzální symptomy a hormonální substituční terapie | trans-title = Menopausal symptoms and hormone replacement therapy | language = Czech | date = 2014 | journal = Praktické Lékárenství | volume = 10 | issue = 2 | pages = 68–73 | issn = 1801-2434 | doi = | pmid = | url = http://www.medvik.cz/link/bmc14059249 <!-- | url2 = http://www.solen.sk/pdf/95e898d92100a736e32110dd1b846a9e.pdf-->}}</ref><ref name="Josefkolektiv2010">{{cite book|author1=Marek Josef|author2=a kolektiv|title=Farmakoterapie vnitřních nemocí: 4., zcela přepracované a doplněné vydání|url=https://books.google.com/books?id=bUqECwAAQBAJ&pg=PA380|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="Ciba1953">{{cite book|title=Ciba Symposium: 1953/57:Index|url=https://books.google.com/books?id=yQgbAQAAMAAJ|year=1953|publisher=Ciba|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>
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&nbsp;mg/mL.<ref name="KleemannEngel2014">{{cite book|author1=A. Kleemann|author2=J. Engel|author3=B. Kutscher|author4=D. Reichert|title=Pharmaceutical Substances, 5th Edition, 2009: Syntheses, Patents and Applications of the most relevant APIs|url=https://books.google.com/books?id=fO2IAwAAQBAJ&pg=PA1167|date=14 May 2014|publisher=Thieme|isbn=978-3-13-179525-0|pages=1167–1174}}</ref><ref name="Muller1998">{{cite book|author=Muller|title=European Drug Index: European Drug Registrations, Fourth Edition|url=https://books.google.com/books?id=2HBPHmclMWIC&pg=PA150|date=19 June 1998|publisher=CRC Press|isbn=978-3-7692-2114-5|pages=150,349,370}}</ref><ref name="NNR1949" /> It is also available as a [[microcrystalline]] [[aqueous suspension]] for intramuscular injection under the brand name Agofollin Depot.<ref name="Avicenum1973">{{cite book|title=Review of Czechoslovak Medicine|url=https://books.google.com/books?id=odA0AQAAIAAJ|year=1973|publisher=Avicenum - Czechoslovak Medical Press|quote=Oestradiol benzoate, aqueous microcrystalline suspension (Agofollin Depot SPOFA).|page=5}}</ref><ref name="Agofollin-Depot-Label">https://web.archive.org/web/20190519104654/http://www.sukl.cz/download/pil/PI16221.pdf</ref><ref name="MarekJosef2010">{{cite book|author=Marek Josef a kolektiv|title=Farmakoterapie vnitřních nemocí - 4. zcela přepracované a doplněné vydání|url=https://books.google.com/books?id=Xc2OHeo0i0cC&pg=PA377|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="HankaPetr2008" /> [[Sistocyclin]] was the brand name of a product containing 10&nbsp;mg microcrystalline estradiol benzoate and 200&nbsp;mg microcrystalline [[progesterone (medication)|progesterone]] in an aqueous suspension.<ref name="Ufer1968">{{cite book | last1 = Ufer | first1 = Joachim | chapter = Die therapeutische Anwendung der Gestagene beim Menschen | trans-chapter = Therapeutic Use of Progestagens in Humans | pages = 1026–1124 | doi = 10.1007/978-3-642-99941-3_7 | title = Die Gestagene | trans-title = Progestogens | year = 1968 | publisher = Springer-Verlag | isbn = 978-3-642-99941-3 | url = https://books.google.com/books?id=t8GpBgAAQBAJ&pg=PA1058 | 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 | title = Ciba Symposium | url = https://books.google.com/books?id=KwkbAQAAMAAJ | year = 1957 | publisher = Ciba | 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 | title = Ciba Zeitschrift | url = https://books.google.com/books?id=WgpOAQAAIAAJ | 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="Pschyrembel2011">{{cite book|author=Willibald Pschyrembel|title=Praktische Gynäkologie: für Studierende und Ärzte|url=https://books.google.com/books?id=vVaTnHDFzZ0C&pg=PA601|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&nbsp;mg microcrystalline estradiol benzoate and 25 to 50&nbsp;mg microcrystalline [[testosterone isobutyrate]] in aqueous suspension.<ref name="Folivirin-Label" /><ref name="Kubíková2014">{{cite journal | last1 = Kubíková | first1 = Drahomíra | title = Menopauzální symptomy a hormonální substituční terapie | trans-title = Menopausal symptoms and hormone replacement therapy | language = Czech | date = 2014 | journal = Praktické Lékárenství | volume = 10 | issue = 2 | pages = 68–73 | issn = 1801-2434 | doi = | pmid = | url = http://www.medvik.cz/link/bmc14059249 <!-- | url2 = http://www.solen.sk/pdf/95e898d92100a736e32110dd1b846a9e.pdf-->}}</ref><ref name="Josefkolektiv2010">{{cite book|author1=Marek Josef|author2=a kolektiv|title=Farmakoterapie vnitřních nemocí: 4., zcela přepracované a doplněné vydání|url=https://books.google.com/books?id=bUqECwAAQBAJ&pg=PA380|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="Ciba1953">{{cite book|title=Ciba Symposium: 1953/57:Index|url=https://books.google.com/books?id=yQgbAQAAMAAJ|year=1953|publisher=Ciba|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&nbsp;mg estradiol benzoate and 10&nbsp;mg [[monalazone sodium]] has been marketed under the brand name Malun 25.<ref name="Leidenberger2013">{{cite book|author=Freimut A. Leidenberger|title=Klinische Endokrinologie für Frauenärzte|url=https://books.google.com/books?id=YTiuBgAAQBAJ&pg=PA527|date=17 April 2013|publisher=Springer-Verlag|isbn=978-3-662-08110-5|pages=527–}}</ref>


{{Available forms of estradiol}}
{{Available forms of estradiol}}

Revision as of 15:34, 10 June 2019

Estradiol benzoate
Clinical data
Pronunciation/ˌɛstrəˈdaɪoʊl ˈbɛnzoʊeɪt/
ES-trə-DY-ohl BEN-zoh-ayt
Trade namesAgofollin Depot, Benovocyclin, Benzofoline, Dimenformon, Progynon-B, many others
Other namesEB; E2B; Oestradiol benzoate; 17β-Estradiol-3-benzoate; NSC-9566; Benzhormovarine, Difollisterol, Follicormon, Follidimyl, Follidrinbensoat, Oestro-Vitis, Oestroform
Routes of
administration		Intramuscular injection, subcutaneous injection, vaginal
Drug classEstrogen; Estrogen ester
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
BioavailabilityIM: High[1]
Protein bindingEstradiol: ~98% (to albumin and SHBGTooltip sex hormone-binding globulin)[2][3]
MetabolismCleavage via esterases in the liver, blood, and tissues[4][5]
MetabolitesEstradiol, benzoic acid, and metabolites of estradiol[4][5]
Elimination half-lifeIM: 48–120 hrs (2–5 days)[6]
Duration of actionIM (0.3–1.7 mg): 2–3 days[7][8]
IM (5 mg): 4–6 days[9][10][11]
ExcretionUrine
Identifiers
  • [(8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-3-yl] benzoate
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.000.040 Edit this at Wikidata
Chemical and physical data
FormulaC25H28O3
Molar mass376.488 g/mol g·mol−1
3D model (JSmol)
  • C[C@]12CC[C@H]3[C@H]([C@@H]1CC[C@@H]2O)CCC4=C3C=CC(=C4)OC(=O)C5=CC=CC=C5
  • InChI=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
  • Key:UYIFTLBWAOGQBI-BZDYCCQFSA-N

Estradiol benzoate (EB), sold under the brand name Progynon-B among others, is an estrogen medication which is used in hormone therapy for menopausal symptoms and low estrogen levels in women, in hormone therapy for transgender women, and in the treatment of gynecological disorders.[8][12][13] It is also used in the treatment of prostate cancer in men.[8] Estradiol benzoate is used in veterinary medicine as well.[14][15] When used clinically, the medication is given by injection into muscle usually two to three times per week.[8][12][16]

Side effects of estradiol benzoate include breast tenderness, breast enlargement, nausea, headache, and fluid retention.[17] Estradiol benzoate is a synthetic estrogen and hence is an agonist of the estrogen receptor (ER), the biological target of estrogens like estradiol.[4][5] It is an estrogen ester and a prodrug of estradiol in the body.[4][5] Because of this, it is considered to be a natural and bioidentical form of estrogen.[4]

Estradiol benzoate was discovered in 1933 and was introduced for medical use in 1936.[4][18][19][20] It was the first estradiol ester to be discovered, as well as marketed, and was one of the first estrogens to be introduced for medical use.[19][20] Along with estradiol dipropionate, it was among the most widely used esters of estradiol for many years following its introduction.[21] However, in the 1950s, longer-acting estradiol esters that necessitate less frequent injections, such as estradiol valerate and estradiol cypionate, were developed, and have since mostly superseded estradiol benzoate.[9] Nonetheless, estradiol benzoate remains widely available throughout the world.[15] It is not available for medical use in the United States, but is available in this country for use in veterinary medicine.[22][23]

Medical uses

Main articles: Estradiol (medication) § Medical uses, and High-dose estrogen

The medical uses of estradiol benzoate are the same as those of estradiol and other estrogens.[8][12] Estradiol benzoate is used in hormone therapy for the treatment of menopausal symptoms such as hot flashes and vaginal atrophy and in the treatment of hypoestrogenism and delayed puberty due to hypogonadism or other causes in women.[8][12] It is also used in hormone therapy for transgender women.[13][24][25] Aside from hormone therapy, estradiol benzoate is used in the treatment of gynecological disorders such as menstrual disorders, dysfunctional uterine bleeding, and breast engorgement.[8][12] In addition, it is used as a form of high-dose estrogen therapy in the palliative treatment of prostate cancer in men.[8]

Estradiol benzoate has a relatively short duration of action, and is administered by intramuscular injection usually two to three times per week.[8][12] 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.[8][26] The dosage used in hormone therapy for transgender women is 0.5 to 1.5 mg two to three times per week.[13] 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).[8]

Estrogen dosages for menopausal hormone therapy
Route/form Estrogen Low Standard High
Oral Estradiol 0.5–1 mg/day 1–2 mg/day 2–4 mg/day
Estradiol valerate 0.5–1 mg/day 1–2 mg/day 2–4 mg/day
Estradiol acetate 0.45–0.9 mg/day 0.9–1.8 mg/day 1.8–3.6 mg/day
Conjugated estrogens 0.3–0.45 mg/day 0.625 mg/day 0.9–1.25 mg/day
Esterified estrogens 0.3–0.45 mg/day 0.625 mg/day 0.9–1.25 mg/day
Estropipate 0.75 mg/day 1.5 mg/day 3 mg/day
Estriol 1–2 mg/day 2–4 mg/day 4–8 mg/day
Ethinylestradiola 2.5–10 μg/day 5–20 μg/day –
Nasal spray Estradiol 150 μg/day 300 μg/day 600 μg/day
Transdermal patch Estradiol 25 μg/dayb 50 μg/dayb 100 μg/dayb
Transdermal gel Estradiol 0.5 mg/day 1–1.5 mg/day 2–3 mg/day
Vaginal Estradiol 25 μg/day – –
Estriol 30 μg/day 0.5 mg 2x/week 0.5 mg/day
IMTooltip Intramuscular or SC injection Estradiol valerate – – 4 mg 1x/4 weeks
Estradiol cypionate 1 mg 1x/3–4 weeks 3 mg 1x/3–4 weeks 5 mg 1x/3–4 weeks
Estradiol benzoate 0.5 mg 1x/week 1 mg 1x/week 1.5 mg 1x/week
SC implant Estradiol 25 mg 1x/6 months 50 mg 1x/6 months 100 mg 1x/6 months
Footnotes: a = No longer used or recommended, due to health concerns. b = As a single patch applied once or twice per week (worn for 3–4 days or 7 days), depending on the formulation. Note: Dosages are not necessarily equivalent. Sources: See template.
Estrogen dosages for breast cancer
Route/form Estrogen Dosage Ref(s)
Oral Estradiol 10 mg 3x/day
AI-resistant: 2 mg 1–3x/day		 [27][28]
[27][29]
Estradiol valerate AI-resistant: 2 mg 1–3x/day [27][29]
Conjugated estrogens 10 mg 3x/day [30][31][32][33]
Ethinylestradiol 0.5–1 mg 3x/day [31][27][34][33]
Diethylstilbestrol 5 mg 3x/day [31][35][36]
Dienestrol 5 mg 3x/day [34][33][36]
Dimestrol 30 mg/day [30][33][36]
Chlorotrianisene 24 mg/day [30][36]
IMTooltip Intramuscular or SC injection Estradiol benzoate 5 mg 2–3x/week [34][37][35][38]
Estradiol dipropionate 5 mg 2–3x/week [34][35][39][38]
Estradiol valerate 30 mg 1x/2 weeks [37]
Polyestradiol phosphate 40–80 mg 1x/4 weeks [40][41]
Estrone 5 mg ≥3x/week [42]
Notes: (1) Only in women who are at least 5 years postmenopausal.[27] (2) Dosages are not necessarily equivalent.
Estrogen dosages for prostate cancer
Route/form Estrogen Dosage
Oral Estradiol 1–2 mg 3x/day
Conjugated estrogens 1.25–2.5 mg 3x/day
Ethinylestradiol 0.15–3 mg/day
Ethinylestradiol sulfonate 1–2 mg 1x/week
Diethylstilbestrol 1–3 mg/day
Dienestrol 5 mg/day
Hexestrol 5 mg/day
Fosfestrol 100–480 mg 1–3x/day
Chlorotrianisene 12–48 mg/day
Quadrosilan 900 mg/day
Estramustine phosphate 140–1400 mg/day
Transdermal patch Estradiol 2–6x 100 μg/day
Scrotal: 1x 100 μg/day
IMTooltip Intramuscular or SC injection Estradiol benzoate 1.66 mg 3x/week
Estradiol dipropionate 5 mg 1x/week
Estradiol valerate 10–40 mg 1x/1–2 weeks
Estradiol undecylate 100 mg 1x/4 weeks
Polyestradiol phosphate Alone: 160–320 mg 1x/4 weeks
With oral EE: 40–80 mg 1x/4 weeks
Estrone 2–4 mg 2–3x/week
IV injection Fosfestrol 300–1200 mg 1–7x/week
Estramustine phosphate 240–450 mg/day
Note: Dosages are not necessarily equivalent. Sources: See template.

Available forms

See also: Estradiol benzoate/hydroxyprogesterone caproate, Estradiol benzoate/progesterone, and Estradiol benzoate/testosterone isobutyrate

Estradiol benzoate is and has been available as an oil solution for intramuscular injection provided as vials and ampoules at concentrations of 0.167, 0.2, 0.33, 1, 1.67, 2, 5, 10, 20, and 25 mg/mL.[43][44][8] It is also available as a microcrystalline aqueous suspension for intramuscular injection under the brand name Agofollin Depot.[45][46][47][24] Sistocyclin was the brand name of a product containing 10 mg microcrystalline estradiol benzoate and 200 mg microcrystalline progesterone in an aqueous suspension.[48][49][50][51] 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.[52][53][54][55]

A vaginal tablet formulation containing 0.125 mg estradiol benzoate and 10 mg monalazone sodium has been marketed under the brand name Malun 25.[56]

Available forms of estradiol[a]
Route Ingredient Form Dose[b] Brand names[c]
Oral Estradiol Tablet 0.1, 0.2, 0.5, 1, 2, 4 mg Estrace, Ovocyclin
Estradiol valerate Tablet 0.5, 1, 2, 4 mg Progynova
Transdermal Estradiol Patch 14, 25, 37.5, 50, 60, 75, 100 µg/d Climara, Vivelle
Gel pump 0.06% (0.52, 0.75 mg/pump) Elestrin, EstroGel
Gel packet 0.1% (0.25, 0.5, 1.0 mg/pk.) DiviGel, Sandrena
Emulsion 0.25% (25 µg/pouch) Estrasorb
Spray 1.53 mg/spray Evamist, Lenzetto
Vaginal Estradiol Tablet 10, 25 µg Vagifem
Cream 0.01% (0.1 mg/gram) Estrace
Insert 4, 10 µg Imvexxy
Ring 2 mg/ring (7.5 µg/d, 3 mon.) Estring
Estradiol acetate Ring 50, 100 µg/d, 3 months Femring
Injection[d] Estradiol Microspheres 1 mg/mL Juvenum E
Estradiol benzoate Oil solution 0.167, 0.2, 0.333, 1, 1.67, 2, 5, 10, 20, 25 mg/mL Progynon-B
Estradiol cypionate Oil solution 1, 3, 5 mg/mL Depo-Estradiol
Estradiol valerate Oil solution 5, 10, 20, 40 mg/mL Progynon Depot
Implant Estradiol Pellet 20, 25, 50, 100 mg, 6 mon. Estradiol Implants
Notes and sources:
  1. ^ This table includes primarily products available as a single-ingredient estradiol preparation—thus excluding compounds with progestogens or other ingredients included. The table furthermore does not include compounded drugs—only commercially produced products. Availability of each product varies by country.
  2. ^ Doses are given per unit (ex: per tablet, per mL).
  3. ^ Other brand names may be manufactured or previously manufactured.
  4. ^ By intramuscular or subcutaneous injection.
Sources: [57][58][59][60][43][44][61][8][62][14][63][64][65][56]

Contraindications

Main article: Estradiol (medication) § Contraindications

Side effects

Main article: Estradiol (medication) § Side effects

The side effects of estradiol benzoate are the same as those of estradiol. Examples of such side effects include breast tenderness and enlargement, nausea, bloating, edema, headache, and melasma.[17]

Overdose

See also: Estradiol (medication) § Overdose

Interactions

See also: Estradiol (medication) § Interactions

Pharmacology

Estradiol, the active form of estradiol benzoate.

Pharmacodynamics

See also: Pharmacodynamics of estradiol

Estradiol benzoate is an estradiol ester, or a prodrug of estradiol.[4][5] As such, it is an estrogen, or an agonist of the estrogen receptors.[4][5] Estradiol benzoate has very low affinity for the ERs, on the order of 100-fold less than that of estradiol.[66] As such, estradiol benzoate is regarded as essentially inactive in terms of estrogenic effect itself, acting solely as a prodrug to estradiol.[5] Estradiol benzoate is of about 38% higher molecular weight than estradiol due to the presence of its C3 benzoate ester.[67][15] Because estradiol benzoate is a prodrug of estradiol, it is considered to be a natural and bioidentical form of estrogen.[4]

Potencies and durations of natural estrogens by intramuscular injection
Estrogen Form Dose (mg) Duration by dose (mg)
EPD CICD
Estradiol Aq. soln. ? – <1 d
Oil soln. 40–60 – 1–2 ≈ 1–2 d
Aq. susp. ? 3.5 0.5–2 ≈ 2–7 d; 3.5 ≈ >5 d
Microsph. ? – 1 ≈ 30 d
Estradiol benzoate Oil soln. 25–35 – 1.66 ≈ 2–3 d; 5 ≈ 3–6 d
Aq. susp. 20 – 10 ≈ 16–21 d
Emulsion ? – 10 ≈ 14–21 d
Estradiol dipropionate Oil soln. 25–30 – 5 ≈ 5–8 d
Estradiol valerate Oil soln. 20–30 5 5 ≈ 7–8 d; 10 ≈ 10–14 d;
40 ≈ 14–21 d; 100 ≈ 21–28 d
Estradiol benz. butyrate Oil soln. ? 10 10 ≈ 21 d
Estradiol cypionate Oil soln. 20–30 – 5 ≈ 11–14 d
Aq. susp. ? 5 5 ≈ 14–24 d
Estradiol enanthate Oil soln. ? 5–10 10 ≈ 20–30 d
Estradiol dienanthate Oil soln. ? – 7.5 ≈ >40 d
Estradiol undecylate Oil soln. ? – 10–20 ≈ 40–60 d;
25–50 ≈ 60–120 d
Polyestradiol phosphate Aq. soln. 40–60 – 40 ≈ 30 d; 80 ≈ 60 d;
160 ≈ 120 d
Estrone Oil soln. ? – 1–2 ≈ 2–3 d
Aq. susp. ? – 0.1–2 ≈ 2–7 d
Estriol Oil soln. ? – 1–2 ≈ 1–4 d
Polyestriol phosphate Aq. soln. ? – 50 ≈ 30 d; 80 ≈ 60 d
Notes and sources
Notes: All aqueous suspensions are of microcrystalline particle size. Estradiol production during the menstrual cycle is 30–640 µg/d (6.4–8.6 mg total per month or cycle). The vaginal epithelium maturation dosage of estradiol benzoate or estradiol valerate has been reported as 5 to 7 mg/week. An effective ovulation-inhibiting dose of estradiol undecylate is 20–30 mg/month. Sources: See template.

Pharmacokinetics

See also: Pharmacokinetics of estradiol

Following administration, estradiol benzoate acts as a prodrug of estradiol via cleavage by esterases into estradiol and the natural fatty acid benzoic acid.[5] This cleavage occurs not only in the liver, but also in the blood and in tissues.[4][5] Esters of estradiol like estradiol benzoate are readily hydrolyzed to estradiol, but have an extended duration when administered in via intramuscular or subcutaneous injection due to a depot effect afforded by their fatty acid ester moiety and consequent high lipophilicity.[5] A long-lasting local tissue depot is formed by the injection that slowly releases estradiol benzoate into the circulation.[5]

Intramuscular injection of 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.[7][8] 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).[68] 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).[6]

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.[9] 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.[9] This is because estradiol benzoate has a shorter and less bulky fatty acid chain, and in relation to this, is comparatively less lipophilic.[5] 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.[5]

Pharmacokinetics of three estradiol esters by intramuscular injection
Estrogen Dose Cmax Tmax Duration
Estradiol benzoate 5 mg E2: 940 pg/mL
E1: 343 pg/mL		 E2: 1.8 days
E1: 2.4 days		 4–5 days
Estradiol valerate 5 mg E2: 667 pg/mL
E1: 324 pg/mL		 E2: 2.2 days
E1: 2.7 days		 7–8 days
Estradiol cypionate 5 mg E2: 338 pg/mL
E1: 145 pg/mL		 E2: 3.9 days
E1: 5.1 days		 11 days
Notes: All via i.m. injection of oil solution. Determinations via radioimmunoassay with chromatographic separation. Sources: See template.

Template:Hormone levels with intramuscular estradiol benzoate

Intramuscular injection of crystalline aqueous suspension

Microcrystalline estradiol benzoate in aqueous suspension (brand names Agofollin Depot alone and Follivirin in combination with testosterone isobutyrate)[46][52] has been found to have a longer duration of action than amorphous estradiol benzoate in oil solution when administered via intramuscular injection.[69][70][71][72][73][74][75][76]: 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 21 to 39 days.[76][70] Its duration also surpasses that of estradiol valerate and estradiol cypionate.[76] The duration of microcrystalline aqueous suspensions administered by intramuscular injection is dependent both on concentration and on crystal size.[77][78][74][79]

Other routes

In contrast to the intramuscular route, the duration of estradiol benzoate is not prolonged if it is administered directly into the circulation via intravenous injection.[80] Similarly to estradiol valerate and estradiol acetate, estradiol benzoate is also active with oral and sublingual administration.[7][76]: 310  However, it is not marketed for use by these routes.[43] Subcutaneous pellet implantation of estradiol benzoate has been studied, but likewise no estradiol benzoate implants have been marketed.[81]

Chemistry

See also: Estrogen ester and List of estrogen esters § Estradiol esters

Estradiol benzoate is a synthetic estrane steroid and the C3 benzoate (benzenecarboxylate) ester of estradiol.[15][67][82] It is also known as estradiol 3-benzoate or as estra-1,3,5(10)-triene-3,17β-diol 3-benzoate.[15][67][82] 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.

Structural properties of selected estradiol esters
Estrogen Structure Ester(s) Relative
mol. weight		 Relative
E2 contentb		 log Pc
Position(s) Moiet(ies) Type Lengtha
Estradiol
– – – – 1.00 1.00 4.0
Estradiol acetate
C3 Ethanoic acid Straight-chain fatty acid 2 1.15 0.87 4.2
Estradiol benzoate
C3 Benzoic acid Aromatic fatty acid – (~4–5) 1.38 0.72 4.7
Estradiol dipropionate
C3, C17β Propanoic acid (×2) Straight-chain fatty acid 3 (×2) 1.41 0.71 4.9
Estradiol valerate
C17β Pentanoic acid Straight-chain fatty acid 5 1.31 0.76 5.6–6.3
Estradiol benzoate butyrate
C3, C17β Benzoic acid, butyric acid Mixed fatty acid – (~6, 2) 1.64 0.61 6.3
Estradiol cypionate
C17β Cyclopentylpropanoic acid Cyclic fatty acid – (~6) 1.46 0.69 6.9
Estradiol enanthate
C17β Heptanoic acid Straight-chain fatty acid 7 1.41 0.71 6.7–7.3
Estradiol dienanthate
C3, C17β Heptanoic acid (×2) Straight-chain fatty acid 7 (×2) 1.82 0.55 8.1–10.4
Estradiol undecylate
C17β Undecanoic acid Straight-chain fatty acid 11 1.62 0.62 9.2–9.8
Estradiol stearate
C17β Octadecanoic acid Straight-chain fatty acid 18 1.98 0.51 12.2–12.4
Estradiol distearate
C3, C17β Octadecanoic acid (×2) Straight-chain fatty acid 18 (×2) 2.96 0.34 20.2
Estradiol sulfate
C3 Sulfuric acid Water-soluble conjugate – 1.29 0.77 0.3–3.8
Estradiol glucuronide
C17β Glucuronic acid Water-soluble conjugate – 1.65 0.61 2.1–2.7
Estramustine phosphated
C3, C17β Normustine, phosphoric acid Water-soluble conjugate – 1.91 0.52 2.9–5.0
Polyestradiol phosphatee
C3–C17β Phosphoric acid Water-soluble conjugate – 1.23f 0.81f 2.9g
Footnotes: a = Length of ester in carbon atoms for straight-chain fatty acids or approximate length of ester in carbon atoms for aromatic or cyclic fatty acids. b = Relative estradiol content by weight (i.e., relative estrogenic exposure). c = Experimental or predicted octanol/water partition coefficient (i.e., lipophilicity/hydrophobicity). Retrieved from PubChem, ChemSpider, and DrugBank. d = Also known as estradiol normustine phosphate. e = Polymer of estradiol phosphate (~13 repeat units). f = Relative molecular weight or estradiol content per repeat unit. g = log P of repeat unit (i.e., estradiol phosphate). Sources: See individual articles.

History

Estradiol benzoate was one of the first estrogens to be developed and marketed.[19][20] In 1931, Adolf Butenandt found that the benzoic acid ester of estrone had a prolonged duration of action.[11][83] Schwenk and Hildebrant discovered estradiol via reduction of estrone in 1933, and they proceeded to synthesize estradiol benzoate from estradiol the same year.[4][18] Estradiol benzoate was patented by Schering in 1933, and then by Schering-Kahlbaum in 1936 in an oil preparation for injectable use, and was introduced later that year in 1936 under the brand name Progynon-B.[19][20][43] Following its introduction, estradiol benzoate, along with estradiol dipropionate, were the most widely used esters of estradiol for many years.[21] 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.[9]

Society and culture

Generic names

Estradiol benzoate is the generic name of the drug and its INNTooltip International Nonproprietary Name, BANMTooltip British Approved Name, and JANTooltip Japanese Accepted Name, while oestradiol benzoate was formerly its BANMTooltip British Approved Name.[14][15][67][82]

Brand names

The major brand name of estradiol benzoate is Progynon-B.[15][67][82] It has also been sold under a variety of other brand names including Agofollin Depot, Benovocyclin, Benzofoline, Dimenformon, Ovocylin Benzoate, and Ovocyclin M, among many others.[15][67][82]

Availability

Estradiol benzoate is available in Europe and in other parts of the world.[15][43] It was previously available for medical use in the United States, but is no longer marketed in this country.[15][23][43][22] 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).[23][84][85] Outside of the United States, estradiol benzoate is also marketed in combination with progesterone for use as an intramuscular injection.[14][86]

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.[46][52][14]

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.[87]

See also

References

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  46. ^ a b c https://web.archive.org/web/20190519104654/http://www.sukl.cz/download/pil/PI16221.pdf
  47. ^ Marek Josef a kolektiv (1 January 2010). Farmakoterapie vnitřních nemocí - 4. zcela přepracované a doplněné vydání. Grada Publishing a.s. pp. 377–. ISBN 978-80-247-2639-7. 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.
  48. ^ Ufer, Joachim (1968). "Die therapeutische Anwendung der Gestagene beim Menschen" [Therapeutic Use of Progestagens in Humans]. Die Gestagene [Progestogens]. Springer-Verlag. pp. 1026–1124. doi:10.1007/978-3-642-99941-3_7. ISBN 978-3-642-99941-3. 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.
  49. ^ Ciba Symposium. Ciba. 1957. 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.
  50. ^ Ciba Zeitschrift. 1957. p. 3001. 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 [...]
  51. ^ Willibald Pschyrembel (15 June 2011). Praktische Gynäkologie: für Studierende und Ärzte. Walter de Gruyter. pp. 601–. ISBN 978-3-11-150424-7.
  52. ^ a b c https://web.archive.org/web/20190520031642/http://www.sukl.cz/download/pil/PI15789.pdf
  53. ^ Kubíková, Drahomíra (2014). "Menopauzální symptomy a hormonální substituční terapie" [Menopausal symptoms and hormone replacement therapy]. Praktické Lékárenství (in Czech). 10 (2): 68–73. ISSN 1801-2434.
  54. ^ Marek Josef; a kolektiv (14 May 2010). Farmakoterapie vnitřních nemocí: 4., zcela přepracované a doplněné vydání. Grada Publishing a.s. pp. 380–. ISBN 978-80-247-9524-9. 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.
  55. ^ Ciba Symposium: 1953/57:Index. Ciba. 1953. p. 197. 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.
  56. ^ a b Freimut A. Leidenberger (17 April 2013). Klinische Endokrinologie für Frauenärzte. Springer-Verlag. pp. 527–. ISBN 978-3-662-08110-5. Cite error: The named reference "Leidenberger2013" was defined multiple times with different content (see the help page).
  57. ^ "Drugs@FDA: FDA Approved Drug Products". United States Food and Drug Administration. Retrieved 26 July 2018.
  58. ^ Lobo RA (5 June 2007). Treatment of the Postmenopausal Woman: Basic and Clinical Aspects. Academic Press. pp. 177, 217–226, 770–771. ISBN 978-0-08-055309-2.
  59. ^ Falcone T, Hurd WW (14 June 2017). Clinical Reproductive Medicine and Surgery: A Practical Guide. Springer. pp. 179–. ISBN 978-3-319-52210-4.
  60. ^ Becker KL (2001). Principles and Practice of Endocrinology and Metabolism. Lippincott Williams & Wilkins. pp. 889, 1059–1060, 2153. ISBN 978-0-7817-1750-2.
  61. ^ Krishna UR, Sheriar NK (1996). Menopause. Orient Blackswan. pp. 70–. ISBN 978-81-250-0910-8.
  62. ^ "AERODIOL (Oestradiol hemihydrate 150 micrograms/actuation)" (PDF). Servier Laboratories (Aust) Pty Ltd.
  63. ^ Sahin FK, Koken G, Cosar E, Arioz DT, Degirmenci B, Albayrak R, Acar M (2008). "Effect of Aerodiol administration on ocular arteries in postmenopausal women". Gynecol. Endocrinol. 24 (4): 173–7. doi:10.1080/09513590701807431. PMID 18382901. 300 μg 17β-estradiol (Aerodiol®; Servier, Chambrayles-Tours, France) was administered via the nasal route by a gynecologist. This product is unavailable after March 31, 2007 because its manufacturing and marketing are being discontinued.
  64. ^ Plouffe Jr L, Ravnikar VA, Speroff L, Watts NB (6 December 2012). Comprehensive Management of Menopause. Springer Science & Business Media. pp. 271–. ISBN 978-1-4612-4330-4.
  65. ^ Hospital Formulary and Compendium of Useful Information. University of California Press. 1952. pp. 49–. GGKEY:2UAAZRZ5LN0.
  66. ^ Bovee TF, Helsdingen RJ, Rietjens IM, Keijer J, Hoogenboom RL (2004). "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". J. Steroid Biochem. Mol. Biol. 91 (3): 99–109. doi:10.1016/j.jsbmb.2004.03.118. PMID 15276617.
  67. ^ a b c d e f J. Elks (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 897–. ISBN 978-1-4757-2085-3.
  68. ^ Vizziello G, D'Amato G, Trentadue R, Fanizza G (1993). "[Estradiol benzoate test in the study of pituitary block induced by triptorelin]". Minerva Ginecol (in Italian). 45 (4): 185–9. PMID 8506068.
  69. ^ von Wattenwyl, H (1944), "Über eine neue Anwendungsart oestrogener Substanzen" [A new type of application of estrogenic substances], Schweiz. med. Wchnschr. (in German), 74: 159–161
  70. ^ a b Toppozada, Hussein K. (1950). "Oestrogenic Therapy with Prolonged Action". Obstetrical & Gynecological Survey. 5 (4): 531. doi:10.1097/00006254-195008000-00021. ISSN 0029-7828.
  71. ^ Ferin J (January 1952). "Relative duration of action of natural and synthetic estrogens administered parenterally in women with estrogen deficiency". J. Clin. Endocrinol. Metab. 12 (1): 28–35. doi:10.1210/jcem-12-1-28. PMID 14907837.
  72. ^ Ober, K. G.; Klein, Irmhild; Weber, Marianne (1954). "Zur Frage einer Progesteronbehandlung: Experimentelle Untersuchungen mit dem Hooker-Forbes-Test und klinische Beobachtungen mit Kristallsuspensionen" [On the question of progesterone treatment: experimental studies with the Hooker-Forbes test and clinical observations with crystal suspensions]. Archiv für Gynäkologie. 184 (5): 543–616. doi:10.1007/BF00976991. ISSN 0003-9128.
  73. ^ Field-Richards S (April 1955). "A preliminary series of cases of uterine hypoplasia treated by local injection of an oestrogenic emulsion". J Obstet Gynaecol Br Emp. 62 (2): 205–13. doi:10.1111/j.1471-0528.1955.tb14121.x. PMID 14368390. 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.
  74. ^ a b Lens J, Overbeek GA, Polderman J (1949). "The effect of sex hormones in some organic solvents; emulsified in water". Acta Endocrinol. 2 (4): 396–404. doi:10.1530/acta.0.0020396. PMID 18140399.
  75. ^ Ralph I. Dorfman (5 December 2016). Steroidal Activity in Experimental Animals and Man. Elsevier Science. pp. 40–. ISBN 978-1-4832-7299-3. 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.
  76. ^ a b c d Horský, Jan; Presl, Jiří (1981). "Hormonal Treatment of Disorders of the Menstrual Cycle". In J. Horsky; J. Presl (eds.). Ovarian Function and its Disorders: Diagnosis and Therapy. Springer Science & Business Media. pp. 309–332. doi:10.1007/978-94-009-8195-9_11. ISBN 978-94-009-8195-9.
  77. ^ Shearman RP (June 1975). "The development of depot contraceptives". J. Steroid Biochem. 6 (6): 899–902. doi:10.1016/0022-4731(75)90323-4. PMID 1177432.
  78. ^ Edkins, Robert Patrick (1959). "The Modification of the Duration of Drug Action". Journal of Pharmacy and Pharmacology. 11 (S1): 54T–66T. doi:10.1111/j.2042-7158.1959.tb10412.x. ISSN 0022-3573.
  79. ^ Herrmann, U. (1958). "Abhängigkeit der durch Oestrogen- und Progesteron-Kristalle induzierten Abbruchblutung von der Korngröße". Gynecologic and Obstetric Investigation. 146 (4): 318–323. doi:10.1159/000306607. ISSN 1423-002X.
  80. ^ Parkes AS (February 1938). "Effective Absorption of Hormones". Br Med J. 1 (4024): 371–3. doi:10.1136/bmj.1.4024.371. PMC 2085798. PMID 20781252.
  81. ^ Bishop PM, Folley SJ (August 1951). "Absorption of hormone implants in man". Lancet. 2 (6676): 229–32. doi:10.1016/S0140-6736(51)93237-0. PMID 14862159.
  82. ^ a b c d e A. D. Roberts (1991). Dictionary of Steroids: Chemical Data, Structures, and Bibliographies. CRC Press. p. 415. ISBN 978-0-412-27060-4. Retrieved 20 May 2012.
  83. ^ Butenandt, A.; Hildebrandt, F. (1931). "Über ein zweites Hormonkrystallisat aus Schwangerenharn und seine physiologischen und chemischen Beziehungen zum krystallisierten Follikelhormon. [Untersuchungen über das weibliche Sexualhormon, 6. Mitteilung.]". Hoppe-Seyler's Zeitschrift für Physiologische Chemie. 199 (4–6): 243–265. doi:10.1515/bchm2.1931.199.4-6.243. ISSN 0018-4888.
  84. ^ http://www.fda.gov/downloads/AnimalVeterinary/Products/ApprovedAnimalDrugProducts/FOIADrugSummaries/ucm116143.pdf
  85. ^ http://www.fda.gov/downloads/AnimalVeterinary/Products/ApprovedAnimalDrugProducts/FOIADrugSummaries/UCM338208.pdf
  86. ^ "Progesterone". Drugs.com. Retrieved 2018-07-31.
  87. ^ Goldsmith, A., & Toppozada, M. (1983). Long-acting contraception. pp. 94-95 https://www.popline.org/node/423289


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