5α-DHNET shows higher affinity for the androgen receptor (AR) compared to norethisterone with approximately 27% of the affinity of the potentandrogenmetribolone (versus 15% for norethisterone).[1] However, although 5α-DHNET has higher affinity for the AR than does norethisterone, it has significantly diminished and in fact almost abolished androgenic activity in comparison to norethisterone in rodent bioassays.[2][5] Similar findings were observed for ethisterone (17α-ethynyltestosterone) and its 5α-reduced metabolite, whereas 5α-reduction enhanced both the AR affinity and androgenic potency of testosterone and nandrolone (19-nortestosterone) in rodent bioassays.[5] As such, it appears that the C17α ethynyl group of norethisterone is responsible for its loss of androgenicity upon 5α-reduction.[5] Instead of androgenic activity, 5α-DHNET has been reported to possess some antiandrogenic activity.[6]
Notes: Values are percentages (%). Reference ligands (100%) were promegestone for the PRTooltip progesterone receptor, metribolone for the ARTooltip androgen receptor, estradiol for the ERTooltip estrogen receptor, dexamethasone for the GRTooltip glucocorticoid receptor, aldosterone for the MRTooltip mineralocorticoid receptor, dihydrotestosterone for SHBGTooltip sex hormone-binding globulin, and cortisol for CBGTooltip Corticosteroid-binding globulin. Footnotes:a = Active or inactive metabolite, prodrug, or neither of norethisterone. Sources: See template.
^ abcdefKuhl H (August 2005). "Pharmacology of estrogens and progestogens: influence of different routes of administration". Climacteric. 8 (Suppl 1): 3–63. doi:10.1080/13697130500148875. PMID 16112947. S2CID 24616324.
^ abcFragkaki AG, Angelis YS, Koupparis M, Tsantili-Kakoulidou A, Kokotos G, Georgakopoulos C (February 2009). "Structural characteristics of anabolic androgenic steroids contributing to binding to the androgen receptor and to their anabolic and androgenic activities. Applied modifications in the steroidal structure". Steroids. 74 (2): 172–197. doi:10.1016/j.steroids.2008.10.016. PMID 19028512. S2CID 41356223. Many synthetic steroids with high myotrophic activity exhibit myotrophic–androgenic dissociation, since, due to changes introduced in the structure of ring A, they will probably not be substrates for the 5α-reductases [85]. 5α-Reduction does not always amplify the androgenic potency in spite of high RBA of androgens to the AR. This is the case for norethisterone (Fig. 1, 34), a synthetic 19-nor-17α-ethynyl testosterone derivative, which also undergoes enzyme-mediated 5α-reduction and exerts potent androgenic effects in target organs. 5α-Reduced norethisterone displays a higher AR binding but shows a significantly lower androgenic potency than unchanged norethisterone [102,103].
^ abFedotov VP, Gudoshnikov VI, Kurishko AI (1988). "[Effect of synthetic analogs of the sex steroid hormones on the secretory and proliferative activity of the adenohypophysis in vivo and in vitro in rats]". Farmakologiia I Toksikologiia (in Russian). 51 (5): 57–61. PMID 3208885.
^ abcChu YH, Li QA, Zhao ZF, Zhou YP, Cao DC (June 1985). "[Antiprogestational action of 5 alpha-dihydronorethisterone]". Zhongguo Yao Li Xue Bao = Acta Pharmacologica Sinica (in Chinese). 6 (2): 125–129. PMID 2934946.
^ abcLemus AE, Enríquez J, García GA, Grillasca I, Pérez-Palacios G (January 1997). "5alpha-reduction of norethisterone enhances its binding affinity for androgen receptors but diminishes its androgenic potency". The Journal of Steroid Biochemistry and Molecular Biology. 60 (1–2): 121–129. doi:10.1016/s0960-0760(96)00172-0. PMID 9182866. S2CID 33771349.
^Kamischke A, Nieschlag E (January 2004). "Progress towards hormonal male contraception". Trends in Pharmacological Sciences. 25 (1): 49–57. doi:10.1016/j.tips.2003.11.009. PMID 14723979.
^ abcYamamoto T, Tamura T, Kitawaki J, Osawa Y, Okada H (June 1994). "Suicide inactivation of aromatase in human placenta and uterine leiomyoma by 5 alpha-dihydronorethindrone, a metabolite of norethindrone, and its effect on steroid-producing enzymes". European Journal of Endocrinology. 130 (6): 634–640. doi:10.1530/eje.0.1300634. PMID 8205267.
April 15, 2024
dihydronorethisterone, belgian, newspaper, with, website, dhnet, dernière, heure, dhnet, dihydronorethisterone, 17α, ethynyl, dihydro, nortestosterone, 17α, ethynyl, estran, 17β, major, active, metabolite, norethisterone, norethindrone, norethisterone, progest. For the Belgian newspaper with the website DHNet be see La Derniere Heure 5a Dihydronorethisterone 5a DHNET dihydronorethisterone 17a ethynyl 5a dihydro 19 nortestosterone or 17a ethynyl 5a estran 17b ol 3 one is a major active metabolite of norethisterone norethindrone 1 2 3 4 Norethisterone is a progestin with additional weak androgenic and estrogenic activity 1 5a DHNET is formed from norethisterone by 5a reductase in the liver and other tissues 1 2 3 4 5a DihydronorethisteroneClinical dataOther names5a DHNET 5a Dihydro NET Dihydronorethisterone Dihydronorethindrone DHNET 17a Ethynyl 5a dihydro 19 nortestosterone 17a Ethynyl 5a estran 17b ol 3 one STS 737 NSC 85401 19 Nor 5a 17a pregn 20 yn 17 ol 3 oneIdentifiersIUPAC name 5S 8R 9R 10S 13S 14S 17R 17 ethynyl 17 hydroxy 13 methyl 1 2 4 5 6 7 8 9 10 11 12 14 15 16 tetradecahydrocyclopenta a phenanthren 3 oneCAS Number52 79 9 YPubChem CID63023ChemSpider56721UNII2DD235DD5XChEMBLChEMBL3273987CompTox Dashboard EPA DTXSID30966327Chemical and physical dataFormulaC 20H 28O 2Molar mass300 442 g mol 13D model JSmol Interactive imageSMILES C C 12CC C H 3 C H C H 1CC C 2 C C O CC C H 4 C H 3CCC O C4InChI InChI 1S C20H28O2 c1 3 20 22 11 9 18 17 6 4 13 12 14 21 5 7 15 13 16 17 8 10 19 18 20 2 h1 13 15 18 22H 4 12H2 2H3 t13 15 16 17 18 19 20 m0 s1Key OMGILQMNIZWNOK XDQPPUBWSA NPharmacology editUnlike norethisterone which is purely progestogenic 5a DHNET has been found to possess both progestogenic and marked antiprogestogenic activity showing a profile of progestogenic activity like that of a selective progesterone receptor modulator SPRM 4 Moreover the affinity of 5a DHNET for the progesterone receptor PR is greatly reduced relative to that of norethisterone at only 25 of that of progesterone versus 150 for norethisterone 1 5a DHNET shows higher affinity for the androgen receptor AR compared to norethisterone with approximately 27 of the affinity of the potent androgen metribolone versus 15 for norethisterone 1 However although 5a DHNET has higher affinity for the AR than does norethisterone it has significantly diminished and in fact almost abolished androgenic activity in comparison to norethisterone in rodent bioassays 2 5 Similar findings were observed for ethisterone 17a ethynyltestosterone and its 5a reduced metabolite whereas 5a reduction enhanced both the AR affinity and androgenic potency of testosterone and nandrolone 19 nortestosterone in rodent bioassays 5 As such it appears that the C17a ethynyl group of norethisterone is responsible for its loss of androgenicity upon 5a reduction 5 Instead of androgenic activity 5a DHNET has been reported to possess some antiandrogenic activity 6 Norethisterone and 5a DHNET have been found to act as weak irreversible aromatase inhibitors Ki 1 7 mM and 9 0 mM respectively 7 However the concentrations required are probably too high to be clinically relevant at typical dosages of norethisterone 1 5a DHNET specifically has been assessed and found to be selective in its inhibition of aromatase and does not affect other steroidogenesis enzymes such as cholesterol side chain cleavage enzyme P450scc 17a hydroxylase 17 20 lyase 21 hydroxylase or 11b hydroxylase 7 Since it is not aromatized and hence cannot be transformed into an estrogenic metabolite unlike norethisterone 5a DHNET has been proposed as a potential therapeutic agent in the treatment of estrogen receptor ER positive breast cancer 7 vte Relative affinities of norethisterone metabolites and prodrugs Compound Typea PRTooltip Progesterone receptor ARTooltip Androgen receptor ERTooltip Estrogen receptor GRTooltip Glucocorticoid receptor MRTooltip Mineralocorticoid receptor SHBGTooltip Sex hormone binding globulin CBGTooltip Corticosteroid binding globulinNorethisterone 67 75 15 0 0 1 0 3 16 05a Dihydronorethisterone Metabolite 25 27 0 0 3a 5a Tetrahydronorethisterone Metabolite 1 0 0 1 0 3a 5b Tetrahydronorethisterone Metabolite 0 0 3b 5a Tetrahydronorethisterone Metabolite 1 0 0 8 0 Ethinylestradiol Metabolite 15 25 1 3 112 1 3 0 0 18 0Norethisterone acetate Prodrug 20 5 1 0 0 Norethisterone enanthate Prodrug Noretynodrel Prodrug 6 0 2 0 0 0 0Etynodiol Prodrug 1 0 11 18 0 Etynodiol diacetate Prodrug 1 0 0 0 0 Lynestrenol Prodrug 1 1 3 0 0 Notes Values are percentages Reference ligands 100 were promegestone for the PRTooltip progesterone receptor metribolone for the ARTooltip androgen receptor estradiol for the ERTooltip estrogen receptor dexamethasone for the GRTooltip glucocorticoid receptor aldosterone for the MRTooltip mineralocorticoid receptor dihydrotestosterone for SHBGTooltip sex hormone binding globulin and cortisol for CBGTooltip Corticosteroid binding globulin Footnotes a Active or inactive metabolite prodrug or neither of norethisterone Sources See template See also edit5a Dihydroethisterone 5a Dihydronandrolone 5a Dihydronormethandrone 5a DihydrolevonorgestrelReferences edit a b c d e f Kuhl H August 2005 Pharmacology of estrogens and progestogens influence of different routes of administration Climacteric 8 Suppl 1 3 63 doi 10 1080 13697130500148875 PMID 16112947 S2CID 24616324 a b c Fragkaki AG Angelis YS Koupparis M Tsantili Kakoulidou A Kokotos G Georgakopoulos C February 2009 Structural characteristics of anabolic androgenic steroids contributing to binding to the androgen receptor and to their anabolic and androgenic activities Applied modifications in the steroidal structure Steroids 74 2 172 197 doi 10 1016 j steroids 2008 10 016 PMID 19028512 S2CID 41356223 Many synthetic steroids with high myotrophic activity exhibit myotrophic androgenic dissociation since due to changes introduced in the structure of ring A they will probably not be substrates for the 5a reductases 85 5a Reduction does not always amplify the androgenic potency in spite of high RBA of androgens to the AR This is the case for norethisterone Fig 1 34 a synthetic 19 nor 17a ethynyl testosterone derivative which also undergoes enzyme mediated 5a reduction and exerts potent androgenic effects in target organs 5a Reduced norethisterone displays a higher AR binding but shows a significantly lower androgenic potency than unchanged norethisterone 102 103 a b Fedotov VP Gudoshnikov VI Kurishko AI 1988 Effect of synthetic analogs of the sex steroid hormones on the secretory and proliferative activity of the adenohypophysis in vivo and in vitro in rats Farmakologiia I Toksikologiia in Russian 51 5 57 61 PMID 3208885 a b c Chu YH Li QA Zhao ZF Zhou YP Cao DC June 1985 Antiprogestational action of 5 alpha dihydronorethisterone Zhongguo Yao Li Xue Bao Acta Pharmacologica Sinica in Chinese 6 2 125 129 PMID 2934946 a b c Lemus AE Enriquez J Garcia GA Grillasca I Perez Palacios G January 1997 5alpha reduction of norethisterone enhances its binding affinity for androgen receptors but diminishes its androgenic potency The Journal of Steroid Biochemistry and Molecular Biology 60 1 2 121 129 doi 10 1016 s0960 0760 96 00172 0 PMID 9182866 S2CID 33771349 Kamischke A Nieschlag E January 2004 Progress towards hormonal male contraception Trends in Pharmacological Sciences 25 1 49 57 doi 10 1016 j tips 2003 11 009 PMID 14723979 a b c Yamamoto T Tamura T Kitawaki J Osawa Y Okada H June 1994 Suicide inactivation of aromatase in human placenta and uterine leiomyoma by 5 alpha dihydronorethindrone a metabolite of norethindrone and its effect on steroid producing enzymes European Journal of Endocrinology 130 6 634 640 doi 10 1530 eje 0 1300634 PMID 8205267 Retrieved from https en wikipedia org w index php title 5a Dihydronorethisterone amp oldid 1184633524, wikipedia, wiki, book, books, library,
