Hexestrolのソースを表示

{{Short description|Chemical compound}}
{{Drugbox
| Verifiedfields     = 
| Watchedfields      = 
| verifiedrevid      = 
| IUPAC_name         = 4-[4-(4-Hydroxyphenyl)hexan-3-yl]phenol
| image              = Hexestrol.svg
| width              = 250px

<!--Clinical data-->| tradename          = Synestrol, Synoestrol, Estrifar, Estronal
| pregnancy_AU       = <!-- A / B1 / B2 / B3 / C / D / X -->
| pregnancy_US       = <!-- A / B / C / D / X -->
| pregnancy_category = 
| legal_AU           = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 -->
| legal_CA           = 
| legal_UK           = 
| legal_US           = 
| legal_status       = 
| routes_of_administration = [[Oral administration|By mouth]], [[intramuscular injection]] (as an [[ester]])
| class              = [[Nonsteroidal estrogen]]

<!--Pharmacokinetic data-->| bioavailability    = 
| protein_bound      = 
| metabolism         = 
| elimination_half-life = 
| excretion          = <!--Identifiers-->
| CAS_number_Ref     = 
| CAS_number         = 84-16-2
| CAS_supplemental   = 
| ATC_prefix         = 
| ATC_suffix         = 
| PubChem            = 3606
| IUPHAR_ligand      = 2823
| DrugBank_Ref       = 
| DrugBank           = DB07931
| ChemSpiderID_Ref   = 
| ChemSpiderID       = 3480
| UNII_Ref           = {{fdacite|correct|FDA}}
| UNII               = 10BI795R7D
| KEGG_Ref           = 
| KEGG               = D01641
| ChEBI_Ref          = 
| ChEBI              = 31669
| ChEMBL_Ref         = 
| ChEMBL             = 6615
| synonyms           = Hexoestrol; Hexanestrol; Hexanoestrol; Dihydrodiethylstilbestrol; Dihydrostilbestrol; 4,4'-(1,2-Diethylethylene)diphenol; NSC-9894

<!--Chemical data-->
| C                  = 18
| H                  = 22
| O                  = 2
| SMILES             = CCC(C1=CC=C(C=C1)O)C(CC)C2=CC=C(C=C2)O
| StdInChI           = 1S/C18H22O2/c1-3-17(13-5-9-15(19)10-6-13)18(4-2)14-7-11-16(20)12-8-14/h5-12,17-20H,3-4H2,1-2H3
| StdInChIKey        = PBBGSZCBWVPOOL-UHFFFAOYSA-N
}}

'''Hexestrol''', sold under the brand name '''Synestrol''' among others, is a [[nonsteroidal estrogen]] which was previously used for [[estrogen replacement therapy]] and in the treatment of certain [[hormone-dependent cancer]]s as well as [[gynecological disorder]]s but is mostly no longer marketed.<ref name="Elks2014">{{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=PA162|date=14 November 2014|publisher=Springer|isbn=978-1-4757-2085-3|pages=162–}}</ref><ref name="MortonHall2012">{{cite book| vauthors = Morton IK, Hall JM |title=Concise Dictionary of Pharmacological Agents: Properties and Synonyms|url=https://books.google.com/books?id=tsjrCAAAQBAJ&pg=PA140|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-94-011-4439-1|pages=140–}}</ref><ref name="Thomas1997">{{cite book| vauthors = Thomas JA |title=Endocrine Toxicology, Second Edition|url=https://books.google.com/books?id=URc5JMoNirgC&pg=PA144|date=12 March 1997|publisher=CRC Press|isbn=978-1-4398-1048-4|pages=144–}}</ref><ref name="Drugs.com">{{Cite web|url=https://www.drugs.com/international/hexestrol.html|title = Estradiol: Uses, Dosage & Side Effects}}</ref> It has also been used in the form of [[ester]]s such as [[hexestrol diacetate]] (brand name Sintestrol) and [[hexestrol dipropionate]] (brand name Hexanoestrol).<ref name="Elks2014" /><ref name="HorskyPresl2012" /> Hexestrol and its esters are taken [[oral administration|by mouth]], [[sublingual administration|held under the tongue]], or via [[intramuscular injection|injection into muscle]].<ref name="HorskyPresl2012">{{cite book| vauthors = Horsky J, Presl J |title=Ovarian Function and its Disorders: Diagnosis and Therapy|url=https://books.google.com/books?id=7IrpCAAAQBAJ&pg=PA310|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-94-009-8195-9|pages=83,85,145,310}}</ref><ref name="ThomasKeenan2012">{{cite book| vauthors = Thomas JA, Keenan EJ |title=Principles of Endocrine Pharmacology|url=https://books.google.com/books?id=mTagBQAAQBAJ&pg=PA153|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-1-4684-5036-1|pages=153–}}</ref><ref name="F.S.K.2012">{{cite book | vauthors = Barar FS |title=Textbook of Pharmacology|url=https://books.google.com/books?id=ZDJlDwAAQBAJ&pg=PA348|year=2012|publisher=S. Chand Publishing|isbn=978-81-219-4080-1|pages=348–}}</ref>

==Medical uses==
Hexestrol has been used in [[estrogen replacement therapy]], for the treatment of [[breast cancer]] in women and [[prostate cancer]] in men, and for the treatment of certain [[gynecological disorder]]s.<ref name="MortonHall2012" />

{{Estrogen dosages for prostate cancer}}

==Pharmacology==

===Pharmacodynamics===
Hexestrol has approximately 302% and 234% of the [[affinity (pharmacology)|affinity]] of [[estradiol (medication)|estradiol]] for the [[estrogen receptor]]s (ERs) [[ERα]] and [[ERβ]], respectively.<ref name="pmid9048584">{{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 = 863–870 | date = March 1997 | pmid = 9048584 | doi = 10.1210/endo.138.3.4979 | doi-access = free }}</ref> The affinity of hexestrol for the ERs is said to be similar to or slightly higher than that of estradiol.<ref name="pmid391285">{{cite journal | vauthors = Leclercq G, Heuson JC | title = Physiological and pharmacological effects of estrogens in breast cancer | journal = Biochimica et Biophysica Acta (BBA) - Reviews on Cancer | volume = 560 | issue = 4 | pages = 427–455 | date = December 1979 | pmid = 391285 | doi = 10.1016/0304-419x(79)90012-x }}</ref> Along with [[diethylstilbestrol]], hexestrol has been said to be one of the most [[potency (pharmacology)|potent]] [[estrogen (medication)|estrogen]]s known.<ref name="pmid21013428">{{cite journal | vauthors = Solmssen UV | title = Synthetic estrogens and the relation between their structure and their activity | journal = Chemical Reviews | volume = 37 | issue = 3 | pages = 481–598 | date = December 1945 | pmid = 21013428 | doi = 10.1021/cr60118a004 }}</ref> The total [[endometrium|endometrial]] [[cell proliferation|proliferation]] dose per cycle of different forms of hexestrol are 70 to 100&nbsp;mg for [[oral administration|oral]] hexestrol, 45&nbsp;mg for [[sublingual administration|sublingual]] [[hexestrol diacetate]], and 25&nbsp;mg for [[hexestrol dipropionate]] by [[intramuscular injection]].<ref name="HorskyPresl2012" /> These doses are fairly similar to those of estradiol and its esters.<ref name="HorskyPresl2012" /> Hexestrol induces [[mammary gland]] [[breast development|development]] in rodents similarly to other estrogens.<ref name="CampbellDodds1939"/>

Nonsteroidal estrogens like diethylstilbestrol, which is closely related structurally to hexestrol, are known to have dramatically disproportionate estrogenic effects in the [[liver]] and on [[liver protein synthesis]].<ref name="Kuhl2005">{{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 }}</ref>

{{Parenteral potencies and durations of nonsteroidal estrogens}}

===Pharmacokinetics===
[[File:Distribution of hexestrol radioactivity after a subcutaneous injection of tritiated hexestrol in oil solution in female goats.png|thumb|right|400px|[[Distribution (pharmacology)|Distribution]] of hexestrol [[radioactivity]] in [[blood]] and [[tissue (biology)|tissue]]s after a [[subcutaneous injection]] of a [[physiological]] dose of [[tritium]]-[[radiolabel|labeled]] hexestrol in [[oil solution]] in five juvenile female goats.<ref name="pmid13828338">{{cite journal | vauthors = Glascock RF, Hoekstra WG | title = Selective accumulation of tritium-labelled hexoestrol by the reproductive organs of immature female goats and sheep | journal = The Biochemical Journal | volume = 72 | issue = 4 | pages = 673–682 | date = August 1959 | pmid = 13828338 | pmc = 1196992 | doi = 10.1042/bj0720673 }}</ref> Points are one animal each.<ref name="pmid13828338" /> With the exception of [[skeletal muscle]], tissues with a radioactivity concentration of less than 15% of that of the [[endometrium]] are not shown.<ref name="pmid13828338" /> Hexestrol is concentrated in [[target tissue]]s such as the [[uterus]] and [[vagina]] due to binding to [[estrogen receptor]]s.<ref name="pmid4563437">{{cite journal | vauthors = Jensen EV, DeSombre ER | title = Mechanism of action of the female sex hormones | journal = Annual Review of Biochemistry | volume = 41 | pages = 203–230 | date = 1972 | pmid = 4563437 | doi = 10.1146/annurev.bi.41.070172.001223 }}</ref>]]

The [[pharmacokinetics]] and [[distribution (pharmacology)|distribution]] of hexestrol have been studied with [[intravenous injection]] of [[aqueous solution]] in women and with [[subcutaneous injection]] of [[oil solution]] in female goats and sheep.<ref name="pmid13893792">{{cite journal | vauthors = Folca PJ, Glascock RF, Irvine WT | title = Studies with tritium-labelled hexoestrol in advanced breast cancer. Comparison of tissue accumulation of hexoestrol with response to bilateral adrenalectomy and oophorectomy | journal = Lancet | volume = 2 | issue = 7206 | pages = 796–798 | date = October 1961 | pmid = 13893792 | doi = 10.1016/s0140-6736(61)91088-1 }}</ref><ref name="pmid13828338"/>

==Chemistry==
{{See also|Stilbestrol#Stilbestrol derivatives|List of estrogen esters#Hexestrol esters}}

Hexestrol, also known as dihydrodiethylstilbestrol, is a [[synthetic compound|synthetic]] [[nonsteroidal estrogen]] of the [[stilbestrol]] group related to [[diethylstilbestrol]].<ref name="Elks2014" /><ref name="MortonHall2012" /> [[Ester]]s of hexestrol include [[hexestrol diacetate]], [[hexestrol dicaprylate]], [[hexestrol diphosphate]], and [[hexestrol dipropionate]].<ref name="Elks2014" />

==History==
Hexestrol was first described by Campbell, Dodds, and Lawson in 1938.<ref name="CampbellDodds1938">{{cite journal| vauthors = Campbell NR, Dodds EC, Lawson W |title=Œstrogenic Activity of Anol; a Highly Active Phenol Isolated from the By-Products|journal=Nature|volume=142|issue=3608|year=1938|pages=1121|issn=0028-0836|doi=10.1038/1421121a0|bibcode=1938Natur.142.1121C|s2cid=4140616|doi-access=free}}</ref><ref name="CampbellDodds1939">{{cite journal| vauthors = Campbell NR, Dodds EC, Lawson W, Noble RL |title=Biological effects of the synthetic œstrogen hexœstrol|journal=The Lancet|volume=234|issue=6049|year=1939|pages=312–313|issn=0140-6736|doi=10.1016/S0140-6736(00)61997-9}}</ref><ref name="MedChem1956">{{cite book|title=Medicinal Chemistry|url=https://books.google.com/books?id=bpXVAAAAMAAJ|year=1956|publisher=John Wiley & Sons|page=40}}</ref><ref name="CampbellDodds1940">{{cite journal|vauthors=Campbell NR, Dodds EC, Lawson W|title=The nature of the oestrogenic substances produced during the demethylation of anethole|journal=Proceedings of the Royal Society of London. Series B, Biological Sciences|volume=128|issue=851|year=1940|pages=253–262|issn=2053-9193|doi=10.1098/rspb.1940.0009|bibcode=1940RSPSB.128..253C|doi-access=free}}</ref> It was isolated from the [[demethylation]] products of [[anethole]].<ref name="CampbellDodds1938" /><ref name="CampbellDodds1939" /><ref name="MedChem1956" /><ref name="CampbellDodds1940" />

==Society and culture==

===Generic names===
''Hexestrol'' is the [[generic term|generic name]] of the drug and its {{abbrlink|INN|International Nonproprietary Name}}.<ref name="Elks2014" /><ref name="MortonHall2012" />

===Brand names===
Hexestrol has been marketed under a variety of brand names including Synestrol, Synoestrol, Estrifar, and Estronal, among others.<ref name="Elks2014" /><ref name="MortonHall2012" />

===Availability===
Hexestrol has mostly been discontinued and remains available in only a handful of countries.<ref name="Micromedex">{{cite web | title = Micromdex | url = https://www.micromedexsolutions.com/ | publisher = Merative | access-date = 10 March 2023}}</ref><ref name="Drugs.com"/> Esters of hexestrol which have been marketed include [[hexestrol diacetate]], [[hexestrol dicaprylate]], [[hexestrol diphosphate]], and [[hexestrol dipropionate]].<ref name="Elks2014" />

== References ==
{{Reflist}}

{{Estrogens and antiestrogens}}
{{Estrogen receptor modulators}}

[[Category:Abandoned drugs]]
[[Category:4-Hydroxyphenyl compounds]]
[[Category:Stilbenoids]]
[[Category:Synthetic estrogens]]