Estradiol stearate

{{Short description|Chemical compound}}

{{Infobox drug

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| IUPAC_name = [(8R,9S,13S,14S,17S)-3-Hydroxy-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-17-yl] octadecanoate

| image = Estradiol stearate structure.svg

| width = 250px

| tradename = Depofollan

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| routes_of_administration = Intramuscular injection

| class = Estrogen; Estrogen ester

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| CAS_number_Ref = {{cascite|correct|CAS}}

| CAS_number = 82205-00-3

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| UNII_Ref = {{fdacite|correct|FDA}}

| UNII =59G2KR8QBG

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| PubChem = 67100

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| ChemSpiderID = 60448

| synonyms = E2-17-St; Estradiol octadecanoate; Estradiol 17β-stearate; Estradiol 17β-octadecanoate

| C=36 | H=58 | N= | O=3

| SMILES = CCCCCCCCCCCCCCCCCC(=O)O[C@H]1CC[C@H]2[C@@H]3CCc4cc(O)ccc4[C@H]3CC[C@]12C

| StdInChI_Ref =

| StdInChI = 1S/C36H58O3/c1-3-4-5-6-7-8-9-10-11-12-13-14-15-16-17-18-35(38)39-34-24-23-33-32-21-19-28-27-29(37)20-22-30(28)31(32)25-26-36(33,34)2/h20,22,27,31-34,37H,3-19,21,23-26H2,1-2H3/t31-,32-,33+,34+,36+/m1/s1

| StdInChIKey_Ref =

| StdInChIKey = KIADYVOYCQRXRE-IMTRJTTHSA-N

}}

Estradiol stearate (E2-17-St), also known as estradiol octadecanoate and sold under the brand name Depofollan, is a naturally occurring estrogen and an estrogen ester – specifically, the C17β stearate ester of estradiol.{{cite book| vauthors = Elks J |title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies|url=https://books.google.com/books?id=0vXTBwAAQBAJ&pg=RA1-PA129|date=14 November 2014|publisher=Springer|isbn=978-1-4757-2085-3|page=898}}{{cite book|title=Index Nominum 2000: International Drug Directory|url=https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA405|date=January 2000|publisher=Taylor & Francis|isbn=978-3-88763-075-1|pages=405–}}{{cite book | vauthors = Negwer M |title=Organic-chemical Drugs and Their Synonyms: (an International Survey)|url=https://books.google.com/books?id=k6fwAAAAMAAJ|year=1987|publisher=VCH Publishers|isbn=978-0-89573-552-2|quote=Estra-1,3,5(10)-triene-3,173-diol 17-octadecanoate = 3,173-Estradiol 17-stearate = (173)-Estra-1,3,5- (10)-triene-3,17-diol 17-octadecanoate (e) S Depofollan, Estradiol stearate, Ostradiolstearat U Depot-estrogen 8103}}{{cite book| vauthors = Josephy E, Radt F |title=Elsevier's Encyclopædia of Organic Chemistry|url=https://books.google.com/books?id=3oeDq5LQ9bYC|year=1956|pages=1974–1976}}{{cite journal | vauthors = Hochberg RB, Pahuja SL, Larner JM, Zielinski JE | title = Estradiol-fatty acid esters. Endogenous long-lived estrogens | journal = Annals of the New York Academy of Sciences | volume = 595 | issue = 1 | pages = 74–92 | year = 1990 | pmid = 2197972 | doi = 10.1111/j.1749-6632.1990.tb34284.x | s2cid = 19866729 | bibcode = 1990NYASA.595...74H }} It occurs in the body as a very long-lasting metabolite and prohormone of estradiol. The compound is one of the components that collectively constitute lipoidal estradiol, another of which is estradiol palmitate.{{cite book| vauthors = Oettel M, Schillinger E |title=Estrogens and Antiestrogens I: Physiology and Mechanisms of Action of Estrogens and Antiestrogens|url=https://books.google.com/books?id=0BfrCAAAQBAJ&pg=PA235|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-58616-3|pages=235–237}} It is extremely lipophilic and hydrophobic. Estradiol stearate has no affinity for the estrogen receptor, requiring transformation into estradiol via esterases for its estrogenic activity.{{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 = 1180–1186 | date = April 1984 | pmid = 6705734 | doi = 10.1210/endo-114-4-1180 }}{{cite journal | vauthors = Vazquez-Alcantara MA, Menjivar M, Garcia GA, Díaz-Zagoya JC, Garza-Flores J | title = Long-acting estrogenic responses of estradiol fatty acid esters | journal = Journal of Steroid Biochemistry | volume = 33 | issue = 6 | pages = 1111–1118 | date = December 1989 | pmid = 2515394 | doi = 10.1016/0022-4731(89)90417-2 }} The compound does not bind to sex hormone-binding globulin or α-fetoprotein, instead being transported by lipoproteins such as high-density lipoprotein and low-density lipoprotein.

Estradiol stearate has a prolonged duration of action relative to estradiol regardless of whether it is given by intravenous injection or subcutaneous injection.{{cite journal | vauthors = Hochberg RB | title = Biological esterification of steroids | journal = Endocrine Reviews | volume = 19 | issue = 3 | pages = 331–348 | date = June 1998 | pmid = 9626557 | doi = 10.1210/edrv.19.3.0330 | doi-access = free }} This is in contrast to short-chain fatty acid esters of estradiol, such as estradiol benzoate, which do not show a prolonged duration with intravenous injection.{{cite journal | vauthors = Parkes AS | title = Effective Absorption of Hormones | journal = British Medical Journal | volume = 1 | issue = 4024 | pages = 371–373 | date = February 1938 | pmid = 20781252 | pmc = 2085798 | doi = 10.1136/bmj.1.4024.371 }} When administered by intravenous injection in rodents, estradiol stearate has a greatly increased terminal half-life relative to estradiol (6 hours vs. 2 minutes). Estradiol stearate also had a half-life that was 60% longer than that of estradiol arachidonate, despite similar ester chain lengths. In contrast to the long-chain esters, the half-lives of short-chain estradiol esters such as estradiol acetate and estradiol hexanoate were the same as that of estradiol. As such, whereas short-chain estradiol esters are rapidly hydrolyzed, long-chain estradiol esters like estradiol stearate are resistant to metabolism. Thus, the prolongation of effect of short-chain estradiol esters is purely due to their increased lipophilicity and slow release from the injected depot, whereas the prolonged duration of long-chain estradiol esters is due both to this property and to their resistance to metabolism. Estradiol stearate is susceptible to first-pass metabolism in the liver, and hence has much greater potency by subcutaneous injection than by oral administration.

In addition to its endogenous role, estradiol stearate was previously available as a pharmaceutical drug for use via depot intramuscular injection. The medication was introduced between 1938 and 1941 under the brand name Depofollan. It has been used to treat prostate cancer.{{cite journal | vauthors = Medgyaszay A | title = [Intraocular pressure and hormone therapy] | journal = Ophthalmologica | volume = 145 | issue = 3 | pages = 243–248 | year = 1963 | pmid = 13934365 | doi = 10.1159/000304442 }}{{cite book| vauthors = Sellei C, Eckhardt S, Németh L |title=Chemotherapy of Neoplastic Diseases|url=https://books.google.com/books?id=kcxrAAAAMAAJ|year=1970|publisher= Akadémiai Kiadó | location = Budapest |page=251}} Estradiol stearate is a long-acting estrogen and is said to have been the first long-acting estrogen used in medicine, although it was never widely employed.{{cite book|title=Orvostudomány | trans-title = Medicine | language = Hungarian |url=https://books.google.com/books?id=_EdMAAAAYAAJ|year=1960|publisher=Magyar Tudomanyos Akadémia V. Orvosi Tudományok Osztálya (Hungarian Academy of Sciences V. Department of Medical Sciences) |page=11}} It was reported to have a duration of more than one month. The medication was provided as an oil solution in ampoules containing 15 mg estradiol stearate.{{cite book|title=Endokrinologie|url=https://books.google.com/books?id=0BExAAAAIAAJ|year=1951|publisher=Johann Ambrosius Barth Verlag.}} It was manufactured by Chinoin, a Hungarian pharmaceutical company.{{cite book | vauthors = Antalné S, Géza B, István B, Dezső K | title = A Chinoin története (1910–1995) | trans-title = The history of Chinoin | language = Hungarian | url = http://www.gyogyszeresztortenet.hu/wp-content/uploads/2013/08/Egy-mindig-meg%C3%BAjul%C3%B3-v%C3%A1llalat-a-Chinoin-t%C3%B6rt%C3%A9nete.pdf | quote = From the middle of the vitamin D and hannincas years, the research and production of steroid sex hormones was directed by Rezső Weisz. (n) In the latter, the collection of animal raw materials, in addition to chemical operations, required considerable organizational work similar to that of insulin. The intensification of attempts to produce steroid hormones and synthetic steroids, estrogens, over four years may have surpassed even 36 studies of sulfone JDid. Weisz et al., Primarily Kálmán Lányi, developed the most important estrone derivatives of industrial and therapeutic interest, Hogival (estrone acetate), Acrafalin (estradiol propionate) and Depofollan (estradiol stearate), which were marketed in 1938-1940. }}{{cite book | title = Alkaloida Vegyészeti | trans-title = Alkaloid Chemistry | language = Hungarian | veditors = Gyár R, Tiszavasvári T, Novák K, Hermecz I | date = 2005 | chapter = Esti beszélgetés – Magyar Gyógyszerkutatók portréi. | publisher = MTA Gyógyszerkémiai és Gyógyszertechnológiai Munkabizottsága (Hungarian Academy of Sciences' Working Committee on Medicinal Chemistry and Pharmaceutical Technology)| trans-chapter = Evening discussion - Portraits of Hungarian Pharmaceutical Researchers. | location = Budapest | url =

http://www.gyogyszeresztortenet.hu/wp-content/uploads/2013/08/Esti-besz%C3%A9lget%C3%A9s.pdf | archive-url = https://web.archive.org/web/20160805140955/http://www.gyogyszeresztortenet.hu/wp-content/uploads/2013/08/Esti-besz%C3%A9lget%C3%A9s.pdf | archive-date=2016-08-05 | quote = Chinoin has achieved good results in the steroid hormones, synthetic steroids, and estrogens since the twenties, protected by 36 patents. The company was one of the first in the world to produce vitamin D, but was also a successful product for Hogival (estrone acetate), Acrofollin (estradiol propionate), Depofollan (estradiol stearate), Acrolutin (progesterone). }} The compound was studied by Karl Miescher in 1938{{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 }} and was patented by Miescher and Chinoin in 1939 and 1941, respectively.{{Cite patent | country = US | number = 2156599 |url=https://patents.google.com/patent/US2156599A/en|title = Estradiol esters esterified in 3-position and process of making same | inventor = Karl M, Caesar S | gdate = 1939 }}{{Cite patent | country = US | number = 2253669 | url=https://patents.google.com/patent/US2253669A/en|title = Estradiol higher fatty acid ester | inventor = Rezso W | assign1 = Current Assignee Chinoin Private Co Ltd | gdate = 1941 }} A similar clinically used long-acting estradiol ester is estradiol undecylate, which has 11 carbon atoms instead of the 18 carbon atoms in estradiol stearate.

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

{{Structural properties of selected estradiol esters}}