Estradiol benzoate butyrate
{{Short description|Chemical compound}}
{{Distinguish|Estradiol benzoate|Estradiol enantate}}
{{Drugbox
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| IUPAC_name = [(8R,9S,13S,14S,17S)-17-butanoyloxy-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-3-yl] benzoate
| image = Estradiol butyrate benzoate.svg
| width = 250px
| image2 = Estradiol benzoate butyrate molecule ball.png
| width2 = 250px
| tradename = Neolutin N, Redimen, Soluna, Unijab (all combinations)
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| routes_of_administration = Intramuscular injection
| class = Estrogen; Estrogen ester
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| CAS_number_Ref =
| CAS_number = 63042-18-2
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| PubChem = 67081
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| ChemSpiderID_Ref =
| ChemSpiderID = 60431
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = ZE4IGI4UMH
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| synonyms = EBB; Estradiol 3-benzoate 17β-n-butyrate; Estra-1,3,5(10)-triene-3,17β-diol 3-benzoate 17β-n-butyrate
| C=29 | H=34 | O=4
| SMILES = CCCC(=O)O[C@H]1CC[C@@H]2[C@@]1(CC[C@H]3[C@H]2CCC4=C3C=CC(=C4)OC(=O)C5=CC=CC=C5)C
| StdInChI_Ref =
| StdInChI = 1S/C29H34O4/c1-3-7-27(30)33-26-15-14-25-24-12-10-20-18-21(32-28(31)19-8-5-4-6-9-19)11-13-22(20)23(24)16-17-29(25,26)2/h4-6,8-9,11,13,18,23-26H,3,7,10,12,14-17H2,1-2H3/t23-,24-,25+,26+,29+/m1/s1
| StdInChIKey_Ref =
| StdInChIKey = MKYFGNOOEKZNPW-ZRJUGLEFSA-N
}}
Estradiol benzoate butyrate (EBB), sold under the brand names Neolutin N, Redimen, Soluna, and Unijab and formerly known under the developmental code name Unimens, is an estrogen medication which is used in hormonal birth control for women.{{cite journal | vauthors = Toppozada M | title = The clinical use of monthly injectable contraceptive preparations | journal = Obstetrical & Gynecological Survey | volume = 32 | issue = 6 | pages = 335–347 | date = June 1977 | pmid = 865726 | doi = 10.1097/00006254-197706000-00001 }}{{cite book | vauthors = Toppozada MK | chapter = Monthly Injectable Contraceptives | pages = 93–103 | editor1 = Alfredo Goldsmith | editor2 = Mokhtar Toppozada | title = Long-Acting Contraception | year = 1983 | oclc = 35018604 | url = https://scholar.google.com/scholar?cluster=14664537528797672080}} It is formulated in combination with dihydroxyprogesterone acetophenide (DHPA; algestone acetophenide), a progestin, and is used specifically as a combined injectable contraceptive. EBB is not available for medical use alone.{{cite web|url=https://www.drugs.com/international/estradiol.html|title = Estradiol: Uses, Dosage & Side Effects}} The medication, in combination with DHPA, is given by injection into muscle once a month.
Side effects of EBB include breast tenderness, breast enlargement, nausea, headache, and fluid retention.{{cite book| vauthors = Ghosh AK |title=Mayo Clinic Internal Medicine Board Review|url=https://books.google.com/books?id=LS65jBzoD40C&pg=PA222|date=23 September 2010|publisher=OUP USA|isbn=978-0-19-975569-1|pages=222–}} EBB is an estrogen and hence is an agonist of the estrogen receptor, the biological target of estrogens like estradiol.{{cite journal | vauthors = Kuhl H | title = Pharmacology of estrogens and progestogens: influence of different routes of administration | journal = Climacteric | volume = 8 | issue = Suppl 1 | pages = 3–63 | date = August 2005 | pmid = 16112947 | doi = 10.1080/13697130500148875 | s2cid = 24616324 }} It is an estrogen ester and a prodrug of estradiol in the body. Because of this, it is considered to be a natural and bioidentical form of estrogen.{{cite book| vauthors = Kuhnz W, Blode H, Zimmermann H | chapter = Pharmacokinetics of Exogenous Natural and Synthetic Estrogens and Antiestrogens | series = Handbook of Experimental Pharmacology | veditors = Oettel M, Schillinger E |title=Estrogens and Antiestrogens II: Pharmacology and Clinical Application of Estrogens and Antiestrogen| chapter-url=https://books.google.com/books?id=wBvyCAAAQBAJ&pg=PA261|date=6 December 2012| volume = 135 / 2 | pages = 261–322 |publisher=Springer Science & Business Media|isbn=978-3-642-60107-1 | doi = 10.1007/978-3-642-60107-1_15 |quote=Natural estrogens considered here include: [...] Esters of 17β-estradiol, such as estradiol valerate, estradiol benzoate and estradiol cypionate. Esterification aims at either better absorption after oral administration or a sustained release from the depot after intramuscular administration. During absorption, the esters are cleaved by endogenous esterases and the pharmacologically active 17β-estradiol is released; therefore, the esters are considered as natural estrogens.}}
EBB was first described in 1938. It was developed for use as a form of birth control in the 1970s and was introduced for medical use for this indication by the 1980s. The medication is used in combination with DHPA as a combined injectable contraceptive in Peru and Singapore.
Medical uses
EBB is used in combination with DHPA as a once-a-month combined injectable contraceptive to prevent pregnancy in women.{{cite book| vauthors = Hafez ES |title=Human reproduction: conception and contraception|url=https://books.google.com/books?id=EblsAAAAMAAJ|year=1980|publisher=Harper and Row|isbn=978-0-06-141066-6}}
=Available forms=
{{See also|Estradiol benzoate butyrate/dihydroxyprogesterone acetophenide}}
The combination of EBB and DHPA contains 10 mg estradiol benzoate butyrate (EBB), an estrogen, and 150 mg algestone acetophenide (dihydroxyprogesterone acetophenide; DHPA), a progestin.{{cite book|author1=IARC Working Group on the Evaluation of Carcinogenic Risks to Humans|author2=World Health Organization|author3=International Agency for Research on Cancer|title=Combined Estrogen-progestogen Contraceptives and Combined Estrogen-progestogen Menopausal Therapy|url=https://books.google.com/books?id=aGDU5xibtNgC&pg=PA433|year=2007|publisher=World Health Organization|isbn=978-92-832-1291-1|pages=433, 467}}{{cite book|author1=IARC Working Group on the Evaluation of Carcinogenic Risks to Humans|author2=International Agency for Research on Cancer|title=Hormonal Contraception and Post-menopausal Hormonal Therapy|date=1 January 1999|publisher=IARC|isbn=978-92-832-1272-0|page=65|url=https://monographs.iarc.fr/wp-content/uploads/2018/06/mono72.pdf|access-date=17 November 2019|archive-date=28 August 2021|archive-url=https://web.archive.org/web/20210828080855/https://monographs.iarc.who.int/wp-content/uploads/2018/06/mono72.pdf|url-status=dead}}
Side effects
The combination of EBB and DHPA is said to be associated with poor control of menstrual bleeding when used as a once-a-month combined injectable contraceptive.{{cite journal | vauthors = Toppozada MK | title = Existing once-a-month combined injectable contraceptives | journal = Contraception | volume = 49 | issue = 4 | pages = 293–301 | date = April 1994 | pmid = 8013216 | doi = 10.1016/0010-7824(94)90029-9 }}
Pharmacology
File:Estradiol.svg, the active form of EBB.]]
=Pharmacodynamics=
{{See also|Pharmacodynamics of estradiol}}
EBB is an estradiol ester, or a prodrug of estradiol. As such, it is an estrogen, or an agonist of the estrogen receptors. EBB is of about 64% higher molecular weight than estradiol due to the presence of its C3 benzoate and C17β butyrate esters. Because EBB is a prodrug of estradiol, it is considered to be a natural and bioidentical form of estrogen.
The estrogenic potency of oral ethinylestradiol is approximately 30-fold higher than that of parenteral EBB. In accordance, 50 μg/day oral ethinylestradiol has been reported to be about 3 times stronger in estrogenic effect than once-a-month injections of 10 mg EBB.
{{Parenteral potencies and durations of steroidal estrogens}}
=Pharmacokinetics=
{{See also|Pharmacokinetics of estradiol}}
A single 10 mg intramuscular injection of EBB has a duration of approximately 3 weeks.{{cite book| vauthors = Emmens CW, Martin L | chapter = Estrogens | veditors = Dorfman RI |title=Steroidal Activity in Experimental Animals and Man| chapter-url = https://books.google.com/books?id=BbLfBAAAQBAJ&pg=PA36|date=5 December 2016|publisher=Elsevier Science|isbn=978-1-4832-7299-3|pages=36–}} Its duration is shorter than that of estradiol enantate. A preliminary study of the duration of EBB relative to other estradiol esters was conducted in 1952.{{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 }}
Chemistry
{{See also|Estrogen ester|List of estrogen esters#Estradiol esters}}
EBB is a synthetic estrane steroid and the C3 benzoate (benzenecarboxylate) and C17β butyrate (butanoate) diester of estradiol.{{cite book| vauthors = Josephy E, Radt F |title=Elsevier's Encyclopaedia of Organic Chemistry: Tetracyclic and higher-cyclic compounds|url=https://books.google.com/books?id=GP8hAQAAMAAJ|year=1946|publisher=Elsevier|pages=99,680}} It is also known as estradiol 3-benzoate 17β-n-butyrate or as estra-1,3,5(10)-triene-3,17β-diol 3-benzoate 17β-n-butyrate.
The experimental octanol/water partition coefficient (logP) of EBB is 6.3.{{cite web|url=http://www.chemspider.com/Chemical-Structure.60431.html|title = Β-Estradiol-3-benzoate 17-N-butyrate | C29H34O4 | ChemSpider}}
{{Structural properties of selected estradiol esters}}
History
EBB, along with a variety of other estradiol esters, was first described in 1938 by Karl Miescher and colleagues of Ciba in Basel, Switzerland.{{cite journal | vauthors = Miescher K, Scholz C, Tschopp E | title = The activation of female sex hormones: alpha-Oestradiol and its di-esters | journal = The Biochemical Journal | volume = 32 | issue = 4 | pages = 725–732 | date = April 1938 | pmid = 16746680 | pmc = 1264097 | doi = 10.1042/bj0320725 }}{{cite journal | vauthors = Korenchevsky V, Burbank R, Hall K | title = The action of the dipropionate and benzoate-butyrate of oestradiol on ovariectomized rats | journal = The Biochemical Journal | volume = 33 | issue = 3 | pages = 366–371 | date = March 1939 | pmid = 16746921 | pmc = 1264384 | doi = 10.1042/bj0330366 }}{{cite book| vauthors = Lockyer NS |title=Nature|url=https://books.google.com/books?id=xLQiAQAAMAAJ|year=1938|publisher=Macmillan Journals Limited|page=292|quote=The oestradiol benzoate butyrate and dipropionate were supplied by Dr. Miescher (of Ciba Ltd.) who recently described their prolonged effects in rats8.}}{{cite book|title=American journal of cancer|url=https://books.google.com/books?id=_FkXAQAAMAAJ|year=1940|quote=Note: Our thanks are due to Doctor Karl Miescher of Messrs. Ciba in Basel, Switzerland, for a liberal supply of different esters of estradiol used in this work.}} It was developed in combination with DHPA as a combined injectable contraceptive in the 1970s.{{cite journal | vauthors = Minucci D, Arreghini G, Rabasso A | title = [Modification of the endometrium during combined therapy with dihydroxyprogesterone acetophenide and estradiol-3-benzoate-17-n-butyrate] | language = it | journal = Rivista di Ostetricia Ginecologia Pratica e Medicina Perinatale | volume = 54 | issue = 10 | pages = 497–505 | date = 1973 | pmid = 4807299 | trans-title = Modification of the endometrium during combined therapy with dihydroxyprogesterone acetophenide and estradiol-3-benzoate-17-n-butyrate }}{{cite journal | vauthors = Cittadini E, Catalano G | title = [Use of a new combination: dihydroxyprogesterone acetophenide and estradiol-3-benzoate-17 isobutyrate in gynecology] | language = it | journal = Rivista di Ostetricia Ginecologia Pratica e Medicina Perinatale | volume = 54 | issue = 10 | pages = 506–512 | date = 1973 | pmid = 4620236 | trans-title = Use of a new combination: dihydroxyprogesterone acetophenide and estradiol-3-benzoate-17 isobutyrate in gynecology }}{{cite journal | vauthors = Selvaggi L, Putignano G | title = [Response of peripheral receptors to the parenteral administration of an association of dihydroxyprogesterone acetophenide and estradiol-3 benzoate-17-n-butyrate. Preliminary note] | language = it | journal = Minerva Ginecologica | volume = 27 | issue = 12 | pages = 961–963 | date = December 1975 | pmid = 778679 | trans-title = Response of peripheral receptors to the parenteral administration of an association of dihydroxyprogesterone acetophenide and estradiol-3 benzoate-17-n-butyrate. Preliminary note }}{{cite journal | vauthors = Cappello F | title = [Use of a parenteral estroprogestin as an inhibitor of ovulation in a single monthly administration] | language = it | journal = Minerva Ginecologica | volume = 27 | issue = 12 | pages = 964–968 | date = December 1975 | pmid = 778680 | trans-title = Use of a parenteral estroprogestin as an inhibitor of ovulation in a single monthly administration }} The combination was marketed for use as a combined injectable contraceptive in Peru by 1987.{{cite journal | vauthors = Bonnema J, Dalebout JA | title = The abuse of high dose estrogen/progestin combination drugs in delay of menstruation: the assumptions and practices of doctors, midwives and pharmacists in a Peruvian city | journal = Social Science & Medicine | volume = 34 | issue = 3 | pages = 281–289 | date = February 1992 | pmid = 1557669 | doi = 10.1016/0277-9536(92)90270-Z }}{{cite journal | vauthors = Thomas DB, Molina R, Rodriguez Cuevas H, Ray RM, Riotton G, Dabancens A, Benavides S, Martinez L, Salas O, Pallet JA | display-authors = 6 | title = Monthly injectable steroid contraceptives and cervical carcinoma | journal = American Journal of Epidemiology | volume = 130 | issue = 2 | pages = 237–247 | date = August 1989 | pmid = 2665476 | doi = 10.1093/oxfordjournals.aje.a115330 }}
Society and culture
=Brand names=
EBB is marketed in combination with DHPA under the brand names Neolutin N, Redimen, Soluna, and Unijab.{{cite web|url=https://www.datosperu.org/farmaco-soluna-rs-N12759.php|title=Farmaco SOLUNA 150 + 10 registrado en Perú}}{{cite web|url=http://www.mims.com/singapore/drug/info/unijab|title = Unijab Dosage & Drug Information | MIMS Singapore}}{{cite web |url=http://www.corporacionmisalud.com/sistema/vademecum/PLM/productos/32499.htm |title=SOLUNA |website=www.corporacionmisalud.com |url-status=dead |archive-url=https://web.archive.org/web/20141005184908/http://corporacionmisalud.com/sistema/vademecum/PLM/productos/32499.htm |archive-date=2014-10-05}} It was originally developed under the tentative brand name Unimens, but ultimately was not marketed under this particular brand name.{{cite journal | vauthors = Newton JR, D'arcangues C, Hall PE | title = A review of "once-a-month" combined injectable contraceptives | journal = Journal of Obstetrics and Gynaecology | volume = 4 | issue = Suppl 1 | pages = S1-34 | year = 1994 | pmid = 12290848 | doi = 10.3109/01443619409027641 }}{{cite journal | vauthors = Toppozada MK | title = Existing once-a-month combined injectable contraceptives | journal = Contraception | volume = 49 | issue = 4 | pages = 293–301 | date = April 1994 | pmid = 8013216 | doi = 10.1016/0010-7824(94)90029-9 }}
=Availability=
See also
References
{{Reflist}}
{{Estradiol}}
{{Estrogens and antiestrogens}}
{{Estrogen receptor modulators}}