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Estradiol benzoate

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Estradiol benzoate
Clinical data
Pronunciation/ˌɛstrəˈdaɪoʊl ˈbɛnzoʊeɪt/ ES-trə-DYE-ohl BEN-zoh-ayt
Trade namesAgofollin, Benovocyclin, Benzofoline, Dimenformon, Progynon-B, many others
Other names17β-Estradiol-3-benzoate; NSC-9566; Benzhormovarine, Difollisterol, Follicormon, Follidimyl, Follidrinbensoat, Oestro-Vitis, Oestroform
Routes of
administration		Intramuscular injection
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
BioavailabilityIntramuscular: 100%[citation needed]
MetabolismCleavage via esterases in the liver, blood, and tissues[1]
MetabolitesEstradiol, benzoic acid,[1] and metabolites of estradiol
Duration of action4–5 days (5 mg i.m.)[2]
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)
  • O=C(Oc1cc3c(cc1)[C@H]2CC[C@@]4([C@@H](O)CC[C@H]4[C@@H]2CC3)C)c5ccccc5
  • 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, E2B) (INN) (brand name Progynon-B, many others), or oestradiol benzoate (BAN), is a synthetic, steroidal estrogen and an estrogen ester – specifically, the 3-benzoate ester of estradiol – which is marketed in Europe and elsewhere throughout the world.[3][4][5] It acts as a prodrug of estradiol, and hence, is considered to be a natural, bioidentical form of estrogen.[1] Estradiol benzoate was introduced in 1936 and was one of the first forms of estrogen to be marketed.[6][7] Along with estradiol dipropionate, it was one of the most widely used estradiol esters prior to the 1950s.[8] However, estradiol benzoate is now little used, having largely been superseded by longer-acting esters of estradiol like estradiol valerate and estradiol cypionate that require less frequent administration.[2]

Medical uses

Main article: Estradiol § Medical uses

The medical uses of estradiol benzoate are the same as those of estradiol and other estrogens. An example of an indication for the drug is hormone replacement therapy for menopausal symptoms or hypoestrogenism.

Side effects

Main article: Estradiol § Adverse 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.[9]

Pharmacology

Esters of estradiol like estradiol benzoate are readily hydrolyzed prodrugs of estradiol, but have an extended duration when administered in oil via intramuscular injection due to a depot effect afforded by their fatty acid ester moiety.[10] As prodrugs of estradiol, estradiol benzoate and other estradiol esters are estrogens.[10]

Pharmacokinetics

Upon ingestion, regardless of the route of administration, estradiol benzoate behaves as a prodrug via cleavage by esterases into estradiol and the natural fatty acid benzoic acid.[10] This cleavage occurs not only in the liver, but also in the blood and in tissues.[10][1]

Intramuscular administration

Comparison of estradiol esters (5 mg intramuscular)[2]
Estrogen Peak levels Time to peak Duration
Estradiol benzoate E2: 940 pg/mL
E1: 343 pg/mL		 E2: 1.8 days
E1: 2.4 days		 4–5 days
Estradiol cypionate E2: 338 pg/mL
E1: 145 pg/mL		 E2: 3.9 days
E1: 5.1 days		 11 days
Estradiol valerate E2: 667 pg/mL
E1: 324 pg/mL		 E2: 2.2 days
E1: 2.7 days		 7–8 days

A single dose of 2.5 mg estradiol benzoate by intramuscular injection was found to produce plasma estradiol levels of >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).[11]

A single intramuscular injection of 5 mg estradiol benzoate 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 (see table).[2] Compared to two other commonly used estradiol esters (which were also assessed in the study), estradiol benzoate had the shortest duration, at approximately 4 to 5 days, whereas estradiol valerate and estradiol cypionate were found to last for 7–8 days and 11 days, respectively.[2] This is because estradiol benzoate has a shorter and less bulky fatty acid chain and in relation to this is comparatively less lipophilic.[10] For a given estradiol ester, the shorter or less extensive 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 the peak/maximal levels are (and hence more spike-like).[10]

Chemistry

See also: Estrogen ester

Estradiol benzoate is an estrane (C18) steroid and the C3 benzoate (or phenylcarboxylate) fatty acid ester of estradiol. It is also known as estra-1,3,5(10)-triene-3,17β-diol 3-benzoate. Two related estradiol esters are estradiol dipropionate, the 3,17β-dipropionate ester of estradiol, and estradiol acetate, the 3-acetate ester of estradiol.

History

Estradiol benzoate was one of the first estrogens to be developed and marketed.[6][7] In 1931, Adolf Butenandt found that the benzoic acid ester of estrone had a prolonged duration of action.[12][13] Schwenk and Hildebrant discovered estradiol via reduction of estrone in 1933, and they proceeded to synthesize estradiol benzoate from estradiol the same year.[14][15] Estradiol benzoate was patented by Schering-Kahlbaum in 1936 in an oil preparation for injectable use and was introduced later that year under the brand name Progynon-B.[6][7] Following its introduction, estradiol benzoate, along with estradiol dipropionate, were the most widely used esters of estradiol for many years.[8] However, estradiol valerate and estradiol cypionate, which are esters with improved pharmacokinetics which require less frequent administration, were developed and introduced in the 1950s, and have since largely superseded estradiol benzoate in clinical practice.[2]

Society and culture

Availability

Estradiol benzoate is not approved by the FDATooltip Food and Drug Administration for use in humans in the United States.[16] However, it is approved and marketed in this country for veterinary use as a subdermal implant both alone and in combination with the anabolic-androgenic steroid trenbolone acetate (brand names Celerin and Synovex, respectively).[16][17][18]

References

  1. ^ a b c d Kuhnz, W.; Blode, H.; Zimmermann, H. (1993). "Pharmacokinetics of Exogenous Natural and Synthetic Estrogens and Antiestrogens". 135 / 2: 261–322. doi:10.1007/978-3-642-60107-1_15. ISSN 0171-2004. {{cite journal}}: Cite journal requires |journal= (help)
  2. ^ a b c d e f Oriowo MA, Landgren BM, Stenström B, Diczfalusy E (April 1980). "A comparison of the pharmacokinetic properties of three estradiol esters". Contraception. 21 (4): 415–24. doi:10.1016/s0010-7824(80)80018-7. PMID 7389356.
  3. ^ 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.
  4. ^ 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.
  5. ^ Index Nominum 2000: International Drug Directory. Taylor & Francis US. 2000. p. 406. ISBN 978-3-88763-075-1.
  6. ^ a b c Enrique Raviña; Hugo Kubinyi (16 May 2011). The Evolution of Drug Discovery: From Traditional Medicines to Modern Drugs. John Wiley & Sons. p. 175. ISBN 978-3-527-32669-3. Retrieved 20 May 2012.
  7. ^ a b c Folley SJ (December 1936). "The effect of oestrogenic hormones on lactation and on the phosphatase of the blood and milk of the lactating cow" (PDF). The Biochemical Journal. 30 (12): 2262–72. PMC 1263335. PMID 16746289.
  8. ^ a b SCHWARTZ MM, SOULE SD (1955). "Estradiol 17-beta-cyclopentylpropionate, a longacting estrogen". Am. J. Obstet. Gynecol. 70 (1): 44–50. PMID 14388061.
  9. ^ Amit K. Ghosh (23 September 2010). Mayo Clinic Internal Medicine Board Review. OUP USA. pp. 222–. ISBN 978-0-19-975569-1.
  10. ^ a b c d e f Kuhl H (2005). "Pharmacology of estrogens and progestogens: influence of different routes of administration". Climacteric. 8 Suppl 1: 3–63. doi:10.1080/13697130500148875. PMID 16112947.
  11. ^ 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.
  12. ^ A. Labhart (6 December 2012). Clinical Endocrinology: Theory and Practice. Springer Science & Business Media. pp. 512–. ISBN 978-3-642-96158-8.
  13. ^ 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.
  14. ^ Michael Oettel; Ekkehard Schillinger (6 December 2012). Estrogens and Antiestrogens I: Physiology and Mechanisms of Action of Estrogens and Antiestrogens. Springer Science & Business Media. pp. 8–. ISBN 978-3-642-58616-3.
  15. ^ Miescher K, Scholz C, Tschopp E (1938). "The activation of female sex hormones: Mono-esters of alpha-oestradiol". Biochem. J. 32 (8): 1273–80. PMC 1264184. PMID 16746750.
  16. ^ a b Richard Witherspoon (1 June 1994). Presidents List of Articles Which May Be Designated Or Modified As Eligible Articles for Purposes of the U.S. Generalized System of Preferences. DIANE Publishing. pp. 64–. ISBN 978-0-7881-1433-5.
  17. ^ http://www.fda.gov/downloads/AnimalVeterinary/Products/ApprovedAnimalDrugProducts/FOIADrugSummaries/ucm116143.pdf
  18. ^ http://www.fda.gov/downloads/AnimalVeterinary/Products/ApprovedAnimalDrugProducts/FOIADrugSummaries/UCM338208.pdf
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