Lynestrenol

Lynestrenol, sold under the brand names Exluton and Ministat among others, is a progestin medication which is used in birth control pills and in the treatment of gynecological disorders.[2][3][4] The medication is available both alone and in combination with an estrogen.[3][5][6] It is taken by mouth.[7][8]

Lynestrenol
Clinical data
Trade namesExluton, Ministat, others
Other namesLinestrenol; Lynenol;[1] NSC-37725; 17α-Ethynylestr-4-en-17β-ol; 19-Nor-17α-pregn-4-en-20-yn-17-ol[1]
AHFS/Drugs.comInternational Drug Names
Routes of
administration		By mouth
Drug classProgestogen; Progestin
ATC code
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
CompTox Dashboard (EPA)
ECHA InfoCard100.000.139
Chemical and physical data
FormulaC20H28O
Molar mass284.443 g·mol−1
3D model (JSmol)
  (verify)

Lynestrenol is a progestin, or a synthetic progestogen, and hence is an agonist of the progesterone receptor, the biological target of progestogens like progesterone.[9] It has weak androgenic and estrogenic activity and no other important hormonal activity.[9][10] The medication is a prodrug of norethisterone in the body, with etynodiol occurring as an intermediate.[10][11][12]

Lynestrenol was discovered in the late 1950s and was introduced for medical use in 1961.[13][14] It has mostly been used in Europe and elsewhere in the world and was never marketed in the United States.[6][15][16][17]

Medical uses

Lynestrenol is used as a component of oral contraceptives in combination with an estrogen and is used in the treatment of gynecological disorders such as menstrual disorders.[4]

Side effects
Main articles: Norethisterone § Side effects, and Progestin § Side effects

Pharmacology
Norethisterone (3-ketolynestrenol), the active metabolite of lynestrenol.

Lynestrenol itself does not bind to the progesterone receptor and is inactive as a progestogen.[7][8] It is a prodrug, and upon oral administration, is rapidly and almost completely converted into norethisterone, a potent progestogen, in the liver during first-pass metabolism.[7][8] No other metabolites besides norethisterone are formed from lynestrenol.[8] As such, its pharmacological activity is essentially identical to that of norethisterone.[9] The conversion of lynestrenol into norethisterone is catalyzed by CYP2C9 (28.0%), CYP2C19 (49.8%), and CYP3A4 (20.4%), while other cytochrome P450 enzymes are each responsible for no more than 1.0% of the total conversion.[8] It appears that lynestrenol first undergoes hydroxylation of the C3 position, forming etynodiol as an intermediate,[12] followed by oxygenation of the hydroxyl group to form norethisterone.[11]

The peak blood levels are reached within 2 to 4 hours after oral administration, 97% of the administered dose being bound to plasma proteins. Lynestrenol and its metabolites are predominantly excreted in urine, less in feces, active metabolite norethisterone elimination half-life being 16 or 17 hours.

The pharmacokinetics of lynestrenol have been reviewed.[18]

Relative affinities (%) of norethisterone, metabolites, and prodrugs
CompoundTypeaPRARERGRMRSHBGCBG
Norethisterone–67–751500–10–3160
5α-DihydronorethisteroneMetabolite252700???
3α,5α-TetrahydronorethisteroneMetabolite100–10???
3α,5β-TetrahydronorethisteroneMetabolite?00????
3β,5α-TetrahydronorethisteroneMetabolite100–80???
EthinylestradiolMetabolite15–251–31121–300.180
Norethisterone acetateProdrug205100??
Norethisterone enanthateProdrug???????
NoretynodrelProdrug6020000
EtynodiolProdrug1011–180???
Etynodiol diacetateProdrug10000??
LynestrenolProdrug11300??
Notes: Values are percentages (%). Reference ligands (100%) were promegestone for the PR, metribolone for the AR, estradiol for the ER, dexamethasone for the GR, aldosterone for the MR, dihydrotestosterone for SHBG, and cortisol for CBG. Footnotes: a = Active or inactive metabolite, prodrug, or neither of norethisterone. Sources: See template.

Chemistry
See also: List of progestogens and List of androgens/anabolic steroids

Lynestrenol, also known as 17α-ethynyl-3-desoxy-19-nortestosterone or as 17α-ethynylestr-4-en-17β-ol, is a synthetic estrane steroid and a derivative of 19-nortestosterone.[2][3][9][19] It differs from norethisterone (17α-ethynyl-19-nortestosterone) and etynodiol (17α-ethynyl-3-deketo-3β-hydroxy-19-nortestosterone) only by the lack of a ketone group and hydroxyl group at the C3 position, respectively.[11]

Synthesis

Chemical syntheses of lynestrenol have been published.[2][18]

In another approach to analogues, nortestosterone (1) is first converted to the dithioketal (2) by treatment with dithioglycol in the presence of 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 Jones reagent followed by ethynylation of the 17-ketone leads to the orally active progestin (6).

Lynestrenol synthesis:[20][21]

History

Lynestrenol was developed by the Dutch pharmaceutical company Organon in the late 1950s and was introduced for medical use in 1961.[13][14] It received a Dutch patent for lynestrenol in 1957,[13] and lynestrenol subsequently became a component of Lyndiol, the first Dutch contraceptive pill, in 1962.[1][13][14] Around this time, pre- and post-marketing clinical trials of lynestrenol were conducted, and in 1965, a study consisting of 200 Dutch women was published.[13] Lynestrenol was approved, in the United Kingdom, in combination with mestranol in 1963 and in combination with ethinylestradiol in 1969.[16]

Society and culture

Generic names

Lynestrenol is the generic name of the drug and its INN, USAN, BAN, and JAN, while lynestrénol is its DCF and linestrenolo is its DCIT.[2][3][4][6] Lynoestrenol was formerly the BAN of the drug, but it was eventually changed to lynestrenol.[2][3][4][6]

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.[5][22]

Availability

Lynestrenol has been used mainly in Europe[15] and is also marketed elsewhere throughout the world.[6] The drug was never marketed in the United States.[16][17]

gollark: Go(lang) = bad.
gollark: ``` [...] MIPS is short for Millions of Instructions Per Second. It is a measure for the computation speed of a processor. Like most such measures, it is more often abused than used properly (it is very difficult to justly compare MIPS for different kinds of computers). BogoMips are Linus's own invention. The linux kernel version 0.99.11 (dated 11 July 1993) needed a timing loop (the time is too short and/or needs to be too exact for a non-busy-loop method of waiting), which must be calibrated to the processor speed of the machine. Hence, the kernel measures at boot time how fast a certain kind of busy loop runs on a computer. "Bogo" comes from "bogus", i.e, something which is a fake. Hence, the BogoMips value gives some indication of the processor speed, but it is way too unscientific to be called anything but BogoMips. The reasons (there are two) it is printed during boot-up is that a) it is slightly useful for debugging and for checking that the computer[’]s caches and turbo button work, and b) Linus loves to chuckle when he sees confused people on the news. [...]```I was wondering what BogoMIPS was, and wikipedia had this.
gollark: ```Architecture: x86_64CPU op-mode(s): 32-bit, 64-bitByte Order: Little EndianCPU(s): 8On-line CPU(s) list: 0-7Thread(s) per core: 2Core(s) per socket: 4Socket(s): 1NUMA node(s): 1Vendor ID: GenuineIntelCPU family: 6Model: 42Model name: Intel(R) Xeon(R) CPU E31240 @ 3.30GHzStepping: 7CPU MHz: 1610.407CPU max MHz: 3700.0000CPU min MHz: 1600.0000BogoMIPS: 6587.46Virtualization: VT-xL1d cache: 32KL1i cache: 32KL2 cache: 256KL3 cache: 8192KNUMA node0 CPU(s): 0-7Flags: fpu vme de pse tsc msr pae mce cx8 apic sep mtrr pge mca cmov pat pse36 clflush dts acpi mmx fxsr sse sse2 ss ht tm pbe syscall nx rdtscp lm constant_tsc arch_perfmon pebs bts rep_good nopl xtopology nonstop_tsc cpuid aperfmperf pni pclmulqdq dtes64 monitor ds_cpl vmx smx est tm2 ssse3 cx16 xtpr pdcm pcid sse4_1 sse4_2 x2apic popcnt tsc_deadline_timer aes xsave avx lahf_lm pti tpr_shadow vnmi flexpriority ept vpid xsaveopt dtherm ida arat pln pts```
gollark: I think it's a server thing.
gollark: My slightly newer SomethingOrOther 5000 does too.

References
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  15. Rogerio A. Lobo; Jennifer Kelsey; Robert Marcus (22 May 2000). Menopause: Biology and Pathobiology. Academic Press. pp. 585–. ISBN 978-0-08-053620-0.
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  17. https://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm
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  20. M. S. de Winter, C. M. Siegmann and S. A. Szpilfogel, Chem. Ind., 905 (1959).
  21. http://www.chemspider.com/Search.aspx?q=Cingestol
  22. http://pdf.usaid.gov/pdf_docs/pnaap426.pdf
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