Estrogen ester

An estrogen ester is an ester of an estrogen, most typically of estradiol but also of other estrogens such as estrone, estriol, and even nonsteroidal estrogens like diethylstilbestrol.{{cite journal | vauthors = Kuhl H | title = Pharmacology of estrogens and progestogens: influence of different routes of administration | journal = Climacteric | volume = 8 | pages = 3–63 | year = 2005 | issue = Suppl 1 | pmid = 16112947 | doi = 10.1080/13697130500148875 | s2cid = 24616324 | url = http://hormonebalance.org/images/documents/Kuhl%2005%20%20Pharm%20Estro%20Progest%20Climacteric_1313155660.pdf}}{{cite book|author1=Michael Oettel|author2=Ekkehard Schillinger|title=Estrogens and Antiestrogens II: Pharmacology and Clinical Application of Estrogens and Antiestrogen|url=https://books.google.com/books?id=wBvyCAAAQBAJ&pg=PA261|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-60107-1|pages=235–237,261,271|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.}}{{cite book | author1 = R. S. Satoskar | author2 = S. D. Bhandarkar &nirmala N. Rege | title = Pharmacology And Pharmacotherapeutics (New Revised 21 St Ed.) | url = https://books.google.com/books?id=7d493VOD4P8C&pg=PA24 | access-date = 29 May 2012 | year = 1969 | publisher = Popular Prakashan | isbn = 978-81-7991-527-1 | page = 24}} Esterification renders estradiol into a prodrug of estradiol with increased resistance to first-pass metabolism, slightly improving its oral bioavailability.{{cite book | author1 = Gordon L. Amidon | author2 = Ping I. Lee | author3 = Elizabeth M. Topp | title = Transport Processes in Pharmaceutical Systems | url = https://books.google.com/books?id=Rz3BM4C-tXoC&pg=PA188 | access-date = 29 May 2012 | year = 2000 | publisher = CRC Press | isbn = 978-0-8247-6610-8 | pages = 188–189}} In addition, estrogen esters have increased lipophilicity, which results in a longer duration when given by intramuscular or subcutaneous injection due to the formation of a long-lasting local depot in muscle and fat. Conversely, this is not the case with intravenous injection or oral administration.{{cite journal | vauthors = Parkes AS | title = Effective Absorption of Hormones | journal = Br Med J | volume = 1 | issue = 4024 | pages = 371–3 | date = February 1938 | pmid = 20781252 | pmc = 2085798 | doi = 10.1136/bmj.1.4024.371}} Estrogen esters are rapidly hydrolyzed into their parent estrogen by esterases once they have been released from the depot. Because estradiol esters are prodrugs of estradiol, they are considered to be natural and bioidentical forms of estrogen.{{cite journal |vauthors=Düsterberg B, Nishino Y | title = Pharmacokinetic and pharmacological features of oestradiol valerate | journal = Maturitas | volume = 4 | issue = 4 | pages = 315–24 |date=December 1982 | pmid = 7169965 | doi = 10.1016/0378-5122(82)90064-0}}

Estrogen esters are used in hormone therapy, hormonal contraception, and high-dose estrogen therapy (e.g., for prostate cancer and breast cancer), among other indications. The first estrogen ester to be marketed was estradiol benzoate in 1933, which was followed by many more.{{cite book|author=J. Elks|title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies|url=https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA897|date=14 November 2014|publisher=Springer|isbn=978-1-4757-2085-3|pages=897–}}{{cite book|title=Index Nominum 2000: International Drug Directory|url=https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA406|access-date=13 September 2012|year=2000|publisher=Taylor & Francis US|isbn=978-3-88763-075-1|pages=404–406}} One of the most widely used estradiol esters is estradiol valerate, which was first introduced in 1954.{{cite book|author=William Andrew Publishing|title=Pharmaceutical Manufacturing Encyclopedia, 3rd Edition|url=https://books.google.com/books?id=_J2ti4EkYpkC&pg=PA1477|date=22 October 2013|publisher=Elsevier|isbn=978-0-8155-1856-3|pages=1477–}} Other major estradiol esters that are or have been used in medicine include estradiol acetate, estradiol cypionate, estradiol dipropionate, estradiol enantate, estradiol undecylate, and polyestradiol phosphate (an estrogen ester polymer), as well as the nitrogen mustard alkylating antineoplastic agent estramustine phosphate (estradiol normustine phosphate).{{cite journal | vauthors = Oriowo MA, Landgren BM, Stenström B, Diczfalusy E | title = A comparison of the pharmacokinetic properties of three estradiol esters | journal = Contraception | volume = 21 | issue = 4 | pages = 415–24 | date = April 1980 | pmid = 7389356 | doi = 10.1016/s0010-7824(80)80018-7 }}

The most common vehicles for injections of steroids and steroid esters are oil solutions, but aqueous solutions, aqueous suspensions, and emulsions have also been used.{{cite book|author=C. W. Emmens|title=Hormone Assay|url=https://books.google.com/books?id=cCzgBAAAQBAJ&pg=PA394|date=22 October 2013|publisher=Elsevier Science|isbn=978-1-4832-7286-3|pages=394–395}}{{Additional citation needed|date=December 2019}} The durations of estrogen esters are not prolonged if they are given orally, vaginally, or by intravenous injection.

Pharmacology

Estrogen esters are essentially inactive themselves, with esters such as estradiol valerate and estradiol sulfate having about 2% of the affinity of estradiol for the estrogen receptor.{{cite book|last1=Gudermann|first1=T.|title=Klinische Endokrinologie für Frauenärzte|chapter=Endokrinpharmakologie|year=2005|pages=187–220|doi=10.1007/3-540-26406-X_10|isbn=3-540-44162-X}} Likewise, the estrogen ether mestranol (ethinylestradiol 3-methyl ether) has about 1% of the affinity of estradiol for the estrogen receptor. Estrone sulfate has less than 1% of the affinity of estradiol for the estrogen receptor.{{cite journal | vauthors = Kuiper GG, Carlsson B, Grandien K, Enmark E, Häggblad J, Nilsson S, Gustafsson JA | title = Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta | journal = Endocrinology | volume = 138 | issue = 3 | pages = 863–70 | date = March 1997 | pmid = 9048584 | doi = 10.1210/endo.138.3.4979 | doi-access = free }} As such, estrogen esters do not bind to the estrogen receptor except at extremely high concentrations.{{cite journal | vauthors = Hochberg RB | title = Biological esterification of steroids | journal = Endocr. Rev. | volume = 19 | issue = 3 | pages = 331–48 | date = June 1998 | pmid = 9626557 | doi = 10.1210/edrv.19.3.0330 | doi-access = free }} The residual affinity of estrogen esters for the estrogen receptor in bioassays may actually be due to conversion into the parent estrogen, as attempts to prevent or limit this conversion have been found to abolish binding to the estrogen receptor and estrogenicity.{{cite journal | vauthors = Janocko L, Larner JM, Hochberg RB | title = The interaction of C-17 esters of estradiol with the estrogen receptor | journal = Endocrinology | volume = 114 | issue = 4 | pages = 1180–6 | date = April 1984 | pmid = 6705734 | doi = 10.1210/endo-114-4-1180 }}{{cite journal | vauthors = Bjerregaard-Olesen C, Ghisari M, Kjeldsen LS, Wielsøe M, Bonefeld-Jørgensen EC | title = Estrone sulfate and dehydroepiandrosterone sulfate: Transactivation of the estrogen and androgen receptor | journal = Steroids | volume = 105 | pages = 50–8 | date = January 2016 | pmid = 26666359 | doi = 10.1016/j.steroids.2015.11.009 | s2cid = 46663814 }}{{cite book|last1=Clark|first1=Barbara J.|title=Dehydroepiandrosterone|last2=Prough|first2=Russell A.|last3=Klinge|first3=Carolyn M.|chapter=Mechanisms of Action of Dehydroepiandrosterone|volume=108|year=2018|pages=29–73|issn=0083-6729|doi=10.1016/bs.vh.2018.02.003|pmid=30029731|series=Vitamins and Hormones|isbn=9780128143612}}

{{Affinities and estrogenic potencies of estrogen esters and ethers at the estrogen receptors}}

In general, the longer the fatty acid ester chain of an estrogen ester, the greater its lipophilicity, and the longer the duration of the estrogen ester with intramuscular injection. It has been said that, via intramuscular injection, the duration of estradiol benzoate (with an ester of length 1 carbon plus a benzene ring) is 2 to 3 days, of estradiol dipropionate (with two esters each of length 2 carbons) is 1 to 2 weeks, of estradiol valerate (ester of 5 carbons) is 1 to 3 weeks, and of estradiol cypionate (ester of 3 carbons plus a cyclopentane ring) is 3 to 4 weeks.{{cite book|author=H.J. Buchsbaum|title=The Menopause|url=https://books.google.com/books?id=z0LuBwAAQBAJ&pg=PA62|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-1-4612-5525-3|pages=62–}} Estradiol enantate (ester of 7 carbons) has a duration of around 20 days.{{cite journal | vauthors = Recio R, Garza-Flores J, Schiavon R, Reyes A, Diaz-Sanchez V, Valles V, Luz de la Cruz D, Oropeza G, Perez-Palacios G | title = Pharmacodynamic assessment of dihydroxyprogesterone acetophenide plus estradiol enanthate as a monthly injectable contraceptive | journal = Contraception | volume = 33 | issue = 6 | pages = 579–89 | date = June 1986 | pmid = 3769482 | doi = 10.1016/0010-7824(86)90046-6 }}{{cite journal | vauthors = Wiemeyer JC, Fernandez M, Moguilevsky JA, Sagasta CL | title = Pharmacokinetic studies of estradiol enantate in menopausic women | journal = Arzneimittelforschung | volume = 36 | issue = 11 | pages = 1674–7 | year = 1986 | pmid = 3814225 }} Likewise, estradiol undecylate (ester of 10 carbons) has a very extended duration, which is longer than that of all of the aforementioned esters.{{cite journal | vauthors = Vermeulen A | title = Longacting steroid preparations | journal = Acta Clin Belg | volume = 30 | issue = 1 | pages = 48–55 | date = 1975 | pmid = 1231448 | doi = 10.1080/17843286.1975.11716973 }}{{cite book|author1=R. S. Satoskar|author2=S. D. Bhandarkar &nirmala N. Rege|title=Pharmacology and Pharmacotherapeutics|url=https://books.google.com/books?id=7d493VOD4P8C&pg=PA934|year=1973|publisher=Popular Prakashan|isbn=978-81-7991-527-1|pages=934–}}

{{Pharmacokinetics of three estradiol esters by intramuscular injection}}

Polyestradiol phosphate is an atypical estradiol ester.{{cite journal | vauthors = Gunnarsson PO, Norlén BJ | title = Clinical pharmacology of polyestradiol phosphate | journal = Prostate | volume = 13 | issue = 4 | pages = 299–304 | year = 1988 | pmid = 3217277 | doi = 10.1002/pros.2990130405| s2cid = 33063805 }}{{cite journal | vauthors = Stege R, Gunnarsson PO, Johansson CJ, Olsson P, Pousette A, Carlström K | title = Pharmacokinetics and testosterone suppression of a single dose of polyestradiol phosphate (Estradurin) in prostatic cancer patients | journal = Prostate | volume = 28 | issue = 5 | pages = 307–10 | year = 1996 | pmid = 8610057 | doi = 10.1002/(SICI)1097-0045(199605)28:5<307::AID-PROS6>3.0.CO;2-8 | s2cid = 33548251 }} It is a phosphoric acid ester of estradiol in the form of a polymer, with an average polymer chain length of approximately 13 repeat units of estradiol phosphate. It is slowly cleaved into estradiol and phosphoric acid by phosphatases. Compared to conventional estradiol esters, polyestradiol phosphate has an extremely long duration; its elimination half-life is approximately 70 days. Whereas conventional estradiol esters form a long-lasting depot in muscle and fat at the site of injection, this is not the case with polyestradiol phosphate.{{cite book|title=Arzneistoff-Profile|editor1-last=Dinnendahl|editor1-first=V|editor2-last=Fricke|editor2-first=U|publisher=Govi Pharmazeutischer Verlag|location=Eschborn, Germany|year=2010|edition=23|volume=4|isbn=978-3-7741-98-46-3|language=de}} Instead, polyestradiol phosphate is taken up rapidly into the bloodstream following injection (by 90% within 24 hours), where it circulates, and is accumulated in the reticuloendothelial system. Unlike other estradiol esters, polyestradiol phosphate is resistant to hydrolysis, which may be because it is a phosphatase inhibitor and may inhibit its own metabolism.

Estrogen esters also occur naturally in the body, for instance estrogen conjugates like estrone sulfate and estrone glucuronide and the very long-lived lipoidal estradiol, which is constituted by ultra-long-chain esters like estradiol palmitate (ester of 16 carbons) and estradiol stearate (ester of 18 carbons).{{cite journal | vauthors = Hochberg RB, Pahuja SL, Larner JM, Zielinski JE | title = Estradiol-fatty acid esters. Endogenous long-lived estrogens | journal = Ann. N. Y. Acad. Sci. | volume = 595 | pages = 74–92 | year = 1990 | issue = 1 | pmid = 2197972 | doi = 10.1111/j.1749-6632.1990.tb34284.x| bibcode = 1990NYASA.595...74H | s2cid = 19866729 }}

Chemistry

File:Estradiol esterification into estradiol valerate.png plus the fatty acid valeric acid (valerate) equals estradiol valerate, a C17β ester of estradiol and one of the most widely used estrogen esters.{{cite book|last1=Shellenberger|first1=T. E.|title=The Climacteric in Perspective|chapter=Pharmacology of estrogens|year=1986|pages=393–410|doi=10.1007/978-94-009-4145-8_36|isbn=978-94-010-8339-3}}]]

File:Polyestradiol phosphate.svg, a polymer of estradiol phosphate, the C17β phosphoric acid ester of estradiol. It has on average of 13 repeat units.]]

Estradiol esters have an ester moiety, usually a straight-chain fatty acid (e.g., valeric acid) or an aromatic fatty acid (e.g., benzoic acid), attached at the C3 and/or C17β positions of the steroid nucleus. These alkoxy moieties are substituted in place of the hydroxyl groups present in the unesterified estradiol molecule. Fatty acid esters serve to increase the lipophilicity of estradiol, increasing its solubility in fat. This causes them to form a depot with intramuscular or subcutaneous injection and gives them a long duration when administered by these routes.

Some estradiol esters have other moieties instead of fatty acids as the esters. Such esters include sulfuric acid (as in estradiol sulfate), sulfamic acid (as in estradiol sulfamate), phosphoric acid (as in estradiol phosphate), glucuronic acid (as in estradiol glucuronide, and others (e.g., estramustine phosphate (estradiol 3-normustine 17β-phosphate)). These esters are all hydrophilic, and have greater water solubility than estradiol or fatty acid estradiol esters. Unlike fatty acid estradiol esters, water-soluble estradiol esters can be administered by intravenous injection.

A few estrogen esters are polymers. These include polyestradiol phosphate and polyestriol phosphate, which are polymers of estradiol phosphate and estriol phosphate monomers, respectively. The monomers are connected in both cases by phosphate groups via the C3 and C17β positions. Polyestradiol phosphate has an average polymer chain length of approximately 13 repeat units of estradiol phosphate. That is, each polyestradiol phosphate molecule is a polymer consisting on average of 13 estradiol phosphate molecules bonded together. These polymeric estrogen esters are hydrophilic and water-soluble. Upon intramuscular injection, they do not form a depot and instead are rapidly absorbed into the circulation. However, they are only slowly cleaved into monomers, and as a result, have a very long duration in the body even outlasting that of many longer-chain fatty-acid estrogen esters.

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| Chemical structures of estradiol and major estradiol esters

Image:Estradiol.svg|Estradiol

Image:Estradiol 3-acetate.svg|Estradiol acetate

Image:Estradiol benzoate.svg|Estradiol benzoate

Image:Estradiol dipropionate.svg|Estradiol dipropionate

Image:Estradiol valerate.svg|Estradiol valerate

Image:Estradiol 17 beta-cypionate.svg|Estradiol cypionate

Image:Estradiol enanthate.png|Estradiol enantate

Image:Estradiol undecylate.svg|Estradiol undecylate

Image:Polyestradiol phosphate.svg|Polyestradiol phosphate

}}

Estrogen ester

Pharmacology

Chemistry

See also

References

Further reading