Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Ethisterone: Difference between pages

{{Short description|Chemical compound}}

{{Redirect|Pregneninolone|the similarly named steroid|Pregnenolone}}

| Verifiedfields = verified

| Watchedfields = verified

| verifiedrevid = 461096491

| IUPAC_name = (8''R'',9''S'',10''R'',13''R'',14''S'',17''R'')-17-Ethynyl-17-hydroxy-10,13-dimethyl-2,6,7,8,9,11,12,14,15,16-decahydro-1''H''-cyclopenta[''a'']phenanthren-3-one

| image = Ethisterone.svg

| width = 225px

| image2 = Ethisterone molecule ball.png

| width2 = 235px

| tradename = Proluton C, Pranone, others

| pregnancy_category =

| legal_status =

| routes_of_administration = [[Oral administration|By mouth]], [[sublingual administration|sublingual]]<ref name="UCPress1952" />

| class = [[Progestogen (medication)|Progestogen]]; [[Progestin]]; [[Androgen]]; [[Anabolic steroid]]

| bioavailability =

| protein_bound =

| metabolism =

| metabolites = • [[5α-Dihydroethisterone]]<ref name="pmid9182866" />

| elimination_half-life =

| excretion =

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

| CAS_number = 434-03-7

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

| ChEBI_Ref = {{ebicite|correct|EBI}}

| ChEBI = 34749

| ChEMBL_Ref = {{ebicite|correct|EBI}}

| synonyms = Ethinyltestosterone; Ethynyltestosterone; Pregneninolone; Anhydrohydroxyprogesterone; Etisteron; Pregnin; Ethindrone

| SMILES = C[C@]12CCC(=O)C=C1CC[C@@H]3[C@@H]2CC[C@]4([C@H]3CC[C@]4(C#C)O)C

<!-- Definition and medical uses -->

'''Ethisterone''', also known as '''ethinyltestosterone''', '''pregneninolone''', and '''anhydrohydroxyprogesterone''' and formerly sold under the brand names '''Proluton C''' and '''Pranone''' among others, is a [[progestin]] medication which was used in the treatment of [[gynecological disorder]]s but is now no longer available.<ref name="pmid20787798">{{cite journal | vauthors = Swyer GI | title = Oral Hormonal Therapy for Menstrual Disorders | journal = British Medical Journal | volume = 1 | issue = 4654 | pages = 626–634 | date = March 1950 | pmid = 20787798 | pmc = 2037145 | doi = 10.1136/bmj.1.4654.626 }}</ref><ref name="MortonHall1999">{{cite book| vauthors = Morton IK, Hall JM |title=Concise Dictionary of Pharmacological Agents: Properties and Synonyms|url=https://books.google.com/books?id=mqaOMOtk61IC&pg=PA115|date=31 October 1999|publisher=Springer Science & Business Media|isbn=978-0-7514-0499-9|pages=115–}}</ref><ref name="Drugs.com">{{Cite web |url=https://www.drugs.com/international/ethisterone.html |title=Ethisterone | work = Drugs.com |access-date=2018-02-04 |archive-date=2019-06-24 |archive-url=https://web.archive.org/web/20190624142931/https://www.drugs.com/international/ethisterone.html |url-status=dead }}</ref> It was used alone and was not formulated in combination with an [[estrogen (medication)|estrogen]].<ref name="UCPress1952" /><ref name="Krug1963" /> The medication is taken [[oral administration|by mouth]].<ref name="MortonHall1999" />

<!-- Side effects and mechanism -->

[[Side effect]]s of ethisterone include [[virilization|masculinization]] among others.<ref name="MortonHall1999" /><ref name="Becker2001">{{cite book| vauthors = Becker KL |title=Principles and Practice of Endocrinology and Metabolism|url=https://books.google.com/books?id=FVfzRvaucq8C&pg=PA872|year=2001|publisher=Lippincott Williams & Wilkins|isbn=978-0-7817-1750-2|pages=872–}}</ref><ref name="WilkinsJones1958" /> Ethisterone is a progestin, or a [[synthetic compound|synthetic]] [[progestogen (medication)|progestogen]], and hence is an [[agonist]] of the [[progesterone receptor]], the [[biological target]] of progestogens like [[progesterone]].<ref name="pmid18395441" /> It has some [[androgen]]ic and [[anabolic]] activity and no other important [[hormonal agent|hormonal]] activity.<ref name="pmid18395441" /><ref name="Bentley1980" /><ref name="EglenJuchau2012" /><ref name="pmid13942007" /><ref name="pmid13922599" />

<!-- History, society, and culture -->

Ethisterone was discovered in 1938 and was introduced for medical use in [[Germany]] in 1939 and in the [[United States]] in 1945.<ref name="FritzSperoff2012" /><ref name="LauritzenStudd2005" /><ref name="Roth2014" /> It was the second [[progestogen (medication)|progestogen]] to be marketed, following [[injection (medicine)|injected]] [[progesterone]] in 1934, and was both the first [[oral administration|orally active]] progestogen and the first progestin to be introduced.<ref name="Twombly1947">{{cite book| vauthors = Twombly GH |title=Endocrinology of Neoplastic Diseases: A Symposium by Eighteen Authors|url=https://books.google.com/books?id=07svED4WoWoC|year=1947|publisher=Oxford University Press|page=7}}</ref><ref name="Publishing2013">{{cite book|author=William Andrew Publishing|title=Pharmaceutical Manufacturing Encyclopedia, 3rd Edition|url=https://books.google.com/books?id=_J2ti4EkYpkC&pg=PA1504|date=22 October 2013|publisher=Elsevier|isbn=978-0-8155-1856-3|pages=1504–1505}}</ref><ref name="LauritzenStudd2005">{{cite book| vauthors = Lauritzen C, Studd JW |title=Current Management of the Menopause|url=https://books.google.com/books?id=WD7S7677xUUC&pg=PA45|date=22 June 2005|publisher=CRC Press|isbn=978-0-203-48612-2|page=45|quote=Ethisterone, the first orally effective progestagen, was synthesized by Inhoffen and Hohlweg in 1938. Norethisterone, a progestogen still used worldwide, was synthesized by Djerassi in 1951. But this progestogen was not used immediately and in 1953 Colton discovered norethynodrel, used by Pincus in the first oral contraceptive. Numerous other progestogens were subsequently synthesized, e.g., lynestrenol and ethynodiol diacetate, which were, in fact, prhormones converted in vivo to norethisterone. All these progestogens were also able to induce androgenic effects when high doses were used. More potent progestogens were synthesized in the 1960s, e.g. norgestrel, norgestrienone. These progestogens were also more androgenic.}}</ref> Ethisterone was followed by the improved and much more widely used and known progestin [[norethisterone]] in 1957.<ref name="Bardin2013">{{cite book | vauthors = Bardin CW |title=Recent Progress in Hormone Research - Volume 50: Proceedings of the 1993 Laurentian Hormone Conference|url=https://books.google.com/books?id=PkukAgAAQBAJ&pg=PA2|date=22 October 2013|publisher=Elsevier Science|isbn=978-1-4832-8903-8|pages=2–}}</ref><ref name="Marks2010">{{cite book| vauthors = Marks L |title=Sexual Chemistry: A History of the Contraceptive Pill |url= https://books.google.com/books?id=_i-s4biQs7MC&pg=PA74 |year=2010|publisher=Yale University Press|isbn=978-0-300-16791-7|pages=74–}}</ref>

{{TOC limit|3}}

==Medical uses==

Ethisterone was used in the treatment of [[gynecological disorder]]s such as [[irregular menstruation]], [[amenorrhea]], and [[premenstrual syndrome]].<ref name="pmid20787798" /><ref name="Dalton1959">{{cite journal | vauthors = Dalton K | year = 1959 | title = 2. Menstrual Disorders in General Practice | journal = Journal of the College of General Practitioners and Research Newsletter | volume = 2 | issue = 3| pages = 236–242 | pmc=1890213}}</ref>

===Available forms===

Ethisterone was available in the form of 5, 10, and 25&nbsp;mg [[oral administration|oral]] and [[sublingual administration|sublingual]] [[tablet (pharmacy)|tablet]]s, as well as 50&nbsp;, 100&nbsp;, and 250&nbsp;mg oral [[capsule (pharmacy)|capsule]]s.<ref name="UCPress1952">{{cite book |title=Hospital Formulary and Compendium of Useful Information|url=https://books.google.com/books?id=t7VW3PucgboC&pg=PA49|year=1952|publisher=University of California Press|pages=49–|id=GGKEY:2UAAZRZ5LN0}}</ref><ref name="Krug1963">{{cite book| vauthors = Krug EE |title=Pharmacology in nursing|url=https://books.google.com/books?id=eCttAAAAMAAJ|year=1963|publisher=Mosby}}</ref><ref name="KleemannEngel2001">{{cite book| vauthors = Kleemann A, Engel J |title=Pharmaceutical Substances: Syntheses, Patents, Applications|url=https://books.google.com/books?id=ym5qAAAAMAAJ|year=2001|publisher=Thieme|isbn=978-3-13-558404-1|page=800}}</ref> The usual dosage was 25&nbsp;mg, up to four times per day.<ref name="Krug1963" />

==Side effects==

{{See also|Progestin#Side effects|Anabolic steroid#Adverse effects}}

[[Side effect]]s of ethisterone reportedly include [[symptom]]s of [[virilization|masculinization]] such as [[acne]] and [[hirsutism]] among others.<ref name="MortonHall1999" /><ref name="Becker2001" /><ref name="WilkinsJones1958" /> Findings are mixed on the [[anabolic]] effects of high doses of ethisterone.<ref name="pmid14442516">{{cite journal | vauthors = Schedl HP, Delea C, Bartter FC | title = Structure-activity relationships of anabolic steroids: role of the 19-methyl group | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 19 | issue = 8 | pages = 921–935 | date = August 1959 | pmid = 14442516 | doi = 10.1210/jcem-19-8-921 }}</ref>

==Pharmacology==

===Pharmacodynamics===

Ethisterone has weak [[progestogen (medication)|progestogen]]ic activity and weak [[androgen]]ic activity, but does not seem to have [[estrogen (medication)|estrogen]]ic activity.<ref name="pmid18395441" /><ref name="pmid13942007" /><ref name="pmid7025640" />

Ethisterone is a major [[active metabolite]] of [[danazol]] (2,3-isoxazolethisterone), and is thought to contribute importantly to its effects.<ref name="pmid7025640">{{cite journal | vauthors = Barbieri RL, Ryan KJ | title = Danazol: endocrine pharmacology and therapeutic applications | journal = American Journal of Obstetrics and Gynecology | volume = 141 | issue = 4 | pages = 453–463 | date = October 1981 | pmid = 7025640 | doi = 10.1016/0002-9378(81)90611-6 }}</ref>

====Progestogenic activity====

Ethisterone is a [[progestogen (medication)|progestogen]], or an [[agonist]] of the [[progesterone receptor]]s.<ref name="pmid18395441" /> It has about 44% of the [[affinity (pharmacology)|affinity]] of [[progesterone (medication)|progesterone]] for the progesterone receptor.<ref name="BruchhausenDannhardt2013">{{cite book| vauthors = von Bruchhausen F, Dannhardt G, Ebel S, Frahm AW, Hackenthal E, Holzgrabe U |title=Hagers Handbuch der Pharmazeutischen Praxis: Band 8: Stoffe E-O|url=https://books.google.com/books?id=8vSjBgAAQBAJ&pg=PA118|date=2 July 2013|publisher=Springer-Verlag|isbn=978-3-642-57994-3|pages=118–}}</ref> The medication is described as a relatively weak progestogen, similarly to its analogue [[dimethisterone]].<ref name="Kurman2013">{{cite book| vauthors = Kurman RJ |title=Blaustein's Pathology of the Female Genital Tract|url=https://books.google.com/books?id=sM3eBwAAQBAJ&pg=PA390|date=17 April 2013|publisher=Springer Science & Business Media|isbn=978-1-4757-3889-6|pages=390–}}</ref> Its total [[endometrial transformation]] dosage per 10 to 14&nbsp;days in women is 200 to 700&nbsp;mg.<ref name="Henzl1986">{{cite book | vauthors = Henzl MR | chapter = Contraceptive Hormones and their Clinical Use | pages = 643–682 | veditors = Yen SS, Jaffe RB | title = Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management | url = https://books.google.com/books?id=28aBAAAAIAAJ | year = 1986 | publisher = Saunders | isbn = 978-0-7216-9630-0}}</ref>{{Additional citation needed|date=January 2019}} Ethisterone has about 20-fold lower [[potency (pharmacology)|potency]] as a progestogen relative to [[norethisterone]].<ref name="pmid29137347">{{cite journal | vauthors = Regidor PA, Schindler AE | title = Antiandrogenic and antimineralocorticoid health benefits of COC containing newer progestogens: dienogest and drospirenone | journal = Oncotarget | volume = 8 | issue = 47 | pages = 83334–83342 | date = October 2017 | pmid = 29137347 | pmc = 5669973 | doi = 10.18632/oncotarget.19833 }}</ref> It is said to have minimal [[antigonadotropic]] effect and to not suppress [[ovulation]], which has precluded its use in [[hormonal contraception]].<ref name="pmid7025640" />

====Androgenic activity====

Based on ''[[in vitro]]'' research, ethisterone and norethisterone are about equipotent in their {{abbrlink|EC₅₀|half-maximal effective concentration}} values for activation of the [[androgen receptor]] (AR), whereas, conversely, norethisterone shows markedly increased potency relative to ethisterone in terms of its EC₅₀ for the [[progesterone receptor]].<ref name="pmid18395441">{{cite journal | vauthors = McRobb L, Handelsman DJ, Kazlauskas R, Wilkinson S, McLeod MD, Heather AK | title = Structure-activity relationships of synthetic progestins in a yeast-based in vitro androgen bioassay | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 110 | issue = 1–2 | pages = 39–47 | date = May 2008 | pmid = 18395441 | doi = 10.1016/j.jsbmb.2007.10.008 | s2cid = 5612000 }}</ref> As such, there is a considerable separation in the ratios of androgenic and progestogenic activity for ethisterone and norethisterone.<ref name="pmid18395441" /> Moreover, at the larger dosages in which it is used to achieve equivalent progestogenic effect, ethisterone has more androgenic effect relative to norethisterone and other [[19-nortestosterone]] progestins.<ref name="Bentley1980">{{cite book| vauthors = Bentley PJ |title=Endocrine Pharmacology: Physiological Basis and Therapeutic Applications|url=https://books.google.com/books?id=W6M9AAAAIAAJ&pg=PA4|year=1980|publisher=CUP Archive|isbn=978-0-521-22673-8|pages=4–}}</ref><ref name="EglenJuchau2012">{{cite book| vauthors = Eglen RM, Juchau MR, Edwards G, Weston AH, Wise H, Murray D, Brater C, Valdenaire O, Vernier P, Polak AM | display-authors = 6 |title=Progress in Drug Research: Fortschritte der Arzneimittelforschung / Progrès des recherches pharmaceutiques|url=https://books.google.com/books?id=fzUDCAAAQBAJ&pg=PA72|date=6 December 2012|publisher=Birkhäuser|isbn=978-3-0348-8863-9|pages=72–}}</ref> However, the androgenic activity of ethisterone has in any case been described as weak.<ref name="pmid7025640" /> Due to its androgenic activity, ethisterone has been associated with the [[masculinization]] of female [[fetus]]es in women who have taken it during [[pregnancy]].<ref name="WilkinsJones1958">{{cite journal | vauthors = Wilkins L, Jones HW, Holman GH, Stempfel RS | title = Masculinization of the female fetus associated with administration of oral and intramuscular progestins during gestation: non-adrenal female pseudohermaphrodism | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 18 | issue = 6 | pages = 559–585 | date = June 1958 | pmid = 13539170 | doi = 10.1210/jcem-18-6-559 }}</ref> The [[5α-reductase|5α-reduced]] [[metabolite]] of ethisterone, [[5α-dihydroethisterone]], has been found to show reduced androgenic activity relative to ethisterone.<ref name="pmid9182866">{{cite journal | vauthors = Lemus AE, Enríquez J, García GA, Grillasca I, Pérez-Palacios G | title = 5alpha-reduction of norethisterone enhances its binding affinity for androgen receptors but diminishes its androgenic potency | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 60 | issue = 1–2 | pages = 121–129 | date = January 1997 | pmid = 9182866 | doi = 10.1016/s0960-0760(96)00172-0 | s2cid = 33771349 }}</ref> Interestingly, ethisterone showed [[antiandrogen]]ic activity when co-administered with [[androstanolone|dihydrotestosterone]] (DHT) in animals, whereas 5α-dihydroethisterone did not.<ref name="pmid9182866" />

====Estrogenic activity====

[[Testosterone (medication)|Testosterone]] is [[aromatase|aromatized]] into [[estradiol (medication)|estradiol]], and [[norethisterone]], the [[19-nortestosterone]] [[structural analog|analogue]] of ethisterone, has similarly been shown to be aromatized into [[ethinylestradiol]].<ref name="pmid17653961">{{cite journal | vauthors = Kuhl H, Wiegratz I | title = Can 19-nortestosterone derivatives be aromatized in the liver of adult humans? Are there clinical implications? | journal = Climacteric | volume = 10 | issue = 4 | pages = 344–353 | date = August 2007 | pmid = 17653961 | doi = 10.1080/13697130701380434 | s2cid = 20759583 }}</ref> In accordance, high doses of norethisterone have been found to be associated with marked increases in [[urine|urinary]] estrogen [[excretion]] (due to [[metabolism]] into ethinylestradiol), as well as with high rates of [[estrogen (medication)|estrogen]]ic [[side effect]]s such as [[breast enlargement]] in women and [[gynecomastia]] in men and improvement of [[menopause|menopausal]] symptoms in postmenopausal women.<ref name="pmid13942007">{{cite journal | vauthors = Paulsen CA, Leach RB, Lanman J, Goldston N, Maddock WO, Heller CG | title = Inherent estrogenicity of norethindrone and norethynodrel: comparison with other synthetic progestins and progesterone | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 22 | issue = 10 | pages = 1033–1039 | date = October 1962 | pmid = 13942007 | doi = 10.1210/jcem-22-10-1033 }}</ref><ref name="pmid14261416">{{cite journal | vauthors = Paulsen CA | title = Progestin metabolism: Special reference to estrogenic pathways | journal = Metabolism | volume = 14 | issue = 3 | pages = SUPPL:313–SUPPL:319 | date = March 1965 | pmid = 14261416 | doi = 10.1016/0026-0495(65)90018-1 }}</ref> In contrast, ethisterone and other progestogens such as [[progesterone (medication)|progesterone]] and [[hydroxyprogesterone caproate]] do not increase estrogen excretion and are not associated with estrogenic effects, indicating that they have little or no estrogenic activity.<ref name="pmid13942007" /><ref name="pmid13922599">{{cite journal | vauthors = Troop RC, Possanza GJ | title = Gonadal influences on the pituitary-adrenal axis | journal = Archives of Biochemistry and Biophysics | volume = 98 | issue = 3 | pages = 444–449 | date = September 1962 | pmid = 13922599 | doi = 10.1016/0003-9861(62)90210-2 }}</ref> Similarly, although ethisterone showed estrogenic effects in the [[uterus]] and [[vagina]] in rats, few or no such effects were observed in women treated with the medication, even at very high doses.<ref name="SalmonSalmon1940">{{cite journal| vauthors = Salmon UJ, Salmon AA |title=Effect of Pregneninolone (17-Ethinyl Testosterone) on Genital Tract of Immature Female Rats|journal=Experimental Biology and Medicine|volume=43|issue=4|year=1940|pages=709–711|issn=1535-3702|doi=10.3181/00379727-43-11311P|s2cid=83694494}}</ref><ref name="SalmonGeist1940">{{cite journal| vauthors = Salmon UJ, Geist SH |title=Biological Properties of Pregneninolone (17-Ethinyl Testosterone) in Women|journal=Experimental Biology and Medicine|volume=45|issue=2|year=1940|pages=522–525|issn=1535-3702|doi=10.3181/00379727-45-11738P|s2cid=102020650}}</ref> As such, ethisterone does not appear to share the estrogenic activity of norethisterone, at least in humans.<ref name="pmid13942007" /><ref name="pmid13922599" /><ref name="pmid7025640" /> Aside from ethinylestradiol, [[17α-ethynyl-3α-androstanediol]] and [[17α-ethynyl-3β-androstanediol]] may be estrogenic metabolites of ethisterone.<ref name="pmid20814732">{{cite journal | vauthors = Ahlem C, Kennedy M, Page T, Bell D, Delorme E, Villegas S, Reading C, White S, Stickney D, Frincke J | display-authors = 6 | title = 17α-alkynyl 3α, 17β-androstanediol non-clinical and clinical pharmacology, pharmacokinetics and metabolism | journal = Investigational New Drugs | volume = 30 | issue = 1 | pages = 59–78 | date = February 2012 | pmid = 20814732 | doi = 10.1007/s10637-010-9517-0 | s2cid = 24785562 }}</ref>

===Pharmacokinetics===

====Absorption====

Ethisterone is active both [[oral administration|orally]] and [[sublingual administration|sublingual]]ly in humans.<ref name="Springer2013" /> Good oral [[bioavailability]] of ethisterone has been observed in rats.<ref name="Springer2013" /> The medication was the first orally active progestin to be discovered and introduced for clinical use.<ref name="Springer2013" />

====Distribution====

Ethisterone has relatively high [[affinity (pharmacology)|affinity]] for [[sex hormone-binding globulin]], about 14% of that of [[dihydrotestosterone]] and 49% of that of [[testosterone]] in one study.<ref name="pmid7195405">{{cite journal | vauthors = Pugeat MM, Dunn JF, Nisula BC | title = Transport of steroid hormones: interaction of 70 drugs with testosterone-binding globulin and corticosteroid-binding globulin in human plasma | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 53 | issue = 1 | pages = 69–75 | date = July 1981 | pmid = 7195405 | doi = 10.1210/jcem-53-1-69 }}</ref>

====Metabolism====

In terms of [[metabolism]], ethisterone is not converted into [[pregnanediol]] in humans.<ref name="Springer2013" /> This indicates that it is not [[metabolism|metabolized]] into [[progesterone (medication)|progesterone]].<ref name="Springer2013" /> No [[aromatase|aromatization]] of ethisterone has been detected ''[[in vivo]]'', and no [[estrogen (medication)|estrogen]]ic [[metabolite]]s were observed ''[[in vitro]]'' upon [[:wikt:incubation|incubation]] of ethisterone in [[placenta]]l [[homogenate]]s.<ref name="Springer2013" /> This suggests that ethisterone may not be transformed into [[ethinylestradiol]] (17α-ethynylestradiol).<ref name="Springer2013" /> [[5α-Dihydroethisterone]] (5α-dihydro-17α-ethynyltestosterone), formed by [[5α-reductase]], is an [[active metabolite]] of ethisterone.<ref name="pmid9182866" /> [[17α-Ethynyl-3α-androstanediol]] and [[17α-ethynyl-3β-androstanediol]], also formed via 5α-reductase, as well as other [[enzyme]]s, are also potential metabolites of ethisterone.<ref name="pmid20814732" />

==Chemistry==

{{See also|List of progestogens|List of androgens/anabolic steroids}}

Ethisterone is a [[synthetic compound|synthetic]] [[androstane]] [[steroid]] which was derived from [[testosterone (medication)|testosterone]] and is also known by the following synonyms:<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=PA508 |date=14 November 2014 |publisher=Springer |isbn=978-1-4757-2085-3 |page=508}}</ref><ref name="IndexNominum2000">{{cite book|title=Index Nominum 2000: International Drug Directory|url=https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA413|date=January 2000|publisher=Taylor & Francis|isbn=978-3-88763-075-1|pages=413–}}</ref>

* 17α-Ethynyltestosterone (or simply ethinyltestosterone or ethynyltestosterone)

* 17α-Ethynylandrost-4-en-17β-ol-3-one

* 17α-Pregn-4-en-20-yn-17β-ol-3-one (or simply pregneninolone or pregnenynolone)<ref name="Roche1940">{{cite book|title=Roche Review ...|url=https://books.google.com/books?id=Fm4zAQAAIAAJ&q=Pregnenin-17-ol-3-one+anhydrohydroxyprogesterone+OR+ethisterone+OR+prengeninolone|year=1940|publisher=Hoffman-La Roche, and Roche-organon|quote=Hohlweg, Naturwiss., 1938, 26:96, added the ethinyl radical to testosterone and obtained pregneninolone. This substance has been referred to in the literature as Δ4 pregnen-in-20-on-3-ol-17; Δ4 pregnene-in, 17-ol, 3-one; ethinyl testosterone; anhydro-oxy-progesterone; anhydro-hydroxy-progesterone; and pregneninolone.}}</ref><ref name="InhoffenHohlweg1938">{{cite journal| vauthors = Inhoffen HH, Hohlweg W |title=Neue per os-wirksame weibliche Keimdrüsenhormon-Derivate: 17-Aethinyl-oestradiol und Pregnen-in-on-3-ol-17|journal=Die Naturwissenschaften|volume=26|issue=6|year=1938|page=96|issn=0028-1042|doi=10.1007/BF01681040|bibcode=1938NW.....26...96I|s2cid=46648877}}</ref>

* 20,21-Anhydro-17β-hydroxyprogesterone (or simply anhydrohydroxyprogesterone)<ref name="pmid13475464">{{cite journal | vauthors = Davis ME, Wied GL | title = 17-alpha-HYDROXYPROGESTERONE acetate; an effective progestational substance on oral administration | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 17 | issue = 10 | pages = 1237–1244 | date = October 1957 | pmid = 13475464 | doi = 10.1210/jcem-17-10-1237 }}</ref>

Closely related [[structural analog|analogue]]s of ethisterone include [[dimethisterone]] (6α,21-dimethylethisterone), [[norethisterone]] (19-norethisterone), and [[danazol]] (the 2,3-''d''-[[isoxazole]] [[ring (chemistry)|ring]]-fused [[chemical derivative|derivative]] of ethisterone), as well as [[vinyltestosterone]], [[allyltestosterone]], [[methyltestosterone]], [[ethyltestosterone]], and [[propyltestosterone]]. Other ethisterone analogues include [[ethinylandrostenediol]] (17α-ethynyl-5-androstenediol), [[ethandrostate]] (17α-ethynyl-5-androstenediol 3β-cyclohexylpropionate), [[17α-ethynyl-3α-androstanediol]], and [[17α-ethynyl-3β-androstanediol]].

===Synthesis===

[[Chemical synthesis|Chemical syntheses]] of ethisterone have been published.<ref name="Springer2013">{{cite book|title=Die Gestagene|url=https://books.google.com/books?id=t8GpBgAAQBAJ&pg=PA11|date=27 November 2013|publisher=Springer-Verlag|isbn=978-3-642-99941-3|pages=11–12,282}}</ref>

==History==

Ethisterone was [[chemical synthesis|synthesized]] in 1938 by Hans Herloff Inhoffen, Willy Logemann, Walter Hohlweg, and Arthur Serini at [[Schering AG]] in [[Berlin]].<ref name="FritzSperoff2012">{{cite book| vauthors = Fritz MA, Speroff L |title= Clinical Gynecologic Endocrinology and Infertility|url=https://books.google.com/books?id=KZLubBxJEwEC&pg=PA963|date=28 March 2012|publisher=Lippincott Williams & Wilkins|isbn=978-1-4511-4847-3|pages=963–964|quote=The discovery of ethinyl substitution and oral potency led (at the end of the 1930s) to the preparation of ethisterone, an orally active derivative of testosterone. In 1951, it was demonstrated that removal of the 19-carbon from ethisterone to form norethindrone did not destroy the oral activity, and most importantly, it changed the major hormonal effect from that of an androgen to that of a progestational agent. Accordingly, the progestational derivatives of testosterone were designated as 19-nortestosterones (denoting the missing 19-carbon).}}</ref> It was derived from testosterone via [[ethynyl]]ation at the C17α position, and it was hoped, that, analogously to [[estradiol (medication)|estradiol]] and [[ethinylestradiol]], ethisterone would be an orally active form of testosterone.<ref name="Kuhl2011">{{cite journal | vauthors = Kuhl H | title = Pharmacology of Progestogens | journal = J Reproduktionsmed Endokrinol | year = 2011 | volume = 8 | issue = 1 | pages = 157–177 | url = http://www.kup.at/kup/pdf/10168.pdf}}</ref> However, the androgenic activity of ethisterone was attenuated and it showed considerable progestogenic activity.<ref name="Kuhl2011" /> As such, it was developed as a progestogen instead and was introduced for medical use in [[Germany]] in 1939 as Proluton C and by [[Schering-Plough|Schering]] in the [[United States]] in 1945 as Pranone.<ref name="LauritzenStudd2005" /><ref name="Roth2014">{{cite book| vauthors = Roth K |title=Chemische Leckerbissen|url=https://books.google.com/books?id=FsKpBAAAQBAJ&pg=PA69|year=2014|publisher=John Wiley & Sons|isbn=978-3-527-33739-2|page=69|quote=Im Prinzip hatten Hohlweg und Inhoffen die Lösung schon 1938 in der Hand, denn ihr Ethinyltestosteron (11) war eine oral wirksame gestagene Verbindung und Schering hatte daraus bereits 1939 ein Medikament (Proluton C®) entwickelt.}}</ref> Ethisterone remained in use as late as 2000.<ref name="IndexNominum2000" />

==Society and culture==

===Generic names===

''Ethisterone'' is the [[generic term|generic name]] of the drug and its {{abbrlink|INN|International Nonproprietary Name}}, {{abbrlink|USAN|United States Adopted Name}}, and {{abbrlink|BAN|British Approved Name}}, while ''ethistérone'' is its {{abbrlink|DCF|Dénomination Commune Française}}.<ref name="Elks2014" /><ref name="IndexNominum2000" /><ref name="MortonHall1999"/> It has also been referred to as ''ethinyltestosterone'', ''pregneninolone'', and ''anhydrohydroxyprogesterone''.<ref name="Elks2014" /><ref name="IndexNominum2000" /><ref name="MortonHall1999"/>

===Brand names===

Ethisterone has been marketed under a variety of brand names including Amenoren, Cycloestrol-AH Progestérone, Duosterone, Estormon, Etherone, Ethisteron, Luteosterone, Lutocyclin, Lutocylol, Lutogynestryl, Menstrogen, Nugestoral, Oophormin Luteum, Ora-Lutin, Orasecron, Pranone, Pre Ciclo, Prodroxan, Produxan, Progestab, Progesteron lingvalete, Progestoral, Proluton C, Syngestrotabs, and Trosinone among others.<ref name="Elks2014" /><ref name="IndexNominum2000" /><ref name="KleemannEngel2001" /><ref name="Muller1998">{{cite book|author=Muller|title=European Drug Index: European Drug Registrations, Fourth Edition|url=https://books.google.com/books?id=2HBPHmclMWIC&pg=PA457|date=19 June 1998|publisher=CRC Press|isbn=978-3-7692-2114-5|pages=457–}}</ref>

===Availability===

Ethisterone was previously available in [[France]], [[Germany]], [[Italy]], [[Japan]], the [[United Kingdom]], and the [[United States]], among other countries.<ref name="KleemannEngel2001" /> It is no longer marketed and hence is no longer available in any country.<ref name="Micromedex">{{cite web|url=http://www.micromedexsolutions.com |title=IBM Watson Health Products: System Status |publisher=Micromedexsolutions.com |date= |access-date=2022-09-17}}</ref>

== References ==

{{reflist|colwidth=30em}}

== Further reading ==

{{refbegin}}

* {{cite journal | vauthors = Djerassi C | title = Chemical birth of the pill. 1992 | journal = American Journal of Obstetrics and Gynecology | volume = 194 | issue = 1 | pages = 290–298 | date = January 2006 | pmid = 16389046 | doi = 10.1016/j.ajog.2005.06.010 }}

* {{cite journal |doi=10.1002/cber.19380710520 |vauthors=Inhoffen HH, Logemann W, Hohlweg W, Serini A |date=May 4, 1938 |title=Untersuchungen in der Sexualhormon-Reihe (Investigations in the sex hormone series) |journal=[[Chemische Berichte|Ber Dtsch Chem Ges]] |volume=71 |issue=5 |pages=1024–32 }}

* {{cite web | vauthors = Kugener A | date = 2004 | url = http://www.kugener.com/abfrage.php?id=0081 | title = Tabletten der Fa. Schering | archive-url = https://web.archive.org/web/20041019113745/http://www.kugener.com/abfrage.php?id=0081 | archive-date= 2004-10-19 }}

* {{cite journal | vauthors = Petrow V | title = The contraceptive progestagens | journal = Chemical Reviews | volume = 70 | issue = 6 | pages = 713–726 | date = December 1970 | pmid = 4098492 | doi = 10.1021/cr60268a004 }}

* {{cite journal | vauthors = Quinkert G |year=2004 |title=Hans Herloff Inhoffen in His Times (1906-1992) |journal=European Journal of Organic Chemistry |volume=2004 |issue=17 |pages=3727–48 | doi = 10.1002/ejoc.200300813 }}

* {{cite book | vauthors = Sneader W |year=2005 |title=Drug discovery : a history |location=Hoboken NJ |publisher=John Wiley & Sons |isbn=0-471-89980-1 |chapter=Hormone analogues |pages=188–225}}

{{refend}}

{{Progestogens and antiprogestogens}}

{{Androgen receptor modulators}}

{{Progesterone receptor modulators}}

[[Category:Ethynyl compounds]]

[[Category:Abandoned drugs]]

[[Category:Anabolic–androgenic steroids]]

[[Category:Androstanes]]

[[Category:Human drug metabolites]]

[[Category:Enones]]

[[Category:Progestogens]]