5α-dihydronorethisterone 5α-dihydronorethisterone 5α-dihydronorethisterone (5α-dhnet, dihydronorethisterone, 17α-ethynyl-5α-dihydro-19-nortestosterone, or 17α-ethynyl-5α-estran-17β-ol-3-one) is a major active metabolite of norethisterone (norethindrone). norethisterone is a progestin with additional weak androgenic and estrogenic activity. 5α-dhnet is formed from norethisterone by 5α-reductase in the liver and other tissues. 5α-dihydronorethisteroneclinical dataother names5α-dhnet; 5α-dihydro-net; dihydronorethisterone; dihydronorethindrone; dhnet; 17α-ethynyl-5α-dihydro-19-nortestosterone; 17α-ethynyl-5α-estran-17β-ol-3-one; sts-737; nsc-85401; 19-nor-5α,17α-pregn-20-yn-17-ol-3-oneidentifiers iupac 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-tetradecahydrocyclopentaphenanthren-3-one cas number52-79-9 ypubchem cid63023chemspider56721unii2dd235dd5xchemblchembl3273987comptox dashboard (epa)dtxsid30966327 chemical and physical dataformulac20h28o2molar mass300.442 g·mol−13d model (jsmol)interactive image smiles c12cc3(1cc2(c#c)o)cc43ccc(=o)c4 inchi 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-n unlike norethisterone which is purely progestogenic, 5α-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). moreover, the affinity of 5α-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). 5α-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). 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. 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. as such, it appears that the c17α ethynyl group of norethisterone is responsible for its loss of androgenicity upon 5α-reduction. instead of androgenic activity, 5α-dhnet has been reported to possess some antiandrogenic activity. norethisterone and 5α-dhnet have been found to act as weak irreversible aromatase inhibitors (ki = 1.7 μm and 9.0 μm, respectively). however, the concentrations required are probably too high to be clinically relevant at typical dosages of norethisterone. 5α-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), 17α-hydroxylase/17,20-lyase, 21-hydroxylase, or 11β-hydroxylase. since it is not aromatized (and hence cannot be transformed into an estrogenic metabolite), unlike norethisterone, 5α-dhnet has been proposed as a potential therapeutic agent in the treatment of estrogen receptor (er)-positive breast cancer. 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.