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.
^
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.
PMID19028512.
S2CID41356223. 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.
PMID3208885.
^
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.
PMID2934946.
^
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.
PMID9182866.
S2CID33771349.
^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.
PMID14723979.
^
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.
PMID8205267.