View source for Chemistry:Lynestrenol

{{Short description|Androgen and anabolic steroid}}
{{Drugbox
| Watchedfields = changed
| verifiedrevid = 447623820
| IUPAC_name = (8''R'',9''S'',10''R'',13''S'',14''S'',17''R'')-17-ethynyl-13-methyl-2,3,6,7,8,9,10,11,12,14,15,16-dodecahydro-1''H''-cyclopenta[''a'']phenanthren-17-ol
| image = Lynestrenol.svg
| width = 200px

<!--Clinical data-->
| tradename = Exluton, Ministat, others
| Drugs.com = {{drugs.com|international|lynestrenol}}
| pregnancy_category = 
| legal_status = 
| routes_of_administration = [[Medicine:Oral administration|By mouth]]
| class = [[Chemistry:Progestogen (medication)|Progestogen]]; [[Chemistry:Progestin|Progestin]]

<!--Pharmacokinetic data-->
| bioavailability = 
| protein_bound = 
| metabolism = 
| elimination_half-life = 
| excretion = 

<!--Identifiers-->
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 52-76-6
| ATC_prefix = G03
| ATC_suffix = AC02
| ATC_supplemental = {{ATC|G03|DC03}};<br />{{ATC|G03|AA03}} {{ATC|G03|AB02}} {{ATC|G03|FA07}} {{ATC|G03|FB02}} (combinations with [[Chemistry:Estrogen (medication)|estrogen]]s)
| PubChem = 5857
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 5648
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = N2Z8ALG4U5
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D01580
| synonyms = Linestrenol; Lynenol;<ref name="UnitedNations" /> NSC-37725; 17α-Ethynylestr-4-en-17β-ol; 19-Nor-17α-pregn-4-en-20-yn-17-ol<ref name="UnitedNations" />

<!--Chemical data-->
| C=20 | H=28 | O=1 
| SMILES = C#C[C@]2(O)CC[C@H]1[C@H]4[C@H](CC[C@@]12C)[C@@H]3\C(=C/CCC3)CC4
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C20H28O/c1-3-20(21)13-11-18-17-9-8-14-6-4-5-7-15(14)16(17)10-12-19(18,20)2/h1,6,15-18,21H,4-5,7-13H2,2H3/t15-,16+,17+,18-,19-,20-/m0/s1
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = YNVGQYHLRCDXFQ-XGXHKTLJSA-N
}}
<!-- Definition and medical uses -->
'''Lynestrenol''', sold under the brand names '''Exluton''' and '''Ministat''' among others, is a [[Chemistry:Progestin|progestin]] medication which is used in birth control pills and in the treatment of gynecological disorders.<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=PA747|date=14 November 2014|publisher=Springer|isbn=978-1-4757-2085-3|pages=747–}}</ref><ref name="IndexNominum2000">{{cite book|title=Index Nominum 2000: International Drug Directory|url=https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA624|year=2000|publisher=Taylor & Francis|isbn=978-3-88763-075-1|pages=624–}}</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=PA170|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-94-011-4439-1|pages=170–}}</ref> The medication is available both alone and in combination with an [[Chemistry:Estrogen (medication)|estrogen]].<ref name="IndexNominum2000" /><ref name="Muller1998" /><ref name="Drugs.com">{{Cite web|url= https://www.drugs.com/international/lynestrenol.html |title = Lynestreno |work = Drugs.com l}}</ref> It is taken [[Medicine:Oral administration|by mouth]].<ref name="pmid436304" /><ref name="pmid18356043" />

<!-- Side effects and mechanism -->
Lynestrenol is a progestin, or a synthetic [[Chemistry:Progestogen (medication)|progestogen]], and hence is an [[Biology:Agonist|agonist]] of the [[Biology:Progesterone receptor|progesterone receptor]], the [[Biology:Biological target|biological target]] of progestogens like [[Chemistry:Progesterone|progesterone]].<ref name="pmid19434889" /> It has weak [[Biology:Androgen|androgen]]ic and [[Chemistry:Estrogen (medication)|estrogen]]ic activity and no other important hormonal activity.<ref name="pmid19434889" /><ref name="pmid16112947">{{cite journal | vauthors = Kuhl H | title = Pharmacology of estrogens and progestogens: influence of different routes of administration | journal = Climacteric | volume = 8 | pages = 3–63 | date = August 2005 | issue = Suppl 1 | pmid = 16112947 | doi = 10.1080/13697130500148875 | s2cid = 24616324 }}</ref> The medication is a [[Chemistry:Prodrug|prodrug]] of [[Chemistry:Norethisterone|norethisterone]] in the body, with [[Chemistry:Etynodiol|etynodiol]] occurring as an [[Biology:Metabolic intermediate|intermediate]].<ref name="pmid16112947" /><ref name="pmid12215716" /><ref name="pmid2256526" />

<!-- History, society and culture -->
Lynestrenol was discovered in the late 1950s and was introduced for medical use in 1961.<ref name="Gijswijt-HofstraHeteren2002" /><ref name="GaleResearch1991" /> It has mostly been used in [[Earth:Europe|Europe]] and elsewhere in the world and was never marketed in the {{wipe|United States}}.<ref name="Drugs.com" /><ref name="LoboKelsey2000" /><ref name="Gelijns1991" /><ref name="FDA" />

==Medical uses==
Lynestrenol is used as a component of oral contraceptives in combination with an [[Biology:Estrogen|estrogen]] and is used in the treatment of gynecological disorders such as menstrual disorders.<ref name="MortonHall2012" />

==Side effects==

==Pharmacology==
[[File:Norethisterone.svg|thumb|right|225px|[[Chemistry:Norethisterone|Norethisterone]] (3-ketolynestrenol), the active metabolite of lynestrenol.]]

Lynestrenol itself does not bind to the [[Biology:Progesterone receptor|progesterone receptor]] and is inactive as a [[Chemistry:Progestogen (medication)|progestogen]].<ref name="pmid436304">{{cite journal | vauthors = Odlind V, Weiner E, Victor A, Johansson ED | title = Plasma levels of norethindrone after single oral dose administration of norethindrone and lynestrenol | journal = Clinical Endocrinology | volume = 10 | issue = 1 | pages = 29–38 | date = January 1979 | pmid = 436304 | doi = 10.1111/j.1365-2265.1979.tb03030.x | s2cid = 10774483 }}</ref><ref name="pmid18356043">{{cite journal | vauthors = Korhonen T, Turpeinen M, Tolonen A, Laine K, Pelkonen O | title = Identification of the human cytochrome P450 enzymes involved in the in vitro biotransformation of lynestrenol and norethindrone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 110 | issue = 1–2 | pages = 56–66 | date = May 2008 | pmid = 18356043 | doi = 10.1016/j.jsbmb.2007.09.025 | s2cid = 10809537 }}</ref> It is a [[Chemistry:Prodrug|prodrug]], and upon [[Medicine:Oral administration|oral administration]], is rapidly and almost completely [[Biology:Metabolism|converted]] into [[Chemistry:Norethisterone|norethisterone]], a potent progestogen, in the [[Biology:Liver|liver]] during first-pass metabolism.<ref name="pmid436304" /><ref name="pmid18356043" /> No other [[Biology:Metabolite|metabolite]]s besides norethisterone are formed from lynestrenol.<ref name="pmid18356043" /> As such, its pharmacological activity is essentially identical to that of norethisterone.<ref name="pmid19434889">{{cite journal | vauthors = Schindler AE, Campagnoli C, Druckmann R, Huber J, Pasqualini JR, Schweppe KW, Thijssen JH | title = Classification and pharmacology of progestins | journal = Maturitas | volume = 61 | issue = 1–2 | pages = 171–180 | year = 2008 | pmid = 19434889 | doi = 10.1016/j.maturitas.2008.11.013 }}</ref> The conversion of lynestrenol into norethisterone is catalyzed by [[Biology:CYP2C9|CYP2C9]] (28.0%), [[Biology:CYP2C19|CYP2C19]] (49.8%), and [[Biology:CYP3A4|CYP3A4]] (20.4%), while other [[Biology:Cytochrome P450|cytochrome P450]] [[Biology:Enzyme|enzyme]]s are each responsible for no more than 1.0% of the total conversion.<ref name="pmid18356043" /> It appears that lynestrenol first undergoes [[Biology:Hydroxylation|hydroxylation]] of the C3 position, forming [[Chemistry:Etynodiol|etynodiol]] as an [[Biology:Metabolic intermediate|intermediate]],<ref name="pmid2256526">{{cite journal | vauthors = Hammerstein J | title = Prodrugs: advantage or disadvantage? | journal = American Journal of Obstetrics and Gynecology | volume = 163 | issue = 6 Pt 2 | pages = 2198–2203 | date = December 1990 | pmid = 2256526 | doi = 10.1016/0002-9378(90)90561-K }}</ref> followed by [[Chemistry:Ketone|oxygenation]] of the [[Chemistry:Hydroxyl group|hydroxyl group]] to form norethisterone.<ref name="pmid12215716">{{cite journal | vauthors = Stanczyk FZ | title = Pharmacokinetics and potency of progestins used for hormone replacement therapy and contraception | journal = Reviews in Endocrine & Metabolic Disorders | volume = 3 | issue = 3 | pages = 211–224 | date = September 2002 | pmid = 12215716 | doi = 10.1023/A:1020072325818 | s2cid = 27018468 }}</ref>

The [[Medicine:Cmax (pharmacology)|peak blood levels]] are reached within 2 to 4&nbsp;hours after oral administration, 97% of the administered dose being [[Biology:Plasma protein binding|bound to plasma proteins]].{{Citation needed|date=October 2016}} Lynestrenol and its metabolites are predominantly [[Biology:Excretion|excreted]] in [[Biology:Urine|urine]], less in [[Biology:Feces|feces]], [[Biology:Active metabolite|active metabolite]] norethisterone elimination half-life being 16 or 17&nbsp;hours.{{Citation needed|date=October 2016}}

The [[Medicine:Pharmacokinetics|pharmacokinetics]] of lynestrenol have been reviewed.<ref name="Springer2013" />

{{Relative affinities of norethisterone, metabolites, and prodrugs}}

==Chemistry==

Lynestrenol, also known as 17α-ethynyl-3-desoxy-19-nortestosterone or as 17α-ethynylestr-4-en-17β-ol, is a synthetic [[Chemistry:Estrane|estrane]] [[Biology:Steroid|steroid]] and a [[Chemistry:Derivative|derivative]] of 19-nortestosterone.<ref name="Elks2014" /><ref name="IndexNominum2000" /><ref name="pmid19434889" /><ref name="pmid14667980">{{cite journal | vauthors = Stanczyk FZ | title = All progestins are not created equal | journal = Steroids | volume = 68 | issue = 10–13 | pages = 879–890 | date = November 2003 | pmid = 14667980 | doi = 10.1016/j.steroids.2003.08.003 | s2cid = 44601264 }}</ref> It differs from [[Chemistry:Norethisterone|norethisterone]] (17α-ethynyl-19-nortestosterone) and [[Chemistry:Etynodiol|etynodiol]] (17α-ethynyl-3-deketo-3β-hydroxy-19-nortestosterone) only by the lack of a [[Chemistry:Ketone|ketone]] [[Chemistry:Functional group|group]] and hydroxyl group at the C3 position, respectively.<ref name="pmid12215716" />

===Synthesis===
[[Chemistry:Chemical synthesis|Chemical syntheses]] of lynestrenol have been published.<ref name="Elks2014" /><ref name="Springer2013">{{cite book|title=Die Gestagene|url=https://books.google.com/books?id=t8GpBgAAQBAJ&pg=PA15|date=27 November 2013|publisher=Springer-Verlag|isbn=978-3-642-99941-3|pages=15–16,283}}</ref>

In another approach to analogues, nortestosterone ('''1''') is first converted to the di[[Chemistry:Thioketal|thioketal]] ('''2''') by treatment with [[Chemistry:1,2-Ethanedithiol|dithioglycol]] in the presence of [[Chemistry:Boron trifluoride|boron trifluoride]]. (The mild conditions of this reaction compared to those usually employed in preparing the oxygen ketals probably accounts for the double bond remaining at 4,5). Treatment of this derivative with sodium in liquid ammonia affords the 3-desoxy analog ('''3'''). Oxidation by means of [[Chemistry:Jones reagent|Jones reagent]] followed by [[Chemistry:Alkynylation|ethynylation]] of the 17-ketone leads to the orally active progestin ('''6''').

[[File:Lynestrenol synthesis.svg|thumb|left|600px|Lynestrenol synthesis:<ref name=Winter>{{cite report | vauthors = de Winter MS, Siegmann CM, Szpilfogel SA | title = 17-Alkylated 3-deoxo-19-nortestosterones | journal = Chem. Ind | page = 905 | date = 1959 }}</ref><ref>{{Cite web|url=http://www.chemspider.com/Search.aspx?q=Cingestol|title = Cingestol &#124; C20H28O | work = ChemSpider}}</ref>]]{{Clear}}

==History==
Lynestrenol was developed by the Dutch pharmaceutical company [[Philosophy:Organon|Organon]] in the late 1950s and was introduced for medical use in 1961.<ref name="Gijswijt-HofstraHeteren2002">{{cite book| vauthors = Oudtshoorn N | chapter = Drugs for People: The culture of testing hormonal contraceptives for women and menGijswijt-Hofstra M, van Heteren GM, Tansey EM |title=Biographies of Remedies: Drugs, Medicines and Contraceptives in Dutch and Anglo-American Healing Cultures| chapter-url = https://books.google.com/books?id=cIgMvBodsD0C&pg=PA128|year=2002|publisher=Rodopi|isbn=90-420-1577-2|pages=128–129}}</ref><ref name="GaleResearch1991">{{cite book|title=Drugs Available Abroad|url=https://books.google.com/books?id=2x1tAAAAMAAJ|year=1991|publisher=Gale Research|isbn=978-0-8103-7177-4|quote=LYNESTRENOL Countries Where Available and Release Dates: Austria; Belgium (1961); Finland (1972); France (1970); Federal Republic of Germany (1962); Mexico (1973); Netherlands (1962); Republic of South Africa (1974); Spain (1971); Sweden (1964); Switzerland.}}</ref> It received a Dutch [[Social:Patent|patent]] for lynestrenol in 1957,<ref name="Gijswijt-HofstraHeteren2002" /> and lynestrenol subsequently became a component of ''Lyndiol'', the first Dutch contraceptive pill, in 1962.<ref name="UnitedNations">{{cite book|title=Consolidated List of Products Whose Consumption And/or Sale Have Been Banned, Withdrawn, Severely Restricted Or Not Approved by Governments|url=https://books.google.com/books?id=leVCukUgNlsC&pg=PA134|year=1983|publisher=United Nations Publications|isbn=978-92-1-130230-1|pages=134–}}</ref><ref name="Gijswijt-HofstraHeteren2002" /><ref name="GaleResearch1991" /> Around this time, pre- and post-marketing [[Engineering:Clinical trial|clinical trial]]s of lynestrenol were conducted, and in 1965, a study consisting of 200 Dutch women was published.<ref name="Gijswijt-HofstraHeteren2002" /> Lynestrenol was approved, in the {{wipe|United Kingdom}}, in combination with [[Chemistry:Mestranol|mestranol]] in 1963 and in combination with [[Chemistry:Ethinylestradiol|ethinylestradiol]] in 1969.<ref name="Gelijns1991" />

==Society and culture==

===Generic names===
''Lynestrenol'' is the generic name of the drug and its {{abbrlink|INN|International Nonproprietary Name}}, {{abbrlink|USAN|United States Adopted Name}}, {{abbrlink|BAN|British Approved Name}}, and {{abbrlink|JAN|Japanese Accepted Name}}, while ''lynestrénol'' is its {{abbrlink|DCF|Dénomination Commune Française}} and ''linestrenolo'' is its {{abbrlink|DCIT|Denominazione Comune Italiana}}.<ref name="Elks2014" /><ref name="IndexNominum2000" /><ref name="MortonHall2012" /><ref name="Drugs.com"/> ''Lynoestrenol'' was formerly the {{abbrlink|BAN|British Approved Name}} of the drug, but it was eventually changed to ''lynestrenol''.<ref name="Elks2014" /><ref name="IndexNominum2000" /><ref name="MortonHall2012" /><ref name="Drugs.com" />

===Brand names===
Lynestrenol has been marketed alone as Exluton, Exlutona, and Orgametril, in combination with mestranol as Anacyclin, Lyndiol, Lyndiol 1, Lyndiol 2.5, Nonovul, and Noracycline, and in combination with ethinylestradiol as Anacyclin, Fysioquens, Minilyn, and Ministat, among other formulations and brand names.<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=PA467|date=19 June 1998|publisher=CRC Press|isbn=978-3-7692-2114-5|pages=74,467,525}}</ref><ref name="USAID">{{Cite report | vauthors = Kolbe HK, Bergman RF | title = Population/fertility control thesaurus. | work = Population Information Program, Science Communication Division | publisher = Department of Medical and Public Affairs, George Washington University | date = April 1976 }}</ref>

===Availability===
Lynestrenol has been used mainly in [[Earth:Europe|Europe]]<ref name="LoboKelsey2000">{{cite book| vauthors = Magnusson C, Baron JA | chapter = Hormone Replacement Therapy and Breast Cancer | veditors = Lobo RA, Kelsey J, Marcus R |title=Menopause: Biology and Pathobiology| chapter-url = https://books.google.com/books?id=i9HXKhjvNVAC&pg=PA585 |date=22 May 2000|publisher=Academic Press|isbn=978-0-08-053620-0|pages=585–}}</ref> and is also marketed elsewhere throughout the world.<ref name="Drugs.com"/> The drug was never marketed in the {{wipe|United States}}.<ref name="Gelijns1991">{{cite book| vauthors = Gelijns A |title=Innovation in Clinical Practice: The Dynamics of Medical Technology Development|url=https://books.google.com/books?id=MZkrAAAAYAAJ&pg=PA167|year=1991|publisher=National Academies|pages=167–|id=NAP:13513}}</ref><ref name="FDA">{{Cite web|url=https://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm|title = Drugs@FDA: FDA-Approved Drugs}}</ref>

== References ==
{{Reflist}}

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[[Category:Tertiary alcohols]]
[[Category:Ethynyl compounds]]
[[Category:Estranes]]
[[Category:Prodrugs]]
[[Category:Progestogens]]
[[Category:Synthetic estrogens]]

{{Sourceattribution|Lynestrenol}}